TOXICOLOGY HANDBOOK
TOXICOLOGY HANDBOOK 3RD EDITION Lindsay Murray Mark Little Ovidiu Pascu Kerry Hoggett
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Elsevier Australia. ACN 001 002 357 (a division of Reed International Books Australia Pty Ltd) Tower 1, 475 Victoria Avenue, Chatswood, NSW 2067 © 2015 Elsevier Australia. 1st edition © 2006; 2nd edition © 2011 Elsevier Australia. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission in writing from the Publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organisations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors or editors, assume any liability for any injury and/or damage to persons or property as a matter of product liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. National Library of Australia Cataloguing-in-Publication entry ———————————————————————————————————————————— Murray, Lindsay, author. Toxicology handbook / Lindsay Murray, Mark Little, Ovidiu Pascu, Kerry Hoggett. 3rd edition. 9780729542241 (paperback) Includes index. Toxicology–Australia–Handbooks, manuals, etc. Toxicology–Oceania–Handbooks, manuals, etc. Little, Mark. Pascu, Ovidiu. Hoggett, Kerry. 571.95 ——————————————————————————————— Content Strategist: Larissa Norrie Senior Content Development Specialist: Neli Bryant Project Manager: Karthikeyan Murthy Edited by Linda Littlemore Proofread by Tim Learner Technical checking by Christopher Johnston Index by Robert Swanson Typeset by Toppan Best-set Premedia Limited Cover and internal design by Georgette Hall Printed in China by 1010 Printing Int’l Ltd. Last digit is the print number: 9 8 7 6 5 4 3 2 1
FOREWORD This is the third edition of the Toxicology Handbook and confirms clinical toxicology as a sub-specialty in Australasia. Less than 20 years ago a small cohort of emergency doctors independently sought overseas sub-specialty training in toxicology so that they could bring a higher level of expertise to the management of this heterogeneous and vulnerable group of patients in Australasian emergency departments. They joined a small and informal collection of clinical pharmacologists, intensivists and paediatricians to provide telephone advice across the country through the National Poisons Centre system. Within a few years the collaboration flourished and they started local training programs, implemented innovative patient-centred models of care and coordinated research. Wider networks involving rural and remote clinicians, psychiatry, drug and alcohol services and occupational medicine were also formed. It is now axiomatic that we should endeavour to deliver clinical care that is evidence based. There is also clear evidence that patient experience and outcomes are superior in organisations that have a clear and inspirational vision, unambiguous objectives aligned to that vision and clinicians who work in teams with a philosophy of continuous improvement. This handbook is written by clinicians who have worked in such a way. They have designed the content and format of this book to allow the easy dissemination of their expertise and experience for the benefit of patients beyond their own hospitals. It is an authentic clinical handbook and not just a text for the shelf or study. It continues the clear and consistent format of previous editions. The clinical approach is based on risk assessment and enables evidence-based and pragmatic management tailored to the individual needs of patients. This is a key element in progressing the ideal of optimal care for the poisoned patient irrespective of location. The vision has always been to deliver patient care that is safe, effective, personal, timely and efficient. I believe this handbook represents a practical step to deliver on this vision at an individual patient level and as part of a wider system of care. Professor Frank FS Daly MBBS FACEM LWA A/Chief Executive, South Metropolitan Health Service University of Western Australia and the Centre for Clinical Research in Emergency Medicine, Western Australian Institute for Medical Research
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PREFACE
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The Toxicology Handbook was originally conceived as a distillation of the collective experience of the clinical toxicologists of the West Australian Toxicology Service. It was written with the aim of producing a useful but concise bedside text to assist the clinician in treating the acutely poisoned patient in whatever setting they might be practising within Australasia or elsewhere. With this in mind the authors made every effort not only to provide the necessary factual information but to train the user to adopt a rigorous and structured risk assessment-based approach to decision making in the context of clinical toxicology. The second edition provided an opportunity to expand the coverage of toxins and incorporate changes in management informed by new research. Feedback from users of the first two editions of the handbook has validated the practical utility of the structured risk assessment-based approach to the management of poisoning and encouraged us to retain this approach for the third edition. This latest edition necessarily incorporates important information regarding poisoning from recently marketed pharmaceuticals. It also incorporates important modifications in management advice, particularly in the area of envenoming, informed by recently published clinical research. Two of the original authors of the Toxicology Handbook were not available to produce the third edition as their careers have since evolved in other exciting directions. However, the contributions of Frank Daly and Mike Cadogan live on in the third edition in a very real way. The unique qualities of these two exceptional doctors provided the conceptual framework and clinical expertise on which the Toxicology Handbook still rests. We dedicate the third edition to Frank Daly and Mike Cadogan together with our patients, who continue to instruct on a daily basis and remind us just how much we have yet to learn. Lindsay Murray Mark Little Ovidiu Pascu Kerry Hoggett Jason Armstrong
Alan Gault David McCoubrie Kirsty Skinner Jessamine Soderstorm Ioana Vlad
EDITORS Lindsay Murray MBBS FACEM, Consultant Emergency Physician, Lismore Base Hospital, Lismore, NSW, Australia Mark Little MBBS DTM&H (Lond) FACEM MPH&TM IDHA, Consultant Emergency Physician and Clinical Toxicologist, Cairns Hospital, Cairns, Qld; Associate Professor, School of Public Health and Tropical Medicine, Queensland Tropical Health Alliance; Consultant Clinical Toxicologist, NSW Poisons Information Centre, Australia Ovidiu Pascu MD FACEM, Consultant Emergency Physician and Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA; Clinical Toxicologist, WA Poisons Information Centre; Clinical Senior Lecturer in Emergency Medicine, University of Western Australia, Australia Kerry Hoggett MBBS GCertClinTox FACEM, Consultant Emergency Physician and Clinical Toxicologist, Royal Perth Hospital, Perth, WA; VMO Clinical Toxicologist, NSW and WA Poisons Information Centres; Clinical Senior Lecturer, University of Western Australia; Adjunct Clinical Lecturer, University of Notre Dame, WA, Australia
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CONTRIBUTORS
xii i
xi
Jason Armstrong MBChB FACEM, Consultant Emergency Physician and Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA; Clinical Senior Lecturer in Emergency Medicine, University of Western Australia; Medical Director, WA Poisons Information Centre; Consultant Clinical Toxicologist, NSW Poisons Information Centre, Australia Alan Gault MBChB BAO FACEM, Consultant Emergency Physician and Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA; Lecturer, University of Western Australia, Australia David McCoubrie MBBS FACEM, Consultant Emergency Physician and Clinical Toxicologist, Royal Perth Hospital, Perth, WA; Consultant Clinical Toxicologist, WA and NSW Poisons Information Centres, Australia Kirsty Skinner MBChB FACEM, Consultant Emergency Physician and Clinical Toxicology Fellow, Royal Perth Hospital, Perth, WA, Australia Jessamine Soderstrom MBBS FACEM Grad Cert Toxicology, Consultant Emergency Physician and Clinical Toxicologist, Royal Perth Hospital, Perth, WA; Clinical Senior Lecturer, University of Western Australia, Australia Ioana Vlad MD FACEM, Consultant Emergency Physician and Clinical Toxicology Fellow, Sir Charles Gairdner Hospital, Perth, WA, Australia
REVIEWERS David Banfield BMed MPH MMedSc DCH FACEM, Emergency Physician and Co-Director, Calvary Health Care ACT, Bruce, ACT; Emergency Medicine Training Clinical Lecturer, Australian National University Medical School, Canberra, ACT, Australia David Caldicott BSc(Hons)-[NUI] MBBS(Lond) FCEM Dip Clin Tox, Consultant Emergency Physician, Clinical Senior Lecturer, Australian National University, Canberra, ACT; Coordinator of the ACT Investigation of Novel Substances (ACTINOS) Group, Canberra, ACT, Australia Jon Hayman MBBS FACEM, Director of Emergency Medicine Training, Royal Prince Alfred Hospital, Sydney, NSW; Chair of the Emergency Medicine State Training Council Health Education and Training Institute, NSW; Clinical Senior Lecturer, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia Paul Jennings BN GradCertAdvNsg AdvDipMICAStud GradCertBiostats GCHPE MClinEpi PhD, Department of Community Emergency Health and Paramedic Practice, Monash University, Melbourne, Vic; Ambulance Victoria, Melbourne, Vic, Australia Slade Matthews BmedSc(Hons) PhD DipEd GradCertEd(Higher Ed), Senior Lecturer, Sub-Dean Medical Program Stage 1, School of Medical Sciences (Pharmacology), Sydney Medical School, University of Sydney, Sydney, NSW, Australia
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CHAPTER 1
APPROACH TO THE POISONED PATIENT 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9
Overview Resuscitation Risk assessment Supportive care and monitoring Investigations Gastrointestinal decontamination Enhanced elimination Antidotes Disposition
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2 4 12 14 16 19 26 32 32
APPROACH TO THE POISONED PATIENT
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1.1 OVERVIEW Acute poisoning is a common emergency medicine presentation. Between 150 and 400 acute poisoning presentations annually can be expected for each 100 000 population served by an emergency department. Acute poisoning is a dynamic medical illness that frequently represents a potentially life-threatening exacerbation of a chronic psychosocial disorder. However, this is a highly heterogeneous patient population: deliberate self-poisoning, recreational drug abuse, occupational poisoning and envenoming challenge with myriad potential presentations. The clinician needs a robust and simple clinical approach that can address this heterogeneity, but that allows the development of a management plan tailored to the individual patient at that particular presentation at that particular medical facility. Risk assessment is pivotal to that robust approach. It is a distinct cognitive process through which the clinician attempts to predict the likely clinical course and potential complications for the individual at that particular presentation. Risk assessment should wherever possible be quantitative and take into account the agent, dose and time of ingestion, clinical features and progress, and individual patient factors (e.g. weight and co-morbidities). Toxicology management guidelines frequently focus on the agent involved. This makes adaptation of treatment recommendations to an individual patient in a particular location difficult. A risk-assessmentbased approach ensures the clinician addresses potentially time-critical management priorities in an appropriate order, but avoids unnecessary investigations or interventions. Risk assessment is secondary only to resuscitation in the management of acute poisoning. It allows subsequent management decisions regarding supportive care and monitoring, investigations, decontamination, use of enhanced elimination techniques, antidotes and disposition to be made in a sensible structured manner. Ideally, this risk-assessment-based approach is supported by a healthcare system designed to address both the medical and the psychological needs of the poisoned patient. Where the medical needs of a patient exceed local resources, a risk-assessment-based management approach ensures that this is identified early and disposition planning and communication occur in a proactive manner within that organised system. In this handbook, the authors offer a systematic risk-assessmentbased approach to the management of acute poisoning as it presents to the emergency department (see Table 1.1.1). Separate chapters cover the pharmaceutical, chemical and natural toxins of most importance to the practitioner in emergency departments in Australia and New Zealand. It ERRNVPHGLFRVRUJ
Airway Breathing Circulation Detect and correct — Hypoglycaemia — Seizures — Hyper-/hypothermia Emergency antidote administration
Risk assessment
Agent(s) Dose(s) Time since ingestion Clinical features and course Patient factors
Supportive care and monitoring Investigations
Screening—12-lead ECG, paracetamol, blood glucose level (BGL) Specific
Decontamination Enhanced elimination Antidotes Disposition
will also be of use to ambulance and emergency paramedic personnel and staff of general intensive care units. The approach to acute poisoning presented in this book is honed at the bedside and on the telephone. The authors collectively have directly cared for many thousands of patients in the Western Australian Toxicology Service and offered consultation in thousands more acute poisonings across Australia and overseas via the Western Australian, New South Wales, Victorian and Queensland Poisons Information Centres (PICs). The agents covered are carefully selected to cover all common poisonings, rare but life-threatening poisonings and poisonings where particular interventions make a difference to outcome, or which result in frequent consultations with clinical toxicologists through the PIC network. Chapters are also offered on the important antidotes and antivenoms with practical information on administration, dose and adverse effects. All chapters have a risk assessment. All chapters have special sections on ‘pitfalls’ and ‘handy tips’. These are not for show! They are designed to respond to the real questions and mistakes that regularly occur in clinical practice across Australasia. Clinical toxicology has rightly become an area of expertise of the emergency doctor but the infinite variation in presentation constantly confounds and surprises all of us. We hope that the information in this book, when combined with a structured approach, will improve the care delivered to the poisoned patient. ERRNVPHGLFRVRUJ
APPROACH TO THE POISONED PATIENT
Resuscitation
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TABLE 1.1.1 Risk-assessment-based approach to poisoning
APPROACH TO THE POISONED PATIENT
4 4 TOXICOLOGY HANDBOOK
Poisoning is most frequently the presentation of an individual suffering from exacerbation of very significant underlying psychiatric, social or drug and alcohol problems. Excellence in care of the poisoning delivered in a compassionate manner offers an opportunity to intervene and produce a happy outcome in this vulnerable group of patients.
1.2 RESUSCITATION INTRODUCTION Poisoning is a leading cause of death in patients under the age of 40 years and is a leading differential diagnosis when cardiac arrest occurs in a young adult. Unlike cardiac arrest in the older population, resuscitation following acute poisoning may be associated with good neurological outcomes even after prolonged periods (hours) of cardiopulmonary resuscitation (CPR). Therefore, while poisoning is considered part of the differential diagnosis in a patient with cardiac arrest, resuscitation (see Table 1.2.1) should continue until expert advice can be obtained. Extracorporeal membrane oxygenation therapy (ECMO) may provide life-saving bridging therapy in selected cases of severe refractory shock or adult respiratory distress syndrome. Attempts at decontamination of the skin or gastrointestinal tract almost never take priority over resuscitation and institution of supportive care measures.
AIRWAY, BREATHING AND CIRCULATION Acute poisoning is a dynamic medical illness and patients may deteriorate within a few minutes or hours of presentation. Altered TABLE 1.2.1 Resuscitation Airway Breathing Circulation Detect and correct: Seizures Always generalised when due to toxicological causes Benzodiazepines first-line Hypoglycaemia Check bedside blood glucose level (BGL) in all patients with altered mental status Treat if BGL 38.5°C prompts urgent intervention Emergency antidote administration
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DETECT AND CORRECT SEIZURES Toxic seizures are generalised, and can usually be controlled with intravenous benzodiazepines (e.g. diazepam, midazolam or clonazepam). The most common causes of seizures in poisoned patients in Australasia are venlafaxine, tramadol, amphetamines and bupropion. Seizures related to ethanol or benzodiazepine withdrawal are also common. The presence of focal or partial seizures indicates a focal neurological disorder that is either a complication of poisoning or due to a non-toxicological cause, and prompts further investigation. Barbiturates are second-line therapy for refractory seizures in acute poisoning. Pyridoxine may be indicated in intractable seizures secondary to isoniazid. Phenytoin is contraindicated in the management of seizures related to acute poisoning because of poor efficacy and the potential to exacerbate sodium channel blockade, which may be a causative mechanism.
DETECT AND CORRECT HYPOGLYCAEMIA Hypoglycaemia is an easily detectable and correctable cause of significant neurological injury. Bedside blood glucose level (BGL) estimation should be performed as soon as possible in all patients with altered mental status. If the blood glucose is less than 4.0 mmol/L, 50 mL of 50% dextrose should be given intravenously (5 mL/kg 10% dextrose in children) to urgently correct hypoglycaemia. The result may be confirmed later with a formal BGL measurement. ERRNVPHGLFRVRUJ
APPROACH TO THE POISONED PATIENT
5 TOXICOLOGY HANDBOOK
conscious state, loss of airway protective reflexes and hypotension are common threats to life in the poisoned patient. As in all life-threatening emergencies, attention to airway, breathing and circulation are paramount. These priorities are usually managed along conventional lines. Basic resuscitative and supportive care measures ensure the survival of the vast majority of patients. Although commonly used to describe a patient’s mental status, clinical scores such as the Glasgow Coma Scale (GCS) or Alert-VerbalPain-Unresponsive (AVPU) system have never been systematically validated across all poisonings. A patient’s ability to guard their airway is not well correlated to GCS. An increased risk of aspiration has been noted with GCS less than 15. Moreover, a patient’s ability to guard the airway and ventilate effectively may change within a short period of time. In some specific situations, standard resuscitation algorithms do not apply (see Table 1.2.2).
APPROACH TO THE POISONED PATIENT
Various
Opioid mu receptor stimulation
Cholinergic crisis
Hypoventilation
Respiratory failure
Corrosive injury to oropharynx
Mechanism
Acidosis Acidaemia
BREATHING
Airway compromise
AIRWAY
Life-threat
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●
● ● ●
● ● ● ●
Carbamates Nerve agents Organophosphates
Opioids
Ethylene glycol Methanol Salicylates
Alkalis Acids Glyphosate Paraquat
Agent(s)
●
●
Rapid administration of atropine by serial doubling of atropine dose to achieve dry respiratory secretions may restore adequate oxygenation
Prompt administration of naloxone may obviate need for intubation and ventilation
Until late in the clinical course there is usually prominent respiratory compensation ● Intubation and ventilation at standard settings worsens acidaemia and precipitates rapid clinical deterioration, if not death ● Avoid normo- or hypoventilation ● Maintain hyperventilation and consider bolus IV sodium bicarbonate 1–2 mmol/kg to prevent worsening of acidaemia
●
Stridor, dysphagia and dysphonia indicate airway injury and potential for imminent airway compromise ● Early endotracheal intubation or surgical airway often required
●
Comments
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply
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Ventricular tachycardia
Ventricular fibrillation
Fast Na+ channel blockade
Hypocalcaemia
Oxygen free radicalmediated cellular injury, particularly type II pneumocytes
Hypoxaemia
CIRCULATION
Mechanism
Life-threat
● ● ● ●
● ● ●
●
●
●
TOXICOLOGY HANDBOOK
Chloroquine/ hydroxychloroquine Cocaine Flecainide Local anaesthetic agents Procainamide Propranolol Quinine Tricyclic antidepressants
Hydrofluoric acid ingestion or extensive cutaneous burns
Paraquat
Agent(s)
●
●
●
● ●
●
● ●
●
APPROACH TO THE POISONED PATIENT
Continued
Cardioversion or defibrillation unlikely to be efficacious Urgently intubate and hyperventilate Bolus IV sodium bicarbonate 1–2 mmol/kg repeated every 1–2 minutes until restoration of perfusing rhythm Do not await determination of serum pH prior to intubation and sodium bicarbonate boluses Lignocaine is third-line therapy when pH is established at >7.5 Amiodarone and Vaughan Williams type la antidysrhythmic agents (e.g. procainamide) are contraindicated
Defibrillation alone unlikely to be efficacious Bolus IV calcium (e.g. 60–90 mL 10% calcium gluconate) repeated as required every 2 minutes until defibrillation restores perfusing rhythm
Avoid supplemental oxygen; if hypoxia occurs, titrate supplemental oxygen to maintain oxygen saturation of ~90% or PaO2 60 mmHg
Comments
7
APPROACH TO THE POISONED PATIENT
Mechanism
Mechanism
Toxin-induced myocardial sensitisation to catecholamines
Fast sodium channel blockade
Various
Central and peripheral sympathomimetic response
Adenosine antagonism
Life-threat
CIRCULATION cont’d Life-threat
Ventricular ectopy/ ventricular tachycardia
Cardiovascular collapse/arrest
Refractory cardiogenic hypotension
Tachycardia
Supraventricular tachycardia
Local anaesthetic agents
Chloral hydrate Hydrocarbons Organochlorines
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● ●
Theophylline
Amphetamines Cocaine
Calcium channel blockers ● Propranolol ● Local anaesthetic agents
●
●
● ● ●
Agent(s)
Agent(s)
●
● ●
●
●
Adenosine ineffective — Beta-blockers titrated to effect — Urgent haemodialysis indicated
Beta-blockers contraindicated Administer IV benzodiazepines, titrated to gentle sedation and heart rate control
High-dose insulin therapy
Consider intravenous lipid emulsion in addition to standard resuscitation protocols
Cardioversion or defibrillation unlikely to be efficacious ● Administer IV beta-blockers, titrate to ectopy response
●
Comments
Comments
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply—cont’d
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●
Na+–K+-ATPase pump inhibition
Calcium channel blockade
Central and peripheral sympathomimetic response
Asystole Bradycardia Tachycardia
Bradycardia Hypotension Cardiac conduction defects
Acute coronary syndrome
● ●
●
● ●
Central and peripheral sympathomimetic response
Hypertension
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Amphetamines Cocaine
Calcium channel blockers
Digoxin
Amphetamines Cocaine
Agent(s)
Mechanism
Life-threat
Usual resuscitation interventions futile Digoxin-specific antibodies
APPROACH TO THE POISONED PATIENT
Continued
Beta-blockers contraindicated Benzodiazepines GTN Antiplatelet and anticoagulation therapy if no neurological deficits (otherwise cranial CT first) ● Reperfusion therapy along conventional lines
● ● ● ●
Atropine and pacing unlikely to be efficacious Bolus IV calcium (e.g. 60 mL 10% calcium gluconate) may provide temporary haemodynamic stability by increasing HR and BP, while other treatments are organised ● High-dose insulin therapy
● ●
● ●
Beta-blockers contraindicated Administer IV benzodiazepines, titrated to gentle sedation and heart rate control ● If further therapy necessary use agents that can be given by titratable intravenous infusion — Glyceryl trinitrate (GTN) — Phentolamine — Sodium nitroprusside
● ●
Comments
9
APPROACH TO THE POISONED PATIENT
Na+–K+-ATPase pump inhibition
Hyperinsulinaemia
Inhibition of GABA production
Adenosine antagonism
Hypoglycaemia
Seizures
Seizures
Mechanism
Hyperkalaemia
OTHER
Life-threat
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●
●
●
Theophylline
Isoniazid
Sulfonylureas
Digoxin
Agent(s)
Calcium salts are contraindicated Digoxin-specific antibodies
●
●
Urgent haemodialysis indicated
IV pyridoxine 1 g per gram of isoniazid ingested, up to 5 g
Difficult to maintain euglycaemia with dextrose supplementation alone ● Octreotide administration decreases requirement for dextrose supplementation
●
● ●
Comments
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply—cont’d
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10
Hyperthermia is associated with a number of life-threatening acute poisonings and is associated with poor outcome. A temperature greater than 38.5°C during the resuscitation phase of management is an indication for continuous core-temperature monitoring. A temperature greater than 39.5°C is an emergency that requires prompt management to prevent multiple organ failure and neurological injury. Neuromuscular paralysis with intubation and ventilation leads to a cessation of muscle-generated heat production and a rapid reduction of temperature. Profound hypothermia (core temperature 2.5 mmol/kg Life-threatening slow-release verapamil or diltiazem ingestions Symptomatic arsenic trioxide ingestion Lead ingestion ‘Body packers’ (see Chapter 2.17: Body packers and stuffers)
balanced polyethylene glycol electrolyte solution (PEG-ELS). It is rarely performed because risk–benefit analysis reserves this intervention for life-threatening ingestions of sustained-release or enteric-coated preparations; or agents that do not bind to charcoal and where good clinical outcome is not expected with supportive care and antidote administration and the patient presents before established severe toxicity (see Table 1.6.4). Whole bowel irrigation has been performed on unconscious ventilated patients but this is hazardous as fluid may pool in the oropharynx and flow past the tube cuff to produce pulmonary aspiration. Potential complications
• • • • •
Nausea, vomiting and abdominal bloating Non-anion gap metabolic acidosis Pulmonary aspiration Distraction from resuscitation and supportive care priorities Delayed retrieval to a hospital offering definitive care
Contraindications
• • • • • • •
Risk assessment suggesting good outcome can be assured with supportive care and antidote therapy Uncooperative patient Inability to place a nasogastric tube Uncontrolled vomiting Risk assessment suggesting potential for decreased conscious state or seizure in the subsequent 4 hours Ileus or intestinal obstruction Intubated and ventilated patient (relative contraindication)
Technique
• • •
Assign a single nurse to carry out the procedure (this is a full-time job for up to 6 hours). Obtain sufficient supplies of PEG-ELS and make up the solution as directed. Place nasogastric tube and confirm position on chest X-ray. ERRNVPHGLFRVRUJ
APPROACH TO THE POISONED PATIENT
● ● ● ● ● ●
25 TOXICOLOGY HANDBOOK
TABLE 1.6.4 Whole bowel irrigation potentially useful
APPROACH TO THE POISONED PATIENT
26 26 TOXICOLOGY HANDBOOK
• • • • • • • •
Give activated charcoal 50 g (children 1 g/kg) via the nasogastric tube unless agent does not bind to AC. Administer PEG solution via the nasogastric tube at 2 L/hour by continuous infusion (children 25 mL/kg/hour). Administer metoclopramide to minimise vomiting and enhance gastric emptying. Position patient on a commode if possible to accommodate explosive diarrhoea. Continue irrigation until the effluent is clear. This may take up to 6 hours. Cease whole bowel irrigation if abdominal distension or loss of bowel sounds is noted. Abdominal X-ray is useful to assess effectiveness of decontamination of radio-opaque substances such as iron and potassium salts. Expelled packages may be counted in body packers.
References
American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists. Position paper: whole bowel irrigation. Clinical Toxicology 2004; 42:843–854. American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists. Position paper: single-dose activated charcoal. Clinical Toxicology 2005; 43:61–87. Bailey B. Gastrointestinal decontamination triangle. Clinical Toxicology 2005; 1:59–60. Benson BE, Hoppu K, Troutman WG et al. Position paper update: gastric lavage for gastrointestinal decontamination. Clinical Toxicology 2013; 51:140–146. Hojer J, Troutman WG, Hoppu K et al. Position paper update: ipecac syrup for gastrointestinal decontamination. Clinical Toxicology 2013; 51:134–139. Isbister GK, Pavan Kumar VV. Indications for single dose activated charcoal administration. Current Opinion in Critical Care 2011; 17:351–357.
1.7 ENHANCED ELIMINATION Techniques of enhanced elimination (see Table 1.7.1) are employed to increase the rate of removal of an agent from the body with the aim of reducing the severity and duration of clinical intoxication. These interventions are only indicated if it is thought they will reduce mortality, length of stay, complications or the need for other more invasive interventions. In practice, these techniques are useful in the treatment of poisoning by only a few agents that are characterised by:
• • • •
Severe toxicity Poor outcome despite good supportive care/antidote administration Slow endogenous rates of elimination Suitable pharmacokinetic properties. ERRNVPHGLFRVRUJ
Carbamazepine Dapsone Phenobarbitone Quinine Theophylline
Urinary alkalinisation
Phenobarbitone Salicylate
Haemodialysis and haemofiltration
Carbamazepine Lithium Metformin lactic acidosis Potassium Salicylate Theophylline Toxic alcohols Valproic acid
Charcoal haemoperfusion
Theophylline
Accurate risk assessment allows early identification of those patients who may benefit from enhanced elimination and institution of the intervention before severe life-threatening intoxication develops. Some of these techniques require specialised equipment and staff and early identification of candidates facilitates the timely communication, planning and transport necessary to ensure a good outcome. The final decision as to whether to initiate a technique of enhanced elimination depends on a risk–benefit analysis in which the expected benefits of the procedure are balanced against the resource utilisation and risks associated with the procedure. Techniques of enhanced elimination are never carried out to the detriment of resuscitation, good supportive care, decontamination and antidote treatment. Once the decision to initiate a technique of enhanced elimination is made, it is important to establish pre-defined clinical or laboratory end points for therapy.
MULTIPLE-DOSE ACTIVATED CHARCOAL (MDAC) Rationale
Repeated administration of oral activated charcoal progressively fills the entire gut lumen with charcoal. This has the potential to enhance drug elimination in two ways:
•
Interruption of enterohepatic circulation — A number of drugs are excreted in the bile and then reabsorbed from the distal ileum. Charcoal in the small intestine binds drug and prevents reabsorption thus enhancing elimination. — This is only significant if a drug not only undergoes enterohepatic circulation but also has a relatively small volume of distribution. ERRNVPHGLFRVRUJ
APPROACH TO THE POISONED PATIENT
Multiple-dose activated charcoal
27 TOXICOLOGY HANDBOOK
TABLE 1.7.1 Techniques of enhanced elimination and amenable agents
APPROACH TO THE POISONED PATIENT
•
Indications
Enhanced elimination by this technique has been proposed as clinically useful in the following scenarios:
•
28 28 TOXICOLOGY HANDBOOK
Gastrointestinal dialysis — Drug passes across the gut mucosa from a relatively high concentration in the intravascular compartment to a low concentration in the gut lumen, which is maintained by continuing adsorption to charcoal. — This is only effective if the drug is a relatively small molecule, lipid soluble, has a small volume of distribution and low protein binding.
• • • •
Carbamazepine coma — Most common indication for MDAC — Used in the expectation that enhanced elimination will reduce duration of ventilation and length of stay in intensive care Phenobarbitone coma — Rare — Used in the expectation that enhanced elimination will reduce duration of ventilation and length of stay in intensive care Dapsone overdose with methaemoglobinaemia — Very rare — MDAC may enhance elimination of dapsone and reduce the duration of severe prolonged methaemoglobinaemia Quinine overdose — Although MDAC might enhance drug elimination, good outcome can be expected with aggressive supportive care Theophylline overdose — Attempts at enhanced elimination with MDAC should never delay more effective elimination techniques (haemodialysis) following life-threatening overdose.
Contraindications
• •
Decreased level of consciousness or anticipated decreased level of consciousness without prior airway protection Bowel obstruction
Potential complications
Although rare in carefully selected patients, they may include:
• • •
Vomiting (30%) Charcoal aspiration, especially if there is decreased mental status or seizures Constipation ERRNVPHGLFRVRUJ
Technique
• • • • • •
Give an initial dose of activated charcoal 50 g (adults) or 1 g/kg (children) PO. Give repeat doses of 25 g (0.5 g/kg in children) every 2 hours. In the intubated patient, activated charcoal is given via oro- or nasogastric tube after tube placement has been confirmed on chest X-ray. Check for bowel sounds and high nasogastric aspirates prior to administration of each dose. Cease further administration if bowel sounds are inaudible or nasogastric aspirates of high volume. Reconsider the indications and clinical end points for therapy every 6 hours. MDAC should rarely be required beyond 6 hours.
URINARY ALKALINISATION Rationale
The production of an alkaline urine pH promotes the ionisation of acidic drugs and prevents reabsorption across the renal tubular epithelium, thus promoting excretion in the urine. For this method to be effective the drug must be filtered at the glomerulus, have a small volume of distribution and be a weak acid. Indications
Only two drugs of significance in clinical toxicology have the required pharmacokinetic properties for this method to be of interest in management of poisoning.
•
Salicylate overdose — Salicylates are normally eliminated by hepatic metabolism and are not readily excreted in acidic urine. In overdose, metabolism is saturated and elimination half-life greatly prolonged. — Urinary alkalinisation greatly enhances elimination and is indicated in any symptomatic patient in an effort to reduce the duration and severity of symptoms or to avoid progression to severe poisoning and the need for haemodialysis. — Severe established salicylate toxicity indicates immediate haemodialysis rather than a trial of urinary alkalinisation. — Note: Not generally useful in chronic salicylate toxicity due to co-morbidities. ERRNVPHGLFRVRUJ
APPROACH TO THE POISONED PATIENT
Charcoal bezoar formation, bowel obstruction, bowel perforation (rare) Corneal abrasion Distraction of attending staff from resuscitation and supportive care priorities.
29 TOXICOLOGY HANDBOOK
• • •
APPROACH TO THE POISONED PATIENT
30 30 TOXICOLOGY HANDBOOK
•
Phenobarbitone coma — May be attempted in an effort to reduce duration of coma and length of stay in intensive care. — Not first-line as MDAC is a superior technique of enhancing elimination.
Contraindications
•
Fluid overload
Complications
• • •
Alkalaemia (usually well-tolerated) — Fluid overload Hypokalaemia Hypocalcaemia (not usually clinically significant)
Technique
• • • • • • •
Correct hypokalaemia if present (it is difficult to alkalinise the urine in the presence of systemic hypokalaemia). Give 1–2 mmol/kg sodium bicarbonate IV bolus. Commence infusion of 150 mmol sodium bicarbonate in 850 mL 5% dextrose at 250 mL/hour. 20 mmol of potassium chloride may be added to infusion to maintain normokalaemia. Monitor serum bicarbonate and potassium at least every 4 hours. Regularly dipstick urine and aim for urinary pH >7.5. Continue until clinical and laboratory evidence of toxicity is resolving.
EXTRACORPOREAL TECHNIQUES OF ELIMINATION A number of such techniques have been used to enhance elimination of toxins including:
• • • • •
Haemodialysis — Intermittent — Continuous Haemofiltration Haemoperfusion Plasmapheresis Exchange transfusion.
All of the above techniques are invasive and require specialised staff, equipment and monitoring, and may be associated with significant complications. For these reasons they are reserved for life-threatening poisonings where a good outcome cannot be achieved
ERRNVPHGLFRVRUJ
• • • • • • • •
Toxic alcohol poisoning — Methanol — Ethylene glycol Theophylline poisoning Severe salicylate intoxication — Chronic intoxication with altered mental status — Late-presentation acute overdose with established severe toxicity Severe chronic lithium intoxication Phenobarbitone coma Metformin lactic acidosis Massive valproate overdose Massive carbamazepine overdose Potassium salt overdose with life-threatening hyperkalaemia.
Precise clinical indications for extracorporeal elimination in each of these important poisonings are discussed in the relevant sections of Chapter 3. The decision to institute extracorporeal elimination should be made early as soon as the risk assessment indicates potential lethality. In general, intermittent dialysis achieves greater clearance rates than continuous haemodialysis or haemofiltration techniques and is preferred where available. Facilities for charcoal haemoperfusion are not available in most centres. References
Anonymous. Position Statement and Practice Guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. Clinical Toxicology 1999; 37(6):731–751. Dorrington CL, Johnson DW, Brant R. The frequency of complications associated with the use of multiple-dose activated charcoal. Annals of Emergency Medicine 2003; 41(3):370–377. Ouellet GI, Bouchard J, Ghannoum M, Decker BS. Available extracorporeal treatments for poisoning: overview and limitations. Seminars in Dialysis 2014; doi: 10.1111/ sdi.12238. [Epub ahead of print]. Pond SM, Olson KR, Osterloh JD et al. Randomised study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. Journal of the American Medical Association 1984; 251:3104–3108. Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. Journal of Toxicology Clinical Toxicology 2004; 42:1–26.
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•
31 TOXICOLOGY HANDBOOK
by other means, including aggressive supportive care and antidote administration. Haemodialysis effectively enhances elimination of any drug that is a small molecule, has a small volume of distribution, rapid redistribution from tissues and plasma and slow endogenous elimination. Clinical situations that involve life-threatening poisoning with agents fulfilling these criteria include:
APPROACH TO THE POISONED PATIENT
32 32 TOXICOLOGY HANDBOOK
1.8 ANTIDOTES Antidotes are drugs that correct the effects of poisoning. Only a few antidotes exist and many are used only rarely. Specific antidotes likely to be used in clinical practice are discussed in Chapter 4 of this book. Like all pharmaceuticals, antidotes have specific indications, contraindications, optimal administration methods, monitoring requirements, appropriate therapeutic end points and adverse effect profiles. The decision to administer an antidote to an individual patient is based upon a risk–benefit analysis. An antidote is administered when the potential therapeutic benefit is judged to exceed the potential adverse effects, cost and resource requirements. An accurate risk assessment combined with pharmaceutical knowledge of the antidote is essential to clinical decision making. Many antidotes are rarely prescribed, expensive and not widely stocked. Planning of stocking, storage, access, monitoring, training and protocol development are essential components of rational antidote use. It is often appropriate for stocking to be coordinated on a regional basis in association with regional policies concerning the treatment of poisoned patients. It is frequently cheaper and safer to transport an antidote to a patient rather than vice versa. Reference
Dart RC, Borrow SW, Caravati EM et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Annals of Emergency Medicine 2009: 54:386–394.
1.9 DISPOSITION A medical disposition is required for all patients who present with poisoning or potential exposure to a toxic substance. Those who have deliberately self-poisoned also require psychiatric and social review. A risk-assessment-based approach to the management of acute poisoning allows early planning for appropriate medical and psychosocial disposition. Patients must be admitted to an environment capable of providing an adequate level of monitoring and supportive care and, if appropriate, where staff and resources are available to undertake decontamination, enhanced elimination techniques or administration of antidotes. Early risk assessment in the pre-hospital setting, usually by poisons information centre staff, often allows non-intentional exposures to be observed outside of the hospital environment. For those that present to ERRNVPHGLFRVRUJ
EMERGENCY OBSERVATION UNITS Emergency observation units (EOUs) have been established in many emergency departments in Australasia and elsewhere. These units vary in capacity, design and staffing. Ideally, they are located adjacent to emergency departments, staffed by emergency doctors and provide short-term focused goal-oriented care. They have been remarkably successful in:
• • • •
Streamlining treatment in suitable conditions Reducing total bed days Increasing patient satisfaction Reducing inappropriate discharges and litigation.
TOXICOLOGY PATIENTS IN THE EMERGENCY OBSERVATION UNIT In most hospitals where EOUs are established, the units appear to provide an ideal environment for the management of acute poisoning beyond the initial assessment and monitoring phase. Advantages of using the EOU to admit toxicology patients include the ready availability of appropriate resources, staff and training; 24-hour availability of experienced medical staff; an open-plan environment that facilitates observation; and an emergency department ethos that is geared towards rapid assessment and disposition. Adequate resources must be dedicated to the EOU, particularly medical, nursing, psychiatric and social services. Ideal design features and staffing that facilitate the management of toxicology patients in the EOU include:
• • • •
Central nursing stations with clear vision of all areas An environment that protects from self-harm Secure entrances Dedicated areas for private interviews ERRNVPHGLFRVRUJ
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33 TOXICOLOGY HANDBOOK
hospital, it minimises the duration and intensity of monitoring. Frequently, patients can be ‘cleared’ for medical discharge directly from the emergency department immediately following assessment or following a few hours of observation. No arrangements for admission to hospital need to be made unless unexpected signs or symptoms of toxicity develop. At other times the risk assessment will indicate the need for ongoing observation, supportive care or the need for specific enhanced elimination techniques or antidote administration. Under these circumstances, the patient must be admitted to an environment capable of providing a level of care appropriate for the anticipated clinical course. In many hospitals, this is now the emergency observation unit rather than the general medical ward. Where ongoing airway control, ventilation or advanced haemodynamic support is required, admission to an intensive care unit is appropriate.
APPROACH TO THE POISONED PATIENT
34 34 TOXICOLOGY HANDBOOK
• • • • • • • •
Dedicated social work, drug and alcohol, plus outpatient liaison services Appropriate monitors ± telemetry Dedicated resuscitation equipment Duress alarms Appropriate staff, skills and equipment Appropriate 24/7/365 senior staff coverage Dedicated psychiatric services Nurse–patient ratios appropriate for the acuity of patients (e.g. 1 : 4 for monitored ‘step-down’ patients; 1 : 8 for non-monitored general patients).
Criteria need to be developed for admission to the EOU following acute poisoning. Such criteria might include:
• • •
Cardiac monitoring not required (but this can be provided in some EOUs) Adequate sedation in cases of delirium Deterioration not anticipated (based on accurate risk assessment and initial period of observation in the emergency department).
Admission of toxicology patients to the EOU helps counter several of the difficulties encountered when poisoned patients are admitted to other areas of the hospital:
• • • • • •
Admissions scattered all over the hospital Less experienced nursing staff Poor availability of medical staff Frequent security incidents/absconding patients Most clinicians managing patients on general medical wards are junior and have no formal or informal training in clinical toxicology Longer admissions.
RETRIEVAL OF THE POISONED PATIENT Usually, the initial receiving hospital is adequately resourced to provide an acceptable level of supportive care, monitoring and therapy for the poisoned patient. If this is not the case, transfer is necessary. Risk assessment ensures that the need to transfer is recognised early so that appropriate planning and consultation takes place in an effort to ensure as smooth a retrieval as possible (see Table 1.9.1). Poisoning is unusual in that transfer frequently takes place during the most severe phase of the illness. Resuscitation
The need to retrieve a patient to another centre should not distract attending staff from resuscitation and supportive care priorities. Attention ERRNVPHGLFRVRUJ
● ● ● ● ● ●
Risk assessment is vital Identify patients who may need retrieval to another hospital as soon as possible Patients should only be retrieved for specific clinical indications Recognise that transport may occur during the worst phase of the intoxication Consider bringing expertise and resources to the patient, rather than vice versa Assess, manage and stabilise potential resuscitation and supportive care priorities prior to transfer Ensure that transport does not lead to an interval of lower level of care Transport to a centre capable of definitive care
to airway, breathing and circulation ensure an optimum outcome in the majority of cases. Whenever possible, the patient should be stabilised before retrieval begins. Interventions such as intubation, ventilation, initial resuscitation of hypotension, cessation of seizures, assessment of blood glucose and management of hyperthermia are completed before a patient is placed in the transport vehicle, where further assessment and detailed management are often impossible. If the referring team does not possess the necessary skills or resources to complete these resuscitation and stabilisation tasks adequately, this should be communicated to the receiving and retrieval teams, so that these resources can be brought to the patient. Transport
As transport usually occurs during the most severe phase of the poisoning, the patient should never be subjected to an interval of a lower level of care during the transfer. Consideration of the mode and staffing of transport takes this into account. Planning
Planning is required to ensure that any potential complications are identified and managed in a proactive fashion. Thus, if coma requiring intubation and ventilation is anticipated in the next few hours (e.g. controlled-release carbamazepine), early intubation and ventilation should occur prior to transfer. Similarly, if significant hypotension is expected (e.g. calcium channel blockers), appropriate monitoring, intravenous access and resuscitation resources should be ready prior to transfer. Communication
Communication is vital. Retrieval is always to a higher level of care. Thus, transport must occur to a facility with appropriate resources to ERRNVPHGLFRVRUJ
APPROACH TO THE POISONED PATIENT
● ●
35 TOXICOLOGY HANDBOOK
TABLE 1.9.1 Principles of retrieval of the poisoned patient
APPROACH TO THE POISONED PATIENT
36 36 TOXICOLOGY HANDBOOK
manage the potential complications identified by the risk assessment. For example, if haemodialysis may be required (e.g. theophylline or salicylate poisoning), the patient must be transported to a facility capable of instituting this intervention at short notice. Ideally, communication should include the team of clinicians who will ultimately manage the patient. Consultations with other specialist teams (e.g. paediatricians, intensivists or clinical toxicologists) may also occur to assist the process. This improves continuity of care and decreases the inefficiencies and errors that may be associated with multiple handovers. Antidotes
If an antidote is likely to definitively treat the patient and render them stable (e.g. N-acetylcysteine; digoxin-specific antibodies), it is preferable to transfer the antidote to the patient, start treatment, then move the patient only if necessary. Psychosocial assessment
Most episodes of acute poisoning represent an exacerbation of an underlying psychosocial disorder and the final disposition of the patient is made in this context. All patients with deliberate self-poisoning should undergo psychosocial assessment prior to discharge. Ideally, this process begins before the medical treatment of the poisoning is complete so that final disposition is facilitated. References
Daly FFS, Little M, Murray L. A risk assessment based approach to the management of acute poisoning. Emergency Medicine Journal 2006; 23:396–399. Ross MA, Graff LG. Principles of observation medicine. Emergency Medicine Clinics of North America 2001; 19(1):1–17. Warren J, Fromm RE, Orr RA, et al. Guidelines for the inter- and intrahospital transport of critically ill patients. Critical Care Medicine 2004; 32:256–262.
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CHAPTER 2
SPECIFIC CONSIDERATIONS 2.1 Approach to snakebite 2.2 Approach to mushroom poisoning 2.3 Approach to plant poisoning 2.4 Coma 2.5 Hypotension 2.6 Seizures 2.7 Delirium and agitation 2.8 Serotonin syndrome 2.9 Anticholinergic syndrome 2.10 Cholinergic syndrome 2.11 Neuroleptic malignant syndrome 2.12 Alcohol use disorder 2.13 Amphetamine use disorder 2.14 Opioid use disorder 2.15 Sedative-hypnotic use disorder 2.16 Solvent abuse 2.17 Body packers and stuffers 2.18 Osmolar gap 2.19 Acid–base disorders 2.20 The 12-lead ECG in toxicology 2.21 Poisoning during pregnancy and lactation 2.22 Poisoning in children 2.23 Poisoning in the elderly
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38 45 52 58 62 64 65 70 76 80 83 89 98 99 103 106 110 113 116 121 127 128 134
SPECIFIC CONSIDERATIONS
2.1 APPROACH TO SNAKEBITE
38 38 TOXICOLOGY HANDBOOK
See also specific sections in Chapter 5: Black snake, Brown snake, Death adder, Sea snake, Taipan, Tiger snake group. Definite or suspected snakebite is a regular presentation to emergency departments in most parts of Australia. In contrast, severe envenoming is a rare but potentially lethal presentation. Few clinicians have the opportunity to develop sufficient clinical experience to feel comfortable managing envenoming. Snakebite is a time-critical emergency presentation and a simple but robust approach is required to ensure adequate treatment should envenoming develop (see Table 2.1.1). The clinical effects of the medically important Australian snakes are summarised in Table 2.1.2.
RISK ASSESSMENT Once it is appreciated that snakebite is a possibility, the risk assessment is straightforward: there is a risk of life-threatening envenoming and a formal process must begin to exclude that possibility in an appropriate setting. TABLE 2.1.1 Treatment approach to snakebite PRE-HOSPITAL
First aid Pressure bandage with immobilisation (PBI) Transport The patient is transported as soon as possible to a hospital that meets all of the following criteria: Doctor(s) able to manage snakebite Laboratory capable of operating at all hours Adequate antivenom stocking for definitive treatment HOSPITAL
Resuscitation Determine if the patient is envenomed Assessment is performed serially over at least 12 hours and is based upon: History Physical examination Laboratory investigations Determine the type of antivenom required Geographical area (prevalent indigenous snakes) Clinical and laboratory features CSL Snake Venom Detection Kit (SVDK) Administer antivenom if indicated Adjuvant and supportive treatment
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Always present with significant envenoming
Always present with significant envenoming May resolve spontaneously in 12–24 hours
Not present
Brown (Pseudonaja)
Tiger group (Hoplocephalus, Notechis, Tropidechis)
Death adders (Acanthophis)
Category (genus)
Venom-induced consumptive coagulopathy
Systemic symptoms common* Thrombotic microangiopathy (24 HOURS)
Erythromelalgia
Hepatotoxic*
>7 days
Toxin (mushroom species)
Clinical course
Clinical features
DELAYED ONSET (6–24 HOURS)
Syndrome
49
SPECIFIC CONSIDERATIONS
50 50 TOXICOLOGY HANDBOOK
Gyromitrin is activated to monomethylhydrazine, which has a similar mode of action to isoniazid and inhibits pyridoxine-dependent synthesis of GABA. Psilocybin resembles lysergic acid diethylamide (LSD). Coprine inhibits acetaldehyde dehydrogenase, a mode of action similar to disulfiram. Amatoxins (chiefly α-amanitin) inactivate RNA polymerase II and inhibit protein synthesis.
CLINICAL FEATURES A variety of clinical syndromes may develop following ingestion of toxic mushrooms. They are diagnosed on the basis of the clinical features and the timing of the onset and duration of clinical features in relation to mushroom ingestion (see Table 2.2.1). Laboratory abnormalities are important in the diagnosis of some syndromes, especially hepatotoxicity. Identification of the mushroom species by a mycologist is frequently difficult or impossible but may provide important supportive evidence if available. Conventional food poisoning should be considered in the differential diagnosis for any patient who presents with gastrointestinal symptoms following ingestion of mushrooms.
MANAGEMENT Resuscitation
Patients may present with altered conscious state, seizures, cholinergic crisis or significant hypovolaemia secondary to gastrointestinal fluid losses. These priorities are managed along conventional lines as outlined in Chapter 1.2: Resuscitation. Supportive care
Patients may have significant gastrointestinal losses and require large volumes of crystalloid solutions. Meticulous supportive care includes laboratory monitoring of electrolytes as clinically indicated. Seizures, delirium and hallucinations are managed along conventional lines as outlined in Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation. Decontamination
Administration of activated charcoal 50 g (1 g/kg in a child) is indicated if onset of gastrointestinal symptoms is delayed beyond 6 hours after ingestion. Investigations
Examination of any available mushrooms by a mycologist is useful, particularly in cases where ingestion of species containing cyclopeptide hepatotoxins is considered. ERRNVPHGLFRVRUJ
Enhanced elimination
Methods of enhanced elimination are frequently considered in patients with potential cyclopeptide hepatotoxic mushroom poisoning but their effect on outcome has not been studied in controlled trials. If cyclopeptide hepatotoxic mushroom poisoning is suspected, multipledose activated charcoal (see Chapter 1.7: Enhanced elimination) may be useful because amatoxin undergoes enterohepatic circulation.
SPECIFIC CONSIDERATIONS
The Meixner test is a useful screening test in the asymptomatic patient. Hydrochloric acid is added to a sample of the offending mushroom placed on newspaper. A blue colour change suggests the presence of cyclopeptide hepatotoxins, although false positives can occur. Electrolytes and creatinine should be monitored where significant gastrointestinal fluid losses occur. Liver function tests should be monitored for 24–48 hours where ingestion of mushrooms containing cyclopeptide hepatotoxins is suspected.
51
Multiple antidotes and adjuvant therapies have been advocated in patients with potential cyclopeptide hepatotoxic mushroom poisoning but their effect on outcomes has not been evaluated in controlled trials. They include high-dose benzyl penicillin (penicillin G), cimetidine, N-acetylcysteine and silibinin. If delayed onset of gastrointestinal symptoms or rising hepatic transaminases raises suspicion of possible cyclopeptide hepatotoxic mushroom poisoning, commence:
• • •
N-acetylcysteine (see Chapter 4.17: N-acetylcysteine) Silibinin (if available) 5 mg/kg by intravenous infusion over 1 hour followed by a continuous infusion of 20 mg/kg/day for up to 3 days Benzylpenicillin 600 mg/kg/day IV may be given if silibinin is not available.
Atropine may be considered in patients with peripheral cholinergic signs and symptoms (see Chapter 4.1: Atropine). Management of seizures secondary to monomethylhydrazine poisoning from ingestion of Gyromitra mushrooms is similar to the management of isoniazid poisoning and includes administration of pyridoxine (see Chapter 4.23: Pyridoxine). Disposition and follow-up
• •
Asymptomatic paediatric patients may be observed at home following suspected ingestion of wild mushrooms. Patients with early onset gastrointestinal illness are managed supportively in a ward environment. They may be discharged when clinically well. Patients with significant symptoms lasting more than ERRNVPHGLFRVRUJ
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Antidotes
SPECIFIC CONSIDERATIONS
52 52 TOXICOLOGY HANDBOOK
• •
6 hours should have liver function tests and renal function checked prior to discharge. Abnormal liver or renal function prompts further inpatient management. Patients with coma requiring intubation or significant CNS effects require management in an intensive care setting. Cyclopeptide hepatotoxic mushroom poisoning is extremely rare and most clinicians have very limited clinical experience. If this syndrome is suspected due to delayed onset gastrointestinal symptoms or rising hepatic transaminases, early consultation with a hepatologist and clinical toxicologist is recommended. In severe cases, hepatic transplantation has been attempted but prognosis remains poor.
References
Diaz JH. Syndromic diagnosis and management of confirmed mushroom poisonings. Critical Care Medicine 2006; 33:427–436. Enjalbert F, Rapior S, Nouguier-Soulé J et al. Treatment of amatoxin poisoning: 20-year retrospective analysis. Journal of Toxicology-Clinical Toxicology 2002; 40(6):715–757. Persson H. Mushrooms. Medicine 2012; 40(3):135–138. Roberts DM, Hall MJ, Falkland MM et al. Amanita phalloides poisoning and treatment with silibinin in the Australian Capital Territory and New South Wales. Medical Journal of Australia 2013; 198:43–47.
2.3 APPROACH TO PLANT POISONING Numerous pharmacologically-active substances are produced by plants and many pharmaceutical agents and recreational drugs are of plant origin. Serious human poisoning from plant exposures is, however, extremely rare. Exposure to toxic plants may occur unintentionally when they are mistakenly identified as edible plants or when young children ingest parts of plants, usually berries or seeds. Intentional exposure to toxic plants occurs with recreational or medicinal intent or, less commonly, as an attempt at deliberate self-harm. It often involves the ingestion of teas made from the plant. Non-intentional cutaneous and ocular exposures may also cause symptoms. Assessment of plant exposures is difficult even when the plant is positively identified because it is virtually impossible to quantify dose; there is enormous variation in toxin concentrations between species, plant part, location and season.
RISK ASSESSMENT
• •
Most plant exposures are asymptomatic or cause minor irritative symptoms only. Plants containing calcium oxalate crystals may cause more severe irritation to exposed mucous membranes. ERRNVPHGLFRVRUJ
Children: significant plant poisoning is extremely rare. Ingestion of yellow oleander or castor bean seeds can theoretically cause significant poisoning but hospital assessment is not indicated unless symptoms develop.
IMPORTANT PLANT TOXINS Calcium oxalate
Some plants contain needle-like calcium oxalate crystals packaged into bundles that can cause mechanical injury to mucosal membranes when ingested. The plants most commonly associated with this type of injury are Dieffenbachia spp. and Philodendron spp. Toxins capable of causing severe poisoning
A number of plant toxins are known to have caused significant human poisoning or death following ingestion of fresh plant material. Important examples are listed in Table 2.3.1 and discussed here. Aconite (Aconitum spp. and Delphinium spp.) is found in some Asian herbal medicines. It binds to voltage-dependent sodium channels leading to permanent activation of cardiac muscle and voltage-dependent nervous tissue receptors. Dose-dependent toxicity develops rapidly after ingestion and manifests with CNS, cardiovascular and gastrointestinal effects. Bradycardia and hypotension may progress to tachydysrhythmias and cardiac arrest, paraesthesiae may progress to CNS depression, respiratory depression, paralysis and seizures, and nausea and vomiting may progress to diarrhoea and abdominal cramping. Belladonna alkaloids (atropine, scopolamine, hyoscyamine) are found in numerous plant species. Those most commonly associated with human poisoning are belladonna (Atropa spp.), angel’s trumpet (Datura spp.) and henbane (Hyoscyamus spp.). These alkaloids cause competitive blockade of central and peripheral acetylcholine muscarinic receptors leading to the anticholinergic syndrome (see Chapter 2.9: Anticholinergic syndrome). Cardiac glycosides of various types are found in all parts of several plants, including foxglove (Digitalis purpurea), pink and white oleander (Nerium spp.) and yellow oleander (Thevetia spp.). These all have digoxin-like effects on cardiac conduction and Na+–K+ ATPase (see Chapter 3.34: Digoxin: acute poisoning). ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
•
A few plants or parts of plants are capable of causing severe poisoning when ingested in sufficient quantity. Accurate plant identification usually allows refinement of the risk assessment. In the absence of accurate plant identification, risk assessment relies on knowledge of local plants and observation of clinical features and progress.
53 TOXICOLOGY HANDBOOK
• • •
SPECIFIC CONSIDERATIONS
TABLE 2.3.1 Plant toxins with potential to cause serious toxicity or death following a single acute ingestion
54
Plant(s)
Clinical features
Aconite
Aconitum spp. Delphinium spp.
Severe cardiovascular, neurological and gastrointestinal toxicity High mortality from ventricular dysrhythmias and cardiovascular collapse
Belladonna alkaloids
Datura spp. (jimsonweed, angel’s trumpet) Atropa belladonna Hyoscyamus niger (henbane)
Anticholinergic poisoning: tachycardia, delirium, agitation, ileus, urinary retention
Cardiac glycosides
Digitalis spp. (foxglove) Nerium spp. (pink or white oleander) Thevetia spp. (yellow oleander)
Bradycardia, dysrhythmias, GI disturbance, hyperkalaemia
Colchicine
Colchicum autumnale (autumn crocus) Gloriosa superba (glory lily)
GI disturbance, bone marrow depression, multi-system organ failure
Coniine
Conium maculatum (poison hemlock)
Bradycardia, tachycardia, GI disturbance, ascending paralysis, rhabdomyolysis, renal failure
Cyanogenic glycosides
Prunus spp. seed kernels (apricot, plum, pear, cherry, almond)
Tachycardia, bradycardia, coma, acidosis, multisystem organ failure
Hypoglycin
Blighia sapia (ackee)
Hypoglycaemia, acidaemia, vomiting, seizures
Nicotine
Nicotiana spp. (tobacco)
Tachycardia, hypotension, tremor, sweating, GI symptoms, seizures
Psychotropic alkaloids
Ipomea spp. (morning glory) seeds Lophophora williamsii (peyote cactus)
Acute psychosis, visual hallucinations
Ricin
Ricinus communis (castor beans)
GI disturbance, multi-system organ failure
Taxine
Taxus spp. (yew)
Bradycardia, dysrhythmias, GI disturbance
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Toxin(s)
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CLINICAL FEATURES The vast majority of plant exposures remain asymptomatic. Minor transient gastrointestinal symptoms may be observed. The clinical features of oxalate crystal ingestion are immediate onset of pain and swelling usually affecting the lips, tongue, oral cavity and pharynx. Rarely, severe exposures may produce dysphagia, profuse salivation and upper airways obstruction. It may take days for symptoms to subside. Potentially serious exposures manifest onset of signs and symptoms suggestive of the toxic mechanism. As detailed above, the clinical ERRNVPHGLFRVRUJ
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The antimitotic agent, colchicine, is found in all parts of the autumn crocus (Colchicum autumnale) and glory lily (Gloriosa superba), and human colchicine poisoning (see Chapter 3.31: Colchicine) is reported after ingestion of bulbs and leaves. Coniine is an alkaloid found in poison hemlock (Conium maculatum). It is structurally related to nicotine and produces both nicotinic effects and neuromuscular blockade with potential for death by respiratory failure. Amygdalin is a cyanogenic glycoside found in the seeds or pits of apricots, almonds, apples, peaches and wild cherries (Prunus spp.). Laetrile, derived from amygdalin from apricot pits, is sometimes marketed as a health food. After ingestion, amygdalin is hydrolysed to produce cyanide (see Chapter 3.33: Cyanide). Hypoglycin A is found in the unripe fruit and seeds of the ackee tree (Blighia sapida). It interferes with fatty acid metabolism and causes hypoglycaemia. It also causes vomiting, CNS depression and seizures. Nicotine is found in the tobacco plant (Nicotiana tabacum). Excessive ingestion, inhalation or transdermal exposure leads to overstimulation of nicotinic receptors. This manifests with GI symptoms, sweating, mydriasis, tachycardia, hypertension and seizures. Psychotropic alkaloids include lysergic acid and mescaline. They act as direct serotonin agonists and can produce vivid visual hallucinations. Lysergic acid is found in morning glory seeds (Ipomea spp.) and mescaline in the peyote cactus (Lophophora williamsii). Ricin, a lectin, is found in the castor bean plant (Ricinus communis). The highest concentration is in the seeds. An intracellular toxin, it inhibits protein synthesis, leading to a severe gastrointestinal disturbance together with cardiac, haematological, hepatic and renal toxicity. Taxine is a mixture of alkaloids found in yew trees (Taxus spp.), which inhibit both sodium and calcium currents. Ingestion of seeds has produced gastrointestinal symptoms, paraesthesiae, mental status changes, bradycardia, conduction blocks, ventricular dysrhythmias and cardiac arrest.
syndromes that may develop include cardiovascular collapse, anticholinergic syndrome, nicotinic poisoning, cardiac glycoside poisoning, colchicine or cyanide poisoning. SPECIFIC CONSIDERATIONS
MANAGEMENT
56 56 TOXICOLOGY HANDBOOK
Resuscitation
Immediate resuscitation is unlikely to be required except in the patient with delayed presentation after severe poisoning. An important exception is aconite poisoning in which death from ventricular dysrhythmias or respiratory paralysis may occur within hours of ingestion. Resuscitation follows standard ACLS protocols. Successful outcome from cardiac arrest from aconite poisoning using cardiopulmonary bypass is reported. Supportive care and monitoring
The management of most plant poisonings entails supportive care and monitoring along the standard lines described in Chapter 1.4: Supportive care and monitoring. Particular attention to fluid and electrolyte status is required with colchicine (see Chapter 3.31: Colchicine), aconite and ricin poisoning. Maintenance of euglycaemia with dextrose infusion is required in ackee fruit poisoning. Management of seizures and delirium requires administration of titrated doses of benzodiazepines as outlined in Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation. Investigations
Investigations are performed as dictated by clinical signs and symptoms. Serum digoxin levels do not accurately reflect toxicity from cardiac glycoside poisoning of plant origin. Decontamination
Administration of oral activated charcoal 50 g (1 g/kg in a child) is indicated where the risk assessment suggests the possibility of lifethreatening toxicity. Where there is any potential for imminent depression in the level of consciousness or seizures, the airway must be secured prior to administration of activated charcoal. Skin exposure requires thorough washing of the exposed skin and eye exposure requires thorough irrigation of the affected eye. Antidotes
Physostigmine is useful in reversing severe anticholinergic poisoning (see Chapter 4.21: Physostigmine). Cyanide antidotes may be useful in treating cyanogenic glycoside poisoning (see Chapter 4.13: Hydroxocobalamin and Chapter 4.26: Sodium thiosulfate). Digoxin immune Fab in relatively high doses has been used successfully to ERRNVPHGLFRVRUJ
reverse cardiotoxicity from oleander poisoning (see Chapter 4.6: Digoxin immune Fab). Enhanced elimination
Hospital assessment or observation is not required if the patient is asymptomatic or has minor gastrointestinal symptoms only and the plant is identified as not having potential for serious toxicity. This is the case for the vast majority of plant exposure cases. Hospital assessment and observation is necessary if there has been significant ingestion of plant material containing potentially lifethreatening toxins. Any patient with symptoms beyond minor gastrointestinal ones should also be assessed in hospital. The period of observation continues until all risk of serious toxicity has elapsed. Where significant toxicity develops, the level of care and length of stay will be determined by the clinical course. Dermal, mucosal and ophthalmic plant exposures
A wide variety of plants are able to cause either primary or allergic contact dermatitis. Some plants such as nettles have a specialist stinging apparatus that acts like a hypodermic syringe to deliver irritant chemical to the skin. Contact dermatitis is frequently associated with exposure to the sap of certain plants such as the mango tree. It is rarely serious. Allergic contact dermatitis results from type IV hypersensitivity response to plant exposures. Certain plants have a greater propensity to cause allergic contact dermatitis. References
Challoner KR, McCarron MM. Castor bean intoxication. Annals of Emergency Medicine 1990; 19:1177–1183. Chan TY. Aconite poisoning. Clinical Toxicology 2009; 47(4):279–285. Eddleston M, Ariaratnam CA, Sjostrom L et al. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart 2000; 83:301–306. Eddleston M, Rajapakse S, Rajakanthan K et al. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000; 355:967–972. Froberg B, Ibrahim D, Furbee RB. Plant poisoning. Emergency Clinics of North America 2007; 25:375–433. Rajapakse S. Management of yellow oleander poisoning. Clinical Toxicology 2009; 47(3):206–212. Schep LJ, Slaughter RJ, Beasley DM. Nicotinic plant poisoning. Clinical Toxicology 2009; 47(8):771–781. Suchard JR, Wallace KL, Gerkin RD. Acute cyanide toxicity caused by apricot kernel ingestion. Annals of Emergency Medicine 1998; 32:742–744.
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57 TOXICOLOGY HANDBOOK
Disposition
SPECIFIC CONSIDERATIONS
Not useful in plant poisoning.
SPECIFIC CONSIDERATIONS
2.4 COMA
58 58 TOXICOLOGY HANDBOOK
Coma describes an altered mental status where the patient cannot be roused. It is a common manifestation of acute poisoning by many agents (see Table 2.4.1). In a potentially poisoned patient, coma may be the result of:
• • •
Direct toxic effect on the CNS – wakefulness and consciousness depend on complex mechanisms involving many pathways and neurotransmitter systems Secondary effect of poisoning on the CNS – hypoxaemia, hypoglycaemia, hyponatraemia, hypotension, seizures or cerebral oedema Alternative non-toxicological diagnoses – metabolic encephalopathy, neurotrauma, space-occupying lesion or meningoencephalitis.
Coma presents an immediate threat to life, irrespective of the underlying cause. Assessment and management is a core emergency competency. With a few important exceptions, most agents that cause toxic coma produce a relatively benign and temporary alteration in mental status that has a good prognosis with thorough supportive care.
MANAGEMENT Resuscitation
Establishment of airway and ventilation is the immediate priority irrespective of the aetiology of coma. This is initially achieved using positioning techniques, oropharyngeal airway and bag and mask ventilation with 100% oxygen. Definitive control is then achieved as soon as practical with emergency rapid sequence endotracheal intubation. The only exceptions to this process are when hypoglycaemia is detected or there is clinical suspicion of opioid intoxication. In these circumstances, bag and mask ventilation may continue while awaiting a response to administration of concentrated dextrose solution or naloxone. If coma does not rapidly resolve, proceed with rapid sequence endotracheal intubation. Poisoning is a dynamic illness. The patient’s ability to maintain an airway and ventilate effectively may change in a short period of time. Ideally, this is anticipated and prepared for on the basis of an early risk assessment. For example, the patient who presents shortly after ingesting >30 mg/kg of a tricyclic antidepressant is expected to have a rapid decline in level of consciousness within 2 hours. A common pitfall in acute poisoning management is to assume that coma is likely to be short-lived and to leave the airway unprotected for a prolonged period of time. This increases the risk of pulmonary aspiration, hypoxaemia and hypoventilation. Unlike trauma, where convention ERRNVPHGLFRVRUJ
TABLE 2.4.1 Toxicological causes of coma
Cholinergic agents Carbamates Dementia acetylcholinesterase inhibitors (e.g. donepezil) Nicotine Organophosphates Hydrocarbons Essential oils Toluene Local anaesthetics Bupivacaine Cocaine Lignocaine Ropivacaine Mushrooms Gyromitra species Non-steroidal anti-inflammatory agents Ibuprofen Mefenamic acid Opioids Codeine Heroin Morphine Methadone Sedative-hypnotic agents Barbiturates Benzodiazepines Chloral hydrate Gamma-hydroxybutyrate Non-benzodiazepine agents (zolpidem, zopiclone)
SECONDARY EFFECT
Cerebral oedema Salicylates Valproic acid Hypoglycaemia Insulin Sulfonylureas Hypotension Calcium channel blockers Cardiac glycosides (e.g. digoxin) Hypoxaemia (systemic or cellular) Agents causing methaemoglobinaemia Carbon monoxide Cyanide Hydrogen sulfide
Neuroleptic malignant syndrome Antipsychotic agents Seizures Bupropion Isoniazid Tramadol Venlafaxine Serotonin syndrome Monoamine oxidase inhibitors Selective noradrenaline reuptake inhibitors (e.g. venlafaxine) Selective serotonin reuptake inhibitors
ERRNVPHGLFRVRUJ
59 TOXICOLOGY HANDBOOK
Alcohols Ethanol Ethylene glycol Isopropyl alcohol Methanol Antipsychotic agents Amisulpride Chlorpromazine Clozapine Olanzapine Quetiapine Anticonvulsant agents Carbamazepine Lamotrigine Valproic acid Antidepressants Selective serotonin reuptake inhibitors Tricyclic antidepressants Antihistamines Diphenhydramine Promethazine Antimalarial agents Chloroquine Hydroxychloroquine Quinine Baclofen Beta-adrenergic blockers Propranolol Centrally acting alpha-2-agonists Clonidine Oxymetazoline
SPECIFIC CONSIDERATIONS
PRIMARY NEUROLOGICAL EFFECT
SPECIFIC CONSIDERATIONS
60 60 TOXICOLOGY HANDBOOK
dictates intubation at a Glasgow Coma Scale score (GCS) of 8, there is no definite measure of conscious state in poisoning that predicts the need for intubation. A patient’s ability to guard their airway is poorly correlated to GCS. The probability of aspiration is increased with any GCS less than 15, especially where there is delay to presentation. Once neuromuscular paralysis and intubation is achieved, it is vital to ventilate the patient at an appropriate minute volume. Several poisonings are associated with metabolic acidosis and compensatory hyperventilation to achieve respiratory alkalosis (e.g. salicylate, methanol, ethylene glycol). If hyperventilation is not maintained following paralysis and mechanical ventilation, acute respiratory acidosis results in rapid clinical deterioration and possibly death. Risk assessment
Coma is usually a predictable response to poisoning where the agent and dose are known. Where the original risk assessment did not predict coma, it must be reassessed. It usually means that there has been ingestion of a different or additional agents, a larger dose has been ingested or that the patient has a non-toxicological cause for coma. Where the patient presents with coma of unknown origin and there is no definite history of ingestion, the clinician must rigorously evaluate the historical, clinical and laboratory features of the case in order to:
• • •
Diagnose alternative non-toxicological causes of coma Diagnose important complications of coma Diagnose specific toxicities where specific interventions (enhanced elimination techniques or antidotes) are necessary to ensure a good outcome.
Toxic agents usually act on the CNS in a global and symmetrical fashion and any focal or unilateral neurological sign is highly suggestive of an alternative cause. Patients may present having had significant impairment in level of consciousness in the pre-hospital phase for varying periods of time. These patients are at risk of a number of secondary complications, which may have greater impact on morbidity and mortality than the intoxication itself. These complications must be specifically sought and managed in any patient presenting with coma. They include:
• • • • • •
Pulmonary aspiration Rhabdomyolysis Acute renal failure Compartment syndromes Pressure areas Hypoxic brain injury. ERRNVPHGLFRVRUJ
Supportive care, monitoring and disposition
• • • • • • •
Monitoring of conscious state and airway Respiratory toilet and prophylaxis (mobilisation and/or physiotherapy) Fluid monitoring and management Bladder care (indwelling catheter) Prevention of pressure areas Thromboembolism prophylaxis Mobilisation as mental status changes resolve.
SPECIFIC CONSIDERATIONS
All patients requiring intubation and ventilation are admitted to an intensive care unit for ongoing supportive care. The following are important to minimise the complications of coma in the admitted patient:
Investigations
• • •
Screening (12-lead ECG, BGL and serum paracetamol level) — These tests are particularly important in the comatose patient where no ingestion history is available — A measurable paracetamol level may mandate empiric NAC if dose or time of ingestion cannot be determined To detect toxic ingestions for which specific interventions are required — Arterial blood gases, anion gap and lactate — Osmolality and osmolar gap — Specific drug levels: carbamazepine, ethanol, ethylene glycol (when available), methanol (when available), salicylate, valproic acid To detect and assess complications — Arterial blood gases, anion gap and lactate — Urea and electrolytes — Liver function tests — CK — Chest X-ray To exclude or confirm important differential diagnoses — Arterial blood gases, anion gap and lactate — Urea and electrolytes — Liver function tests — Cranial CT scan — Lumbar puncture — Blood and urine cultures — EEG
Enhanced elimination techniques and antidote administration
The vast majority of patients presenting with or developing toxic coma are assured of a good outcome with timely institution of supportive care. ERRNVPHGLFRVRUJ
61 TOXICOLOGY HANDBOOK
•
SPECIFIC CONSIDERATIONS
TABLE 2.4.2 Agents causing coma that may require specific intervention
62 62 TOXICOLOGY HANDBOOK
Carbamazepine Multi-dose activated charcoal Haemodialysis Isoniazid Pyridoxine Opioids Naloxone Organophosphates Atropine Pralidoxime Phenobarbitone Multi-dose activated charcoal Haemodialysis
Salicylate (severe poisoning only) Haemodialysis Sulfonylureas Dextrose Octreotide Toxic alcohols (ethylene glycol, methanol) Ethanol/fomepizole Haemodialysis Valproic acid Haemodialysis
There are a small number of specific agents where specific interventions are indicated (see Table 2.4.2). Details of management of these agents are found in the relevant toxin and antidote sections in Chapter 3 and Chapter 4. Poisoning with carbamazepine, valproic acid or phenobarbitone should be excluded with specific drug levels in any comatose patient with access to these anticonvulsant agents. Toxic alcohol and salicylate poisoning must be excluded in any comatose patient with metabolic acidosis. References
Daly FFS, Little M, Murray L. A risk assessment approach to the management of acute poisoning. Emergency Medicine Journal 2006; 23:396–399. International Liaison Committee on Resuscitation. 2005 American Heart Association Guidelines for Cardiopulmonary and Emergency Cardiovascular Care – Part 10.2: Toxicology in ECC. Circulation 2005; 112(24 Supplement I):IV126–IV132. Isbister GK, Downes F, Sibbritt D et al. Aspiration pneumonitis in an overdose population: frequency, predictors and outcomes. Critical Care Medicine 2004; 32:88–93.
2.5 HYPOTENSION Hypotension is assessed and managed during the resuscitation phase of poisoning management. If detected later in the clinical course, the clinician returns to the resuscitation phase and specifically addresses priorities in the usual order (initially airway, breathing and circulation). Hypotension is common in poisoned patients. It is usually mild, secondary to peripheral vasodilation and responsive to basic fluid resuscitation. However, poisoning secondary to cardiotropic medications is frequently associated with refractory hypotension of multifactorial ERRNVPHGLFRVRUJ
2 3
4
5
6
7
8 9 10
Commence continuous ECG monitoring until patient is stabilised and risk assessment is reviewed. Ensure adequate intravenous access. Correct cardiac dysrhythmias. Under certain circumstances, standard resuscitation guidelines need to be disregarded and the administration of specific antidotes may be a priority (see Chapter 1.2: Resuscitation). Give 10–20 mL/kg of IV crystalloid to ensure euvolaemia. Further fluid challenge may be indicated but depends on the individual risk assessment. For example, in iron or colchicine intoxication, fluid losses may be large and fluid requirements ongoing. In contrast, in calcium channel blocker intoxication excessive fluid resuscitation may lead to pulmonary oedema. Consider specific antidotes: Digoxin-specific antibodies (digoxin) Calcium (calcium channel blockers). Consider atropine and electrical pacing. Unfortunately, these interventions rarely provide a definitive solution in the poisoned patient. Commence inotropic agents. The agent of choice depends on the intoxication and the results of invasive haemodynamic monitoring. It is usually wise to commence with the agent most available and with which the attending staff are most familiar. Choices include: Noradrenaline (norepinephrine) Adrenaline (epinephrine) Dobutamine. Commence central haemodynamic monitoring. Consider high-dose insulin therapy (see Chapter 4.14: Insulin (high dose)). Consider extraordinary manoeuvres such as extracorporeal membrane oxygenation (ECMO).
• •
• • •
Reference
Vanden Hoek TL, Morrison LJ, Shuster M et al. Part 12: Cardiac arrest in special situations: 2010 American Heart Association guidelines for cardiopulmonary and emergency cardiovascular care. Circulation 2010; 122:S829–S861.
ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
1 Check cardiac rhythm and review a current 12-lead ECG.
63 TOXICOLOGY HANDBOOK
origin and mortality is much higher. Similarly, hypotension that is refractory to basic fluid resuscitation heralds a much worse outcome unless perfusion is rapidly restored. In a hypotensive patient, following attention to airway and breathing, a series of interventions may be followed until a satisfactory response is achieved:
SPECIFIC CONSIDERATIONS
2.6 SEIZURES
64
Toxic seizures are usually generalised and self-limiting and easily controlled with intravenous benzodiazepines. The most common causes of toxic seizures in Australasia are venlafaxine, bupropion, tramadol and amphetamines (see Table 2.6.1 for a summary of causes). Toxic seizures are frequently of delayed onset as a result of extended-release formulations of several of these agents. Seizures are also a prominent manifestation of a number of withdrawal syndromes, in particular those associated with ethanol and benzodiazepines. In certain poisonings, seizures herald severe intoxication and a grave prognosis unless definitive care is rapidly instituted (e.g. chloroquine, propranolol, salicylates, theophylline, tricyclic antidepressants). Seizures of any cause are treated as a matter of priority. Prolonged seizure activity is associated with irreversible CNS injury. Secondary
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64 TABLE 2.6.1 Toxicological causes of seizures Anticonvulsants Carbamazepine Topiramate Antidepressants Bupropion Citalopram Desvenlafaxine Escitalopram Tricyclics Venlafaxine Antidysrhythmic agents Quinidine Antihistamines Antimalarial agents Chloroquine Hydroxychloroquine Quinine Antipsychotic agents Atypical antipsychotics Butyrophenones Olanzapine Phenothiazines Quetiapine Baclofen Isoniazid Hypoglycaemic agents Insulin Sulfonylureas
Local anaesthetic agents Lignocaine Nicotine Non-steroidal anti-inflammatory agents Mefenamic acid Opioids Dextropropoxyphene Pethidine Propranolol Tramadol Salicylates Sympathomimetic agents Amphetamine and its derivatives Cocaine Synthetic cannabinoids and cathinones Theophylline Withdrawal syndromes Alcohol Barbiturates Benzodiazepines Non-benzodiazepine sedativehypnotic agents (e.g. gamma-hydroxybutyrate, zopiclone, zolpidem)
ERRNVPHGLFRVRUJ
See Chapter 1.2: Resuscitation. 1 Attention to airway, breathing and circulation. If coma preceded onset
2 3 4 5 6 7
8
of seizures (e.g. tricyclic antidepressant poisoning), proceed to rapid sequence intubation and ventilation as the steps below are taken. Administer oxygen. Check cardiac rhythm and output. Establish intravenous access. Check bedside blood glucose level and correct hypoglycaemia if present. Give an intravenous benzodiazepine (e.g. diazepam 5–10 mg; children 0.1–0.3 mg/kg/dose over 3–5 minutes). Repeat if necessary. Consider barbiturates as second-line therapy for refractory seizures in acute poisoning (e.g. phenobarbitone 100–300 mg slow IV; children 10–20 mg/kg slow IV; or thiopentone 3–5 mg/kg if ventilated). Pyridoxine is a third-line agent that may be indicated in intractable seizures secondary to isoniazid and other hydrazines (gram for gram dose to match suspected isoniazid dose, or 5 g IV; children 70 mg/kg not exceeding 5 g).
References
Kunisaki TA, Augenstein WL. Drug- and toxin-induced seizures. Emergency Medical Clinics of North America 1994; 12(4):1027–1056. Shah ASV, Eddleston M. Should phenytoin or barbiturates be used as second-line anticonvulsant therapy for toxicological seizures? Clinical Toxicology 2010; 48:800–805.
2.7 DELIRIUM AND AGITATION See also Chapter 2.9: Anticholinergic syndrome. Delirium is characterised by an altered conscious state with impaired cognition. The key diagnostic features are shown in Table 2.7.1. Intoxication with a variety of agents may present with agitation and delirium (Table 2.7.2). The alteration in CNS function is usually a transient direct toxic effect that resolves along with other features of ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
MANAGEMENT
65 TOXICOLOGY HANDBOOK
hypoxia and acidosis increase the susceptibility for dysrhythmias. Secondary hyperpyrexia and rhabdomyolysis may lead to dehydration, hyperkalaemia and renal failure. Phenytoin is not indicated in the management of toxic seizures. The presence of focal or partial seizures indicates a focal neurological disorder that is either a complication of poisoning or non-toxicological in origin. In either case, prompt further investigation is warranted.
SPECIFIC CONSIDERATIONS
TABLE 2.7.1 Diagnostic features of delirium (based on DSM-V criteria)
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1 Disturbance in attention (reduced ability to direct, focus, sustain and shift attention) and awareness 2 Change in cognition (memory deficit, disorientation, language disturbance, perceptual disturbance) that is not better accounted for by a pre-existing, established or evolving dementia 3 The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day 4 There is evidence from the history, physical examination or laboratory findings that the disturbance is caused by a direct physiological consequence of a general medical condition, an intoxicating substance, medication use or more than one cause
intoxication. Secondary complications or concomitant medical emergencies may contribute to altered CNS function and these are listed in Tables 2.7.3 and 2.7.4.
DUTY OF CARE The patient with delirium has an altered mental state with cognitive impairment and is not competent to make decisions about their own welfare. The clinician has a duty of care to the patient to protect them from serious harm or death. The clinician also has a duty of care to other patients, staff, visitors and the community at large to protect them from being harmed by the actions of the delirious patient. Failure to control the situation (allowing the patient to abscond or injure themselves) represents an act of omission. While the delirium persists, temporary physical restraint and pharmacological sedation, perhaps against the patient’s wishes at the time, is appropriate.
MANAGEMENT Resuscitation
Airway, breathing and circulation are managed as appropriate. Atypical seizures or non-convulsive status epilepticus should be considered and treated with benzodiazepines. Check bedside serum glucose as soon as possible in all patients with altered mental status to exclude hypoglycaemia. If the serum glucose is 38.5°C is an indication for continuous coretemperature monitoring. A temperature >39.5°C is an emergency that requires prompt management to prevent multiple organ failure and neurological injury. ERRNVPHGLFRVRUJ
TABLE 2.7.3 Complications of agitation in the poisoned patient Aspiration pneumonitis Deep vein thrombosis and pulmonary embolism Fluid, electrolyte and acid–base disturbances, most commonly dehydration Hypoventilation, hypoxia Hyperthermia Physical injury to the patient or others Rhabdomyolysis
Risk assessment
Delirium is usually a predictable response to poisoning where the agent and dose are known. If the original risk assessment did not predict delirium, it must be reassessed. It usually indicates that there has been ingestion of different or additional agents, or that the patient has a non-toxicological cause for delirium. ERRNVPHGLFRVRUJ
67 TOXICOLOGY HANDBOOK
Alcohol Anticholinergic syndrome Antidepressants Bupropion Monoamine oxidase inhibitors Venlafaxine Atypical antipsychotic agents Clozapine Olanzapine Quetiapine Baclofen Benzodiazepines and other sedative-hypnotic agents (e.g. zolpidem) Cannabis Hallucinogenic agents Dimethyltryptamine (DMT) Ketamine Phencyclidine 2,5-Dimethoxy-4-iodophenethylamine (2C-I) Neuroleptic malignant syndrome (NMS) Nicotine Salicylates Serotonin syndrome Sympathomimetic syndrome Amphetamine and its derivatives Cocaine Synthetic cannabinoids Synthetic cathinones Theophylline Withdrawal syndromes
SPECIFIC CONSIDERATIONS
TABLE 2.7.2 Toxicological causes of agitation and delirium
SPECIFIC CONSIDERATIONS
TABLE 2.7.4 Other conditions mimicking or contributing to agitation
68 68 TOXICOLOGY HANDBOOK
Acid–base disturbance Behavioural disturbance CNS infection (e.g. encephalitis) Dementia Electrolyte disturbance (e.g. hyponatraemia) Endocrine emergency (e.g. thyroid storm) Head injury Hypoglycaemia Hypoxia Organ failure (e.g. hepatic encephalopathy) Psychosis Seizures (e.g. non-convulsive status) Stroke Trauma (e.g. subdural haemorrhage) Withdrawal (e.g. alcohol or sedative-hypnotic agents) TABLE 2.7.5 Agents or syndromes associated with delirium and agitation that may require specific interventions Agent
Possible interventions
Anticholinergic agents
Physostigmine (see Chapter 4.21: Physostigmine)
Neuroleptic malignant syndrome
Bromocriptine
Salicylates
Urinary alkalinisation Haemodialysis
Serotonin syndrome
Cyproheptadine (see Chapter 4.3: Cyproheptadine) Neuromuscular paralysis, intubation and ventilation
Theophylline
Multi-dose activated charcoal Haemodialysis
Where the patient presents with delirium but no definite history of ingestion, the clinician must rigorously evaluate the historical, clinical and laboratory features of the case in order to diagnose:
• • •
Important complications of delirium (see Table 2.7.3) Alternative (non-toxicological) causes (see Table 2.7.4) Toxicities or syndromes where specific interventions (enhanced elimination techniques or antidotes) are necessary to ensure a good outcome (see Table 2.7.5).
Supportive care and monitoring
The patient is managed in a calm environment to minimise external stimulation and crowding. Repeated reassurance and explanation are ERRNVPHGLFRVRUJ
• • •
Monitoring of conscious state and airway Respiratory toilet and prophylaxis (mobilisation and/or chest physiotherapy) Fluid monitoring and management ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
69 TOXICOLOGY HANDBOOK
important. One-on-one nursing is usually necessary to allow close observation and management during the initial stages. If the patient remains extremely agitated with an immediate risk of harming themselves or others, temporary physical restraint is required until pharmacological sedation can be achieved. The medical team’s duty of care to the patient should be explained. Physical restraint is achieved quickly by broadbased control of the arms and legs. It must never threaten the airway or breathing and is only used as a temporary measure until appropriate pharmacological sedation is instituted. For sedation, intravenous benzodiazepines titrated to effect are first-line agents. It is best to use an agent with a duration of effect likely to match the anticipated duration of delirium, usually diazepam. In mild cases, oral dosing may be appropriate. In more severe cases, or in any case with physical restraint, intravenous dosing will be required. Repeated doses of intravenous diazepam 5 mg should be given every 2–5 minutes until gentle sedation is achieved. Antipsychotic agents such as haloperidol or droperidol are secondline agents. They are highly effective but associated with acute extrapyramidal (akathisia and dystonia) and anticholinergic effects. They should be avoided if anticholinergic syndrome is suspected. Droperidol has been associated with QT prolongation, cardiac dysrhythmias and sudden death in a very small number of cases. Recent reviews suggest this is extremely rare, but it should be avoided if QT prolongation or significant electrolyte disturbance is suspected. Atypical antipsychotic agents (e.g. olanzapine) are rapidly acting and frequently have a calming effect without major sedation in patients with prominent psychotic symptoms. They may be given sublingually, orally or intramuscularly. They are associated with fewer extrapyramidal effects than haloperidol or droperidol. Once agitation is adequately controlled, the patient is admitted to an area capable of providing a sufficient level of ongoing close supervision and monitoring, and where further intravenous sedation can be administered if required. This is usually an emergency observation or high-dependency unit. Delirium may persist for days, depending on the cause. Patients with anticholinergic delirium frequently develop urinary retention and attempts to achieve adequate sedation are doomed to failure until this is relieved by placement of an indwelling urinary catheter. General supportive care as detailed in Chapter 1.4: Supportive care and monitoring includes:
SPECIFIC CONSIDERATIONS
• • • •
70
Bladder care (indwelling urinary catheter) Prevention of pressure areas Thromboembolism prophylaxis Mobilisation as mental status changes resolve.
Investigations
Investigations in acute poisoning are used either as screening tests or for specific purposes. Specific investigations in the patient with agitation or delirium should be ordered selectively where it is anticipated that the results will refine risk assessment, exclude significant complications or exclude potential non-toxicological diagnoses. Enhanced elimination techniques and antidote administration
There are relatively few instances where these interventions are required in the management of agitation or delirium (see Table 2.7.5). For the use of physostigmine in anticholinergic delirium see Chapter 2.9: Anticholinergic syndrome and Chapter 4.21: Physostigmine.
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70
References
Carter LC, Dawson AH. Acute delirium. In: Dart RC, ed. Medical Toxicology. 3rd edn. Philadelphia: Lippincott Williams & Wilkins; 2004: Ch 15. Chan EW, Taylor DM, Knott JC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient; a multicenter, randomized, double-blind, placebo-controlled clinical trial. Annals of Emergency Medicine 2013; 61:72–81. Horowitz BZ, Bizovi K, Moreno R. Droperidol – behind the black box warning. Academic Emergency Medicine 2002; 9(6):615–618. Isbister GK, Calver LA, Page CB et al. Randomised controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Annals of Emergency Medicine 2010; 56:392–401.
2.8 SEROTONIN SYNDROME Serotonin syndrome is the clinical manifestation of excessive stimulation of serotonin receptors in the CNS. This occurs when excess serotonin (5-hydroxytryptamine) accumulates in the CNS, secondary to a number of pharmacological mechanisms: inhibition of serotonin metabolism (monoamine oxidase inhibitors), prevention of serotonin reuptake in nerve terminals (serotonin reuptake inhibitors), serotonin release or increased intake of serotonin precursors (tryptophan).
CLINICAL FEATURES Serotonin syndrome manifests as a wide variety of signs and symptoms that reflect the triad of clinical features: mental status changes, autonomic stimulation and neuromuscular excitation (see Table 2.8.1). There is a continuous clinical spectrum of severity ranging from very mild symptoms in ambulatory patients to a fulminant life-threatening ERRNVPHGLFRVRUJ
TABLE 2.8.1 Clinical features of serotonin syndrome
Diarrhoea* Flushing Hypertension Hyperthermia† Mydriasis* Sweating* Tachycardia*
Neuromuscular excitation Clonus (esp. ocular and ankle)* Hyperreflexia* Increased tone (lower limbs > upper limbs)* Myoclonus* Rigidity Tremor
*Clinical features significantly associated with diagnosis (Hunter Serotonin Toxicity Criteria). † Hyperthermia >38°C is not significantly associated with the diagnosis but is present in severe cases.
syndrome characterised by generalised rigidity, autonomic instability, marked mental status changes and hyperthermia. Without prompt intervention, this severe syndrome progresses to rhabdomyolysis, renal failure, disseminated intravascular coagulation (DIC) and death. Symptoms are usually of rapid onset and may be evident within hours of changes in medication or overdose. Similarly, the syndrome resolves over hours (up to 24–48 in severe forms) following discontinuation of the causative agent and the institution of supportive care. Serotonin syndrome after deliberate self-poisoning usually develops within the first 8 hours and frequently after the patient presents to hospital.
DIAGNOSIS Serotonin syndrome is a clinical diagnosis and requires the history of ingestion of one or more serotonergically-active agents (or a change in their dose), the presence of characteristic clinical features and a high index of suspicion. Some symptoms are more significantly associated with the diagnosis (see Table 2.8.1) and diagnostic algorithms have been developed (see Figure 2.8.1) Clinical settings in which serotonin syndrome may develop include:
• • • • •
Introduction or increase in dose of a single serotonergic drug Change in therapy from one serotonergic drug to another without an adequate intervening ‘washout’ period Drug interaction between two serotonergic agents Interaction between serotonergic drug and an illicit drug or herbal preparation Deliberate self-poisoning with serotonergic agent(s).
Numerous agents are implicated in the development of serotonin syndrome, of which the most important ones are listed in Table 2.8.2. ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
Apprehension Anxiety Agitation, psychomotor acceleration and delirium* Confusion
Autonomic stimulation
71 TOXICOLOGY HANDBOOK
Mental status changes
FIGURE 2.8.1 Algorithm for diagnosis of serotonin syndrome
SPECIFIC CONSIDERATIONS
Serotonergic agent ingestion or overdose
72
Spontaneous clonus
yes
no
Inducible clonus OR Ocular clonus
yes
no
Tremor
Agitation OR Diaphoresis OR Hypertonia AND Pyrexia (>38oC) no
yes
Hyperreflexia
72 TOXICOLOGY HANDBOOK
yes
yes
S E R O T O N I N T O X I C I T Y
no
no
NOT clinically significant serotonin toxicity Source: Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Medical Journal of Australia 2007; 187(6):361–365.
TABLE 2.8.2 Agents implicated in development of serotonin syndrome Analgesics and antitussives Dextromethorphan Fentanyl Pethidine Tramadol Antidepressants Tricyclic antidepressants Illicit drugs Amphetamines Methylenedioxymethamphetamine (MDMA; ecstasy) Herbal preparations Spirulina St John’s wort (Hypericum perforatum) Lithium Monoamine oxidase inhibitors (MAOIs) Moclobemide Phenelzine Tranylcypromine
Selective serotonin reuptake inhibitors (SSRIs) Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Serotonin and noradrenaline reuptake inhibitors (SNRIs) Bupropion Desvenlafaxine Duloxetine Venlafaxine Tryptophan
ERRNVPHGLFRVRUJ
DIFFERENTIAL DIAGNOSIS Careful consideration of drug history, clinical features and clinical course is essential to distinguish serotonin syndrome from neuroleptic malignant syndrome, anticholinergic syndrome and malignant hyperthermia (see Table 2.8.3). Other differential diagnoses include CNS infections and intoxication with salicylates, theophylline, nicotine or sympathomimetic agents.
SPECIFIC CONSIDERATIONS
The severe life-threatening form most commonly develops after deliberate self-poisoning with multiple serotonergic medications, especially a selective serotonin reuptake inhibitor (SSRI) in combination with a monoamine oxidase inhibitor (MAOI). Lifethreatening serotonin syndrome does not develop after ingestion of single SSRIs.
MANAGEMENT
• • • • • • •
Attention to airway, breathing and circulation is paramount. If there is coma, recurrent seizures, hyperthermia greater than 39.5°C or severe rigidity compromising ventilation, proceed to rapid sequence intubation and ventilation while continuing with the steps below. Administer oxygen. Establish intravenous access. Check bedside blood glucose level. Check temperature. A temperature >38.5°C is an indication for continuous core-temperature monitoring. A temperature >39.5°C is an emergency and requires prompt intervention with neuromuscular paralysis, intubation and ventilation to prevent further musclegenerated heat production and severe hyperthermia leading to multiple organ failure, neurological injury and death. Give titrated intravenous benzodiazepines (e.g. diazepam 5–10 mg; children 0.1–0.3 mg/kg/dose over 3–5 minutes) to achieve gentle sedation. Hypertension and tachycardia usually respond satisfactorily to benzodiazepines given to achieve sedation. If refractory, a shortacting intravenous infusion of a vasodilator such as GTN or sodium nitroprusside is commenced and titrated to effect.
Risk assessment
Mild serotonin syndrome (normal mental status and vital signs) is a self-limiting condition. Complete resolution over a period of hours is anticipated. ERRNVPHGLFRVRUJ
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Resuscitation
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Anticholinergic agent
Anticholinergic syndrome
Neuromuscular tone Reflexes
Mental status
SPECIFIC CONSIDERATIONS
Generalised rigidity
Normal
Adapted from Boyer EW, Shannon M. The serotonin syndrome. New England Journal of Medicine 2005; 352(11):1112–1120.
Sweaty and Decreased mottled
Hot, red Decreased and dry or absent
↑HR, Mydriasis BR RR and Temp
Lead-pipe rigidity
Hyporeflexia
Normal
Agitation
Agitated delirium
Bradyreflexia Mutism, staring, bradykinesia, coma
Hyperactive Increased, esp. Hyperreflexia Agitation lower limbs and progressing clonus to coma
20 mmHg diastolic change or >25 mmHg systolic change within 24 hours) — Diaphoresis — Urinary incontinence Tachycardia plus tachypnoea Negative work-up for infectious, toxic, metabolic and neurological causes
Adapted from Gurrera RJ, Caroff SN, Cohen A et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. Journal of Clinical Psychiatry 2011; 72:1222–1228.
• • • • • • • • • • • • • •
The following risk factors for NMS have been suggested: High doses of neuroleptic agent Increased dose of neuroleptic agent within the previous 5 days Large magnitude dosage increase Parenteral administration Simultaneous use of two or more neuroleptic agents Use of haloperidol or depot fluphenazine Young age Male sex Psychiatric co-morbidity Genetic factors Pre-existing organic brain disorders (infectious encephalitis, AIDS, tumours) Dehydration High CK levels during episodes of psychosis not associated with NMS Other pre-existing medical disorders (trauma, infection, malnutrition, premenstrual phase, thyrotoxicosis).
DIFFERENTIAL DIAGNOSIS Neuroleptic malignant syndrome is a diagnosis of exclusion and the following important alternative diagnoses that share some general features with NMS must be considered:
• • •
Acute lethal (malignant) catatonia Malignant hyperthermia Serotonin syndrome (see Chapter 2.8: Serotonin syndrome) ERRNVPHGLFRVRUJ
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●
SPECIFIC CONSIDERATIONS
TABLE 2.11.2 Criteria for diagnosis of NMS
SPECIFIC CONSIDERATIONS
• • • •
Anticholinergic syndrome (see Chapter 2.9: Anticholinergic syndrome) Sympathomimetic syndrome Encephalitis Metabolic encephalopathies.
The clinical features of NMS are compared with those of serotonin syndrome, anticholinergic syndrome and malignant hyperthermia in Table 2.8.3. Acute lethal (malignant) catatonia is clinically very similar to NMS. The diagnostic criteria are nearly identical but NMS is distinguished by a history of recent antipsychotic medication use. Neuroleptic malignant syndrome is usually characterised by bradykinesia and mutism, whereas acute lethal catatonia may be characterised by abnormal posturing and waxy flexibility.
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• • • • • • •
Respiratory failure Dehydration Renal failure Multiple-organ failure Thromboembolism Residual catatonia and parkinsonian symptoms Recurrence after rechallenge with an antipsychotic agent may occur in 30–50% of patients who suffer NMS
MANAGEMENT Resuscitation
• • • • •
• •
Attention to airway, breathing and circulation is paramount. If there is coma, hyperthermia >39.5°C or severe rigidity compromising ventilation, proceed to rapid-sequence intubation and ventilation while continuing with the steps below. Administer oxygen. Establish intravenous access. Detect and correct hypoglycaemia. Detect and correct hyperthermia. A temperature >38.5°C is an indication for continuous core-temperature monitoring. A temperature >39.5°C is an emergency and requires prompt intervention with neuromuscular paralysis, intubation and ventilation to prevent further muscle-generated heat production, and severe hyperthermia leading to multiple-organ failure, neurological injury and death. Avoid any agent with dopamine antagonist effects. Intravenous benzodiazepines are controversial in the management of NMS. They are frequently used to achieve muscle relaxation and control of delirium in mild-to-moderate cases (e.g. diazepam ERRNVPHGLFRVRUJ
Depending on severity, further investigations may be required to exclude alternative diagnoses and detect significant complications:
• • • • • • • • • • • • •
Chest X-ray 12-lead ECG Full blood count Renal function and electrolytes Creatine kinase Serum calcium and magnesium Liver function tests Arterial blood gases Blood and urine cultures Cranial CT Lumbar puncture MRI brain Electroencephalogram.
Supportive care
• • • • • •
Cease causative agent(s). Reassure patient. Administer intravenous fluids and institute fluid balance monitoring. Monitor temperature. In mild-to-moderate cases, supplemental benzodiazepine sedation may be indicated. Consider thromboembolism prophylaxis.
Antidote therapy
The roles of bromocriptine, dantrolene and electroconvulsive therapy (ECT) have not been defined by prospective trials. It is not known whether they increase survival or shorten the clinical course when compared with good supportive care alone. Bromocriptine is a dopamine agonist that may be given orally or via a nasogastric tube. It is indicated in moderate and severe cases. Dosing commences at 2.5 mg every 8 hours, increasing to 5 mg every 4 hours ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
Investigations
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5–10 mg over 3–5 minutes titrated to achieve gentle sedation). However, because benzodiazepines may play a role in the aetiology of NMS, more specific agents such as bromocriptine are preferred in severe cases. Hypertension and tachycardia may initially be treated with a parenteral vasodilator such as GTN or sodium nitroprusside. Bromocriptine (see below) is indicated if there is significant autonomic instability.
SPECIFIC CONSIDERATIONS
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(30 mg/day). Adverse effects include postural hypotension, headache, nausea, vomiting, dyskinesia and erythromelalgia (painful erythematous lower limbs). Autonomic instability and fever usually improve within 24 hours of commencing bromocriptine therapy but neuromuscular changes and delirium may take longer to resolve (1–2 days and several days, respectively). If bromocriptine is used, it should be continued for 1–2 weeks before tapering the dose. Dantrolene is indicated if there is severe muscle rigidity and fever. It is administered intravenously 2–3 mg/kg/day up to a total dose of 10 mg/kg/day. Once oral treatment can be tolerated, it may be given in an oral dose of 100–400 mg/day in divided doses for 10 days, or the patient may be switched to bromocriptine. Electroconvulsive therapy (ECT) has been reported to improve fever, sweating and consciousness level in some patients. It is thought to act by increasing central dopaminergic activity. Improvement may be seen after the third or fourth treatment. It has been advocated for:
• • • •
Severe NMS refractory to supportive care and antidote treatment Severe NMS that is difficult to differentiate from acute lethal catatonia Treatment of residual catatonic symptoms after NMS When the psychiatric disorder underlying severe NMS is psychotic depression or catatonia.
Disposition and follow-up
Following cessation of the causative agent, patients with normal mental status (no delirium or seizures) and normal vital signs may be reassured and considered for discharge following a period of observation (e.g. 12 hours). An oral benzodiazepine (e.g. diazepam 5 mg 6–8 hourly) may be used for symptomatic treatment for 24 hours. Other patients usually require admission for further supportive care with or without specific antidote treatment. The patient should be advised of the adverse effect or drug interaction prior to discharge and subsequent psychopharmacotherapy will need careful review. Recurrence after rechallenge with an antipsychotic agent may occur in 30–50% of patients who suffer NMS. References
Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurology Clinics of North America 2004; 22:389–411. Gurrera RJ, Caroff SN, Cohen A et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. Journal of Clinical Psychiatry 2011; 72:1222–1228. Rusyniak DE, Sprague JE. Toxin-induced hyperthermic syndromes. Medical Clinics of North America 2005; 89:1277–1296. Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs 2009; 23(6):477–492.
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BOX 2.12.1 Psychiatric definition of alcohol use disorder (DSM-V) ●
Alcohol is often taken in larger amounts or over a longer period than was intended. ● There is a persistent desire or unsuccessful efforts to cut down or control alcohol use. ● A great deal of time is spent in activities necessary to obtain alcohol, use alcohol or recover from its effects. ● Craving or a strong desire or urge to use alcohol occurs. ● Recurrent alcohol use results in a failure to fulfil major role obligations at work, school or home. ● Alcohol use continues despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol. ● Important social, occupational or recreational activities are given up or reduced because of alcohol use. ● Recurrent alcohol use occurs in situations in which it is physically hazardous. ● Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol. ● Tolerance occurs, as defined by either of the following: — A need for markedly increased amounts of alcohol to achieve intoxication or desired effect — A markedly diminished effect with continued use of the same amount of alcohol. ● Withdrawal occurs, as manifested by either of the following: — The characteristic withdrawal syndrome for alcohol — Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms. The presence of a least 2 of these symptoms indicates an alcohol use disorder (AUD). The severity of AUD is defined as: ● Mild: the presence of 2 to 3 symptoms ● Moderate: the presence of 4 to 5 symptoms ● Severe: the presence of 6 or more symptoms. Adapted from Diagnostic and Statistical Manual of Mental Disorders. 5th edn. Arlington, Virginia: American Psychiatric Association; 2013.
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Alcohol abuse and dependence is formally defined as alcohol use disorder (AUD) (see Box 2.12.1). Alcohol withdrawal is a potentially life-threatening medical condition. More harm occurs in the community as a result of the acute health and social effects of alcohol use than from the consequences of longterm alcohol dependence (see Table 2.12.1). Upwards of 30% of all emergency department presentations are alcohol-related. The incidence
SPECIFIC CONSIDERATIONS
2.12 ALCOHOL USE DISORDER
SPECIFIC CONSIDERATIONS
TABLE 2.12.1 Medical complications of chronic alcohol abuse
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Cardiovascular Atrial fibrillation Cardiomyopathy Electrolytes Hypocalcaemia Hypokalaemia Hypomagnesaemia Hypophosphataemia Endocrine Hypoglycaemia Hypogonadism Osteoporosis Steatosis Haematological Anaemia Coagulopathy Leucopenia Macrocytosis Thrombocytopenia Gastrointestinal Alcoholic hepatitis Cirrhosis Gastritis Malabsorption Oesophageal varices and gastrointestinal haemorrhage Pancreatitis
Malignancy Breast Colorectal Hepatic Larynx Oesophagus Oropharynx Malnutrition Folate deficiency Niacin deficiency (pellagra) Stomatitis Vitamin C deficiency (scurvy) Neurological Dementia Cerebellar degeneration Korsakoff’s syndrome Peripheral neuropathy Wernicke’s encephalopathy Psychiatric Alcoholic hallucinosis Depression and suicide Delusions
Adapted from Sivilotti ML. Ethanol, isopropanol and methanol. In: Dart RC, ed. Medical Toxicology. 3rd edn. Philadelphia: Lippincott Williams & Wilkins; 2003.
of alcohol-related problems is even higher in the population that presents to emergency departments with deliberate self-poisoning with either self-harm or recreational intent.
SCREENING AND BRIEF INTERVENTION STRATEGIES Presentation to the emergency department, particularly with acute poisoning, provides an ideal opportunity to identify individuals with alcohol-related problems and provide brief intervention with the aim of improving long-term outcomes. In most settings, doctors identify fewer than 50% of patients with alcohol-related problems. Factors associated with failure to identify these individuals include:
• • •
Inadequate training about substance abuse Negative attitudes towards patients with substance abuse Scepticism about effectiveness of treatments ERRNVPHGLFRVRUJ
A number of tools have been developed to assist identification of potentially hazardous alcohol consumption and are suitable for application in the emergency department. The Alcohol Use Disorders Identification Test (AUDIT) identifies patients with at-risk, hazardous or harmful drinking with a sensitivity of 51–97% and a specificity of 78–96% (see Box 2.12.2). The ‘CAGE’ questions detect alcohol abuse and dependence with a sensitivity of 43–94% and specificity of 70–97% (see Box 2.12.3). The following single question when administered to trauma patients, using a cut-off of three drinks, correlates well with the AUDIT score: ‘On a typical day when you are drinking, how many drinks do you have?’ Abbreviated screening tools such as this consume minimal time and do not require detailed training. Early detection of alcohol problems allows implementation of brief intervention strategies such as ‘FRAMES’, which has been shown to decrease alcohol consumption in non-dependent patients (see Box 2.12.4).
ALCOHOL WITHDRAWAL The alcohol withdrawal syndrome usually develops within 6–24 hours of cessation or reduction in alcohol consumption in dependent individuals. It commonly develops in patients admitted to hospital. Pathophysiology
Ethanol dependence affects multiple neurotransmitter systems. Down-regulation of neuro-inhibitory GABA receptors leads to symptoms of GABA excess in withdrawal. Alcohol also inhibits the excitatory NMDA glutamate receptor and withdrawal abruptly removes this inhibition. Increased dopaminergic and noradrenergic neurotransmission also occur. Clinical features
Alcohol withdrawal manifests as a constellation of clinical autonomic and neurological features with a wide spectrum of severity and a typical time course. Autonomic excitation
•
Occurs within hours of cessation and peaks at 24–48 hours — Tremor — Anxiety and agitation ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
Belief that alcohol problems are not in the realm of the generalist clinician Excessive time required to perform formal screening procedures.
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1 or 2 Never Never Never Never
How often do you have 6 or more drinks on one occasion?
How often during the last year have you found that you were not able to stop drinking once you had started?
How often during the last year have you failed to do what was normally expected from you because of drinking?
How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session?
Never
How often do you have a drink containing alcohol?
How many drinks containing alcohol do you have on a typical day when you are drinking?
Score
Questions pertain to behaviour in the last year
ERRNVPHGLFRVRUJ Less than monthly
Less than monthly
Less than monthly
Less than monthly
3 or 4
Monthly or less
1
Monthly
Monthly
Monthly
Monthly
5, 6 or 7
Weekly
Weekly
Weekly
Weekly
8 or 9
Two to three times per week
3
SPECIFIC CONSIDERATIONS
Two to four times per month
2
BOX 2.12.2 The Alcohol Use Disorders Identification Test (AUDIT) Score (WHO 1992)
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92 Daily or almost daily
Daily or almost daily
Daily or almost daily
Daily or almost daily
10 or more
Four or more times per week
4
ERRNVPHGLFRVRUJ No
Hazardous alcohol usage. Help required Hazardous alcohol usage. Help urged Drinking exceeding safe levels Normal usage
Has a relative or friend or doctor or other health worker been concerned about your drinking or suggested you cut down?
Score >20
Score 16–19
Score 8–15
Score 0–7
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No
Have you or someone else been injured as a result of your drinking?
SPECIFIC CONSIDERATIONS
Yes, during the last year
Yes, but not in the last year
Daily or almost daily Yes, during the last year
Weekly
Daily or almost daily
4
Yes, but not in the last year
Monthly
Less than monthly
Never
Weekly
How often during the last year have you been unable to remember what happened the night before because you had been drinking?
Monthly
Less than monthly
Never
3
How often during the last year have you had a feeling of guilt or remorse after drinking?
2
1
Score
93
SPECIFIC CONSIDERATIONS
BOX 2.12.3 ‘CAGE’ questions
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Two or more positive responses identify patients with lifetime risk of alcohol problems. Cut down: Have you ever tried to cut down your drinking? Annoyed: Have you ever been annoyed by criticism of your drinking? Guilty: Do you feel guilty about your drinking? Eye-opener: Do you need an eye-opener when you get up in the morning?
BOX 2.12.4 ‘FRAMES’ acronym Feedback: review problems caused by alcohol with the patient Responsibility: point out that changing behaviour is the patient’s responsibility Advice: advise the patient to cut down or abstain from alcohol Menu: provide options to assist the patient to change behaviour Empathy: use an empathetic approach Self-efficacy: encourage optimism that the patient can change behaviour
— Sweating — Tachycardia — Hypertension — Nausea and vomiting — Hyperthermia Neuro-excitation
•
Occurs within 12–48 hours of cessation — Hyperreflexia — Nightmares — Hallucinations (visual, tactile and occasionally auditory) — Generalised tonic–clonic seizures
Delirium tremens
• • •
Severe form with mortality approaching 8% Up to 20% of patients admitted to urban hospitals with alcohol withdrawal Associated with medical co-morbidities and delayed presentation — Hallucinations — Confusion, disorientation and clouding of consciousness — Autonomic hyperactivity — Respiratory and cardiovascular collapse — Death ERRNVPHGLFRVRUJ
Co-morbidities
A number of important co-morbidities should be considered, detected and managed in all patients with high or regular alcohol intake:
• • • • • • • • • • •
Wernicke’s encephalopathy (see Table 2.12.2) Dehydration Hypoglycaemia Electrolyte abnormalities Coagulation disorders/thrombocytopenia Anaemia, usually macrocytic Alcoholic gastritis and gastrointestinal bleeding Pancreatitis Alcoholic liver disease and hepatic encephalopathy Subdural haemorrhage Alcoholic ketoacidosis.
Management
Mild forms of alcohol withdrawal are managed with simple supportive care in an outpatient setting. Symptoms typically settle in 2–7 days. Relapse is common without implementation of adequate psychosocial support. Withdrawal in a residential setting with professional supervision with or without medication is more appropriate in the following circumstances:
• • •
History of severe alcohol withdrawal Poor social support Failure of unsupervised outpatient withdrawal.
Inpatient alcohol withdrawal is indicated for the minority of patients in whom there is a significant risk of delirium tremens, seizures or significant co-morbidities:
•
Presentation with severe alcohol withdrawal — Abnormal vital signs after initial treatment — Hallucinations ERRNVPHGLFRVRUJ
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Acute confusion Reduced level of consciousness Coma Memory disturbance Ataxia Ophthalmoplegia Nystagmus Unexplained hypotension Hypothermia
SPECIFIC CONSIDERATIONS
TABLE 2.12.2 Signs of Wernicke’s encephalopathy
SPECIFIC CONSIDERATIONS
• •
96 96 TOXICOLOGY HANDBOOK
— Altered conscious state — Seizures Presence of medical complications or co-morbidities (see above) Presence of significant psychiatric co-morbidities.
Management approach to severe alcohol withdrawal in the hospital setting Resuscitation, supportive care and monitoring
•
• • • • • • •
Florid delirium tremens constitutes a medical emergency and is managed in an area fully equipped for resuscitation and monitoring with the following priorities: — Immediate attention to airway, breathing and circulation — Establishment of IV access — Control of seizures and delirium by administration of repeated doses of IV diazepam 5–10 mg until seizures and agitation are controlled — Detection and treatment of hypoglycaemia. Alcohol withdrawal onset, severity, progress and response to therapy is best monitored with an alcohol withdrawal chart incorporating an easily calculated alcohol withdrawal score (AWS) (see Box 2.12.5). Institute monitoring for alcohol withdrawal in any patient judged to be at risk of developing alcohol withdrawal, not just patients who present in established withdrawal. Give regular oral diazepam 5–20 mg PO as dictated by AWS to maintain adequate control of withdrawal. Give thiamine 200 mg IV tds for the first 24 hours and then review. This should be continued for 3 days if there is altered mental status and even higher doses should be given if Wernicke’s encephalopathy is strongly suspected (see Table 2.12.2). Ensure adequate hydration, electrolyte balance and nutrition. Detect and treat co-morbidities. Note: Phenytoin is not indicated in the treatment or prevention of alcohol-related seizures.
Investigations as indicated
EUC, FBE, LFTs, coagulation profile, serum lipase Disposition and follow-up
• •
Medical admission is indicated if: — Large doses of diazepam are required to control withdrawal — Medical co-morbidities require care. Referral to residential or home detoxification and rehabilitation services for assessment and psychosocial support is considered once acute withdrawal is controlled or resolving. ERRNVPHGLFRVRUJ
0 – Orientated 1 – Disorientated 2 – Uncooperative
= The patient is fully orientated in time, place and person = Disorientated but cooperative = Disorientated and uncooperative
Agitation/ anxiety
0 – Calm 1 – Anxious 2 – Panicky
= Rests normally = Appears anxious = Appears very agitated all the time, panics or gets out of bed for no reason
Hallucination
0 – None 1 – Anxious
= No evidence of hallucinations = Distortion of real objects or hallucinations but accepted as not real when pointed out = Believes the hallucinations are real and cannot be reassured
2 – Can’t dissuade Perspiration
0 – Nil 1 – Moist/wet 2 – Soaking
= No abnormal sweating = Mild-to-moderate perspiration = Soaking sweat
Tremor
0 – Nil 1 – With intention
= No tremor = Tremor when moving hands and arms = Constant tremor of arms even at rest
2 – At rest Temperature
0 – 37.5°C or less 1 – 37.6°C to 38.5°C 2 – >38.5°C
Adapted with permission from the Alcohol Withdrawal Chart at Sir Charles Gairdner Hospital, Nedlands, Western Australia.
References
Friedman PD. Alcohol use in adults. The New England Journal of Medicine 2013; 368:365–373. Hall W, Zador D. The alcohol withdrawal syndrome. Lancet 1997; 349:1897–1900. Holmwood C. Alcohol related problems in Australia: is there a role for general practice? Medical Journal of Australia 2002; 177:102–103. Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England Journal of Medicine 2003; 348:1786–1795. Lieber CS. Medical disorders of alcoholism. New England Journal of Medicine 1995; 333(16):1058–1065. Reed DN, Saxe A, Montanez M et al. Use of a single question to screen trauma patients for alcohol dependence. Journal of Trauma 2005; 59:619–623. Sechi GP, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurology 2007; 6:442–455. Tjipto AC, Taylor D McD, Liew H. Alcohol use among young adults presenting to the emergency department. Emergency Medicine Australasia 2006; 18(2):125–130.
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SPECIFIC CONSIDERATIONS
BOX 2.12.5 Alcohol withdrawal score (AWS)
SPECIFIC CONSIDERATIONS
2.13 AMPHETAMINE USE DISORDER
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Amphetamine use disorder is defined by DSM-V along the lines of substance use disorder in general as outlined for alcohol (see Box 2.12.1). Life-time prevalence of stimulant use disorder is estimated at 3.3% and peaks in 16–29-year-olds. Amphetamine and other stimulant-related presentations represent a significant burden on emergency departments, accounting for over 1% of all presentations. Most of these presentations relate to medical, social and psychiatric sequelae of acute amphetamine intoxication. The management of these presentations together with the clinical toxicology of amphetamines is dealt with in Chapter 3.8: Amphetamines and other sympathomimetics. Long-term amphetamine abuse is associated with medical, psychiatric and social sequelae (see Table 2.13.1). These sequelae may result directly in hospital presentation or complicate the management of intercurrent illness. Amphetamines, particularly methamphetamine, are highly addictive and patients may also present in withdrawal or develop withdrawal during admission for other reasons. No pharmacological agent has been demonstrated to be effective in the treatment of amphetamine withdrawal, dependence or abuse. Management relies on counselling and social support.
AMPHETAMINE WITHDRAWAL Prolonged or heavy use of amphetamines results in tachyphylaxis (reduced response to repeated doses). This phenomenon is thought to be due to depleted concentrations of neurotransmitters. The symptoms are largely psychiatric and mood-related, and include depression, fatigue, insomnia, increased appetite and cognitive impairment. Symptoms TABLE 2.13.1 Effects of long-term amphetamine abuse Medical Cardiomyopathy (rare) Poor dentition Weight loss Psychiatric Confusion Emotional lability Insomnia Memory loss Paranoia Paranoid psychosis Social Damage to social relationships Neglect of social, interpersonal and occupational responsibilities
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Romanelli F, Smith KM. Clinical effects and management of amphetamines. Pharmacotherapy 2006; 26(8):1148–1156. Sara GE, Burgess PM, Harris MG et al. Stimulant use and stimulant use disorders in Australia: findings from the national survey of mental health and wellbeing. Medical Journal of Australia 2011; 195:607–610. Shoptaw SJ, Kao U, Heinzerling K et al. Treatment for amphetamine withdrawal. Cochrane Database of Systematic Reviews 2009; 2:C0003021. Srisurapanont M, Jarusuraisin N, Krittirattanapaiboon P. Treatment for amphetamine dependence and abuse. Cochrane Database of Systematic Reviews 2001; 4:C0003022.
2.14 OPIOID USE DISORDER Opioid use disorder is defined by DSM-V along the lines of substance use disorder in general as outlined for alcohol (see Box 2.12.1). Opioidrelated presentations represent an increasing burden on the health system. In particular, there has been a doubling of hospital admissions and deaths related to prescription opioids in the past decade in Australia and the United Kingdom. The management of these presentations together with the clinical toxicology of opioids is dealt with in Chapter 3.57: Opioids.
OPIOID WITHDRAWAL Opioid withdrawal syndrome is the physiological response that develops when there is abrupt cessation or rapid reduction in opioid dose in a dependent individual, or when that individual is administered an opioid antagonist or partial agonist. Pathophysiology
The opioids exert their analgesic effects by agonist activity at CNS µ receptors. These mediate their effects by decreasing intracellular cAMP via membrane-bound G-proteins. Prolonged opioid use leads to a process of cellular adaptation and down-regulation through multiple mechanisms. When opioids are ceased a withdrawal syndrome develops. Clinical features
Although unpleasant, uncomplicated opioid withdrawal is not life threatening. This is in contrast to withdrawal from alcohol or sedativehypnotics. The symptoms are usually sufficiently uncomfortable to prompt efforts to obtain opioids by the individual concerned. ERRNVPHGLFRVRUJ
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References
SPECIFIC CONSIDERATIONS
usually peak 2–4 days following cessation of use but may continue for 7–14 days. Amphetamine withdrawal in itself is rarely severe enough to warrant medical admission. Management consists of referral for appropriate psychosocial support.
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100
The timing of onset of symptoms depends on the elimination kinetics of the specific opioid, the usual dose ingested and the degree of dependence. Symptoms may begin within 6 hours of the last heroin dose, peak at 36–48 hours and resolve within 1 week. In contrast, onset of symptoms may be delayed 2–3 days after cessation of methadone, peak at several days and last for up to 2 weeks. Patients may present with withdrawal symptoms associated with cessation of more than one agent. The clinical manifestations of opioid withdrawal include intense craving, dysphoria, autonomic hyperactivity and gastrointestinal distress. More specifically, symptoms include:
• • • • • • • • • • • • • • •
Anxiety, restlessness and dysphoria Insomnia Intense craving Yawning Lacrimation Salivation Rhinorrhoea Anorexia, nausea and vomiting Abdominal cramps and diarrhoea Mydriasis Piloerection Diaphoresis Flushing Myalgia and arthralgia Hypertension and tachycardia in severe cases.
Altered mental status, delirium, hyperthermia and seizures do not occur. Their presence should alert the clinician to an alternative diagnosis or complication. Co-morbidities
Co-morbidities that should be considered in patients with opioid withdrawal include:
• • • • •
Alcohol or sedative-hypnotic withdrawal syndrome Dehydration Electrolyte abnormalities Infective complications of intravenous drug abuse Psychiatric morbidities.
Management
Administration of opioids in sufficient dose will abolish all physiological manifestations of the withdrawal syndrome. Administration of opioids to ERRNVPHGLFRVRUJ
Severe withdrawal syndrome (e.g. following administration of antagonist) Significant complications (e.g. severe dehydration) Significant intercurrent illness (e.g. sepsis) Psychiatric co-morbidity.
Pharmacological treatment of opioid withdrawal is categorised into three types: opioid replacement therapy (e.g. methadone; buprenorphine), antagonist detoxification (e.g. naltrexone) and symptomatic treatment. Opioid replacement therapy
Methadone is used in opioid withdrawal and for maintenance in abstinence programs. Methadone maintenance treatment achieves significant reduction in heroin use and reduces mortality from heroin overdose but does not produce an overall reduction in mortality when compared with drug-free maintenance. To commence methadone, patients should be referred for evaluation and ongoing management by a specialist drug and alcohol service. Methadone doses typically start at 20–40 mg/day and are tapered over many weeks (e.g. by 3–5% each week). Buprenorphine is a high-affinity partial µ-opioid agonist used as an alternative to methadone. Doses start at 2–16 mg/day and are tapered over many weeks. Buprenorphine treatment is as effective as methadone in maintenance treatment of heroin dependence but less effective in achieving treatment retention, particularly with low-dose or flexible-dose regimens. Detoxification
Rapid detoxification using naltrexone, buprenorphine and clonidine in various combinations, or by rapid tapering of methadone, has been successful in selected patients. Efficacy depends on patient selection and ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
• • • •
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control withdrawal may be the appropriate course of action, particularly where the management of co-morbidities demands attention. Managed withdrawal (detoxification) is a necessary step towards drug-free treatment. The aims of early management of drug detoxification are safe cessation or dose reduction, management of symptoms and medical complications and retention of the patient in a treatment program. Most patients with opioid withdrawal can be managed in an outpatient setting. Information and reassurance provided in a nonjudgemental way are vital to engage the patient in a realistic withdrawal treatment program. Admission to hospital may be required in the following circumstances:
SPECIFIC CONSIDERATIONS
TABLE 2.14.1 Symptomatic treatment of opioid withdrawal
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2
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Dehydration Fluid resuscitation Nausea and vomiting Metoclopramide 10 mg or prochlorperazine 5 mg or ondansetron 4 mg PO, 6 hourly as required Abdominal cramps and diarrhoea Hyoscine 20 mg PO every 6 hours or atropine–diphenoxylate (25 mcg–2.5 mg) two tablets PO every 6–8 hours Myalgia and arthralgia Paracetamol (1 g every 4 hours, not exceeding 4 g per day) or ibuprofen (400 mg every 6 hours) Anxiety, dysphoria and insomnia Diazepam 5–10 mg PO every 6–8 hours for 2–3 days Clonidine Centrally acting alpha-2-adrenergic receptor agonist used to attenuate the physical and psychological symptoms of opioid withdrawal Adverse effect is postural hypotension, especially in patients with dehydration and bradycardia Give a test dose of 75 micrograms PO, followed by lying and standing blood pressure monitoring for 1 hour If symptomatic postural hypotension does not occur, commence 50 micrograms PO three times a day. The dose may be increased if tolerated (e.g. up to 200–300 micrograms three times daily) before tapering over the subsequent 5 days
close clinical supervision by a team experienced in specialised drug and alcohol treatment. Ultra-rapid detoxification is an invasive procedure involving the precipitation of severe opioid withdrawal using naltrexone, often under general anaesthesia. This technique does not improve abstinence rates and carries a high risk of serious adverse events including death. Supportive care
Patients should be reassured and assessed for potential co-morbidities and complications. Fluid resuscitation for dehydration may be required. The presence of altered mental status, fever or seizures prompts further investigation for an alternative cause. Several medications are of value in providing symptomatic relief (see Table 2.14.1). Presentation with drug-related problems provides an opportunity for patient counselling regarding the risks of drug abuse and dependence and engagement in strategies to change behaviour. References
Anonymous. Deaths and severe adverse events associated with anesthesia-assisted rapid opioid detoxification – New York City, 2012. Morbidity and Mortality Weekly Report 2013; 38:777–780.
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Sedative-hypnotic use disorder is defined by DSM-V along the lines of substance use disorder in general as outlined for alcohol (see Box 2.12.1). Sedative-hypnotics include benzodiazepines, barbiturates, nonbenzodiazepine agents (zolpidem, zopiclone), baclofen, gammahydroxybutyrate, chloral hydrate and paraldehyde. Deliberate self-poisoning with these agents is extremely common and the management of these presentations together with the clinical toxicology of the specific sedative-hypnotics is dealt with in Chapter 3.15: Baclofen, Chapter 3.16: Barbiturates, Chapter 3.17: Benzodiazepines, Chapter 3.27: Chloral hydrate and Chapter 3.37: Gamma-hydroxybutyrate (GHB).
SEDATIVE-HYPNOTIC WITHDRAWAL Abrupt cessation or reduction in dose of a sedative-hypnotic agent can produce a characteristic withdrawal syndrome in a dependent individual not dissimilar to that of alcohol withdrawal. Withdrawal syndromes are described for:
• • • • • • •
Benzodiazepines Barbiturates Non-benzodiazepine sedative-hypnotic agents (zolpidem, zopiclone) Baclofen Gamma-hydroxybutyrate (GHB) Chloral hydrate Paraldehyde.
Pathophysiology
The sedative-hypnotic agents all modulate activity of the gammaaminobutyric acid (GABA) neurotransmitter complex. Abrupt withdrawal leads to symptoms of GABA excess. ERRNVPHGLFRVRUJ
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Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England Journal of Medicine 2003; 348:1786–1795. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database of Systematic Reviews 2009; 3:CD002209. Mattick RP, Breen C, Kimber J, Davoli M et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2014; 2:C0002207. Olmedo R, Hoffman RS. Withdrawal syndromes. Emergency Medicine Clinics of North America 2000; 18(2):273–288. Roxburgh A, Bruno R, Larance B, Burns L. Prescription of opioid analgesics and related harms in Australia. Medical Journal of Australia 2011; 195:280–284. Tetrault JM, O’Connor PG. Substance abuse and withdrawal in the critical care setting. Critical Care Clinics 2008; 24:767–788.
SPECIFIC CONSIDERATIONS
Clinical features
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There is a high degree of inter-individual difference in the rate of onset, type and severity of withdrawal symptoms. Variability is determined by dose and duration of therapy, rapidity of withdrawal, elimination kinetics of the agent and patient factors. Onset of symptoms generally occurs within 2–10 days of abrupt cessation, although withdrawal of very-short-acting agents (e.g. GHB) or agents administered by the intrathecal route (e.g. baclofen) may produce symptoms within hours. The clinical presentation may reflect withdrawal from more than one class of agent. A severe and potentially lethal syndrome similar to delirium tremens and including seizures occurs rarely. This is in contrast to opioid or cannabis withdrawal, which does not cause delirium, autonomic instability or seizures (see Chapter 2.14: Opioid use disorder and Chapter 3.23: Cannabinoids (marijuana)). The commonly observed clinical features resemble those of alcohol withdrawal (see Chapter 2.12: Alcohol use disorder), although psychomotor and autonomic nervous system signs may be more prominent:
• • • • • • • • •
Irritability and agitation Anorexia Inattention Memory disturbances Insomnia Palpitations Perceptual disturbances, including photophobia and hyperacusis Hallucinations Increased spasticity (baclofen).
Co-morbidities
Co-morbidities that should be considered in patients with sedativehypnotic withdrawal include:
• • • •
Alcohol withdrawal syndrome Dehydration Electrolyte abnormalities Psychiatric morbidities.
Management
Where withdrawal develops as a result of an interruption in regular benzodiazepine (or other sedative-hypnotic agent) use due to an intercurrent medical illness, it is best to reverse the withdrawal syndrome by reinstitution of the offending agent until the precipitating illness is treated. ERRNVPHGLFRVRUJ
SPECIFIC CONSIDERATIONS
Where the aim is to achieve permanent safe withdrawal or dose reduction, alternative management strategies are adopted. The usual strategy is to substitute a longer acting benzodiazepine for the agent being ceased and then to slowly taper the dose. Tapering is titrated to individual patient symptoms. If withdrawal symptoms increase, the dose may be increased transiently or tapering attempted more slowly. Typically, withdrawal takes weeks to complete with dosage decreases of approximately 15% per week. Management of severe sedative-hypnotic withdrawal with delirium or seizures is similar to alcohol withdrawal syndrome (see Chapter 2.12: Alcohol use disorder). Several scores have been used to assess the severity of the benzodiazepine withdrawal syndrome in order to guide admission decisions and benzodiazepine dosing. However, most scores have not been prospectively validated and should be used with caution. In most patients, sedative-hypnotic withdrawal is mild and management in an outpatient setting is appropriate. Presentation with drug-related problems provides an opportunity for patient counselling regarding the risks of drug abuse and dependence and engagement in strategies to change behaviour. Withdrawal in a residential setting, with supervision by specialised staff with training in drug and alcohol issues, is appropriate in selected circumstances:
• • •
History of severe withdrawal Poor social support Failure of unsupervised outpatient withdrawal.
• • • • • • •
Presentation in severe withdrawal Abnormal vital signs after initial treatment Hallucinations Altered conscious state Seizures Presence of medical complications or co-morbidities Presence of significant psychiatric co-morbidities.
Inpatient sedative-hypnotic withdrawal is appropriate for a minority of patients in whom there is a significant risk of delirium or seizures:
References
Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England Journal of Medicine 2003; 348:1786–1795. Leo RJ, Baer D. Delirium associated with baclofen withdrawal: a review of common presentations and management strategies. Psychosomatics 2005; 46:503–507.
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Disposition
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McDonough M, Kennedy N, Glasper A et al. Clinical features of gammahydroxybutyrate (GHB) withdrawal: a review. Drug and Alcohol Dependence 2004; 75:3–9. Olmedo R, Hoffman RS. Withdrawal syndromes. Emergency Medicine Clinics of North America 2000; 18(2):273–288.
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2.16 SOLVENT ABUSE A solvent is defined as a liquid that has the ability to dissolve, suspend or extract another material without chemical change to either the material or solvent. Organic solvents are found in numerous household and industrial products, including glues, household cleaners, degreasers, thinners, paints, pharmaceuticals, cosmetics and pesticides. The group includes aliphatic, cyclic, aromatic and halogenated hydrocarbons, ethers, esters, glycols, ketones, aldehydes and amines (see Table 2.16.1). Common solvents include isopropanol, toluene and xylene. Other volatile hydrocarbons more commonly used as fuels, such as petrol, kerosene and butane (used as lighter fuel), have similar physicochemical properties, clinical effects and abuse potential. The recreational abuse of solvents involves inhalation of these volatile substances for the purpose of achieving an alteration in mental status, principally euphoria. Inhalational organic solvent abuse is a major public health problem particularly afflicting adolescents and Indigenous communities. The agent with the highest potential for abuse is toluene, found primarily in glues, spray paints and lacquers.
PHYSICOCHEMICAL PROPERTIES The organic solvents are all volatile liquids and well absorbed via the inhalational route. Peak blood concentrations are achieved within 15–30 minutes of inhalation. These agents are highly lipid soluble and following absorption are preferentially distributed to lipid-rich organs notably the CNS and liver. After inhalation stops, excretion by the lungs takes place. Solvents are also metabolised by the liver with elimination half-lives in the order of 15–72 hours.
MECHANISM OF TOXICITY While agents vary in their end-organ specificity, acute solvent toxicity generally correlates with the volatility of an agent. They are lipophilic and potent CNS depressants. High volatility is associated with a greater risk of micro-aspiration and pneumonitis. Myelin toxicity is thought to be the cause of the neuropsychiatric consequences associated with long-term inhalational abuse and occupational exposure. Myocardial sensitisation to catecholamines may be associated with cardiac dysrhythmias and sudden death. ERRNVPHGLFRVRUJ
Nitrites Amyl nitrite Butyl nitrite Cyclohexyl nitrite Oxygenated compounds Acetone Butanone Diethyl ether Dimethyl ether Ethyl acetate Methyl acetate Methyl isobutyl ketone Nitrous oxide
Adapted from Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the clinical toxicology of volatile substances. Drug Safety 1990; 5:359–383.
MODES OF ABUSE Solvent abusers always employ the inhalational route with the following methods described:
• • •
‘Huffing’: the liquid solvent is poured into a bag or piece of cloth such as a sock and the liquid-soaked material is then held up to the face as the abuser inhales deeply ‘Bagging’: the liquid is poured into a bag and the bag held over the head ‘Sniffing’ or ‘snorting’: liquid is inhaled directly from the container. ERRNVPHGLFRVRUJ
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Aliphatic hydrocarbons Acetylene n-Butane Cyclopropane Isobutane n-Hexane Propane Aromatic hydrocarbons Toluene Xylene Mixed hydrocarbons Petrol Kerosene Halogenated hydrocarbons Bromochlorodifluoromethane Carbon tetrachloride Chlorodifluoromethane Chloroform Dichlorodifluoromethane Dichloromethane (methylene chloride) 1,2-Dichloropropane Enflurane Ethyl chloride Halothane Isoflurane Methoxyflurane Tetrachloroethylene 1,1,1-Trichloroethane Trichloroethylene Trichlorofluoromethane
SPECIFIC CONSIDERATIONS
TABLE 2.16.1 Chemicals used for inhalational abuse
CLINICAL FEATURES
SPECIFIC CONSIDERATIONS
The solvent abuser may present with acute solvent neurotoxicity or with the CNS, metabolic, behavioural and social complications associated with chronic abuse.
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Acute inhalational exposure
Acute inhalation predominantly affects the CNS, causing altered cognition that resembles ethanol intoxication. There is general impairment of psychomotor function, as measured by reaction time, manual dexterity, coordination and body balance. Patients are euphoric, disinhibited, lethargic and ataxic with slurred speech and inappropriate affect. More severe intoxication is characterised by confusion, depressed level of consciousness, seizures and coma. Inhalational exposure to solvents also causes intense irritation to the mucous membranes of the eye, nose, throat and lower airways. Inadvertent aspiration can induce chemical pneumonitis. Sudden death, particularly associated with butane and propane, may occur during acute exposure. Possible mechanisms are asphyxiation or cardiac dysrhythmias induced by sensitisation of the myocardium to endogenous circulating catecholamines. Chronic inhalational abuse
There is strong evidence to suggest that long-term toluene exposure leads to persistent neurotoxicity characterised by structural and functional brain abnormalities, as well as neuropsychological impairment. Neuro-imaging studies suggest injury preferentially affects white matter structures (lipid-rich myelinated structures), a pattern which could be explained by the lipid-dependent distribution to myelinated areas of the brain. Persistent neurotoxicity is characterised by impaired cognition and poor performance on most neuropsychological tests, including those testing working memory and executive cognitive function. Although the individuals engaging in chronic toluene abuse are likely to come from a background of psychomotor, emotional and social deprivation, it does appear that the abuse itself is associated with adverse effects in cognitive and intellectual abilities. These effects further exacerbate the pre-existing problems and complicate efforts to achieve detoxification, long-term abstinence and rehabilitation. It remains controversial as to whether long-term abstinence is associated with significant improvement in neuropsychological function. Chronic toluene abuse is also associated with a normal anion gap metabolic acidosis largely due to distal renal tubular acidosis. Acidaemia, hyperchloraemia and hypokalaemia may be profound (25% of chronic abusers have serum K+ 100 ms (2.5 small squares) is associated with seizures QRS >160 ms (4 small squares) is associated with ventricular dysrhythmias Right axis deviation of the terminal QRS as defined by — Terminal R wave >3 mm in aVR — R/S ratio >0.7 in aVR.
SYSTEMATIC ANALYSIS OF THE 12-LEAD ECG OF A POISONED PATIENT 1 Determine rate and rhythm. 2 Determine PR interval – is there any degree of heart block? 3 Determine QRS duration in lead II. The studies examining QRS
duration in tricyclic antidepressant intoxication use manual measurements to measure QRS in limb lead II. This may not correspond with the QRS as calculated by an automated ECG machine using complex algorithms. It is best to check the interval manually in lead II. 4 Check for right axis deviation of the QRS. A large terminal R wave in aVR or increased R/S ratio indicates slow rightward conduction and is characteristic of fast sodium channel blockade. If not pathological, it remains static in appearance and severity throughout the course of the poisoning. Comparison with pre-poisoning ECGs is useful. 5 Determine QT interval. A prolonged QT interval predisposes to the development of torsades de pointes, a polymorphic ventricular tachycardia. Torsades de pointes is potentially fatal because of its propensity to degenerate into ventricular fibrillation. Torsades de ERRNVPHGLFRVRUJ
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Hyperkalaemia Peaked T waves Conduction abnormalities
SPECIFIC CONSIDERATIONS
• •
SPECIFIC CONSIDERATIONS
FIGURE 2.20.4 QT interval nomogram for determining ‘at risk’ QT-HR pairs from a single 12-lead ECG
20
40
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80
100
120
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Heart rate (bpm)
The mean QT interval as measured manually on multiple leads of a 12-lead ECG is plotted against the heart rate (HR) measured on the ECG. If the point is above the line, the QT-HR is regarded ‘at risk’ for the development of torsades de pointes. Chan A, Isbister GK, Kirkpatrick CMJ et al. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. Quarterly Journal of Medicine 2007:100:609–615.
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QT interval (ms)
pointes is more likely to occur where there is coexisting bradycardia. The dysrhythmogenic risk for drug-induced QT prolongation is accurately predicted by the ‘QT nomogram’, which plots QT versus heart rate (see Figure 2.20.4), and is more reliable than derived calculations such as the QTc. 6 Check for evidence of increased cardiac ectopy or automaticity. 7 Check for evidence of hyperkalaemia. 8 Check for evidence of myocardial ischaemia. References
Boehnert MT, Lovejoy FH. Value of the QRS duration verus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. New England Journal of Medicine 1985; 313:474–479. Chan A, Isbister GK, Kirkpatrick CMJ et al. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. Quarterly Journal of Medicine 2007; 100:609–615. Holstege CP, Eldridge DL, Rowden AK. ECG manifestations: the poisoned patient. Emergency Medicine Clinics of North America 2006; 24(1):159–177. Liebelt EL, Francis D, Woolf AD. ECG lead AVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Annals of Emergency Medicine 1995; 26:195–201. Niemann JT, Bessen HA, Rothstein RJ et al. Electrocardiographic criteria for tricyclic antidepressant cardiotoxicity. American Journal of Cardiology 1986; 57:1154–1159. Wolfe TR, Caravati EM, Rollins DE. Terminal 40-ms frontal plane QRS axis as a marker for tricyclic antidepressant overdose. Annals of Emergency Medicine 1989; 18:348–351.
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1 Absorption – delayed gastric emptying and intestinal transit time
slow drug absorption and may prolong the period where decontamination is of potential benefit 2 Distribution – increased blood volume (45–50%) increases volume of distribution and potentially decreases plasma levels; dilution of plasma proteins increases free drug levels 3 Elimination – hepatic enzyme systems are altered by circulating hormones; renal blood flow and glomerular filtration rate increase. Most drugs cross the placenta by diffusion and maternal blood levels are the most significant determinant of fetal exposure. Maternal blood levels are usually greater than those of the fetus, although for some agents they are the same and for others fetal levels exceed maternal levels (e.g. valproic acid and diazepam). On a practical level, acute management of overdose in the pregnant patient rarely differs from that of the non-pregnant patient. In particular, paracetamol and iron overdose, which are relatively common in this group, are managed along standard lines. Excellence in supportive care of the poisoned mother ensures the best physiological conditions to minimise fetal compromise. Early detection and correction of hypoxia, hypotension, hypoglycaemia and seizures in the mother ensure the best outcome for the fetus. Fetal monitoring may be useful in detecting fetal compromise and the response to treatment. Greater circulating volumes, increased respiratory rate and physiological resting tachycardia in the pregnant patient disguise hypovolaemia and respiratory compromise until later stages. Oral activated charcoal and whole bowel irrigation do not pose any special risks to pregnant patients and these forms of decontamination are implemented whenever indicated as for non-pregnant patients. Poisoning with a limited number of agents poses a potentially greater risk to the fetus than the mother and the threshold for treatment is lowered. These include:
• •
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Management decisions regarding poisoning or envenoming in the pregnant or lactating patient take into consideration the risks to the fetus or infant of the poisoning or its treatment. Pregnancy-induced physiological changes affect drug pharmacokinetics and pharmacodynamics in the following ways:
SPECIFIC CONSIDERATIONS
2.21 POISONING DURING PREGNANCY AND LACTATION
SPECIFIC CONSIDERATIONS
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Lead Salicylates.
Consideration of the need to emergently deliver near-term infants in poisoned mothers is a complicated issue that should be managed with toxicology and obstetric expertise. In general, if the fetus survives a maternal intentional ingestion, the risk of teratogenicity is low. The teratogenic risk is theoretically greater when the exposure occurs during the first trimester. It is important that the pregnant patient be counselled regarding these risks once she has recovered. Assistance in providing such advice can be obtained by contacting the drug information services at tertiary women’s hospitals. Australian drug risk classifications for pregnancy are available for all therapeutic agents. Paracetamol overdose treated with N-acetylcysteine does not appear to be associated with fetal abnormality even when the exposure occurs during the first trimester. The decision to continue breastfeeding during acute poisoning involves a risk–benefit analysis. Most drugs are excreted in breast milk. The percentage of maternal dose likely to be received by an infant is very low (5
>87
>400
>0.40
Coma, respiratory depression, hypotension, except in patients with marked tolerance
Note: To convert SI units to mg/dL, multiply by 4.61. To convert mg/dL to SI units, multiply by 0.22.
Improvement in conscious state is usually seen within 2–4 hours, but 6–12 hours may elapse before patients are ambulant. INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serum, blood and breath alcohol levels. • Serum ethanol levels assist risk assessment in patients with CNS depression. However, elevated serum ethanol concentrations cannot be assumed to be the sole contributor to CNS depression and an appropriate evaluation for other causes is required. • Serum ethanol concentration is not the same as whole blood ethanol level, which defines legal driving limits. Whole blood concentrations are approximately 10% lower than corresponding serum concentrations. • Breath ethanol estimation provides a convenient bedside estimation of blood ethanol concentration but the result is influenced by minute ventilation.
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SI units (mmol/L)
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Ethanol dose (g/kg)
SPECIFIC TOXINS
MANAGEMENT
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Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines as outlined in Chapter 1.2: Resuscitation. • Basic resuscitative measures ensure the survival of the vast majority of patients. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Give thiamine 200 mg PO or IV tds to patients with potential thiamine deficiency. • Close clinical and physiological monitoring is indicated. • Monitor for urinary retention and place an indwelling urinary catheter as required. Decontamination • Activated charcoal does not bind ethanol and is not indicated. Enhanced elimination • Elimination of ethanol is enhanced by haemodialysis. However, as a good outcome is ensured with thorough supportive care, this intervention is not routinely indicated. Antidotes • None available.
DISPOSITION AND FOLLOW-UP
•
Patients with mild CNS depression are managed supportively in a ward environment. When the patient is cooperative, clinically well, ambulant, passing urine, eating and drinking, discharge may occur. • Patients with significant CNS depression require intubation and admission to an intensive care unit. • Where appropriate, patients are counselled regarding ethanol abuse prior to discharge, as discussed in Chapter 2.12: Alcohol use disorder.
HANDY TIPS
•
A serum ethanol concentration confirms the diagnosis of ethanol intoxication but does not exclude other causes of CNS depression (e.g. co-ingestion, trauma, metabolic disorder). • Anticipate alcohol withdrawal during the observation period in patients with alcohol dependence.
PITFALLS
• • •
Failure to regard ethanol intoxication as potentially life threatening Failure to detect and manage coexisting intoxications or other medical conditions in the ethanol intoxicated patient Discharge of ethanol intoxicated patients before they are competent to make decisions about their own welfare and ensure their own safety
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Presentations
Ethanol is found in varying concentrations in a large number of beverages, and domestic and commercial products: Beers: 2.8–12.0% Wines: 9–14% Spirits: 35–50% Methylated spirits: 95% Mouth wash, food extracts and flavourings (e.g. vanilla extract 35% ethanol), cough and cold syrups, perfumes and cosmetics.
3.2 ALCOHOL: ETHYLENE GLYCOL Ethylene glycol (EG) is a toxic alcohol. Deliberate self-poisoning is usually lethal without timely intervention. RISK ASSESSMENT
• • • • • •
Ingestion of >1 mL/kg (1 g/kg) is potentially lethal. All deliberate self-poisonings are assumed to be potentially lethal. Unintentional ingestion of less than a mouthful is benign and does not require hospital evaluation unless symptoms develop. Co-ingestion of ethanol complicates risk assessment (see Investigations below). Dermal and inhalation exposure does not lead to EG intoxication. Children: minor ingestions such as a taste or lick do not require hospital evaluation unless symptoms develop.
Toxic mechanism
Ethylene glycol causes CNS effects similar to those of ethanol. The more important toxic effects are due to metabolites rather than the parent compound. A severe anion gap metabolic acidosis develops secondary to accumulation of glycolic acid and lactate (increased NADH and decreased conversion of lactate to pyruvate). Calcium oxalate crystals form in tissues, including renal tubules, myocardium, muscles and brain. Hypocalcaemia follows. Acute oliguric renal failure occurs secondary to the nephrotoxic effects of both glycolic acid and calcium oxalate.
Toxicokinetics
Ethylene glycol is rapidly absorbed following ingestion. Peak concentrations occur within 1–2 hours. It is distributed across the total body water with rapid CNS penetration. Ethylene glycol is metabolised sequentially by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) to glycoaldehyde and glycolic acid, which in turn is converted to glyoxylic acid and oxalic acid (see Appendix 4: Alcohol pathways). In the absence of ADH inhibition (ethanol or fomepizole) the elimination half-life of EG is 3–9 hours. Ethanol in a serum concentration of 11–22 mmol/L (50–100 mg/dL) competitively inhibits ADH preventing metabolism of EG to glycoaldehyde. Elimination half-life increases to 14–17 hours, as EG has to be eliminated exclusively by the kidney.
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Baselt RC. Disposition of toxic drugs and chemicals in man. 5th edn. Foster City, California: Chemical Toxicology Institute; 2000. Lieber CS. Medical disorders of alcoholism. New England Journal of Medicine 1995; 333(16):1058–1065. O’Connor PG, Schottenfeld RS. Patients with alcohol problems. New England Journal of Medicine 1998; 338(9):592–602. Tjipto AC, Taylor DMcD, Liew H. Alcohol use among young adults presenting to the emergency department. Emergency Medicine Australasia 2006; 18(2):125–130.
SPECIFIC TOXINS
References
CLINICAL FEATURES
• •
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•
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• •
The clinical course of EG intoxication is often described as occurring in three stages (CNS, cardiopulmonary and renal), but these are artificial descriptions of a rapid clinical course. Initial clinical features develop within the first 1–2 hours and are similar to those of ethanol intoxication: — Euphoria, nystagmus, drowsiness, nausea and vomiting. Progressively severe features develop over the subsequent 4–12 hours: — Dyspnoea, tachypnoea, tachycardia, hypertension and decreased conscious level progressing to shock, coma, seizures and death. Flank pain and oliguria indicate acute renal failure. Late cranial neuropathies (involving cranial nerves II, V, VII, VIII, IX, X and XII) are described up to 5–20 days later.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations • EUC (including chloride), serum lactate, serum osmolality, arterial blood gases and calcium, magnesium and phosphate levels — Elevated osmolar gap, anion gap acidosis and hyperlactataemia are surrogate markers of intoxication. — Venous bicarbonate concentration is a useful surrogate marker of intoxication in the asymptomatic patient if ABGs are not available. — Anion gap acidosis with elevated lactate (± elevated osmolar gap), associated with hypocalcaemia and rising creatinine, is pathognomonic of EG intoxication. — An elevated serum lactate level must be interpreted with care as some laboratory assays do not differentiate between lactate and glycolate. — See Chapter 2.18: Osmolar gap and Chapter 2.19: Acid– base disorders for discussion of interpreting acid–base disturbances, anion and osmolar gaps. • Breath or serum ethanol level — Required to determine whether there has been co-ingestion of ethanol, or to titrate ethanol treatment. • Serum EG level — Not readily available at most locations in a clinically useful timeframe. Where available, it provides definitive confirmation of EG intoxication. • Urine microscopy — Presence of calcium oxalate crystals in the urine is pathognomonic of ethylene glycol intoxication but their absence does not exclude the diagnosis.
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation.
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Decontamination • Gastrointestinal decontamination is not indicated. Enhanced elimination • Haemodialysis is the definitive management of EG intoxication. During haemodialysis, the elimination half-life of EG is reduced to 2.5–3.5 hours, depending on flow rates. • Lactate-free dialysates with added bicarbonate may assist correction of acidaemia. • Indications for haemodialysis: — History of large EG ingestion with osmolar gap >10 — Acidaemia with pH 8 mmol/L (50 mg/dL) if available. • End points for haemodialysis: — Correction of acidosis — Osmolar gap 0.25 mL/kg (2.5 mL in a 10-kg toddler) can theoretically lead to development of toxicity requiring specific management.
Toxic mechanism
Production and accumulation of formic acid produces a severe anion gap acidosis and direct cellular toxicity due to inhibition of cytochrome oxidase. Retinal injury and oedema leads to blindness. In the brain, subcortical white matter haemorrhages and putamenal oedema classically occur. Late hyperlactataemia occurs due to inhibition of cellular oxidative metabolism.
Toxicokinetics
Methanol is rapidly absorbed after ingestion with peak levels occurring within 30–60 minutes. Dermal and inhalational absorption occur, but reports of intoxication are rare. It is rapidly distributed across the total body water with a volume of distribution of 0.7 L/kg. Methanol is metabolised in the liver by alcohol dehydrogenase (ADH) to formaldehyde, which in turn is metabolised by aldehyde dehydrogenase (ALDH) to formic acid (see Appendix 4: Alcohol pathways). The elimination half-life is 24 hours. Ethanol in a serum concentration of 22 mmol/L (100 mg/dL; 0.1%) competitively inhibits ADH so that methanol cannot be metabolised to formaldehyde. Methanol elimination half-life increases to 48 hours, as methanol is eliminated exclusively by the kidney and pulmonary routes. CLINICAL FEATURES
•
Mild CNS depression similar to that of ethanol intoxication is evident within 1 hour of ingestion. Nausea, vomiting and abdominal pain may occur. • Following a latent period of 12–24 hours, symptoms of headache, dizziness, vertigo, dyspnoea, blurred vision and photophobia develop. • Features of severe intoxication include tachypnoea, drowsiness and blindness.
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• • • • •
SPECIFIC TOXINS
RISK ASSESSMENT
•
Progressive obtundation leading to coma and seizures heralds the onset of cerebral oedema. Papilloedema is characteristic with progressive demyelination and up to one-third of patients suffer irreversible visual complications. • Those who recover from serious CNS toxicity frequently display extrapyramidal movement disorders. INVESTIGATIONS
SPECIFIC TOXINS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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Specific investigations • EUC (including chloride), serum lactate, serum osmolality and arterial or venous blood gases — Anion gap acidosis, hyperlactataemia and elevated osmolar gap are surrogate markers of intoxication. — Venous bicarbonate concentration is a useful surrogate marker of intoxication in the asymptomatic patient if ABGs are not available. — See Chapter 2.18: Osmolar gap and Chapter 2.19: Acid– base disorders for discussion of interpreting acid–base disturbances, anion and osmolar gaps. • Breath or serum ethanol level — Required to determine whether there has been co-ingestion of ethanol, or to titrate ethanol treatment. • Serum methanol levels — Not usually readily available in a clinically useful timeframe. • Radiology — Brain CT scan demonstrates characteristic ischaemic or haemorrhagic injury to the basal ganglia in patients with permanent neurological sequelae. MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Patients with severe methanol intoxication are acidaemic with a degree of respiratory compensation: — Intubation without maintaining hyperventilation exacerbates acidaemia and may result in an acute decompensation, or even death — Maintain hyperventilation and consider bolus IV sodium bicarbonate 1–2 mmol/kg to prevent worsening of acidaemia pending haemodialysis — Systemic acidosis enhances formic acid inhibition of cytochrome oxidase. If pH 0.1 mg/kg of brodifacoum will cause anticoagulation but this equates to 2 g/kg of 0.005% bait or 3 × 50-g pellet packs in a 75-kg adult. • Anticoagulation is usually associated with repeated ingestion. In this scenario, severe, prolonged (weeks to months) anticoagulation requiring massive doses of vitamin K is anticipated.
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Children: it is estimated that a young child needs to ingest >30 g of a 0.005% preparation as a single dose to cause significant anticoagulation. This has never been reported.
Toxic mechanism
These agents inhibit hepatic vitamin K-dependent production of clotting factors II, VII, IX and X in the same way as warfarin. Several mechanisms confer increased potency and prolonged duration of action: greater affinity for vitamin K1-2,3-epoxide reductase, disruption of vitamin K cycle at several sites and hepatic accumulation. These agents have prolonged elimination half-lives.
CLINICAL FEATURES
• • •
Patients are usually asymptomatic. Severe coagulopathy manifests as bruising, petechial or purpural rashes, gingival bleeding, epistaxis or haematuria. Following acute single ingestions, coagulopathy may not be evident for 12 hours, and is frequently delayed 24–48 hours. Peak effects occur at 72–96 hours.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • INR — In patients who are not anticoagulated, INR will be normal during the first 6–12 hours after deliberate overdose. Following massive overdose, perform serial INRs every 12 hours for 48 hours to rule out toxicity. Vitamin K must be withheld until anticoagulation is documented. Normal INR at 48 hours excludes toxic ingestion. — Following repeated ingestion over several days, INR is abnormal at presentation. Vitamin K therapy may commence immediately. Outpatient INR estimations are required to monitor therapy. • Superwarfarin levels — Useful to confirm diagnosis in cases where paediatric non-accidental injury or occult poisoning is suspected. — Useful in determining when it is safe to withdraw vitamin K therapy.
MANAGEMENT
Resuscitation, supportive care and monitoring • In patients with evidence of haemorrhage, attention to airway, breathing and circulation are paramount. These priorities can usually be managed along conventional lines, as outlined in Chapter 1.2: Resuscitation.
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These agents are completely absorbed following oral administration. They are highly lipid soluble and have large volumes of distribution. They are concentrated in the liver. Superwarfarins undergo hepatic metabolism and enterohepatic recirculation and have very prolonged elimination phases of weeks to months.
SPECIFIC TOXINS
Toxicokinetics
•
If there is active uncontrolled haemorrhage, administer fresh frozen plasma (10–15 mL/kg), Prothrombinex-HT (25–50 IU/kg) and vitamin K 10 mg IV. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring.
SPECIFIC TOXINS
Decontamination • Activated charcoal is not indicated following accidental ingestions. • Following massive single acute deliberate self-poisoning, administer 50 g activated charcoal to cooperative patients who are able to drink it themselves and present within 12 hours of ingestion. Enhanced elimination • Not clinically useful. Antidotes • Vitamin K (phytomenadione) is indicated where there is documented anticoagulation from repeated deliberate ingestion or following acute deliberate self-poisoning. Prophylactic vitamin K is contraindicated. In patients with proven anticoagulation, vitamin K is titrated to achieve safe INR levels (4 L/kg) and are metabolised in the liver. Half-lives are variable and range between 6 and 18 hours.
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CLINICAL FEATURES
• • • •
CNS depression. Anticholinergic syndrome including delirium (see Chapter 2.9: Anticholinergic syndrome). Seizures, hyperthermia and rhabdomyolysis are rare. Significant hypotension requiring inotropic support and cardiac conduction abnormalities secondary to fast sodium channel blockade (e.g. diphenhydramine) occur rarely after massive overdose.
Specific investigations as indicated • Serial 12-lead ECGs — An ECG should be performed on presentation and at 6 hours post-ingestion to detect QRS or QT interval prolongation. Further serial ECGs are only necessary if an abnormality is noted. MANAGEMENT
Resuscitation, supportive care and monitoring • Resuscitation is rarely required but the patient should be monitored initially and for 6 hours if symptomatic because of the risk of QRS or QT prolongation. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Manage anticholinergic delirium as outlined in Chapter 2.9: Anticholinergic syndrome. • Manage seizures as outlined in Chapter 2.6: Seizures. • Hypotension usually responds to fluid administration. If not, an α1-adrenergic agonist (noradrenaline) is second-line therapy. • In the rare event of QRS prolongation complicated by ventricular dysrhythmias, intubate, hyperventilate and give IV bolus sodium bicarbonate, as outlined in Chapter 4.25: Sodium bicarbonate.
Decontamination • Activated charcoal is not routinely indicated because the onset of sedation occurs in the first few hours and simple supportive care ensures a good outcome. Enhanced elimination • Not clinically useful. Antidotes • Physostigmine administration is considered in patients with severe anticholinergic delirium not controlled with benzodiazepines (see Chapter 4.21: Physostigmine). DISPOSITION AND FOLLOW-UP
•
Patients who remain asymptomatic and have a normal 12-lead ECG at 6 hours may be discharged. Discharge should not occur at night.
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
SPECIFIC TOXINS
INVESTIGATIONS
•
Patients with mild sedation or anticholinergic features but a normal 12-lead ECG at 6 hours may be managed supportively in a ward environment. They are fit for medical discharge when well, ambulant, passing urine, eating and drinking. • Patients with significant agitation or delirium, and those requiring intubation, require admission to a high-dependency or intensive care unit. • Ongoing cardiac monitoring is reserved for patients with abnormal ECGs, until changes resolve. HANDY TIP
SPECIFIC TOXINS
•
PITFALLS
• •
Antihistamines may be abused for their anticholinergic properties.
Failure to recognise anticholinergic delirium because of concomitant sedative effects. Failure to detect and relieve urinary retention. This exacerbates agitation and prevents control with benzodiazepine sedation.
CONTROVERSY
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Role of physostigmine in the management of antihistamineinduced anticholinergic delirium.
Presentations
Alkylamines Brompheniramine 2 mg/5 mL in decongestant elixirs Chlorpheniramine 0.5–6 mg/tablet or 5 mL of elixir in cold and flu formulations Dexchlorpheniramine maleate 2 mg modified-release tablets (20, 40) Dexchlorpheniramine maleate 6 mg modified-release tablets (20, 40) Dexchlorpheniramine 2.5 mg/1 mL syrup (100 mL) Ethanolamines Dimenhydrinate 50 mg/hyoscine hydrobromide 0.2 mg/caffeine 20 mg tablets (10) Diphenhydramine hydrochloride 50 mg capsules (10) Diphenhydramine hydrochloride 50 mg tablets (10) Diphenhydramine 2.5 mg/mL in cough syrup formulations Doxylamine succinate 25 mg capsules (20) Doxylamine succinate 6.25 mg per tablet in cold and flu preparations Doxylamine 5–6.25 mg per tablet with paracetamol–codeine combination analgesics Phenothiazines Pheniramine maleate 43.5 mg tablets (10, 50) Promethazine hydrochloride 10 mg tablets (50) Promethazine hydrochloride 25 mg tablets (50) Promethazine hydrochloride 1 mg/1 mL elixir (100 mL) Promethazine hydrochloride 25 mg/1 mL ampoules Promethazine hydrochloride 50 mg/2 mL ampoules Promethazine hydrochloride in cold and flu formulations and analgesics (e.g. Pain Stop) Trimeprazine 7.5 mg/5 mL syrup (100 mL) Trimeprazine 6 mg/1 mL syrup (100 mL) Others Cyproheptadine tablets 4 mg (50, 100)
References
Burns MJ, Linden CH, Graudins A et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Annals of Emergency Medicine 2000; 35(4):374–381.
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Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: successful treatment with sodium bicarbonate. Annals of Emergency Medicine 1992; 21:318–321.
Arsenic is a metal found in elemental, inorganic and organic forms. The inorganic and organic forms exist as trivalent (arsenite) and pentavalent (arsenate) forms. Most commercially available arsenic-containing products are produced from arsenic trioxide, one of the more toxic trivalent inorganic compounds. Acute ingestion, usually in the context of deliberate self-poisoning, is followed by severe gastroenteritis with a characteristic sequential life-threatening multiple organ failure. Subacute exposures occur from industrial accidents, food contamination and ingestion of arsenic-containing herbal medicines. Chronic intoxication usually follows long-term drinking of contaminated artesian water. The organic arsenoids found in seafood are non-toxic. RISK ASSESSMENT
SPECIFIC TOXINS
3.14 ARSENIC
•
•
Children: any ingestion of arsenic insecticide should be regarded as potentially lethal.
Toxic mechanism
Arsenic binds to numerous cellular enzymes, interferes with cellular respiration and inhibits DNA replication and repair. It binds to sulfhydryl (SH−) groups and substitutes for phosphate in ATP. It produces reactive oxygen intermediates causing lipid peroxidation.
Toxicokinetics
Absorption occurs via dermal, respiratory and gastrointestinal routes. Elimination half-life is 3–5 days following acute ingestion. Arsenic initially distributes to kidneys and liver. Following chronic ingestion, arsenic is distributed to liver, kidneys, lungs, nervous system, spleen, hair and nails. Arsenic undergoes hepatic methylation and the metabolites are excreted in the urine. A small amount of inorganic arsenic is excreted in the urine unchanged. The organic arsenoids found in seafood are excreted unchanged. CLINICAL FEATURES
Acute toxicity • Following large ingestions there is rapid onset of severe watery diarrhoea (‘choleroid’ or ‘rice water diarrhoea’), vomiting and abdominal pain. • Gastrointestinal haemorrhage may occur. • Encephalopathy, seizures and cardiovascular collapse develop within hours. • Hypersalivation is characteristic, as is a garlic odour.
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Acute or subacute ingestion of inorganic arsenic leads to a dose-dependent sequential pattern of multiple organ failure: — Ingestion of >1 mg/kg is potentially lethal — Ingestion of 10 years) drinking of contaminated artesian water.
SPECIFIC TOXINS
• • • • •
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Acute cardiomyopathy, ECG changes (prolonged QT) and cardiac dysrhythmias are described. Acute adult respiratory distress syndrome, renal failure and hepatic injury follow. Bone marrow depression develops within 24–72 hours in survivors, reaching a nadir in 2–3 weeks. Alopecia occurs in survivors of the initial phase. Peripheral neuropathy may develop with a delay of 1–3 weeks. It is an ascending predominantly motor neuropathy, may mimic Guillain-Barré syndrome and may progress to respiratory failure.
Subacute toxicity • Initially manifests with gastrointestinal symptoms, leucopenia, deranged liver function and haematuria. • Peripheral neuropathy develops after several weeks. Chronic toxicity • Insidious onset over years of a multi-system disorder manifested by constitutional symptoms, cutaneous lesions (hyperkeratosis of palms and soles, hyperpigmentation), nail changes (Mees’ lines), painful peripheral neuropathy (glove-stocking type distribution), and malignancies of the skin or bladder. INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Spot urinary arsenic (normal 1000 microgram/L (13 500 nmol/L). • 24-hour urinary arsenic excretion (normal 200 microgram/L or 2700 nmol/L). • Succimer is the agent of choice where oral administration is available (see Chapter 4.28: Succimer). • Dimercaprol (British Anti-Lewisite (BAL)) should be administered by IM injection where oral administration is not feasible because of GI symptoms (see Chapter 4.7: Dimercaprol). • 2,3-dimercaptopropane-1-sulfonic acid (DMPS) is not readily available in Australasia but is suitable for IV or PO administration and is preferred to dimercaprol for parenteral administration if available. DISPOSITION AND FOLLOW-UP
• •
Chronic intoxication can be managed on an outpatient basis. Patients who are clinically well without gastrointestinal symptoms at 12 hours following acute ingestion of arsenic are not poisoned and may be discharged. • Patients in whom clinical features develop following acute ingestion of inorganic arsenic require admission for observation, aggressive supportive care and chelation.
HANDY TIPS
• •
Chelation therapy of acute arsenic intoxication is not delayed pending confirmatory levels. Discovery of elevated arsenic levels in an asymptomatic patient undergoing a ‘heavy metal screen’ usually reflects increased excretion of non-toxic organic arsenic compounds contained in seafood. • Patients should be instructed to avoid eating seafood or seaweed for 3–4 days prior to 24-hour urinary arsenic level. • Cutting or burning pine impregnated with copper chrome arsenate preservative may cause symptoms of mucosal irritation from
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Decontamination • Activated charcoal does not bind arsenic and is not indicated. • Cooperative patients who present following deliberate selfpoisoning with arsenic trioxide confirmed on abdominal X-ray should undergo whole bowel irrigation with polyethylene glycol (see Chapter 1.6: Gastrointestinal decontamination). Therapy may be guided by monitoring arsenic transit on serial abdominal X-rays.
SPECIFIC TOXINS
The immediate life-threat in early acute arsenic poisoning is hypovolaemia and shock secondary to profound gastrointestinal fluid losses. • General supportive care measures and meticulous fluid resuscitation are indicated, as outlined in Chapter 1.4: Supportive care and monitoring.
smoke or sawdust but does not cause arsenic poisoning. Elevated arsenic levels are associated with long-term occupational or domestic exposure to this compound. PITFALL
•
Ordering ‘heavy metal screens’ on patients with non-specific symptoms without exposure assessment – these are rarely clinically useful.
CONTROVERSIES
SPECIFIC TOXINS
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There is no evidence to support any treatment intervention for chronic arsenic poisoning, although vitamin and mineral supplements and antioxidant therapy have been recommended. Prevention of exposure is the priority. • Analysis of hair for metals is frequently subject to artefacts and is not recommended. • Relative efficacy of various chelating agents.
Presentations
Inorganic Found naturally in ground water in some regions. Used in the production of semiconductors, glass, pesticides and wood preservatives. Used medically to induce remission in acute promyleocytic leukaemia. Found in many traditional and herbal remedies. Organic Found predominantly in fish and shellfish as non-toxic arsenobetaine and arsenocholine.
References
Graeme KA, Pollack CK. Heavy metal toxicity: arsenic and mercury. Journal of Emergency Medicine 1998; 16(1):45–46. Ratnaike RN. Acute and chronic arsenic toxicity. Postgraduate Medical Journal 2003; 79:391–396. Xu Y, Wang Y, Zheng Q. Clinical manifestations and arsenic methylation after a rare subacute arsenic poisoning accident. Toxicological Sciences 2008; 103(2): 278–284.
3.15 BACLOFEN Large overdoses are characterised by rapid onset of delirium, respiratory depression, coma and seizures and are potentially lethal without timely institution of good supportive care. RISK ASSESSMENT
•
Ingestions >200 mg in adults are expected to cause significant CNS effects including delirium, respiratory depression, coma and seizures. • Ingestions of smaller doses cause relatively mild symptoms. • Good supportive care should result in a favourable outcome in all cases.
Toxic mechanism
Baclofen is a synthetic derivative of GABA. At therapeutic doses, it acts principally on spinal GABAB receptors inhibiting the release of excitatory amino acids (glutamate and
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aspartate). In overdose, brain GABA receptors are stimulated thereby inhibiting excitatory neurotransmitters in the CNS and leading to sedation or coma. Baclofen also mediates pre-and postsynaptic inhibition, causing seizures in overdose, and withdrawal syndromes.
Toxicokinetics
Baclofen is rapidly and completely absorbed following oral administration. Peak serum concentrations are achieved within 2 hours. It readily penetrates the blood–brain barrier. Its volume of distribution is 0.7 L/kg and it is primarily excreted unchanged in the urine. About 15% is metabolised by the liver. The mean elimination half-life is 3.5 hours.
Clinical features of intoxication develop within 2 hours of overdose and include: — Central nervous system – Delirium – Respiratory depression – Profound and prolonged coma – Seizures — Cardiovascular – Sinus bradycardia or tachycardia – Hypertension or hypotension – 1st degree heart block and QT prolongation (rare). • Delirium is most evident just prior to the onset of coma or upon awakening. • Following large ingestions, coma may be profound. The patient may appear brain dead with fixed dilated pupils, hypotonia and areflexia (including absent brainstem reflexes). • The duration of coma is usually between 24 and 48 hours.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
MANAGEMENT
Resuscitation, supportive care and monitoring • Baclofen poisoning is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Respiratory depression and coma necessitate advanced airway management with early intubation and ventilation. • Level of consciousness should be closely monitored during the first few hours. • Seizures, should they occur, are managed with titrated doses of IV diazepam. • Hypotension usually responds to fluid boluses. Inotropes are not usually required. • Tachycardia, bradycardia and hypertension are rarely severe enough to require specific treatment. Decontamination • Activated charcoal is not indicated unless the airway is first protected by endotracheal intubation.
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SPECIFIC TOXINS
CLINICAL FEATURES
Enhanced elimination • Not clinically useful. Antidotes • None available. DISPOSITION AND FOLLOW-UP
SPECIFIC TOXINS
• •
Following baclofen overdose, all patients are closely observed for at least 4 hours. Patients who are asymptomatic at 4 hours following ingestion may be discharged. Discharge should never occur at night. • Those manifesting minor CNS features such as delirium require medical admission for ongoing supportive care until all clinical features resolve. • Patients with significant CNS depression require intubation and are admitted to an intensive care unit.
HANDY TIPS
•
Baclofen overdose should be considered in any patient with access to this agent who presents with coma. It is not detected on routine drug screening. • Baclofen is sometimes administered by continuous intrathecal infusion via a reservoir and pump system. Pump malfunctions resulting in even small intrathecal boluses can produce profound coma. • Baclofen withdrawal syndrome occurs between 24 and 48 hours post cessation of baclofen and is manifested by seizures, hallucinations, dyskinesia and visual disturbances.
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PITFALL
•
Failure to reinstitute therapeutic baclofen following recovery from an overdose, thereby precipitating a withdrawal syndrome which may be mistaken for ongoing intoxication.
CONTROVERSY
•
Management of intrathecal overdose is controversial. Current recommendations, in addition to standard resuscitation measures, include: — Emptying reservoir — Lumbar puncture and removal of 30–50 mL of CSF.
Presentations Baclofen Baclofen Baclofen Baclofen
10 mg tablets (100) 25 mg tablets (100) 0.05 mg/mL solution for intrathecal injection (1 mL, 20 mL) 2 mg/mL solution for intrathecal injection (5 mL)
Reference
Leung NY, Whyte IM, Isbister GK. Baclofen overdose: defining the spectrum of toxicity. Emergency Medicine Australasia 2006; 18:77–82.
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3.16 BARBITURATES Pentobarbitone, Phenobarbitone, Primidone, Thiopentone Barbiturate overdose is an uncommon presentation, but can cause profound and prolonged coma mimicking brain death. It is potentially lethal but recognition of the diagnosis and good supportive care will assure a favourable outcome. RISK ASSESSMENT
•
Children: most barbiturate toxicity in children occurs in the context of therapeutic administration. Acute ingestion of >8 mg/kg of phenobarbitone or >40 mg/kg of primidone would be expected to produce neurological symptoms and requires medical assessment.
Toxic mechanism
Barbiturates cause CNS depression by enhancing gamma-aminobutyric acid (GABA) mediated inhibitory neurotransmission. They bind to the GABAA receptor complex and increase the duration of chloride channel opening (in contradistinction to benzodiazepines, which increase the frequency of opening). They also antagonise the effect of the excitatory neurotransmitter glutamate by causing receptor blockade in the CNS. Inhibition of medullary cardiorespiratory centres and hypothalamic autonomic nuclei results in hypotension, hypothermia and respiratory arrest.
Toxicokinetics
All barbiturates are well absorbed from the gastrointestinal tract but only some agents are clinically effective after oral administration. Because of their rapid redistribution from the CNS and large volumes of distribution, the highly lipid soluble ‘short-acting’ barbiturates (thiopentone and pentobarbitone) are only useful medically if given by intravenous administration. In contrast, the less lipid-soluble ‘long-acting’ barbiturates such as phenobarbitone and primidone are distributed more slowly to the CNS, have slower redistribution from the CNS, slower onset of clinical effect and smaller volumes of distribution, of around 0.9 L/kg. For these reasons, they are suitable for oral administration. All barbiturates are metabolised by saturable hepatic microsomal pathways. Primidone is first metabolised to two active metabolites, phenobarbitone and phenylethylmalonamide (PEMA). Phenobarbitone undergoes both enterohepatic and enteroenteric recirculation. Approximately 25–50% of an ingested dose of phenobarbitone is excreted unchanged in the urine. The elimination half-life of phenobarbitone is long with considerable inter-individual variation (35–140 hours) and, as a result of saturable kinetics, may be prolonged even further after overdose. CLINICAL FEATURES
•
Barbiturate toxicity may develop with therapeutic administration of phenobarbitone or primidone. Symptoms are mild and neurological in nature; they resolve with cessation of administration.
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Ingestion of >8 mg/kg of phenobarbitone is expected to produce toxic neurological symptoms in the non-tolerant individual. Multiples of this dose are expected to produce profound prolonged coma. • Self-administration of thiopentone or pentobarbitone (often by medical or veterinary professionals) by the intravenous route is likely to be lethal unless the mechanics of administration are such that the rapid onset of coma prevents administration of all of the intended dose.
SPECIFIC TOXINS
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Barbiturate overdose is characterised by profound, prolonged and potentially fatal depression of the central nervous and cardiovascular systems. • Onset of toxicity is within seconds to minutes of intravenous overdose of thiopentone or pentobarbitone or within 1–2 hours of ingestion of phenobarbitone or primidone. — Central nervous system – Ataxia, lethargy, slurred speech, drowsiness, vertigo and nystagmus are followed by coma, hypotonia, hypothermia and respiratory arrest at higher doses. – Profound coma with complete loss of neurological function can develop. Clinical features mimic brain death with absent pupillary responses, vestibulo-ocular reflexes and deep tendon reflexes. – Profound respiratory depression occurs, with CheyneStokes respiration progressing to apnoea. — Cardiovascular system – Tachycardia is frequently observed. – In very large ingestions, hypotension occurs as a result of depression of medullary vasomotor nuclei as well as peripheral vasodilation and direct myocardial depression. — Other – Hypothermia – Reduced bowel sounds – Skin bullae over pressure areas can occur (‘barbiturate blisters’) but are not specific for barbiturate toxicity. • The duration of coma from poisoning with the short-acting barbiturates (e.g. pentobarbitone) is not usually longer than 24–48 hours. In contrast, poisoning from long-acting barbiturates (e.g. phenobarbitone, primidone) may last days or weeks necessitating prolonged intensive care. INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serum barbiturate levels — Phenobarbitone assays are readily available in most locations. Other barbiturate assays can be obtained at specialised centres. — CNS depression correlates well with serum phenobarbitone (see Table 3.16.1). — Levels are useful to confirm ingestion and serial levels are essential in the management of the comatose patient with barbiturate poisoning. They allow monitoring of clinical progress and are used to guide the use of enhanced elimination techniques. — A phenobarbitone level of >100 mg/L (>430 micromol/L) prompts consideration of haemodialysis. — Serum levels are not usually helpful in the absence of coma.
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Clinical features
15–25 mg/L (65–108 micromol/L)
Usual therapeutic range
30–80 mg/L (130–345 micromol/L)
Increasing sedation
>80 mg/L (>345 micromol/L)
Coma requiring intubation
•
Other investigations may be required to exclude alternative causes of coma — Note: the electroencephalogram (EEG) in barbiturate coma may demonstrate profound suppression of activity to the point of mimicking brain death.
MANAGEMENT
Resuscitation, supportive care and monitoring • All patients are managed in an area equipped for cardiopulmonary monitoring and resuscitation. • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • The need for intubation is anticipated and performed early in the patient with a declining level of consciousness. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Activated charcoal 50 g is administered via a nasogastric tube to the unconscious patient only after the airway is secured by endotracheal intubation. Enhanced elimination • Barbiturate pharmacokinetics render them amenable to enhanced elimination techniques. The aim of instituting these interventions is to reduce duration of coma and length of ventilation in intensive care. • Techniques of enhanced elimination are only considered for poisoning by long-acting barbiturates (phenobarbitone, primidone) where very slow endogenous clearance rates can otherwise result in prolonged intensive care requirements. • Multiple-dose activated charcoal (MDAC) substantially increases the rate of elimination of phenobarbitone by interrupting enterohepatic and enteroenteric circulation (see Chapter 1.7: Enhanced elimination for details on performing this intervention). It is indicated in the intubated comatose patient as long as bowel sounds remain present. • Haemodialysis, haemoperfusion and haemodiafiltration efficiently remove phenobarbitone. These invasive interventions are indicated for the patient with markedly elevated levels (>100 mg/L,
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Level
SPECIFIC TOXINS
TABLE 3.16.1 Correlation of serum phenobarbitone levels and clinical features
>430 micromol/L) or where there are clinical manifestations of severe poisoning, in particular persistent hypotension despite inotropes and with evidence of end-organ dysfunction such as oliguria. These interventions may also be considered where levels are rising or have plateaued despite MDAC, or where continued MDAC is not feasible due to ileus. Antidotes • None available. DISPOSITION AND FOLLOW-UP
SPECIFIC TOXINS
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All children suspected of ingesting >8 mg/kg of phenobarbitone or >40 mg/kg of primidone must be referred to hospital for assessment and observation. They may be discharged home if they remain asymptomatic 6 hours post-ingestion. • Adult patients who deliberately self-poison with phenobarbitone or primidone should be observed in a closely monitored setting for at least 6 hours. If they do not develop neurological signs or symptoms during that time, further observation is not required. • Patients who develop clinical evidence of toxicity require admission for ongoing observation and serial barbiturate levels. Significant CNS depression prompts endotracheal intubation and intensive care admission.
HANDY TIPS
•
Consider barbiturate poisoning in the patient with profound coma of unknown origin and hypotonia. Have a high index of suspicion if the patient has a medical or veterinary background, or has a history of epilepsy. • A lower threshold for instituting haemoperfusion or haemodialysis is appropriate in elderly patients and patients with coexisting cardiac, respiratory or renal disease. • Hypotensive patients are often intolerant of intermittent high-flow dialysis so continuous modalities may be preferred, although at the expense of compromised clearance.
PITFALLS
•
Failure to consider the diagnosis of barbiturate toxicity. Along with carbamazepine and valproate poisoning, it is an unusual but eminently treatable cause of coma. • Excessive focus on methods of enhancing elimination at the expense of ensuring optimal supportive care measures are in place.
CONTROVERSIES
• •
Urinary alkalinisation has been shown to enhance elimination of phenobarbitone but it is inferior to MDAC and not recommended. Although MDAC effectively enhances phenobarbitone elimination, it has not been shown to reduce duration of coma or length of stay in intensive care. • There are no adequate clinical trials in support of haemodialysis or other enhanced elimination techniques for the treatment of barbiturate overdose. Recommendations are empiric and based on risk–benefit analysis.
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Presentations
Pentobarbitone sodium: available as a veterinary preparation (used to euthanase animals) Phenobarbitone 15 mg/5 mL elixir (100 mL, 500 mL) Phenobarbitone 30 mg tablets (200) Phenobarbitone sodium 200 mg/1 mL ampoules Primidone 250 mg tablets (100, 200) Thiopentone sodium 500 mg ampoules for reconstitution
Ebid A-HIM, Abdel-Rahman HM. Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose. Therapeutic Drug Monitoring 2001; 23(3):209–216. Frenia ML, Schauben JL, Wears RL et al. Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. Clinical Toxicology 1996; 34(2):169–175. Pond SM, Olson KR, Osteroloh JD et al. Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. Journal of the American Medical Association 1984; 251(23):3104–3108. Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning – a systematic review. Clinical Toxicology 2011; 49:2–12.
SPECIFIC TOXINS
References
3.17 BENZODIAZEPINES
Also covers the non-benzodiazepine sedative-hypnotics: Zolpidem, Zopiclone Benzodiazepines are involved in up to one-third of deliberate selfpoisonings. An excellent prognosis is expected with supportive care of CNS depression. Flumazenil is a useful diagnostic and therapeutic tool in carefully selected cases. RISK ASSESSMENT
• • • • • •
Isolated benzodiazepine overdose usually causes only mild sedation, irrespective of the dose ingested, and can be easily managed with simple supportive care. Alprazolam overdose is associated with a greater degree of CNS depression and is more likely to require intubation and ventilation. Zolpidem and zopiclone rarely cause severe CNS or respiratory depression when taken alone. Co-ingestion of other CNS depressants (e.g. alcohol, opioids, antidepressants) increases the risk of complications, prolonged length of stay and death. The elderly and patients with cardiorespiratory co-morbidities may suffer greater complications. Children: ingestion of one or two benzodiazepine tablets usually manifests as mild sedation and ataxia within 2 hours.
Toxic mechanism
Benzodiazepines act by enhancing gamma-aminobutyric acid (GABA) mediated neurotransmission. They bind to the GABAA receptor complex and increase the
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Alprazolam, Bromazepam, Clobazam, Clonazepam, Diazepam, Flunitrazepam, Midazolam, Nitrazepam, Oxazepam, Temazepam, Triazolam
frequency of chloride channel opening. Zolpidem and zopiclone are non-benzodiazepine sedative-hypnotics that also act at the GABAA receptor complex.
Toxicokinetics
Benzodiazepines are rapidly absorbed orally. Most are highly protein bound and have volumes of distribution that vary from 0.5 to 4 L/kg. Benzodiazepines undergo hepatic metabolism. Many have active metabolites. For example, diazepam is metabolised to N-desmethyldiazepam, oxazepam and temazepam, and alprazolam is metabolised to 1-and 4-hydroxyalprazolam. Duration of effect following overdose depends on CNS tolerance and redistribution, rather than rate of elimination. Clinical features of intoxication are poorly correlated to serum benzodiazepine levels.
SPECIFIC TOXINS
CLINICAL FEATURES
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Onset of symptoms occurs within 1–2 hours. Ataxia, lethargy, slurred speech and drowsiness are followed by decreased responsiveness. Profound coma is rare, except with alprazolam or in mixed ingestions. Apnoea is a complication of airway obstruction. • In very large ingestions hypothermia, bradycardia and hypotension may occur. Resolution of CNS depression usually occurs within 12 hours. More prolonged coma is common in the elderly.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities can usually be managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Basic resuscitative measures ensure the survival of the vast majority of patients. • Monitor for urinary retention and place an indwelling catheter as required. Decontamination • Activated charcoal is not indicated because the onset of sedation occurs in the first few hours and simple supportive care ensures a good outcome. Enhanced elimination • Not clinically useful. Antidotes • Flumazenil is a competitive benzodiazepine antagonist with a limited role in benzodiazepine overdose. Its indications include: — Management of airway and breathing when resources are not available to safely intubate and ventilate the patient — Diagnostic tool to avoid further investigation — Reversal of conscious sedation. • For further information on the indications, contraindications and administration see Chapter 4.9: Flumazenil.
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•
•
Profound coma, tachycardia or 12-lead ECG changes suggest a co-ingested agent and the need to revise the risk assessment. • Flumazenil may be life saving in selected patients when the airway and breathing cannot be controlled by other means.
PITFALL
•
Administration of flumazenil when contraindicated because of the risk of seizures due to co-ingestions or benzodiazepine dependence.
Presentations
Alprazolam 0.25 mg tablets (50) Alprazolam 0.5 mg tablets (50) Alprazolam 1 mg tablets (50) Alprazolam 2 mg tablets (50) Bromazepam 3 mg tablets (30, 60) Bromazepam 6 mg tablets (30, 60) Clobazam 10 mg tablets (50) Clonazepam 0.5 mg tablets (100) Clonazepam 2 mg tablets (100) Clonazepam 2.5 mg/1 mL liquid Clonazepam 1 mg/2 mL ampoules Diazepam 2 mg tablets (30, 50, 90) Diazepam 5 mg tablets (30, 50) Diazepam 1 mg/mL liquid (5, 10, 100 mL) Diazepam for injection 10 mg/2 mL ampoules Flunitrazepam 1 mg tablets (30) Lorazepam 1 mg tablets (50)
Lorazepam 2.5 mg tablets (50) Midazolam 5 mg/1 mL ampoules Midazolam 5 mg/5 mL ampoules Midazolam 15 mg/3 mL ampoules Midazolam 50 mg/10 mL ampoules Nitrazepam 5 mg tablets (25, 30, 50) Oxazepam 15 mg tablets (25, 50, 90) Oxazepam 30 mg tablets (25, 50) Temazepam 10 mg tablets (25, 50) Triazolam 0.125 mg tablets (50) Zolpidem 5 mg tablets (7, 14) Zolpidem 10 mg tablets (2, 7, 10, 14, 20) Zolpidem 6.25 mg controlled-release tablets (2, 14, 20) Zolpidem 12.5 mg controlled-release tablets (2, 14, 20) Zopiclone 7.5 mg tablets (10, 30)
References
Buckley NA, Dawson AH, Whyte IM. Relative toxicity of benzodiazepines in overdose. British Medical Journal 1995; 310:219–221. Garnier R, Guerault E, Muzard D et al. Acute zolpidem poisoning—analysis of 344 cases. Journal of Toxicology–Clinical Toxicology 1994; 32(4):391–394. Isbister GK, O’Regan L, Sibbritt D et al. Alprazolam is relatively more toxic than other benzodiazepines in overdose. British Journal of Clinical Pharmacology 2004; 58(1): 88–95.
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SPECIFIC TOXINS
Paediatric patients following accidental exposure may be observed at home. If significant ataxia or drowsiness occurs, referral to hospital for supportive care, usually overnight, is appropriate. • Patients with mild sedation are managed supportively in a ward environment. They may be discharged when clinically well. Discharge should not occur at night. • Patients with significant CNS depression requiring intubation or flumazenil infusion are admitted to a high-dependency or intensive care unit (rare).
3.18 BENZTROPINE Frequently prescribed to patients on antipsychotics to ameliorate dyskinaesias, this is a potent anticholinergic agent in overdose. Excessive doses of benztropine, like other anticholinergic agents, are sometimes consumed for recreational purposes. RISK ASSESSMENT
SPECIFIC TOXINS
• •
Toxicokinetics
There is little information on the pharmacokinetics of benztropine and even less on its toxicokinetics. It appears to be well absorbed following oral administration. The onset of therapeutic action is between 1 and 2 hours following oral administration. Metabolism is probably hepatic with metabolites excreted in the urine.
Toxic mechanism
A synthetic drug containing the active tropine component of atropine and the diphenylmethyl portion of diphenhydramine (antihistamine). It acts as an anticholinergic, antihistaminergic and dopamine reuptake inhibitor.
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Any overdose of this agent is likely to precipitate anticholinergic symptoms and require medical care. Anticholinergic syndrome can also occur with excessive therapeutic doses.
CLINICAL FEATURES
•
The clinical features are those of the anticholinergic syndrome (see Chapter 2.9: Anticholinergic syndrome) and include: delirium, mydriasis, blurred vision, sinus tachycardia, warm flushed dry skin, urinary retention and ileus. • The maximal effects are normally observed within 6 hours and may persist for a period from 12 hours to 5 days.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Other tests including EUC, CT head and lumbar puncture are indicated if necessary to exclude important alternative diagnoses such as intracranial infection.
MANAGEMENT
Resuscitation, supportive care and monitoring • Management is supportive and consists principally of sedation with benzodiazepines, intravenous fluids and insertion of an indwelling urinary catheter. • Control of delirium can be challenging. Physical restraints are sometimes necessary. • Once adequate sedation is attained, one-to-one nursing in a calm, closely monitored environment is essential to ensure patient safety. • For a more detailed description of the management of anticholinergic syndrome see Chapter 2.9: Anticholinergic syndrome.
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Decontamination • Activated charcoal may be useful if administered within 2 hours of ingestion. • It is of little value, not to mention technically challenging, once delirium is established. Enhanced elimination • Not clinically useful.
•
HANDY TIP
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PITFALL
•
Once initial control of delirium is attained, admission to a high-dependency area with one-to-one nursing in a calm, reassuring environment is essential. Staff should be aware that the delirium might persist for several days. Insert an indwelling urinary catheter as soon as possible. Urinary retention is almost universal in anticholinergic delirium and, if not relieved, will exacerbate the patient’s agitation. Failure to distinguish anticholinergic delirium from psychosis or antisocial personality disorder.
CONTROVERSY
•
The role of physostigmine: early use of this drug in severe benztropine-induced anticholinergic delirium is increasingly favoured.
Presentations
Benztropine mesylate 2 mg tablets (60) Benztropine mesylate 2 mg/2 mL ampoules
3.19 BETA-BLOCKERS Atenolol, Bisoprolol, Carvedilol, Esmolol, Metoprolol, Oxprenolol, Pindolol, Propranolol, Sotalol Isolated beta-blocker overdose, other than with propranolol or sotalol, usually results in little or no toxicity and does not require specific care. In contrast, propranolol or sotalol overdose may be life threatening. RISK ASSESSMENT
• •
Toxicity does not correlate well with ingested dose. The following factors increase risk of severe toxicity: — Ingestion of propanolol/sotalol — Underlying heart or lung disease
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SPECIFIC TOXINS
Antidote • Physostigmine is considered in cases where the delirium is not easily controlled with benzodiazepines (see Chapter 4.22: Physostigmine).
— Co-ingestion/regular treatment with calcium channel blocker or digoxin — Advanced age. • The threshold dose for severe toxicity from propranolol may be as little as 1 g. • Toxicity usually manifests within the first few hours, with the exception of overdose with controlled-release preparations or sotalol. • PR interval prolongation even in the absence of bradycardia is an early sign of toxicity.
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Children: there is risk of toxicity following ingestion of any dose of propranolol or sotalol. Ingestion of one or two tablets of other agents does not cause significant toxicity.
Toxic mechanism
Competitive antagonists at beta-1 and beta-2 receptors. Excessive beta-adrenergic blockade leads to decreased intracellular cAMP concentration and resultant blunting of the metabolic, chronotropic and inotropic effects of catecholamines. Propranolol also has Na+-blocking effects (class I effects) leading to QRS widening and ventricular dysrhythmias and, being lipid soluble, enters the CNS where it exerts direct toxicity. Sotalol also blocks cardiac K+ channels interfering with cardiac repolarisation and leading to QT prolongation.
Toxicokinetics
Rapidly absorbed from GIT with peak serum concentrations occurring from 1 to 3 hours post-ingestion. Rapidly distributed with a variable volume of distribution depending on the agent. Propranolol is distinguished from other agents by being extremely lipophilic. Metabolism and elimination vary with the different agents. Propranolol undergoes extensive hepatic metabolism with an elimination half-life of 12 hours but this may be prolonged following overdose. CLINICAL FEATURES
Occur within 4 hours with the onset of beta-blockade manifested by a fall in heart rate. More severe manifestations may also occur during this period following propranolol overdose or where there are other factors predisposing to severe effects. Cardiovascular • Hypotension and bradycardia. • Bradydysrhythmias observed include sinus bradycardia, 1st to 3rd degree heart block, junctional or ventricular bradycardia. • QRS widening is observed following propranolol overdose and the magnitude is a predictor of ventricular dysrhythmias. • QT prolongation and torsades de pointes are observed following sotalol overdose. Central nervous system • Delirium, coma and seizures (propranolol). Other • Bronchospasm, pulmonary oedema. • Hyperkalaemia. • Hypo/hyperglycaemia.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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Specific investigations as indicated • EUC
Decontamination • Activated charcoal may be administered to patients who present within 2 hours but caution should be exercised following propranolol overdose because of the risk of imminent coma and seizures. Enhanced elimination • Not clinically useful. Antidotes • High-dose insulin therapy may be considered (see Chapter 4.14: Insulin (high dose)). DISPOSITION AND FOLLOW-UP
• •
HANDY TIP
•
Patients who remain asymptomatic and have a normal ECG at 6 hours following the overdose may be medically cleared. Patients with clinical or ECG manifestations of toxicity require admission to an intensive care or high-dependency unit.
Approach management of a propranolol overdose more like a tricyclic antidepressant or other Na-channel blocker overdose rather than a beta-blocker overdose.
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Resuscitation, supportive care and monitoring • Acute beta-blocker poisoning is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Resuscitation is most likely to be required following propranolol overdose. Prompt intubation and ventilation and administration of sodium bicarbonate are necessary to control ventricular dysrhythmias (propanolol overdose is managed as a tricyclic antidepressant overdose). • Immediate life-threats and treatment options include: — Bradycardia and hypotension – Atropine 0.01–0.03 mg/kg IV (temporising measure) – Isoprenaline: 4 microgram/minute IV infusion – Adrenaline – High-dose insulin (see Chapter 4.15: Insulin (high dose)) — Wide QRS – Sodium bicarbonate 1–2 mEq/kg boluses over 1–2 min — Torsades de pointes (QT prolongation from sotalol) – Isoprenaline – Magnesium – Overdrive pacing. • Close clinical observation and continuous ECG monitoring are mandatory for at least 4 hours. • Invasive monitoring of haemodynamic parameters is very useful in sick patients.
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MANAGEMENT
CONTROVERSIES
SPECIFIC TOXINS
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Glucagon was previously regarded as a specific antidote to beta-blocker poisoning but it offers no advantages over standard inotropes and chronotropes. It is no longer used to treat betablocker poisoning. • Precise indications for high-dose insulin therapy (see Chapter 4.15: Insulin (high dose)) are as yet undefined but it is increasingly instituted early in the management of propranolol toxicity with haemodynamic compromise. • The role of intravenous lipid emulsion in propranolol poisoning is as yet undefined. It may be considered in life-threatening toxicity where response to other interventions is inadequate (see Chapter 4.16: Intravenous lipid emulsion).
Presentations
Atenolol 50 mg tablets (30) Bisoprolol fumarate 2.5 mg tablets (28) Bisoprolol fumarate 5 mg tablets (28) Bisoprolol fumarate 10 mg tablets (28) Carvedilol 3.125 mg tablets (30) Carvedilol 6.25 mg tablets (60) Carvedilol 12.5 mg tablets (60) Carvedilol 25 mg tablets (60) Esmolol hydrochloride 100 mg/10 mL ampoules Metoprolol tartrate 50 mg tablets (100) Metoprolol tartrate 100 mg tablets (60) Metoprolol tartrate 5 mg/5 mL ampoules Metoprolol succinate controlled-release 23.75 mg tablets (15) Metoprolol succinate controlled-release 47.5 mg tablets (30) Metoprolol succinate controlled-release 95 mg tablets (30)
Metoprolol succinate controlled-release 190 mg tablets (30) Oxprenolol hydrochloride 20 mg tablets (100) Oxprenolol hydrochloride 40 mg tablets (100) Pindolol 5 mg tablets (100) Pindolol 15 mg tablets (50) Propranolol hydrochloride 10 mg tablets (100) Propranolol hydrochloride 40 mg tablets (100) Propranolol hydrochloride 160 mg tablets (50) Sotalol hydrochloride 80 mg tablets (60) Sotalol hydrochloride 160 mg tablets (60) Sotalol hydrochloride 40 mg/4 mL ampoules
References
Love J, Howell JM, Litovitz TL et al. Acute beta-blocker overdose: factors associated with the development of cardiovascular morbidity. Journal of Toxicology–Clinical Toxicology 2000; 38:275–281. Reith DM, Dawson AH, Epid D et al. Relative toxicity of beta-blockers in overdose. Journal of Toxicology–Clinical Toxicology 1996; 34:273–278. Taboulet P, Cariou A, Berdeaux A et al. Pathophysiology and management of selfpoisoning with beta-blockers. Journal of Toxicology–Clinical Toxicology 1993; 31:531–551.
3.20 BUPROPION This antidepressant agent is now used to suppress nicotine craving and is only available as an extended-release preparation. There is a high risk of seizures following an overdose of any amount and potential for life-threatening cardiotoxicity occurs with very high doses. Supportive care and adequate benzodiazepine sedation usually ensure a good outcome.
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RISK ASSESSMENT
• • •
There is high risk of seizures following overdose of any amount. The first seizure usually occurs 2–8 hours following ingestion but may be delayed up to 24 hours. Risk of seizures is increased if there is a preexisting lowered seizure threshold or co-ingestion of other centrally acting sympathomimetic or serotonergic agents. • Severe cardiotoxicity, haemodynamic instability and cardiac deaths have occurred at doses >9 g.
TABLE 3.20.1 Dose-related risk assessment: Bupropion Dose
Effect
Any dose
Seizures, tachycardia, hypertension, tremors, agitation, hallucinations, GI symptoms
>4.5 g
Seizure risk of 50% and first seizure usually within 8 hours of ingestion
>9 g
Seizures universal. Risk of cardiovascular complications, including haemodynamic instability, prolonged QRS and QT intervals and ventricular dysrhythmias Fatal without good supportive care
Toxic mechanism
Bupropion is a monocyclic antidepressant that suppresses nicotine craving by an unknown mechanism. It increases the levels of CNS excitatory neuroamines by inhibiting noradrenaline and dopamine reuptake. Also causes minimal serotonin reuptake inhibition and moderate anticholinergic effects.
Toxicokinetics
Well absorbed orally with peak plasma levels occurring within 2–3 hours. Relatively large volume of distribution (19.8–47 L/kg). Metabolised to active metabolites, which are renally excreted. CLINICAL FEATURES
•
Clinical features develop progressively over 8 hours and include tachycardia, hypertension, tremors, GI disturbance, agitation, hallucinations, altered mental state and seizures. • First seizure, heralded by neurological symptoms, usually occurs during this period but may be delayed up to 24 hours post-ingestion. • Cardiovascular effects and ECG manifestations, including shock, QRS widening and tachydysrhythmias, are reported after massive overdose and usually manifest within 6 hours.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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SPECIFIC TOXINS
Children: any child suspected of ingesting >10 mg/kg requires assessment and observation in hospital.
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Specific investigations as indicated • Serial ECGs: — Perform a 12-lead ECG on all patients at presentation and at 6 and 12 hours post-ingestion. — For ingestions >4.5 g, 12-lead ECGs should be reviewed every 2 hours (or if symptoms occur).
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Resuscitation, supportive care and monitoring • Bupropion overdose is a life-threatening emergency and is managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Early intubation and ventilation is indicated when the history and clinical progression suggest ingestion of >9 g. • Clinical features that require immediate intervention include: — Seizures: give IV diazepam 2.5–5 mg and repeat if necessary as described in Chapter 2.6: Seizures. — Broad-complex tachycardias: manage aggressively with intubation, hyperventilation and administration of sodium bicarbonate 1–2 mmol/kg repeated every 1–2 minutes to achieve serum alkalinisation as described in Chapter 4.25: Sodium bicarbonate. • Control agitation and tachycardia with titrated doses of IV diazepam: give 2.5–5 mg every 2–5 minutes until gentle sedation achieved. • Continue close monitoring for at least 12 hours following ingestions of >9 g. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Activated charcoal or other attempts at decontamination are generally contraindicated because of the high risk of seizures, unless the airway is secured. • If >9 g is ingested and there is any evidence of toxicity, give activated charcoal 50 g via the nasogastric tube following endotracheal intubation. Enhanced elimination • Not clinically useful. Antidotes • None available.
DISPOSITION AND FOLLOW-UP
•
Because of the risk of seizures following bupropion overdose, all patients are observed with IV access in place for a minimum of 24 hours and until symptom-free. • Patients who are clinically well at 24 hours following ingestion do not require further medical observation. Discharge should never occur at night. • Patients with cardiotoxicity or seizures are admitted for monitoring and supportive care until all clinical features of toxicity, including sinus tachycardia, resolve.
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PITFALLS
• • •
It is useful to give early prophylactic doses of IV benzodiazepines in order to prevent seizures. The dose is titrated to achieve a calm patient and a fall in the heart rate towards 100 bpm. Failure to anticipate and prepare for delayed onset of symptoms and seizures. Failure to administer benzodiazepines early and in sufficient dose. Administration of activated charcoal or initiation of whole bowel irrigation shortly before onset of seizures or cardiovascular toxicity.
CONTROVERSIES
•
The role of whole bowel irrigation (WBI): patients who present early after massive ingestion of bupropion would appear to be candidates for WBI. However, the risk of seizures occurring during the procedure is such that it is contraindicated. • Intravenous lipid emulsion and extracorporeal membrane oxygenation have been advocated in the management of severe bupropion toxicity but their role is as yet undefined.
Presentations
Bupropion hydrochloride 150 mg sustained-release tablets (10, 60, 100, 120)
References
Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Medical Journal of Australia 2003; 178:61–63. Morazin F, Lumbroso A, Harry P. Cardiogenic shock and status epilepticus after massive bupropion overdose. Clinical Toxicology 2007; 45(7):794–797. Shepherd G, Veliz LI, Keys DC. Intentional bupropion overdoses. Journal of Emergency Medicine 2004; 27(2):147–151. Spiller HA, Bosic GM, Beuhler M et al. Unintentional ingestion of bupropion in children. Journal of Emergency Medicine 2010; 38(3):332–336. Starr P, Klein-Schwartz W, Spiller H et al. Incidence and onset of delayed seizures after overdose of extended-release bupropion. American Journal of Emergency Medicine 2009; 27:911–915.
3.21 BUTTON BATTERIES Ingestion of button batteries is almost exclusively a paediatric problem. The majority pass through the gastrointestinal (GI) tract easily and without complication. Larger batteries may lodge in the oesophagus, causing significant complications including death, particularly if diagnosis is delayed. RISK ASSESSMENT
•
Ingested batteries of diameter 9 g) and for patients manifesting signs of significant cardiotoxicity.
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Ingested batteries of 20 mm diameter or greater are more likely to lodge in the oesophagus and may cause severe local corrosive injury within 2 hours. Local corrosive injury may also occur after insertion of smaller batteries into the aural or nasal cavities. Age is an important predictor of severity with most severe oesophageal injuries and fatalities occurring in children younger than 4 years old. Delayed diagnosis of oesophageal button battery is associated with worse outcome. A new battery is more dangerous than a spent battery when lodged in the oesophagus; however, a spent battery retains sufficient residual voltage to generate external current and can still produce a corrosive injury. Button batteries may contain manganese, silver, lithium or zinc but the quantities available for absorption are insufficient to cause systemic heavy metal toxicity.
Mechanism of injury
The most significant mechanism is the generation of hydroxide ions at the negative pole of the battery caused by the current created through the adjacent tissue. The resulting hydroxide accumulation produces results equivalent to localised alkaline corrosive injury with tissue liquefactions and necrosis. Corrosive injury may develop within 2 hours of lodgement. The severity and type of injury depends on the size of the current produced, the location and orientation of the battery and the length of time it remains in the oesophagus. Potential complications include oesophageal perforation, tracheooesophageal fistula, aorto-oesophageal fistula and stricture formation. CLINICAL FEATURES
•
Many children are asymptomatic initially and present to hospital because ingestion was witnessed or suspected by parents or carers, or only after signs and symptoms of oesophageal obstruction or injury develop. • Where ingestion is unwitnessed, presentation may be delayed and symptoms relatively non-specific. Button battery ingestion should be considered in the presence of any of the following presenting complaints: airway obstruction, cough, fever, dysphagia, sore throat, chest discomfort, decreased oral intake, or coughing or choking with eating and drinking. • Where oesophageal injury is established, perforations and fistulas may not be clinically evident for up to 28 days and strictures may present after weeks to months.
INVESTIGATIONS
•
History or suspicion of possible button battery ingestion mandates plain anteroposterior (together with a lateral if an object is identified above the diaphragm) X-ray of the neck, chest and abdomen to localise the object and guide further management. • Mercury and other heavy metal levels are not required routinely.
MANAGEMENT
Resuscitation and supportive care • Resuscitation is rarely needed following acute ingestion unless airway obstruction occurs.
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Decontamination • A button battery lodged in the oesophagus requires endoscopic removal as soon as possible, and ideally within 2 hours of ingestion. • Endoscopy allows both removal of the battery and examination for local complications to guide further management. The presence of a mucosal burn prompts further investigation to exclude perforation. • A button battery located beyond the oesophagus in an asymptomatic child can be allowed to pass naturally. • Batteries lodged in the nose or ears should be removed urgently. DISPOSITION AND FOLLOW-UP
• •
Children with a battery lodged in the oesophagus are referred for urgent upper GI endoscopy and removal. Children in whom the battery has passed beyond the pylorus are unlikely to develop complications and can be discharged with advice to observe and return if symptoms develop. A follow-up X-ray in 10–14 days to confirm passage may be reassuring if passage in the stool has not been observed.
HANDY TIPS
•
Batteries typically have a ‘double ring’ or ‘halo’ shape on anteroposterior view, and a ‘step-off’ appearance on lateral view radiography. • A high index of suspicion is required for investigation of small children when a history of ingestion is not available. • Magnet co-ingestion prompts urgent endoscopy and removal.
PITFALLS
• •
Failure to perform an X-ray in non-specific presentations where button battery ingestion was not witnessed. Mistaking a button battery on X-ray for a coin, ECG electrode or other external object. Batteries have a distinctive appearance and lateral X-ray may help to identify the object. • Delayed referral for endoscopic removal.
CONTROVERSIES
•
Management of established oesophageal burns. Currently there are no clearly established guidelines for management of established burns with regard to repeat endoscopy, use of steroids, antibiotic therapy and feeding. • Management of button batteries located in the stomach. Some authors recommend repeat X-ray at 4 days when a larger button battery (>15 mm) is initially seen in the stomach, with endoscopic retrieval if it has not passed through the pylorus by this time. Smaller batteries can usually be managed expectantly at home without repeat imaging.
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Delayed presentation may require resuscitation following standard protocols for cardiovascular collapse secondary to haemorrhage or sepsis from oesophageal perforation, or for respiratory distress from tracheo-oesophageal fistula.
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Sources
Button batteries are found in numerous devices including watches, cameras, remote controls, electronic games and hearing aids. More recently, manufactured devices tend to have smaller button batteries.
References
SPECIFIC TOXINS
Jatana KR, Litovitz T, Reilly JS et al. Pediatric button battery injuries: 2013 task force update. International Journal of Pediatric Otorhinolaryngology 2013; 77:1392–1399. Litovitz T, Whitaker N, Clark L et al. Emerging battery-ingestion hazard: clinical implications. Pediatrics 2010; 125:1168–1177.
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3.22 CALCIUM CHANNEL BLOCKERS Amlodipine, Diltiazem, Felodipine, Lercanidipine, Nifedipine, Nimodipine, Verapamil Verapamil and diltiazem commonly cause cardiovascular collapse following overdose and this may be delayed 4–16 hours after ingestion of the extended-release (XR) preparations. The other agents are less commonly associated with severe toxicity. RISK ASSESSMENT
• • • • • • • •
Ingestion of as little as 2–3 times the normal therapeutic dose of verapamil or diltiazem XR preparations can cause severe toxicity in susceptible individuals. All deliberate self-poisonings are regarded as potentially serious. Ingestion of >10 tablets of verapamil or diltiazem XR preparations in an adult is likely to cause life-threatening toxicity. Onset of effects is up to 2 hours following ingestion of standard preparations and 16 hours following XR preparations. The other calcium channel blockers (CCBs) are less likely to cause life-threatening toxicity but may be associated with bradycardia and hypotension. Co-ingestion of other cardiotoxic medications (e.g. beta-blockers or digoxin) significantly increases the risk of serious toxicity. Advanced age and co-morbidities (e.g. cardiac disease) increase the risk of significant toxicity. Children: ingestion of 2 or more tablets of any strength of XR verapamil or diltiazem is potentially lethal. All children suspected of ingesting any quantity of XR preparations should be assessed in hospital. Children who are suspected of ingesting >2 tablets of other preparations should also be assessed in hospital.
Toxic mechanism
Calcium channel blockers prevent the opening of L-type calcium channels, resulting in decreased calcium influx. This leads to vascular smooth muscle relaxation, slowing of cardiac conduction and reduced force of cardiac contraction. Verapamil and diltiazem cause central cardiac effects and peripheral vasodilation. The dihydropyridines chiefly cause the latter. Hypotension results from severe peripheral vasodilation, bradycardia and decreased contractility, associated with hyperglycaemia and lactic acidosis.
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Toxicokinetics
Calcium channel blockers are well absorbed, with peak levels occurring within 1–2 hours (standard preparations) and 6–12 hours for XR preparations. However, in overdose peak levels may not occur until 6 hours for standard preparations and 22 hours for XR preparations. They have high volumes of distribution (e.g. verapamil 3–7 L /kg) and are protein bound, but free levels often increase in overdose. Calcium channel blockers undergo hepatic metabolism. There is a high first-pass effect after absorption, giving bioavailability of approximately 40%. This may increase in overdose due to saturation of hepatic metabolism. Verapamil is metabolised to an active metabolite norverapamil, and diltiazem is metabolised to diacetyldiltiazem, which has vasodilator activity.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial 12-lead ECGs — Perform a 12-lead ECG at presentation and 8 hours postingestion. Additional ECGs should be performed if there are abnormal vital signs, and at 12, 18 and 24 hours following ingestion of XR products. — Profound bradycardia, first, second and third degree heart block may occur. • EUC • BGL • Serum calcium • Serum lactate and arterial blood gases • Chest X-ray • Echocardiogram • Pulmonary artery capillary wedge pressure, cardiac output, systemic resistance
MANAGEMENT
Key objectives in the management of CCB poisoning are early identification of patients at risk, initiation of appropriate monitoring, consideration of gastrointestinal decontamination and referral to a facility capable of advanced resuscitation and intensive care.
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Following ingestion of standard preparations, onset of symptoms may occur within 1–2 hours. In XR preparations, onset of significant toxicity may be delayed 12–16 hours with peak effects beyond 24 hours. • Cardiovascular — Bradycardia, first-degree heart block and hypotension (e.g. SBP 95 mmHg) are early signs. — Progression to refractory shock and death may occur. — Myocardial ischaemia, stroke or non-occlusive mesenteric ischaemia may complicate the clinical picture. • Central nervous system — Seizures and coma are rare. — Coma usually indicates a co-ingested agent. • Metabolic — Hyperglycaemia and lactic acidosis occur in severe intoxication.
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Resuscitation, supportive care and monitoring • Acute CCB overdose is a time-critical emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Potential early life-threats that require immediate intervention include: — Hypotension — Cardiac dysrhythmia — Cardiac arrest. • Mentation and airway protective reflexes are usually preserved until cardiac arrest. Rapid-sequence endotracheal intubation and ventilation may be required in cases of severe established toxicity. • Early invasive blood pressure monitoring is advised for evolving shock. • Hypotension (SBP 10 tablets of verapamil XR or diltiazem XR. Enhanced elimination • Rarely indicated (albumin dialysis has been advocated in selected cases – see below). Antidotes • As discussed in Resuscitation, supportive care and monitoring above: — High-dose insulin euglycaemic therapy (see Chapter 4.15: Insulin (high dose)). This is now regarded as the mainstay of therapy in CCB poisoning and should be started as soon as significant calcium channel blocker toxicity is detected — Calcium (see Chapter 4.2: Calcium).
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DISPOSITION AND FOLLOW-UP
•
Patients who are clinically well with normal vital signs and 12-lead ECG at 4 hours following standard preparations or 16 hours following XR preparations may be discharged. Discharge should not occur at night. • Patients with manifestations of intoxication are referred to an intensive care unit.
•
If rapid-sequence endotracheal intubation is required, avoid agents that will exacerbate hypotension or bradycardia. Preferred agents include ketamine, fentanyl and rocuronium or vecuronium.
PITFALLS
• •
Failure to anticipate potential for delayed onset of severe toxicity following ingestion of XR preparations. Failure to initiate aggressive decontamination (activated charcoal followed by whole bowel irrigation) in patients who present early following life-threatening overdose of XR diltiazem or verapamil. • Delay in institution of high-dose insulin therapy once evidence of toxicity develops.
SPECIFIC TOXINS
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•
The role of intravenous lipid emulsion in CCB poisoning is as yet undefined. It may be considered in life-threatening toxicity where response to other interventions is inadequate (see Chapter 4.16: Intravenous lipid emulsion). • Albumin dialysis has been advocated in cardiogenic shock from CCB poisoning, unresponsive to other measures.
Presentations Benzothiazepines: Diltiazem 60 mg tablets (90) Diltiazem extended-release capsules 180 mg (30) Diltiazem extended-release capsules 240 mg (30) Diltiazem extended-release capsules 360 mg (30) Dihydropyridines: Amlodipine besylate 5 mg tablets (30) Amlodipine besylate 10 mg tablets (30) Amlodipine besylate 5 mg/atorvastatin 10 mg tablets (30) Amlodipine besylate 5 mg/atorvastatin 20 mg tablets (30) Amlodipine besylate 5 mg/atorvastatin 40 mg tablets (30) Amlodipine besylate 5 mg/atorvastatin 80 mg tablets (30) Amlodipine besylate 10 mg/atorvastatin 10 mg tablets (30) Amlodipine besylate 10 mg/atorvastatin 20 mg tablets (30)
Amlodipine besylate 10 mg/atorvastatin 40 mg tablets (30) Amlodipine besylate 10 mg/atorvastatin 80 mg tablets (30) Amlodipine besylate 5 mg tablets/ olmesartan medoxomil 20 mg (10, 30) Amlodipine besylate 5 mg tablets/ olmesartan medoxomil 40 mg (10, 30) Amlodipine besylate 10 mg tablets/ olmesartan medoxomil 40 mg (10, 30) Amlodipine besylate 5 mg/olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg tablets (10, 30) Amlodipine besylate 5 mg/olmesartan medoxomil 40 mg/hydrochlorothiazide 12.5 mg tablets (10, 30) Amlodipine besylate 5 mg/olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg tablets (10, 30) Amlodipine besylate 10 mg/ olmesartan medoxomil 40 mg/ hydrochlorothiazide 12.5 mg tablets (10, 30)
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Amlodipine besylate 10 mg/ olmesartan medoxomil 40 mg/ hydrochlorothiazide 25 mg tablets (10, 30) Amlodipine besylate 5 mg/perindopril arginine 5 mg tablets (10, 30) Amlodipine besylate 5 mg/perindopril arginine 10 mg tablets (10, 30) Amlodipine besylate 10 mg/perindopril arginine 5 mg tablets (10, 30) Amlodipine besylate 10 mg/perindopril arginine 10 mg tablets (10, 30) Amlodipine besylate 5 mg/valsartan 80 mg tablets (7, 14, 28, 30, 56) Amlodipine besylate 5 mg/valsartan 160 mg tablets (7, 14, 28, 30, 56) Amlodipine besylate 5 mg/valsartan 320 mg tablets (7, 14, 28, 30, 56) Amlodipine besylate 10 mg/valsartan 160 mg tablets (7, 14, 28, 30, 56) Amlodipine besylate 10 mg/valsartan 320 mg tablets (7, 14, 28, 30, 56) Amlodipine besylate 5 mg/valsartan 160 mg/hydrochlorothiazide 12.5 mg tablets (7, 28) Amlodipine besylate 5 mg/valsartan 160 mg/hydrochlorothiazide 25 mg tablets (7, 28) Amlodipine besylate 10 mg/valsartan 160 mg/hydrochlorothiazide 12.5 mg tablets (7, 14, 28, 30, 56) Amlodipine besylate 10 mg/valsartan 160 mg/hydrochlorothiazide 25 mg tablets (7, 14, 28, 30, 56) Amlodipine besylate 10 mg/valsartan 320 mg/hydrochlorothiazide 25 mg tablets (7, 14, 28, 30, 56) Felodipine extended-release tablets 2.5 mg (30) Felodipine extended-release tablets 5 mg (30) Felodipine extended-release tablets 10 mg (30) Felodipine 2.5 mg/ramipril 2.5 mg modified-release tablets (30)
Felodipine 5 mg/ramipril 5 mg modifiedrelease tablets (30) Lercanidipine hydrochloride 10 mg tablets (28, 30, 100, 500) Lercanidipine hydrochloride 20 mg tablets (28, 30, 100, 500) Lercanidipine hydrochloride 10 mg/ enalapril maleate 10 mg tablets (28) Lercanidipine hydrochloride 10 mg/ enalapril maleate 20 mg tablets (28) Nifedipine 10 mg tablets (60) Nifedipine 20 mg tablets (60) Nifedipine controlled-release tablets 20 mg (30) Nifedipine controlled-release tablets 30 mg (30) Nifedipine controlled-release tablets 60 mg (30) Nimodipine 30 mg tablets (100) Nimodipine 10 mg/50 mL ampoules Phenylalkylamines: Verapamil hydrochloride immediaterelease tablets 40 mg (100) Verapamil hydrochloride immediaterelease tablets 80 mg (100) Verapamil hydrochloride immediaterelease tablets 120 mg (100) Verapamil hydrochloride immediaterelease tablets 160 mg (60) Verapamil hydrochloride sustained-release capsules 160 mg (30) Verapamil hydrochloride sustained-release capsules 240 mg (30) Verapamil hydrochloride sustained-release tablets 180 mg (30) Verapamil hydrochloride sustained-release tablets 240 mg (30) Verapamil hydrochloride 5 mg/2 mL ampoules Verapamil hydrochloride 180 mg/ trandolapril 2 mg sustained-release tablets (28) Verapamil hydrochloride 240 mg/ trandolapril 4 mg sustained-release tablets (28)
References
Buckley N, Dawson A, Whyte I. Calcium channel blockers. Medicine 2007; 35(11):134–139. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and β-blocker toxicity. Toxicological Reviews 2004; 23(4): 223–238. Mégarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/ euglycaemia) therapy in acute calcium channel antagonist and β-blocker toxicity. Toxicological Reviews 2004; 23(4): 215–222. Olsen KR, Erdman AR, Woolf AD et al. Calcium channel blocker ingestion: an evidencebased guideline for out-of-hospital management. Clinical Toxicology 2005; 43:797–822. Pichon N, Dugard A, Clavel M et al. Extracorporeal albumin dialysis in three cases of acute calcium channel blocker poisoning with life-threatening refractory cardiogenic shock. Annals of Emergency Medicine 2012; 59:540–544.
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Yuan TH, Kerns WP, Tomaszewski CA et al. Insulin-glucose as an adjunctive therapy for severe calcium channel antagonist poisoning. Clinical Toxicology 1999; 37(4): 463–474.
3.23 CANNABINOIDS (marijuana) Delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabinol, cannabidiol
RISK ASSESSMENT
• •
There are no reports of death directly attributed to recreational use of marijuana. Adults may experience unpleasant symptoms in a dosedependent manner: — Low-dose effects: 50 microgram/kg (3–4 mg) are associated with mild sedation, disinhibition, mild disorientation and euphoria — High-dose effects: 250 microgram/kg (15 mg) are associated with tachycardia, postural hypotension, CNS depression, anxiety, perceptual disturbances and even psychotic symptoms. • Co-ingestion of other CNS depressants has an additive effect. • Chronic use leads to long-term neuropsychiatric sequelae and a withdrawal syndrome is described in habitually heavy users.
•
Children: ingestion may lead to life-threatening coma in a child.
Toxic mechanism
Marijuana is a psychoactive drug with central sympathomimetic and antiemetic properties. It acts on cannabinoid receptors in the central and peripheral nervous system (CB1) and on immune cells (CB2). It has been shown to augment dopamine release. Delta-9-tetrahydrocannabinoid (THC) is the most potent component.
Toxicokinetics
Rapidly and completely absorbed by inhalation. Bioavailability is reduced if ingested. Cannabinoids are highly protein bound, lipid soluble and have large volumes of distribution (10 L/kg). They undergo hepatic metabolism to form active and inactive metabolites that are excreted in the urine. Elimination half-life of the metabolites is several days. CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, psychiatric sequelae or withdrawal. In adults, acute symptoms last up to 4 hours following inhalation and up to 8 hours following ingestion. Clinical features of intoxication include:
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Marijuana is the most widely used recreational illicit drug in Australasia. It is a psychoactive drug that can cause unpleasant but benign symptoms in adults. Cannabis ingestion by children leads to significant CNS depression.
SPECIFIC TOXINS
Slang terms include hashish, dope, marijuana, ganja, grass, pot and weed.
SPECIFIC TOXINS
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Central nervous system — Ataxia, incoordination, impaired judgement — Sedation — CNS depression — Coma in children that can last up to 36 hours • Cardiovascular — Tachycardia — Orthostatic hypotension — Syncope • Psychiatric — Euphoria and relaxation — Agitation — Anxiety and panic attacks — Time distortion, hallucinations, delusions — Acute psychosis • Respiratory complications (rare) — Pneumothorax — Pneumomediastinum. Chronic cannabis users may also present repeatedly to emergency departments with cannabinoid hyperemesis syndrome. This syndrome is characterised by repeated episodes of vomiting separated by weeks or months and can be difficult to control. Severe cases may be complicated by acid–base disturbance and acute renal failure. Repeated therapeutic showering or bathing in hot water to achieve temporary control of symptoms is frequently observed. The diagnosis should only be made after alternative aetiologies are excluded. The vomiting resolves with abstinence. INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serum or urine cannabinoid levels are not readily available and do not assist acute management. They are sometimes performed for forensic indications. • Spot blood levels of 11-carboxy-THC greater than 40 microgram/L indicate chronic consumption. • Urine screening tests may be positive for 1–3 days after acute use, or 10 days to 4 weeks after chronic use. • Passive smoking of cannabis may give positive results after an acute exposure for several days on some screening tests. • False positive urine screens occur.
MANAGEMENT
Resuscitation, supportive care and monitoring • Cannabis intoxication is benign and self-limiting. • Tachycardia and hypotension are managed with fluids and sedation as appropriate. • Treat severe agitation with IV diazepam 5 mg every 2–5 minutes until sedation is achieved. Once sedated, the patient should be rousable to voice but calm.
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Adult patients with mild dysphoria or agitation are given oral diazepam 5 mg and reassured. Cannabinoid hyperemesis syndrome sufferers may require intravenous fluids and antiemetics.
Decontamination • Not clinically useful. Enhanced elimination • Not clinically useful.
•
Children who may have ingested marijuana should be observed in hospital for 4 hours. If they do not develop symptoms during that period they may then be safely discharged. • Patients with intoxication adequately controlled with benzodiazepine sedation may be managed supportively in a ward environment. They may be discharged when asymptomatic. Patients with cannabinoid hyperemesis syndrome frequently require short admissions for intravenous fluids and antiemetic therapy. They should be counselled and supported to achieve and maintain abstinence following discharge.
HANDY TIPS
PITFALL
• •
Cannabis poisoning is not life threatening and acute toxicity is very low. Profound coma or 12-lead ECG changes suggest a co-ingested agent and the need to revise the risk assessment.
•
Failure to anticipate the potential in paediatric ingestions for rapid onset of coma, hypotonia, abnormal movements, tachycardia and bradycardia lasting 24–36 hours.
CONTROVERSY
•
Cannabis impairs coordination, cognition and behaviour in a dose-dependent manner; however, the impairment of driving ability and correlation with blood or urine cannabinoid levels has not been established.
Presentations
Any part or extract of the hemp plant (Cannabis sativa) can be dried or converted to a resin extract.
References
Allen JH, de Moore GM, Heddle R et al. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut 2004; 53:1566–1570. Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998: 352:1611–1615. Reece AS. Chronic toxicology of cannabis. Clinical Toxicology 2009; 47(6):517–524. Sydney S, Beck JE, Tekawa IE et al. Marijuana use and mortality. American Journal of Public Health 1997; 87:585–590.
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DISPOSITION AND FOLLOW-UP
SPECIFIC TOXINS
Antidotes • None available.
3.24 CARBAMAZEPINE Deliberate self-poisoning with this anticonvulsant agent results in predictable dose-dependent CNS and anticholinergic effects. Management is primarily supportive with the selected use of enhanced elimination techniques. RISK ASSESSMENT
SPECIFIC TOXINS
•
Clinical features are dose dependent (see Table 3.24.1) but onset varies depending on whether the preparation is immediate or controlled release.
TABLE 3.24.1 Dose-related risk assessment: Carbamazepine Dose
Effect
20–50 mg/kg
Mild-to-moderate CNS and anticholinergic effects
>50 mg/kg
Fluctuating mental status with intermittent agitation and risk of progression to coma within the first 12 hours Risk of hypotension and cardiotoxicity with extreme doses
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• •
Following larger overdoses, anticholinergic effects may be prominent prior to development of coma. Following massive ingestions, coma is anticipated to last several days, secondary to ongoing absorption, slow elimination and the presence of an active metabolite.
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Pregnancy: carbamazepine is teratogenic. Overdose in the first trimester warrants referral for further antenatal assessment.
•
Children: one 400-mg tablet is enough to cause significant intoxication in a toddler and suspected ingestion of this dose or greater warrants observation in hospital for 8 hours.
Toxic mechanism
Carbamazepine is structurally similar to the tricyclic antidepressant imipramine. It inhibits inactivated sodium channels, thus preventing further action potentials. It also blocks noradrenaline reuptake and is an antagonist at muscarinic, nicotinic and N-methyl-D-aspartate central adenosine receptors.
Toxicokinetics
Carbamazepine is slowly and erratically absorbed. Following large overdoses, ileus secondary to anticholinergic effects may result in ongoing absorption for several days. Carbamazepine has a small volume of distribution (0.8–1.2 L/kg) and undergoes hepatic metabolism by cytochrome P450 3A4 to form an active metabolite (carbamazepine 10,11-epoxide). This is metabolised to inactive metabolites that are excreted in the urine. CLINICAL FEATURES
Clinical features of intoxication are usually evident within 4 hours of ingestion, but may not reach their most severe extent until 8–12 hours, particularly with controlled-release preparations. Ongoing
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serum carbamazepine levels (see Table 3.24.2) — Useful to confirm the diagnosis. — In mild-to-moderate intoxication management is guided by clinical features, so repeated levels are not required. — In cases with coma, monitoring of carbamazepine levels every 6 hours is essential to monitor the patient’s clinical course. TABLE 3.24.2 Correlation of serum levels and clinical features: Carbamazepine Carbamazepine level
Clinical features
8–12 mg/L (34–51 micromol/L)
Therapeutic range
>12 mg/L (51 micromol/L)
Nystagmus and ataxia
>20 mg/L (85 micromol/L)
CNS and anticholinergic effects
>40 mg/L (170 micromol/L)
Coma, seizures and cardiac conduction abnormalities
•
Serial 12-lead ECGs — Ingestions >50 mg/kg may be associated with evidence of sodium channel blockade (1st degree heart block and increased QRS duration). A repeat ECG should be examined at the onset of significant intoxication, and every 12 hours thereafter. Abnormalities prompt more frequent ECG evaluation.
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation.
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INVESTIGATIONS
SPECIFIC TOXINS
erratic absorption for several days frequently complicates large overdoses producing a fluctuating clinical course. • Mild-to-moderate CNS effects include nystagmus, dysarthria, ataxia, sedation, delirium, mydriasis, ophthalmoplegia and myoclonus. • Anticholinergic effects, such as urinary retention, tachycardia and dry mouth, are common in the early stages. • Coma requiring intubation and ventilation may be delayed until 8–12 hours post-ingestion. A fluctuating mental status with intermittent agitation may also occur. • Large overdoses may be complicated by seizures, hypotension and cardiac conduction abnormalities. Cardiac dysrhythmias (VT, VF, asystole) are associated with massive overdoses.
•
SPECIFIC TOXINS
In the rare event of ventricular dysrhythmias, resuscitation should include the use of IV bolus sodium bicarbonate, as outlined in Chapter 4.25: Sodium bicarbonate. • Basic resuscitative measures ensure the survival of the vast majority of patients. General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Seizures and agitated delirium may be managed with benzodiazepines as outlined in Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation.
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Decontamination • Activated charcoal is considered for ingestions 30 mg/kg. Ingestion of >5 g of chloroquine in adults is usually fatal without intervention. The dose-related risk assessment is less well-defined for hydroxychloroquine, but appears to be similar to chloroquine.
•
Children: ingestion of even one tablet is regarded as potentially lethal in a child less than 6 years of age.
Toxic mechanism
These drugs have a direct toxic effect on the CNS via effects on voltage-dependent Na+ channels. CNS toxicity is compounded by cerebral hypoperfusion from cardiovascular effects. Cardiovascular manifestations are related to blocking of multiple inward and outward membrane currents. Hypotension and cardiogenic shock are due to a direct cardiodepressant effect. Hypokalaemia is believed to be due to a transport-dependent mechanism.
Toxicokinetics
Both agents have similar toxicokinetics. Absorption after ingestion is rapid and complete. They are extensively tissue bound and have a volume of distribution of >50 L/kg. They are partially metabolised and have prolonged half-lives of several weeks. More than 50% of chloroquine is excreted unchanged. CLINICAL FEATURES
Onset of symptoms occurs within 1–2 hours. Clinical features include:
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Buckley NA, Isbister GK, Stokes B et al. Hyperbaric oxygen for carbon monoxide poisoning: a systematic review and critical analysis of the evidence. Toxicological Reviews 2005: 24(2):75–92. Buckley NA, Juurlink DN, Isbister G et al. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database of Systematic Reviews 2011; 4:CD002041. Hampson NB, Piantodosi CA, Thom SR, Weaver LK. Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning. American Journal of Respiratory and Critical Care Medicine 2012; 186:1095–1101. Scheinkestel CD, Bailey M, Myles PS et al. Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial. Medical Journal of Australia 1999; 170:203–210. Weaver LK, Hopkins RO, Chan KJ et al. Hyperbaric oxygen for acute carbon monoxide poisoning. New England Journal of Medicine 2002; 347(14):1057–1067.
SPECIFIC TOXINS
References
• •
Non-specific symptoms of dizziness, nausea and vomiting Cardiovascular — Rapid onset of hypotension — Cardiac conduction defects (QRS widening, QT prolongation) — Cardiac arrest • Central nervous system — Depressed conscious state — Seizures • Metabolic — Hypokalaemia due to intracellular shift of potassium.
SPECIFIC TOXINS
INVESTIGATIONS
Specific investigations as indicated • EUC — Detect and monitor hypokalaemia • Serial ECGs — Detect and monitor QRS and QT prolongation — Sinus arrest, varying degrees of heart block • Specific levels are not routinely available and do not assist in management. They may be useful retrospectively to confirm the diagnosis.
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
MANAGEMENT
Resuscitation, supportive care and monitoring • Chloroquine or hydroxychloroquine overdose is a life-threatening emergency and is managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Clinical features that require immediate intervention include: — Coma: prompt intubation and ventilation is indicated at the first sign of a depressed conscious state — Broad complex tachycardias: manage aggressively with intubation, hyperventilation and serum alkalinisation. Give sodium bicarbonate 1–2 mmol/kg IV for QRS prolongation. Aim for a pH of 7.5–7.55 (see Chapter 4.25 Sodium bicarbonate) — Hypotension: initially treat with fluid resuscitation but vasopressors are often required and adrenaline by titrated IV infusion is the first-line agent — Seizures: controlled with intravenous benzodiazepines. • Ensure normokalaemia. Hypokalaemia should be anticipated, but avoid aggressive replacement, as total body potassium is not depleted. • High-dose diazepam (0.5 mg/kg IV bolus then an infusion of 1 mg/kg IV over 24 hours) post-intubation has been advocated. Its protective mechanism is unclear. Decontamination • Administration of activated charcoal is withheld until the airway is protected. Enhanced elimination • Not clinically useful.
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Antidote • None available. DISPOSITION AND FOLLOW-UP
HANDY TIPS
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Anticipate catastrophic deterioration in any patient presenting early following chloroquine overdose. Intubate and hyperventilate at the first sign of cardiotoxicity or clinical deterioration. • Avoid over-enthusiastic correction of hypokalaemia as total body potassium is not depleted and excessive administration can lead to life-threatening hyperkalaemia as toxicity resolves.
CONTROVERSY
•
The mechanism of action of high-dose diazepam infusion in chloroquine and hydroxychloroquine toxicity is unclear and its efficacy is unproven.
Presentations
Chloroquine phosphate 155 mg tablets (no longer available in Australia) Hydroxychloroquine sulfate 200 mg tablets (100) (720) available online
References
Clemessy JL, Favier C, Borron SW et al. Hypokalaemia related to acute chloroquine ingestion. Lancet 1995; 346(8979):877–880. Clemessy J-L, Taboulet P, Hoffman JR et al. Treatment of acute chloroquine poisoning: a 5-year experience. Critical Care Medicine 1996; 24:1189–1195. Marquardt K, Albertson TE. The treatment of hydroxychloroquine overdose. Journal of Emergency Medicine 2005; 28(4):437–443. Riou B, Barriot P, Rimailho A et al. Treatment of severe chloroquine poisoning. New England Journal of Medicine 1988; 318:1–6. Smith ER, Klein-Schwartz W. Are 1–2 dangerous? Chloroquine and hydroxychloroquine exposure in toddlers. Journal of Emergency Medicine 2005; 28 (4):437–443.
3.27 CHLORAL HYDRATE Chloral hydrate is still available for use as a sedative in children undergoing procedures. It was withdrawn as a sedative-hypnotic for adults because of its narrow therapeutic index. In overdose it causes rapid onset of CNS depression and cardiac dysrhythmias and these are frequently lethal without intervention.
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All children suspected of ingesting even one chloroquine or hydroxychloroquine tablet must be assessed and observed in hospital. • Patients who are asymptomatic at 6 hours following ingestion may be discharged. Discharge should never occur at night. • Patients with signs of cardiotoxicity or seizures are admitted for observation and supportive care until all clinical features of toxicity including sinus tachycardia resolve. • Admission to ICU is indicated following massive ingestions (>30 mg/kg) and for patients manifesting signs of significant cardiotoxicity.
SPECIFIC TOXINS
•
RISK ASSESSMENT
•
Ingestion of >100 mg/kg, twice the upper limit of therapeutic dosing, is associated with high risk of coma and life-threatening cardiac dysrhythmias.
Toxic mechanism
Chloral hydrate has a direct irritant action on mucosal surfaces. The mechanism of action of the toxic metabolite trichloroethanol (TCE) on the CNS and cardiovascular system is unclear. Cardiac dysrhythmias are thought to be caused by sensitisation of the myocardium to circulating catecholamines. Chloral hydrate also decreases myocardial contractility and shortens the refractory period, which enhances cardiotoxicity.
SPECIFIC TOXINS
Toxicokinetics
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Chloral hydrate is rapidly absorbed following oral administration. It is then rapidly converted to the active metabolite TCE by hepatic alcohol dehydrogenase. TCE is conjugated with glucuronic acid and excreted in the urine and to a limited extent in the bile. Chloral hydrate has an elimination half-life of only 4–5 minutes whereas TCE has an elimination half-life of 8–12 hours after therapeutic doses and up to 35 hours after overdose. CLINICAL FEATURES
Chloral hydrate overdose is characterised by rapid (20 microgram/kg, but large doses are sometimes tolerated with minor effects. • Onset of clinical features is rapid, usually within 2 hours of ingestion and always within 6 hours.
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Children: ingestion of 2 tablets is potentially lethal without supportive care: — >10 microgram/kg: bradycardia and hypotension — >20 microgram/kg: respiratory depression or apnoea.
Toxic mechanism
Clonidine is a centrally acting α2-adrenergic agonist. It acts as a sympathoplegic agent, decreasing central nervous sympathetic outflow. It also increases endothelial nitric oxide levels and decreases renin activity.
CLINICAL FEATURES
• •
Onset of toxicity is rapid. Transient early hypertension (not usually clinically significant) is reported in 20–50% of cases. Lethargy, miosis, slurred speech and ataxia usually occur within 2 hours, and always within 6 hours. The patient can frequently be roused with a stimulus, only to become deeply somnolent again when not disturbed. • Severe intoxication is associated with coma, bradycardia and hypotension. Sinus bradycardia (rate sometimes as low as 30/ minute) is common and is frequently present without hypotension or signs of decreased end-organ perfusion. Heart block is reported. • Hypothermia, respiratory depression and apnoea are reported, but uncommon. • Symptoms resolve within 24 hours.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial ECGs
MANAGEMENT
Resuscitation, supportive care and monitoring • The patient is initially managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Basic resuscitative measures ensure the survival of the vast majority of patients. • Intubation and ventilation is only required in the most severe intoxications. • Bradycardia is common but specific management (e.g. atropine, catecholamine infusion or pacing) is rarely required and only if there is hypotension or evidence of decreased end-organ perfusion. • Give 10–20 mL/kg of crystalloid IV to patients with symptomatic hypotension.
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Clonidine is rapidly and completely absorbed with peak concentration and therapeutic effects occurring within 1–3 hours. Clonidine has a large volume of distribution of 3–6 L/kg. It is metabolised in the liver, but half the ingested dose is eliminated unchanged in the urine. Elimination half-life is 6–24 hours. Protein binding is approximately 20–40%.
SPECIFIC TOXINS
Toxicokinetics
Decontamination • Oral activated charcoal is contraindicated because of the risk of subsequent CNS depression.
SPECIFIC TOXINS
Enhanced elimination • Not clinically useful. Antidotes • Naloxone inconsistently provides transient reversal of the CNS and respiratory depression associated with clonidine intoxication. • A trial of administration may be warranted as a temporising measure if airway or breathing is compromised, but definitive care with intubation and ventilation is more reliable. • Administer repeated doses of 0.1 mg IV every 30–60 seconds up to a total dose of 0.4 mg while supporting airway and ventilation. • For further information on the indications, contraindications and administration see Chapter 4.19: Naloxone. DISPOSITION AND FOLLOW-UP
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• •
Paediatric patients should be observed in hospital following potential accidental exposure. Patients who are clinically well without symptoms at 6 hours following ingestion may be discharged. Discharge should never occur at night. • Patients with mild symptoms may be managed supportively in a ward environment. Discharge is appropriate when the patient is clinically well, ambulant, passing urine, eating and drinking. • Patients with significant CNS depression requiring intubation require admission to an intensive care unit.
HANDY TIPS
• • •
PITFALLS
• • •
Consider the diagnosis of clonidine ingestion in any small child who presents with lethargy, bradycardia and miosis. Bradycardia is frequently asymptomatic and specific management is not required. Adults who overdose on clonidine are frequently opioid dependent and use clonidine to ameliorate symptoms of opioid withdrawal – avoid naloxone in these patients, as it will exacerbate opioid withdrawal.
Failure to recognise the potential lethality of accidental paediatric ingestion of clonidine. Failure to recognise respiratory depression in children, especially at night. Iatrogenic anticholinergic delirium from excessive doses of atropine administered in response to bradycardia.
CONTROVERSY
•
Role of naloxone.
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Presentations
Clonidine 100 microgram tablets (100) Clonidine 150 microgram tablets (100) Clonidine 150 microgram/mL 1 mL ampoules
References
Deliberate self-poisoning with this atypical antipsychotic agent is uncommon because its use is restricted and closely supervised. Coma may occur and care is supportive. RISK ASSESSMENT
•
A clear dose–response is not defined but the threshold for severe poisoning including coma may be as low as 100 mg in adults. • Clinical manifestations of toxicity are more likely to develop in patients who do not normally take clozapine.
•
Children: ingestion of a single tablet usually results in symptoms and prompts referral to hospital for assessment and observation. Ingestion of >2.5 mg/kg is associated with sedation, hypersalivation, tachycardia, ataxia and agitation. Extrapyramidal effects may develop over the following days.
Toxic mechanism
Clozapine is a tricyclic dibenzodiazepine atypical antipsychotic. It is an antagonist at mesolimbic dopamine (D1 and D2), serotonin (5-HT) and peripheral alpha (α1) receptors. Compared to other antipsychotic agents in its class, it is a potent antagonist at muscarinic (M1), histamine (H1) and gamma-aminobutyric acid (GABA) receptors.
Toxicokinetics
Clozapine is rapidly absorbed following oral administration. It is highly protein bound and has a moderate volume of distribution of 0.5–3 L/kg. Clozapine is metabolised in the liver by oxidation (cytochrome P450 1A2, 2D6) to metabolites that are excreted in the urine and faeces. A significant first-pass effect occurs. CLINICAL FEATURES
• • • •
Onset of intoxication is rapid, occurring within 4 hours of ingestion. CNS depression, including coma requiring intubation, may occur early. Lethargy, confusion, sedation, tachycardia and orthostatic hypotension are common. Anticholinergic effects, such as agitation, ileus or urinary retention, often occur.
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3.29 CLOZAPINE
SPECIFIC TOXINS
Erickson SJ, Duncan A. Clonidine poisoning – an emerging problem: epidemiology, clinical features, management and preventative strategies. Journal of Paediatrics and Child Health 1998; 34(3):280–282. Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Critical Care Medicine 1990; 18(10):1124–1128. Seger DL. Clonidine toxicity revisited. Journal of Toxicology – Clinical Toxicology 2002; 40:145–155.
• • • • • •
Mydriasis and miosis are both described. Hypersalivation is characteristic and may be considered pathognomonic. Seizures occur in approximately 5–10% of patients. Extrapyramidal effects are more common in children. QT prolongation is uncommon. Toxicity usually resolves within 24 hours.
INVESTIGATIONS
SPECIFIC TOXINS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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Specific investigations as required • Serial ECGs — Patients should have a 12-lead ECG at presentation and at 6 hours. If normal, ECG monitoring may cease. If there is prolongation of the QT >450 ms, monitoring should continue until the patient is clinically well and ECG changes have resolved. Torsades de pointes has not been reported. • Clozapine levels — These are readily available and although not helpful in guiding management may be useful to confirm the diagnosis. MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Basic resuscitative measures ensure a good outcome in the vast majority of patients. • Coma may develop and require rapid-sequence intubation and ventilation. • Treat seizures with benzodiazepines, as outlined in Chapter 2.6: Approach to seizures. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Close clinical and physiological monitoring is indicated. • Monitor fluid balance and urine output. Decontamination • Activated charcoal is not indicated unless the airway is first protected by endotracheal intubation. Enhanced elimination • Not clinically useful. Antidotes • None available.
DISPOSITION AND FOLLOW-UP
•
Patients who are clinically well at 6 hours following ingestion are fit for medical discharge.
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Patients who manifest clinical features of intoxication require admission for appropriate supportive care. Parents of small children who have ingested clozapine are advised that abnormal (extrapyramidal) movements might occur up to 7 days later.
HANDY TIPS
Consider the diagnosis of clozapine overdose in a sedated patient with features of anticholinergic poisoning but small pupils and prominent hypersalivation. • Therapeutic use of clozapine is associated with agranulocytosis and myocarditis. These are not clinical features of acute poisoning.
PITFALL
•
Failure to recognise and correct urinary retention.
Presentations Clozapine Clozapine Clozapine Clozapine Clozapine
25 mg tablets (28, 100) 50 mg tablets (100) 100 mg tablets (28, 100) 200 mg tablets (100) suspension 50 mg/mL 100 mL
SPECIFIC TOXINS
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Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Clinical Toxicology 2001; 39(1):1–14. Cobaugh DJ, Erdman AR, Booze LL et al. Atypical antipsychotic medication poisoning; an evidence based consensus guideline for out-of-hospital medication poisoning. Clinical Toxicology 2007; 45:918–942. Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Safety 2005; 26(11):1029–1044. Reith D, Monteleone JP, Whyte IM et al. Features and toxicokinetics of clozapine in overdose. Therapeutic Drug Monitoring 1998; 20(1):92–97. Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs 2003; 17(5):307–324. Wong DC, Curtis LA. Are 1 or 2 dangerous? Clozapine and olanzapine exposure in toddlers. The Journal of Emergency Medicine 2004; 27:273–277.
3.30 COCAINE Cocaine has powerful sympathomimetic and local anaesthetic properties. It is potentially lethal in overdose if severe hyperthermia, hypertension, myocardial ischaemia or pro-dysrhythmic effects occur. RISK ASSESSMENT
• • •
Ingestions of >1 g are potentially lethal. The toxic dose is highly variable and small doses, particularly in non-tolerant patients, may result in significant intoxication. The presence of hyperthermia, headache, cardiac conduction abnormalities, focal neurological signs or chest pain heralds potentially life-threatening complications.
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SPECIFIC TOXINS
TABLE 3.30.1 Dose-related risk assessment: Cocaine
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Dose
Effect
1–3 mg/kg
Safe local anaesthetic dose
20–30 mg
Usual dose in a line of cocaine to be snorted
1 g
Potentially lethal
• •
Pregnancy: cocaine is teratogenic and associated with an increased incidence of miscarriage and fetal demise. Lactation: cocaine is excreted in breast milk and can result in infant intoxication.
•
Children: ingestion is potentially lethal.
Toxic mechanism
Toxicity results from sympathomimetic, vasospastic and sodium channel blocking (local anaesthetic) effects. Sympathomimetic effects are due to blockade of presynaptic catecholamine reuptake and can result in vascular dissection, intracranial haemorrhage and acute cardiomyopathy. Vasospasm and endothelial fissuring result in acute coronary syndrome. Blockade of myocardial fast sodium channels may result in ventricular dysrhythmias, as occur in tricyclic antidepressant cardiotoxicity. Central nervous system excitation may result in psychomotor acceleration, seizures and hyperthermia.
Toxicokinetics
Well absorbed through the mucous membranes of nasopharynx, pulmonary alveolar tree and gastrointestinal tract. Peak concentrations achieved fastest with IV and inhalational administration. Bioavailability depends on route (intranasal 25–80%; smoked 60–70%). Highly lipid soluble, with a volume of distribution of 2 L/kg. Cocaine is rapidly metabolised by liver and plasma cholinesterases to water-soluble metabolites. Only 1% of the drug appears unchanged in the urine. Metabolites may persist in the blood and urine for up to 36 hours. Clinical duration of effect is approximately 60 minutes, with biological half-lives being reported between 0.5 and 1.5 hours. CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, medical complications of abuse or psychiatric sequelae. The onset of cocaine intoxication is rapid, with major clinical manifestations occurring within the first hour and usually lasting several hours. They include: • Central nervous system — Euphoria — Anxiety, dysphoria, agitation and aggression — Paranoid psychosis with visual and tactile hallucinations — Hyperthermia, rigidity and myoclonic movements — Seizures • Cardiovascular — Tachycardia and hypertension may be severe — Dysrhythmias and cardiac conduction abnormalities — Acute coronary syndromes—vasospastic and/or thrombotic — QT prolongation — Acute pulmonary oedema
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • EUC — Detect renal failure and hyponatraemia. • ECG, CK and troponin — Detect myocardial ischaemia, infarction, acute coronary syndrome, QT prolongation and rhabdomyolysis. — A Brugada-type pattern of ECG changes (RBBB with ST elevation in leads V1, V2 and V3) can occur in cocaine intoxication. — Overall, the sensitivity of ECG for detecting myocardial infarction is lower in cocaine users. • Chest X-ray ± CT chest angiogram — Detect aortic dissection or pulmonary aspiration. • CT head — Detect intracranial haemorrhage. • Note: Decreased mental status or focal neurological signs prompts exclusion of hypoglycaemia, aortic dissection or intracranial haemorrhage. • Note: Serum or urine cocaine levels are not readily available and do not assist acute management.
MANAGEMENT
Resuscitation, supportive care and monitoring • Cocaine intoxication is a life-threatening emergency and is managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Clinical features that require immediate intervention include: — Cardiac dysrhythmias including ventricular tachycardia — Hypertension — Hyperthermia — Seizures — Severe agitation. • Ventricular tachycardia is treated with an IV bolus of 50–100 mmol sodium bicarbonate. Ventricular dysrhythmias refractory to
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INVESTIGATIONS
SPECIFIC TOXINS
Peripheral sympathomimetic — Hyperthermia — Muscle fasciculations — Mydriasis, sweating and tremor. • Clinical features associated with the following medical complications: — Hyperthermia-induced rhabdomyolysis, renal failure and cerebral oedema — Aortic and carotid dissection — Subarachnoid and intracerebral haemorrhage — Ischaemic colitis — Pneumothorax — Pneumomediastinum.
•
SPECIFIC TOXINS
• • • •
•
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bicarbonate and defibrillation are treated with lignocaine 1.5 mg/kg IV followed by an infusion of 2 mg/minute. Acute coronary syndromes are treated by standard therapies, with the exception of beta-blockers. This includes aspirin and nitroglycerin. Thrombolytics are contraindicated in the presence of severe hypertension, seizures, intracerebral haemorrhage or aortic dissection. Urgent coronary angiography is indicated in the setting of ST elevation that persists after nitroglycerin and calcium antagonists. Sinus tachycardia and hypertension are treated with titrated parenteral benzodiazepines. Supraventricular tachycardia refractory to benzodiazepine sedation is treated with verapamil 5 mg IV or adenosine 6–12 mg IV. Cardioversion is indicated if unstable. Hypertension refractory to benzodiazepine sedation, consider: — Phentolamine 1 mg IV repeated every 5 minutes — Titrated vasodilator infusion (sodium nitroprusside or glyceryl trinitrate). — Note: Beta-adrenergic blockers are contraindicated. Seizures and agitated delirium are managed with 5 mg diazepam as an IV bolus every 2–5 minutes, repeated until seizures stop or gentle sedation is achieved (see Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation). Hyperthermia: — Temperature >38.5°C is an indication for continuous coretemperature monitoring, benzodiazepine sedation and fluid resuscitation. — Temperature >39.5°C requires rapid external cooling to prevent multiple organ failure and neurological injury. Paralysis, intubation and ventilation may be required.
Decontamination • Gastrointestinal decontamination with activated charcoal is not indicated except in the specific instance of cocaine body packers as discussed in Chapter 2.17: Body packers and stuffers. Enhanced elimination • Not clinically indicated. Antidotes • None available. DISPOSITION AND FOLLOW-UP
•
Children with potential ingestions should be observed in hospital for 4 hours. If they do not develop symptoms during that period they may then be safely discharged. • Patients whose intoxication is adequately controlled with benzodiazepine sedation and have a normal blood pressure and 12-lead ECG may be managed supportively in a ward environment. They are discharged when clinically well. • Patients with significant alteration of conscious state, hyperthermia or ongoing chest pain are admitted to a highdependency or intensive care unit.
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Cocaine body packers or stuffers must undergo gastrointestinal decontamination under medical supervision.
HANDY TIPS
PITFALLS
• • •
Failure to recognise and treat hyperthermia. Failure to adequately sedate the agitated patient with cocaine intoxication. Administration of beta-blockers.
CONTROVERSIES
•
Despite theoretical concerns, intravenous lignocaine does not appear to cause cardiovascular or CNS toxicity when used to treat dysrhythmias in cocaine toxicity. • Indications for coronary angiography and thrombolytic therapy in cocaine-associated chest pain with ECG abnormalities.
Presentations
Prescription medications Cocaine eye drops 15 mL bottles Illicit cocaine derivatives Cocaine hydrochloride powder or paste: processed from the alkaloid extracted from coca leaves, it cannot be smoked as it decomposes at high temperatures. Cocaine base (crack cocaine) or free-base: created by combining cocaine hydrochloride with an alkaline substance to render it heat stable.
References
Afonso L, Mohammad T, Thatai D. Crack whips the heart: a review of the cardiovascular toxicity of cocaine. American Journal of Cardiology 2007; 100(6):1040–1043. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. New England Journal of Medicine 2001; 345(5):351–358. Zimmerman JL. Cocaine intoxication. Critical Care Clinics 2012; 28:517–526.
3.31 COLCHICINE Colchicine overdose is uncommon but potentially lethal. Toxicity is characterised by severe gastroenteritis followed by multi-system organ failure. Aggressive decontamination and supportive care are the cornerstones of management.
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Early control of agitation with IV benzodiazepine sedation calms the patient, improves tachycardia, hypertension and hyperthermia and is safe. • Administration of beta-adrenergic blockers is contraindicated in the management of cocaine intoxication because it causes unopposed alpha-receptor stimulation. • Ongoing chest pain or headache requires further investigation. • Acute coronary syndrome is managed according to normal protocols. CT brain scan should be performed prior to anticoagulation or angiography if headache is a feature.
SPECIFIC TOXINS
•
RISK ASSESSMENT
•
Any intentional ingestion of colchicine is considered potentially lethal. The doses outlined in Table 3.31.1 are useful in predicting outcome, although fatalities are reported with acute ingestion of as little as 0.2 mg/kg.
SPECIFIC TOXINS
TABLE 3.31.1 Dose-related risk assessment: Colchicine
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Dose
Effect
0.8 mg/kg
Severe poisoning involving cardiovascular collapse, coagulopathy, acute renal failure Approaching 100% mortality
•
Children: ingestion of one or two colchicine tablets is not problematic. Larger ingestions may cause severe gastrointestinal symptoms and any symptomatic child should be assessed in hospital.
Toxic mechanism
Colchicine is a naturally occurring alkaloid. It is found in certain plants, including the autumn crocus (Colchicum autumnale) and glory lily (Gloriosa superba). It is used in the treatment of acute gout and has also been advocated in familial Mediterranean fever and pericarditis. It binds tubulin and prevents microtubule formation, thus inhibiting mitosis, as well as other essential intracellular processes. Following overdose, tissues with high cellular turnover (GIT, bone marrow) are preferentially affected.
Toxicokinetics
Colchicine is rapidly absorbed, with peak levels occurring from 0.5 to 2 hours postingestion. Bioavailability is only 45% as a result of extensive first-pass metabolism. It is extensively tissue bound with a volume of distribution of 2 L/kg. Elimination is by hepatic metabolism, with an elimination half-life of up to 30 hours following overdose. CLINICAL FEATURES
Colchicine overdose usually presents with severe gastroenteritis followed by onset of multi-organ toxicity (if more than 0.5 mg/kg is ingested) in the second 24 hours (see Table 3.31.2).
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Specific colchicine levels are not routinely available. • Appropriate laboratory and radiological investigations are used to identify and monitor fluid, electrolyte and acid–base status and development of organ toxicity as outlined above.
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Time
Effect
2–24 hours
Nausea, vomiting, diarrhoea, abdominal pain. Severe GI fluid losses can result in haemodynamic instability. Peripheral leucocytosis commonly seen on blood film
2–7 days
Bone marrow suppression and pancytopenia, rhabdomyolysis, renal failure, progressive metabolic acidosis, respiratory insufficiency, ARDS, cardiac dysrhythmias and risk of sudden cardiac death
>7 days
Rebound leucocytosis and transient alopecia. Complete recovery is expected in patients who survive to this stage
SPECIFIC TOXINS
TABLE 3.31.2 Clinical progression of severe colchicine toxicity
MANAGEMENT
Decontamination • Administer activated charcoal 50 g (1 g/kg in children) as soon as possible to any patient who has potentially ingested >0.5 mg/kg of colchicine, because prevention of absorption of even a small amount may be life saving. Enhanced elimination • Multiple-dose oral activated charcoal may enhance elimination, but is technically difficult in the vomiting patient. It has not been shown to affect outcome and is not routinely recommended. Antidotes • Colchicine-specific antibodies were used successfully in a single case of colchicine overdose, but are not currently available. DISPOSITION AND FOLLOW-UP
•
All adult cases of deliberate self-poisoning are admitted for observation.
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Resuscitation, supportive care and monitoring • Patients may present in hypovolaemic shock due to massive GI fluid losses. They require resuscitation with large volumes of intravenous crystalloid solutions. • Aggressive supportive care in an intensive care environment offers the best chance of survival in severe colchicine poisoning. This includes meticulous management of fluid, electrolyte and acid–base status and infectious complications. • Early respiratory insufficiency and cardiac arrest is anticipated; airway protection and ventilatory assistance are implemented as necessary. • Close clinical, physiological and laboratory monitoring is indicated. • Patients with severe toxicity require invasive monitoring.
• • HANDY TIP
•
SPECIFIC TOXINS
PITFALLS
• •
Patients who do not develop gastrointestinal symptoms within 24 hours of ingestion are medically cleared. Patients with significant toxicity require admission to an intensive care unit. Admit ALL colchicine overdoses. Arrange early transfer to intensive care if more than 0.5 mg/kg is ingested or any symptoms develop. Failure to identify ingestion of colchicine at presentation. Failure to anticipate the severity of colchicine poisoning.
CONTROVERSY
•
Utility of granulocyte colony-stimulating factor (GCSF) in the treatment of severe leucopenia.
Presentations
Colchicine 500 microgram tablets (30)
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References
Harris R, Gillet M. Colchicine poisoning – overview and new directions. Emergency Medicine 1998; 10:161–167. Jayaprakash V, Ansell G, Galler D. Colchicine overdose: the devil is in the detail. New Zealand Medical Journal 2007; 120(1248):81–88.
3.32 CORROSIVES Alkalis: Ammonia, Potassium hydroxide, Sodium hydroxide, Sodium hypochlorite Acids: Hydrochloric acid, Sulfuric acid Other: Glyphosate, Paraquat, Phenols, Potassium permanganate, Mercuric chloride, Zinc chloride Ingestion of corrosive agents causes injury to the upper airway and gastrointestinal tract. Upper airway injury is a life-threatening emergency. Endoscopy and CT scanning stratify the risk for delayed sequelae in symptomatic patients. RISK ASSESSMENT
•
Deliberate or unintentional ingestion of concentrated sulfuric acid (H2SO4), sodium hydroxide (NaOH) solutions and solid preparations are associated with severe corrosive injury to the pharynx, upper airway, oesophagus and stomach. These agents are not associated with systemic toxicity. • Stridor, dyspnoea, dysphonia or throat pain indicates airway injury and an immediate threat to life. • Significant gastro-oesophageal injury is indicated by any two of the following: stridor, drooling or vomiting. • Ingestion of >60 mL of concentrated hydrochloric acid (HCl) leads to severe injury to the stomach and duodenum with necrosis and
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Children: unintentional ingestion of household drain and oven cleaners or automatic dishwashing powders can cause severe corrosive injury. Unintentional ingestion of household bleach is usually benign. Ingested button batteries may cause local corrosive injury if they lodge in the oesophagus (see Chapter 3.21: Button batteries).
Toxic mechanism Corrosive agents cause direct chemical injury to tissues. The extent of injury is dependent on pH, concentration and volume ingested. Alkaline agents cause liquefactive necrosis, resulting in deep and progressive mucosal damage. Acids cause protein denaturation and coagulative necrosis. CLINICAL FEATURES
• • • • • • • •
Following corrosive ingestion, patients may experience immediate pain in the mouth and throat, drooling, odynophagia, vomiting and abdominal pain. Laryngeal oedema may cause rapidly progressive stridor, hoarseness and respiratory distress. Oesophageal perforation and mediastinitis are associated with chest pain, dyspnoea, fever, subcutaneous emphysema and a pleural rub. Thirty per cent of patients with grade IIB or III injury (see below) will develop oesophageal strictures. Grade II and III injuries are associated with oesophageal carcinoma 40–50 years later. Perforation of the stomach or small intestine produces clinical features of peritonitis. Gastrointestinal tract perforation is complicated by septic shock and multi-organ failure. Patients who ingest large amounts of concentrated acids usually present in shock with profound metabolic acidosis and progress to multi-organ failure and death despite laparotomy and surgical debridement of necrotic tissue.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated All patients with persistent vomiting, oral burns, drooling or abdominal pain require further investigation to define the extent of injury and
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SPECIFIC TOXINS
perforation, rapid onset of severe multi-organ failure and is usually fatal. • Ingestion of 20 micromol/L (0.05 mg/dL)
Symptomatic
>40 micromol/L (0.1 mg/dL)
Potentially toxic
>100 micromol/L (0.25 mg/dL)
Lethal
MANAGEMENT
Resuscitation, supportive care and monitoring • Cyanide poisoning poses multiple immediate threats to life: coma, seizures, shock and profound lactic acidosis. • Immediate intubation and ventilation with 100% oxygen is indicated in severe poisoning. • Resuscitation proceeds along conventional lines, as outlined in Chapter 1.2: Resuscitation. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Removal from the source of hydrogen cyanide gas exposure is vital. • Remove clothes and wash skin with soap and water. Clothing should be bagged. • Cyanide is rapidly absorbed and the onset of symptoms occurs within minutes. Resuscitation takes priority over decontamination. Activated charcoal is contraindicated until the airway has been secured by endotracheal intubation.
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Specific investigations as indicated • EUC • Arterial blood gases and serum lactate — Serum lactate strongly correlates with severity of intoxication. — In smoke inhalation victims without severe burns, the sensitivity, specificity and positive predictive value of a serum lactate >10 mmol/L for cyanide levels >40 micromol/L (0.1 mg/dL) are 87%, 94% and 95%, respectively. • Cyanide levels — These do not aid acute management but confirm diagnosis in retrospect. — Take blood before antidotes are commenced (use a heparinised tube).
SPECIFIC TOXINS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
Enhanced elimination • Not clinically useful.
SPECIFIC TOXINS
Antidotes • In a patient with suspected cyanide poisoning and serious clinical effects (altered mental status, seizures, hypotension, significant metabolic acidosis), administer a cyanide antidote. • The available antidotes are hydroxocobalamin, thiosulfate and dicobalt edetate (see Chapter 4.5: Dicobalt edetate, Chapter 4.14: Hydroxocobalamin and Chapter 4.27: Sodium thiosulfate for administration details). • Under most circumstances, hydroxocobalamin is the preferred antidote if available.
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• • •
Patients who are clinically well at 4 hours may be discharged. Patients with a history of acetonitrile ingestion must be observed for at least 24 hours. Patients managed supportively who show rapid clinical improvement, with normal mental status and vital signs, may be managed in a ward environment. • Patients with objective evidence of cyanide intoxication require aggressive supportive care, intubation and ventilation and consideration for antidote treatment. • Patients with severe cyanide intoxication and cardiovascular instability require management in an intensive care setting.
HANDY TIPS
•
Consider the diagnosis of cyanide poisoning where a sustained lactic acidosis is noted in the patient presenting following sudden collapse. • Despite the presence of effective antidotes, early aggressive supportive care alone may be sufficient to achieve a good outcome in most cases. • The decision to give an antidote must be made before cyanide levels are available.
PITFALLS
• •
Failure to recognise cyanide intoxication. Inability to immediately access cyanide antidotes.
CONTROVERSY
•
The indications and efficacy of cyanide antidotes are not established.
Sources
Industrial Cyanide salts are used in metallurgy and ore extraction Hydrogen cyanide is a fumigant (aeroplanes, buildings, ships) Nitriles that yield cyanide are used in manufacture of plastics and synthetic fibres Non-industrial Cyanide is the product of combustion of natural substances and synthetic material and therefore commonly produced in fires Solvent in artificial nail remover
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3.34 DIGOXIN: ACUTE OVERDOSE See also 3.35: Digoxin: Chronic poisoning. Acute digoxin toxicity manifests with early onset of vomiting and hyperkalaemia and can progress to life-threatening cardiac dysrhythmias and cardiovascular collapse. Cardiovascular complications are refractory to conventional resuscitation measures. Digoxin immune Fab is a highly effective antidote. RISK ASSESSMENT
• •
Acute digoxin intoxication occurs if more than 10 times the daily defined dose is ingested. Potentially lethal digoxin intoxication is predicted by: — Dose ingested >10 mg (adult) or >4 mg (child) — Serum digoxin level >15 nmol/L (12 ng/mL) at any time — Serum potassium >5.5 mmol/L. • Potentially lethal natural cardiac glycoside intoxication can occur following ingestion of certain plants or plant parts, or of concoctions or teas brewed using glycoside-containing plants or toad skins.
•
Children: ingestion of up to 75 microgram/kg is safe and does not require hospital observation or treatment unless symptoms develop.
Toxic mechanism
Digoxin inhibits the membrane Na+–K+-ATPase pump, leading to a reduced sodium gradient and reduced calcium extrusion from the cell. This results in increased concentrations of intracellular calcium (enhanced automaticity, positive inotropic effect) and extracellular potassium. Digoxin also enhances vagal tone, resulting in decreased sinoatrial and atrioventricular node (AV) conduction velocities.
Toxicokinetics
Digoxin is well absorbed after oral administration, with bioavailability 60–80%. Peak effects usually occur after 6 hours. Its volume of distribution is large (5–10 L/kg). Digoxin undergoes minimal hepatic metabolism and is eliminated unchanged by the kidneys. The elimination half-life is 30–40 hours and prolonged further in renal impairment.
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Baud FJ, Barriot P, Toffis V et al. Elevated blood cyanide levels in victims of smoke inhalation. New England Journal of Medicine 1991; 325:1761–1766. Braitberg G, Vanderpyl MMJ. Treatment of cyanide poisoning in Australasia. Emergency Medicine 2000; 12(3):232–240. Hall A, Saiers J, Baud F. Which cyanide antidote? Critical Reviews in Toxicology 2009; 39(7):541–552. Reade MC, Davies SR, Morley PT et al. Review article: management of cyanide poisoning. Emergency Medicine Australasia 2012; 24:225–238.
SPECIFIC TOXINS
References
SPECIFIC TOXINS
CLINICAL FEATURES
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Nausea and vomiting are early clinical features of acute digoxin poisoning and develop within 2–4 hours of ingestion. Peak serum digoxin levels are reached at approximately 6 hours and death secondary to cardiovascular collapse may follow at 8–12 hours. Specific clinical features include: • Gastrointestinal — Nausea, vomiting and abdominal pain • Cardiovascular — Bradycardias – First, second or third degree AV block – AF with ventricular response 10 mg (adult) or >4 mg (child) — Serum digoxin level >15 nmol/mL (12 ng/mL) — Serum potassium >5 mmol/L. • Digoxin immune Fab dosing is empirical or based on the dose of digoxin known to be ingested (see Chapter 4.6: Digoxin immune Fab). DISPOSITION AND FOLLOW-UP
•
Patients with falling serial serum digoxin levels, normal serum potassium, no gastrointestinal symptoms and no evidence of cardiotoxicity at 6 hours do not require further medical care or observation. • Patients who have received digoxin immune Fab, have normal serum potassium, manifest no significant cardiac dysrhythmia and
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In cardiac arrest, standard resuscitation measures are futile. Advanced cardiac life support is initiated while 20 ampoules (or as many as are available) of digoxin immune Fab are sourced and administered. This may be life-saving. Attempts at resuscitation should continue for at least 30 minutes after the administration of digoxin immune Fab. • If digoxin immune Fab is not immediately available, temporising measures are instituted to deal with imminent life threats: — Hyperkalaemia – Administer sodium bicarbonate 100 mEq IV bolus (1 mEq/kg in children). – Give insulin 10 units and 50 mL 50% dextrose simultaneously as an IV bolus (0.1 units/kg insulin and 2 mL/kg 10% dextrose in children). – Note: Calcium is contraindicated. — Atrioventricular block – Give atropine 0.6 mg IV bolus. Repeat until desired clinical effect is achieved to a maximum of 1.8 mg (20 microgram/kg/dose in children). – External pacing is rarely effective. — Ventricular tachydysrhythmias – Administer lignocaine 1 mg/kg (max 100 mg) IV over 2 minutes.
SPECIFIC TOXINS
•
remain clinically well over the next 24 hours do not require further medical care or observation. HANDY TIPS
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SPECIFIC TOXINS
• • • • •
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Early accurate risk assessment allows administration of digoxin immune Fab before life-threatening toxicity develops. If digoxin immune Fab is not immediately available, it is usually quicker and safer to arrange for it to be transported to the patient rather than for the patient to be transported to a hospital with antidote stocks. Serum K >5.5 mmol/L predicts 100% mortality without digoxin immune Fab. Calcium is contraindicated in the treatment of digoxin or cardiac glycoside-induced hyperkalaemia. Digoxin is sometimes co-ingested with other cardiotropic medications, such as calcium channel blockers. The aetiology of bradycardia or AV block may not be clear. Therapeutic trial of digoxin immune Fab may assist risk assessment. Do not repeat digoxin levels following administration of digoxin immune Fab; most laboratories measure both bound and unbound digoxin, resulting in alarmingly high serum levels that are of no clinical relevance. Serum digoxin levels are an unreliable indication of dose following ingestion of natural cardiac glycosides. Failure to stock sufficient digoxin immune Fab. In a large overdose, antidote needs to be gathered from all available sources.
CONTROVERSIES
•
Dose of digoxin immune Fab. Less than the currently recommended initial doses may be sufficient to reverse toxicity. Further monitoring and supplementary doses according to response are necessary if this approach is adopted. • Multiple-dose activated charcoal may be associated with improved outcomes in plant glycoside poisoning, particularly where digoxin immune Fab is not immediately available.
Presentations
Digoxin 62.5 microgram tablets (200) Digoxin 250 microgram tablets (100) Digoxin 50 microgram/mL elixir (60 mL) Digoxin 50 microgram/2 mL ampoules Digoxin 500 microgram/2 mL ampoules Note: Natural sources of cardiac glycosides with similar toxicity: Plants: foxglove, lily of the valley, oleander, rhododendron Animals: toad (Bufo spp.) venom and body parts – used in some traditional Chinese medicines.
• •
References
Antman EM, Wenger TL, Butler VP et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter study. Circulation 1990; 81(6):1744–1752.
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Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicological Reviews 2004: 23(3):135–143. De Silva HA, Fonseka MM, Pathmeswaran A et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebocontrolled trial. Lancet 2003; 361:1935–1938. Eddleston M, Rajapakse S, Rajakanthan JS et al. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000; 355(9208):967–972. Woolf AD, Wenger T, Smith TW et al. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. New England Journal of Medicine 1992; 326:1739–1744.
Chronic digoxin poisoning is an underdiagnosed condition that carries significant morbidity and mortality. Digoxin has a narrow therapeutic index and intoxication commonly develops in elderly patients with multiple co-morbidities. Use of digoxin immune Fab reduces mortality and may reduce hospital length of stay and cost of care. RISK ASSESSMENT
• • •
Chronic digoxin poisoning, although variable in severity, is a life-threatening condition. Untreated, mortality within a week is 15–30%. The probability of digoxin intoxication is predicted by considering serum digoxin level and clinical features (see Table 3.35.1).
TABLE 3.35.1 Probability of digoxin toxicity
Clinical features
Serum digoxin level 1.5 ng/mL (1.9 nmol/L)
Serum digoxin level 2.5 ng/mL (3.2 nmol/L)
Bradycardia only
10%
50%
GI symptoms only
25%
60%
GI symptoms and bradycardia
60%
90%
Automaticity alone
70%
90%
Automaticity plus any other feature
>80%
100%
Adapted from Abad-Santos F, Carca AJ, Ibanez C et al. Digoxin level and clinical manifestations as determinants in the diagnosis of digoxin toxicity. Therapeutic Drug Monitoring 2000; 22(2):163–168.
Toxic mechanism
Digoxin inhibits the membrane Na+–K+-ATPase pump, which in turn leads to increased intracellular calcium (enhanced automaticity, positive inotropic effect) and increased
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See also 3.34: Digoxin: Acute overdose.
SPECIFIC TOXINS
3.35 DIGOXIN: CHRONIC POISONING
extracellular potassium. Digoxin also enhances vagal tone leading to a decrease in sinoatrial and atrioventicular (AV) node conduction velocity.
Toxicokinetics
Digoxin is well absorbed after oral administration, with bioavailability 60–80%. Peak effects usually occur after 6 hours. Its volume of distribution is large (5–10 L/kg). Digoxin undergoes minimal hepatic metabolism and is eliminated unchanged by the kidneys. The elimination half-life is 30–40 hours and prolonged further in renal impairment.
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The clinical manifestations of chronic digoxin toxicity are non-specific. Digoxin intoxication commonly develops in elderly patients in the context of intercurrent illness, particularly where this leads to impaired renal function and digoxin elimination. It is often difficult to determine whether the unwell patient with an elevated serum digoxin level has digoxin toxicity or another cause for the observed clinical features. Onset is insidious over days or weeks. Clinical features include: • Cardiovascular — Bradycardias – First, second or third degree AV block – AF with slow ventricular response (50 mg/kg can cause coma and respiratory depression. Overdose is life threatening without timely support of airway and ventilation. Maximal toxicity is usually evident by the time of arrival at the emergency department. Co-ingestion of ethanol or other CNS depressants increases the risk of respiratory depression, apnoea and death. Children: any ingestion may be associated with rapid onset of coma and is regarded as potentially fatal.
Toxic mechanism
GHB is a short-chain carboxylic acid that occurs naturally in the brain. It is both a precursor and metabolite of gamma-aminobutyric acid (GABA) and may be a neurotransmitter itself. The mechanism of action is unclear. Hypotheses include agonist activity at GABAB receptors, activity at specific GHB receptors, dopaminergic modulation, increased acetylcholine and serotonin levels and interaction with endogenous opioids.
Toxicokinetics
GHB is rapidly absorbed following oral administration with peak plasma concentrations occurring 25–60 minutes post-ingestion. The presence of food reduces bioavailability. It has variable distribution. Gamma-butyrolactone (GBL) is rapidly transformed in the
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•
SPECIFIC TOXINS
Includes GHB precursors: gamma-butyrolactone, 1,4-butanediol.
liver to GHB. 1,4-butanediol (BD) is metabolised rapidly to GHB by alcohol dehydrogenase. The presence of alcohol competitively inhibits metabolism and delays the onset of effect. GHB is rapidly oxidised to carbon dioxide and water with saturable kinetics. The elimination half-life is usually less than one hour and elimination is complete within 4–8 hours.
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Clinical effects of GHB occur within 20 minutes of ingestion and peak at 30–60 minutes. Standard recreational doses produce rapid onset of euphoria and drowsiness, as well as enhanced sexual desire, performance and orgasm. In overdose, a brief period of euphoria is followed by rapid onset of coma. The patient can be roused with an external stimulus, only to become deeply somnolent again when not disturbed. Sudden recovery of consciousness occurs, usually within 2–3 hours. Recovery is characterised by a short period of agitation or delirium, and vomiting. Complete recovery is expected within 8 hours. Deaths are reported and occur from airway obstruction, pulmonary aspiration or respiratory arrest. Typical clinical features observed following overdose include: • Central nervous system — CNS depression — Agitation and delirium — Miosis — Myoclonic movements may be noted in rare cases, sometimes mimicking generalised seizures • Respiratory — Airway obstruction — Respiratory depression — Cheyne–Stokes-type breathing • Cardiovascular — Bradycardia — Mild hypotension responsive to intravenous fluids — Non-specific ECG changes • General — Mild hypothermia — Vomiting — Sweating. Tolerance to GHB develops with regular use and a withdrawal syndrome is described. Clinical features of GHB withdrawal include hallucinations, paranoia, insomnia, anxiety, sweating, palpitations and agitation. Clinical features of withdrawal may develop within 1–12 hours of the last dose of GHB and persist for 3–21 days.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations • Rarely required, except to exclude alternative diagnoses for coma. • Blood and urine GHB levels are not readily available, do not correlate with toxic symptoms and do not assist management.
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Serum and urine levels may be useful retrospectively in forensic cases; however, GHB is rapidly cleared from the blood and may not be detected in samples taken later in the clinical course. It is detectable somewhat longer in the urine, but not reliably after 12 hours.
Decontamination • Activated charcoal is not indicated because absorption and onset of CNS depression occurs rapidly. Enhanced elimination • Not clinically useful. Antidotes • None available. DISPOSITION AND FOLLOW-UP
• •
Patients who are clinically well 2 hours following ingestion may be discharged. Discharge should not occur at night. Patients with mild symptoms are managed supportively in a ward environment. They are fit for medical discharge when ambulant, passing urine, eating and drinking. • Patients with significant CNS depression requiring intubation are admitted to an intensive care unit. Short-term ventilation in the emergency department is an alternative when the diagnosis is certain.
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The resolution of coma may be abrupt. Care is required as patients may be agitated and forcefully extubate themselves.
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Resuscitation, supportive care and monitoring • Acute GHB intoxication is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation. Basic resuscitative measures ensure the survival of the vast majority of patients. • Potential early life threats that require immediate intervention include: — Coma — Respiratory depression — Loss of airway protective reflexes. • Attention to airway, breathing and circulation are paramount. These priorities can usually be managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Bradycardia is common. Specific management (e.g. atropine, catecholamine infusion or pacing) is not usually required. • Myoclonic movements do not require specific management. If seizures are suspected, they should be managed as outlined in Chapter 2.6: Seizures. • Close clinical and physiological monitoring is indicated.
SPECIFIC TOXINS
MANAGEMENT
•
The diagnosis of GHB intoxication is frequently made in retrospect. It should be suspected in any young person found collapsed in a nightclub, although alternative diagnoses, particularly alcohol intoxication, are more likely. • Standard urine toxicological screens do not detect GHB. PITFALL
•
Coma lasting longer than 8 hours suggests an alternative diagnosis (e.g. co-ingested agent or complication) and should prompt further investigation.
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•
Physostigmine has been advocated in the management of GHB poisoning. There is no evidence to suggest that the use of physostigmine confers any additional benefits over supportive measures alone.
Presentation and Sources GHB is a white crystalline powder. It is usually distributed dissolved in water to form a clear colourless liquid. It may be ingested directly or added to drinks. The concentration is often 1 g/mL but this is extremely variable. Precursors are found in several household solvents: • Gamma-butyrolactone (GBL) is an oily liquid • Acetone-free nail polish remover pads • 1,4-butanediol (BD) is a water soluble liquid. References
Allen L, Alsalim W. Gamma-hydroxybutyrate overdose and physostigmine. Emergency Medicine Journal 2006; 23(4):300–301. Chin RL, Sporer KA, Cullison B et al. Clinical course of gamma-hydroxybutyrate overdose. Annals of Emergency Medicine 1998; 31:716–722. Schep LJ, Knudsen K, Slaughter RJ et al. The clinical toxicology of gammahydroxybutyrate, gamma-butyrolactone and 1,4-butanediol. Clinical Toxicology 2012; 50:458–470. Traub SJ, Nelson LS, Hoffman RS. Physostigmine as treatment for gammahydroxybutyrate toxicity: a review. Journal of Toxicology – Clinical Toxicology 2002; 40(6):781–787.
3.38 GLYPHOSATE Glyphosate is a widely used herbicide. Severe toxicity occurs as result of deliberate ingestion of a concentrated formulation. It manifests with gastrointestinal corrosive symptoms and, in large ingestions, severe metabolic acidosis, hyperkalaemia and cardiovascular collapse can occur. RISK ASSESSMENT
• • •
Ingestion of concentrated formulations poses the greatest risk. Dose is frequently difficult to quantify but correlates to severity (see Table 3.38.1). Acute corrosive injury to the upper airways poses an immediate potential threat to life.
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Effect
150 mL 100% concentrate
Severe gastrointestinal symptoms. Risk of early upper airways swelling. May develop multi-system toxicity, especially metabolic acidosis, hyperkalaemia and hypotension
>300 mL 100% concentrate
Potentially fatal. Death usually from refractory shock
•
Tachycardia, abnormal chest X-ray, metabolic acidosis, hyperkalaemia, acute renal impairment and older age are associated with poorer prognosis. • Diluted glyphosate solutions pose little risk when ingested, with toxicity confined to minor gastrointestinal irritation. • Cutaneous exposures cause skin irritation, but do not cause systemic toxicity.
•
Children: minor ingestions do not need hospital assessment unless symptoms develop.
Toxic mechanism
Glyphosate (glycine phosphonate) does not inhibit cholinesterase enzymes. Toxicity is thought to be predominantly due to the surfactant and possibly other co-formulants rather than glyphosate per se. The mechanism of toxicity is poorly understood but may involve disruption of cellular membranes and uncoupling of mitochondrial oxidative phosphorylation. Concentrated glyphosate solutions also cause direct corrosive injury to the gastrointestinal tract when ingested.
Toxicokinetics
Glyphosate is poorly but rapidly absorbed following ingestion with peak concentrations occurring within 4 to 6 hours. It is not metabolised, but eliminated unchanged by the kidneys with an elimination half-life of 4 to 6 hours. The elimination half-life is prolonged in renal impairment. CLINICAL FEATURES
•
Gastrointestinal — Corrosive injury to the oropharynx, oesophagus, stomach and duodenum manifests with nausea, vomiting, diarrhoea and abdominal pain — Corrosive injury is rarely severe and Grade III injuries (see Chapter 3.32: Corrosives) are not reported after glyphosate ingestion • Cardiovascular — Myocardial depression — Hypotension — Cardiovascular collapse
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Dose
SPECIFIC TOXINS
TABLE 3.38.1 Dose-related risk assessment: Glyphosate
•
Respiratory — Upper respiratory tract irritation and drooling — Aspiration pneumonitis — Non-cardiogenic pulmonary oedema has been reported • Metabolic — Hyperkalaemia — Metabolic acidosis • Patients may develop hepatic and renal dysfunction. • Multi-organ dysfunction secondary to myocardial depression and systemic acidosis can also occur.
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Glyphosate levels are not readily available and not clinically useful • EUC, LFTs — Detect and monitor hyperkalaemia. — Detect and monitor hepatic and renal dysfunction. • Arterial blood gas, venous lactate — Detect and monitor metabolic acidosis. • Chest X-ray — Detect aspiration pneumonitis, pulmonary oedema. • Endoscopy/CT chest — This is not routinely required as severe corrosive injury of the gastrointestinal tract is unusual.
MANAGEMENT
Resuscitation, supportive care and monitoring • Manage the patient in an area equipped for cardiorespiratory monitoring and resuscitation. • Intubate and ventilate if any evidence of airway compromise from oropharyngeal corrosive injury. • Treat hypotension initially with volume replacement. Give a bolus of 10–20 mL/kg of crystalloid solution IV. Those patients unresponsive to fluid challenge are likely to require invasive monitoring and vasopressor therapy. Decontamination • Not indicated and technically difficult due to vomiting. Enhanced elimination • Haemodialysis enhances the elimination of glyphosate, but is not generally indicated. It may be useful when the clinical course is complicated by severe acidosis and acute renal injury. Antidotes • None available.
DISPOSITION AND FOLLOW-UP
•
Patients who are clinically well after 4 hours of observation may be discharged. Discharge should not occur at night.
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Patients with objective evidence of glyphosate intoxication are admitted to an area with resources and staff available to monitor fluid balance and observe for potential cardiorespiratory compromise. • A patient known to have ingested >150 mL of 100% glyphosate is admitted to a high-dependency or intensive unit in anticipation of multiple organ effects within 24 hours. • Adult patients with dermal occupational exposure do not require referral to hospital unless they are symptomatic.
PITFALLS
• •
Intubate early if stridor develops. Failure to appreciate potential for cardiovascular compromise following large ingestions. Confusion between glyphosate and organophosphate poisoning. These are two distinct clinical entities.
CONTROVERSY
•
SPECIFIC TOXINS
•
Utility of haemodialysis in severe glyphosate poisoning.
Presentation and Sources Numerous glyphosate formulations are available. Concentrated preparations are usually 36–50% glyphosate while ready-to-use diluted preparations are approximately 10%. All preparations also contain polyoxyethyleneamine surfactant. References
Bradberry SM, Proudfoot AT, Vale JA. Glyphosate poisoning. Toxicological Reviews 2004; 23(3):159–167. Chen H-H, Lin J-L, Huang W-H et al. Spectrum of corrosive esophageal injury after intentional paraquat or glyphosate-surfactant herbicide ingestion. International Journal of General Medicine 2013; 6:677–683. Lee CH, Shih CP, Hsu KH et al. The early prognostic features of glyphosate-surfactant intoxication. American Journal of Emergency Medicine 2008; 26:275–281. Lee HL, Chen KW, Chi CH et al. Clinical presentations and prognostic factors of glyphosate-surfactant herbicide intoxication: a review of 131 cases. Academic Emergency Medicine 2000; 7(8):906–910. Roberts DM, Buckley NA, Mohamed F et al. A prospective observational study of the clinical toxicology of glyphosate-containing herbicides in adults with acute self-poisoning. Clinical Toxicology 2010; 48:129–136.
3.39 HYDROCARBONS Aliphatic: Essential oils (includes eucalyptus oil), Kerosene, Petroleum distillates, Turpentine Aromatic: Benzene, Toluene, Xylene Halogenated: Carbon tetrachloride, Methylene chloride, Tetrachloroethylene, Trichloroethylene See also Chapter 2.16: Solvent abuse. Hydrocarbons, whether ingested or inhaled, can cause rapid onset of CNS depression, seizures and (rarely) cardiac dysrhythmias. Aspiration
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can lead to chemical pneumonitis. Other end-organ effects are uncommon and usually associated with long-term occupational exposure. RISK ASSESSMENT
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• • • •
The major risks following acute ingestion are early CNS depression and seizures. For most petroleum distillates, more than 1–2 mL/kg is required to cause significant systemic toxicity. Ingestion of as little as 10 mL of eucalyptus oil or other essential oils may lead to CNS depression and seizures, always within 1–2 hours. Ingestion may be complicated by aspiration, resulting in a pneumonitis that evolves over hours. Large or prolonged inhalational exposure may also produce asphyxia. High-viscosity compounds (motor oil, petroleum jelly) have very low risk of systemic toxicity or chemical pneumonitis. Children: — There is a small risk of pulmonary aspiration and chemical pneumonitis following ingestion of any hydrocarbon — Ingestion of 5 mL of eucalyptus oil or other essential oils is associated with the rapid onset of coma.
Toxic mechanism
Disruption of lung surfactant produces a chemical pneumonitis. The mechanism of CNS depression is unclear. Dysrhythmias are secondary to myocardial sensitisation to endogenous catecholamines. Mechanisms of negative inotropic effects are unclear. Chlorinated hydrocarbons (carbon tetrachloride) are metabolised to produce a hepatotoxic metabolite.
Toxicokinetics
The hydrocarbons of concern are volatile. Absorption following inhalational exposure is determined by concentration, duration of exposure and minute ventilation. Absorption following ingestion is inversely related to the molecular weight of the hydrocarbon. Minimal absorption occurs following dermal exposure. Distribution to the CNS is determined by lipid solubility. Most hydrocarbons are eliminated unchanged through expired air. Some compounds produce metabolites that are excreted in the bile or urine. CLINICAL FEATURES
•
Respiratory — Immediate coughing and gagging indicates aspiration. — The development of chemical pneumonitis is heralded by wheeze, tachypnoea, hypoxia, haemoptysis and pulmonary oedema. In mild cases, pulmonary signs may be delayed 4–6 hours. Features typically worsen over 24–72 hours and resolve over 5–7 days. • Cardiovascular — Dysrhythmias occur early in poisoning (pre-hospital). • Neurological — Profound CNS depression, coma and seizures may occur with massive acute exposures. Onset is within 2 hours. — Chronic toluene abuse results in ataxia, dementia and peripheral neuropathy (see Chapter 2.16: Solvent abuse). • Gastrointestinal — Nausea and vomiting.
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Other — Chemical phlebitis and local tissue injury occur following IV or SC injection. — High-pressure injection injuries can produce extensive tissue injury involving tendons and deep structures. — Hepatic and renal injury occurs in carbon tetrachloride (CCl4) poisoning. — Toluene is nephrotoxic. — Benzene is associated with haemolysis and leukaemia.
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial ECGs and continuous cardiac monitoring if ectopy or bigeminy are noted at initial assessment • FBC, EUC, LFTs, arterial blood gases • Chest X-ray: radiographic changes lag behind clinical features of pneumonitis • Chronic toluene abuse leads to a renal tubular acidosis characterised by hypokalaemic hyperchloraemic non-anion gap metabolic acidosis
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Resuscitation, supportive care and monitoring • Resuscitation proceeds along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Close clinical and physiological monitoring is indicated. • In the event of ventricular dysrhythmias (VT, VF): — Commence advanced cardiac life support — Intubate, hyperventilate and correct hypoxia — Administer propranolol 1 mg IV or metoprolol 5 mg IV (0.1 mg/kg in children) — Correct hypokalaemia and hypomagnesaemia — Withhold catecholamine inotropes if possible. • Manage seizures along conventional lines, as outlined in Chapter 2.6: Seizures. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Chemical pneumonitis is managed supportively with supplemental oxygen and bronchodilators. Non-invasive ventilation or intubation and ventilation is required in severe cases. Corticosteroids and prophylactic antibiotics are not indicated. • Fever is common following significant aspiration with pneumonitis. Withhold antibiotics until there is objective evidence of pulmonary sepsis. Decontamination • Remove patient from the exposure, remove clothing and wash skin. • Activated charcoal does not bind hydrocarbons. • Gastrointestinal decontamination of any kind is contraindicated following ingestion because induction of vomiting increases the risk of hydrocarbon aspiration.
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Enhanced elimination • Not clinically useful. Antidotes • None available. DISPOSITION AND FOLLOW-UP
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Children suspected of ingesting small amounts of hydrocarbons may be observed at home providing they remain asymptomatic. Any respiratory symptoms beyond an initial cough mandates hospital assessment and observation. • Patients who are clinically well without cough, dyspnoea, wheeze or any alteration in vital signs (including pulse oximetry) at 6 hours are fit for medical discharge. • Patients with any symptoms or alteration in vital signs are admitted for observation and supportive care. • Patients with high-pressure injection injuries require surgical referral for urgent debridement.
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PITFALL
•
Coughing or gagging following ingestion suggests aspiration.
•
Failure to recognise dry cough as a symptom of evolving pneumonitis.
CONTROVERSIES
• •
Mechanisms of myocardial toxicity. Chronic occupational solvent encephalopathy.
Sources
Most commercial hydrocarbon products are mixtures. Hydrocarbons are organic compounds derived from many sources, including petroleum, plant oils and animal fats. They are widely used in both commercial and household settings as fuel, lubricants, paint thinners and solvents.
References
Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the toxicology of volatile substances. Drug Safety 1990; 5(5):359–383. Kopec KT, Brent J, Banner W et al. Management of cardiac dysrhythmias following hydrocarbon abuse: clinical toxicology teaching case from NAACT acute and intensive care symposium. Clinical Toxicology 2014; 52:141–145. Tibballs J. Clinical effects and management of eucalyptus oil ingestion in infants and young children. Medical Journal of Australia 1995; 163(4):177–180.
3.40 HYDROFLUORIC ACID Hydrofluoric acid (HF) is found in car wheel cleaners, rust removing solutions and in preparations for glass etching and other industrial processes. Exposure may be dermal, inhalational, ocular or oral. Accidental dermal exposure is common. Toxicity ranges from minor dermal injury to life-threatening systemic complications. Ingestion of HF is potentially lethal.
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• • •
Any dermal exposure may lead to delayed severe pain and tissue injury. Inhalational exposure can lead to pulmonary injury. Systemic life-threatening fluorosis is associated with ingestion or extensive dermal exposures: — Dermal exposure with 100% HF solution to 2.5% body surface area (BSA) — Dermal exposure with 70% HF to 8% BSA — Dermal exposure with 23% HF to 11% BSA — Ingestion of ≥ 100 mL of low-concentration HF (6%) by an adult — Ingestion of any volume of higher concentrations of HF.
•
Children: any ingestion of a HF-containing product is potentially lethal.
Toxic mechanism
Fluoride ions bind directly with calcium and magnesium, as well as interfering with cellular potassium channels to cause cell dysfunction and death. Systemic toxicity and ventricular dysrhythmias are secondary to hypocalcaemia, hyperkalaemia, hypomagnesaemia and acidosis.
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Toxicokinetics
CLINICAL FEATURES
•
Dermal exposure — Skin contact with HF in concentrations 10%) causes permanent corneal injury. • Exposure of the skin to concentrated H2O2 solutions (>10%) causes local injury. • Gas embolism can also arise where H2O2 solutions are used medically to irrigate closed body cavities.
•
Children: minor exposures to domestic products containing 3% H2O2 are unlikely to cause significant injury. Any exposure to concentrated H2O2 solutions (>10%) or where symptoms develop is of concern and warrants hospital assessment.
Toxic mechanism
Hydrogen peroxide causes toxicity by three mechanisms: direct corrosive injury, oxygen gas formation and lipid peroxidation. Hydrogen peroxide is corrosive and exposure can cause local tissue damage to the skin, mucosal membranes or cornea. Metabolism of ingested H2O2 liberates large quantities of oxygen. Once the amount of oxygen produced
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exceeds its maximal solubility in the blood, oxygen bubbles form and venous or arterial gas embolism may occur. Rapid accumulation of oxygen in closed body cavities can cause mechanical distension and complications such as rupture of a hollow viscus. Intravascular foaming may occur and can seriously impede left ventricular output. Direct cytotoxic effects from lipid peroxidation are also thought to occur.
Toxicokinetics
Following ingestion, H2O2 is readily absorbed through the stomach mucosa and into the portal venous system. It is then rapidly metabolised, predominantly by catalases within red cells, to yield oxygen and water; 30 mL of 35% H2O2 solution liberates almost 3.5 L of oxygen at standard temperature and pressure. CLINICAL FEATURES
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • EUC, FBE, ABGs. • Chest and abdominal X-rays may demonstrate perforation or oxygen gas embolism.
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Ingestion — Clinical features of corrosive injury include nausea, vomiting, haematemesis and foaming at the mouth. — More severe corrosive injury is manifested by blistering of the mouth and oropharynx, laryngospasm, stridor, cyanosis and respiratory arrest. — Tachycardia, lethargy, confusion, coma, seizures and cardiac arrest and sudden death within minutes may occur with larger ingestions of concentrated H2O2 (>10%) solutions. — Painful gastric distension and belching may occur secondary to liberation of large volumes of gas in the stomach. — Cerebral oxygen gas embolism manifests with progressive neurological disturbance. • Inhalation — Usually produces little more than coughing and transient dyspnoea. — Highly concentrated solutions can produce severe irritation. Coughing and dyspnoea can progress to shock, coma, seizures and pulmonary oedema. • Dermal — Inflammation, blistering and skin necrosis can occur, usually following exposure to concentrated solutions. Subcutaneous emphysema may be detected. • Ocular — Exposure of the cornea to 3% H2O2 solution produces immediate onset of stinging, irritation, lacrimation and blurred vision. — Subepithelial corneal and conjunctival bubbles may be observed. — Exposure to concentrated solutions may produce corneal ulceration and even perforation. — Transient injury is reported after insertion of soft contact lenses stored in 3% H2O2 solution without neutralisation.
SPECIFIC TOXINS
•
• • •
Chest X-ray is also indicated if there is evidence of pulmonary irritation following inhalational exposure. Cerebral CT or MRI scanning is indicated if CNS effects develop and will demonstrate cerebral gas embolism and infarction. Upper gastrointestinal endoscopy is considered if there is persistent vomiting, haematemesis, significant oral burns, abdominal pain, dysphagia or stridor and the patient has ingested a solution of >10% concentration.
SPECIFIC TOXINS
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Resuscitation, supportive care and monitoring • Early aggressive airway management is critical to the survival of the patient who has ingested concentrated H2O2 solution. Endotracheal intubation or, rarely, a surgical airway may be required for life-threatening laryngeal oedema. • The patient is initially managed in an area equipped for cardiorespiratory monitoring and resuscitation. • High-flow oxygen via a tight-fitting mask is administered to all patients. • Hyperbaric oxygen therapy is of value in treating cerebral gas embolism. • Close cardiorespiratory monitoring is essential for any patient at risk of gas embolism. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Gastrointestinal decontamination is not indicated due to the rapid decomposition of H2O2. • Immediate eye irrigation with copious amounts of water or saline for at least 15 minutes is indicated after ophthalmic exposure. • Clothing should be removed and the exposed skin washed with copious amounts of water following dermal exposure. Enhanced elimination • Not useful. Antidotes • None available.
DISPOSITION AND FOLLOW-UP
• • • • •
Minor unintentional exposures to 3% solutions in either children or adults do not require hospital evaluation unless persistent symptoms develop. Any patient who has ingested or inhaled concentrated (>10%) hydrogen peroxide, or has ongoing symptoms, is admitted for close observation and monitoring. Those patients with evidence of corrosive injury to the airway or gastrointestinal tract require admission for definitive management. Patients in whom arterial or venous gas embolism is suspected should be referred for consideration of hyperbaric oxygen therapy. Patients with eye exposures and any signs or symptoms of corneal injury should be referred for formal ophthalmological evaluation.
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PITFALL
•
Premature discharge of a patient with vague neurological signs or symptoms; this may indicate cerebral gas embolism.
CONTROVERSIES
•
Presentations
Solutions ranging in concentration from 3% to 90% are used in various applications: Household products (mostly 3% H2O2): disinfectants, bleaches, fabric stain removers, contact lens disinfectants, hair dyes, tooth-whitening products Industrial products: bleaching agent in paper industry Medical products: wound irrigation solutions, sterilising solutions for ophthalmic and endoscopic instruments.
• • •
SPECIFIC TOXINS
Indications for CT scanning. It may be appropriate to scan any patient with abdominal pain as a means to detect evidence of both oesophageal injury and portal venous gas embolism. • Indications for hyperbaric oxygen therapy. It is usually recommended in any case where venous or arterial gas emboli are suspected or documented.
References
3.42 INSULIN Deliberate self-administered insulin overdose causes profound and prolonged hypoglycaemia that may result in life-threatening seizures, coma and permanent neurological injury. RISK ASSESSMENT
•
Deliberate self-poisoning with insulin by subcutaneous injection causes life-threatening persistent hypoglycaemia with the risk of permanent neurological injury if not treated aggressively. • Hypoglycaemia may last for days; patients require prolonged periods of close monitoring and treatment. • The severity and duration of hypoglycaemia is unpredictable, is not dependent on the insulin preparation administered and correlates poorly with the dose injected. • Poor outcome is associated with delayed presentation with established hypoglycaemic coma. The prognosis is excellent with early effective glucose replenishment.
Toxic mechanism
Insulin is released from the beta pancreatic islet cells at a low basal rate, which increases in response to various stimuli. Exogenous insulin is used for the treatment of type 1 and
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Byrne B, Sherwin R, Courage C et al. Hyperbaric oxygen therapy for systemic gas embolism after hydrogen peroxide ingestion. Journal of Emergency Medicine 2014; 46:171–175. French LK, Horowitz BZ, McKeown NJ. Hydrogen peroxide ingestion associated with portal venous gas and treatment with hyperbaric oxygen: a case series and review of the literature. Clinical Toxicology 2010; 48:533–538. Watt BE, Proudfoot AT, Vale JA. Hydrogen peroxide poisoning. Toxicological Reviews 2004; 23:51–57.
type 2 diabetes mellitus, severe hyperkalaemia and calcium channel blocker overdose. Insulin stimulates the transfer of glucose, potassium, phosphate and magnesium into cells. It promotes synthesis and storage of glycogen, protein and triglycerides.
Toxicokinetics
In overdose, the pharmacokinetic properties of insulin change. The duration of action is extended (days) and does not depend on the type of insulin preparation used. Instead, it is determined by the slow and erratic release from subcutaneous adipose tissue at the injection site, in addition to the prolonged clearance of the absorbed insulin. Endogenous insulin is degraded by the liver (60%) and kidneys (40%).
SPECIFIC TOXINS
CLINICAL FEATURES
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The clinical features are those of hypoglycaemia. They usually manifest within 2 hours after administration: • Autonomic symptoms — Nausea and vomiting — Diaphoresis — Tachycardia and palpitations • Central nervous system — Agitation and tremor — Confusion and visual disturbances — Seizures — Hemiplegia — Coma. • The hyperinsulinaemic state commonly persists for >3 days. • Persistent, untreated hypoglycaemia may cause permanent neurological injury and death.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial blood glucose levels (BGLs) — Perform every 15 minutes during the resuscitation phase and until dextrose infusion requirement has stabilised. Frequency may be reduced to hourly then 2 hourly after that. • EUC, serum phosphate and magnesium — Detect and monitor hypokalaemia, hypophosphataemia and hypomagnesaemia associated with insulin excess. • Insulin levels — Insulin levels are elevated, but do not predict the magnitude or duration of glucose administration and are not clinically useful. — Insulin and C-peptide levels are helpful in the extremely rare circumstance where it is necessary to exclude an endogenous hyperinsulinaemic state.
MANAGEMENT
Resuscitation, supportive care and monitoring • Insulin overdose is a life-threatening emergency and the patient should be managed in an area capable of detecting and managing hypoglycaemia with close clinical and physiological monitoring.
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• • • • • •
Decontamination • Not clinically useful. Enhanced elimination • Not clinically useful. Antidotes • Glucose as outlined in Chapter 4.12: Glucose. DISPOSITION AND FOLLOW-UP
•
Patients who are clinically well with normal BGL at 6 hours following exposure have not administered a significant insulin dose and do not require further medical care. • Confirmed significant deliberate self-poisoning with insulin requires admission to an intensive care or high-dependency unit for several days of ongoing exogenous IV glucose administration via a central line and careful monitoring of BGL and serum potassium levels.
HANDY TIPS
•
Anticipate the need for large ongoing glucose requirement and insert a central line early so that 50% glucose infusion may commence. • Diabetic patients have a diminished counter-regulatory hormonal response to hypoglycaemia and may require increased glucose replacement.
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•
If symptoms of hypoglycaemia occur or BGL is 120 mg/kg
Potentially lethal
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SPECIFIC TOXINS
TABLE 3.43.2 Classical stages of severe iron poisoning Time post-ingestion
Clinical features
0–6 hours
Direct corrosive effect on GI tract characterised by vomiting, diarrhoea and abdominal pain. Fluid losses may be sufficient to cause hypovolaemic shock
6–12 hours
Progressive increase in iron absorption and distribution. Some resolution of symptoms may be observed, giving false hope of recovery
12–48 hours
Disruption of cellular metabolism manifested as shock from vasodilation and third-space losses, anion gap metabolic acidosis and hepatorenal failure
2–5 days
Acute hepatic failure with jaundice, coma, hypoglycaemia, coagulopathy and elevated aminotransferases. This phase is rare, but has a high mortality
2–6 weeks
Delayed sequelae, including cirrhotic liver disease and GI fibrosis/strictures
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Toxic mechanism
Local Direct corrosive effect on the gastrointestinal (GI) mucosa manifests with symptoms ranging from vomiting and diarrhoea to haematemesis and melaena. Large GI fluid losses may contribute to significant hypovolaemia. Systemic toxicity does not occur in the absence of GI symptoms. Systemic Iron acts as a direct cellular toxin via poorly understood mechanisms. The chief target organs are the cardiovascular system and the liver. CNS toxicity is secondary to cardiovascular instability and metabolic derangements. Severe metabolic acidosis is observed following large overdoses and attributed to lactic acid formation and the liberation of hydrogen ions from the hydration of free ferric ions in the plasma. Coagulopathy is frequently observed and attributed to interference with the coagulation cascade.
Toxicokinetics
Absorption of iron from the GI tract is normally finely regulated according to the requirements of the body. In overdose these mechanisms are overwhelmed and the bioavailability of iron increases significantly. Absorbed iron shifts intracellularly over a period of hours. Elimination is minimal under normal conditions. CLINICAL FEATURES
Iron toxicity is classically described as having five stages (see Table 3.43.2), although this is an over-simplification. Not all patients
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experience all stages and the duration of each stage is imprecise and they usually overlap. Iron toxicity is more accurately conceptualised as two overlapping stages with a pathophysiological basis: gastrointestinal and systemic toxicity. INVESTIGATIONS
MANAGEMENT
Resuscitation, supportive care and monitoring • An early priority is the restoration of adequate circulating volume. Give boluses of 10–20 mL/kg of crystalloid and assess response. • Ongoing fluid replacement is essential in the face of continuing gastrointestinal and third-space losses.
Decontamination • Iron is not adsorbed to activated charcoal. • Whole bowel irrigation (WBI) is the decontamination method of choice and recommended for ingestions >60 mg/kg confirmed on X-ray (see Chapter 1.6: Gastrointestinal decontamination). • Surgical or endoscopic removal may be considered in potentially lethal ingestions if WBI fails or is impractical. Enhanced elimination • Not clinically useful. Antidotes • Desferrioxamine chelation therapy is indicated if systemic toxicity (shock, metabolic acidosis, altered mental status) is present or predicted by a serum iron level >90 micromol/L (500 microgram/dL) at 4–6 hours post ingestion. For further details see Chapter 4.4: Desferrioxamine. DISPOSITION AND FOLLOW-UP
•
Children thought to have ingested 90 micromol/L (500 microgram/ dL) are thought to be predictive of systemic toxicity. • Arterial or venous blood gas — An anion gap metabolic acidosis is a useful marker of systemic toxicity. • Abdominal X-ray — Useful in confirming ingestion, and planning and monitoring decontamination. • Note: Hyperglycaemia and elevated white cell counts are frequently observed in iron poisoning, but do not correlate with toxicity.
SPECIFIC TOXINS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
SPECIFIC TOXINS
ingestions are evaluated in hospital. The child who remains asymptomatic at 6 hours and has an abdominal X-ray negative for iron may be safely discharged. • All adults who have deliberately self-poisoned with iron are evaluated in hospital. If the history suggests ingestion of 1.5 g (20 mg/kg)
May develop symptoms
>3 g (40 mg/kg)
Seizures, metabolic acidosis and coma
>10 g (130 mg/kg)
Uniformly fatal without intervention
Toxic mechanism
Isoniazid is structurally related to pyridoxine, nicotinic acid and NAD. Toxicity results from a deficiency of the active form of pyridoxine, pyridoxine-5-phosphate (P5P). Isoniazid interferes with the enzyme responsible for the conversion of pyridoxine to P5P, pyridoxine phosphokinase, binds to and inactivates P5P and enhances urinary excretion of P5P. Because P5P is an essential co-factor for the conversion of glutamic acid to GABA in the CNS, an acute GABA deficiency manifesting as status seizures develops. The severe lactic acidosis is due to the status seizures and direct inhibition of conversion of lactate to pyruvate.
Toxicokinetics
Absorption following oral administration is rapid and complete. Peak serum levels occur within 1–2 hours. Volume of distribution is 0.6 L/kg. Isoniazid undergoes hepatic metabolism by either acetylation to form acetyl-isoniazid, or hydrolysis by cytochrome P450 to form hydrazine derivatives. Some drug is excreted unchanged in the urine. There are ‘fast’ and ‘slow’ acetylators such that the elimination half-life varies from 1 to 4 hours. CLINICAL FEATURES
• • •
Initial symptoms are light-headedness, blurred vision, photophobia, nausea and vomiting. Physical examination may reveal tachycardia, dilated pupils, slurred speech, ataxia and hyperreflexia. If a sufficient dose is ingested, patients rapidly develop confusion, depressed level of consciousness, coma, status seizures, severe lactic acidosis and death. • Seizures are typically generalised tonic–clonic. They may resolve spontaneously but then recur promptly. Complications of prolonged status seizures, including hyperpyrexia, pulmonary aspiration and rhabdomyolysis, may be observed.
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•
SPECIFIC TOXINS
RISK ASSESSMENT
INVESTIGATIONS
SPECIFIC TOXINS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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Specific investigations as indicated • Arterial blood gas — Severe anion gap metabolic acidosis with a high serum lactate is a major feature of isoniazid overdose. The pH may range from 6.8 to 7.3. • Isoniazid levels — Not routinely available, difficult to interpret and do not aid in acute management. They may be useful to confirm the diagnosis retrospectively. MANAGEMENT
Resuscitation, supportive care and monitoring • Isoniazid overdose is a medical emergency and managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Aggressive supportive care of airway, breathing and circulation is paramount until seizures are controlled and adequate doses of pyridoxine administered. • The patient presenting unconscious or with seizures undergoes prompt rapid-sequence intubation and ventilation. • Seizures are controlled with high-dose intravenous diazepam while supplies of pyridoxine are secured and administered. • EEG monitoring if available is useful in the intubated patient. Decontamination • Activated charcoal is only given once the airway is secured with endotracheal intubation and never takes precedence over resuscitation and supportive care. Enhanced elimination • Haemodialysis effectively removes isoniazid, but the time course of the poisoning is such that this intervention is not clinically useful. Antidotes • Urgent administration of IV pyridoxine is indicated if coma or seizures develop (see Chapter 4.24: Pyridoxine). • Give 1 g for each gram of isoniazid ingested. • If the ingested dose is unknown, give 5 g of pyridoxine and review response.
DISPOSITION AND FOLLOW-UP
•
Asymptomatic patients can be observed for 6 hours and discharged if no symptoms develop and no treatment is given. • All patients who develop neurological toxicity should be admitted to an intensive care or high-dependency unit. • Any patient who develops seizures is intubated and managed in intensive care.
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HANDY TIPS
•
Always consider isoniazid overdose in the differential diagnosis of status epilepticus, particularly if the patient or a household member has a history of tuberculosis. • Rapidly ascertain location of all available pyridoxine when confronted with a possible isoniazid overdose. • Good resuscitation and use of benzodiazepines can assure a good outcome even in the absence of pyridoxine.
•
Inability to secure adequate doses of IV pyridoxine.
CONTROVERSIES
• •
Value of prophylactic administration of pyridoxine to patients with a history of ingestion of >1.5 g of isoniazid. Hospital stocking levels of pyridoxine. At least 5 g is required to treat one isoniazid overdose.
Presentations
SPECIFIC TOXINS
PITFALL
Isoniazid 25 mg tablets (100) Isoniazid 100 mg tablets (100)
Maw G, Aitken P. Isoniazid overdose: a case series, literature review and survey of antidote availability. Clinical Drug Investigation 2003; 23:479–485.
3.45 LEAD Acute lead intoxication is usually due to ingestion. It is rare, but potentially life threatening. Chronic environmental lead exposure remains a major public health issue in some regions and occupations. Evaluation of patients with possible lead exposure requires a detailed risk assessment. RISK ASSESSMENT
•
Acute or subacute severe lead intoxication occurs in the context of ingestion or inhalational occupational exposure to lead. It is associated with encephalopathy, cerebral oedema and death. • Chronic occupational or environmental exposure usually leads to a vague multi-system disorder with the potential for permanent neurological and neuropsychological sequelae. • Risk of long-term neurological sequelae loosely correlates to blood lead level (see Table 3.45.1).
• •
Pregnancy: major malformations are reported in children born to mothers with elevated lead levels. Children: childhood exposure to lead is neurotoxic and associated with impaired intellectual development. There appears to be no threshold below which lead is not deleterious during early childhood development.
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Reference
TABLE 3.45.1 Blood lead level and clinical effects Effects
10 microgram/dL (0.48 micromol/L)
Subtle developmental, learning, motor and intellectual abnormalities in children
>30 microgram/dL (1.4 micromol/L)
Non-specific constitutional symptoms such as abdominal pain, malaise, headaches, hypertension and insomnia Subclinical impairment of peripheral nerve conduction and psychometric testing may occur Clinically overt peripheral neuropathies involving ulnar and radial nerves (wrist drop) are classical but rare Renal injury in the form of a chronic interstitial nephritis or Fanconi’s syndrome may occur Decreased fertility reported in both sexes
>100 microgram/dL (4.8 micromol/L)
Severe gastrointestinal symptoms, encephalopathy, seizures and coma
SPECIFIC TOXINS
Blood lead level
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Toxic mechanism
Lead has no physiological function. It has toxic effects through interference with intracellular functions, including maintenance of cell wall integrity, haem synthesis, neurotransmitter systems and steroid production. Major target organs affected by lead are the nervous system, kidneys and the reproductive and haematopoietic systems.
Toxicokinetics
Absorption is via oral, topical and inhaled routes. Absorption from lead foreign bodies such as shotgun pellets lodged in joints or other body cavities also occurs. Oral absorption is greater in children than adults (bioavailability 50% and 20%, respectively). Lead bioavailability is increased with high-fat, low-calcium diets. Fumes from lead smelting, or inhaled lead dust, are rapidly absorbed by the lungs. Dermal absorption of organic lead compounds through intact skin can occur. Lead is absorbed and bound by red cells, then distributed widely throughout the body. The bony skeleton acts as a major lead store. Other sites of deposition are the CNS, kidneys and spleen. Bone stores can re-mobilise decades after exposure has ceased, resulting in persistently high levels for months to years. Lead easily crosses the placenta and significant fetal transfer can occur. Urinary excretion is the predominant elimination pathway. CLINICAL FEATURES
•
Acute — Acute ingestion of lead leads to abdominal pain, nausea, vomiting, haemolytic anaemia and hepatitis. — Cerebral oedema, encephalopathy, seizures and coma are pre-terminal conditions.
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— Clinical effects generally correlate with levels although there is wide interindividual variation (see Table 3.45.1). • Chronic — Vague constitutional symptoms and multi-system effects include impaired concentration, anorexia, vague abdominal pain, emotional lability, weight loss, arthralgia and impaired coordination. — Subclinical impairment of higher centre functions, including IQ.
Specific investigations as indicated • Whole blood lead level — Most useful indicator of lead exposure. • FBC — Normochromic, normocytic anaemia with basophilic stippling of erythrocytes is classical but rarely seen. • EUC, LFTs • Free erythrocyte protoporphyrin (FEP) — FEP is a surrogate measure of total body burden of lead, but has low sensitivity at levels below 25 microgram/dL (1.2 micromol/L). — FEP is elevated in chronic lead intoxication due to the inhibition of haemoglobin synthesis. • Abdominal X-ray — Assists identification of ingested lead foreign bodies. • Nerve conduction and psychomotor testing — May be useful in chronic exposures to demonstrate objective evidence of lead neurotoxicity. MANAGEMENT
Resuscitation, supportive care and monitoring • Acute resuscitation is rarely required. • In cases of acute lead-induced encephalopathy, management of airway, breathing and circulation are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Administer mannitol 1 g/kg and dexamethasone 10 mg (1.5 mg/kg in children) if cerebral oedema is present. • Seizures are treated with benzodiazepines, as outlined in Chapter 2.6: Seizures. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring.
Decontamination • Lead foreign body ingestion — Endoscopic retrieval if located above the gastro-oesophageal junction. — If beyond the gastro-oesophageal junction and the patient is asymptomatic, commence a high-residue diet plus oral polyethylene glycol to drink at home. Repeat abdominal
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
SPECIFIC TOXINS
INVESTIGATIONS
X-rays every 24 hours to confirm passage of the foreign body within 72 hours. — If the foreign body is still present at 72 hours, admit the patient for formal whole bowel irrigation with polyethylene glycol (see Chapter 1.6: Gastrointestinal decontamination). • Shrapnel or bullets adjacent to synovial tissue — Surgical excision if feasible is indicated in the patient with symptoms or rising lead levels.
SPECIFIC TOXINS
Enhanced elimination • Not clinically useful.
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Antidotes • Chelation therapy is indicated in symptomatic lead poisoning or if long-term neurological injury is anticipated. • Sodium calcium edetate (EDTA), an intravenous chelator, is indicated for acute lead-induced encephalopathy or the symptomatic patient with blood level >100 microgram/dL (4.8 micromol/L). For administration see Chapter 4.25: Sodium calcium edetate. • Succimer (DMSA), an oral chelator, is used in symptomatic patients without encephalopathy and asymptomatic patients with blood lead levels >60 microgram/dL (2.9 micromol/L) for adults or >45 microgram/dL (2.17 micromol/L) for children. For administration see Chapter 4.27: Succimer. HANDY TIPS
•
Diagnosis of chronic lead intoxication identifies an index case. Other family members or colleagues should be screened and all potential exposures considered. • Lead levels 10 microgram/L (0.48 micromol/L) mandates strenuous efforts to identify the source and prevent further exposure, especially in children. • Lead intoxication is a notifiable disease in most jurisdictions.
PITFALLS
• •
Using dicobalt edetate (antidote for cyanide) instead of sodium calcium edetate (EDTA). Failure to identify source of lead exposure in chronic poisoning, and prevent further exposure.
CONTROVERSIES
•
Thresholds for chelation in pregnant women, children and asymptomatic adults remain controversial and are constantly under review. • Value of chelation therapy for children with mild-to-moderate elevated lead levels (5 mmol/L occurring at 4–8 hours post ingestion are not unusual following acute overdose.
MANAGEMENT
Resuscitation, supportive care and monitoring • The patient who presents late with severe GI symptoms requires fluid resuscitation. Give normal saline 10–20 mL/kg IV and reassess. • Maintain adequate hydration and sodium repletion with intravenous normal saline as necessary. Urine output is ideally >1 mL/kg/hour.
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• •
Monitor fluid and electrolyte status, renal function, serum lithium and clinical features of neurotoxicity. Continuous cardiac monitoring is not required in the absence of co-ingestants.
Enhanced elimination • Elimination of lithium can be enhanced with haemodialysis; however, in the patient with normal renal function whose hydration and sodium repletion are ensured, this relatively minor enhancement of elimination is not clinically useful. • Haemodialysis is reserved for patients with established renal failure, particularly those who present late with clinical features of lithium neurotoxicity. Antidotes • None available.
SPECIFIC TOXINS
Decontamination • Activated charcoal does not effectively adsorb lithium and is not indicated.
DISPOSITION AND FOLLOW-UP
Patients with no clinical evidence of neurotoxicity and a serum lithium level 2.5 mmol/L. It is most likely to be useful in the presence of established renal impairment. Prolonged and repeated haemodialysis sessions may be necessary to eliminate lithium. Antidotes • None available. DISPOSITION AND FOLLOW-UP
•
Patients with chronic lithium toxicity always require admission. Resolution of neurological symptoms may be very slow (weeks) and sometimes incomplete.
HANDY TIPS
•
Consider the diagnosis of chronic lithium toxicity in any individual on lithium who presents unwell, particularly if there is evidence of neurological dysfunction. • The patient’s clinical condition may worsen over the initial stages of inpatient management. • Lithium neurotoxicity may persist long after serum lithium returns to therapeutic range because of slow redistribution and clearance of lithium from the CNS.
PITFALL
•
Failure to check a lithium level in the unwell patient on lithium therapy.
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Resuscitation, supportive care and monitoring • Acute resuscitation is unlikely to be necessary except in cases of extreme neurotoxicity with coma and seizures. • Acute volume resuscitation may be required to adequately restore and maintain effective renal perfusion. • Careful attention to correcting any water and sodium deficits and maintaining renal function is essential to maximise lithium excretion. • Lithium and any drugs that may impair lithium excretion are ceased. • Renal function, urine output, electrolytes and serum lithium levels are closely monitored.
SPECIFIC TOXINS
MANAGEMENT
CONTROVERSIES
•
SPECIFIC TOXINS
The indications for haemodialysis are unproven and have not been evaluated in clinical trials. Most patients can be managed without dialysis provided they receive adequate fluid and electrolyte resuscitation and normal renal function is rapidly re-established. • Continuous arterio- or venovenous haemofiltration has been proposed as an alternative to haemodialysis for enhancement of lithium elimination. Although lower clearances are achieved with these methods, they are often easier to institute and may minimise rapid transcellular fluid and electrolyte shifts. At the moment they can only be recommended if haemodialysis is not available.
Lithium carbonate 250 mg standard-release tablets (200) Lithium carbonate 450 mg slow-release tablets (100)
References
Hansen HE, Amdisen A. Lithium intoxication. Quarterly Journal of Medicine 1978; 47:123–144. Oakley P, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible individuals. Australian and New Zealand Journal of Psychiatry 2001; 35:833–840. Waring WS. Management of lithium toxicity. Toxicology Reviews 2006; 25(4):221–230.
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Presentations
3.48 LOCAL ANAESTHETIC AGENTS Amethocaine, Articaine, Benzocaine, Bupivacaine, Levobupivacaine, Lignocaine, Mepivacaine, Prilocaine, Ropivacaine Local anaesthetic (LA) toxicity is nearly always the result of a therapeutic error. It occurs because of incorrect dose, route of administration or technique. Care for this potentially life-threatening toxicity is primarily supportive, although use of intravenous lipid emulsion plays an important role in management of severe cases. RISK ASSESSMENT
• • • •
Most cases of LA toxicity arise from inadvertent intravascular administration rather than gross overdose. Clinical manifestations correspond to the concentration achieved in the systemic circulation. Onset of clinical manifestations is rapid. Maximal recommended doses for agents are listed in Table 3.48.1 but toxicity can occur when lower doses are administered by direct intravenous or intra-arterial injection. Larger doses can be safely given when co-administered with adrenaline. • Methaemoglobinaemia is not dose-related, but is more likely to complicate administration of benzocaine, lignocaine or prilocaine.
•
Children: although paediatric fatalities are reported following ingestion of lignocaine-containing local and topical anaesthetic preparations, ingested doses 6 mg/kg may have been ingested or symptoms develop. • Local anaesthetic toxicity usually occurs in a hospital or clinic setting. Once resuscitated, the patient should be managed in a high-dependency or intensive care setting until toxicity resolves.
HANDY TIP
•
The development of any neurological symptoms during or shortly after administration of a LA prompts close observation in an area equipped for cardiorespiratory monitoring and resuscitation.
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CONTROVERSY
Presentations
Amethocaine HCl 0.5% eye drops Amethocaine HCl 1% eye drops Amethocaine HCl gel 4% (30 g) Articaine HCl 40 mg/mL/adrenaline 1 : 100 000 vials (1.7 mL, 2.2 mL) Benzocaine topical oropharyngeal and otic preparations Bupivacaine HCl 0.125% injectable (100 mL, 200 mL) Bupivacaine HCl 0.25% injectable (20 mL, 100 mL) Bupivacaine HCl 0.5% injectable (4 mL, 10 mL, 20 mL) Bupivacaine HCl 0.125%/fentanyl citrate 5 microgram/mL injectable (20 mL, 200 mL) Bupivacaine HCl 0.25%/adrenaline 1 : 400 000, injectable (20 mL) Bupivacaine HCl 0.5%/adrenaline 1 : 200 000, injectable (20 mL) Bupivacaine HCl 0.5%/glucose 80 mg/mL injectable (4 mL) Levobupivacaine 0.0625% injectable (200 mL) Levobupivacaine 0.125% injectable (200 mL) Levobupivacaine 0.25% injectable (10 mL) Levobupivacaine 0.5% injectable (10 mL) Levobupivacaine 0.75% injectable (10 mL) Lignocaine HCl 2% oral liquid (200 mL) Lignocaine HCl 0.5% injectable (5 mL) Lignocaine HCl 1% injectable (2 mL, 5 mL, 20 mL) Lignocaine HCl 2% injectable (5 mL, 20 mL) Lignocaine HCl 2% gel (10 g, 20 g, 30 g) Lignocaine HCl 4% cream (5 g, 30 g) Lignocaine HCl 4% topical solution (30 mL) Lignocaine HCL 5% ointment (15 g) Lignocaine HCl 10% pump spray (50 mL) Lignocaine HCL 5% patch (30) Lignocaine HCL 5%/phenylephrine HCl 0.5% nasal spray (15 mL, 50 mL) Lignocaine 2.5%/prilocaine 2.5% eutectic mixture, cream (5 g, 30 g)
Lignocaine 2.5%/prilocaine 2.5% eutectic mixture, patches (1 g) Lignocaine HCL 5%/chlorhexidine 0.05% syringe (10 mL) Lignocaine HCL 20 mg/mL/adrenaline 12.5 microgram/mL cartridges (2.2 mL) Lignocaine HCl 3%/cetrimol 0.5% gel (25 g) Lignocaine HCl 2%/cetrimol 0.25% spray (125 mL) Lignocaine HCl 1%/cetrimol 1%/ chlorhexidine 0.2% cream (50 g) Lignocaine HCl 2%/adrenaline 1 : 80,000 injectable (5 mL) Lignocaine HCl 1%/adrenaline 1 : 100,000 injectable (5 mL) Lignocaine HCl 2%/adrenaline 1 : 200,000 injectable (20 mL) Lignocaine HCl 1%/adrenaline 1 : 200,000 injectable (20 mL) Mepivacaine 2% cartridges (2.2 mL) Mepivacaine 3%/adrenaline 1 : 100,000 cartridges (1.8 mL, 2.2 mL) Prilocaine HCl 0.5% injectable (50 mL) Prilocaine HCl 1% injectable (5 mL) Prilocaine HCl 2% injectable (2 mL, 5 mL) Prilocaine HCl 4% cartridges (2.2 mL) Prilocaine HCl 3%/adrenaline 1 : 300 000 cartridges (2.2 mL) Prilocaine HCl 3%/felypressin 0.03 IU/mL cartridges (2.2 mL) Ropivacaine HCl 2 mg/mL injectable (10 mL, 20 mL, 100 mL, 200 mL) Ropivacaine HCl 5 mg/mL injectable (10 mL) Ropivacaine HCl 7.5 mg/mL injectable (10 mL, 20 mL, 100 mL, 200 mL) Ropivacaine HCl 10 mg/mL injectable (10 mL, 20 mL) Ropivacaine HCl 2 mg/mL/fentanyl 2 microgram/mL injectable (100 mL, 200 mL) Ropivacaine HCl 2 mg/mL/fentanyl 4 microgram/mL injectable (100 mL, 200 mL)
References
Balit CR, Lynch AM, Gilmore SP et al. Lignocaine and chlorhexidine toxicity in children resulting from mouthpaint ingestion: a bottling problem. Journal of Paediatrics and Child Health 2006; 42(6):350–353.
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The threshold for trial of intravenous lipid emulsion in the management of CNS or cardiovascular manifestations of LA toxicity.
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Curtis LA, Dolan TS, Seibert HE. Are one or two dangerous? Lidocaine and topical anesthetics exposure in children. Journal of Emergency Medicine 2009; 37:32–39. Felice KL, Schumann HM. Intravenous lipid emulsion for local anesthetic toxicity: a review of the literature. Journal of Medical Toxicology 2008; 4(3):184–191. Weinberg G. Lipid rescue resuscitation from local anaesthetic cardiac toxicity. Toxicological Reviews 2006; 25(3):139–145.
3.49 MERCURY
SPECIFIC TOXINS
Elemental mercury, Inorganic mercury, Organic mercury, Merbromin
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Mercury intoxication is now rare. Most exposures come from consumption of seafood. Accidental ingestion of elemental thermometer mercury or amalgam mercury present minimal risk. Occupational exposures and deliberate self-poisoning with mercury may cause serious morbidity or mortality. RISK ASSESSMENT
•
Benign presentations — Accidental ingestion of elemental mercury (e.g. from a broken thermometer) in a normal intact gastrointestinal tract. — Incidental discovery of elevated mercury levels in an asymptomatic patient undergoing a ‘heavy metal screen’. — Concern about dental amalgams. • Potentially serious presentations — Inhalation of mercury aerosol (after vacuuming or prolonged stasis) or vapour (heating of elemental mercury). Pneumonitis, acute non-cardiac pulmonary oedema and neurological injury may occur. — Ingestion of inorganic mercury salts, leading to haemorrhagic gastroenteritis, acute renal failure and shock. Potential lethal dose is 30–50 mg/kg. — Exposure to organic mercury compounds by ingestion, inhalation or dermal application, leading to neurological injury. • Undefined risk — Injection of elemental mercury SC or IV, leading to mercuric pulmonary emboli. This creates depots from which distribution of mercury to the brain may occur over the long term. — Intentional ingestion of merbromin (Mercurochrome) is associated with high mercury levels, although long-term sequelae are not reported.
•
Children: minor unintentional ingestion or skin exposure to elemental mercury or Mercurochrome antiseptic solution does not warrant medical assessment, observation or investigation.
Toxic mechanism
Mercury is a metal with no natural cellular function. It binds to sulfhydryl (SH–) groups at multiple intracellular sites, causing inhibition of enzymes and disruption of cellular membranes.
Toxicokinetics
There is minimal absorption of elemental mercury from an intact gastrointestinal (GI) tract. In contrast, elemental mercury is well absorbed from the respiratory tract when inhaled as either an aerosol (produced when it is vacuumed) or vapour (produced when it
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is heated). About 10% of a dose of inorganic mercury is absorbed following ingestion. Inorganic mercury is also significantly absorbed when applied to skin or mucous membranes. Organic mercury is readily absorbed from both the GI tract and via inhalation. Absorption also occurs across disrupted skin. Mercury has a large volume of distribution and is deposited in the kidneys, liver, spleen and CNS. The high lipid solubility of elemental and organic mercury compounds favours distribution to the CNS. Mercuric ions are excreted by the kidney and across the GI tract into faeces. The elimination half-life of elemental mercury and inorganic mercury is 30–60 days. Organic mercury is eliminated primarily in the faeces and undergoes enterohepatic circulation. Half-life is approximately 70 days. CLINICAL FEATURES
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Acute exposure to elemental mercury – acute intoxication develops following inhalation of vaporised or aerosolised mercury. Within a few hours there is the abrupt onset of headache, nausea, vomiting, chills, fever, salivation, metallic taste, visual disturbances, dyspnoea and dry cough. Respiratory failure secondary to interstitial pneumonitis may occur over the following days. • Acute exposure to inorganic mercury salts – acute ingestion causes severe haemorrhagic gastroenteritis within hours. The patient experiences severe local oropharyngeal pain, a metallic taste, nausea, vomiting and diarrhoea. Grey discolouration of the mucous membranes may be noted. Massive fluid loss leading to hypotension, shock and acute tubular necrosis follows. • Acute exposure to organic mercury – acute manifestations include GI symptoms, tremor, respiratory distress and dermatitis, renal tubular dysfunction and ECG (ST segment) changes. Delayed neurotoxicity develops weeks or months after initial exposure and is usually permanent. It is most severe in children who have suffered prenatal exposure. Organic mercury is excreted in breast milk and can produce toxicity in infants. Delayed neurological sequelae include: — Psychological – poor concentration, short- and long-term memory loss, emotional lability, depression and coma — Cerebellar – ataxia, incoordination and dysdiadochokinesis — Sensory – glove-stocking paraesthesia of distal limbs, tunnel vision, deafness, scanning speech with slurring and dysphagia — Motor – spasticity, tremor, weakness and paralysis. • Chronic mercury toxicity – chronic exposure to elemental mercury vapour or inorganic mercury salts leads to the insidious onset of a multi-system disorder with prominent neuropsychiatric symptoms: — Neurological – tremor, neurasthenia (fatigue, depression, headaches, hypersensitivity, lack of concentration, general weakness), erethism (blushing and intense shyness), emotional lability, insomnia, delirium, mixed sensorimotor neuropathy, ataxia, tunnel vision, anosmia — Gastrointestinal – metallic taste, burning pain in the mouth, gingivostomatitis, loose teeth, nausea, hypersalivation — Renal dysfunction – Proximal tubular atrophy with mercuric deposits within the renal interstitium and macrophages — Acrodynia (usually children) – erythematous, oedematous, hyperkeratotic indurated rash of the palms, soles and face. It often progresses to desquamation and ulceration.
SPECIFIC TOXINS
•
INVESTIGATIONS
SPECIFIC TOXINS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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Specific investigations as indicated • Whole blood mercury level (normal: 200 microgram/L (1000 nmol/L) is associated with symptoms. — Level may be >500 microgram/L (2500 nmol/L) following acute inorganic mercury exposure. — Confirms recent exposure but does not reflect total body burden. • 24 hour urine mercury level (normal: 100 microgram/L (500 nmol/L) is associated with neuropsychiatric disturbance. • X-rays — Elemental mercury is radio-opaque and X-rays confirm ingestion, subcutaneous or intravenous injection. — Intravenous injection produces multiple mercuric pulmonary emboli and a characteristic ‘milky way’ appearance on chest X-ray. • Endoscopy — May be indicated to assess corrosive GI injury. MANAGEMENT
Resuscitation, supportive care and monitoring • Accidental oral or skin exposure to elemental mercury does not require medical assessment or management. • Following other acute exposure, attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Inhalational exposure to mercury vapour requires close clinical and physiological monitoring and general supportive care measures, as outlined in Chapter 1.4: Supportive care and monitoring. • Ingestion of inorganic mercury requires aggressive fluid resuscitation and general supportive care measures for multiple organ failure. • Exposure to organic mercury requires general supportive care measures, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Decontamination is aimed at preventing further exposure to mercury. — Environmental – Seek advice regarding mercury spills. – Avoid vacuuming. – Discard contaminated carpets or surfaces. — Individual – Elemental mercury. Remove contaminated clothing. Remove mercury from skin.
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Administration of oral polyethylene glycol solution enhances removal from the GI tract following deliberate ingestion of massive volumes. Surgical excision of subcutaneous mercury depots or residues following SC injection should be undertaken where feasible. – Organic mercury compounds. Administer activated charcoal.
DISPOSITION AND FOLLOW-UP
•
Patients exposed to mercury vapour or aerosol are counselled regarding appropriate measures to cease exposure and clean up remnant environmental contamination. • Symptomatic patients require admission for further management. • Patients with potential ingestion of inorganic or organic mercury require admission for observation and aggressive management should clinical features develop.
HANDY TIP
PITFALL
•
Dimercaprol is contraindicated following elemental or organic mercury exposure, as there is concern that it increases distribution of mercury to the brain.
•
Ordering ‘heavy metal screens’ on patients with non-specific symptoms without exposure assessment – these are rarely clinically useful.
CONTROVERSIES
•
The indications for chelation therapy. Dimercaprol does not reduce symptoms of organic mercury intoxication. Succimer reduces mercury levels but has not been shown to alter prognosis. • Value of long-term chelation therapy following IV or SC injection of mercury if decontamination cannot be adequately achieved.
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Antidotes • Chelation therapy with dimercaprol, penicillamine or succimer (see Chapter 4.7: Dimercaprol, Chapter 4.20: Penicillamine and Chapter 4.27: Succimer). — Chelation therapy is indicated when there are objective clinical features of mercury intoxication or if markedly elevated urine or blood mercury levels indicate potential for significant morbidity. — Chelation is only useful once further exposure to mercury is terminated by decontamination of the environment or individual. — Note: Dimercaprol is only used for inorganic mercury salt exposure.
SPECIFIC TOXINS
Enhanced elimination • Not clinically useful for elemental or inorganic mercury toxicity. • Administration of polythiol resin may interrupt enterohepatic circulation of organic mercury compounds.
•
The literature does not support the routine replacement of mercury dental amalgams.
Sources
SPECIFIC TOXINS
Elemental mercury (Hg0): dental amalgam, thermometers, barometers, manufacture of chlorine and caustic soda, paints, pigments and gold mining Inorganic mercury (mercuric acetate, mercuric arsenate, mercuric bromide, mercuric chloride, mercuric potassium cyanide, mercuric sulfide): disinfectants, fireworks and explosives, processing of fur and leather, waterproofing and antifouling paints, photographic plates, batteries Organic mercury (alkoxyalkyl mercury, alkyl mercury, methyl mercury): embalming fluid, fungicides, pesticides, wood preservatives, seafood Merbromin
Brownawall AM, Berent S, Brent RL et al. The potential adverse effects of dental amalgam. Toxicological Reviews 2005; 24(1):1–10. Clarkson TW, Magos L, Myers GJ. The toxicology of mercury: current exposures and clinical manifestations. New England Journal of Medicine 2003; 349:1731–1737. Kales SN, Goldman RH. Mercury exposure: current concepts, controversies, and a clinic’s experience. Journal of Occupational and Environmental Medicine 2002; 44:143–154.
3.50 METFORMIN
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References
Metformin can produce life-threatening lactic acidosis. This may occur in patients on therapeutic doses who develop renal failure or, less commonly, following large acute ingestions. Early recognition and haemodialysis are life saving. RISK ASSESSMENT
•
Lactic acidosis in a patient on therapeutic metformin usually occurs in the context of acute renal failure or severe sepsis and is associated with a mortality exceeding 50%. • Metformin overdose is usually benign, but severe lactic acidosis is reported. The threshold dose of concern remains undefined but is thought to be >10 g. • Lactic acidosis is more likely to develop following acute overdose if there is pre-existing impairment of renal function or if cardiovascular toxicity of co-ingestants results in impaired renal perfusion. • The prognosis for severe lactic acidosis from metformin overdose remains good provided there is early recognition and institution of haemodialysis.
•
Children: unintentional ingestion of up to 1700 mg is benign and does not require hospital assessment.
Toxic mechanism
Metformin inhibits gluconeogenesis, reduces hepatic glucose output and stimulates peripheral glucose uptake. The chief agent of toxicity is lactate. Metformin can produce a type B (non-aerobic) lactic acidosis, possibly by changing the intracellular redox potential and increasing cellular production, and by inhibiting hepatic uptake of lactate.
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Toxicokinetics
Metformin is rapidly and well absorbed following oral administration, with peak levels occurring at 2 hours. It is not metabolised and elimination is entirely dependent on renal excretion. CLINICAL FEATURES
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Electrolytes, renal function tests, arterial blood gases, serum lactate — Confirm diagnosis of lactic acidosis. — Indicated in any unwell patient on metformin and any patient with clinical deterioration following metformin overdose.
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • General supportive care measures, as outlined in Chapter 1.4: Supportive care and monitoring ensure a good outcome in the majority of patients. • Administration of sodium bicarbonate to control severe acidosis (see Chapter 4.24: Sodium bicarbonate) and control of hyperkalaemia help stabilise the severely unwell patient while awaiting haemodialysis. Decontamination • Administer oral activated charcoal to the co-operative patient who presents within 2 hours of deliberately self-poisoning with >10 g of metformin.
Enhanced elimination • Haemodialysis not only rapidly corrects acidosis, but also removes metformin, thus preventing further lactate production. It is urgently indicated in: — Any unwell patient with lactic acidosis from therapeutic administration
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Acute metformin overdose is usually asymptomatic. Lactic acidosis, if it develops, manifests some hours following the overdose, with worsening non-specific features including altered sensorium, nausea, vomiting, diarrhoea, dyspnoea, tachycardia, hypotension and cool peripheries. • Lactic acidosis may progress to coma, shock and death. • Hypoglycaemia, if it develops at all, is usually minor and easily corrected by dextrose administration. • Patients who develop lactic acidosis on therapeutic metformin present unwell with a history of progressively worsening clinical features as described above. There is nearly always coexisting acute renal failure and/or sepsis.
SPECIFIC TOXINS
• •
— Worsening lactic acidosis following acute overdose where signs of clinical instability are present or emerging. • Haemodialysis may need to be prolonged >15 hours. Antidotes • None available. DISPOSITION AND FOLLOW-UP
SPECIFIC TOXINS
• •
Children who acutely ingest up to 1700 mg of metformin may be safely observed at home. Deliberate self-poisoning with >10 g of metformin mandates observation for at least 8 hours. Patients who remain well with a normal bicarbonate at the end of that period may be medically cleared. • Patients who present with or develop lactic acidosis require critical care admission, monitoring and assessment for urgent haemodialysis.
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Consider the diagnosis of lactic acidosis when confronted with any unwell patient on metformin or any patient who becomes unwell following acute self-poisoning with metformin.
PITFALLS
•
Treating metformin overdose as a sulfonylurea overdose – they are both antidiabetic medications but belong to different classes and have different toxicities and risk assessments. • Failure to consider the diagnosis of metformin-induced lactic acidosis.
CONTROVERSIES
•
Precise indications for initiating haemodialysis in metforminassociated lactic acidosis following overdose. It is probably safe to tolerate lactates of up to 10 mmol/L, provided the patient has normal renal function and a stable cardiovascular system. • Relative efficacy of various haemodialysis methods. Both intermittent and continuous haemodialysis techniques have been used successfully.
Presentations Metformin Metformin Metformin Metformin Metformin Metformin Metformin Metformin
hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride hydrochloride
500 mg tablets (100) 850 mg tablets (60) 1000 mg tablets (90) 500 mg controlled release tablets (120) 1000 mg controlled release tablets (60) 250 mg/glibenclamide 1.25 mg tablets (90) 500 mg/glibenclamide 2.5 mg tablets (90) 250 mg/glibenclamide 5 mg tablets (90)
References
Guo PYF, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged haemodialysis: recovery after massive overdose of metformin. Seminars in Dialysis 2006; 19(1):80–83.
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Seidowsky A, Nseir S, Houdret N et al. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Critical Care Medicine 2009; 37(7):2191–2196. Spiller HA, Weber JA, Winter ML et al. Multicenter case series of pediatric metformin ingestion. Annals of Pharmacotherapy 2000; 34:1385–1388. Teale KFH, Devine A, Stewart H et al. The management of metformin overdose. Anaesthesia 1998; 53:698–701.
RISK ASSESSMENT
•
Acute overdose — Toxicity is not described following acute deliberate selfpoisoning (single ingestion). — Methotrexate levels taken following acute overdose suggest that toxic levels are not attained where less than 500 mg is ingested (5 mg/kg in children) (see Table 3.51.1 and Table 3.51.2).
TABLE 3.51.1 Dose-related risk assessment: Acute methotrexate overdose Dose
Toxicity
Single dose 5 mg/kg in children)
Toxic levels possible
TABLE 3.51.2 Threshold blood levels for toxicity following a single acute overdose of methotrexate Time since ingestion (h)
•
Methotrexate level (micromol/L)
6
5
12
1
24
0.1
Repeated supratherapeutic ingestion — Associated with potentially lethal bone marrow suppression. — Toxicity may develop if the weekly therapeutic oral dose is taken on as few as 3 consecutive days. — Patients with renal impairment and the malnourished are more susceptible to methotrexate-induced bone marrow suppression.
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The toxic effects of this antimetabolite are employed therapeutically in the treatment of a variety of neoplastic conditions, psoriasis and rheumatoid arthritis. Toxicity is not described following acute overdose, but severe toxicity occurs following repeated supratherapeutic dosing. Folinic acid is used as an antidote in selected cases.
SPECIFIC TOXINS
3.51 METHOTREXATE
•
Intrathecal overdose — Potentially lethal.
•
Children: toxicity is not reported after acute ingestion, but single ingestion suspected to be >2.5 mg/kg warrants referral to hospital for assessment including a methotrexate level.
Toxic mechanism
SPECIFIC TOXINS
Methotrexate is a structural analogue of folate. It acts by competitive inhibition of dihydrofolate reductase and thymidylate synthetase, resulting in decreased DNA and RNA synthesis, and hence decreased cell replication. Methotrexate toxicity is related to inhibition of dividing cells (e.g. gastrointestinal tract, bone marrow, hair). Renal and hepatic injuries are also noted.
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Toxicokinetics
Intestinal absorption of orally administered methotrexate is saturable. Peak levels occur at 1–2 hours post ingestion. The volume of distribution is 0.4–0.8 L/kg, with 50% protein binding. Up to 80% is excreted by the kidney unchanged. Hepatic metabolism creates a nephrotoxic metabolite (7-hydroxymethotrexate), which accumulates at high doses. Elimination half-life increases with dose, accounting for the accumulation and severe toxicity seen with inadvertent daily dosing. In supratherapeutic toxicity, intracellular polyglutamated forms of methotrexate mediate prolonged anti-metabolite effects even after serum levels have declined. CLINICAL FEATURES
• •
Most patients remain asymptomatic after acute ingestion. Following repeated supratherapeutic ingestion, patients present with clinical features and complications of gastrointestinal, bone marrow, hepatic and renal injury. Stomatitis is an early sign. Nausea, vomiting and diarrhoea are common. Pallor and fatigue indicate anaemia, which reaches a nadir at 7–14 days.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Methotrexate level and renal function — Following acute single overdose, a timed methotrexate level and renal function tests determine the need for folinic acid rescue. — If folinic acid is indicated, follow-up methotrexate levels determine the duration of therapy. • EUC, FBC, liver function tests
MANAGEMENT
Resuscitation, supportive care and monitoring
In patients presenting with established methotrexate toxicity
•
Attention to airway, breathing and circulation are paramount and managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Supportive care includes meticulous fluid resuscitation and management of sepsis.
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In patients presenting following acute overdose
Ingestion 5 mg/kg in children). — Administer activated charcoal. — Ensure adequate hydration. — Commence folinic acid. — Check renal function and methotrexate level at 6 or more hours post ingestion. • If renal function is normal and the serum methotrexate level is below thresholds for toxicity (see Table 3.51.2), further folinic acid is not indicated and the patient may be medically cleared if otherwise well. A follow-up FBC is recommended at 7 days. • Folinic acid is indicated if a methotrexate level cannot be obtained within 24 hours, the patient is symptomatic, renal function is abnormal or the methotrexate level is above the threshold for toxicity. Decontamination Oral activated charcoal 50 g (1 g/kg in children) is indicated in cooperative patients who present within 2 hours of acute overdose of >5 mg/kg.
SPECIFIC TOXINS
•
•
Antidotes • Folinic acid (Leucovorin) is indicated in patients at potential risk of methotrexate toxicity (see above). Administer folinic acid 15 mg PO, IM or IV every 6 hours. For a single acute methotrexate overdose, therapy may be ceased when the methotrexate level is confirmed to be below threshold for toxicity (see Table 3.51.2). It is otherwise continued until the serum methotrexate is 3 g but torsades de pointes is not reported. • Co-ingestion of moclobemide with other serotonergic agents is associated with a high risk of severe serotonin syndrome, irrespective of dose (see Chapter 2.8: Serotonin syndrome). • Phenelzine and tranylcypromine are associated with dosedependent, potentially lethal serotonin and sympathomimetic toxicity. Symptoms are delayed and prolonged. — Dose-related risk assessment phenelzine: – >2 mg/kg associated with toxicity – 4–6 mg/kg potentially fatal. — Dose-related risk assessment tranylcypromine: – >1 mg/kg associated with toxicity – 170 mg has caused a fatality.
•
Children: potential ingestion of 1–2 phenelzine or tranylcypromine tablets may be associated with toxicity and referral to hospital for assessment and observation is indicated. Isolated ingestion of moclobemide is benign and referral to hospital is not indicated.
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Toxic mechanism
MAOIs inhibit monoamine oxidase (A and B) in a selective or non-selective, reversible or irreversible manner. MAO-A metabolises serotonin, noradrenaline and dopamine. MAO-B metabolises phenylethylamine and benzylamine at central and peripheral synaptic sites. Irreversible blockade requires new enzyme synthesis over days to re-establish enzymatic function. Irreversible non-selective agents in overdose lead to an accumulation of serotonin, adrenaline, noradrenaline, dopamine and phenylethylamine, resulting in serotonin and sympathomimetic toxicity that can persist for days.
CLINICAL FEATURES
•
Moclobemide overdose (no co-ingestions) — Minor symptoms only. — Nausea, anxiety and tachycardia may occur. — Serotonin syndrome is rare. • Moclobemide overdose in combination with another serotonergic agent — Serotonin syndrome frequently develops within 6–12 hours (see Chapter 2.8: Serotonin syndrome). • Phenelzine or tranylcypromine overdose — Patients are usually asymptomatic for the first 6–12 hours. — Onset of toxicity is heralded by restlessness, agitation, tachycardia, involuntary movements, grimacing, clonus and hyperreflexia. — A rapid decline in conscious state follows. — Muscle rigidity develops, leading to respiratory compromise, hypoxia, respiratory acidosis, hyperthermia and rhabdomyolysis. — Autonomic instability is demonstrated by swings from hypertension to hypotension. — Disseminated intravascular coagulation (DIC) and multiple organ failure may occur. — Even with optimal supportive care, intoxication may last several days. • Classically described MAOI adverse reactions — Serotonin syndrome — Tyramine reaction: after the ingestion of a tyramine- containing food (e.g. cheese) patients complain of severe occipital headache, associated with pronounced hypertension, sweating, agitation, mydriasis and sometimes chest pain. Complications of acute hypertensive crises include: – Intracranial haemorrhage – Rhabdomyolysis – Acute renal failure – DIC.
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All MAOIs are well absorbed after oral administration and reach peak levels within 2–3 hours. There is considerable first-pass metabolism (e.g. moclobemide bioavailability 60–80%). They have moderate volumes of distribution (moclobemide 1.2 L/kg). These agents undergo hepatic metabolism to metabolites that are excreted in the urine. Phenelzine, tranylcypromine and selegiline have active metabolites.
SPECIFIC TOXINS
Toxicokinetics
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
SPECIFIC TOXINS
Specific investigations as indicated • Serial ECGs (moclobemide) — Mild QT prolongation is described following moclobemide overdose. A 12-lead ECG is reviewed at presentation and at 6 hours. If the QT is >450 ms, further monitoring is indicated. • EUC, FBC, CK, troponin, arterial blood gases, chest X-ray, cranial CT scan, EEG
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MANAGEMENT
Resuscitation, supportive care and monitoring • A basic level of supportive care and monitoring is sufficient for pure moclobemide overdose. • Serotonin syndrome and severe sympathomimetic toxicity are potentially life-threatening emergencies and managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Attention to airway, breathing and circulation are paramount (see Chapter 1.2: Resuscitation). • Hypertension and tachycardia are usually controlled with titrated IV benzodiazepines. Severe hypertension (including tyramine reactions) may require parenteral vasodilator therapy. Caution is required, as the onset of autonomic instability may rapidly produce hypotension. Consider: — Titrated vasodilator infusion (sodium nitroprusside, glyceryl trinitrate) — α-antagonism (phentolamine 2–3-mg increments every 10–15 minutes until control achieved). — Note: β-Adrenergic blockers are contraindicated as unopposed α-agonist stimulation may result. • Seizures and agitated delirium may be managed with benzodiazepines, as outlined in Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation. • Hyperthermia resulting from MAOI toxicity requires aggressive therapy. — Temperature >38.5°C is an indication for continuous coretemperature monitoring, benzodiazepine sedation and fluid resuscitation. — Temperature >39.5°C requires rapid treatment to prevent multiple organ failure and neurological injury. Paralysis, intubation, ventilation and active cooling are indicated. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Life-threatening serotonin syndrome requires specific care, including paralysis and intubation and ventilation to avoid fatalities (see Chapter 2.8: Serotonin syndrome). • Close clinical and physiological monitoring is indicated. Decontamination • Moclobemide overdose has a good prognosis with standard supportive care. Decontamination is not indicated.
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•
Patients who are alert and cooperative and who have ingested >1 mg/kg of tranylcypromine or >2 mg/kg of phenelzine are given 50 g oral activated charcoal if they present within 2 hours. Activated charcoal is contraindicated in the symptomatic patient due to the potential for imminent deterioration of conscious state and seizures.
DISPOSITION AND FOLLOW-UP
•
Patients who are clinically well without features of serotonin toxicity at 12 hours may be discharged. Discharge should not occur at night. • Patients with symptomatic moclobemide overdose are managed supportively in a ward environment following a period of 6 hours close observation. When the patient is clinically well, ambulant, passing urine, eating and drinking, discharge may occur. • Patients with severe serotonin syndrome or phenelzine/ tranylcypromine overdose usually require management in an intensive care unit.
HANDY TIP
•
PITFALLS
• •
Hyperthermia in the setting of MAOI toxicity requires rapid and aggressive therapy.
Failure to recognise and treat hyperthermia. Failure to observe a patient for a sufficient period of time following deliberate self-poisoning with phenelzine or tranylcypromine, or following moclobemide overdose in combination with other serotonergically active agents.
CONTROVERSY
•
The role of specific serotonin antagonists in the management of MAOI toxicity.
Presentations
Moclobemide 150 mg tablets (60) Moclobemide 300 mg tablets (60) Phenelzine sulfate 15 mg tablets (100) Selegiline hydrochloride 5 mg tablets (100) Tranylcypromine sulfate 10 mg tablets (50)
References
Downes MA, Whyte IM, Isbister GK. QTc abnormalities in deliberate self-poisoning with moclobemide. Internal Medicine Journal 2005; 35:388–391.
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Antidotes • A trial of cyproheptadine is indicated in patients with symptoms consistent with mild-to-moderate serotonin syndrome refractory to benzodiazepines (see Chapter 4.3: Cyproheptadine).
SPECIFIC TOXINS
Enhanced elimination • Not clinically useful.
Isbister GK, Hackett LP, Dawson AH et al. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. British Journal of Clinical Pharmacology 2003; 56(4):441–450. Kaplan RF, Feinglass NG, Webster W. Phenelzine overdose treated with dantrolene sodium. Journal of the American Medical Association 1986; 255:642–644. Mills KC. Monoamine oxidase inhibitor toxicity. Emergency Medicine 1993; 15:58–71
3.54 NEW ORAL ANTICOAGULANTS
SPECIFIC TOXINS
Apixaban, Dagibatran, Rivaroxaban
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These new oral anticoagulants (NOACs) are increasingly prescribed to treat thromboembolic disease and reduce risk of stroke in atrial fibrillation. Most NOAC-related bleeding occurs in the context of therapeutic administration, often as a result of drug interactions, renal failure or significant underlying pathology predisposing to bleeding complications. Clinical experience with deliberate self-poisoning with NOACs is limited. Assessment and management is further complicated by the poor correlation of anticoagulant activity with classic coagulation tests and the lack of reliable strategies to reverse anticoagulation. RISK ASSESSMENT
• •
NOACs are potent anticoagulant agents and overdose with any amount could result in clinically significant bleeding. Classic coagulation tests correlate poorly with the anticoagulant effect of these agents and have a limited role in refining risk assessment.
•
Children: there are no published reports of NOAC overdose in children but accidental ingestion of even 1 or 2 tablets will produce significant anticoagulation and an undefined risk of bleeding.
Toxic mechanism
Dagibatran is a direct competitive inhibitor of both free and fibrin-bound thrombin. Apixaban and rivaroxaban are direct factor Xa inhibitors. They inhibit free factor Xa as well as factor Xa bound in the prothrombinase complex or associated with thrombin.
Toxicokinetics
Dagibatran has a bioavailability of only 6% following oral administration but this is increased to 75% if the granules are removed from the capsules prior to ingestion. Peak concentrations occur 2–4 hours after ingestion. Dagibatran is metabolised by the liver to form active metabolites. Volume of distribution is 50–70 L and protein binding is 35%. Elimination is predominantly renal with a terminal elimination half-life of 12–24 hours. This is prolonged in the presence of renal impairment. Apixaban and rivaroxaban have similar kinetics. Bioavailability is >50% following oral administration. Peak concentrations are reached 3–4 hours after ingestion. Volumes of distribution are relatively small (90 seconds suggests high drug level Normal aPTT suggests minimal drug present
Variable
Thrombin clotting time (TT, TCT)
Very sensitive Normal value excludes presence of drug Exceeds measurement time of coagulometer at high concentration
Not useful
Haemoclot assay (dilute thrombin time)
Useful to derive levels
Not useful
Factor IIa assay
Best correlation with bleeding risk
Not useful
Factor Xa assay
Not useful
Good correlation with levels
Notes: 1 Combination of INR >2 and aPTT >90 seconds suggests high plasma levels of dabigatran. 2 Normal INR and normal aPTT suggest low plasma levels of dabigatran. 3 Combination of normal PT and aPTT suggests low plasma levels of apixaban and rivaroxaban. 4 Factor IIa, Xa and Haemoclot assays are available in few hospitals and can take more than 24 hours to perform. 5 Thromboelastography is effective at measuring anticoagulant activity of NOACs but specific assays have not yet been developed.
•
Traditional reversal agents do not effectively reverse anticoagulation from these agents. Various combinations of recombinant factor VIIa, factor VIII inhibitor bypass activity (FEIBA), prothrombin complex concentrates, tranexamic acid and fresh frozen plasma (FFP) have been recommended in institutional protocols.
DISPOSITION AND FOLLOW-UP
•
All patients who overdose on NOACs are admitted to hospital for observation and serial coagulation studies until normalised.
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PITFALLS
• • •
There is no evidence that administration of reversal agents in the absence of bleeding has any beneficial effects. Do not rely on point-of-care (POC) coagulation testing. Correlation with NOAC levels or bleeding risk is not validated.
Failure to admit and monitor patients who have ingested small overdoses of any NOAC. Failure to prevent falls in patients with significant anticoagulation. Administration of coagulation factors in the absence of significant bleeding. This is associated with a risk of thromboembolic complications.
CONTROVERSIES
•
Administration of reversal agents in the absence of active bleeding. There is no evidence that this intervention is associated with clinical benefit. • The role of early dialysis following dabigaran overdose in the absence of active bleeding.
Presentations
Dabigatran etexilate 75 mg capsules (10, 60) Dabigatran etexilate 110 mg capsules (10, 60) Dabigatran etexilate 150 mg capsules (10, 60) Apixaban 2.5 mg tablets (20, 30, 60) Apixaban 5 mg tablets (60) Rivaroxaban 10 mg tablets (10, 15, 30, 100) Rivaroxaban 15 mg (28, 42) Rivaroxaban 20 mg (28)
References
Chiew AL, Khamoudes D, Chan BS. Use of continuous veno-venous haemodiafiltration therapy in dabigatran overdose. Clinical Toxicology 2014; 52:283–287. Koscielny J, Rutkauskaite E. Rivaroxaban and hemostasis in emergency care. Emergency Medicine International 2014; Feb 20 [Epub ahead of print]. Kumar R, Smith RE, Henry BL. A review of and recommendations for the management of patients with life-threatening dabigatran-associated hemorrhage: a single-center university hospital experience. J Intensive Care Medicine 2014; Mar 25 [Epub ahead of print]. Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Practice and Research in Clinical Haematology 2013; 26:191–202. Pernod G, Albaladejo P, Godier A. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants,
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SPECIFIC TOXINS
HANDY TIPS
All patients with NOAC-related bleeding are admitted to hospital for active treatment as above. Dagibatran overdose must be managed in a hospital with capacity for haemodialysis. Following dabigatran overdose, patients are medically cleared if the INR and aPTT remain normal at 12 hours post ingestion. Following factor Xa inhibitor overdose, patients are medically cleared if the PT and aPTT remain normal at 12 hours post ingestion.
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• • • •
thrombin or factor-Xa inhibitors: proposals of the Working Group on Perioperative Haemostasis (GIHP) – March 2013. Archives of Cardiovascular Disease 2013; 106:382–393. Wood P. New oral anticoagulants: an emergency department overview. Emergency Medicine Australasia 2013; 25:503–514.
SPECIFIC TOXINS
3.55 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Celecoxib, Diclofenac, Etoricoxib, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Naproxen, Parecoxib, Piroxicam, Sulindac, Tiaprofenic acid Overdose with any of the NSAIDs, unless the ingestion is massive, is benign. Management is symptomatic and supportive. Ibuprofen accounts for over two-thirds of NSAID deliberate self-poisoning cases. RISK ASSESSMENT
•
Overdose with these agents is generally benign, even following large ingestions. Dose-related risk assessment is best defined for ibuprofen (see Table 3.55.1).
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Effect
300 mg/kg
Risk of multi-system organ dysfunction
•
Massive overdose is associated with severe multi-system organ dysfunction including shock, coma, seizure, acute renal failure and metabolic acidosis. Fatalities are reported. • Overdose with any amount of mefenamic acid is commonly associated with self-limiting seizures.
•
Children: significant symptoms usually are not observed until the dose ingested exceeds 300 mg/kg of ibuprofen (or equivalent of other NSAID). Minor unintentional ingestion of 0.5 mg/kg may cause clinical features of intoxication including lethargy, agitation,
TABLE 3.56.1 Dose-related risk assessment: Olanzapine Dose (adult)
Effect
300 mg
Increasing sedation progressing to coma likely to require intubation Hypotension secondary to peripheral alpha blockade
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Deliberate self-poisoning with this second-generation atypical antipsychotic agent is associated with sedation, delirium and coma in ascending doses. Thorough supportive care ensures a good outcome.
tachycardia and extrapyramidal effects. Referral to hospital for monitoring and supportive care is warranted. Delayed extrapyramidal effects may occur over the following days. Toxic mechanism
Olanzapine is an antagonist at dopamine (D2), serotonin (particularly 5-HT2), histamine (H1), muscarinic (M1) and peripheral alpha (α) receptors.
Toxicokinetics
SPECIFIC TOXINS
Olanzapine is well absorbed after oral or sublingual administration. The volume of distribution is 10–20 L/kg. It undergoes hepatic metabolism by oxidative (cytochromes P450 1A2 and 2D6) and conjugative (glucuronidation) pathways to inactive water-soluble metabolites. There is a large first-pass effect after oral dosing.
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CLINICAL FEATURES
• • • • • • •
Onset of clinical features of intoxication occurs within 2–4 hours. Sedation, ataxia, miosis, orthostatic hypotension and tachycardia are common. Fluctuating mental status with intermittent agitated delirium occurs with moderate doses, usually lasting less than 24 hours. Urinary retention frequently complicates this presentation. Coma when it occurs following large ingestions lasts from 18 to 48 hours. Non-specific ST-T wave changes occur in 15% of overdoses, but clinically significant QT prolongation is rare. Extrapyramidal effects are uncommon. Seizures are rare.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial ECGs — An ECG is performed at presentation and at 6 hours. If the ECG is normal at that time, further ECG monitoring may be ceased in the unintubated patient. — In the intubated patient, 12-lead ECGs are assessed for QT prolongation every 4 hours until clinical improvement occurs.
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Intubation and ventilation may be required if significant sedation occurs. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Severe agitated delirium is managed, as outlined in Chapter 2.7: Delirium and agitation. • Close clinical and physiological monitoring is indicated. • Monitor for urinary retention and insert an indwelling urinary catheter if required.
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Decontamination • Oral activated charcoal is not indicated, because the onset of sedation and coma occurs early and supportive care ensures a good outcome. Enhanced elimination • Not clinically useful. Antidotes • None available. DISPOSITION AND FOLLOW-UP
HANDY TIP
PITFALL
•
Benzodiazepines are first-line agents for the management of olanzapine-induced agitated delirium. However, subsequent fluctuations in mental status may mandate intubation and ventilation.
•
Undetected urinary retention contributes to agitation and is managed with an indwelling catheter.
CONTROVERSIES
• •
The role of physostigmine in the management of agitated delirium. It is not clear that the delirium is entirely of anticholinergic origin. Physostigmine is also reported to reverse olanzapine-induced coma. The efficacy, clinical utility and indications for physostigmine in this situation are undefined.
Presentations Olanzapine Olanzapine Olanzapine Olanzapine Olanzapine Olanzapine Olanzapine Olanzapine Olanzapine Olanzapine Olanzapine
2.5 mg tablets (28) 5 mg tablets (28) 7.5 mg tablets (28) 10 mg tablets (28) 15 mg tablets (28) 20 mg tablets (28) 5 mg wafers (28) 10 mg wafers (28) 15 mg wafers (28) 20 mg wafers (28) 10 mg powder, injectable
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All paediatric patients are observed in hospital following possible unintentional ingestion of >0.5 mg/kg. If they remain clinically well without sedation at 4 hours following ingestion they can be safely discharged. Parents are advised that abnormal (extrapyramidal) movements sometimes occur up to 3 days after ingestion. • Patients with mild sedation, normal blood pressure and normal 12-lead ECG may be managed supportively in a ward environment. Medical discharge occurs when the patient is clinically well, ambulant, passing urine, eating and drinking. • Patients with significant agitation or delirium, and those requiring intubation, require admission to a high-dependency or intensive care unit, often for up to 48 hours.
SPECIFIC TOXINS
•
Olanzapine pamoate monohydrate 210 mg powder + solvent, injectable Olanzapine pamoate monohydrate 300 mg powder + solvent, injectable Olanzapine pamoate monohydrate 405 mg powder + solvent, injectable
References
SPECIFIC TOXINS
Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Journal of Toxicology–Clinical Toxicology 2001; 39(1):1–14. Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Safety 2005; 26(11):1029–1044. Palenzona S, Meier PJ, Kupferschmidt H et al. Clinical picture of olanzapine poisoning with special reference to fluctuating mental status. Journal of Toxicology – Clinical Toxicology 2004; 42(1):27–32.
Buprenorphine, Codeine, Dextropropoxyphene, Fentanyl, Heroin, Hydromorphone, Methadone, Morphine, Oxycodone, Pethidine Opioid intoxication causes CNS and respiratory depression. Death is due to respiratory failure. Good supportive care ensures survival. The specific antidote, naloxone, can assist the management of airway and breathing. Some opioids possess unexpected toxic effects (e.g. dextropropoxyphene).
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3.57 OPIOIDS
RISK ASSESSMENT
• •
Life-threatening CNS and respiratory depression frequently occur just above the analgesic dose. Opioid use by naïve patients (no tolerance) or co-ingestion of other CNS depressants (antidepressants, benzodiazepines, ethanol) increases the severity of CNS depression and the likelihood of a fatal outcome without supportive care. • Certain agents have specific risk assessments based on particular toxicities (see Table 3.57.1).
•
Children: opioid intoxication is the leading cause of death by poisoning in children. Ingestion of a single opioid tablet or a
TABLE 3.57.1 Opioid risk assessment: Special cases Drug
Effect
Dextropropoxyphene
10 mg/kg likely to cause symptoms 20 mg/kg may cause CNS depression, seizures and cardiac dysrhythmias (fast sodium channel blocking effect)
Methadone and oxycodone
QT prolongation
Pethidine
Repeated therapeutic doses are associated with seizures Implicated in serotonin syndrome
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mouthful of methadone syrup can cause respiratory arrest. More than 2 mg/kg of codeine may cause symptoms in children and >5 mg/kg can cause respiratory arrest. Toxic mechanism
Agonist activity at µ-receptors is responsible for euphoria, analgesia, physical dependence, sedation and respiratory depression. Multiple other opioid actions are responsible for side effects such as nausea and vomiting (dopamine receptors), constipation (peripheral µ-receptors in the gut wall), pruritus (histamine release) and seizures.
CLINICAL FEATURES
• • • • • • • • •
The classic opioid toxidrome consists of: — CNS depression — Respiratory depression (rate and depth of respirations) — Miosis. The duration of effects depends on the pharmacokinetics of the individual agent. Heroin intoxication is typically short (e.g. less than 6 hours), while methadone and oxycodone intoxication may last more than 24 hours. Death is caused by loss of airway protective reflexes and apnoea. Nausea and vomiting may occur, promoting pulmonary aspiration. Bradycardia is common. Tachycardia may occur as a response to hypoxia and hypercarbia. Hypothermia, skin necrosis, compartment syndrome, rhabdomyolysis and hypoxic brain injury may complicate prolonged non-lethal intoxication. Methadone and oxycodone are associated with QT prolongation although torsades de pointes is rare. Dextropropoxyphene intoxication is also associated with seizures, hypotension and ventricular dysrhythmias. Pethidine is associated with serotonin syndrome.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated: • Specific blood levels and urine screening do not assist clinical management. • Specific investigations are only indicated to diagnose and assess secondary complications.
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount and ensure the survival of the vast majority of patients.
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Oral absorption of opioids is variable. Most, with the exception of controlled-release preparations, are absorbed rapidly. Volumes of distribution are usually large (e.g. codeine 2.6 L/kg; methadone 3.6 L/kg; morphine 3.4 L/kg). Most undergo hepatic metabolism to form metabolites that are excreted in the urine, some of which are active. Morphine, for example, is one of three active metabolites of codeine.
SPECIFIC TOXINS
Toxicokinetics
SPECIFIC TOXINS
• • • •
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These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Close clinical and physiological monitoring is indicated. In the rare event of ventricular dysrhythmias in dextropropoxyphene intoxication, resuscitation includes serum alkalinisation by the administration of IV bolus sodium bicarbonate, as outlined in Chapter 4.24: Sodium bicarbonate.
Decontamination • Opioid intoxication is associated with CNS and respiratory depression, and vomiting. A good outcome is expected with supportive care and, possibly, antidote administration. Therefore, activated charcoal is not routinely indicated. • Oral activated charcoal may reduce length of stay if administered to a patient presenting early after overdose with controlledrelease morphine tablets. Enhanced elimination • Not clinically useful. Antidotes • Respiratory and CNS depression can be reversed with titrated doses of naloxone (see Chapter 4.18: Naloxone). Continuous naloxone infusion may be required following overdose of long-acting opioids or slow-release preparations. DISPOSITION AND FOLLOW-UP
• • • • •
The period of observation required to detect CNS depression varies with the opioid. For most standard-release oral preparations 4 hours is sufficient. A patient who ingests controlled-release opioid preparations must be observed for at least 12 hours before medical clearance. Following ingestion of standard preparations, patients with mild sedation who have not required naloxone may be managed in a ward environment after an initial observation period of 4 hours. Any child who has potentially ingested an opioid (unless 50 mg (5 mL of 1% solution) causes symptoms
Adult
Estimated mean lethal ingested dose is 125 mg/kg Dose required to induce toxicity from dermal absorption not defined
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3.58 ORGANOCHLORINES
endrin, aldrin, dieldrin and chlordane have the lowest LD50s in animal models. • Toxicity occurs in three main settings: — Acute deliberate self-poisoning by ingestion – rapid onset of neurological symptoms, seizures and coma — Excessive dermal application or accidental ingestion of lindane – agitation and seizures — Occupational exposures via dermal or inhalational routes – usually no acute symptoms.
SPECIFIC TOXINS
•
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Children: ingestion is potentially life threatening. Topical lindane used as a lice treatment can cause agitation and seizures, particularly with repeat use or prolonged application.
Toxic mechanism
Lindane and the cyclodienes (aldrin, dieldrin, heptachlor, endrin, chlordane, endosulfan) are non-competitive antagonists acting at the chlorine ion channel of GABAA receptors. DDT acts by inhibiting sodium channel closure following depolarisation. Both mechanisms are neuroexcitatory.
Toxicokinetics
These agents are rapidly absorbed following ingestion. The degree of dermal absorption depends on the agent, concentration, solvent (usually hydrocarbon) and skin integrity. Lindane and the cyclodienes are well absorbed across skin. Organochlorines are highly lipid soluble and widely distributed to fat stores. Accumulation may occur with repeated occupational exposure. Organochlorines undergo hepatic microsomal metabolism prior to elimination in the urine. They have non-linear kinetics, due to slow redistribution from fat stores. Elimination of some organochlorines may take weeks to months. CLINICAL FEATURES
•
• • • • •
Principal clinical features of toxicity are: — Nausea and vomiting — Anxiety, agitation and confusion — Perioral paraesthesia, fasciculation and myoclonic movements — Seizures – these are usually of short duration but may be recurrent — Sedation and coma. Clinical features develop within 1–2 hours of acute ingestion and over hours to days following excessive dermal application. Hypotension, cardiac dysrhythmias and ventricular ectopy are rare complications of severe intoxication. Hypoxaemia and acidosis contribute to myocardial sensitisation to catecholamines. Hepatitis and renal dysfunction are reported following acute intoxication. Vomiting and aspiration may be complicated by a severe chemical pneumonitis from the hydrocarbon vehicle in which many of these agents are formulated.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Arterial blood gases — Hypoxaemia and acidosis.
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•
Serial 12-lead ECGs — Increased ventricular ectopy may herald the onset of ventricular tachydysrhythmias. • EUC, liver function tests — Hepatic and renal failure. • Serum and fat organochlorine levels — Not readily available and do not assist management.
Decontamination • Resuscitation takes priority over decontamination and activated charcoal is not indicated until the airway is secured by endotracheal intubation. • Following excessive dermal exposure, wash the skin with soap and water. Enhanced elimination • Not clinically useful. Antidotes • None available. DISPOSITION AND FOLLOW-UP
•
Children with potential ingestions should be observed in hospital for 4 hours. If they do not develop symptoms during that period they may then be safely discharged. • Excessive dermal exposure only warrants referral to hospital if symptoms occur. • Patients with objective evidence of organochlorine intoxication as evidenced by gastrointestinal or neurological symptoms are managed in a hospital location capable of managing seizures. Those that develop features of major intoxication (recurrent seizures or coma) require admission to the intensive care unit for ongoing supportive care. • Patients may be safely discharged once all symptoms resolve. Follow-up is not necessary if asymptomatic.
HANDY TIPS
•
The seizures associated with acute intoxication are usually rapid in onset, short duration and controlled with benzodiazepines.
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Resuscitation, supportive care and monitoring • Organochlorine poisoning is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Potential life threats that require immediate intervention include: — Coma (see Chapter 2.4: Coma) — Seizures (see Chapter 2.6: Seizures) — Ventricular dysrhythmias. • Control agitation with carefully titrated doses of benzodiazepines. • Institute general supportive care, as outlined in Chapter 1.4: Supportive care and monitoring.
SPECIFIC TOXINS
MANAGEMENT
PITFALL
•
Ventricular dysrhythmias associated with organochlorines are rare and may respond to IV beta-blockers (e.g. metoprolol or propranolol).
•
Failure to recognise the onset of acute toxicity, manifested by vomiting, agitation or perioral paraesthesia.
CONTROVERSY
SPECIFIC TOXINS
•
The chronic subclinical effect of the organochlorines, including their carcinogenic potential.
Presentations
Most organochlorines are solid at room temperature and dissolved in hydrocarbon for ease of application. Industrial formulations Aldrin, Chlordane, Dichlorodiphenyltrichloroethane (DDT), Dieldrin, Endosulfan, Endrin, Ethylan, Heptachlor, Hexachlorobenzene, Isobenzan, Lindane, Methoxychlor Medical formulations Lindane 1% shampoo or lotion
References
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Aks SE, Krantz A, Hryhorczuk DO et al. Acute accidental lindane ingestion in toddlers. Annals of Emergency Medicine 1995; 26(5):647–651. Baselt R. Disposition of Toxic Chemicals and Drugs in Man. 5th edn. Foster City, California: Chemical Toxicology Institute; 2000. CDC. Unintentional topical lindane ingestions – United States, 1998–2003. MMWR Morbidity Mortality Weekly Report 2005; 54(21):533–535.
3.59 ORGANOPHOSPHORUS AGENTS (organophosphates and carbamates) Organophosphates: Chlorpyrifos, Coumaphos, Diazinon, Dichlorvos, Dimethoate, Fenthion, Malathion, Parathion, Trichlorfon Carbamates: Aldicarb, Carbendazim, Carbendazole, Carbazine, Propoxur Chemical nerve agents: Sarin (GB), Soman (GD), Tabun (GA), VX Deliberate self-poisoning with organophosphate and carbamate insecticides is responsible for more than 100 000 deaths worldwide each year. Although agent-dependent variations in clinical features occur, these agents generally cause death by respiratory failure. Attention to the principles of resuscitation and supportive care, together with use of antidotes, is essential to achieve a good outcome. RISK ASSESSMENT
• •
Deliberate self-poisoning by ingestion of organophosphates almost always produces life-threatening toxicity. Deliberate self-poisoning by ingestion of carbamates produces similar serious toxicity, but is usually of shorter duration and less likely to be life threatening. • Onset of clinical manifestations of poisoning may be delayed up to 12 hours with some agents.
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• •
Inadvertent or accidental occupational dermal or inhalational exposure can cause toxicity but is rarely life threatening. Significant secondary poisoning of staff (nosocomial poisoning) does not occur.
•
Children: any ingestion of organophosphates or carbamates is potentially lethal.
Toxicokinetics
These agents are well absorbed after ingestion. Dermal and inhalational represent important routes following occupational exposure. Agents generally have large volumes of distribution and some accumulation in lipid stores. Carbamates are distributed less to the CNS. Lipid solubility is a feature of the thioates. Thioates (e.g. malathion, parathion, fenthion) act as indirect agents; they require metabolism to their active forms. Metabolism of organophosphate compounds is primarily hydrolysis by serum HDL-bound esterase enzymes (paraoxonases). Others undergo hepatic microsomal (cytochrome P450) metabolism with excretion of inactive metabolites in the urine. Most carbamates are metabolised in the liver by oxidation, hydrolysis or conjugation and then excreted in the urine. CLINICAL FEATURES
• • • • • •
Timing of symptom onset depends on the agent, dose and route of exposure. Symptoms may occur within minutes following ingestion of some agents (e.g. dimethoate, chlorpyrifos) or be delayed by many hours. The constellation and progression of symptoms is variable and either muscarinic or nicotinic features can predominate. Dimethoate intoxication is characterised by the early onset of coma, cardiovascular collapse and death within 24 hours. Chlorpyrifos is associated with early cholinergic symptoms. Fenthion is associated with few early symptoms but the late onset (up to 2 days) of paralysis. Typical clinical syndromes include:
Acute intoxication — Muscarinic effects – Diarrhoea, urination, miosis, bronchorrhoea, bronchospasm, emesis, lacrimation, salivation (‘DUMBBELS’ mnemonic) – Bradycardia and hypotension — Nicotinic effects – Fasciculation, tremor, weakness, respiratory muscle paralysis – Tachycardia and hypertension
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Organophosphates inhibit acetylcholinesterase (AChE) enzymes, and increase acetylcholine (ACh) concentration at both muscarinic and nicotinic cholinergic receptors. Clinical features are secondary to the widespread effects of increased ACh at CNS, autonomic (parasympathetic and sympathetic) and skeletal muscle neuromuscular synapses. Irreversible loss of an alkyl side chain and permanent binding of the organophosphate (‘ageing’) prevents reactivation of AChE by the antidote, pralidoxime. The time taken for ageing to occur depends on the individual agent. Ageing does not occur with carbamates. Organophosphates and carbamates are frequently formulated with hydrocarbon solvents (e.g. xylene). Inhalation of solvent fumes can produce headache and dizziness but this does not indicate organophosphate poisoning. The insecticides themselves have very low vapour pressures and are only inhaled when aerosolised.
SPECIFIC TOXINS
Toxic mechanism
SPECIFIC TOXINS
– Note: tachycardia is frequently present due to hypoxia and hypotension — Central nervous system – Agitation, coma, seizures — Respiratory – Chemical pneumonitis if hydrocarbon solvent aspirated – For further detail on the cholinergic syndrome, see Chapter 2.10: Cholinergic syndrome
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Intermediate syndrome — Delayed onset of paralysis occurring 2–4 days after apparent recovery from initial muscarinic symptoms. This syndrome is associated with particular agents (e.g. fenthion, diazinon, malathion) but the pathophysiology is not well understood. Hypotheses include prolonged motor end-plate stimulation, delayed redistribution from lipid stores and inadequate initial pralidoxime dosing Delayed neurotoxicity — Organophosphate-induced delayed neuropathy (OPIDN) is rare and occurs 1–5 weeks post acute exposure to particular agents (e.g. fenthion, chlorpyrifos, parathion). It is an ascending sensorimotor polyneuropathy thought to be secondary to ageing of axonal neuropathy target esterase (NTE) Chronic organophosphate-induced neuropsychiatric disorder — Long-term neuropsychiatric disorder, which may occur following acute intoxication or chronic low-level exposure. INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Red cell and plasma (butyryl-, pseudo-) cholinesterase activities — The diagnosis and management of acute anticholinesterase poisoning is primarily clinical, but measures of cholinesterase activity can be useful in making a definitive diagnosis and to monitor therapy. — Access to these assays can be difficult and samples must be processed promptly due to ongoing in vitro reactions. — Significant clinical features generally occur at levels 10 g or >200 mg/kg. • The risk of hepatic injury following a single acute ingestion without NAC is predicted by plotting a serum paracetamol level taken 4–15 hours later on the Prescott or Rumack–Matthew nomogram (see Figure 3.60.1 for a modified version of this nomogram). The probability of hepatotoxicity (defined as peak AST or ALT >1000 IU/L) is: — 1–2% if 4-hour level is 1980 micromol/L (300 mg/L).
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Buckley NA, Eddleston M, Li Y et al. Oximes for acute organophosphate poisoning. Cochrane Database of Systematic Reviews 2011; 2. Eddleston M, Eyer P, Worek F et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005; 366:1452–1459. Eddleston M, Eyer P, Worek F et al. Pralidoxime in acute organophosphorus insecticide poisoning: a randomised controlled trial. PLoS Medicine 2009; 6(6):e1000104. Published online 30 June 2009. Little M, Murray L. Consensus statement: risk of nosocomial organophosphate poisoning in emergency departments. Emergency Medicine Australasia 2004; 16:456–458. Pawar KS, Bholte RR, Pillay CP et al. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomized controlled trial. Lancet 2006; 368:2136–2141. Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning. British Medical Journal 2007; 334(7594):629–634.
SPECIFIC TOXINS
References
SPECIFIC TOXINS
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Time (hours)
Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008; 188:296–301.
(µmol/L)
Blood paracetamol concentration
FIGURE 3.60.1 Paracetamol treatment nomogram recommended for use in Australia and New Zealand
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Blood paracetamol concentration (mg/L)
• • • •
Children: there are no reports of death following single acute non-intentional paracetamol exposure in children under 8 years of age. Ingestion of 8 hours after overdose with elevated hepatic transaminases are assumed to have early paracetamolinduced hepatotoxicity. The patient who presents >24 hours following an overdose and has normal hepatic transaminases and no detectable paracetamol has little risk of developing clinically significant hepatotoxicity. For massive ingestions (>500 mg/kg) standard NAC administration protocols may be insufficient to prevent hepatotoxicity.
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•
SPECIFIC TOXINS
TABLE 3.60.1 Clinical phases of acute paracetamol overdose Phase 1 (1000 IU/L. In survivors, ALT/AST rapidly return to baseline. Prothrombin time and INR are at their most abnormal within hours of peak AST/ALT. Hyperbilirubinaemia also occurs and renal function may be impaired
Phase 3 (3–4 days)
In very severe cases, hepatotoxicity progresses to fulminant hepatic failure with coagulopathy, jaundice, encephalopathy and multiple organ failure. Death may occur in this phase. Non-survivors demonstrate metabolic acidosis with elevated lactate despite resuscitation, renal failure (serum creatinine >300 micromol/L), worsening coagulopathy (PT >100 seconds) and encephalopathy
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Phase 4 Recovery phase during which hepatic structure (4 days–2 weeks) and function return to normal
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG and BGL. An untimed ‘screening’ paracetamol level is not useful following deliberate self-poisoning with paracetamol and should be replaced by a specific timed level (see below). Specific investigations as indicated • A recommended approach to initial investigations is outlined in Table 3.60.2. • Serum paracetamol — If the time of ingestion is known, a timed paracetamol level is taken at 4 or more hours to establish risk of hepatotoxicity and need for treatment. — If NAC is commenced within 8 hours of a single acute ingestion, the first serum paracetamol level is the only investigation required. — Following massive (>500 mg/kg) overdose, the paracetamol level is repeated towards the end of the NAC infusion. A detectable paracetamol concentration is an indication to continue infusion of NAC. • Hepatic transaminases — If NAC is commenced later than 8 hours, baseline and serial hepatic transaminase levels are also taken to detect and
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TABLE 3.60.2 Recommended initial investigations according to time from paracetamol ingestion to NAC treatment
24 hours
Serum paracetamol
At 4 hours or as soon thereafter as possible
At presentation
At presentation
Transaminases (ALT/AST)
Not indicated
At presentation and at end of 20-hour NAC infusion
At presentation
INR/prothrombin time
Not indicated
Not indicated
At presentation
Creatinine and urea
Not indicated
Not indicated
At presentation
Glucose
Not indicated
Not indicated
At presentation
Arterial blood gas
Not indicated
Not indicated
At presentation
Adapted from Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008; 188:296–301.
monitor hepatic injury. The magnitude of elevation of ALT or AST is not, however, linked to outcome. • Coagulation studies — Elevation of the INR is an important marker of hepatic injury. • Platelet count, renal function and acid–base status — Useful to assess and monitor clinical status and prognosis of established hepatotoxicity. MANAGEMENT
Resuscitation, supportive care and monitoring • Resuscitation is required only in the rare instances of coma due to massive acute ingestion, and delayed presentation with established hepatic failure. In such cases, urgent attention to airway, breathing and circulation, plus correction of hypoglycaemia are required. • General supportive care and monitoring measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Patients with rising hepatic aminotransferase levels and INR >2.5 should have 4-hourly recording of vital signs and bedside serum glucose, and close monitoring of fluid balance. Decontamination • Oral activated charcoal is not life saving. — It may be offered to the cooperative adult who presents within the first hour following overdose, in which case it may sufficiently reduce the 4-hour paracetamol level to such a degree that NAC will be unnecessary.
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Test
SPECIFIC TOXINS
Time after paracetamol ingestion
— It is never justified following acute ingestion of paracetamol by small children.
SPECIFIC TOXINS
Enhanced elimination • Not clinically useful.
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Antidotes • Intravenous NAC is indicated in all patients in whom the risk assessment suggests potential for poor outcome and in patients who present late with clinical or biochemical evidence of hepatic injury. • Presentation 24 hours post ingestion: — NAC is only indicated if paracetamol is detectable or hepatic transaminases are elevated. It is continued until hepatic transaminases are falling and the patient is improving clinically. NAC may be commenced pending biochemical assessment in the patient with nausea, vomiting, abdominal pain or encephalopathy. • A management flow chart for acute paracetamol exposure with known time of ingestion is shown in Figure 3.60.2. • Note: See Chapter 4.17: N-acetylcysteine for full details on dosing and administration of NAC. DISPOSITION AND FOLLOW-UP
•
Patients in whom NAC is commenced within 8 hours of ingestion do not require further investigation or follow-up (except in the case of ingestion of >500 mg/kg when a repeat paracetamol level is indicated at the end of infusion). They are fit for medical discharge at the termination of the 20-hour infusion. • Patients in whom NAC is commenced later than 8 hours following ingestion (or unknown time of ingestion) have hepatic transaminases tested at baseline and at the end of the 20-hour infusion. If they are normal at that time, NAC is ceased. If abnormal, NAC continues at 100 mg/kg/16 hours and hepatic transaminases are tested every 12–24 hours until falling. If hepatic transaminases exceed 1000 IU/L, serial testing also includes INR, renal function and platelet count. • In uncommon cases, rising INR and hepatic transaminases herald fulminant hepatic failure and the need to transfer to a liver transplant service. Arrangements for transfer to such
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1–8 hours
>8 hours
Activated charcoal*
Measure serum paracetamol level within 4–8 hours of ingestion
Commence NAC infusion
UNDER nomogram treatment line
Medical treatment not required
Measure serum paracetamol level & ALT
Plot serum paracetamol level on nomogram
Plot serum paracetamol level on nomogram
UNDER treatment line or >24 hrs post OD
OVER nomogram treatment line
OVER nomogram treatment line
ALT normal
Commence NAC infusion
Continue NAC infusion
No further investigation required
Measure ALT at end of NAC infusion
yes
ALT normal
no
333
no
yes
STOP NAC
No further treatment required
Continue NAC and monitor
*Cooperative adult patients who have potentially ingested greater than 10 g or 200 mg/kg, whichever is less Source: Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008; 188:296–301.
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3.0 at 48 hours or >4.5 at any time — Oliguria or creatinine >200 micromol/L — Acidosis with pH 50 g/day), prolonged fasting and use of particular medications (inducers of cytochrome P450 2E1 and 3A4; isoniazid, rifampicin and carbamazepine) are likely to increase the risk of hepatotoxicity. • Antidotal treatment of massive (>500 mg/kg) paracetamol overdose. It has been proposed that NAC infusion rates be increased in this group of patients. At the very least, most authorities recommend continuing the ‘third bag’ of NAC until paracetamol is no longer detected in the serum.
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Paracetamol 500 mg/pseudoephedrine 30 mg/chlorpheniramine 2 mg tablets (6, 12, 24, 30, 60) Paracetamol 325 mg/pseudoephedrine 30 mg/chlorpheniramine 2 mg tablets (10, 30, 50) Paracetamol 500 mg/pseudoephedrine 30 mg/chlorpheniramine 2 mg/codeine phosphate 9.5 mg (24) Paracetamol 500 mg/chlorpheniramine 2 mg tablets (24) Paracetamol 500 mg/doxylamine succinate 5.1 mg/codeine phosphate 10 mg tablets (20) Paracetamol 500 mg/doxylamine succinate 5.1 mg/codeine phosphate 9.6 mg tablets (10, 20) Paracetamol 500 mg/doxylamine succinate 5 mg/codeine phosphate 8 mg tablets (20, 24) Paracetamol 500 mg/doxylamine succinate 2 mg/codeine phosphate 10 mg capsules (20) Paracetamol 450 mg/codeine phosphate 9.75 mg/doxylamine succinate 5 mg tablets (20) Paracetamol 450 mg/codeine phosphate 9.75 mg/doxylamine succinate 5 mg caplets (20)
Paracetamol 450 mg/codeine phosphate 30 mg/doxylamine succinate 5 mg tablets (20) Paracetamol 450 mg/orphenadrine citrate 35 mg tablets (100) Paracetamol 500 mg/codeine phosphate 10 mg tablets (24, 48, 96) Paracetamol 500 mg/codeine phosphate 8 mg tablets (12, 20, 24, 48, 50, 96, 100) Paracetamol 500 mg/codeine phosphate 30 mg tablets (20, 50) Paracetamol 500 mg/codeine phosphate 9.6 mg caplets (12, 20, 24, 40, 48) Paracetamol 500 mg/codeine phosphate 15 mg caplets (12) Paracetamol 500 mg/codeine phosphate 15 mg tablets (20, 50) Paracetamol liquid 120 mg/codeine phosphate 5 mg per 5 mL (100, 200 mL) Paracetamol liquid 120 mg/codeine phosphate 5 mg/promethazine 6.5 mg per 5 mL (100 mL, 200 mL) Paracetamol 500 mg/caffeine 65 mg caplets (12, 18, 24, 36, 48, 96) Paracetamol 500 mg/ibuprofen 150 mg tablets (10, 16, 30) Paracetamol 325 mg/tramadol 37.5 mg tablets (20, 50)
References
Daly FSS, Fountain JS, Murray L et al. Guidelines for the management of paracetamol poisoning in Australia and New Zealand: explanation and elaboration. A consensus statement from toxicologists consulting to the Australasian Poisons Information Centres. Medical Journal of Australia 2008; 188:296–301. Ferner RE, Dear JW. Management of paracetamol poisoning. British Medical Journal 2011; 342d2218. O’Grady JG. Acute liver failure. Postgraduate Medical Journal 2005; 81:148–154. Prescott LF, Illingworth RN, Critchley JA. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. British Medical Journal 1979; 2:1097. Rumack BH, Bateman DH. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clinical Toxicology 2012; 50:91–98. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871–876.
3.61 PARACETAMOL: MODIFIED-RELEASE FORMULATIONS Acetaminophen; N-acetyl-p-aminophenol (APAP) See also Chapter 3.60: Paracetamol: Acute overdose, Chapter 3.62: Paracetamol: Repeated supratherapeutic ingestion. Modified-release paracetamol preparations are formulated to combine immediate-release and delayed-release layers with increased total dose per tablet. Delayed absorption and biphasic release means standard
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risk-assessment and treatment algorithms are not applicable and prolonged biochemical assessment is required. RISK ASSESSMENT
Risk assessment is still being refined but is currently based on dose and serial timed paracetamol concentrations. The threshold dose for paracetamol-induced hepatic injury in adults is extremely variable but usually considered to be >200 mg/kg (or >10 g). • Two timed paracetamol levels at least 4 hours apart are plotted on the paracetamol treatment nomogram (see Figure 3.60.1). If either level is above the treatment line, there is judged to be a risk of hepatotoxicity.
•
Children: ingestion of 200 mg/kg. — Check paracetamol level at 4 hours post ingestion (or on arrival if presentation greater than 4 hours post-ingestion) and 4 hours later if the initial level plot is below the nomogram treatment line. If both levels are below the treatment line, NAC may be discontinued. — NAC is continued beyond the standard 20-hour infusion until paracetamol is undetectable. (Recheck paracetamol level shortly before the end of each infusion.) • Unknown time of ingestion — If paracetamol is detectable, but the time of ingestion unknown (this commonly occurs where coma or delirium prevents history taking), NAC is commenced immediately. It may be ceased later when history is available or if there is no detectable paracetamol and hepatic transaminases are normal at the end of the 20-hour NAC infusion. • Presentation >24 hours post ingestion — NAC is only indicated if paracetamol is detectable or hepatic transaminases are elevated. It is continued until paracetamol
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is undetectable, hepatic transaminases are stable or falling and the patient is improving clinically. NAC may be commenced pending biochemical assessment in the patient with nausea, vomiting, abdominal pain or encephalopathy. • Note: See Chapter 4.17: N-acetylcysteine for full details on dosing and administration of NAC. DISPOSITION AND FOLLOW-UP
HANDY TIP
•
Consider the possibility of ingestion of modified-release preparations of paracetamol where history suggests the ingestion of multiples of 18 tablets or large packets containing 96 or 192 tablets.
PITFALLS
• •
Failure to recognise ingestion of a modified-release formulation. Failure to commence NAC based on history of ingested dose in early presenters. If NAC is withheld pending serial paracetamol levels then the 8-hour ‘window’ period of maximal efficacy will have elapsed. • Failure to check paracetamol units. Different units are used to report paracetamol levels (micromol/L, mol/L and mg/L). Incorrect plotting of level may lead to a potentially lethal error.
CONTROVERSY
•
Risk assessment based on paracetamol levels remains undefined for modified-release preparations.
Presentations
Paracetamol controlled release tablets 665 mg (96, 192)
References
Chiew A, Day P, Salonikas C et al. The comparative pharmacokinetics of modifiedrelease and immediate-release paracetamol in a simulated overdose model. Emergency Medicine Australasia 2010; 22:548–555. Daly FSS, Fountain JS, Murray L et al. Guidelines for the management of paracetamol poisoning in Australia and New Zealand: explanation and elaboration. A consensus statement from toxicologists consulting to the Australasian Poisons Information Centres. Medical Journal of Australia 2008; 188:296–301. Roberts DM, Buckley NA. Prolonged absorption and delayed peak paracetamol concentration following poisoning with extended-release formulation. Medical Journal of Australia 2008; 188:310–311.
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Because of the prolonged absorption and biphasic elimination properties of the modified-release preparation, repeat serum paracetamol concentrations must be performed to ensure complete elimination prior to ceasing NAC. • Patients in whom NAC is commenced later than 8 hours following ingestion (or unknown time of ingestion) or have evidence of hepatic toxicity are admitted for further clinical and biochemical monitoring as described in Chapter 3.60: Paracetamol: Acute overdose.
SPECIFIC TOXINS
•
3.62 PARACETAMOL: REPEATED SUPRATHERAPEUTIC INGESTION Acetaminophen, N-acetyl-p-aminophenol (APAP)
SPECIFIC TOXINS
See also Chapter 3.60: Paracetamol: Acute overdose, Chapter 3.61: Paracetamol: Modified-release formulations. Repeated supratherapeutic ingestion of paracetamol refers to staggered dosing with therapeutic intent of >4 g/day in adults or >60 mg/kg/day in children. In adults, it usually occurs in the context of self-medication for acute pain or exacerbations of chronic pain. In children, it is usually a therapeutic error. Repeated supratherapeutic ingestion is responsible for all deaths related to paracetamol in children less than 6 years of age and up to 15% of those in adults. Standard nomograms do not apply. The decision to treat is based on an estimation of dose in conjunction with biochemical testing (serum paracetamol level and hepatic aminotransferase levels). RISK ASSESSMENT
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• • •
The Rumack–Matthew and Prescott nomograms are not useful. Risk assessment is based on dose history and biochemical testing. Adults (and children >6 years) are referred for biochemical risk assessment if there is a history of ingestion of: — 10 g or >200 mg/kg (whichever is less) over a single 24-hour period or — 6 g or 150 mg/kg/24 hours (whichever is less) for the preceding 48 hours or longer. • Patients who may be more susceptible to paracetamol poisoning (e.g. alcoholism, isoniazid use or prolonged fasting) are referred for biochemical risk assessment if they ingest >4 g or 100 mg/kg/24 hours. • Biochemical risk assessment is based on an untimed serum paracetamol level and a hepatic transaminase level (ALT or AST) at presentation: — ALT or AST < 50 IU/L and paracetamol level 66 micromol/L (>10 mg/L) – Higher risk group – Commence N-acetylcysteine (NAC) pending further evaluation.
•
Children: patients 200 mg/kg over a single 24-hour period or — >150 mg/kg/24 hours for the preceding 48 hours
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or — >100 mg/kg/24 hours for the preceding 72 hours. Toxic mechanism
Supratherapeutic doses of paracetamol can result in depletion of hepatic glutathione stores. Once glutathione levels are depleted to below 30% of normal, the same toxicity is observed as following acute paracetamol overdose.
Toxicokinetics
See Chapter 3.60: Paracetamol: Acute overdose.
Patients who go on to develop hepatic injury following supratherapeutic paracetamol overdose encounter the same four clinical phases as for acute paracetamol poisoning (see Table 3.60.1).
INVESTIGATIONS
•
Serum paracetamol level and hepatic transaminase levels (ALT/AST) — Determine the risk of hepatotoxicity and requirement for NAC. • Liver function tests, urea and electrolytes, prothrombin time-INR, acid–base status and blood glucose — Monitor the clinical course of those patients with hepatic injury (see Chapter 3.60: Paracetamol: Acute overdose).
MANAGEMENT
Resuscitation, supportive care and monitoring • Resuscitative efforts are only required in the rare instance where a patient presents late in established hepatic failure with jaundice, altered conscious state and hypoglycaemia. In such cases, urgent attention to airway, breathing and circulation, plus correction of hypoglycaemia and coagulopathy, are required. • General supportive care and monitoring measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Patients with worsening hepatic transaminase levels and INR >2.5 should have 4-hourly recording of vital signs and bedside serum glucose, and close monitoring of fluid balance.
Decontamination • Gastrointestinal decontamination is not indicated. Enhanced elimination • Not clinically useful. Antidotes • N-acetylcysteine is indicated immediately if there are clinical features of hepatitis and a history of repeated supratherapeutic ingestion of paracetamol. Otherwise, it is commenced following biochemical risk assessment (see above). • Intravenous NAC is continued for at least 8 hours. Serum ALT or AST measurement is repeated after that time. A rapid rise in
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•
SPECIFIC TOXINS
CLINICAL FEATURES
SPECIFIC TOXINS
hepatic transaminase levels is consistent with evolving paracetamol hepatic injury and NAC is continued at 100 mg/kg over 16 hours until the patient is clinically well and the ALT and INR are falling. Falling or static serum AST/ALT values suggest a resolving injury or alternative diagnosis and NAC may be ceased. • Note: For a detailed description of NAC and its administration see Chapter 4.17: N-acetylcysteine. • A management flow chart for repeated therapeutic ingestion of paracetamol is shown in Figure 3.62.1.
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FIGURE 3.62.1 Management flow chart for repeated supratherapeutic paracetamol ingestion Does the patient meet the criteria for repeated supratherapeutic ingestion?
Adults and Children 6+ years • At least 10 g or 200 mg/kg (whichever is lower) over a single 24-hour period • At least 6 g or 150 mg/kg (whichever is lower) per 24-hour period for the preceding 48 hours • More than 4 g/day or 100 mg/kg (whichever is less) in patients with pre-disposing risk factors Children • 200 mg/kg or more over a single 24-hour period • 150 mg/kg or more per 24-hour period for the preceding 48 hours • 100 mg/kg or more per 24-hour period for the preceding 72 hours
no
No further management required
yes Measure serum paracetamol level and ALT
ALT normal and serum paracetamol level 50 mL of 20% solution acidosis, renal and hepatic injury and in a 70-kg patient cardiovascular collapse Mortality universal with death occurring within 12 hours–7 days
• • •
Inhalational exposures do not cause significant intoxication. Dermal exposure may cause toxicity if there is prolonged exposure or exposure to broken skin. Risk assessment can be refined using urinary and serum paraquat assays (see below).
•
Children: ingestion of a teaspoonful (5 mL) may be fatal.
Toxic mechanism
Paraquat is a water-soluble para-substituted quaternary bipyridyl cation herbicide. It is a caustic agent specifically transported into pneumocytes, where it causes superoxide production and depletes superoxide dismutase and NADPH. Oxygen free radicals cause lipid peroxidation, further free radical production and damage to cell membrane integrity.
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Toxicokinetics
Absorption is rapid but incomplete. Bioavailability increases with dose and kinetics become non-linear. Peak blood levels occur within 2–4 hours. Oral absorption is further reduced by the presence of food in the stomach. Inhalational and dermal absorption via intact skin are minimal. Prolonged exposure to concentrated solutions, or contact on broken skin, may rarely result in systemic absorption. Distribution is rapid to highly vascular tissues such as kidney, liver, heart, muscle and lungs. Paraquat is not metabolised and is predominantly excreted by the kidneys. Biliary excretion is minor. CLINICAL FEATURES
TABLE 3.63.2 Clinical progression: Paraquat Time
Effect
Immediate
Vomiting and symptoms of gastrointestinal injury
Hours
Corrosive injury to lips and oral cavity. Metabolic acidosis develops early in large ingestions
48 hours
Progressive pulmonary injury with rapid development of pulmonary fibrosis
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Regular oxygen saturations — Detect developing hypoxia and determine oxygen requirement. • Serial pulmonary function testing — Detect developing alveolitis and pulmonary fibrosis.
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Patients may initially appear well but complain of oral burns. Central tongue ulceration (‘paraquat tongue’) and gastrointestinal symptoms are universal. Corrosive injury may be severe. Oesophageal perforation and mediastinitis are reported. • Following large ingestions, multiple organ effects become apparent within hours. Tachycardia and tachypnoea accompany metabolic acidosis with elevated lactate. Cardiovascular collapse and multi-system organ failure may lead to death within 24 hours in severe cases. • Patients with moderate ingestion may not develop systemic toxicity during the first 48 hours but then develop acute renal failure and progressive pulmonary injury characterised by early alveolitis and secondary pulmonary fibrosis. The initial symptoms are of increasing dyspnoea and hypoxia, which progresses until death occurs within days to weeks. The renal injury resolves in survivors.
SPECIFIC TOXINS
• •
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Acid–base status, lactate, FBC, EUC, LFT — Detect signs of multi-organ failure. — Detect development and progress of acidosis and response to treatment. — Lactate >4.4 mmol/L is associated with fatal outcome. • Chest X-ray — Detect fibrosis and aspiration. • Urinary paraquat — The qualitative (dithionite) colorimetric spot test can be performed by most laboratories on urine, gastric fluids or dialysate. — It is a reliable test for the presence of paraquat if performed within 12 hours of ingestion and may remain positive for several days following large ingestions. — Sodium dithionite reduces paraquat; a positive test is based on reduction to a blue cation. The reaction occurs within 1 minute. — A positive test demonstrates paraquat has been absorbed, but does not indicate prognosis. • Serum paraquat levels — Not readily available within a clinically useful time frame but invaluable in defining prognosis (see Figure 3.63.1). — Ideally, samples should be collected 4–24 hours after exposure.
FIGURE 3.63.1 Paraquat survival nomogram Plasma levels of paraquat (microgram/mL)
SPECIFIC TOXINS
•
5.5 5.0
4.0 Percentages denote the Probability of Survival
3.0
2.0
1.0
0 0
4
8
12
16
20
24
28
Hours after swallowing Adapted from Hart TB, Nevitt A, Whitehead A. A new statistical approach to the prognostic significance of plasma paraquat concentrations. Lancet 1984; 2(8413):1222–1223.
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Decontamination • At the scene, administer food or soil to adsorb paraquat and reduce gastrointestinal absorption. • Administer 50 g of activated charcoal (1 g/kg in children) PO immediately on arrival at hospital. • Fuller’s earth is a clay soil adsorbent that has been traditionally used, but is now often not readily available and offers no advantage over activated charcoal. Enhanced elimination • Haemodialysis or haemoperfusion is considered with the greatest urgency in patients near the threshold lethal dose (from about a mouthful up to 0.25 mL/kg of 20% solution). It is not indicated for minor exposures (splashes, licks or tastes) and will not prevent fatal outcome following large deliberate self-poisoning ingestions. • Haemodialysis and haemoperfusion may remove paraquat if performed early before distribution to tissues. The time beyond which dialysis is of benefit (due to distribution of paraquat to tissues) is uncertain. Maximal benefit is attained if performed within 2 hours but this intervention may be considered up to 4 hours post ingestion unless signs of severe toxicity are already evident. Antidotes • None available. • Note: Many adjunct therapies have been proposed, including N-acetylcysteine, corticosteroids, vitamins C and E, cyclophosphamide and salicylic acid. Studies to date are hypothesis-generating and inconclusive. Given its safety, it is
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Resuscitation, supportive care and monitoring • Paraquat intoxication is a time-critical emergency. • This is the only poisoning in which decontamination takes priority over resuscitation or transport to hospital and ideally decontamination occurs at the scene (see below). • Patients are managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Patients who arrive acutely unwell after deliberate self-poisoning with large ingestions should be managed palliatively as soon as the diagnosis is established. • The aim of management in moderate and accidental ingestions is to improve prognosis by reducing the dose that reaches the lungs through early decontamination and haemodialysis. • Immediate management of airway, breathing and circulation is rarely required. However, stridor, dysphagia and dysphonia indicate airway injury and potential imminent airway compromise. Early intubation or surgical airway is indicated in this setting. • Do not administer supplemental oxygen unless oxygen saturation 91%. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring.
SPECIFIC TOXINS
MANAGEMENT
reasonable to commence all patients on N-acetylcysteine (see Chapter 4.17: N-acetylcysteine). In addition, dexamethasone (8 mg tds IV) and salicylic acid (100 mg/kg/day in divided doses) may be considered as semi-experimental but mechanistically plausible anti-inflammatory therapies. DISPOSITION AND FOLLOW-UP
SPECIFIC TOXINS
•
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Patients who are clinically well 6–12 hours after exposure, without oral burns and with a negative dithionite test, have not absorbed paraquat systemically and may be discharged. • Adult patients with moderate self-poisoning or accidental ingestions should be managed in an intensive care setting. An early paraquat level is useful in determining prognosis and utility of care. • Patients with a history of massive ingestion (e.g. >100 mL of 20% paraquat) and early clinical features of intoxication have a hopeless prognosis and are managed palliatively from the outset.
HANDY TIP
PITFALL
•
Immediate pre-hospital gastrointestinal decontamination with anything that is available (food, soil, charcoal) may be life saving.
•
Failure to advise carers to avoid oxygen unless there is profound hypoxia.
CONTROVERSIES
• • •
The efficacy and indications for haemodialysis and the time beyond which it is unlikely to provide any benefit. The role of immunosuppressive therapies such as methylprednisolone and cyclophosphamide is not established. Predictive value of serum paraquat levels. They appear to be more accurate at predicting death than survival.
Presentations
Paraquat alone: 6.4%, 20%, 24%, 25% w/v Paraquat concentrate 36% has been discontinued but may still be accessible. Paraquat–Diquat mixtures: 1.25% and 1.25%, 2.5% and 2.5%, 10% and 5%, 10% and 10%, 12.5% and 7.5%, 13.5% and 11.5% Most products contain colouring (blue-green or red-brown) and stenching agents.
References
Dinis-Oliveira PJ, Duarte JA, Sanchez-Navarro A et al. Paraquat poisonings: mechanisms of lung toxicity, clinical features and treatment. Critical Reviews in Toxicology 2008; 38:13–71. Eddleston M, Wilks MF, Buckley NA. Prospects for treatment of paraquat-induced lung fibrosis with immunosuppressive drugs and the need for better prediction of outcome: a systematic review. Quarterly Journal of Medicine. 2003; 96(11):809–824. Gawarammana IB, Buckley NA. Medical management of paraquat ingestion. British Journal of Pharmacology 2011; 5:745–757. Senarathna L, Eddleston M, Wilks MF. Prediction of outcome after paraquat poisoning by measurement of the plasma paraquat concentration. Quarterly Journal of Medicine 2009; 102:251–259.
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3.64 PHENOTHIAZINES AND BUTYROPHENONES (antipsychotic agents)
RISK ASSESSMENT
• • • • •
The antipsychotic agents cause dose-dependent CNS depression, tachycardia, hypotension and anticholinergic effects. Chlorpromazine can cause coma requiring intubation and ventilation with ingestions >5 g. Cardiac dysrhythmias are very uncommon, with the exception of thioridazine in large doses. Seizures are uncommon after any dose. Children: lethargy, coma, agitation, tachycardia and extrapyramidal effects may occur after small ingestions. Ingestion of even one tablet warrants hospital observation. Extrapyramidal effects may develop up to 72 hours post ingestion.
Toxic mechanism
The major therapeutic action of the phenothiazines is mediated via central dopamine (D2) antagonism. Their adverse effects are secondary to antagonist action at multiple other receptors, including histaminic (H1), GABAA, muscarinic (M1), α1- and α2-adrenergic and serotonergic (5-HT) receptors. Cardiotoxicity is secondary to sodium and potassium channel blocking effects. The butyrophenones are a separate class of drug, but have similar pharmacological and pharmacokinetic properties.
Toxicokinetics
The antipsychotics are rapidly absorbed following oral administration at therapeutic doses and undergo extensive first-pass metabolism with variable bioavailability. Absorption may be slow and erratic following overdose. Antipsychotics are lipid soluble with large volumes of distribution. They undergo extensive hepatic metabolism by cytochrome P450 enzymes. Many have active metabolites and prolonged elimination half-lives. Chlorpromazine has early, intermediate and late elimination phases (2–3 hours, 11–15 hours and up to 60 days, respectively). CLINICAL FEATURES
• • • • •
Onset of clinical features of intoxication occurs within 2–4 hours of overdose. Sedation, ataxia, orthostatic hypotension and tachycardia are common. Fluctuating mental status with intermittent agitated delirium may occur with moderate doses and usually lasts 20 mg/kg
Ataxia, dysarthria and nystagmus
>100 mg/kg
Potential for coma and seizures
SPECIFIC TOXINS
Toxic mechanism
Toxicokinetics
Absorption is slow and erratic following oral overdose. Peak serum levels may be delayed up to 24–48 hours. Volume of distribution is 0.6 L/kg and protein binding is high (90%). Phenytoin undergoes hepatic hydroxylation (cytochrome P450 2C9) to form an inactive metabolite. Metabolism is saturable (Michaelis-Menten kinetics) and plasma levels and elimination half-life rise dramatically with small increases in daily dose. Elimination half-lives in poisoned patients may vary from 24 to 230 hours. Cytochrome P450 2C9 exhibits genetic polymorphism and there is inter-individual variation in elimination rates.
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Phenytoin blocks sodium channels and suppresses membrane post-tetanic potentiation and hyperexcitability.
CLINICAL FEATURES
• • •
• • • • •
Chronic toxicity usually presents with gradual onset of ataxia. Dysarthria and nystagmus are also evident. Mild gastrointestinal symptoms may occur within 2 hours of acute overdose. Onset of neurological toxicity develops slowly over hours following acute overdose. Clinical features of toxicity include: slow horizontal nystagmus, dysarthria, ataxia, tremor, vertical nystagmus, drowsiness, involuntary movements and ophthalmoplegia. Neurological symptoms of toxicity typically resolve over 2–4 days as serum levels slowly fall. Coma, rigidity and seizures occur rarely and only after massive overdose. Hypernatraemia and hyperglycaemia resulting in non-ketotic hyperosmolar coma are reported after massive ingestion. Permanent cerebellar injury is rarely reported after prolonged and severe intoxication. Rapid IV administration of phenytoin (and propylene glycol diluent) is associated with hypotension, bradycardia, ventricular dysrhythmias and asystole.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serum phenytoin levels — Useful to confirm the diagnosis.
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— Correlate with clinical toxicity: – Nystagmus is associated with levels >20 mg/L (80 micromol/L) – Severe ataxia is associated with levels of 30–40 mg/L (120–160 micromol/L) – Coma is associated with levels >50 mg/L (200 micromol/L). — In mild to moderate intoxication, management is guided by clinical features; repeated levels are not required. — Serial phenytoin levels are useful in severe intoxication to monitor ongoing absorption and response to interventions.
Decontamination • Give activated charcoal to the cooperative patient who presents within 4 hours of acute oral overdose. This may reduce toxicity and length of hospital stay. Enhanced elimination • Multiple-dose activated charcoal may enhance elimination but there is no evidence that outcome is improved; this intervention is not routine. • Charcoal haemoperfusion and plasmapheresis have been used in severe phenytoin intoxication and may enhance elimination, but are not routine. Antidotes • None available. DISPOSITION AND FOLLOW-UP
•
Children may be observed at home following unintentional exposures. Hospital assessment is only indicated if significant ataxia or drowsiness develops. • Patients with nystagmus, ataxia or drowsiness are managed supportively in a ward environment. • Patients with coma requiring intubation or seizures require admission to the intensive care unit. • Patients are medically fit for discharge as soon as they are able to walk safely.
HANDY TIPS
•
Consider the diagnosis of phenytoin toxicity in any patient on chronic therapy who presents with difficulty walking.
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Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • General supportive care as outlined in Chapter 1.4: Supportive care and monitoring ensure a good outcome in the majority of patients. • Bed rails should be raised at all times and ambulation should be initially only attempted with supervision. • ECG monitoring is not necessary following oral phenytoin overdose or for chronic phenytoin toxicity.
SPECIFIC TOXINS
MANAGEMENT
• • PITFALLS
• •
It may take several days for phenytoin toxicity to resolve. Coma is rare in isolated phenytoin overdose. Other causes should be considered and excluded. Failure to order a phenytoin level in the patient on chronic therapy who presents with ataxia or non-specific symptoms. Allowing a patient with phenytoin toxicity to fall during unsupervised attempts at mobilisation.
CONTROVERSY
SPECIFIC TOXINS
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Utility of techniques of enhanced elimination. These techniques have not been demonstrated to provide any clinical benefit.
Presentations Phenytoin Phenytoin Phenytoin Phenytoin Phenytoin Phenytoin
sodium 30 mg capsules (200) sodium 100 mg capsules (200) 50 mg tablets (200) 30 mg/5 mL suspension (500 mL) sodium 100 mg/2 mL ampoules (contain propylene glycol diluent) sodium 250 mg/5 mL ampoules (contain propylene glycol diluent)
References
Anonymous. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. Journal of Toxicology – Clinical Toxicology 1999; 37(6):731–751. Craig S. Phenytoin poisoning. Neurocritical Care 2005; 3(2):161–170. Curtis DL, Piibe R, Ellenhorn MJ et al. Phenytoin toxicity: a review of 94 cases. Veterinary and Human Toxicology 1989; 31(92):164–165. Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. Quarterly Journal of Medicine 1998; 91:325–332. Skinner CG, Chang AS, Matthew AR et al. Randomised controlled study on the use of multiple-dose activated charcoal in patients with supratherapeutic phenytoin levels. Clinical Toxicology 2012; 50:764–769. Wyte CD, Berk WA. Severe oral phenytoin overdose does not cause cardiovascular morbidity. Annals of Emergency Medicine 1991; 20(5):510–512.
3.66 POTASSIUM CHLORIDE Deliberate self-poisoning by ingestion of potassium chloride is rare but can result in life-threatening hyperkalaemia and cardiac arrest. The principal preparation of concern is slow-release potassium chloride, which is available in bottles of 100 tablets without prescription. A good outcome depends on early risk assessment, gastrointestinal decontamination and haemodialysis where indicated. RISK ASSESSMENT
• •
Small ingestions are usually benign in patients with normal renal function. Ingestion of >2.5 mmol/kg of potassium may theoretically temporarily overwhelm the capacity of the kidneys to excrete potassium and lead to hyperkalaemia.
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• •
The lethal dose of KCl tablets (each containing 8 mmol KCl) in an adult is not well defined. Massive ingestion (>40 × 600-mg tablets) prompts early planning for haemodialysis in case severe hyperkalaemia cannot be controlled by other means. • Patients with renal impairment or cardiac disease may be at higher risk. • Abdominal X-ray assists risk assessment as slow-release potassium tablets are radio-opaque. Children: ingestion of three 600-mg KCl tablets may cause significant hyperkalaemia in a 10-kg toddler.
Toxic mechanism
Potassium is the principal intracellular cation. Hyperkalaemia interferes with electrical conduction in both nerve and muscle and, if severe, causes cardiac arrest. Potassium salts have a direct irritant effect on the gastrointestinal mucosa when ingested.
Toxicokinetics
Potassium is rapidly absorbed from the small intestine. It is distributed to the intracellular compartment. Potassium is excreted in the urine (90–95%), faeces and sweat. Hyperkalaemia develops when the rate of absorption from the gut exceeds the combined rates of redistribution to the intracellular compartment and urinary excretion.
SPECIFIC TOXINS
•
355
•
Following overdose of potassium salts, GI symptoms including abdominal pain, nausea and vomiting are common and occur early. Ileus and mucosal perforation may occur. • As hyperkalaemia progresses (serum potassium 6–8 mmol/L), lethargy, confusion, weakness, paraesthesia and hyporeflexia develop. • Paralysis and bradycardia herald cardiac arrest (serum K >8 mmol/L).
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial 12-lead ECGs demonstrate a progression of abnormalities as serum potassium rises: peaked T waves (plasma K >6.0 mmol/L), PR prolongation, loss of P waves with atrial paralysis, widening of QRS, QT prolongation, sine wave appearance and finally asystole. • EUC with serial potassium concentrations. • Abdominal X-ray. Useful to confirm number of slow-release potassium chloride tablets ingested. Serial X-rays also have a role in monitoring success of decontamination.
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. Refer to Chapter 1.2: Resuscitation.
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•
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Initial efforts are directed at detecting a rising serum potassium and acting to achieve temporary control while arrangements are made for urgent haemodialysis. • Obtain an urgent serum potassium level and control hyperkalaemia aggressively: — Calcium chloride 10 mL 10% (0.15 mL/kg in children) IV through a running line — Nebulised salbutamol 10–20 mg (in children 2.5 mg if 5 years) — Dextrose 50 mL 50% and insulin 10 U IV (10 mL/kg 10% dextrose and insulin 0.1 U/kg in children) — Sodium bicarbonate 50–100 mmol slow IV (1 mmol/kg in children). • General supportive care measures including adequate intravenous fluids to maintain urine output are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Activated charcoal does not bind potassium chloride and is not indicated. • Slow-release potassium chloride tablets are amenable to removal by whole bowel irrigation (WBI). However, decontamination cannot be achieved rapidly enough to prevent lethal hyperkalaemia following large overdoses. Institution of WBI must never delay initiation of haemodialysis if it is indicated. The chief value of WBI lies in completing decontamination once hyperkalaemia has been controlled with haemodialysis. Enhanced elimination • Haemodialysis is the definitive treatment of hyperkalaemia following massive potassium chloride overdose. Initiation of haemodialysis provides immediate control of hyperkalaemia. Haemodialysis must be started before hyperkalaemic cardiac arrest occurs. • Planning for haemodialysis begins at the risk assessment stage and is indicated if: — Ingested dose >40 × 600-mg KCl tablets confirmed on X-ray — Renal impairment — Cardiovascular instability — Serum potassium >8.0 mmol/L — Rapidly rising serum potassium. • Haemodialysis continues until decontamination of the gastrointestinal tract with WBI is confirmed on X-ray. • Serum potassium is monitored closely after haemodialysis is ceased. A rising potassium indicates incomplete decontamination, ongoing absorption and the need to reinstitute haemodialysis. Antidotes • None. A number of pharmacological interventions are useful to provide temporary control of hyperkalaemia (see above). DISPOSITION AND FOLLOW-UP
•
Patients demonstrating toxicity or having ingested a toxic dose are managed in a critical care area with dialysis facilities.
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Patients are medically fit for discharge once decontamination is complete and serum potassium is stable off haemodialysis.
HANDY TIPS
Slow-release potassium chloride tablets are radio-opaque. Massive potassium ingestion is potentially lethal. Measures to reduce serum potassium do not constitute definitive care. They are initiated only in an effort to provide sufficient time for the patient to receive definitive care with haemodialysis. • Resonium A (cation exchange resin) 20–50 g (0.5–1.0 g/kg in children) binds only 1 mmol of potassium per gram. It is not useful following massive slow-release potassium chloride overdose.
CONTROVERSY
•
Indications for haemodialysis and WBI.
Presentations
Potassium chloride 600 mg (8 mmol KCl) slow-release tablets (100)
SPECIFIC TOXINS
• •
Reference
3.67 QUETIAPINE Quetiapine is a second-generation atypical antipsychotic agent. Deliberate self-poisoning is associated with sedation, delirium, coma, tachycardia and hypotension. It is currently a leading cause of toxic coma requiring intensive care admission. Thorough supportive care ensures a good outcome. RISK ASSESSMENT
•
Quetiapine intoxication is associated with predictable dosedependent CNS depression ranging from sedation to coma and a characteristic brisk tachycardia (see Table 3.67.1). • Mild hypotension is sometimes observed. It may be profound with massive ingestion. • Minor QT prolongation may occur but there are no reports of torsades de pointes. TABLE 3.67.1 Dose-related risk assessment: Quetiapine Dose
Effect
120 beats/minute)
>3 g
Increasing risk of CNS depression, coma and hypotension Delirium and seizures may occur
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Su M, Stork C, Ravuri S et al. Sustained-release potassium chloride overdose. Clinical Toxicology 2001; 39(6):641–648.
•
Co-ingestion of ethanol or other sedative-hypnotic agents increases the risk of coma and loss of airway protective reflexes.
•
Children: extrapolation from adult data and paediatric experience with other atypical antipsychotic agents suggests that sedation, tachycardia and delirium may occur with ingestion of >100 mg.
Toxic mechanism
Quetiapine is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5-HT2A), histaminic (H1), muscarinic (M1) and peripheral alpha (α1) receptors.
SPECIFIC TOXINS
Toxicokinetics
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Quetiapine is rapidly but incompletely absorbed. It is lipid soluble and highly protein bound, with a large volume of distribution (10 L/kg). Quetiapine is almost completely metabolised by hepatic cytochrome P450 3A4 to an active metabolite, 7-hydroxyquetiapine. CLINICAL FEATURES
• • • • • •
Onset of clinical features of intoxication occurs within 2–4 hours and may last 24–72 hours. Sedation and sinus tachycardia are common. Coma, if it occurs, usually lasts from 18–48 hours. Hypotension. Clinically significant QT prolongation is rare and torsades de pointes is not reported. Seizures occur in 100 mg quetiapine or if any symptoms develop. If they remain clinically well without sedation at 4 hours (8 hours following ingestion of modified-release preparations), they may be discharged. Parents are advised that abnormal (extrapyramidal) movements might occur up to 3 days after ingestion. • Patients who have ingested 3 g, or manifest clinical features of intoxication, require admission for appropriate supportive care.
HANDY TIPS
• •
Sinus tachycardia exceeding 120 beats/minute is usual. No specific intervention is required. Adrenaline infusion may paradoxically exacerbate the hypotension of quetiapine toxicity. This is thought to be due to excessive β2-mediated vasodilation. Noradrenaline is the preferred inotropic agent and an excellent response is usually observed.
CONTROVERSY
•
The agitated delirium associated with quetiapine intoxication is likely to be of central anticholinergic origin; however, the role of physostigmine is yet to be determined.
Presentations Quetiapine Quetiapine Quetiapine Quetiapine Quetiapine Quetiapine Quetiapine Quetiapine Quetiapine
25 mg tablets (60) 100 mg tablets (90) 200 mg tablets (60) 300 mg tablets (60) 50 mg modified-release tablets (60) 150 mg modified-release tablets (60) 200 mg modified-release tablets (60) 300 mg modified-release tablets (60, 100) 400 mg modified-release tablets (60)
References
Balit CR, Isbister GK, Hackett LP. Quetiapine: a case series. Annals of Emergency Medicine 2003; 42:751–758. Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Journal of Toxicology – Clinical Toxicology 2001; 39(1):1–14.
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•
SPECIFIC TOXINS
DISPOSITION AND FOLLOW-UP
Hawkins DJ, Unwin P. Paradoxical and severe hypotension in response to adrenaline infusion in massive quetiapine overdose. Critical Care and Resuscitation 2008; 10(4):320–322. Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Safety 2005; 26(11):1029–1044. Ngo A, Ciranni M, Olson KR. Acute quetiapine overdose in adults: a 5-year retrospective case series. Annals of Emergency Medicine 2008; 52:541–547. Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical antipsychotic medication overdose. American Journal of Emergency Medicine 2009; 27:607–616.
SPECIFIC TOXINS
3.68 QUININE
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Quinine toxicity is characterised by ‘cinchonism’, consisting of nausea, vomiting, tinnitus, vertigo and deafness. Larger overdoses may result in life-threatening cardiotoxicity and severe, potentially permanent, visual disturbance. RISK ASSESSMENT
•
All cases of deliberate self-poisoning should be regarded as having the potential to cause cardiotoxicity and delayed visual disturbance. • Ingestion of >1 g usually produces some degree of cinchonism. • Cardiotoxicity, CNS disturbances and blindness are more commonly observed when the ingested dose is >5 g and almost universal if >10 g.
•
Children: ingestion of 600 mg (two tablets) by a child 24 hours in overdose. Elimination is largely via hydroxylation with approximately 20% being excreted unchanged in the urine. Quinine does not undergo enterohepatic circulation. CLINICAL FEATURES
•
Cinchonism — Characterised by nausea, vomiting, alterations in hearing, tinnitus, and vertigo. — Occurs early following overdose and resolves as blood quinine concentration falls. • Cardiovascular — Hypotension, sinus tachycardia, QRS widening and prolongation of the QT and PR intervals. — Wide-complex tachycardia and torsades de pointes are reported.
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial 12-lead ECGs • EUC, formal visual field mapping • Quinine blood levels: These correlate well with toxicity (>10 mg/L at 6 hours is associated with cardiovascular toxicity and visual disturbance) but are not available in a clinically relevant time frame and do not assist clinical decision making.
MANAGEMENT
Resuscitation, supportive care and monitoring • The patient is initially managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Clinical features that require immediate intervention include: — Coma – Urgent intubation and ventilation is indicated. — Wide-complex tachydysrhythmias – Immediate intubation and hyperventilation, and serum alkalinisation with sodium bicarbonate are indicated (see Chapter 4.24: Sodium bicarbonate for details on administration). — Torsades de pointes – Correct hypoxia and hypokalaemia and administer magnesium sulfate 10 mmol (0.05 mmol/kg in children) IV over 15 minutes. If heart rate is 5 g of quinine or who has any degree of visual disturbance.
• • • • • HANDY TIPS
PITFALL
All children who are suspected of ingesting 600 mg or more of quinine must be observed and monitored for 6 hours post ingestion. All patients who deliberately self-poison with quinine should be observed and monitored for at least 6 hours. Patients who are asymptomatic and have a normal ECG at 6 hours following ingestion are cleared for medical discharge. Patients with symptoms or an abnormal ECG must be admitted for ongoing observation and monitoring until symptoms resolve. All patients with quinine toxicity must have careful assessment of vision prior to medical clearance. Those patients with abnormal vision or visual fields require ophthalmological review and follow-up. Patients who develop coma, seizures, an abnormal ECG or cardiac dysrhythmia during the initial 6 hours observation are admitted to an intensive care unit.
• •
Consider quinine overdose in any patient with deliberate selfpoisoning who complains of visual disturbance. Anticipate the onset of visual disturbance in any patient who has ingested >5 g of quinine. The patient’s vision should be carefully assessed the morning following admission.
•
Failure to warn the patient that visual disturbance may develop 6–8 hours later. It is very disturbing for the patient to awake the following morning and unexpectedly discover they are blind.
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CONTROVERSY
•
It was previously believed that the visual disturbance was a complication of retinal arterial vasospasm. Various interventions including vasodilators, stellate ganglion blocks and hyperbaric oxygen therapy were used in attempts to prevent blindness. It now appears that the blindness occurs from direct retinal toxicity and cannot be prevented by any of these interventions. Attempts at decontamination and enhanced elimination with multiple-dose activated charcoal offer the best chance of minimising retinal toxicity.
References
Boland ME, Roper SM, Henry JA. Complications of quinine poisoning. Lancet 1985; 1(8425):384–385. Guly U, Driscoll P. The management of quinine-induced blindness. Archives of Emergency Medicine 1992; 9:317–322. Huston M, Levinson M. Are one or two dangerous? Quinine and quinidine exposure in toddlers. Journal of Emergency Medicine 2006; 31(4):395–401. Langford NJ, Good AM, Laing WJ et al. Quinine intoxications reported to the Scottish Poisons Information Bureau 1997–2002: a continuing problem. British Journal of Clinical Pharmacology 2003; 56:576–578.
3.69 RISPERIDONE Deliberate self-poisoning with this atypical antipsychotic agent is associated with tachycardia and acute dystonic reactions. CNS depression is unusual and rarely significant. Supportive care ensures a good outcome. RISK ASSESSMENT
• • • •
The dose–effect profile is not well defined. Common clinical features of toxicity include sinus tachycardia (50%) and acute dystonia (10%). CNS depression is rare when risperidone is taken alone. Children: ingestion of >1 mg is associated with clinical features of toxicity. Acute dystonic reactions are more frequent following paediatric exposure and frequently delayed.
Toxic mechanism
Risperidone is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5-HT2A), alpha (α2) and peripheral alpha (α1) receptors. Compared with other antipsychotic agents in its class, it has much lower affinity for histamine (H1) and muscarinic (M1) receptors.
Toxicokinetics
Risperidone is rapidly and well absorbed after oral administration. It is highly protein bound and has a moderate volume of distribution (1.5 L/kg). Risperidone undergoes hepatic metabolism by oxidation (cytochrome P450 2D6) to an active metabolite (9-hydroxyrisperidone), which is eliminated by the kidneys. Renal impairment prolongs the elimination half-life.
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Quinine bisulfate 300 mg (50) Quinine dihydrochloride 600 mg/10 mL ampoules Quinine sulfate 300 mg (50)
SPECIFIC TOXINS
Presentations
CLINICAL FEATURES
• • • • • • •
The onset of clinical features of intoxication is rapid and usually occurs within 4 hours. Sinus tachycardia is common. Mild sedation may be observed but is uncommon. Miosis and mydriasis are reported. Acute dystonias occur frequently. QT prolongation may occur but torsades de pointes is not reported. Clinical features of toxicity resolve within 24 hours.
SPECIFIC TOXINS
INVESTIGATIONS
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial ECGs — Perform an ECG at presentation and at 4 hours. — Sinus tachycardia is common. — Prolongation of the QT interval is reported but is not sufficient in magnitude to pose a risk of torsades de pointes (see Figure 2.20.4).
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • Acute resuscitation is unlikely to be necessary unless there are co-ingestions. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Activated charcoal is not routinely indicated. Enhanced elimination • Not clinically useful. Antidotes • Benztropine may be required to treat acute dystonia.
DISPOSITION AND FOLLOW-UP
• • • • •
All symptomatic children and those thought to have ingested >1 mg should be referred for hospital assessment and observation. Patients who are clinically well, not sedated and have a normal 12-lead ECG at 4 hours may be medically cleared. Symptomatic patients are admitted for supportive care until all clinical features of toxicity resolve. Cardiac monitoring is not indicated beyond 4 hours post ingestion unless the QT interval is prolonged. At discharge, parents should be advised that abnormal (extrapyramidal) movements might occur up to 3 days after ingestion.
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PITFALL
•
Coma, seizures or significant alteration in vital signs prompts consideration of alternative diagnoses and revision of the risk assessment.
•
Failure to warn parents of the possibility of delayed abnormal (extrapyramidal) movements after unintentional paediatric exposure. 0.5 mg tablets (20, 60) 1 mg tablets (60) 2 mg tablets (60) 3 mg tablets (60) 4 mg tablets (60) 0.5 mg orally disintegrating tablets (28) 1 mg orally disintegrating tablets (28) 2 mg orally disintegrating tablets (28) 3 mg orally disintegrating tablets (28) 4 mg orally disintegrating tablets (28) 1 mg/mL solution (30 mL, 100 mL) 25 mg extended-release microspheres with 2 mL solvent pre-filled
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37.5 mg extended-release microspheres with 2 mL solvent pre-filled 50 mg extended-release microspheres with 2 mL solvent pre-filled
References
Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Journal of Toxicology – Clinical Toxicology 2001; 39(1):1–14. Cobaugh DJ, Erdman AR, Booze LL et al. Atypical antipsychotic medication poisoning: an evidence based consensus guideline for out-of-hospital management. Clinical Toxicology 2007; 45(8):918–942. Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Safety 2005; 26(11):1029–1044. Page CB, Calver LA, Isbister GK. Risperidone overdose causes extrapyramidal effects but not cardiac toxicity. Journal of Clinical Psychopharmacology 2010; 30:387–390. Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical antipsychotic medication overdose. American Journal of Emergency Medicine 2009; 27:607–616.
3.70 SALICYLATES Acetylsalicylic acid (aspirin), Methyl salicylate Acute intoxication presents with classical symptoms of vomiting, tinnitus, hyperventilation, respiratory alkalosis and metabolic acidosis. Severe toxicity may result in coma and seizures. Chronic intoxication presents with non-specific clinical features and the diagnosis is frequently missed. Morbidity and mortality are greater in chronic intoxication. Urinary alkalinisation and haemodialysis are highly effective methods of enhancing elimination.
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Risperidone Risperidone Risperidone Risperidone Risperidone Risperidone Risperidone Risperidone Risperidone Risperidone Risperidone Risperidone syringe Risperidone syringe Risperidone syringe
SPECIFIC TOXINS
Presentations
RISK ASSESSMENT
SPECIFIC TOXINS
• • •
The severity of clinical features following acute aspirin overdose is dose-related (see Table 3.70.1) and progresses over hours. Chronic poisoning has an increased risk of an adverse outcome. In terms of the salicylate dose, 5 g of methyl salicylate is equivalent to 7.5 g of acetylsalicylate (i.e. 1 mL of ‘oil of wintergreen’ is equivalent to 1400 mg of aspirin).
TABLE 3.70.1 Dose-related risk assessment: Acute acetylsalicylic acid (aspirin) overdose Dose
Effect
300 mg/kg
Severe intoxication Metabolic acidosis, altered mental state, seizures
>500 mg/kg
Potentially lethal
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Children: rarely ingest a dose of aspirin sufficient to cause toxicity but small ingestions of methyl salicylate-containing products are sufficient to cause severe toxicity, for example >5 mL of oil of wintergreen may cause serious toxicity and even death in a child 150 mg/kg. Following ingestion of >300 mg/ kg, administer activated charcoal 50 g via a nasogastric tube, after first securing the airway if necessary. In either case, a second dose of activated charcoal 50 g is indicated after 4 hours if serum salicylate levels continue to rise.
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Enhanced elimination • Urinary alkalinisation is indicated in patients with symptomatic salicylate poisoning. Further details on the rationale and use of this intervention are provided in Chapter 1.7: Enhanced elimination and Chapter 4.25: Sodium bicarbonate. • Haemodialysis effectively removes salicylate but is rarely required if early decontamination and urinary alkalinisation are implemented. Consider this intervention in the following circumstances: — Urinary alkalinisation not feasible — Serum salicylate levels rising to >4.4 mmol/L (>60 mg/dL, >600 mg/L) despite decontamination and urinary alkalinisation — Severe toxicity as evidenced by altered mental status, acidaemia or renal failure — Very high serum salicylate levels: – Acute poisoning >7.2 mmol/L (>100 mg/dL, >1000 mg/L) – Chronic poisoning >4.4 mmol/L (>60 mg/dL, >600 mg/L). — The threshold to dialyse is lower in the elderly >4.4 mmol/L (>60 mg/dL, >600 mg/L). Antidotes • None available. DISPOSITION AND FOLLOW-UP
•
All children suspected of ingesting methyl salicylate products should be observed in hospital for signs of salicylate toxicity for at least 6 hours. • All symptomatic patients require admission for careful monitoring and enhanced elimination techniques. Therapy is ceased when salicylate level falls to within the normal range (1.1–2.2 mmol/L, 15–30 mg/dL, 150–300 mg/L) and the clinical features and acid–base abnormalities have resolved. • Patients with significant toxicity are admitted to an intensive care or high-dependency unit.
HANDY TIPS
•
Urgent haemodialysis is indicated in any patient who requires intubation for salicylate poisoning (but not if intubated because of co-ingestants). • Consider salicylate toxicity and order a serum salicylate level in any elderly patient with altered mental status and metabolic acidosis.
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Although salicylate classically causes an elevated anion gap metabolic acidosis, many bedside gas machines record a normal or low anion gap by mistaking salicylate ions for chloride.
PITFALLS
Presentations
Aspirin 100 mg tablets (30, 90, 112) Aspirin 100 mg enteric coated tablets (28, 84, 140, 168) Aspirin 300 mg dispersible tablets (24, 42, 48, 60, 96) Aspirin 320 mg tablets (20) Aspirin 500 mg dispersible tablets (16, 120) Aspirin 650 mg tablets (100) Aspirin 100 mg/clopidogrel 75 mg tablets (30) Aspirin 300 mg/codeine 8 mg dispersible tablets (60) Aspirin 25 mg/dipyridamole 200 mg controlled release tablets (60) Methyl salicylate is found in oil of wintergreen (98% methyl salicylate) and various products marketed for topical application, including certain Asian herbal remedies.
References
Davis JE. Are one or two dangerous? Methyl salicylate exposure in toddlers. Journal of Emergency Medicine 2007; 32(1):63–69. O’Malley GF. Management of the salicylate poisoned patient. Emergency Medicine Clinics of North America 2007; 25(2):333–336. Pearlman BL, Gambhir R. Salicylate intoxication: a clinical review. Postgraduate Medicine 2009; 121(4):162–168.
3.71 SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline Deliberate self-poisoning with the selective serotonin reuptake inhibitors (SSRIs) is common and usually follows a benign course. Serotonin toxicity develops in a small minority. Among the SSRIs, citalopram and escitalopram appear to be unique in their ability to cause dosedependent QT interval prolongation. RISK ASSESSMENT
• •
Overdose with SSRIs is usually benign, irrespective of dose. Mild symptoms of serotonin toxicity occur in less than 20% of patients and usually last 300 mg escitalopram is associated with QT prolongation but torsades de pointes occurs rarely. • Co-ingestion of other serotonergic agents, such as monoamine oxidase inhibitors, venlafaxine, bupropion or tramadol, greatly increases the risk of severe serotonin syndrome.
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Children: unintentional paediatric ingestion of up to 3 tablets is benign and referral to hospital is not required unless symptoms develop.
Toxic mechanism
The SSRIs enhance central serotonergic neurotransmission by inhibiting serotonin reuptake. They have little affinity for adrenergic, dopaminergic, cholinergic, serotonergic or histamine receptors.
Toxicokinetics
The SSRIs are rapidly absorbed following oral administration. They are protein bound and have large volumes of distribution. They undergo hepatic metabolism to form less active and water-soluble metabolites. Didesmethylcitalopram is the metabolite of citalopram thought to be responsible for QT prolongation. Elimination half-lives are approximately 24 hours. CLINICAL FEATURES
• • • •
Many patients remain asymptomatic. Minor symptoms usually begin within 4 hours and resolve within 12 hours. Nausea is common. Mild serotonin syndrome occurs in less than 20% and manifests as anxiety, tremor, tachycardia, bradycardia and mydriasis (see Chapter 2.8: Serotonin syndrome). Severe serotonin syndrome does not develop unless there is co-ingestion of other serotonergically active drugs. • Seizures are uncommon and most strongly associated with citalopram and escitalopram (incidence about 2%) and usually heralded by increased anxiety, sweating, tremor, tachycardia and mydriasis. They are short-lived and easily controlled with benzodiazepines. • QT prolongation occurs after citalopram and escitalopram overdose and is dose-dependent. There are rare reports of cardiac dysrhythmias (wide-complex bradycardia and torsades de pointes) following citalopram overdose.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial 12-lead ECGs — Dose-dependent prolongation of the QT interval is described in citalopram intoxication, with 68% of patients having QTc >440 ms and 12% >500 ms in one series. QT prolongation is also described with escitalopram intoxication.
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— Following citalopram overdose of >600 mg or escitalopram overdose of >300 mg, perform a 12-lead ECG at presentation and continue cardiac monitoring for at least 8 hours post ingestion. — Monitoring should continue until any risk of torsades de pointes, as predicted by plotting a nomogram of QT against heart rate, resolves (see Figure 2.20.4). — If >1000 mg citalopram or >500 mg escitalopram is ingested, continue ECG monitoring until 12 hours post ingestion, prior to a decision based on a 12-lead ECG performed at that time.
Decontamination • Alert and cooperative patients who have ingested >600 mg citalopram or >300 mg escitalopram may drink 50 g of activated charcoal if it can be administered within 4 hours after the overdose. • Overdose with other SSRIs has an excellent outcome with minimal supportive care; activated charcoal is not indicated unless warranted by co-ingestants. Enhanced elimination • Not clinically useful. Antidotes • None available. DISPOSITION AND FOLLOW-UP
•
Paediatric patients may be observed at home following possible unintentional exposure. If significant symptoms occur, referral to hospital for supportive care is appropriate. • Patients are observed with cardiac monitoring in place for at least 8 hours after ingestion of >600 mg citalopram or >300 mg escitalopram and 12 hours after ingestion of >1000 mg of
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Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. Refer to Chapter 1.2: Resuscitation. • Seizures and agitation are managed with benzodiazepines, as outlined in Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation. • Management of serotonin syndrome is discussed in Chapter 2.8: Serotonin syndrome. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Increasing anxiety, sweating, tremor, tachycardia and mydriasis may herald the onset of seizures. Administer IV diazepam 5 mg every 2–5 minutes until gentle sedation is achieved and the heart rate falls towards 100 beats/minute. • Continuous cardiac monitoring continues for 8 hours following ingestion of >600 mg citalopram or >300 mg escitalopram, and 12 hours following ingestion of >1000 mg of citalopram or >500 mg escitalopram. If the QT suggests no risk of torsades de pointes at that time, monitoring may cease.
SPECIFIC TOXINS
MANAGEMENT
SPECIFIC TOXINS
citalopram or >500 mg escitalopram. Monitoring should continue if significant abnormalities are detected (see Chapter 2.20: The 12-lead ECG in toxicology). • All other patients who deliberately self-poison with SSRIs are observed for 6 hours. Asymptomatic patients with a normal ECG are fit for medical discharge at the end of that time. • Patients with clinical features of SSRI intoxication require supportive care in a ward environment, usually for no more than 12–24 hours. They are fit for medical discharge as soon as clinical features resolve. • Patients who develop severe serotonin syndrome require management in an intensive care unit.
PITFALL
• •
Coma indicates co-ingestion or complication and is not secondary to SSRI intoxication. Citalopram and escitalopram are unique among the SSRIs in causing dose-dependent QT prolongation. Cardiac dysrhythmias are rare, but activated charcoal and ECG monitoring are indicated as described above.
•
Failure to administer benzodiazepines to patients with increasing anxiety, sweating, tremor, tachycardia and mydriasis.
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CONTROVERSY
•
Activated charcoal reduces citalopram and escitalopram absorption and decreases maximal QT prolongation. However, given that torsades de pointes is extremely rare, the number needed to treat with activated charcoal to prevent dysrhythmia is not known.
Presentations
Citalopram hydrobromide 10 mg tablets (28) Citalopram hydrobromide 20 mg tablets (28) Citalopram hydrobromide 40 mg tablets (28) Escitalopram oxalate 10 mg tablets (28) Escitalopram oxalate 20 mg tablets (28) Escitalopram oxalate 10 mg/mL oral solution (28 mL) Fluvoxamine maleate 50 mg tablets (30) Fluvoxamine maleate 100 mg tablets (30) Fluoxetine hydrochloride 20 mg tablets (28) Fluoxetine hydrochloride 20 mg capsules (28) Paroxetine hydrochloride 20 mg tablets (30) Sertraline hydrochloride 50 mg tablets (30) Sertraline hydrochloride 100 mg tablets (30)
References
Hayes BD, Klein-Schwartz W, Clark RF, Muller AA, Miloradovich JE. Comparison of toxicity of acute overdose with citalopram and escitalopram. Journal of Emergency Medicine 2010; 39(1):44–48. Isbister GK, Bowe SJ, Dawson A et al. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. Clinical Toxicology 2004; 42(3):277–285.
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3.72 STRYCHNINE This heterocyclic ergot-type alkaloid is used as a rodenticide. Deliberate self-poisoning by ingestion leads to the onset of generalised skeletal muscle spasm within 30 minutes. Death from respiratory failure may follow promptly. Paralysis, intubation and ventilation are life saving if instituted before hypoxic neurological injury and multiple organ failure occurs.
SPECIFIC TOXINS
Isbister GK, Friberg LE, Duffull SB. Application of pharmacokinetic-pharmacodynamic modelling in the management of QT abnormalities after citalopram overdose. Intensive Care Medicine 2006; 32(7):1060–1065. Isbister GK, Friberg LE, Stokes B et al. Activated charcoal decreases QT prolongation after citalopram overdose. Annals of Emergency Medicine 2008; 52(1):86–87. Jimmink A, Caminada K, Hunfeld NG et al. Clinical toxicology of citalopram after acute intoxication with the sole drug or in combination with other drugs: overview of 26 cases. Therapeutic Drug Monitoring 2008; 30(3):365–371. Van Gorp F, Duffull S, Hackett LP, Isbister GK. Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal. British Journal of Clinical Pharmacology 2011; 73:402–410. Van Gorp F, Whyte IM, Isbister GK. Clinical and ECG effects of escitalopram overdose. Annals of Emergency Medicine 2009: 54(3):404–408.
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• • •
Ingestion of as little as 30–100 mg by an adult is potentially lethal (i.e. 1 g of 0.03% powder). Death can occur within 30 minutes. Any deliberate ingestion is likely to be rapidly lethal without early intervention. Sublethal doses lead to painful generalised muscle spasms and stiffness precipitated by external stimuli.
•
Children: an accidental taste is potentially lethal in a small child.
Toxic mechanism
Strychnine is a competitive glycine antagonist at brainstem and spinal postsynaptic receptors. Glycine antagonism results in loss of normal descending inhibitory motor tone and the onset of skeletal muscle spasm. Ventilatory failure occurs secondary to severe muscular spasm.
Toxicokinetics
Strychnine is rapidly and completely absorbed following ingestion or inhalation. It is not absorbed across intact skin. It has a large volume of distribution (13 L/kg). Up to 30% of the dose is excreted unchanged in the urine. The remainder undergoes hepatic microsomal (cytochrome P450) metabolism to inactive metabolites. The elimination half-life is 10–16 hours. CLINICAL FEATURES
• •
Onset of nausea, agitation, twitching and muscle spasms occurs within minutes of ingestion. Generalised painful muscle spasms of all voluntary muscles (risus sardonicus, opisthotonos) precipitated by any external sensory stimulus rapidly progress, in severe cases, to hyperthermia, rhabdomyolysis, lactic acidosis and respiratory paralysis. • Death is from ventilatory failure.
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• • •
Loss of consciousness does not occur until secondary hypoxia develops. If the acute phase is survived, myoglobinuria, renal failure and hypoxic brain injury may complicate recovery. Muscle spasms and rigidity resolve within 24 hours if ventilation and oxygenation are maintained.
INVESTIGATIONS
SPECIFIC TOXINS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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Specific investigations as indicated • Serum strychnine levels are not readily available and do not assist management. Serum and urine levels are useful to confirm the diagnosis retrospectively, especially in forensic cases. • EUC, CK, arterial blood gases, lactate and troponin. MANAGEMENT
Resuscitation, supportive care and monitoring • Strychnine intoxication is a time-critical life-threatening emergency. • Potential early life threats that require immediate intervention include: — Generalised muscle rigidity — Respiratory failure. • Prompt neuromuscular paralysis, intubation and ventilation are life saving. • Resuscitation proceeds along conventional lines, as outlined in Chapter 1.2: Resuscitation. • The patient is not unconscious and it is essential to ensure adequate sedation. • Mild intoxication, manifested by minor muscular twitching without generalised spasm or respiratory compromise, is managed with IV diazepam 5 mg every 5–10 minutes, titrated to achieve reduction of spasm. Decontamination • Resuscitation takes priority over decontamination. Activated charcoal is not indicated until the airway is secured. Enhanced elimination • Not clinically useful. Antidotes • None available.
DISPOSITION AND FOLLOW-UP
•
Exposed patients who are clinically well without twitching or muscle spasm at 4 hours post ingestion are not poisoned and are cleared for medical discharge. Discharge should not occur at night. • Patients with objective evidence of strychnine intoxication (muscle spasm or twitching) are managed in an intensive care unit. The patient is clear for medical discharge once muscle spasm and
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PITFALLS
• •
Patients with mild symptoms must be observed very carefully for any signs of progression. Muscle spasm heralds the imminent onset of lethal muscle rigidity – prepare for immediate paralysis, intubation and ventilation. Following deliberate self-poisoning, many patients do not reach hospital alive. Failure to institute prompt paralysis and intubation leading to secondary complications, including hyperthermia, lactic acidosis, rhabdomyolysis and hypoxic brain injury.
CONTROVERSY
•
Forced diuresis, dialysis and urinary acidification have been suggested, but are not recommended.
Presentations
Preparations available to the public contain 0.3% to 0.5% strychnine, but those used by licensed exterminators may contain from 5% to 100% strychnine. Strychnine has been added as an adulterant to street drugs such as amphetamines, cocaine and heroin.
References
Edmunds M, Sheehan TM, Van’t Hoff W. Strychnine poisoning: clinical and toxicological observations on a non-fatal case. Journal of Toxicology – Clinical Toxicology 1986; 24:245–255. Makarovsky I, Markel G, Hoffman A et al. Strychnine: a killer from the past. Israeli Medical Association Journal 2008; 10(2):142–145. Palatnick W, Meatherall R, Sitar D et al. Toxicokinetics of acute strychnine poisoning. Journal of Toxicology – Clinical Toxicology 1997; 35:617–620.
3.73 SULFONYLUREAS Glibenclamide, Gliclazide, Glimepiride, Glipizide Acute sulfonylurea overdose results in profound and prolonged hypoglycaemia with onset usually within 8 hours of ingestion. Hypoglycaemia can also develop at therapeutic doses, particularly in the setting of acquired or preexisting renal dysfunction. Although initial control of hypoglycaemia requires administration of concentrated glucose solutions, early administration of the specific antidote, octreotide, greatly simplifies subsequent management. RISK ASSESSMENT
• •
Acute poisoning with sulfonylureas can result in profound hypoglycaemia. Ingestion of just one tablet can produce hypoglycaemia in the non-diabetic patient.
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•
Sulfonylurea-induced hypoglycaemia is likely to be prolonged and relapse is common following initial resolution that follows glucose administration. Elderly patients are at particular risk of sulphonylurea-induced hypoglycaemia, particularly those with impaired renal or hepatic function, on multiple medications or frequently hospitalised. The hypoglycaemic response is more severe in the non-diabetic patient. Onset of hypoglycaemia may be delayed up to 8 hours following overdose (and even longer for modified-release preparations). There is a wide variation in the duration of hypoglycaemic effect depending on the preparation and dose. It may be several days following large ingestions. Children: ingestion of one tablet of any sulfonylurea is sufficient to cause profound, potentially fatal, hypoglycaemia in a child. Onset of hypoglycaemia is usually within 8 hours of the time of ingestion but may be delayed up to 18 hours. The diagnosis should be considered in any child who presents with hypoglycaemia.
Toxic mechanism
The sulfonylureas are antidiabetic agents employed in the treatment of type 2 diabetes mellitus. They stimulate endogenous insulin release from pancreatic beta cells through the inhibition of K+ efflux. Overdose results in a hyperinsulinaemic state.
Toxicokinetics
Sulfonylureas are rapidly and completely absorbed, with peak serum levels occurring within 4–8 hours. Volumes of distribution are variable, but mostly small. They are metabolised in the liver to active and inactive metabolites, which undergo renal excretion. Elimination half-life varies between agents and is prolonged following overdose. CLINICAL FEATURES
•
Autonomic and CNS manifestations of hypoglycaemia including: — Sweating, tachycardia and confusion — Altered mental status progressing to coma.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG and paracetamol level Specific investigations as indicated • Serial BGLs • EUC • Insulin levels may have some application if available
MANAGEMENT
Resuscitation, supportive care and monitoring • Administer concentrated IV glucose solutions as part of the initial resuscitation of the already hypoglycaemic patient. • Give adults 50 mL of 50% glucose as an IV bolus and children 5 mL/kg of 10% glucose IV.
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Maintain euglycaemia by continued administration of concentrated glucose solution until octreotide can be started. BGLs are monitored closely with bedside testing. They should be checked at least hourly in the initial phase of treatment. This frequency can be reduced in the stable patient on octreotide.
Antidote • Octreotide is the specific antidote for sulfonylurea-induced hyperinsulinaemia. Give adults a 50 microgram IV bolus followed by 25 microgram/hour continuous infusion for at least 24 hours. Give children 1 microgram/kg IV followed by 1 microgram/kg/hour continuous infusion. • See Chapter 4.19: Octreotide for further details. DISPOSITION AND FOLLOW-UP
• •
• • •
All children with suspected sulfonylurea ingestion require observation in hospital and monitoring of BGLs with bedside testing for at least 18 hours. All adult patients with definite or suspected sulfonylurea overdose require observation for clinical features of hypoglycaemia and monitoring of BGLs with bedside testing for at least 8 hours (12 hours for modified-release preparations) from the time of the overdose. Patients who remain asymptomatic, euglycaemic and clinically well after an appropriate duration of observation may be discharged. Symptomatic patients with hypoglycaemia treated with IV glucose and octreotide are admitted. They are medically fit for discharge once they maintain euglycaemia on a normal diet for at least 12 hours from the time of discontinuation of octreotide. The patient who develops hypoglycaemia on therapeutic doses of a sulfonylurea requires admission for oral or IV glucose administration, monitoring of the BGL, treatment of intercurrent medical conditions and re-evaluation of diabetic therapy.
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Early institution of octreotide therapy can completely avoid the need for hypertonic dextrose infusions and central venous access. — Octreotide may be administered SC if IV access is not readily available. • Do not ignore BGLs 50 mg/kg is expected to lead to life-threatening toxicity, manifested by tachydysrhythmias and seizures (see Table 3.74.1).
Effect
5–10 mg/kg
Therapeutic loading dose
>10 mg/kg
Potential for toxicity
>50 mg/kg
Life-threatening toxicity
•
Patients with chronic toxicity have a poor prognosis. This is frequently compounded by failure to make the diagnosis or appreciate the severity of the condition. • Elderly patients with coexisting medical illnesses tolerate theophylline toxicity poorly and are more likely to have a poor outcome. • Serum theophylline levels, when available, further refine risk assessment (see Investigations below).
•
Children: ingestion of even one 200-mg modified-release tablet will produce toxicity in a 10-kg child. Ingestion of multiple tablets can be life threatening.
Toxic mechanism
Multiple toxic mechanisms have been proposed for theophylline, including competitive antagonism of adenosine, altered intracellular calcium transport and inhibition of phosphodiesterase leading to elevated intracellular cAMP concentrations.
Toxicokinetics
Theophylline is well absorbed after oral administration. Absorption is delayed with modified-release preparations and peak levels may not occur until up to 15 hours following ingestion. It is rapidly distributed with a small volume of distribution (0.5 L/ kg). Metabolism is via the cytochrome P450 system to active and inactive metabolites. Metabolism is variable and saturable. Elimination half-life may be greatly prolonged in severe intoxication. Aminophylline is a water-soluble complex of theophylline molecules suitable for intravenous administration. It rapidly dissociates in vivo to release theophylline. CLINICAL FEATURES
• •
Early manifestations of toxicity in acute overdose include anxiety, vomiting, tremor and tachycardia. Severe poisoning is associated with: — Cardiac dysrhythmias: – Supraventricular tachycardia – Atrial fibrillation and flutter – Ventricular tachycardia — Refractory hypotension — Seizures
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Dose
SPECIFIC TOXINS
TABLE 3.74.1 Dose-related risk assessment: Acute theophylline overdose
SPECIFIC TOXINS
— Metabolic abnormalities: – Hypokalaemia (severe, refractory) – Hypophosphataemia, hypomagnesaemia – Hyperglycaemia – Metabolic acidosis. • Cardiac dysrhythmias and seizures occur late and indicate an extremely poor prognosis. • Chronic toxicity usually develops in elderly or infant patients and generally presents with vomiting and tachycardia. The metabolic effects are less pronounced than for acute overdose, but seizures and dysrhythmias occur frequently and at lower serum theophylline concentrations.
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INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial serum theophylline levels: — Extremely useful in predicting the risk of life-threatening toxicity — In acute overdose, levels correlate well with clinical severity (see Table 3.74.2) and are repeated every 2–4 hours until falling — Levels >330 micromol/L (60 mg/L) may be associated with severe toxicity in elderly patients — In chronic intoxication, severe toxicity can occur at levels >220 micromol/L (40 mg/L). • UEC and acid–base status TABLE 3.74.2 Correlation of serum levels and toxicity: Acute theophylline overdose Level (micromol/L)
Level (mg/L)
Toxicity
55–110
10–20
Therapeutic
110–220
20–40
Minor toxicity
220–440
40–80
Moderate toxicity
440–550
80–100
Severe toxicity
>550
>100
Usually fatal without urgent intervention
MANAGEMENT
Resuscitation, supportive care and monitoring • Theophylline poisoning is a life-threatening emergency that is managed in an area equipped for cardiorespiratory monitoring and resuscitation.
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•
Decontamination • Oral activated charcoal is indicated following acute overdose even if presentation is delayed. Aggressive control of vomiting with antiemetics, such as ondansetron 4 mg IV or tropisetron 2 mg IV, is usually necessary for success in the unintubated patient. Enhanced elimination • Haemodialysis is the definitive life-saving intervention in severe theophylline poisoning and highly effective in achieving good clinical outcome if commenced early. • Arrangements for urgent haemodialysis are made as soon as potentially life-threatening theophylline toxicity is anticipated. Commonly accepted indications are: — Serum theophylline >550 micromol/L (100 mg/L) in the setting of acute overdose — Serum theophylline >330 micromol/L (60 mg/L) in the setting of chronic toxicity — Clinical manifestations of severe toxicity – dysrhythmia, hypotension or seizures. • Multiple-dose activated charcoal enhances the elimination of theophylline, but use of this modality delays effective treatment with haemodialysis. Antidotes • None available.
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SPECIFIC TOXINS
•
Potential immediate life-threats include: — Hypotension — Seizures — Ventricular and supraventricular tachycardia (SVT). Aggressive resuscitation and control of seizures is required in severe theophylline toxicity. The patient who presents with established severe toxicity has an extremely poor prognosis. Supportive care measures do not ensure survival and are instituted in an effort to allow sufficient time for definitive treatment with haemodialysis. Hypotension usually responds to fluid administration, although a noradrenaline infusion may be needed in resistant cases. Give 10–20 mL/kg of IV crystalloid solution as an initial response (see Chapter 2.5: Hypotension). Treat seizures with benzodiazepines, as outlined in Chapter 2.6: Seizures. Supraventricular tachycardia is controlled with beta-blockade using carefully titrated doses of propranolol or metoprolol, or an esmolol infusion. Beware bronchospasm in susceptible individuals (asthmatics). Administer propranolol 0.5–1 mg or metoprolol 5 mg (0.1 mg/kg in children) by slow IV injection and repeat after 5 minutes if response inadequate. An esmolol infusion is prepared at a concentration of 10 mg/mL in 5% dextrose and commenced at a rate of 0.05 mg/kg/minute (20 mL/hour in a 70-kg adult) and titrated to response. Metabolic disturbances do not generally require specific therapy, although severe hypokalaemia, if present, should be corrected with potassium supplementation.
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DISPOSITION AND FOLLOW-UP
SPECIFIC TOXINS
• •
Patients who have acutely ingested theophylline syrup and are asymptomatic at 6 hours may be medically cleared. Overdose of modified-release tablets requires observation for 12 hours although serial levels may hasten medical clearance. • All symptomatic patients are admitted to a monitored environment for close observation and serial theophylline levels. If the initial risk assessment, subsequent clinical progress or theophylline levels indicate potential for severe toxicity, retrieval to a facility with an intensive care unit capable of emergency haemodialysis is undertaken as soon as possible, preferably before clinical deterioration.
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Patients at risk of death should be identified and dialysed before clinical deterioration. Most theophylline overdoses are of modified-release preparations and clinical deterioration is delayed many hours. Cardiac dysrhythmias (including SVT), hypotension or seizures are predictive of poor outcome in both acute and chronic toxicity. Any one of these clinical features mandates urgent haemodialysis.
PITFALLS
•
Failure to identify high-risk cases early based on dosing history. This delays arrangements for haemodialysis until the patient is clinically unstable. • Failure to closely observe and follow theophylline levels.
CONTROVERSIES
•
Beta-blocker use in asthmatic patients with theophylline toxicity. If beta-blockers are used, short-acting, cardioselective agents such as esmolol given by titrated infusion are preferred. • Charcoal haemoperfusion is described as the modality of choice for enhancing theophylline elimination. However, the technique is not widely available and standard haemodialysis is effective and usually able to be implemented more quickly.
Presentations
Aminophylline 25 mg/mL ampoules (10 mL) Theophylline 200 mg modified-release tablets (100) Theophylline 250 mg modified-release tablets (100) Theophylline 300 mg modified-release tablets (100) Theophylline 5.32 mg/mL oral liquid (500 mL)
References
Minton NA, Henry JA. Treatment of theophylline overdose. American Journal of Emergency Medicine 1996; 14:606–612. Shannon M. Life-threatening events after theophylline overdose: a 10-year prospective analysis. Archives of Internal Medicine 1999; 159:989–994.
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3.75 THYROXINE Overdose of thyroxine is rarely sufficient to produce significant symptoms of hyperthyroidism. When these do occur, they are mild, delayed in onset and may last up to 2 weeks. They can usually be successfully managed in the outpatient setting. RISK ASSESSMENT
The majority of patients with acute thyroxine overdose remain asymptomatic or experience only mild-to-moderate symptoms of hyperthyroidism some 2–7 days later. • Symptoms are not expected unless >10 mg of thyroxine is ingested. • The elderly and patients with cardiovascular co-morbidities are at increased risk of complications should hyperthyroid symptoms occur. • Severe toxicity is more likely to occur following chronic abuse of thyroid hormones.
•
Children: ingestion of up to 5 mg is associated with minimal symptoms. Severe thyrotoxicosis has not been reported after unintentional paediatric ingestion of thyroxine.
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383
Thyroxine (T4) is converted to tri-iodothyronine (T3) in the liver and kidney. T3 binds to the nucleus and influences multiple metabolic processes (cardiovascular, metabolic, growth and development).
Toxicokinetics
Oral bioavailability is high (80%) with a maximal absorption at 2 hours post ingestion. Onset of the hormonal effect is delayed and maximal effects are not attained until 1–3 weeks. Thyroxine is extensively distributed and bound completely to proteins. The elimination half-life is 6–7 days after therapeutic dosing and is shortened to a mean of 3 days following overdose. CLINICAL FEATURES
• •
Following acute ingestion, most patients remain asymptomatic. Where symptoms do develop, they are not usually apparent until >24 hours following the ingestion but may then last more than 1 week. • Signs and symptoms when they do occur are those of adrenergic stimulation and include fever, agitation, sweating, tachycardia, hypertension, headache, diarrhoea and vomiting. • Chronic ingestion of excessive thyroxine causes severe illness characterised by angina pectoris, myocardial infarction, myocarditis, ventricular and atrial dysrhythmias, left ventricular hypertrophy, thyrotoxicosis and thyroid storm.
INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level
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Toxic mechanism
Specific investigations as indicated • Thyroid function tests after overdose usually show marked elevation of thyroxine concentration that is without clinical correlate. They do not assist in management following either accidental paediatric ingestion or deliberate self-poisoning and are not indicated.
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Resuscitation, supportive care and monitoring • Resuscitation measures are rarely required. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. • Beta-blockers rapidly control the sympathomimetic symptoms of thyroid excess. In symptomatic patients with no contraindications to beta-blockade, administer oral propranolol 10–40 mg (0.2–0.5 mg/kg in children) every 6 hours. • If beta-blockers are contraindicated, calcium channel blockers are a suitable alternative. Administer diltiazem 60–180 mg (1–3 mg/kg in children) every 8 hours. • Close clinical and physiological monitoring is indicated for patients with severe symptoms. Decontamination • Give oral activated charcoal 50 g to cooperative patients who present within 1 hour of ingesting >10 mg of thyroxine. • Oral activated charcoal is not indicated in children following unintentional ingestion. Enhanced elimination • Not clinically useful. Antidotes • None available.
DISPOSITION AND FOLLOW-UP
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PITFALLS
• •
Children suspected of ingesting up to 5 mg of thyroxine may be observed at home provided they remain asymptomatic. Adult patients with acute deliberate self-poisoning rarely require immediate management. Disposition occurs as dictated by the medical and psychiatric condition, with advice to report symptoms of thyroid toxicity. If these occur, supportive therapy with beta-blockers is indicated, usually for a period of 1 week. Thyroxine may be restarted after a week if indicated.
Many patients remain asymptomatic. If symptoms occur, onset is usually delayed >24 hours post ingestion.
Unnecessary admission for prolonged medical observation. Failure to anticipate or recognise the delayed onset of symptoms following large overdoses.
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Presentations Thyroxine Thyroxine Thyroxine Thyroxine
50 microgram tablets (200) 75 microgram tablets (200) 100 microgram tablets (200) 200 microgram tablets (200)
3.76 TRAMADOL Tramadol is a centrally acting synthetic opioid analgesic. Most available formulations are sustained release and, in overdose, frequently cause delayed-onset seizures. Tramadol overdose may also cause mild sedation and respiratory depression. RISK ASSESSMENT
• •
Opioid effects (sedation and respiratory depression) are usually mild and rarely require intervention. The major potential risk is seizures and these are usually delayed in onset (>6 hours). Seizures should be anticipated in patients who ingest >1.5 g tramadol. • Serotonin syndrome may develop if there is co-ingestion of other serotonergically active agents.
•
Children: CNS depression and seizures can occur with ingestion of >10 mg/kg.
Toxic mechanism
Tramadol is a weak partial agonist at µ opioid receptors. It also inhibits serotonin and noradrenaline reuptake in the CNS. The toxic effects in overdose seem to be primarily a result of the inhibition of CNS serotonin and noradrenaline reuptake.
Toxicokinetics
Tramadol is well absorbed orally and peak levels occur at 1–3 hours after ingestion of standard preparations and 2–12 hours after ingestion of sustained-release preparations. Peak levels may be further delayed after overdose. The volume of distribution is 2–3 L/kg. It is extensively metabolised in the liver and one of the metabolites, O-desmethyltramadol, is pharmacologically active. Elimination is in the urine with elimination half-lives of 5–7 hours for the parent drug and 6–8 hours for the active metabolite. CLINICAL FEATURES
• •
Opioid agonist effects are not prominent and consist of mild sedation, mild respiratory depression and miosis. Coma requiring intubation is unusual except in the presence of co-ingestants, especially ethanol or benzodiazepines.
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Lewander WJ, Lacouture PG, Silva JE et al. Acute thyroxine ingestion in pediatric patients. Pediatrics 1989; 84:262–265. Litovitz TL, White JD. Levothyroxine ingestions in children: an analysis of 78 cases. American Journal of Emergency Medicine 1985; 3:297–300. Shilo L, Kovatz S, Hadari R et al. Massive thyroid hormone overdose: clinical manifestations and management. Israeli Medical Association Journal 2002; 4: 298–299. Tunget CL, Clark RF, Turchen SG et al. Raising the decontamination level for thyroid hormone ingestions. American Journal of Emergency Medicine 1995; 13:9–13.
SPECIFIC TOXINS
References
• •
Serotonergic and noradrenergic effects are more prominent and may include tachycardia, agitation, mydriasis and seizures. Seizures are the most serious clinical effect. They are delayed in onset (usually >6 hours after overdose of the sustained-release preparation), of short duration and easily controlled with benzodiazepines. • Serotonin syndrome may develop, especially if there is co-ingestion of other serotonergically active drugs (see Chapter 2.8: Serotonin syndrome).
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Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Specific investigations are only indicated to diagnose and assess secondary complications.
MANAGEMENT
Resuscitation, supportive care and monitoring • Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • The need for intubation is anticipated and performed early in the patient with a declining level of consciousness. • Seizures are treated with titrated doses of IV benzodiazepines, as outlined in Chapter 2.6: Seizures. • Increasing agitation, tachycardia, tremor and myoclonic jerks herald onset of seizures and these symptoms are controlled with titrated IV doses of diazepam: give 2.5–5 mg every 2–5 minutes until gentle sedation is achieved and the heart rate falls towards 100 beats/minute. • Serotonin syndrome, if it develops, should be identified and managed as described in Chapter 2.8: Serotonin syndrome. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Administration of oral activated charcoal 50 g is considered in the patient who is alert and cooperative and presents within 2 hours of ingestion of >1.5 g of a sustained-release tramadol preparation. • The potential for seizures must be considered when making a risk–benefit analysis of the value of administering activated charcoal. • In the patient who is intubated, activated charcoal may be safely administered via a nasogastric tube. Enhanced elimination • Not clinically useful. Antidotes • Naloxone may reverse CNS and respiratory depression secondary to µ opioid agonist activity (see Chapter 4.18: Naloxone).
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However, this is rarely a clinically significant problem with pure tramadol overdose and naloxone is rarely useful. DISPOSITION AND FOLLOW-UP
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Prophylactic administration of intravenous benzodiazepines to patients with clinical features of toxicity such as agitation, tachycardia, tremor or myoclonic jerking will usually prevent seizures. Failure to anticipate and prepare for delayed symptoms or seizures. Administration of activated charcoal shortly before onset of seizures.
Presentations Tramadol Tramadol Tramadol Tramadol Tramadol Tramadol Tramadol Tramadol Tramadol
hydrochloride 50 mg capsules (20) hydrochloride 50 mg sustained-release tablets (20) hydrochloride 100 mg sustained-release tablets (10, 20) hydrochloride 150 mg sustained-release tablets (20) hydrochloride 200 mg sustained-release tablets (10, 20) hydrochloride 300 mg sustained-release tablets (10) hydrochloride 100 mg/1 mL oral liquid (10 mL) 50 mg/mL ampoules (2 mL) 37.5 mg/paracetamol 325 mg (20, 50)
References
Persson H, Sjöberg G. Acute toxicity of tramadol: analyses of 287 cases (abstract). Clinical Toxicology 2008; 46:398. Sachdeva DK, Stadnyk JM. Are one or two dangerous? Opioid exposure in toddlers. Journal of Emergency Medicine 2005; 29(1):77–84. Shadnia S, Soltaninejad K, Heyardi K et al. Tramadol intoxication: a review of 114 cases. Human and Experimental Toxicology 2008; 27:201–205. Spiller HA, Gorman SE, Villalobos D et al. Prospective multicenter evaluation of tramadol exposure. Journal of Toxicology – Clinical Toxicology 1997; 35(4):361–364.
3.77 TRICYCLIC ANTIDEPRESSANTS (TCAs) Amitriptyline, Clomipramine, Dothiepin, Doxepin, Imipramine, Nortriptyline, Trimipramine
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Children suspected of ingesting >10 mg/kg of sustained-release tramadol must be assessed and observed in hospital for at least 12 hours. Discharge should not occur at night. • Because of the risk of seizures, all adult patients who have ingested >1.5 g of sustained-release tramadol must be observed with IV access in place for a minimum of 12 hours and until symptom free. • Patients who are significantly sedated or require benzodiazepine administration for seizure or symptom control should be admitted for continued observation and supportive care until symptom free. Discharge should not occur at night. • Patients who require intubation for coma or severe serotonin syndrome are admitted to intensive care.
SPECIFIC TOXINS
•
Tricyclic antidepressant (TCA) poisoning remains a major cause of morbidity and mortality. Deliberate self-poisoning may lead to the rapid onset of CNS and cardiovascular toxicity. Prompt intubation, hyperventilation and sodium bicarbonate administration at the first evidence of severe toxicity are life saving. RISK ASSESSMENT
SPECIFIC TOXINS
• • • •
Ingestion of >10 mg/kg is potentially life threatening (see Table 3.77.1). Onset of severe toxicity usually occurs within 2 hours of ingestion. Seizures and myoclonus are more common with dothiepin. Children: ingestion of >10 mg/kg of amitriptyline, dothiepin, doxepin or trimipramine tablets is potentially lethal in a 10-kg toddler. Any child who is suspected of ingesting >5 mg/kg is referred to hospital for 6 hours of observation.
TABLE 3.77.1 Dose-related risk assessments: Tricyclic antidepressants Effect
388
10 mg/kg
Potential for all major effects (coma, hypotension, seizures, cardiac dysrhythmias) to occur within 2–4 hours of ingestion Anticholinergic effects likely but often masked by coma
>30 mg/kg
Severe toxicity with pH-dependent cardiotoxicity and coma expected to last >24 hours
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Dose
Toxic mechanism
TCAs are noradrenaline and serotonin reuptake inhibitors and GABAA receptor-blockers. Myocardial toxicity is chiefly due to blockade of inactivated fast sodium channels. Other toxic effects are mediated by blockade at muscarinic (M1), histaminic (H1) and peripheral post-synaptic α1-adrenergic receptors. TCAs cause reversible inhibition of potassium channels and direct myocardial depression unrelated to conduction abnormalities.
Toxicokinetics
TCAs are rapidly absorbed following oral administration, with peak levels occurring within 2 hours. TCAs are highly bound to plasma and tissue proteins and have large volumes of distribution (5–20 L/kg). TCAs undergo hepatic metabolism by oxidation (cytochrome P450 2D6) to active metabolites. Some enterohepatic circulation occurs. CLINICAL FEATURES
Severe toxicity is characterised by rapid deterioration in clinical status within 1–2 hours of ingestion. Patients may present alert and orientated, only to rapidly develop coma, seizures, hypotension and cardiac dysrhythmias.
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INVESTIGATIONS
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • Serial ECGs — Vital tool in the management of TCA intoxication (see Chapter 2.20: The 12-lead ECG in Toxicology). — Diagnostic features include: – Prolongation of QRS interval – Large terminal R wave in aVR – Increased R/S ratio (>0.7) in aVR – QT prolongation is also noted secondary to potassium channel blockade – See Appendix 2 for examples of ECGs in TCA poisoning. — QRS widening reflects degree of fast sodium channel blockade. — QRS >100 ms is predictive of seizures. — QRS >160 ms is predictive of ventricular tachycardia.
MANAGEMENT
Resuscitation, supportive care and monitoring • Acute TCA poisoning is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation. • Close clinical and physiological monitoring is mandatory for at least 6 hours post ingestion. • Cardiac monitoring is continued until resolution of toxicity. • Potential early life-threats that require immediate intervention include: — Coma — Respiratory acidosis — Seizures — Cardiac dysrhythmia — Cardiac arrest.
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Central nervous system — Sedation and coma usually precede cardiovascular signs — Seizures — Delirium secondary to anticholinergic effects is often obscured by coma • Cardiovascular — Sinus tachycardia and mild elevation of blood pressure — Hypotension due to alpha blocking effects and impaired contractility — Broad-complex tachydysrhythmias — Broad-complex bradycardia occurs pre-arrest • Anticholinergic effects — Can occur on presentation or may be delayed and prolonged — Agitation, restlessness, delirium — Mydriasis — Dry, warm, flushed skin — Tachycardia, urinary retention, ileus — Myoclonic jerks
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At the onset of CNS depression (e.g. GCS 7.5. — Type Ia antidysrhythmic agents (e.g. procainamide), amiodarone and beta-blockers are contraindicated. Hypotension is treated with IV crystalloid solutions (10–20 mL/ kg), sodium bicarbonate 100 mmol (2 mmol/kg) and adrenaline or noradrenaline infusion (see Chapter 2.5: Hypotension). Seizures are managed with benzodiazepines, as outlined in Chapter 2.6: Seizures. General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Intubated patients are hyperventilated to maintain serum pH 7.50–7.55.
Decontamination • Activated charcoal is not indicated for ingestions 1 g/kg is potentially lethal.
SPECIFIC TOXINS
TABLE 3.78.1 Dose-related risk assessment: Valproic acid Dose
Effect
1000 mg/kg
Potentially lethal with profound prolonged coma and multiple organ toxicity, including cerebral oedema, hypotension, lactic acidosis, hypoglycaemia, hyperammonaemia, hypernatraemia, hypocalcaemia and bone marrow suppression
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•
Children: unintentional ingestions of 400 mg/kg is suspected, serum valproate levels are repeated every 4–6 hours until they decrease. • In the comatose patient, valproate levels are essential to determining the risk of life-threatening multi-system valproate toxicity and need for haemodialysis. • Serial EUC, acid–base status and full blood counts are followed in all comatose patients to detect and manage multi-system toxicity. TABLE 3.78.2 Correlation of clinical effects with serum valproate level Serum valproate
Clinical effects
500 mg/L)
Usually manifest coma and may have other organ effects
>7000 micromol/L (>1000 mg/L)
Frequently develop life-threatening multiple organ effects
>14 000 micromol/L (>2000 mg/L)
Death expected without urgent haemodialysis
MANAGEMENT
Resuscitation, supportive care and monitoring • All patients are managed in an area equipped for cardiopulmonary monitoring and resuscitation.
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INVESTIGATIONS
SPECIFIC TOXINS
Following large ingestions, coma is accompanied by: — Metabolic abnormalities (anion gap metabolic acidosis, hypoglycaemia, hypernatraemia, hypocalcaemia and hyperammonaemia) — Other evidence of systemic toxicity, including hypotension, renal impairment and bone marrow depression. • In very severe poisoning, cerebral oedema, prolonged coma, cardiovascular instability and death occur. • In severe poisoning, coma and manifestations of toxicity may persist for several days after serum valproate levels return to normal.
•
SPECIFIC TOXINS
Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • The need for intubation is anticipated and performed early in the patient with a declining level of consciousness. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring.
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Decontamination • Oral activated charcoal is not indicated in patients who have ingested 1000 mg/kg with serum level >7000 micromol/L (1000 mg/L) — Serum level >10 400 micromol/L (1500 mg/L) at any time — Severe valproic acid poisoning with lactic acidosis or cardiovascular instability. • Haemodialysis is ideally performed before multi-system organ dysfunction is evident. Antidotes • None available. DISPOSITION AND FOLLOW-UP
•
Patients who ingest 1 g/kg) if the patient presents within 4 hours. Progressive CNS depression renders the procedure difficult and hazardous. In the intubated patient, WBI may not be feasible; early haemodialysis is highly effective and a more appropriate intervention in this life-threatening situation • Carnitine has been suggested as an antidote for valproateinduced mitochondrial effects. These recommendations are based on case reports and extrapolation from treatment of children with selected inborn errors of metabolism. Carnitine is not recommended at this time.
SPECIFIC TOXINS
•
RISK ASSESSMENT
• • • •
TABLE 3.79.1 Dose-related risk assessment: Venlafaxine Effect
4.5 g
Risk of seizures approaches 100% Hypotension Minor QRS and QT prolongation on 12-lead ECG
>7 g
Hypotension Left ventricular dysfunction
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Dose
6
SPECIFIC TOXINS
14% of patients have seizures but the incidence is dose dependent (see Table 3.79.1). Onset of seizures may be delayed up to 16 hours following overdose. Preexistent seizure disorder may increase the probability of seizures. There is a high risk of serotonin syndrome if other serotonergic agents are co-ingested (see Table 2.8.2), irrespective of the dose of venlafaxine. • Massive ingestion (>7 g) is associated with cardiovascular effects.
•
Children: accidental ingestion of 38.5°C is an indication for continuous core-temperature monitoring, benzodiazepine sedation and fluid resuscitation. Temperature >39.5°C requires rapid treatment to prevent multiple organ failure and neurological injury. Paralysis, intubation and ventilation are indicated, as described in Chapter 2.8: Serotonin syndrome. • General supportive care measures as outlined in Chapter 1.4: Supportive care and monitoring are indicated.
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• •
SPECIFIC TOXINS
CLINICAL FEATURES
Decontamination • Activated charcoal is administered to patients who are alert and cooperative and present within 2 hours following ingestion of >4.5 g of venlafaxine or desvenlafaxine. • Activated charcoal is contraindicated in the awake patient with more delayed presentation or symptoms, due to the risk of seizures. Enhanced elimination • Not clinically useful.
SPECIFIC TOXINS
Antidotes • None available.
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DISPOSITION AND FOLLOW-UP
•
Because of the risk of seizures following venlafaxine or desvenlafaxine overdose, all patients must be observed with IV access in place for a minimum of 16 hours and until symptom free. Seizures can be delayed up to 24 hours post ingestion in some individuals. • For ingestions 4.5 g require cardiac monitoring and serial ECGs for a period of 12 hours post ingestion. ECG monitoring may then cease if there is no evidence of QRS or QT prolongation. • Patients with severe venlafaxine intoxication or serotonin syndrome require management in an intensive care unit.
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Early administration of titrated doses of intravenous benzodiazepines may prevent seizures. The dose is titrated to achieve a calm patient and a fall in the heart rate towards 100 beats/minute. • Coma is not secondary to venlafaxine intoxication and indicates co-ingestion or complication.
PITFALLS
• • •
Failure to anticipate and prepare for delayed onset of symptoms and seizures. Failure to administer benzodiazepines early and in sufficient dose. Administration of activated charcoal or initiation of whole bowel irrigation (WBI) shortly before onset of seizures or cardiovascular toxicity.
CONTROVERSIES
•
Both single-dose oral activated charcoal and WBI reduce venlafaxine absorption, with the combination of both treatments producing the greatest reduction in maximal venlafaxine concentrations. However, the risk of seizures occurring following delayed administration of activated charcoal or during WBI means that a risk–benefit analysis does not clearly favour these interventions.
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There is little clinical experience with desvenlafaxine overdose and it is not yet known whether the seizure risk is the same. A similar management approach is advised until further clinical data become available.
Presentations
Desvenlafaxine succinate controlled release tablets 50 mg (7, 28) Desvenlafaxine succinate controlled release tablets 100 mg (28) Venlafaxine controlled release tablets 37.5 mg (28) Venlafaxine controlled release tablets 75 mg (28) Venlafaxine controlled release tablets 150 mg (28)
Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. British Journal of Clinical Pharmacology 2007; 64(2):192–197. Isbister GK. Electrocardiogram changes and arrhythmias in venlafaxine overdose. British Journal of Clinical Pharmacology 2009; 67(5):572–576. Kumar VV, Oscarsson S, Friberg LE et al. The effect of decontamination procedures on the pharmacokinetics of venlafaxine in overdose. Clinical Pharmacology and Therapeutics 2009; 27:911–915. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Quarterly Journal of Medicine 2003; 96(5):369–374.
SPECIFIC TOXINS
References
399
Over-anticoagulation is a frequent complication of warfarin therapy. Deliberate self-poisoning with warfarin occurs in patients with or without a requirement to maintain therapeutic anticoagulation. All patients are usually asymptomatic at presentation. The approach to therapy is determined by both the magnitude of over-anticoagulation and the indication (or not) for therapeutic anticoagulation. Patients with active bleeding require urgent combination reversal therapy. Vitamin K is the specific antidote. RISK ASSESSMENT
•
Therapeutic over-anticoagulation presents as an asymptomatic patient with an elevated INR or with active bleeding; the risk of bleeding increases progressively as the INR rises above 5. • In patients not on therapeutic warfarin who overdose: — Acute ingestion 2 mg/kg can produce a significant increase in INR within 72 hours. • Active bleeding constitutes an emergency and requires urgent combination therapy (see below).
•
Children: single acute unintentional ingestion of 12 hour delay before anticoagulation occurs is secondary to the half-lives of existing vitamin K-dependent coagulation factors (6, 24, 40 and 60 hours for factors VII, IX, X and II, respectively). Peak effects are observed by 72 hours. Toxicity renders patients coagulopathic and vulnerable to haemorrhage.
Toxicokinetics
Warfarin is rapidly absorbed with 100% bioavailability. It has a small volume of distribution (0.2 L/kg) and is 99% protein bound. Warfarin is metabolised in the liver (cytochrome P450) to form metabolites that undergo enterohepatic recirculation. Warfarin and its metabolites are excreted in urine and faeces with an elimination half-life of 35 hours.
SPECIFIC TOXINS
CLINICAL FEATURES
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Over-anticoagulated patients are usually asymptomatic. Severe coagulopathy may manifest as bruising, petechial or purpural rashes, gingival bleeding, epistaxis, gastrointestinal bleeding or haematuria.
INVESTIGATIONS
• •
Management of warfarin-induced coagulopathy is based on measurement of INR. Other investigations are performed to assess potential complications as dictated by the individual risk assessment.
Screening tests in deliberate self-poisoning • 12-lead ECG, BGL and paracetamol level Specific investigations as indicated • INR — In patients not previously anticoagulated, the INR is normal for the first 12–24 hours after accidental or deliberate overdose and a normal INR at 48 hours excludes warfarin overdose. — In patients with excessive anticoagulation, but a therapeutic requirement, the INR is measured at presentation and at 6-hourly intervals thereafter. MANAGEMENT
Resuscitation, supportive care and monitoring • In patients with evidence of haemorrhage, attention to airway, breathing and circulation are paramount. These priorities can usually be managed along conventional lines, as outlined in Chapter 1.2: Resuscitation. • If there is active uncontrolled haemorrhage, administer prothrombin complex concentrate (25–50 IU/kg), fresh frozen plasma (150–300 mL or 10–15 mL/kg) if prothrombin complex concentrate is unavailable and vitamin K 5–10 mg IV. • General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. Decontamination • Following deliberate self-poisoning in cooperative patients on therapeutic anticoagulation, administer 50 g oral activated charcoal if they present within 1 hour of ingestion. • Activated charcoal is not indicated in other patients.
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• • •
Children who ingest 0.5 mg/kg are given 10 mg vitamin K PO and discharged. They do not require INRs or follow-up. Patients with no therapeutic requirement for anticoagulation are treated with oral vitamin K (5 mg bd for 2 days) and medically cleared. Follow-up INR is indicated at 48 hours • Patients with a therapeutic requirement for anticoagulation are admitted and receive titrated vitamin K doses, as discussed in Chapter 4.29: Vitamin K. • Therapeutic over-anticoagulation is managed on an outpatient basis, unless there is active bleeding or an INR >9.
HANDY TIP
PITFALL
•
Warfarin levels may be useful in cases where paediatric nonaccidental injury or occult poisoning is suspected.
•
Failure to carefully titrate vitamin K dose in patients requiring therapeutic anticoagulation.
Presentations Warfarin Warfarin Warfarin Warfarin
1 mg 2 mg 3 mg 5 mg
tablets tablets tablets tablets
(50) (50) (50) (50)
References
Isbister GK, Hackett LP, Whyte, IM. Intentional warfarin overdose. Therapeutic Drug Monitoring 2003; 25(6):715–722. Levine M, Pizon AE, Padilla-Jones A, Ruha A-M. Warfarin overdose: a 25-year experience. Journal of Medical Toxicology 2014: doi 10.1007. Tran HA, Chanilal SD, Harper PL et al. An update of consensus guidelines for warfarin reversal. Medical Journal of Australia 2013: 198(4):1–7.
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Antidotes • Vitamin K (phytomenadione) is administered prophylactically to patients who have ingested a potentially anticoagulating dose of warfarin but have no therapeutic requirement for anticoagulation. This obviates the need for repetitive coagulation testing. In patients with a therapeutic requirement for anticoagulation, vitamin K dose is carefully titrated in an effort to maintain an INR in the optimal therapeutic range (see Chapter 4.29: Vitamin K). • Accepted guidelines for management of therapeutic overanticoagulation, including vitamin K administration, are shown in Appendix 5: Therapeutic over-warfarinisation.
SPECIFIC TOXINS
Enhanced elimination • Not clinically useful.
CHAPTER 4
ANTIDOTES 4.1 Atropine 4.2 Calcium 4.3 Cyproheptadine 4.4 Desferrioxamine 4.5 Dicobalt edetate 4.6 Digoxin immune Fab 4.7 Dimercaprol 4.8 Ethanol 4.9 Flumazenil 4.10 Folinic acid 4.11 Fomepizole 4.12 Glucose 4.13 Hydroxocobalamin 4.14 Insulin (high-dose) 4.15 Intravenous lipid emulsion 4.16 Methylene blue 4.17 N-acetylcysteine 4.18 Naloxone 4.19 Octreotide 4.20 Penicillamine 4.21 Physostigmine 4.22 Pralidoxime 4.23 Pyridoxine 4.24 Sodium bicarbonate 4.25 Sodium calcium edetate 4.26 Sodium thiosulfate 4.27 Succimer 4.28 Vitamin K
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4.1 ATROPINE Atropine is a competitive muscarinic antagonist, used to treat druginduced bradycardia and poisoning by acetylcholinesterase inhibitors. Presentations Atropine Atropine Atropine Atropine Atropine
sulfate sulfate sulfate sulfate sulfate
0.1 mg/mL 0.4 mg/mL 0.5 mg/mL 0.6 mg/mL 1.2 mg/mL
prefilled syringe (10 mL) ampoules ampoules ampoules ampoules
TOXICOLOGICAL INDICATIONS
ANTIDOTES
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Poisoning by agents that impair AV conduction such as cardiac glycosides, beta-blockers and calcium channel blockers Organophosphate and carbamate poisoning
CONTRAINDICATIONS
•
Relative contraindications include: — Closed angle glaucoma — Obstructive disease of the gastrointestinal tract — Obstructive uropathy.
Mechanism of action
Atropine is a competitive antagonist of acetylcholine at muscarinic receptors. It reverses the excessive parasympathetic stimulation that results from inhibition of acetylcholinesterase. It does not act at nicotinic receptors.
Pharmacokinetics
Atropine has a poor oral bioavailability and undergoes hepatic metabolism with an elimination half-life of 2–4 hours. It crosses the blood–brain and placental barriers. About 50% is excreted unchanged in urine. ADMINISTRATION
•
Place the patient in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care. Organophosphate and carbamate poisoning • Administer an initial IV bolus of 1.2 mg. • Further doses are given every 2–3 minutes, doubling the dose each time until drying of respiratory secretions is achieved. Heart rate is not a useful end point as tachycardia may persist due to nicotinic effects or respiratory distress. • Very large doses (up to 100 mg) may be required in severe cases and ongoing atropine administration by infusion may be necessary. Bradycardia caused by drug-induced AV conduction blockade • Administer an IV bolus of 0.6 mg. • Repeat doses of 0.6 mg are given as required up to a maximum of 1.8 mg.
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THERAPEUTIC END POINTS
• •
Drying of respiratory secretions in organophosphate poisoning. Note: The development of anticholinergic features indicates excessive dosing.
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
•
Excessive atropine administration manifests with clinical features of anticholinergic poisoning, including delirium, tachycardia, mydriasis and urinary retention. — No further atropine should be administered while features of anticholinergic poisoning are present. — Benzodiazepine sedation may be necessary to control delirium and an indwelling urinary catheter should be inserted because of the risk of urinary retention.
Pregnancy: no restriction on use. Paediatric: initial paediatric dose is 20 microgram/kg.
•
PITFALLS
• •
Very large doses of atropine may be required to treat organophosphate poisoning—anticipate this need and procure sufficient stocks as soon as possible.
405 Failure to administer sufficient doses of atropine in organophosphate or carbamate poisoning. Administration of excessive atropine leading to iatrogenic anticholinergic poisoning.
References
Bardin PG, Van Eeden SF. Organophosphate poisoning: grading the severity and comparing treatment between atropine and glycopyrrolate. Critical Care Medicine 1990; 18(9):956–960. Eddleston M, Buckley NA, Eyer P et al. Management of acute organophosphorus pesticide poisoning. Lancet 2008; 371:597–607.
4.2 CALCIUM Calcium is a cation that is essential for normal organ (including muscle and nerve tissue) and cell function. Presentations Calcium Calcium Calcium Calcium Calcium
gluconate 1 g/10 mL vials (0.22 mmol calcium ions/mL) gluconate 5 g/50 mL vials (0.22 mmol calcium ions/mL) chloride 0.74 g/5 mL ampoules (1.01 mmol calcium ions/mL) chloride 1 g/10 mL ampoules (0.68 mmol calcium ions/mL) chloride 1 g/10 mL single-use syringe (0.68 mmol calcium ions/mL)
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SPECIFIC CONSIDERATIONS
TOXICOLOGICAL INDICATIONS
• • • • • •
Calcium channel blocker poisoning Hydrofluoric acid skin exposure Hypocalcaemia of systemic fluorosis secondary to ingestion of, or extensive skin exposure to, hydrofluoric acid Hypocalcaemia secondary to ethylene glycol poisoning Iatrogenic hypermagnesaemia Hyperkalaemia
CONTRAINDICATIONS
• •
Hypercalcaemia Digoxin toxicity (controversial)
ANTIDOTES
Mechanism of action
Pharmacokinetics
Ninety-nine per cent of the body’s calcium is contained within bone. Of the calcium in plasma, about half is ionised and physiologically active while the other half is bound to albumin. Plasma calcium concentration is maintained at close to 2.5 mmol/L by a number of hormonal homeostatic mechanisms.
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Calcium acts as a physiological antagonist to the effects of hyperkalaemia and hypermagnesaemia on the cardiac conducting system and skeletal muscle. Administration of calcium in hypocalcaemic states restores or maintains ionised calcium at a concentration sufficient to prevent cardiac dysrhythmias. In hydrofluoric acid poisoning, calcium ions bind to fluoride ions and prevent further tissue penetration and injury. Elevation of the ionised calcium concentration may help overcome the deleterious effects of calcium channel blocker poisoning.
ADMINISTRATION
• Place the patient in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care. • Cardiac monitoring is mandatory during infusion of calcium salts. Hypocalcaemia/hyperkalaemia/hypermagnesaemia • Administer 0.5–1 g (5–10 mL) of calcium chloride or 1–2 g
(10–20 mL) of calcium gluconate IV over 5–10 minutes, preferably into a large vein. Repeat every 10–15 minutes as required. • Further administration of calcium salts is guided by serum calcium concentrations, which should not exceed the normal range. Calcium channel blocker poisoning • Give 2 g (20 mL) of calcium chloride IV or 6 g (60 mL) of calcium gluconate IV over 5–10 minutes. This dose may be repeated every 20 minutes for up to three doses. Hydrofluoric acid skin exposure • Topical 2.5% calcium gel — Minor burns. — For burns to the hand, put gel in a glove and place hand in the glove. • Local injection of calcium gluconate 1 g/10 mL — Consider if topical application fails to stop pain. — Inject 0.5 mL/cm2 depots intradermally and subcutaneously using a 25 G needle to achieve local tissue infiltration. — Not suitable for finger exposures. — Do not inject calcium chloride, as this can cause tissue injury.
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Bier’s block (forearm regional intravenous injection) — Consider for large HF exposures to fingers, hand or forearm or if gel application to these regions has failed. — Insert intravenous line distally in affected forearm. — Dilute 1 g (10 mL) calcium gluconate in 40 mL of normal saline. — Inject diluted calcium gluconate solution intravenously with pneumatic tourniquet inflated (Bier’s block technique). — Release cuff after 20 minutes. • Intra-arterial infusion — Insert arterial line into radial, brachial or femoral artery of affected limb. — Dilute 1 g (10 mL) of calcium gluconate in 40 mL of normal saline. — Infuse diluted calcium gluconate solution over 4 hours and repeat as necessary. Hydrofluoric acid inhalation injury • Give nebulised 2.5% calcium gluconate solution. THERAPEUTIC END POINTS
• • •
Hypocalcaemia/hypermagnesaemia/hyperkalaemia: normalisation of serum calcium Calcium channel blocker poisoning: haemodynamic improvement Hydrofluoric acid skin exposure: resolution of pain
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
ANTIDOTES
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407
Transient hypercalcaemia manifested by tetany and seizures — Interrupt calcium salt administration and check serum calcium concentration. • Vasodilation, hypotension, dysrhythmias, syncope or cardiac arrest due to over-rapid administration — Interrupt calcium salt administration. — Institute advanced cardiac life support as appropriate. • Local tissue damage from extravasation of calcium chloride
SPECIFIC CONSIDERATIONS
Pregnancy: no restriction on use. Paediatric: paediatric dose for hypocalcaemia or calcium channel blocker poisoning is 1.0 mL/kg 10% calcium gluconate solution over 5–10 minutes and repeated after 10–15 minutes if necessary.
HANDY TIPS
•
QT duration and clinical features of hypocalcaemia may be a more useful guide to calcium requirements than serum calcium concentrations. • Calcium gluconate can safely be given via a peripheral line whereas calcium chloride is best given via a central line because of the risk of tissue damage from extravasation. It should not be given in the same intravenous line as sodium bicarbonate. • 2.5% calcium gluconate gel for treatment of skin exposure to hydrofluoric acid can be prepared by mixing 10 mL of 10%
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calcium gluconate solution with 30 mL lubricant gel (e.g. K-Y jelly) or by mixing 3.5 g calcium gluconate powder in 150 mL of lubricant gel. • Do not use calcium salt solution to irrigate the eye after ocular hydrofluoric acid exposure as it may cause corrosive injury. • Pain refractory to calcium administration in late-presentation hydrofluoric acid burns may indicate established tissue damage rather than therapeutic failure. • Very large doses of calcium chloride may be required to maintain eucalcaemia following hydrofluoric acid ingestion. CONTROVERSIES
ANTIDOTES
• •
References
Graudins A, Burns MJ, Aaron CK. Regional intravenous infusion of calcium gluconate for hydrofluoric acid burns of the upper extremity. Annals of Emergency Medicine 1997; 30:604–607. Vance MV, Curry SC, Kunkel DB et al. Digital hydrofluoric acid burns: treatment with intraarterial calcium infusion. Annals of Emergency Medicine 1986; 15:890–896.
4.3 CYPROHEPTADINE
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Efficacy and optimal dosing of calcium salts in calcium channel blocker poisoning. Most effective route of administration of calcium salts for hydrofluoric acid skin exposures.
Cyproheptadine is a histamine and serotonin antagonist with anticholinergic properties. It has been advocated for control of symptoms in mild-to-moderate serotonin syndrome. Presentations
Cyproheptadine 4 mg tablets (50, 100) TOXICOLOGICAL INDICATION
•
Mild-to-moderate serotonin syndrome
CONTRAINDICATIONS
• • • •
Known hypersensitivity Acute asthma Closed angle glaucoma Bladder neck obstruction
Mechanism of action
Cyproheptadine acts as a competitive antagonist at histamine H1 and serotonin 5-HT1A and 5-HT2 receptors. It exerts centrally mediated hormonal effects such as the inhibition of adrenocorticotrophic hormone (ACTH), probably secondary to serotonin antagonism. It also has moderate local anaesthetic action and mild peripheral anticholinergic action.
Pharmacokinetics
Cyproheptadine is well absorbed following oral administration, with peak plasma levels observed after 1–3 hours. Elimination is primarily by hepatic glucuronidation with urinary excretion of metabolites.
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ADMINISTRATION
• • • •
Administer an initial dose of 8 mg orally and observe for clinical response. If a response is observed, continue treatment with 8 mg every 8 hours for 24 hours. Therapy should not be required beyond 24 hours, provided agents that may precipitate serotonin syndrome are withheld. A longer duration of therapy may be required to treat serotonin syndrome associated with an irreversible MAO inhibitor.
THERAPEUTIC END POINTS
•
Resolution or amelioration of the clinical features associated with serotonin syndrome within 1–2 hours of the initial dose
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
SPECIFIC CONSIDERATIONS
Pregnancy: no restriction on use. Paediatric: paediatric dose is not well established. For 7–14-yearolds an initial dose of 4 mg followed by 4 mg every 8 hours for 24 hours is suggested.
HANDY TIPS
•
Cyproheptadine is not a life-saving antidote. It may ameliorate the symptoms of mild-to-moderate serotonin syndrome, but a good outcome will be achieved in these cases with simple supportive care including mild benzodiazepine sedation. • Cyproheptadine is not useful in the management of severe serotonin syndrome. Early intubation and neuromuscular paralysis is the key to achieving a good outcome in this circumstance.
PITFALLS
• •
Failure to assess clinical response to initial dose. Reliance on cyproheptadine to the detriment of good supportive care in the management of serotonin syndrome.
Reference
Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. Journal of Emergency Medicine 1998; 16(4):615–619.
4.4 DESFERRIOXAMINE An effective iron chelator that is used to treat systemic iron toxicity or prevent the development of systemic toxicity following acute iron overdose. Presentations
Desferrioxamine mesylate 500 mg vials (powder for reconstitution) Desferrioxamine mesylate 2 g vials (powder for reconstitution)
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ANTIDOTES
Insignificant adverse effects at therapeutic doses
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TOXICOLOGICAL INDICATIONS
•
Acute iron poisoning — Established systemic iron toxicity with clinical features of severe gastroenteritis, shock, metabolic acidosis and altered mental state — Significant risk of systemic iron toxicity, as predicted by serum iron levels >90 micromol/L or 500 microgram/dL at 4–6 hours post ingestion • Chronic iron overload
CONTRAINDICATIONS
•
None
ANTIDOTES
Mechanism of action
Pharmacokinetics
The volume of distribution is 1 L/kg and it does not substantially enter tissue compartments. Steady-state concentrations are achieved at 6–12 hours during intravenous infusion. DFO undergoes hepatic metabolism, producing multiple metabolites, one of which is responsible for the drug’s toxic effects. Some drug is excreted unchanged in the urine. The elimination half-life is 3 hours but substantially increased in renal failure. Ferrioxamine has a smaller volume of distribution than DFO, is not metabolised but excreted unchanged in the urine, and is dialysable.
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Desferrioxamine (DFO) binds avidly to free ferric ion in the plasma to form ferrioxamine. This stable complex is highly water soluble and is readily excreted in the urine. DFO is able to remove iron bound to transferrin and haemosiderin, but not from outside the intravascular compartment. 1000 mg of DFO is able to bind 85 mg of ferric iron.
ADMINISTRATION
• • • • • •
Cardiac monitoring is mandatory during DFO administration. Reconstitute 500 mg of powder with 5 mL sterile water and dilute in 100 mL normal saline or 5% dextrose. Commence IV infusion at an initial dose of 15 mg/kg/hour. Reduce the infusion rate if hypotension develops. The rate may be increased in life-threatening toxicity up to 40 mg/ kg/hour, providing significant hypotension does not supervene. Continue the infusion until therapeutic end points have been achieved, but avoid infusions prolonged >24 hours.
THERAPEUTIC END POINTS
• •
Patient clinically stable Serum iron 24 hours), possible development of ARDS Toxic retinopathy Secondary infections including Yersinia sepsis and mucormycosis: ferrioxamine complex acts as a siderophore promoting growth of these organisms
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SPECIFIC CONSIDERATIONS
Pregnancy: there is no evidence of human teratogenicity with DFO, and although it is not known if DFO crosses the placenta, it should never be withheld in the treatment of pregnant patients with severe iron poisoning. Paediatric: administration and dose are as for adults.
• • • •
PITFALLS
• •
DFO is ideally administered before iron moves intracellularly and systemic toxicity develops. Intramuscular DFO administration is not indicated in acute iron poisoning. Although urine may change to the classical vin rosé colour during DFO administration, this is an unreliable sign of effective chelation. Six hours of DFO chelation is usually sufficient and it is extremely rare to require therapy beyond 24 hours. Administration of DFO when not clinically indicated Excessive duration of DFO administration
ANTIDOTES
HANDY TIPS
CONTROVERSIES
There are no controlled trials or dose–response studies to support the efficacy of DFO chelation for human iron poisoning. The optimal indications, dose, route of administration and end points for therapy are not well defined.
References
Howland MA. Risks of parenteral deferoxamine for acute iron poisoning. Journal of Toxicology – Clinical Toxicology 1996; 34(5):491–497. Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. Journal of Toxicology – Clinical Toxicology 1996; 42(5):485–489.
4.5 DICOBALT EDETATE Cobalt edetate, Cobalt EDTA, Cobalt tetracemate This agent was developed as a cyanide antidote based on the known ability of cobalt to form stable complexes with cyanide. The severe direct toxic effects that occur when it is administered to a patient without cyanide poisoning limit the use of this agent. Presentations
Dicobalt edetate 300 mg/20 mL ampoules TOXICOLOGICAL INDICATIONS
•
Unequivocal acute cyanide poisoning
CONTRAINDICATIONS
•
Suspected cyanide poisoning without definite signs of poisoning, such as impairment or loss of consciousness
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Pharmacodynamics
Dicobalt edetate is an inorganic cobalt salt. At least one of the cobalt atoms is available to bind cyanide. One mole of cobalt binds six moles of cyanide to form stable complexes. Cobalt cyanides are much less toxic than free cyanide.
Pharmacokinetics
Dicobalt edetate is able to cross the blood–brain barrier. The cyanide–cobalt complex is excreted in the urine. ADMINISTRATION
ANTIDOTES
•
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This antidote is only administered to critically ill patients in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care. Cardiac monitoring is mandatory. • Administer 300 mg (1 ampoule) IV over 1 minute, followed immediately with 50 mL of 50% dextrose IV to protect against toxicity. • A repeat second or third dose of 300 mg is given if an immediate clinical response is not observed.
THERAPEUTIC END POINTS
• • •
Improvement in conscious state Haemodynamic stability Improvement in metabolic acidosis
ADVERSE DRUG REACTIONS
•
Significant adverse reactions have been reported, usually when it is inappropriately administered in the absence of cyanide poisoning. • These reactions are due to direct toxicity of the cobalt salt and include: seizures; oedema of the face, larynx and neck; chest pain; dyspnoea; hypotension; vomiting; and urticarial rashes.
SPECIFIC CONSIDERATIONS
Pregnancy: safety in pregnancy is not confirmed. Administration should not be withheld if indicated. Paediatric: paediatric dose is 7.5 mg/kg IV (maximum dose 300 mg).
HANDY TIPS
•
Never give dicobalt edetate to a patient without clinical features of definite severe cyanide poisoning including impaired level of consciousness. • The occurrence of adverse outcomes is minimised by adhering to strict clinical criteria for giving the antidote.
PITFALLS
•
Administration of dicobalt edetate to a patient without cyanide poisoning or one displaying only minor clinical manifestations of cyanide poisoning • Inadvertent or mistaken administration of sodium calcium edetate (EDTA), an antidote used in the treatment of lead poisoning
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CONTROVERSY
•
The relative efficacy of dicobalt edetate as an antidote for cyanide poisoning in humans has not been established.
References
Hall A, Saiers J, Baud F. Which cyanide antidote? Critical Reviews in Toxicology 2009; 39(7):541–552. Reade MC, Davies SR, Morley PT et al. Review article: management of cyanide poisoning. Emergency Medicine Australasia 2012; 24:225–238.
4.6 DIGOXIN IMMUNE FAB These antibody fragments promptly and safely reverse the toxicity of digoxin and other cardiac glycosides.
TOXICOLOGICAL INDICATIONS
Cardiac glycoside poisoning where there is an imminent threat to life or where the risk assessment suggests such a threat is an absolute indication for immediate administration of digoxin immune Fab. Administration is also indicated in any patient whose manifestations of digoxin toxicity are sufficient to warrant inpatient care. More specifically: • Acute digoxin overdose — Cardiac arrest — Life-threatening cardiac dysrhythmia — Ingested dose >10 mg (adult) or >4 mg (child) — Serum digoxin level >15 nmol/L (12 ng/mL) — Serum potassium >5 mmol/L • Chronic digoxin poisoning — Cardiac arrest — Life-threatening cardiac dysrhythmia — Cardiac dysrhythmia or increased automaticity not likely to be tolerated for a prolonged period — Moderate-to-severe gastrointestinal symptoms — Any symptoms in presence of impaired renal function • Other cardiac glycoside poisoning — Oleander — Bufotoxin (cane toad)
CONTRAINDICATIONS
•
None
Mechanism of action
Digoxin immune Fab is created by papain cleavage of IgG molecules raised in sheep against digoxin bound to albumin. 40 mg (one ampoule) of Fab binds 0.5 mg of digoxin. Digoxin immune Fab binds directly to the free intravascular and interstitial digoxin with much greater affinity than the Na+/K+-ATPase receptor. A concentration gradient is created and intracellular digoxin dissociates from tissues and moves to the intravascular space where binding to immune Fab continues.
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Digoxin-specific immune antigen binding fragments as lyophilised powder 40 mg ampoules
ANTIDOTES
Presentations
Pharmacokinetics
Digoxin bound to Fab fragments is excreted in the urine, with an elimination half-life of 16–30 hours. ADMINISTRATION
•
Place the patient in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care. Cardiac monitoring is mandatory during antidote administration and until toxicity is reversed. • Calculate the dose required (see below), dilute in 100 mL normal saline and administer over 30 minutes. • Dose is calculated on the presumption that one ampoule of Fab binds 0.5 mg of digoxin.
CALCULATION OF DOSE
ANTIDOTES
•
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Acute digoxin overdose — Known digoxin dose – Number of ampoules = ingested dose (mg) × 0.8 (bioavailability) × 2 — Unknown digoxin dose – Commence empiric dosing with 5 ampoules if the patient is haemodynamically stable or 10 ampoules if unstable. – Give repeat doses of 5 ampoules every 30 minutes until reversal of digoxin toxicity is achieved. • Chronic digoxin poisoning — Number of ampoules serum digoxin (ng/mL ) × body weight (kg) = 100 — Alternatively, commence empiric dosing with 2 ampoules and observe for clinical response. If there is no reversal of digoxin toxicity after 30 minutes, give a further 2 ampoules. • Other cardiac glycoside poisoning — If the patient is stable, commence with an empiric dose of 5 ampoules and repeat every 30 minutes until reversal of toxicity is observed. — Large doses may be required before a clinical response is achieved. Up to 30 ampoules have been used to successfully reverse severe yellow oleander poisoning.
DURATION OF TREATMENT
• • •
A single dose given over 30 minutes is usually sufficient. Following an adequate dose, a response is normally apparent by 20 minutes and maximal by 4 hours. Rarely, digoxin toxicity may recur beyond 24 hours and necessitate further administration of digoxin immune Fab.
THERAPEUTIC END POINTS
• •
Restoration of normal cardiac rhythm and conduction Resolution of gastrointestinal symptoms
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ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
This is an extremely safe antidote – adverse effects of any kind occur in less than 5% of cases. Adverse effects include: • Hypokalaemia • Allergy (extremely rare) • Exacerbation of underlying cardiac failure • Loss of rate control of preexisting atrial fibrillation. SPECIFIC CONSIDERATIONS
• • • • •
PITFALLS
• •
In cardiac arrest thought to be due to digoxin poisoning, give high-dose digoxin immune Fab (20 ampoules if available) by rapid intravenous injection, while continuing cardiopulmonary resuscitation. Digoxin levels following treatment may appear very high. This is because most serum digoxin assays measure both free and Fab-bound digoxin. Some laboratories are able to assay free digoxin. Hyperkalaemia due to acute digoxin poisoning is treated with Fab, not intravenous calcium, as digoxin causes elevation in intracellular myocardial calcium levels. It is not necessary to bind the total body digoxin load to control toxicity. The administration of less than the calculated dose of digoxin immune Fab may still be sufficient. Administration of digoxin immune Fab to patients with non-life threatening chronic digoxin toxicity is shown to significantly reduce length-of-stay in hospital. Unavailability of sufficient digoxin immune Fab to treat lifethreatening poisoning. Withholding digoxin immune Fab from patients with chronic digoxin poisoning because of concerns about expense of the antidote. The risk of death and cost of prolonged unnecessary admission to a monitored bed greatly exceed the cost of 2 ampoules of digoxin immune Fab.
CONTROVERSIES
•
It may be pharmacokinetically more appropriate to give smaller initial doses of digoxin immune Fab and follow up with repeat doses or an infusion. • The dose of digoxin immune Fab is not well defined in poisoning by other cardiac glycosides, such as those contained in oleander.
References
Antman EM, Wenger TL, Butler VP et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter study. Circulation 1990; 81(6):1744–1752.
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HANDY TIPS
ANTIDOTES
Pregnancy: no restriction on use. Paediatric: no restriction on use.
Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicological Reviews 2004; 23(3):135–143. Di Domenico R, Walton S, Sanoski CA et al. Analysis of the use of digoxin Fab for the treatment of non life threatening digoxin toxicity. Journal of Cardiovascular Pharmacology and Therapeutics 2000; 5(2):77–85. Eddleston M, Rajapakse S, Rajakanthan JS et al. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000; 355(9208):967–972. Lapostolle F, Borron SW, Verdier C et al. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Critical Care Medicine 2008; 36:3014–3018. Woolf AD, Wenger T, Smith TW et al. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. New England Journal of Medicine 1992; 326:1739–1744.
4.7 DIMERCAPROL ANTIDOTES
British antilewisite, 2,3-dimercaptopropanol This rarely used intramuscular chelator is the most toxic of all chelating agents and is reserved for the treatment of severe poisoning from lead, inorganic arsenic and mercury. Presentations
Dimercaprol 300 mg, benzyl benzoate 600 mg, peanut oil 2100 mg/3 mL ampoules
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TOXICOLOGICAL INDICATIONS
• • • • •
Arsenic poisoning Inorganic mercury poisoning Gold intoxication Severe lead poisoning or lead encephalopathy (adjunct to EDTA) Other heavy metal poisoning — Dimercaprol has been used to chelate bismuth, antimony, chromium, nickel, tungsten and zinc, but clinical experience is limited.
CONTRAINDICATIONS
• •
Peanut allergy G6PD deficiency
Pharmacodynamics
Dimercaprol binds metal ions to form stable dimercaptides, which can then be excreted in the urine.
Pharmacokinetics
Dimercaprol is not absorbed orally. In fact, because it is formulated in peanut oil, it is only suitable for IM administration. Blood concentrations peak about 30 minutes after IM administration and distribution occurs rapidly. It is metabolised predominantly by glucuronic conjugation and the metabolites are excreted in the urine. Dimercaprol–metal conjugates are removed by dialysis. ADMINISTRATION
•
Therapy is always commenced in an intensive care setting due to the severity of the underlying condition and adverse effects.
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Alkalinise the urine prior to commencing therapy in order to reduce risk of nephrotoxicity (prevents dissociation of dimercaprol–metal conjugates in the urine). Severe inorganic arsenic or mercury poisoning • Give 3 mg/kg IM every 4 hours for 48 hours then • Give 3 mg/kg IM every 12 hours for 7–10 days depending on clinical response. Lead encephalopathy • Commence dimercaprol 4 hours before commencing EDTA. • Give 4 mg/kg every 4 hours for 5 days. • See Chapter 4.25: Sodium calcium edetate for further information.
SPECIFIC CONSIDERATIONS
Pregnancy: safety not established. Administration should not be withheld if clinically indicated. Lactation: safety not established. Paediatric: dose and administration as for adults.
HANDY TIPS
PITFALL
• • • •
Never give intravenously. Dimercaprol is most effective when administered shortly after the exposure. Never give more than 4 mg/kg as a single dose due to high incidence of adverse effects. If the patient is well enough, chelation with the orally-active analogue of dimercaprol (succimer) is always preferable.
•
Failure to access supplies promptly – dimercaprol is difficult to obtain and stocked by relatively few hospitals.
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Dimercaprol is associated with an extremely high incidence (about 50%) of adverse effects at therapeutic dose. These include: • Pain and sterile abscess formation at injection sites • Fever (especially in children) and myalgia • Chest pain, hypertension and tachycardia • Headache, nausea and vomiting • Peripheral paraesthesias; burning sensation of lips, mouth, throat and eyes • Lacrimation, rhinorrhoea and excessive salivation • Risk of intravascular haemolysis in patients with G6PD deficiency • Nephrotoxicity secondary to the dissociation of dimercaprol–metal complexes in acid urine • Hypertensive encephalopathy at supratherapeutic doses. Unfortunately, many of these adverse effects may need to be tolerated in view of the severity of the underlying intoxication and lack of alternative viable chelating agents. For life-threatening adverse effects, subsequent doses should be reduced.
ANTIDOTES
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
CONTROVERSY
•
Dosing regimens are usually historical and clinical efficacy is poorly established.
References
Gold H. BAL (British anti-lewisite). American Journal of Medicine 1948; 4:1. Vilensky JA, Redman K. British anti-lewisite (dimercaprol): an amazing history. Annals of Emergency Medicine 2003; 41:378–383.
ANTIDOTES
4.8 ETHANOL Competitively blocks the formation of toxic metabolites in toxic alcohol ingestions by having a higher affinity for the enzyme alcohol dehydrogenase (ADH). Its chief application is in methanol and ethylene glycol ingestions, although it has been used with other toxic alcohols. Ethanol is now regarded as the second choice antidote in those countries with access to the specific ADH blocker, fomepizole. Presentations
Pure ethanol 20 mL ampoule (pharmaceutical grade) Commercial alcoholic beverages with alcohol content from 5% to 70% TOXICOLOGICAL INDICATIONS
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• •
Methanol poisoning (confirmed or suspected) Ethylene glycol poisoning (confirmed or suspected)
CONTRAINDICATIONS
•
Recent ingestion of disulfiram (or drugs that may cause a disulfiram-like reaction)
Mechanism of action
Alcohol dehydrogenase has a much higher affinity (up to 20×) for ethanol than for ethylene glycol or methanol. Ethanol competitively inhibits the conversion of these other alcohols to their toxic metabolites by blocking the receptor sites of ADH. Inhibition is virtually complete at ethanol concentrations greater than 100 mg/dL (22 mmol/L).
Pharmacokinetics
Ethanol is rapidly absorbed after oral administration and distributed throughout the total body water. It rapidly crosses both the placenta and the blood–brain barrier. Elimination is principally by enzymatic oxidation in the liver in a two-step process involving alcohol dehydrogenase and aldehyde dehydrogenase. Metabolic capacity is saturated at relatively low concentrations. The rate of metabolism is extremely variable between individuals. ADMINISTRATION
•
Therapy should be commenced in a monitored area with personnel and equipment available to monitor mental status and blood or breath alcohol levels every 2 hours. • Ethanol may be administered by the oral, nasogastric or intravenous route to maintain a blood ethanol concentration of 100–150 mg/dL (22–33 mmol/L).
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ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
• •
Local phlebitis from intravenous solutions Ethanol intoxication — Reduce rate of ethanol administration if blood ethanol concentration exceeds 150 mg/dL (33 mmol/L). • Hypoglycaemia in children Pregnancy: ethanol and the toxic alcohols readily cross the placenta. There is no contraindication to ethanol administration in the pregnant woman with toxic alcohol poisoning. Paediatric: there is no contraindication to ethanol administration in the child with toxic alcohol poisoning, but the child should be carefully monitored for hypoglycaemia.
• • •
PITFALLS
• •
Ethanol for intravenous therapy is difficult to procure – alcoholic spirits suitable for oral administration are ubiquitous. Administration of ethanol may be delayed in the patient who already has a high ethanol level. Breath ethanol estimations may be substituted for repeated blood ethanol levels during maintenance therapy. Delay in starting therapy. Failure to monitor blood ethanol levels closely resulting in sub- or supratherapeutic concentrations.
CONTROVERSIES
•
Relative merits of fomepizole over ethanol in the management of toxic alcohol poisoning. • Clinical efficacy of ethanol in the treatment of poisoning with other toxic alcohols, including glycol ethers, diethylene glycol, triethylene glycol, propylene glycol and butanediol. • Necessity to continue to maintain ethanol levels after commencement of haemodialysis.
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SPECIFIC CONSIDERATIONS
HANDY TIPS
ANTIDOTES
Oral or nasogastric administration • Loading dose: 1.8 mL/kg of 43% ethanol, or 3 × 40 mL shots of vodka in a 70-kg adult. • Note: Omit the loading dose of ethanol in the already ethanolintoxicated patient. • Maintenance: 0.2–0.4 mL/kg/hour of 43% ethanol, or 40-mL shot each hour. Intravenous administration • Loading dose: 8 mL/kg of 10% ethanol. • Maintenance infusion rate: 1–2 mL/kg/hour of 10% ethanol. • Note: A 10% ethanol solution is prepared by adding 100 mL of 100% ethanol to 900 mL of 5% dextrose. • Remember: the required maintenance dose is extremely variable. The doses outlined above are a guide only and must be adjusted to maintain blood alcohol concentrations in the desired range. • Continue maintenance ethanol therapy until the toxic alcohol poisoning has been definitively treated with haemodialysis.
References
Barceloux DG, Krenzelok EK, Olson K et al. American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Journal of Toxicology – Clinical Toxicology 1999; 37(5):537–560. Beatty L, Green K, Magee K, Zed P. A systematic review of ethanol and fomepizole use in toxic alcohol ingestion. Emergency Medicine International 2013; 2013:638057. Lepik KJ, Levy AR, Sobolev BG et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Annals of Emergency Medicine 2009; 53:439–450.
4.9 FLUMAZENIL Competitive benzodiazepine antagonist with a limited role in the management of benzodiazepine poisoning. Presentations ANTIDOTES
Flumazenil 0.5 mg/5 mL ampoules
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TOXICOLOGICAL INDICATIONS
•
Benzodiazepine overdose — Accidental paediatric ingestion with compromised airway and breathing — Deliberate self-poisoning with compromised airway and breathing, and equipment and skills to intubate and ventilate not readily available (rare) — Note: Isolated benzodiazepine overdose rarely causes CNS depression sufficient to warrant intervention. • To confirm diagnosis of benzodiazepine intoxication — Useful if it avoids invasive or expensive further investigation to exclude alternative diagnoses • Reversal of procedural sedation with benzodiazepines
CONTRAINDICATIONS
• • • •
Known seizure disorder Known or suspected co-ingestion of pro-convulsant drugs Known or suspected benzodiazepine dependence QRS prolongation on ECG (suggests possibility of co-ingestion of tricyclic antidepressant)
Mechanism of action
Flumazenil is a 1,4-imidazobenzodiazepine structurally similar to midazolam. It acts as a competitive antagonist at the benzodiazepine receptor sites in the CNS. Binding inhibits benzodiazepine activity at the GABA–benzodiazepine complex and reverses the CNS effects of benzodiazepines.
Pharmacokinetics
Flumazenil has a volume of distribution of 1 L/kg at steady state. It undergoes rapid and extensive hepatic metabolism to inactive metabolites. Elimination half-life is 40–80 minutes. These pharmacokinetic properties are unaltered following benzodiazepine overdose. ADMINISTRATION
•
Flumazenil should only be administered in an environment where equipment and personnel are available to manage a seizure.
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• • •
Give an initial dose of 0.1–0.2 mg IV and repeat every minute until reversal of sedation is achieved. Maximal response should be observed with a dose not exceeding 2 mg. Re-sedation is expected and normally occurs at around 90 minutes. If necessary, repeated doses may be given to maintain adequate reversal of benzodiazepine sedation. Occasionally a flumazenil infusion may be of value. • Note: Patients must be observed for re-sedation for several hours following the last dose of flumazenil. Benzodiazepine withdrawal syndrome • Manifests as agitation, tachycardia and seizures. • Mild benzodiazepine withdrawal will be short-lived and does not require specific management. • Severe withdrawal syndrome requires administration of benzodiazepines in titrated doses. Seizures • Most commonly occur in patients with benzodiazepine dependence, co-ingestion of pro-convulsant drugs or an underlying seizure disorder. • Withhold further flumazenil. • Repeated or prolonged seizures require administration of benzodiazepines in titrated doses.
ANTIDOTES
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
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Pregnancy: safety not established. Administration should not be withheld if clinically indicated. Paediatric: give 0.01–0.02 mg/kg repeated every minute as necessary. Flumazenil administration is extremely safe in children who have ingested benzodiazepines, as they are unlikely to be benzodiazepine-dependent.
HANDY TIP
•
PITFALLS
• • •
Flumazenil may be life-saving if personnel and equipment for definitive airway control are not available. Unnecessary administration to patients with mild benzodiazepine poisoning. Administration when contraindicated due to risk of seizures. Failure to observe for re-sedation.
CONTROVERSY
•
Role of flumazenil in management of the undifferentiated overdose patient.
References
Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center’s ten-year experience with flumazenil administration to acutely poisoned adults. The Journal of Emergency Medicine 2012; 43:677–682.
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SPECIFIC CONSIDERATIONS
Ngo AS, Anthony CR, Samuel M et al. Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department? Resuscitation 2007; 74(1):27–37. Seger D. Flumazenil: treatment or toxin. Journal of Toxicology – Clinical Toxicology 2004; 42(2):209–216. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Treatment of benzodiazepine overdose with flumazenil. Clinical Therapeutics 1992; 14:978–995.
4.10 FOLINIC ACID Leucovorin, 5-formyltetrahydrofolic acid
ANTIDOTES
This agent is the active form of folic acid. It is routinely used for ‘folinic acid rescue therapy’ following administration of high doses of parenteral methotrexate in oncological practice. Its applications in clinical toxicology are rather more limited.
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Presentations Calcium Calcium Calcium Calcium Calcium Calcium Calcium
folinate folinate folinate folinate folinate folinate folinate
15 mg tablets (10) 15 mg/2 mL ampoules 50 mg/5 mL plastic vials 50 mg/5 mL ampoules 100 mg/10 mL plastic vials 100 mg/10 mL ampoules 300 mg/30 mL plastic vial
TOXICOLOGICAL INDICATIONS
•
Supratherapeutic methotrexate ingestion — This usually occurs in the context of accidental daily dosing of methotrexate rather than the usual weekly dosing. — Folinic acid therapy is indicated if: – Clinical features of methotrexate toxicity are evident or – The weekly dose has been administered daily for more than 3 consecutive days. • Single acute oral methotrexate overdose — Methotrexate toxicity has never been reported in this scenario. — Folinic acid should be given empirically, if more than 500 mg (5 mg/kg in children) is ingested, until methotrexate levels are available to more fully assess risk of toxicity. — If less than 500 mg of methotrexate is ingested, consider folinic acid when methotrexate levels are not available within 24 hours. • Adjunct treatment for methanol poisoning • Massive pyrimethamine and trimethoprim poisoning
CONTRAINDICATIONS
•
Known hypersensitivity
Mechanism of action
Folinic acid is the reduced biologically active form of folic acid and is essential for DNA/ RNA synthesis. Methotrexate acts as an antimetabolite, preventing the reduction of folic
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acid to folinic acid, by inhibiting dihydrofolate reductase. Administration of exogenous folinic acid bypasses this inhibition and restores DNA/RNA synthesis. Folates also enhance the elimination of formate in methanol poisoning.
Pharmacokinetics
Oral bioavailability of folinic acid is almost 100% after a 15-mg dose, but falls with higher doses. The active isomer has a volume of distribution of 13.6 L and an elimination half-life of 35 minutes. Elimination is predominantly by metabolism to an active metabolite, 5-methyltetrahydrofolate, which has a volume of distribution of 40 L and an elimination half-life of over 400 minutes.
ADVERSE DRUG REACTIONS
• • •
Anaphylaxis (rare) Seizures (rare) Hypercalcaemia with rapid IV administration (>160 mg/minute)
SPECIFIC CONSIDERATIONS
Pregnancy: no restriction on use. Paediatric: dosing for oral methotrexate overdose is not determined for children.
HANDY TIP
PITFALL
•
Folinic acid administration is rarely necessary following acute single methotrexate overdose.
•
Administration of folic acid instead of folinic acid (folic acid is not an effective antidote for methotrexate toxicity).
CONTROVERSIES
•
The indications (if any) for folinic acid administration following single acute overdose of methotrexate. — The length of treatment in chronic toxicity is controversial and should perhaps continue until there is evidence of bone marrow recovery. • The value of adjunctive treatment with folinic acid in methanol poisoning.
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Methotrexate overdose • Give 15 mg PO, IM or IV every 6 hours. • For single acute methotrexate overdose, therapy may be ceased when methotrexate level is confirmed to be below the threshold for toxicity (see Table 3.51.2) for an acute single overdose. It is otherwise continued for at least 3 days or until the serum methotrexate is 15 mg/kg). SPECIFIC CONSIDERATIONS
• • • •
•
Patients with preexisting conditions that interfere with oxygenation, such as anaemia or coronary artery disease, may require methylene blue administration at MetHb concentrations as low as 10%. Pulse oximetry is unreliable, as MetHb and methylene blue interfere with the readings. Replacement of the blue discolouration of methaemoglobinaemia with that of methylene blue means that this clinical sign is an unreliable guide to response to therapy. Consider the following problems if MetHb levels are not falling after 2 doses of methylene blue: — Massive ongoing exposure to oxidising agent — Sulfhaemoglobinaemia (e.g. by sulfonamides) — G6PD deficiency — Methaemoglobin reductase deficiency — Abnormal haemoglobin — Excessive methylene blue. If methylene blue fails to control methaemoglobinaemia, consider exchange transfusion or hyperbaric oxygen therapy.
CONTROVERSIES
•
Whether a certain MetHb concentration mandates methylene blue treatment. Most clinicians continue to monitor asymptomatic patients with elevated levels even >20% and do not treat unless symptoms of hypoxaemia develop. • Role, indications and dosing of methylene blue in refractory toxic shock states require further study.
References
Clifton J, Leiken JB. Methylene blue. American Journal of Therapeutics 2003; 10:289–291. Lo JCY, Darracq MA, Clark RF. A review of methylene blue treatment for cardiovascular collapse. The Journal of Emergency medicine 2014; 46:670–679.
4.17 N-ACETYLCYSTEINE N-acetylcysteine (NAC) is the most widely used sulfhydryl donor in the treatment of paracetamol poisoning. Standard therapy consists of a
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HANDY TIPS
ANTIDOTES
Pregnancy: no restrictions on use. Lactation: no restrictions on use. Paediatric: Initial paediatric dose is 1 mg/kg.
series of three infusions given over 20 hours. It is almost completely protective against paracetamol-induced hepatotoxicity when administered within 8 hours of an overdose. Adverse effects are limited to mild anaphylactoid reactions. Presentations
200 mg/mL injectable (10 mL, 30 mL) TOXICOLOGICAL INDICATIONS
ANTIDOTES
• • • •
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Acute paracetamol overdose Repeated supratherapeutic paracetamol ingestion Paracetamol-induced fulminant hepatic failure Note: NAC is indicated in the above situations where there is judged to be a risk of hepatotoxicity. Risk assessment is based on dose ingested, serum paracetamol and hepatic transaminase levels, and is discussed in detail in Chapter 3.60: Paracetamol: Acute overdose, Chapter 3.61: Paracetamol: Modified-release preparations and Chapter 3.62: Paracetamol: Repeated supratherapeutic ingestion • NAC has been investigated for use in poisonings by a variety of other agents, including chemotherapeutic agents, paraquat, carbon tetrachloride, chloroform, acrylonitrile, cyclophosphamide and amanita mushrooms
CONTRAINDICATIONS
•
None
Mechanism of action
NAC prevents N-acetyl-p-benzoparaquinone imine (NAPQI)-induced hepatotoxicity when given within 8 hours of an acute paracetamol overdose. It ameliorates the clinical course of toxicity when given after that time or following repeated supratherapeutic ingestion. Four possible mechanisms may contribute to this action: 1 Increased glutathione availability 2 Direct binding to NAPQI 3 Provision of inorganic sulfate 4 Reduction of NAPQI back to paracetamol. The antioxidant properties of NAC may offer benefit in a number of other poisonings in which oxidative stress is an important toxic mechanism and may also explain its beneficial effects in liver failure of any cause.
Pharmacokinetics
NAC metabolism is complex, with a variety of sulfur-containing compounds being produced. Plasma half-life following IV administration is 6 hours and 30% is eliminated unchanged in the urine. ADMINISTRATION
•
Patients are carefully monitored for anaphylactoid reaction during and after the initial dose of NAC. Cardiac monitoring is not required after that time. • Give 150 mg/kg (0.75 mL/kg) NAC diluted in 200 mL of 5% dextrose IV over 15 minutes followed by • 50 mg/kg (0.25 mL/kg) NAC diluted in 500 mL of 5% dextrose IV over 4 hours
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• • •
followed by 100 mg/kg (0.5 mL/kg) NAC diluted in 1000 mL of 5% dextrose IV over 16 hours. The standard treatment duration is 20.25 hours; however, it may be interrupted before this time where risk of hepatotoxicity is excluded. The infusion may be continued beyond 20 hours in patients with late presentation, repeated supratherapeutic ingestion or biochemical evidence of hepatotoxicity. Repeat the final dose of 100 mg/kg NAC diluted in 1000 mL of 5% dextrose IV over 16 hours until such time as transaminases begin to fall and the patient is improving clinically.
THERAPEUTIC END POINTS
•
Absent or resolving hepatotoxicity as determined by transaminases Anaphylactoid reactions (incidence of 10–50%), including hypotension, flushing, rash and angio-oedema — These usually occur during or shortly after the initial dose and can be treated with an oral H1-blocker (e.g. loratadine 10 mg PO) or promethazine 12.5 mg IV. — The infusion need only be ceased if the reaction is severe, in which case it may be restarted as soon as the reaction is settling.
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SPECIFIC CONSIDERATIONS
Pregnancy: NAC crosses the placenta. When indicated, it is beneficial for both mother and fetus. Paediatric: the dose of NAC is the same as for adults. However, it should be infused in smaller volumes of 5% dextrose (use 0.45% sodium chloride with 5% dextrose if there are concerns about hyponatraemia). • Children 20 kg body weight: — 150 mg/kg in 100 mL of 5% dextrose over 15 minutes followed by — 50 mg/kg in 250 mL of 5% dextrose over 4 hours followed by — 50 mg/kg in 250 mL of 5% dextrose over 8 hours followed by — 50 mg/kg in 250 mL of 5% dextrose over 8 hours.
HANDY TIP
•
Always chart NAC infusions using the chart supplied in the package insert, which describes NAC volume rather than milligrams. This practice reduces the chance of a dosing error.
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ANTIDOTES
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
PITFALLS
•
Failure to initiate NAC empirically in the patient who presents more than 8 hours following a paracetamol overdose of >200 mg/kg. • Failure to warn patient and staff of the high likelihood of a mild anaphylactoid reaction occurring early in treatment.
CONTROVERSIES
ANTIDOTES
•
The practice of giving the initial dose of NAC over 60 minutes rather than 15 minutes does not appear to significantly reduce the incidence of anaphylactoid reactions. • The value of NAC in patients who present more than 24 hours post overdose with elevated transaminases, but who are otherwise well. • The optimal regimen for administration of NAC is not defined. Multiple protocols now exist including a number of protocols of shorter duration. • Use of increased concentrations and prolonged infusions of NAC have been advocated following massive (>500 mg/kg) paracetamol overdose or the ingestion of modified release presentations.
References
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Bateman DN, Dear JW, Thanacoody HR et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomized controlled trial. Lancet 2014; 383:697–704. Daly FSS, Fountain JS, Murray L et al. Guidelines for the management of paracetamol poisoning in Australia and New Zealand – explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. Medical Journal of Australia 2008; 188:296–301. Kerr F, Dawson A, Whyte IM et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Annals of Emergency Medicine 2005; 45:409–413. Prescott LF, Illingworth RN, Critchley JA. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. British Medical Journal 1979; 2:1097. Rumack BH, Bateman DH. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clinical Toxicology 2012; 50:91–98.
4.18 NALOXONE This opioid antagonist is a useful adjunct in the management of opioid intoxication. Presentations
Naloxone hydrochloride 400 microgram/1 mL ampoules Naloxone hydrochloride 800 microgram/2 mL pre-filled syringe Naloxone hydrochloride 2 mg/5 mL pre-filled syringe TOXICOLOGICAL INDICATIONS
• •
Reversal of CNS and respiratory depression caused by opioid intoxication Empirical treatment for coma thought to be secondary to opioids
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•
Avoid in the opioid-dependent individual unless: — Significant respiratory depression (respiratory rate 140 ms). — Commence an infusion of 150 mmol sodium bicarbonate diluted in 850 mL normal saline at 250 mL/hour.
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— Check ABGs hourly and maintain serum pH in range of 7.50–7.55. — Cease infusion following resolution of cardiovascular toxicity as determined by clinical and ECG criteria. — Note: In practice it is far easier and safer, and of comparable efficacy, to maintain serum alkalinisation with hyperventilation in the intubated patient. Prevention of redistribution of salicylate to CNS • The pH must be maintained above 7.4 at all times. • The salicylate-poisoned patient with severe metabolic acidosis is critically ill and usually intubated, and serum pH may be maintained >7.4 by hyperventilation. • Give sodium bicarbonate 2 mmol/kg IV bolus in an unwell unintubated patient with salicylate poisoning. • Then intubate, hyperventilate and recheck ABGs. • Serum alkalinisation is maintained until definitive care with haemodialysis. Urinary alkalinisation • Correct hypokalaemia if present. • Give 1–2 mmol/kg sodium bicarbonate IV bolus. • Commence infusion of 150 mmol sodium bicarbonate in 850 mL 5% dextrose at 250 mL/hour. • 20 mmol of KCl may be added to infusion to maintain normokalaemia. • Monitor serum bicarbonate and potassium at least every 4 hours. • Regularly dipstick urine and aim for urinary pH >7.5. • Continue until clinical and laboratory evidence of toxicity is resolving. Note: Sodium bicarbonate (NaHCO3) should not be administered through an intravenous line running fluids containing calcium or magnesium. ADVERSE DRUG REACTIONS
• • • • •
Alkalosis (serum pH >7.6 is detrimental to cardiovascular function) Hypernatraemia and hyperosmolarity Fluid overload and acute pulmonary oedema Hypokalaemia Local tissue inflammation secondary to extravasation
SPECIFIC CONSIDERATIONS
Pregnancy: no restriction on use. Lactation: no restriction on use. Paediatric: doses are the same as for adults on mmol/kg basis. Reduced fluid volumes should be used in children.
HANDY TIPS
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Rapid correction of acidosis by administration of sufficient doses of sodium bicarbonate is an essential component of the resuscitation of a patient with severe tricyclic antidepressant poisoning.
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The frail elderly patient or patient with underlying cardiac disease may not tolerate the fluid and osmotic load associated with sodium bicarbonate administration. Insufficient doses of sodium bicarbonate when attempting resuscitation of severe tricyclic antidepressant poisoning. Failure to correct hypokalaemia when attempting urinary alkalinisation. Failure to recognise and rapidly treat acidaemia in the patient with severe salicylate poisoning.
Utility and indications for urinary alkalinisation in toxic rhabdomyolysis Value and indications for prophylactic serum alkalinisation in tricyclic antidepressant poisoning Relative efficacy of hyperventilation versus administration of sodium bicarbonate in the management of tricyclic antidepressant toxicity • Precise mechanism by which urinary alkalinisation enhances salicylate elimination
References
Bradberry SM, Thanacoody HK, Watt BE et al. Management of the cardiovascular complications of tricyclic antidepressant poisoning: role of sodium bicarbonate. Toxicological Reviews 2005; 24(3):195–204. Proudfoot AT, Krenzelok EP, Brent J et al. Does urine alkalinization increase salicylate elimination? If so, why? Toxicological Reviews 2003; 22(3):129–136.
4.25 SODIUM CALCIUM EDETATE Calcium disodium versenate, Calcium disodium edetate, Calcium disodium ethylenediaminetetraacetic acid (EDTA) An intravenous heavy metal chelating agent primarily used in the treatment of severe lead poisoning, including lead encephalopathy. Presentations
Sodium calcium edetate 1 g/5 mL ampoules TOXICOLOGICAL INDICATIONS
• • • • •
Lead encephalopathy Severely symptomatic lead poisoning without encephalopathy Asymptomatic or mildly symptomatic lead poisoning (lead level >70 microgram/dL or 3.38 micromol/L) Second-line chelating agent when succimer is either not available or not tolerated by the patient Other heavy metal poisoning (efficacy unknown)
CONTRAINDICATIONS
•
Relative contraindication: anuric renal failure
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ANTIDOTES
CONTROVERSIES
Mechanism of action
EDTA binds to divalent and trivalent metals, the calcium component of EDTA is displaced and a stable water-soluble chelate is formed, which is readily excreted in the urine.
Pharmacokinetics
Absorption of EDTA is incomplete following oral administration and this antidote is only administered by the intravenous route. The volume of distribution is small and approximates that of the extracellular fluid compartment. It is not metabolised. Excretion is urinary and largely dependent on the glomerular filtration rate. With normal renal function, the elimination half-life is 20–60 minutes. ADMINISTRATION
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• • •
Lead encephalopathy — This patient is critically unwell and managed in intensive care. — Commence dimercaprol (BAL) at 4 mg/kg IM every 4 hours and continue for 5 days (see Chapter 4.7: Dimercaprol). — Dilute EDTA 50–75 mg/kg in 500 mL of normal saline or 5% dextrose and infuse over 24 hours starting 4 hours after first dose of dimercaprol. Symptomatic lead poisoning without encephalopathy — This patient is unwell and managed in a high-dependency environment. — Commence dimercaprol (BAL) at 3 mg/kg IM every 4 hours and continue for 5 days (see Chapter 4.7: Dimercaprol). — Dilute EDTA 25–50 mg/kg in 500 mL of normal saline or 5% dextrose and infuse over 24 hours starting 4 hours after first dose of dimercaprol. EDTA therapy is usually continued for a maximum of 5 days. Therapy is then interrupted for 2 to 4 days to allow redistribution of the lead prior to consideration of a further 5-day course. In the setting of encephalopathy, EDTA (and dimercaprol) should be continued until the patient is clinically stable. Once clinically improved, chelation may be switched to oral succimer if tolerated.
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
•
Local pain and thrombophlebitis due to rapid IV administration. Local phlebitis may be minimised by: — Infusing dilute solution (4 hours. • General systemic — Malaise, fatigue, thirst, chills, fever, myalgias, dermatitis, headache, anorexia, urinary frequency, sneezing, nasal congestion, lacrimation, glycosuria, hypotension, transaminase elevations and ECG changes • Nephrotoxicity secondary to the dissociation of EDTA-metal complexes in acid urine. The risk of nephrotoxicity during therapy is reduced by: — Ensuring adequate hydration and urine flow of 1–2 mL/kg/hour — Limiting daily dose to 2 g (1 g in children) — Continuous therapy for no longer than 5 days — Daily monitoring of renal function.
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HANDY TIP
PITFALL
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The asymptomatic patient or minimally symptomatic patient, able to tolerate oral therapy, should be treated with oral succimer rather than EDTA.
•
Inadvertent or mistaken administration of dicobalt edetate, an antidote used in the treatment of cyanide poisoning.
CONTROVERSIES
•
EDTA may cause redistribution of lead from the soft tissues to the CNS. For this reason EDTA is not given as sole therapy for lead toxicity with levels >70 microgram/dL (3.38 micromol/L). • Ability of EDTA chelation to reverse the neurobehavioural effects of lead poisoning is unknown. • Utility of diagnostic EDTA chelation lead mobilisation test to evaluate total body lead burden.
ANTIDOTES
Pregnancy: safety is not established. Administration should not be withheld if clinically indicated. Paediatric: the doses of EDTA are the same for children, but may be diluted in a smaller volume of fluid. Oral succimer is preferred as a chelation agent whenever possible.
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Bradberry S, Vale A. A comparison of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning. Clinical Toxicology 2009; 47:841–858. Treatment guidelines for lead exposure in children: Committee on Drugs. Pediatrics 1995; 96:155–160.
4.26 SODIUM THIOSULFATE Sodium thiosulfate enhances the endogenous cyanide detoxification capacity of the body. It is suitable to use alone in the treatment of mild to moderately severe cases of cyanide poisoning, but should be used in conjunction with other antidotes in severe cyanide toxicity. Presentations
Sodium thiosulfate 12.5 g/50 mL vials TOXICOLOGICAL INDICATIONS
• •
Reasonable suspicion of cyanide poisoning May also be useful in poisoning from other agents including: — Chlorate — Cisplatin — Bromate — Bromine — Iodine
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— Mustard gas — Nitrogen mustard. CONTRAINDICATIONS
•
None: sodium thiosulfate has little toxicity at the recommended doses
Mechanism of action
The major route for detoxification of cyanide is by conversion to thiocyanate. This conversion is catalysed by the enzyme rhodanese. The capacity of rhodanese is limited by the availability of suitable sulfur donors. Sodium thiosulfate acts as a sulfur donor for rhodanese and greatly enhances the endogenous cyanide elimination capacity of the body.
Pharmacokinetics
ANTIDOTES
Thiosulfate is rapidly distributed throughout the extracellular space following intravenous injection. Distribution into the brain is limited. Most is eliminated unchanged by renal excretion, with an elimination half-life of 0.5–3 hours. A small amount is oxidised to sulfate via a two-step hepatic process.
• • •
Place the patient in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care. Administer 12.5 g sodium thiosulfate (50 mL of 25% solution) IV over 10 minutes or 200 mg/kg IV over 10 minutes. Repeat after 30 minutes if clinical features of cyanide toxicity persist.
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ADMINISTRATION
THERAPEUTIC END POINTS
• • •
Improvement in conscious state Haemodynamic stability Improvement in metabolic acidosis
ADVERSE DRUG REACTIONS
• • •
Adverse effects are mild and of minor importance compared with the risks associated with cyanide poisoning. Rapid injection may be associated with nausea and vomiting. Other minor adverse effects associated with thiocyanate production are hypotension, nausea, headache, abdominal pain and disorientation.
SPECIFIC CONSIDERATIONS
Pregnancy: safety is not established. Administration should not be withheld if clinically indicated. Paediatric: the recommended dose of 400 mg/kg is relatively higher than for adults.
HANDY TIPS
• •
Collect blood for cyanide level before antidote administration. The combination of sodium thiosulfate, oxygen and supportive therapy is probably sufficient to treat mild to moderately severe cases of cyanide toxicity.
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Sodium thiosulfate is valuable in doubtful cases of poisoning, such as smoke inhalation, where it may have both therapeutic and diagnostic value. • In severe poisoning sodium thiosulfate should be given together with other antidotes, with which it acts synergistically. CONTROVERSY
•
There are no clinical trials that assess the efficacy of thiosulfate in humans. It has a relatively slow onset of action and should probably be regarded as a second-line antidote for acute cyanide poisoning.
References
4.27 SUCCIMER 2,3-Dimercaptosuccinic acid (DMSA) This orally active metal chelator is used to treat lead and other heavy metal poisoning. Presentations
ANTIDOTES
Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for empiric treatment of cyanide poisoning? Annals of Emergency Medicine 2007; 49:806–813. Reade MC, Davies SR, Morley PT et al. Review article: management of cyanide poisoning. Emergency Medicine Australasia 2012; 24:225–238.
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TOXICOLOGICAL INDICATIONS
•
Adult lead poisoning — Symptomatic — Asymptomatic with blood lead level >60 microgram/dL (>2.9 micromol/L) • Paediatric lead poisoning — Symptomatic — Asymptomatic with blood lead level >45 microgram/dL (2.17 micromol/L) • Other heavy metal poisoning — Has been used to chelate mercury, arsenic, bismuth, antimony and copper, but clinical experience is limited
CONTRAINDICATIONS
• •
Known hypersensitivity Ongoing heavy metal exposure
Mechanism of action
Succimer is a water-soluble analogue of dimercaprol, which binds to heavy metal ions via sulfhydryl groups. The succimer–metal complexes can then be excreted in the urine.
Pharmacokinetics
Following oral administration, succimer is rapidly absorbed and undergoes rapid metabolism. Metabolites and some unchanged drug are excreted in the urine.
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Succimer 100 mg tablets (100), obtained under the Special Access Scheme in Australia
ADMINISTRATION
•
ANTIDOTES
Lead poisoning — May be administered on an outpatient basis. — Give 10 mg/kg orally 3 times per day for 5 days. then — Give 10 mg/kg orally 2 times per day for 14 days. — Blood lead levels are followed after completion of this initial course. — Further courses are indicated if blood levels rebound in the absence of continued lead exposure. — For more severe poisoning, succimer may be used after initial chelation with parenteral agent (sodium calcium edetate) (see Chapter 4.25: Sodium calcium edetate). • Other heavy metal poisoning — In the absence of any guidelines, administration is the same as for lead poisoning.
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT
• •
Hypersensitivity reactions Gastrointestinal upset is very common with this foul-smelling drug — Symptomatic care for gastrointestinal symptoms. — Converting to parenteral therapy may occasionally be necessary. • Transient liver function test abnormalities (occurs in up to 60% of patients) • Reversible neutropenia (rare)
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SPECIFIC CONSIDERATIONS
Pregnancy: safety is not established. Consideration is given to chelation therapy at lower blood levels because of the susceptibility of the fetal central nervous system to lead. Paediatric: the doses for succimer are the same. It is generally accepted that the blood lead level threshold for chelation is lower in children than adults.
HANDY TIPS
•
The asymptomatic patient or minimally symptomatic patient, able to tolerate oral therapy, should be treated with oral succimer rather than sodium calcium edetate. • Succimer can be given on an outpatient basis to compliant patients.
PITFALL
•
It may be difficult to obtain succimer – it is only available in Australia under the Special Access Scheme.
CONTROVERSY
•
The threshold blood lead level for succimer chelation in children is extremely controversial. Although relatively low blood lead levels may have an adverse effect on neurodevelopment, the evidence to date does not suggest that chelation therapy improves outcome.
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References
Bradberry S, Vale A. Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning. Clinical Toxicology 2009; 47; 617–631. Dietrich KN, Ware HH, Salganik M et al. Effect of chelation on the neuropsychological and behavioral development of lead-exposed children after school entry. Pediatrics 2004; 114:19–26. Treatment guidelines for lead exposure in children: Committee on Drugs. Pediatrics 1995; 96: 155–160.
4.28 VITAMIN K Phytomenadione, Phytonadione, Vitamin K1 An essential cofactor in the synthesis of clotting factors II, VII, IX and X. It is used for the reversal of coumadin-induced coagulopathy.
TOXICOLOGICAL INDICATIONS
•
Significant coumadin-induced coagulopathy: — Therapeutic over-warfarinisation — Intentional warfarin overdose — Ingestion of long-acting anticoagulant rodenticides (e.g. brodifacoum)
CONTRAINDICATIONS
•
Known hypersensitivity
Mechanism of action
Phytomenadione is a synthetic fat-soluble analogue of naturally-occurring vitamin K1, an essential cofactor in the synthesis of clotting factors II, VII, IX and X. The coumadin anticoagulants inhibit vitamin K1 2,3-epoxide reductase, thus preventing the formation of vitamin K hydroxyquinone, the active form of vitamin K. This leads to impaired formation of clotting factors. Administration of high doses of vitamin K is able to overcome this effect and restore normal levels of clotting factors.
Pharmacokinetics
Oral bioavailability is variable and dependent on bile salts, but is usually about 50%. It is rapidly metabolised by the liver, with an elimination half-life of about 2 hours. The increase in blood coagulation factors is delayed 6–12 hours after an oral dose and 3–6 hours after an IV dose. ADMINISTRATION
The approach and dosing of Vitamin K varies according to the clinical indication and relative need to maintain anticoagulation. Therapeutic over-warfarinisation • See Appendix 5: Therapeutic over-warfarinisation. Warfarin overdose • No therapeutic requirement for warfarin anticoagulation (patient took someone else’s warfarin) — Give vitamin K 5 mg PO or IV daily for 2 days. — INR can be checked at 48 hours as an outpatient.
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Phytomenadione 2 mg/0.2 mL ampoules Phytomenadione 10 mg/1 mL ampoules
ANTIDOTES
Presentations
ANTIDOTES
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Therapeutic requirement for warfarin anticoagulation — Closely monitor INR (at least every 6 hours). — Give vitamin K 0.5–2 mg IV if INR >5. — Continue close monitoring of INR. — Give repeat doses of vitamin K 0.5–2 mg IV if INR remains at or returns to >5. — Start heparin if INR falls to 9) requires immediate reversal of anticoagulation by administration of prothrombin complex concentrate and fresh frozen plasma, in addition to vitamin K administration to achieve sustained reversal. Minor facial flushing, chest tightness, dyspnoea or dizziness with IV administration Anaphylaxis following IV administration (rare) Warfarin resistance and over-correction of anticoagulation — Manage with heparinisation until warfarin resistance has resolved and therapy can be re-established.
SPECIFIC CONSIDERATIONS
Pregnancy: no restriction on use. Paediatric: treat suspected paediatric ingestion of warfarin tablets (>0.5 mg/kg) empirically with a single dose of vitamin K solution 5 mg PO. This obviates the need for repeated blood tests.
HANDY TIPS
• • •
Never give vitamin K by the intramuscular route. The injectable formulation of vitamin K is suitable for oral administration. Single unintentional acute ingestion of an anticoagulant rodenticide by a child does not involve a sufficient dose to cause anticoagulation. Neither medical assessment nor vitamin K therapy is necessary.
PITFALLS
•
Administration of excessive doses of vitamin K in patients with an absolute indication for anticoagulation. The resulting warfarin resistance necessitates prolonged heparin administration prior to successful reintroduction of warfarin therapy. • Administration of vitamin K prior to demonstration of anticoagulant effect in adults who self-poison with long-acting anticoagulant rodenticides.
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• •
The threshold INR for vitamin K administration following therapeutic over-warfarinisation or warfarin overdose. Duration of therapy in deliberate self-poisoning. Administration of Vitamin K for 2–7 days has been advocated due to prolonged warfarin half-life in overdose.
Baker RI, Coughlin PB, Gallus AS et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Medical Journal of Australia 2004; 181(9):492–497. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Annals of Emergency Medicine 2000; 36(3):262–267. Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms. Journal of Thrombosis and Haemostasis 2006; 4:1853–1863. Isbister GK, Hackett LP, Whyte IM. Intentional warfarin overdose. Therapeutic Drug Monitoring 2003; 25(6):715–722.
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CHAPTER 5
ENVENOMINGS 5.1 Black snake 5.2 Brown snake 5.3 Death adder 5.4 Tiger snake group 5.5 Taipan 5.6 Sea snake 5.7 Australian scorpions 5.8 Bluebottle jellyfish (Physalia species) 5.9 Stonefish 5.10 Box jellyfish 5.11 Irukandji syndrome 5.12 Blue-ringed octopus 5.13 Redback spider 5.14 Funnel-web (big black) spider 5.15 White-tailed spider 5.16 Ticks
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5.1 BLACK SNAKE
ENVENOMINGS
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Pseudechis australis: mulga or king brown snake Pseudechis butleri: Butler’s or yellowbellied black snake Pseudechis colletti: Collett’s snake Pseudechis guttatus: blue-bellied or spotted black snake Pseudechis papuanus: Papuan black snake Pseudechis porphyriacus: red-bellied or common black snake
Mulga snakes are large aggressive snakes found throughout inland and northern Australia. They usually inflict a large, painful bite, produce a significant amount of venom and are potentially lethal. Envenoming by the Collett’s snake is rare, has only been reported in snake handlers and has features of envenoming similar to mulga snakes. Red-bellied black snakes are found along the southeastern coastal areas and the envenoming is not usually lethal, even without treatment. TOXINS
Distribution of mulga snakes
Upper Swan
Perth Hills Moree
Kalgoorlie NOT Eyre Peninsula
Mildura Orange
Distribution of red-bellied black snakes Big Tableland to Mt Elliot Proserpine to Eungella
Bourke
Mulga snake venom contains haemotoxins, myotoxins, neurotoxins and anticoagulant toxins. It has no procoagulant toxins. Red-bellied and bluebellied black snake venoms have less potent toxins.
CLINICAL PRESENTATION AND COURSE
Wilcannia Gladstone
Mulga snake, Collett’s snake, Butler’s snake and Papuan black snake • These snakes characteristically inflict a large, painful bite leading to extensive local tissue swelling. Regional lymphadenitis may develop. • Systemic features of headache, abdominal pain, nausea, vomiting or diarrhoea occur in almost all envenomed patients within a short time of the bite. Generalised myalgia and muscle weakness develop within 6 hours of envenoming and last several days in untreated patients. • Myotoxicity is frequent, peak CK concentrations occur within 24–72 hours of the bite and myoglobinuria may develop.
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Anticoagulant coagulopathy is frequent but clinical features, such as bleeding gums, are rare. Acute haemolysis may occur and result in anaemia, although rarely of sufficient magnitude so as to require a blood transfusion.
See Chapter 2.1: Approach to snakebite for a guide to the principles of snakebite management. Pre-hospital • Apply a pressure bandage with immobilisation (PBI). • Transport to a hospital capable of providing definitive care. Hospital Resuscitation and supportive care • Black snake envenoming is rarely an immediate life-threatening emergency. However, patients should still be managed in an area capable of cardiorespiratory monitoring and resuscitation. • Watch for evidence of myotoxicity. Antivenom • CSL monovalent Black Snake Antivenom (see Chapter 6.1) is used to treat envenoming by mulga, Collett’s, Butler’s and Papuan black snakes. Early administration (within 3 hours of the bite) appears to prevent myotoxicity. • Administration of one ampoule (18,000 units) of CSL monovalent Black Snake Antivenom is indicated following early presentation after a bite by one of the above snakes where there are systemic symptoms of envenoming, laboratory evidence of anticoagulant coagulopathy or laboratory evidence of myotoxicity (CK rise above 1000 IU/L). • CSL monovalent Tiger Snake Antivenom or CSL monovalent Black Snake Antivenom (see Chapters 6.1 and 6.4) is used to treat envenoming by red-bellied and blue-bellied black snakes. The antivenoms are equally effective but Tiger Snake Antivenom has the advantages of being more widely available, cheaper and of lower volume. • Administration of CSL monovalent Tiger Snake Antivenom or CSL monovalent Black Snake Antivenom is indicated following early
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ENVENOMINGS
Red-bellied and blue-bellied black snakes • Envenoming by the red-bellied or blue-bellied black snake is usually associated with local pain along with systemic symptoms including nausea, vomiting and abdominal pain. • A small proportion of cases develop myotoxicity. This is usually characterised by myalgias and a minor CK rise but is occasionally more severe. • Anticoagulant coagulopathy may occur but is not usually associated with clinically significant bleeding. • Minor, but unpleasant, long-term neurological sequelae, such as anosmia and areas of numbness, paraesthesia or pain in the region of the bite site, are reported.
presentation after a bite by a red-bellied or blue-bellied black snake where there are significant systemic symptoms or laboratory evidence of anticoagulant coagulopathy. Early administration (within 4 hours of the bite) may prevent myotoxicity. INVESTIGATIONS
ENVENOMINGS
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The diagnosis of envenoming is based on the correlation of history, clinical features and laboratory data. Routine laboratory investigations following snakebite include: FBC, EUC, CK and coagulation profile (INR, APTT, fibrinogen, d-dimer) at presentation and at intervals thereafter (see Chapter 2.1: Approach to snakebite). • CK is used as a marker of myotoxicity. However, it may not become grossly abnormal (>1000 IU/L) for many hours. CK levels are repeated every 6 hours if the patient is symptomatic. If the patient is asymptomatic with mild elevation of CK or APTT, recheck every 12 hours. • The anticoagulant coagulopathy of black snake envenoming is characterised by: — Elevated APTT and INR (usually mild) — Normal fibrinogen — Normal d-dimer and fibrin degradation products — Normal platelet count. • The Snake Venom Detection Kit (SVDK) is not used to diagnose envenoming. Instead, it is used to determine the correct monovalent antivenom if one or more snake types could be responsible for the observed clinical features.
DIFFERENTIAL DIAGNOSIS
• •
Elevation of the CK may also be observed in taipan and tiger snake envenoming. In contrast to the venom-induced consumptive coagulopathy (VICC) observed in brown, taipan and tiger snake envenoming, the abnormalities of APTT and INR in black snake envenoming are usually mild and the d-dimer and fibrinogen level normal. • Death adders may cause a painful bite. Presentation may include early clinical features of a symmetrical descending flaccid paralysis (e.g. ptosis or diplopia), but myotoxicity and coagulation defects do not occur.
DISPOSITION AND FOLLOW-UP
•
All patients must be admitted for observation to a hospital capable of providing definitive care (see Chapter 2.1: Approach to snakebite). • Patients who have no clinical features and no laboratory evidence of myotoxicity at 12 hours are not envenomed and may be discharged. Discharge should not occur at night.
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Envenomed patients may be discharged following antivenom administration if they are clinically well, their coagulation studies and CK are improving, and there is no evidence of clinically significant renal failure.
HANDY TIPS
•
PITFALLS
•
Failure to recognise that snakebite may have occurred, institute early PBI or to manage the patient in a hospital setting for an appropriate duration. • Inaccurate snake identification. • Misinterpretation of a SVDK result. • Administration of antivenom to a patient who is not envenomed.
ENVENOMINGS
The mulga snake is sometimes referred to as the king brown snake; however, it is not a brown snake and Brown Snake Antivenom should not be administered. • Envenoming by the red-bellied black snake or blue-bellied black snake is frequently mild and antivenom may not be indicated. If antivenom is indicated, Tiger Snake Antivenom may be used as an alternative to Black Snake Antivenom. • Envenoming by an Australian snake, associated with local pain, headache, nausea and vomiting, and a mild anticoagulant coagulopathy (increased APTT but normal fibrinogen), is highly suggestive of black snake envenoming.
• The point at which slowly evolving myotoxicity is treated with antivenom. Antivenom prevents progression of muscle injury, but does not reverse injury that has already occurred. Many experienced clinicians treat with antivenom if CK exceeds 1000 IU/L. However, early administration of antivenom (within 5 hours of the bite) may prevent myotoxicity altogether. • The indications for antivenom administration following red-bellied black snake envenoming and the antivenom of choice (Tiger or Black Snake Antivenom).
References
Churchman A, O’Leary MA, Buckley NA et al. Clinical effects of red-bellied black snake (Pseudechis porphyriacus) envenoming and correlation with venom concentrations: Australian Snakebite Project (ASP-11). Medical Journal of Australia 2010; 193:696–700. Currie BJ. Snakebite in tropical Australia: a prospective study in the ‘Top End’ of the Northern Territory. Medical Journal of Australia 2004; 181:693–697. Johnston CI, Brown SGA, O’Leary MA et al. Mulga snake (Pseudechis australis) envenoming: a spectrum of myotoxicity, anticoagulant coagulopathy, haemolysis and the role of early antivenom therapy – Australian Snakebite Project (ASP-19). Clinical Toxicology 2013; 51:417–424. White J. A clinician’s guide to Australian venomous bites and stings: Incorporating the updated CSL antivenom handbook. Melbourne: CSL Ltd, 2012.
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5.2 BROWN SNAKE
ENVENOMINGS
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Pseudonaja affinis: dugite Pseudonaja guttata: spotted brown snake Pseudonaja inframacula: peninsula brown snake Pseudonaja ingrami: Ingram’s brown snake Pseudonaja mengdeni: western brown snake or gwardar Pseudonaja modesta: ringed brown snake Pseudonaja nuchalis: tropical brown snake Pseudonaja textilis: eastern brown snake
Distribution of brown snakes
Rottnest Island
Brown snakes are the most common cause of severe envenoming and death from snakebite in Australia. The most important manifestation of envenoming is venom-induced consumptive coagulopathy (VICC). TOXINS
The venom contains procoagulants, cardiotoxins and a potent presynaptic neurotoxin (textilotoxin).
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Patients may present asymptomatic with no obvious bite site. Non-specific systemic features of envenoming include headache, nausea, vomiting and abdominal pain. Envenoming may be heralded by pre-syncope or sudden collapse. Early death occurs rarely, probably secondary to direct cardiotoxicity. The hallmark of brown snake envenoming is VICC. This develops soon after the bite and may manifest clinically as bleeding gums, persistent haemorrhage at venesection sites or intracerebral haemorrhage. Partial VICC occurs in about 20% of brown snake envenomings. • Thrombotic microangiopathy, characterised by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and acute renal failure, occurs in about 10% of brown snake envenomings. Oliguria may be present from the time of envenoming. • Myotoxicity does not occur and significant neurotoxicity is rare, despite the presence of a neurotoxin in the venom. Mild diplopia and ptosis are observed occasionally.
MANAGEMENT
See Chapter 2.1: Approach to snakebite for a guide to the principles of snakebite management. Pre-hospital • Apply a pressure bandage with immobilisation (PBI). • Transport to a hospital capable of providing definitive care.
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Hospital Resuscitation and supportive care • Brown snake envenoming is a potentially life-threatening emergency and patients should be managed in an area capable of cardiorespiratory monitoring and resuscitation. • Potential early life-threats that require immediate intervention include: — Hypotension — VICC with uncontrolled haemorrhage. • In cardiac arrest secondary to brown snake envenoming, undiluted antivenom administered as a rapid IV push may be life saving. Antivenom • CSL Brown Snake Antivenom (see Chapter 6.2) is the specific treatment of envenoming. A dose of one ampoule (1000 units) is indicated for systemic envenoming, as evidenced by collapse or objective clinical evidence of VICC or partial VICC.
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The diagnosis of envenoming is based on the correlation of history, clinical features and laboratory data. Envenoming is diagnosed if there is a history of collapse, objective clinical evidence of VICC or laboratory abnormalities consistent with brown snake envenoming during 12 hours of observation. Routine laboratory investigations following snakebite include: FBC, EUC, CK and coagulation profile (INR, APTT, fibrinogen, d-dimer) at presentation and at intervals thereafter (see Chapter 2.1: Approach to snakebite). ‘Complete’ VICC is defined as: — Elevated INR (at least >3 but usually unrecordable) — Undetectable fibrinogen — Elevated d-dimer (>100 × normal). ‘Partial VICC’ is defined as: — INR abnormal but