Toxicology Handbook [2nd Edition] 0729539393, 9780729579391, 9780729539395

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TOXICOLOGY HANDBOOK

     

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TOXICOLOGY HANDBOOK Second edition Lindsay Murray | Frank Daly | Mark Little | Mike Cadogan

Sydney  Edinburgh  London  New York  Philadelphia  St Louis  Toronto

Churchill Livingstone is an imprint of Elsevier

Elsevier Australia. ACN 001 002 357 (a division of Reed International Books Australia Pty Ltd) Tower 1, 475 Victoria Avenue, Chatswood, NSW 2067 This edition © 2011 Elsevier Australia This publication is copyright. Except as expressly provided in the Copyright Act 1968 and the Copyright Amendment (Digital Agenda) Act 2000, no part of this publication may be reproduced, stored in any retrieval system or transmitted by any means (including electronic, mechanical, microcopying, photocopying, recording or otherwise) without prior written permission from the publisher. Every attempt has been made to trace and acknowledge copyright, but in some cases this may not have been possible. The publisher apologises for any accidental infringement and would welcome any information to redress the situation. This publication has been carefully reviewed and checked to ensure that the content is as accurate and current as possible at time of publication. We would recommend, however, that the reader verify any procedures, treatments, drug dosages or legal content described in this book. Neither the author, the contributors, nor the publisher assume any liability for injury and/or damage to persons or property arising from any error in or omission from this publication. National Library of Australia Cataloguing-in-Publication Data ___________________________________________________________________ Title: Toxicology handbook / Lindsay Murray ... [et al.]. Edition: 2nd ed. ISBN: 9780729539395 (pbk.) Notes: Includes index. Subjects: Toxicology--Australia--Handbooks, manuals, etc. Toxicology--Oceania--Handbooks, manuals, etc. Other Authors/Contributors: Murray, Lindsay. Dewey Number: 571.95 ________________________________________________________________ Publisher: Sophie Kaliniecki Developmental Editor: Neli Bryant Publishing Services Manager: Helena Klijn Project Coordinator: Geraldine Minto Edited by Sybil Kesteven Proofread by Kerry Brown Cover design by Georgette Hall Internal design and typesetting by TnQ Books and Journals Index by Robert Swanson Printed by 1010 Printing International Limited

CONTENTS Foreword Preface Authors Contributors Reviewers CHAPTER 1 APPROACH TO THE POISONED PATIENT

1.1 Overview 1.2 Resuscitation 1.3 Risk assessment 1.4 Supportive care and monitoring 1.5 Investigations 1.6 Gastrointestinal decontamination 1.7 Enhanced elimination 1.8 Antidotes 1.9 Disposition

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 Approach to 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 abuse, dependence and withdrawal 2.13 Amphetamine abuse, dependence and withdrawal 2.14 Opioid dependence and withdrawal 2.15 Sedative-hypnotic dependence and withdrawal 2.16 Solvent abuse, dependence and withdrawal 2.17 Body packers and stuffers 2.18 Osmolality and the 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

CHAPTER 3 SPECIFIC TOXINS

3.1 Alcohol: Ethanol 3.2 Alcohol: Ethylene glycol 3.3 Alcohol: Isopropanol (isopropyl alcohol) 3.4 Alcohol: Methanol (methyl alcohol) 3.5 Alcohol: Other toxic alcohols 3.6 Amiodarone 3.7 Amisulpride

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2 4 10 13 15 17 24 29 30 36 44 50 55 59 61 62 66 72 76 80 85 93 94 97 100 104 107 109 113 119 120 126 130 133 136 138 142 144 146

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3.8 Amphetamines 3.9 Angiotensin converting enzyme inhibitors 3.10 Anticoagulant rodenticides 3.11 Anticonvulsants: Newer agents 3.12 Antihistamines (non-sedating) 3.13 Antihistamines (sedating) 3.14 Arsenic 3.15 Beta-blockers 3.16 Baclofen 3.17 Barbiturates 3.18 Benzodiazepines 3.19 Benztropine 3.20 Bupropion 3.21 Button batteries 3.22 Calcium channel blockers 3.23 Cannabinoids (marijuana) 3.24 Carbamazepine 3.25 Carbon monoxide 3.26 Chloroquine and hydroxychloroquine 3.27 Chloral hydrate 3.28 Clonidine 3.29 Clozapine 3.30 Cocaine 3.31 Colchicine 3.32 Corrosives 3.33 Cyanide 3.34 Digoxin: Acute overdose 3.35 Digoxin: Chronic poisoning 3.36 Diphenoxylate-atropine 3.37 Gamma-hydroxybutyrate (GHB) 3.38 Glyphosate 3.39 Hydrocarbons 3.40 Hydrofluoric acid 3.41 Hydrogen peroxide 3.42 Insulin 3.43 Iron 3.44 Isoniazid 3.45 Lead 3.46 Lithium—acute overdose 3.47 Lithium—chronic poisoning 3.48 Local anaesthetic agents 3.49 Mercury 3.50 Metformin 3.51 Methotrexate 3.52 Mirtazapine 3.53 Monoamine oxidase inhibitors (MAOIs) 3.54 Non-steroidal anti-inflammatory drugs (NSAIDs) 3.55 Olanzapine 3.56 Opioids 3.57 Organochlorines 3.58 Organophosphorus agents (organophosphates   and carbamates) 3.59 Paracetamol: Acute overdose 3.60 Paracetamol: Repeated supratherapeutic ingestion

148 152 154 157 159 162 164 168 171 173 177 179 181 184 186 190 193 196 200 202 205 208 210 214 216 219 222 226 230 232 235 237 240 244 247 250 254 256 260 263 265 269 273 276 279 280 284 287 290 295 298 302 312

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 Glucagon 4.13 Glucose 4.14 Hydroxocobalamin 4.15 Insulin (high dose) 4.16 Intravenous lipid emulsion 4.17 Methylene blue 4.18 N-acetylcysteine 4.19 Naloxone 4.20 Octreotide 4.21 Penicillamine 4.22 Physostigmine 4.23 Pralidoxime 4.24 Pyridoxine 4.25 Sodium bicarbonate 4.26 Sodium calcium edetate 4.27 Sodium thiosulfate 4.28 Succimer 4.29 Vitamin K

CHAPTER 5 ENVENOMINGS

5.1 Black snake 5.2 Brown snake

372 373 376 377 379 381 383 385 387 389 391 392 394 396 398 400 401 403 406 408 410 411 413 415 417 420 422 424 426 430 433

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CHAPTER 4 ANTIDOTES

316 320 323 326 328 331 334 336 340 343 346 348 352 354 357 361 364 368

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3.61 Paraquat 3.62 Phenothiazines and butyrophenones (antipsychotic agents) 3.63 Phenytoin 3.64 Potassium chloride 3.65 Quetiapine 3.66 Quinine 3.67 Risperidone 3.68 Salicylates 3.69 Selective serotonin reuptake inhibitors (SSRIs) 3.70 Strychnine 3.71 Sulfonylureas 3.72 Theophylline 3.73 Thyroxine 3.74 Tramadol 3.75 Tricyclic antidepressants (TCAs) 3.76 Valproic acid (sodium valproate) 3.77 Venlafaxine and desvenlafaxine 3.78 Warfarin

5.3 Death adder 5.4 Tiger snake 5.5 Taipan 5.6 Sea snake 5.7 Australian scorpions 5.8 Bluebottle jellyfish (Physalia species) 5.9 Stonefish 5.10 Box jellyfish (Chironex fleckeri) 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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CHAPTER 6 ANTIVENOMS

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6.1 CSL Black Snake Antivenom 6.2 CSL Brown Snake Antivenom 6.3 CSL Death Adder Antivenom 6.4 CSL Tiger Snake Antivenom 6.5 CSL Taipan Antivenom 6.6 CSL Sea Snake Antivenom 6.7 CSL Polyvalent Snake Antivenom 6.8 CSL Stonefish Antivenom 6.9 CSL Box Jellyfish Antivenom 6.10 CSL Redback Spider Antivenom 6.11 CSL Funnel-web Spider Antivenom

436 439 442 445 447 449 450 452 454 457 459 461 463 465 470 471 473 475 477 479 481 482 484 486 488

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vi APPENDICES

Appendix 1: Poisons information telephone numbers Appendix 2: Example ECGs Appendix 3: Conversion factors and therapeutic ranges   for important toxins Appendix 4: Alcohol pathways Appendix 5: Theraupeutic over-warfarinisation Appendix 6: Management of allergic reactions to antivenoms

492 493 498 499 500 502

Index

503

FOREWORD Poisoning is a common emergency department presentation, and the third major injury cause of hospital admissions after falls and motor vehicle crashes. Alcohol, benzodiazepines, antidepressants, paracetamol and heroin are frequently involved, yet there are literally thousands of hazardous substances that can be ingested, as well as envenomings by terrestrial animals and sea creatures. The challenge for the emergency physician is to be able to recognise the poisoned patient, provide supportive care, administer a specific antidote in a minority of cases, escalate management up to a full intensive care level when necessary, and know when a patient is safe to be ‘medically cleared’ pending a thorough psychiatric examination (in cases of deliberate self-harm). This presents a huge challenge to any doctor, who individually may infrequently see a severe poisoning and/or can be confronted with a first case of a particular type. Clinical Toxicology has developed rapidly as a subspecialty of Emergency Medicine in Australasia, led by a small group of expert clinicians dedicated to providing information, advice, research and teaching in this important area. The authors are in the vanguard of this group. All regularly direct and assist toxicology patient care in emergency departments, intensive care units and small rural hospitals across the country, locally as well through the national Poisons Information Centres. Their risk assessment-based approach is maintained in this new version that builds on the success of the first edition. This handbook has been updated and expanded with the addition of many new chapters, yet it retains its award-winning format recognised for its lucidity and readability. The compact size of the book belies the true wealth of clear, practical evidence-based information covering a vast array of poisonings and their management in a logical, consistent format. This book should live in the pocket or at the bedside, be used daily and be referred to as a prevailing standard of care not just in Australasia, but internationally. With the exception of some envenomings, the book will be just as valuable to clinicians in the UK, Europe and Asia as no doubt it will again prove to be here in Australasia. It is a truly outstanding text that will improve the care of poisoned patients to their benefit, and the reader’s edification. Professor Anthony FT Brown MB ChB, FRCP, FRCS(Ed), FACEM, FCEM Senior Staff Specialist, Department of Emergency Medicine, Royal Brisbane and Women’s Hospital Professor, Discipline of Anaesthesiology and Critical Care, University of Queensland Editor-in-Chief, Emergency Medicine Australasia Senior Court of Examiners, ACEM August 2010

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PREFACE

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The overwhelmingly enthusiastic response to the first edition of the Toxicology Handbook confirmed the need amongst emergency medical personnel for readily accessible and practical toxicology information in the context of a systematic approach to the care of the poisoned patient. Feedback from the users of the handbook from Poisons Information Centres and Emergency Departments in urban, regional and rural settings has allowed us to expand and refine the factual information for the second edition while retaining the standardised formats and risk assessment based approach of the first edition. Routine use of the handbook by junior medical staff in our own Emergency Departments and Toxicology Units in Perth has allowed us to refine any written advice that is potentially liable to misinterpretation by inexperienced users. For the second edition we have added chapters to provide an approach to poisoning by plants and mushrooms and an approach to dealing with the issues of drug dependence, tolerance and withdrawal that frequently complicate management of the poisoned patient. We have also added new chapters for a number of important specific toxins and antidotes, and extensively revised the envenoming chapters in the light of recently published research. Our sincere hope is that the Toxicology Handbook continues to contribute to excellence in the provision of care of the poisoned patient.

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Lindsay Murray Frank Daly Mark Little Mike Cadogan Jason Armstrong

Kerry Hoggett David McCoubrie Mark Monaghan Jessamine Soderstrom Ovidiu Pascu

A UTHORS Lindsay Murray MBBS FACEM, Consultant Emergency Physician and Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA; Clinical Associate Professor of Emergency Medicine, University of Western Australia Frank Daly MBBS FACEM, Consultant Clinical Toxicologist, Emergency Physician and Director of Clinical Service Redesign, Royal Perth Hospital; Professor in Emergency Medicine, University of Western Australia; Consultant Clinical Toxicologist WA and NSW Poisons Information Centres Mark Little MBBS DTM&H (Lond) FACEM MPH&TM IDHA, Consultant Emergency Physician and Clinical Toxicologist, Royal Perth Hospital; Clinical Senior Lecturer in Emergency Medicine, University of Western Australia; Consultant Clinical Toxicologist, WA and NSW Poisons Information Centres Mike Cadogan MA (Oxon) MBChB FACEM, Consultant Emergency Physician, Sir Charles Gairdner Hospital, Perth

CONTRIBUTORS Jason Armstrong MBChB FACEM, Consultant Emergency Physician and Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth; Clinical Senior Lecturer in Emergency Medicine, University of Western Australia; Medical Director, WA Poisons Information Centre; Consultant Clinical Toxicologist, NSW Poisons Information Centre Kerry Hoggett MBBS GCertClinTox FACEM, Emergency Physician, Clinical Toxicology Fellow, Royal Perth Hospital David McCoubrie MBBS FACEM, Consultant Emergency Physician and Clinical Toxicologist, Royal Perth Hospital; Consultant Clinical Toxicologist, WA and NSW Poisons Information Centres Mark Monaghan MBBS FACEM, Consultant Emergency Physician and Fellow in Clinical Toxicology 2005–2007, Fremantle Hospital; Consultant Clinical Toxicologist, WA and NSW Poisons Information Centres Jessamine Soderstrom MBBS FACEM Grad Cert Toxicology, Clinical Toxicologist, Emergency Physician, Royal Perth Hospital, Perth, Clinical Senior Lecturer, University of Western Australia Ovidiu Pascu MD FACEM, Consultant Emergency Physician and Clinical Toxicologist, Sir Charles Gairdner Hospital, WA, WA and NSW Poisons Information Centres; Clinical Senior Lecturer in Emergency Medicine, University of Western Australia

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REVIEWERS Belinda Bray PhD, Lecturer, Science Communication, University of Auckland Philip G. Kerr PhD, Lecturer in Medicinal Chemistry, School of Biomedical Sciences, Charles Sturt University; Australasian Regional Representative for International Council for Medicinal and Aromatic Plants (ICMAP) Ian Spence BSc PhD, Associate Dean (International), Faculty of Science and Honorary Associate Professor, Discipline of Pharmacology, Sydney Medical School, The University of Sydney Scott Twaddell BMedSc(Hons) BMed GCClinTox FRACP, Clinical Pharmacologist and Toxicologist, Respiratory and General Physician, Staff Specialist Physician, John Hunter Hospital and Calvary Mater Newcastle Hospital; Conjoint Lecturer in Medicine, University of Newcastle

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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

 verview O Resuscitation Risk assessment Supportive care and monitoring Investigations Gastrointestinal decontamination Enhanced elimination Antidotes Disposition

2 4 10 13 15 17 24 29 30

APPROACH TO THE POISONED PATIENT

2 2 TOXICOLOGY HANDBOOK

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 which 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 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. Separate chapters cover the pharmaceutical, chemical and natural toxins of most importance to the practitioner in emergency departments in Australia and New Zealand. It 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 over 30 000 patients in the Western Australian Toxicology Service and offered consultation in over 12 000 acute poisonings across Australia and overseas via the Western Australian, New South Wales and Queensland Poisons Information Centres (PICs). The agents covered are carefully selected to cover all common poisonings, rare but life-threatening poisonings, 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 physician 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.

APPROACH TO THE POISONED PATIENT

Resuscitation Airway Breathing Circulation Detect and correct — hypoglycaemia — seizures — hyper-/hypothermia Emergency antidote administration Risk assessment Agent Dose Time since ingestion Clinical features and course Patient factors Supportive care and monitoring Investigations Screening—12-lead ECG, paracetamol Specific Decontamination Enhanced elimination Antidotes Disposition

3 TOXICOLOGY HANDBOOK

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 should continue until expert advice can be obtained. Cardiopulmonary bypass has been used successfully in a number of poisonings. Attempts at decontamination of the skin or gastrointestinal tract 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 conscious state, loss of airway protective reflexes and hypotension are common threats to life in the poisoned patient. TABLE 1.2.1 Resuscitation Airway Breathing Circulation Detect and correct: Seizures Always generalised when due to toxicologic causes Benzodiazepines first-line Hypoglycaemia Check bedside blood sugar level (BSL) in all patients with altered mental status Treat if BSL 38.5°C prompts urgent intervention Emergency antidote administration

DETECT AND CORRECT SEIZURES Toxic seizures are generalised, and can usually be controlled with intravenous benzodiazepines (e.g. diazepam, midazolam, lorazepam or clonazepam). The most common causes of seizures in poisoned patients in Australasia are venlafaxine, bupropion, tramadol and amphetamines. The presence of focal or partial seizures indicates a focal neurological disorder that is either a complication of poisoning or due to a nontoxicologic cause, and prompts further investigation. Barbiturates are second-line therapy for refractory seizures in acute poisoning. Pyridoxine is a third-line agent that may be indicated in intractable seizures secondary to isoniazid. Phenytoin is contraindicated in the management of seizures related to acute poisoning.

DETECT AND CORRECT HYPOGLYCAEMIA Hypoglycaemia is an easily detectable and correctable cause of significant neurological injury. Bedside serum glucose estimation should be performed as soon as possible in all patients with altered mental status. If the serum 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 serum glucose measurement. Hypoglycaemia in acute poisoning is associated with insulin, sulfonylurea oral hypoglycaemic agents, beta-blockers, quinine, chloroquine, salicylates and valproic acid.

DETECT AND CORRECT HYPER-/HYPOTHERMIA Hyperthermia is associated with a number of life-threatening acute poisonings and is associated with poor outcome.

APPROACH TO THE POISONED PATIENT

5 TOXICOLOGY HANDBOOK

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-Verbal-Pain-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 12. 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).

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TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply Life-threat

Mechanism

Agent(s)

Comments

Corrosive injury to oropharynx

l Alkalis l Acids l Glyphosate l Paraquat

l Stridor,

Acidosis Acidaemia

Various

l Ethylene glycol l Methanol l Salicylates

l Until

Hypoventilation

Opioid mu receptor stimulation

l Opioids

l Prompt

Respiratory failure

Cholinergic crisis

l Carbamates l Nerve agents l Organophosphates

l Rapid

AIRWAY

Airway compromise

dysphagia and dysphonia indicate airway injury and potential for imminent airway compromise l Early endotracheal intubation or surgical airway often required

BREATHING

late in the clinical course there is usually prominent respiratory compensation l Intubation and ventilation at standard settings may worsen acidaemia and precipitate rapid clinical deterioration, if not death. l Avoid normo- or hypoventilation l Maintain hyperventilation and consider bolus IV NaHCO3 1–2 mmol/kg to prevent worsening of acidaemia administration of naloxone may obviate need for intubation and ventilation administration of atropine by serial doubling of atropine dose to achieve dry respiratory secretions may restore adequate oxygenation

Acidosis; Hypoxaemia; Multiple organ failure (MOF)

Oxygen-free radical mediated cellular injury, particularly type II pneumocytes

l Paraquat

l Avoid supplemental oxygen l If hypoxia occurs, titrate supplemental

Ventricular fibrillation

Hypocalcaemia

l Hydrofluoric

l Defibrillation alone unlikely to be efficacious l Bolus IV calcium (e.g. 60–90 mL 10% calcium

Ventricular tachycardia

Fast Na+ channel blockade

oxygen to maintain oxygen saturation of ~90% or PaO2 60 mmHg

CIRCULATION

acid ingestion or massive cutaneous burn

l Chloroquine l Cocaine l Flecainide l Local anaesthetic

agents

l Procainamide l Propranolol l Quinine l Tricyclic

antidepressants

Ventricular ectopy/ Ventricular tachycardia

Halogen-induced myocardial sensitisation to catecholamines

l Chloral hydrate l Organochlorines

gluconate) repeated as required every 2 minutes until defibrillation restores perfusing rhythm

l Cardioversion

or defibrillation unlikely to be efficacious l Urgently intubate and hyperventilate l Bolus IV NaHCO3 1–2 mmol/kg repeated every 1–2 minutes until restoration of perfusing rhythm l Do not await determination of serum pH prior to intubation and NaHCO3 boluses l Lignocaine is third-line therapy when pH is established at >7.5 l Amiodarone and Vaughan Williams type Ia antiarrhythmic agents (e.g. procainamide) are contraindicated l Cardioversion

or defibrillation unlikely to be efficacious l Administer IV beta-blockers, titrate to ectopy response Continued

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APPROACH TO THE POISONED PATIENT

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TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply—cont’d Life-threat

Mechanism

Agent(s)

Comments

Refractory hypotension

Various

l Beta-blockers l Calcium channel

l High-dose

insulin–dextrose therapy

blockers anaesthetic agents

l Local

Tachycardia

Central and peripheral sympathomimetic response

l Amphetamines l Cocaine

l Beta-blockers contraindicated l Administer IV benzodiazepines,

Supraventricular tachycardia

Adenosine antagonism

l Theophylline

l Urgent

Hypertension

Central and peripheral sympathomimetic response

l Amphetamines l Cocaine

l Beta-blockers contraindicated l Administer IV benzodiazepines,

Asystole Bradycardia Tachycardia

Na+/K+ ATPase pump inhibition

l Digoxin

l Usual resuscitation interventions l Digoxin-specific antibodies

sedation and heart rate control

titrated to gentle

haemodialysis indicated

titrated to gentle sedation and heart rate control l If further therapy necessary use agents that can be given by titratable intravenous infusion — Glycerol trinitrate (GTN) — Phentolamine — Nitroprusside futile

Bradycardia Hypotension Cardiac conduction defects

Calcium channel blockade

l Calcium

Acute coronary syndrome

Central and peripheral sympathomimetic response

l Amphetamines l Cocaine

Hyperkalaemia

Na+/K+ ATPase pump inhibition

l Digoxin

l Calcium salts are contraindicated l Digoxin-specific antibodies

Hypoglycaemia

Hyperinsulinaemia

l Sulfonylureas

l Difficult

Refractory seizures

Inhibition of GABA production

l Isoniazid

l IV

Seizures

Adenosine antagonism

l Theophylline

l Urgent

blockers

channel

l Atropine and pacing unlikely to be efficacious l 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 l High-dose insulin–dextrose therapy l Beta-blockers contraindicated l Benzodiazepines l GTN l Antiplatelet and anticoagulation

therapy if no neurological deficits (otherwise cranial CT first) l Reperfusion therapy along conventional lines

OTHER

to maintain euglycaemia with dextrose supplementation alone l Octreotide administration obviates need for dextrose supplementation pyridoxine 1 g per gram of isoniazid ingested, up to 5 g

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haemodialysis indicated

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10 10 TOXICOLOGY HANDBOOK

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 l Life-threatening slow-release verapamil or diltiazem ingestions l Symptomatic arsenic trioxide ingestion l Lead ingestion l ‘Body packers’ (see Chapter 2.17: Body packers and stuffers)

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. Complications l Nausea,

l Non-anion

Contraindications l Risk

assessment suggests good outcome can be assured with supportive care and antidote therapy l Uncooperative patient l Inability to place a nasogastric tube l Uncontrolled vomiting l Risk assessment suggests potential for decreased conscious state or seizure in the subsequent four hours l Ileus or intestinal obstruction l Intubated and ventilated patient (relative contraindication). Technique l Assign

a single nurse to carry out procedure (this is a full-time job for up to 6 hours) l Obtain sufficient supplies of PEG-ELS and make up solution as directed l Place nasogastric tube l Give activated charcoal 50 g (children 1 g/kg) via the nasogastric tube in non-metallic ingestions l Administer PEG solution via the nasogastric tube at 2 L/hour (children 25 mL/kg/hour) l Administer metoclopramide to minimise vomiting and enhance gastric emptying l Position patient on a commode if possible to accommodate explosive diarrhoea l Continue irrigation until the effluent is clear. This may take up to 6 hours l Cease whole bowel irrigation if abdominal distension or loss of bowel sounds are noted

23 TOXICOLOGY HANDBOOK

vomiting and abdominal bloating gap metabolic acidosis l Pulmonary aspiration l Distraction from resuscitation and supportive care priorities l Delayed retrieval to a hospital offering definitive care.

APPROACH TO THE POISONED PATIENT

TABLE 1.6.4 Whole bowel irrigation potentially useful

APPROACH TO THE POISONED PATIENT

24 24 TOXICOLOGY HANDBOOK

l Abdominal

x-ray is useful to assess effectiveness of decontamination of radio-opaque substances such as iron and potassium salts l 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 2004; 43:61–87. American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists. Position Paper: Ipecac syrup. Clinical Toxicology 2004; 42:133–143. American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists. Position Paper: Gastric lavage. Clinical Toxicology 2004; 42:933–943. Bailey B. Gastrointestinal decontamination triangle. Clinical Toxicology 2005; 1:59–60.

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: l Severe toxicity l Poor outcome despite good supportive care/antidote administration l Slow endogenous rates of elimination l Suitable pharmacokinetic properties. 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.

Haemodialysis and haemofiltration Lithium Metformin lactic acidosis Potassium Salicylate Theophylline Toxic alcohols Valproic acid Charcoal haemoperfusion Theophylline

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: l Interruption of entero-hepatic 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 entero-hepatic circulation but also has a relatively small volume of distribution l 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. Indications

Enhanced elimination by this technique has been proposed as clinically useful in the following scenarios: l 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

APPROACH TO THE POISONED PATIENT

Multiple-dose activated charcoal Carbamazepine Dapsone Phenobarbitone Quinine Theophylline Urinary alkalinisation Phenobarbitone Salicylate

25 TOXICOLOGY HANDBOOK

TABLE 1.7.1 Techniques of enhanced elimination and amenable agents

APPROACH TO THE POISONED PATIENT

26 26 TOXICOLOGY HANDBOOK

l Phenobarbitone

coma — Rare — Used in the in the expectation that enhanced elimination will reduce duration of ventilation and length of stay in intensive care l Dapsone overdose with methaemoglobinaemia — Very rare — MDAC may enhance elimination of dapsone and reduce the duration of severe prolonged methaemoglobinaemia l Quinine overdose — Although MDAC might enhance drug elimination, good outcome can be expected with aggressive supportive care l Theophylline overdose — Attempts at enhanced elimination with MDAC should never delay more effective elimination with haemodialysis following lifethreatening overdose.

Absolute contraindications l Decreased

level of consciousness or anticipated decreased level of consciousness without prior airway protection l Bowel obstruction Complications

Although rare in carefully selected patients, they may include: l Vomiting (30%) l Charcoal aspiration, especially if there is decreased mental status or seizures l Constipation l Charcoal bezoar formation, bowel obstruction, bowel perforation (rare) l Corneal abrasion l Distraction of attending staff from resuscitation and supportive care priorities. Technique l Give

an initial dose of activated charcoal 50 g (adults) or 1 g/kg (children) PO l Give repeat doses of 25 g (0.5 g/kg in children) every 2 hours l In the intubated patient, activated charcoal is given via oro- or nasogastric tube after tube placement has been confirmed on chest x-ray l Check for bowel sounds prior to administration of each dose l Cease further administration if bowel sounds are inaudible l Reconsider the indications and clinical end points for therapy every 6 hours. MDAC should rarely be required beyond 6 hours.

The production of an alkaline urine pH promotes the ionisation of highly 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. l Salicylate overdose — Salicylates are normally eliminated by hepatic metabolism and fail to be 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. l 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 superior. Contraindications l Fluid

overload.

Complications l Alkalaemia

(usually well-tolerated)

l Hypokalaemia

l Hypocalcaemia

(not usually clinically significant).

Technique l Correct

hypokalaemia if present 1–2 mmol/kg sodium bicarbonate IV bolus l Commence infusion of 100 mmol sodium bicarbonate in 1000 mL 5% dextrose at 250 mL/hour l 20 mmol of potassium chloride may be added to infusion to maintain normokalaemia l Given

APPROACH TO THE POISONED PATIENT

Rationale

27 TOXICOLOGY HANDBOOK

URINARY ALKALINISATION

APPROACH TO THE POISONED PATIENT

28 28 TOXICOLOGY HANDBOOK

l Follow

serum bicarbonate and potassium at least every 4 hours dipstick urine and aim for urinary pH >7.5 l Continue until clinical and laboratory evidence of toxicity is resolving. l Regularly

EXTRACORPOREAL TECHNIQUES OF ELIMINATION A number of such techniques have been used to enhance elimination of toxins including: l Haemodialysis — Intermittent — Continuous l Haemoperfusion l Plasmapheresis l 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 lifethreatening poisonings where a good outcome cannot be achieved by other means, including aggressive supportive care and antidote administration. Haemodialysis is the most frequently used of these techniques and 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: l Toxic alcohol poisoning — Methanol — Ethylene glycol l Theophylline poisoning l Severe salicylate intoxication — Chronic intoxication with altered mental status — Late-presentation acute overdose with established severe toxicity l Severe chronic lithium intoxication l Phenobarbitone coma l Metformin lactic acidosis l Massive valproate overdose l Massive carbamazepine overdose l Potassium salt overdose with life-threatening hyperkalaemia. Precise clinical indications for haemodialysis in each of these important poisonings are discussed in the relevant sections of Chapter 3. The decision to dialyse should be made early as soon as the risk assessment indicates potential lethality. In general, intermittent dialysis

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. 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. Winchester JF. Dialysis and haemoperfusion in poisoning. Advances in Renal Replacement Therapy 2002; 9(1):26–30.

1.8  ANTIDOTES Antidotes are drugs that correct the effects of poisoning. Only a few antidotes exist for a limited number of poisonings and many are used only extremely 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. References

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.

APPROACH TO THE POISONED PATIENT

References

29 TOXICOLOGY HANDBOOK

achieves greater clearance rates than continuous haemodialysis techniques and is preferred where available.

APPROACH TO THE POISONED PATIENT

30 30 TOXICOLOGY HANDBOOK

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, administration of antidotes or enhanced elimination techniques. 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 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 monitoring. No arrangements for admission to hospital need 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 then admission to an intensive care unit is appropriate.

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 physicians and provide short-term focused goal-oriented care. They have been remarkably successful in: l Streamlining treatment in suitable conditions l Reducing total bed days l Increasing patient satisfaction l 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

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 then transfer is necessary. Risk

APPROACH TO THE POISONED PATIENT

31 TOXICOLOGY HANDBOOK

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 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: l Central nursing stations with clear vision of all areas l An environment that protects from self-harm l Secure entrances l Dedicated areas for private interviews l Dedicated social work, drug and alcohol, plus outpatient liaison services l Appropriate monitors +/- telemetry l Dedicated resuscitation equipment l Duress alarms l Appropriate staff, skills and equipment l Appropriate 24/7/365 senior staff coverage l Dedicated psychiatric services l 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: l Cardiac monitoring not required (but this can be provided in some EOUs) l Adequate sedation in cases of delirium l 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: l Admissions scattered all over hospital l Less experienced nursing staff l Poor availability of medical staff l Frequent security incidents/absconding patients l Most clinicians managing patients on general medical wards are junior and have no formal or informal training in clinical toxicology l Longer admissions.

APPROACH TO THE POISONED PATIENT

32 32 TOXICOLOGY HANDBOOK

TABLE 1.9.1 Principles of retrieval of the poisoned patient l Risk assessment is vital l Identify patients who may

need retrieval to another hospital as soon as possible l Patients should only be retrieved for specific clinical indications l Recognise that transport may occur during the worst phase of the intoxication l Consider bringing expertise and resources to the patient, rather than vice versa l Assess, manage and stabilise potential resuscitation and supportive care priorities prior to transfer l Ensure that transport does not lead to an interval of lower level of care l Transport to a centre capable of definitive care

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. 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 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

Communication is vital. Retrieval is always to a higher level of care. Thus transport must occur to a facility with appropriate resources to 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), then 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.

APPROACH TO THE POISONED PATIENT

Communication

33 TOXICOLOGY HANDBOOK

occur prior to transfer. Similarly, if significant hypotension is expected (e.g. calcium channel blockers), then appropriate monitoring, intravenous access and resuscitation resources should be ready prior to transfer.

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CHAPTER 2

SPECIFIC CONSIDERATIONS 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23

 pproach to snakebite A Approach to mushroom poisoning Approach to plant poisoning Coma Hypotension Approach to seizures Delirium and agitation Serotonin syndrome Anticholinergic syndrome Cholinergic syndrome Neuroleptic malignant syndrome Alcohol abuse, dependence and withdrawal Amphetamine abuse, dependence and withdrawal Opioid dependence and withdrawal Sedative-hypnotic dependence and withdrawal Solvent abuse, dependence and withdrawal Body packers and stuffers Osmolality and the osmolar gap Acid–base disorders The 12-lead ECG in toxicology Poisoning during pregnancy and lactation Poisoning in children Poisoning in the elderly

36 44 50 55 59 61 62 66 72 76 80 85 93 94 97 100 104 107 109 113 119 120 126

2.1  APPROACH TO SNAKEBITE

SPECIFIC CONSIDERATIONS

See also specific sections in Chapter 5: Black Snake, Brown Snake, Death Adder, Sea Snake, Taipan, Tiger Snake

Definite or suspected snakebite is a regular presentation 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 36 TOXICOLOGY HANDBOOK

36

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-immobilisation bandaging (PIB) 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 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 monovalent antivenom required Geographic area (prevalent indigenous snakes) Clinical and laboratory features CSL Snake Venom Detection Kit (SVDK) Administer the dose of monovalent antivenom required to definitively treat the envenoming Adjuvant and supportive treatment

TABLE 2.1.2 Clinical effects of Australian Elapidae snakes Category (Genus)

Venom-induced consumptive coagulopathy

Neurotoxicity (pre-synaptic)

Neurotoxicity (post-synaptic)

Rhabdomyolysis

Renal failure

Other effects

Not present

Not present

Uncommon

Microangiopathic haemolytic anaemia and thrombocytopenia

Brown (Pseudonaja)

Always present with significant envenoming

Very rare

Tiger (Notechis)

Always present with significant envenoming

Slow onset over hours (possibly up to 12–24 hours)

Not present

Not present

Slow onset over hours (possibly up to 12–24 hours)

May resolve spontaneously in 12–24 hours Death adders (Acanthophis)

Not present

Primary mechanism poorly understood Slow onset over hours May be severe and result in renal failure

Not present

Uncommon Primary mechanism poorly understood

Microangiopathic haemolytic anaemia and thrombocytopenia

May also occur secondary to rhabdomyolysis Not present

Local bite site pain often present

Continued

37

TOXICOLOGY HANDBOOK

SPECIFIC CONSIDERATIONS

38 38

TOXICOLOGY HANDBOOK

SPECIFIC CONSIDERATIONS

TABLE 2.1.2 Clinical effects of Australian Elapidae snakes—cont’d Category (Genus) Black (Pseudechis)

Venom-induced consumptive coagulopathy

Neurotoxicity (pre-synaptic)

Neurotoxicity (post-synaptic)

Not present

Not present

Not present

Mild anticoagulant effect may be seen with raised APTT

Rhabdomyolysis

Renal failure

Other effects

May develop over hours to days

Secondary to rhabdomyolysis

Bite site pain may be significant

May be severe and result in renal failure

Envenoming usually associated with nausea, vomiting, abdominal pain and headache

Fibrinogen remains normal Taipan (Oxyuranus)

Always present with significant envenoming

May be rapid in onset

Not present

May develop over minutes to hours

Uncommon Primary mechanism poorly understood May occur secondary to rhabdomyolysis

Sea snakes Not present (Hydrophiidae)

May be rapid in onset

Not present

May develop over minutes to hours

Secondary to rhabdomyolysis

Microangiopathic haemolytic anaemia and thrombocytopenia

First aid

First aid aims to delay lymphatic spread of venom proximally from the bite site and delay systemic effects until the patient is in a facility that can administer adequate doses of antivenom if required. l Keep the patient as calm and still as possible l Do no harm and avoid unproven and harmful techniques such as tourniquets, ice, cutting, sucking or electric shocks l Apply pressure-immobilisation bandaging (PIB) — Pressure bandage over the entire limb — Immobilisation of limb — Immobilisation of the whole patient l If the bite is on the trunk, apply local pressure over the site and immobilise the patient l PIB may be left on for many hours while subsequent management steps are completed. There are anecdotal reports of sudden deterioration upon removal of the bandage up to 12 hours after the bite. No patient who received early and appropriate PIB has subsequently died l Do not wash the wound, as a wound swab may be required later for the CSL Snake Venom Detection Kit (SVDK) l The PIB is not removed until: — The patient has been fully assessed in an appropriate hospital and found to show no objective evidence of envenoming (normal initial physical examination and laboratory investigations) OR



— Antivenom administration has commenced if found to be envenomed.

Transport

All patients should be transported to a hospital that complies with all the following criteria: 1 Doctor(s) present, able and willing to undertake snakebite management, including definitive treatment of severe envenoming and potential early complications (e.g. anaphylaxis) 2 Laboratory facilities capable of performing necessary investigations on a 24-hour basis

SPECIFIC CONSIDERATIONS

PRE-HOSPITAL CARE

39 TOXICOLOGY HANDBOOK

There is no clinical risk stratification process that allows the clinician to identify patients who can be discharged early or without laboratory investigations. Patients with no obvious bite mark and no symptoms may be envenomed. As a result, many patients each year who turn out not to be envenomed are transferred to larger centres for investigation and observation. It is unusual that a snake is identified with sufficient reliability to preclude further observation or investigation.

SPECIFIC CONSIDERATIONS

3 Antivenom stocks adequate for definitive treatment of severe

envenoming by all snakes indigenous to that geographic area, or able to obtain antivenom within a clinically suitable timeframe. If the initial receiving hospital does not comply with these criteria, the stable patient is transferred or retrieved to a hospital that does. If the patient is unstable, resuscitation commences and antivenom is brought in by a retrieval service or any other means possible. During the retrieval phase the patient should be observed for clinical evidence of envenoming. If there is objective evidence of envenoming (e.g. definite history of a bite with hypotension or abnormal bleeding) antivenom treatment may begin at the peripheral site, or commence during transfer.

HOSPITAL MANAGEMENT Resuscitation l Most

40 TOXICOLOGY HANDBOOK

40

patients present with a history of possible bite and do not require immediate resuscitation l Until early envenoming is excluded, patients should be assessed and managed in an area equipped with cardio-respiratory monitoring and resuscitation l Establish intravenous access l Rarely, management of immediate threats to airway, breathing and circulation, or control of seizures is required. Resuscitation proceeds along conventional lines as outlined in Chapter 1.2: Resuscitation l Potential early life-threats associated with Australian terrestrial snake envenoming include: — Hypotension (brown, taipan, tiger) — Respiratory failure secondary to paralysis (death adder, taipan, tiger; rarely, brown) — Seizures (taipan) — Severe venom-induced consumptive coagulopathy (VICC) with uncontrolled haemorrhage (brown, taipan, tiger). Determine whether the patient is envenomed or not

The aim is to seek objective evidence of envenoming based on history, physical examination and laboratory data (see Table 2.1.3). Serial physical examinations (looking for bleeding, neurotoxicity and rhabdomyolysis) and investigations (FBE, EUC, CK and coagulation studies) are performed until envenoming is diagnosed or 12 hours have expired. Abnormalities on initial physical examination or laboratory studies consistent with snake envenoming prompt immediate antivenom therapy as outlined below. If the patient remains clinically well and initial laboratory studies are normal, the PIB is removed. If there is sudden clinical deterioration, it is immediately reapplied, laboratory studies repeated and antivenom administered.

TABLE 2.1.3 Assessment of snakebite

Geographic area of bite Appearance of snake (Usually only useful for death adders and red-bellied black snakes) Anatomic site of bite Number of strikes Use of PIB Early symptoms (e.g. collapse, nausea, vomiting, bleeding, weakness) Pre-hospital course (e.g. hypotension, bleeding from IV sites, urine output)

Vital signs Mental status Evidence of bite (lack of any evidence does not exclude envenoming) Lymphadenopathy Evidence of abnormal bleeding (e.g. gingival sulci) Evidence of descending symmetrical flaccid paralysis (ocular, small muscles of face and bulbar function affected first) Respiratory function (e.g. PEFR)

Laboratory investigations Whole blood clotting test utilising a clean glass tube (Useful at peripheral sites; clotting time >20 minutes abnormal) Coagulation profile (INR and APTT required) Fibrinogen, D-Dimer, fibrin degradation products Full blood count Creatine kinase (CK) Renal function and urinalysis (blood/ myoglobin) Consider also lactate dehydrogenase (LDH)

Note: The Commonwealth Serum Laboratories Snake Venom Detection Kit (SVDK) is not used to determine whether a patient is envenomed (see section below).

If there is no discernible deterioration upon removal of the PIB the patient is observed and physical examination and laboratory studies repeated at 1, 6 and 12 hours. If at any time clinical examination or laboratory results suggest envenoming, antivenom is administered. If there is no evidence of envenoming at 12 hours after removal of PIB the patient is ready for discharge. However, patients should not be discharged at night as subtle delayed neurotoxicity might not be detected. Determine the type of monovalent antivenom required

Monovalent antivenom is recommended in preference to polyvalent antivenom as it is more specific, cheaper, safer and associated with a lower probability of serum sickness. Polyvalent antivenom contains the equivalent of one ampoule of each monovalent antivenom. It contains a large protein load. The choice of monovalent antivenom is based upon: l Knowledge of snakes found in the area l Clinical presentation

SPECIFIC CONSIDERATIONS

Physical examination

41 TOXICOLOGY HANDBOOK

History

l Constellation

of laboratory abnormalities Serum Laboratories Snake Venom Detection Kit (SVDK).

l Commonwealth

SPECIFIC CONSIDERATIONS

Determine the dose of monovalent antivenom required to treat the envenoming definitively

42 42 TOXICOLOGY HANDBOOK

l Once

the appropriate monovalent antivenom(s) is selected, the dose should be considered. Ideally, antivenoms are given in an initial dose likely to provide definitive treatment. l Currently recommended doses of antivenom are largely based on clinical experience and consensus but have recently been revised in the light of prospective studies measuring snake venom concentrations. Dosing recommendations may be further modified as improved data is acquired regarding venom, antivenom and targetorgan interactions in human cases l For current dosing recommendations refer to the sections on specific monovalent antivenoms in Chapter 6. l Clinician(s) administering antivenom must be prepared to manage anaphylaxis (see Appendix 6). l Given the low prevalence of severe anaphylactic and anaphylactoid reactions to CSL antivenoms (1% for monovalent; 5% for polyvalent), premedication to prevent allergic reactions is not routinely indicated l Following the administration of antivenom, the patient’s clinical status is monitored and laboratory investigations repeated after 6 and 12 hours and then every 12 hours until normalised l Even with adequate antivenom administration, it may take from 10 to 20 hours for coagulation studies to return to normal in patients with VICC l Further doses of antivenom are unlikely to be required unless the patient’s clinical condition appears to be deteriorating. Adjuvant therapy

Patients who receive snake antivenom are counselled about the possibility of serum sickness 4–21 days after antivenom administration. Prednisolone 1 mg/kg/day (up to 50 mg/day) for 5 days may attenuate the severity of serum sickness. TABLE 2.1.4 Indications for polyvalent antivenom l Appropriate monovalent antivenoms not available l No SVDK result available and the range of possible

snakes requires the mixing of three or more monovalent antivenoms l Severe envenoming, there is insufficient time to wait for SVDK results and the range of possible snakes would require the mixing of three or more monovalent antivenoms l Exhausted monovalent AV stocks Source: White J. CSL Antivenom Handbook. Melbourne: CSL Ltd, 2001.

References Brown SGA, Caruso N, Borland M et al. Clotting factor replacement and recovery from snake venom-induced consumptive coagulopathy. Intensive Care Medicine 2009; 35(9):1532–1538. Clinical Toxinology Resources web site at http://www.toxinology.com Sutherland SK, Coulter AR, Harris RD. Rationalisation of first-aid measures for elapid snakebite. Lancet 1979; 1(8109):183–185. White J. CSL Antivenom Handbook. Melbourne: CSL Ltd, 2001.

43 TOXICOLOGY HANDBOOK

The use of blood products such as fresh frozen plasma or cryoprecipitate in the management of venom-induced consumptive coagulopathy (VICC) is controversial. There is some evidence that the administration of these products following antivenom administration is associated with earlier recovery from VICC and randomised controlled clinical trials are currently being conducted to determine the efficacy and safety of clotting factor replacement after venom neutralisation in VICC. Blood products are indicated if there is uncontrolled or life-threatening haemorrhage. Other direct complications of Australian snake envenoming that may require specific monitoring or treatment include: l Paralysis l Rhabdomyolysis l Acute renal failure l Microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia l Local wound complications.

SPECIFIC CONSIDERATIONS

BOX 2.1.1  The CSL Snake Venom Detection Kit (SVDK) The SVDK indicates the right monovalent antivenom to use once a decision has been made to give antivenom. The SVDK is not used to determine whether or not a patient is envenomed. False positives and negatives occur; if the SVDK does not match the clinical picture, treat the patient not the SVDK result. If there is doubt about the snake responsible for the envenoming and the SVDK is not helpful (e.g. possible early tiger or brown snake envenoming in a geographic location where the two snakes coexist), two monovalent antivenoms are superior to polyvalent antivenom. The SVDK is ideally performed by a meticulous and experienced technician according to the enclosed instructions. The SDVK is performed using a bite-site swab, which can be accessed by cutting a ‘key-hole’ in the PIB. The SVDK may also be performed on urine (second-line). The SVDK should not be performed on serum or blood. The first test well to turn blue within the allotted time (10 minutes) gives the result. Other wells may subsequently turn blue but are ignored. If no well turns blue within the allotted time the test is negative and subsequent changes are ignored.

SPECIFIC CONSIDERATIONS

2.2  APPROACH TO MUSHROOM POISONING

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Poisoning from ingestion of mushrooms occurs worldwide usually when wild mushrooms containing toxins are misidentified as comestible species, collected and eaten. More than one individual may be poisoned simultaneously. The most common presentation is a benign self-limited gastrointestinal disturbance but a number of other important toxic syndromes, including potentially lethal hepatotoxicity, are recognised. Assessment and management is based on the recognition of the principal clinical syndromes that may develop following ingestion of toxic mushrooms. Patients may present with mixed poisoning after ingestion of multiple mushroom species.

RISK ASSESSMENT l The

vast majority of mushroom poisoning cases in Australasia manifest with acute gastrointestinal toxicity. A rapid resolution of symptoms and good outcome with supportive care is anticipated l A variety of other toxic syndromes may develop and a favourable outcome can usually be anticipated with good supportive care l Worldwide, cyclopeptide hepatotoxic poisoning accounts for the majority of mushroom-related deaths. This form of poisoning is reported but extremely rare within Australasia l Cyclopeptide hepatotoxic poisoning must be considered where gastrointestinal symptoms develop greater than 6 hours following ingestion of mushrooms l Children: Accidental ingestion of wild mushrooms by children is usually benign.

MUSHROOM SPECIES AND TOXINS There are thousands of mushroom species and reliable mushroom identification, even by expert mycologists, is difficult. In the clinical setting, identification is frequently impossible because the mushrooms are either unavailable, decomposing, partly digested or cooked. Numerous toxins are identified and are usually species-specific (see Table 2.2.1). Acute gastroenteritis is the most frequent manifestation of mushroom poisoning. The causative toxins are not well-identified and probably heterogeneous in nature. The cholinergic syndrome is secondary to muscarine, a quarternary ammonium peripheral muscarinic agonist that does not stimulate nicotinic receptors and does not cross the blood–brain barrier. Glutaminergic toxicity is due to muscimol, which resembles GABA and stimulates central GABA receptors, and ibotenic acid, which resembles glutamic acid and stimulates central glutaminergic receptors. 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

TABLE 2.2.1 Clinical syndromes of mushroom poisoning Syndrome

Toxin (mushroom species)

Clinical course

Clinical features

EARLY ONSET (WITHIN 6 HOURS)

Miscellaneous gastrointestinal*

Malaise, abdominal pain, nausea, vomiting, diarrhoea

Onset 30 min–3 hours Resolution 6–24 hours

Multiple mushroom genera but toxic mechanisms not identified

Cholinergic*

Vomiting, diarrhoea, lacrimation, salivation, urinary incontinence, bronchorrhoea, bronchospasm, miosis

Onset 30 min–2 hours

Muscarine (Clitocybe and Inocybe species)

Hallucinogenic*

Ataxia, anxiety, mydriasis, tachycardia, dyskinesias, delirium and hallucinations

Onset within minutes

Psilocybin (Psilocybe species)

Disulfiram-like*

Nausea, vomiting, tachycardia, facial flushing, sweating, chest pain

Onset following ethanol consumption within 2 hours of mushroom ingestion

Coprine (Coprinus species)

Duration up to 6 hours Glutaminergic*

Dizziness, drowsiness, delirium, dysphoria, hallucinations, myoclonus, hyperreflexia, seizures

Onset 30 min–2 hours

Ibotenic acid Muscimol (Amanita muscaria and pantherina) Continued

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SPECIFIC CONSIDERATIONS

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SPECIFIC CONSIDERATIONS

TABLE 2.2.1 Clinical syndromes of mushroom poisoning—cont’d Syndrome

Clinical features

Clinical course

Toxin (mushroom species)

Epileptogenic

Nausea, vomiting, diarrhoea Headache, ataxia, fatigue, nystagmus, tremor, vertigo, seizures (rare) Delayed hepatotoxicity with raised transaminases (rare) Delayed haemolysis and methaemoglobinaemia (rare)

GI symptoms within 4–6 hours

Gyromitrin (Gyromitra species)

Nausea, vomiting, epigastric pain and diarrhoea Haemolytic anaemia, haemoglobinuria, immune-complex nephritis and acute renal failure

Onset 30 min–3 hours

Nausea, vomiting and rhinitis Acute bronchopneumonia

Onset within 6 hours Within days

Inhalation of dried Lycoperdonosis spores

Onset 6–24 hours

Three classes of cyclopeptide

18–36 hours

l l l

Immunohaemolytic

Pneumonic

Onset 2–3 days Onset 1–3 days after hepatic injury Paxillus species

In the following days

DELAYED ONSET (6–24 HOURS)

Hepatotoxic*

Nausea, vomiting, abdominal cramps and diarrhoea Transient clinical improvement during asymptomatic increase in hepatic transaminases Severe gastroenteritis with fulminant hepatic failure and pancreatitis

2–6 days

 matoxins A Phallotoxins Virotoxins (Amanita, Galerina and Lepiota species)

TABLE 2.2.1 Clinical syndromes of mushroom poisoning—cont’d Toxin (mushroom species)

Syndrome

Clinical features

Clinical course

Erythromelalgia

Burning pain, redness and oedema of the hands and feet, exacerbated by heat and relieved by cold

Onset 24–72 hours Resolution 8 days to 5 months

Acromelic acids

GREATLY DELAYED ONSET (>24 HOURS)

Nephrotoxic

Anorexia, headache, nausea, vomiting, abdominal pain and flank pain Interstitial nephritis and acute renal failure

Onset 24–36 hours

Orellanine (Cortinarius and A. smithiana species)

Rhabdomyolysis

Fatigue, myalgias, muscle weakness and myocarditis (very rare)

Onset 24–72 hours

(Tricholoma and Russula species)

*denotes syndromes described in Australia

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SPECIFIC CONSIDERATIONS

dehydrogenase, a mode of action similar to disulfiram. Amatoxins (chiefly α-amanitin) inactivate RNA polymerase II and inhibit protein synthesis.

SPECIFIC CONSIDERATIONS

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 of the patient who presents with gastrointestinal symptoms following ingestion of mushrooms.

MANAGEMENT 48 48 TOXICOLOGY HANDBOOK

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: Approach to 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. 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. Enhanced elimination

Methods of enhanced elimination are frequently considered in patients with potential cyclopeptide hepatotoxic mushroom poisoning but their

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: l N-acetylcysteine (see Chapter 4.18: N-acetylcysteine) l Penicillin 1 million units/kg/day l 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. 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 4.24: Pyridoxine). Disposition and follow-up l Asymptomatic

paediatric patients may be observed at home following suspected ingestion of wild mushrooms l 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 greater than 6 hours should have liver function tests and renal function checked prior to discharge. Abnormal liver or renal function prompts further inpatient management l Patients with coma requiring intubation or significant CNS effects require management in an intensive care setting l 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 hepatic unit and clinical toxicologist is recommended. 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.

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Antidotes

SPECIFIC CONSIDERATIONS

effect on outcome has not been studied in controlled trials. If cyclopeptide hepatotoxic mushroom poisoning is suspected, multiple-dose activated charcoal (see Chapter 1.7: Enhanced elimination) may be useful because α-amanitin undergoes enterohepatic circulation.

SPECIFIC CONSIDERATIONS

2.3  APPROACH TO PLANT POISONING

50 50 TOXICOLOGY HANDBOOK

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. Nonintentional 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 l Most

plant exposures are asymptomatic or cause minor irritative symptoms only l Plants containing calcium oxalate crystals may cause more severe irritation to exposed mucous membranes l A few plants or parts of plants are capable of causing severe poisoning when ingested in sufficient quantity l Accurate plant identification usually allows refinement of the risk assessment l In the absence of accurate plant identification, risk assessment relies on knowledge of local plants and observation of clinical features and progress l Children: Significant plant poisoning is extremely rare. Ingestion of yellow oleander or castor beans 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.

Plant(s)

Clinical features

Aconite

Aconitum spp. Delphinium spp.

Tachycardia, GI disturbance, multi-system organ failure, lactic acidosis

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 oleander) Thevetia spp. (yellow oleander)

Bradycardia, dysrhythmias, GI disturbance, hyperkalaemia

Colchicine

Colchicum autumnale (autumn crocus) Gloriosa superba (glory lily)

GI disturbance, bone marrow depression, multisystem organ failure

Coniine

Conium maculatum (poison hemlock)

Bradycardia, tachycardia, GI disturbance, ascending paralysis, rhabdomyolysis, renal failure

Cyanogenic glycosides

Prunus spp. seed kernels (apricots, 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 williamsonii (peyote cactus)

Acute psychosis, visual hallucinations

Ricin

Ricinus communis (castor beans)

GI disturbance, multisystem organ failure

Taxine

Taxus spp. (yew)

Bradycardia, dysrhythmias, GI disturbance

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Toxin(s)

SPECIFIC CONSIDERATIONS

TABLE 2.3.1 Plant toxins with potential to cause serious toxicity or death following a single acute ingestion

SPECIFIC CONSIDERATIONS

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52

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 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). 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 (Coniium 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 williamsonii).

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 syndromes that may develop include anticholinergic syndrome, nicotinic poisoning, cardiac glycoside poisoning, colchicine or cyanide poisoning.

MANAGEMENT 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: Approach to 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.

SPECIFIC CONSIDERATIONS

CLINICAL FEATURES

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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, haematologic, 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.

SPECIFIC CONSIDERATIONS

Decontamination

54 54 TOXICOLOGY HANDBOOK

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 4.22: Physostigmine). Cyanide antidotes may be useful in treating cyanogenic glycoside poisoning (see Chapter 4.14 Hydroxocobalamin and Chapter 4.27 Sodium thiosulfate). Digoxin immune Fab in relatively high doses has been used successfully to reverse cardiotoxicity from oleander poisoning (see Chapter 4.6: Digoxin immune Fab). Enhanced elimination

Not useful in plant poisoning. Disposition

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 life-threatening 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 specialist stinging apparatus that act 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.

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: l Direct toxic effect on the CNS: wakefulness and consciousness depend on complex mechanisms involving many pathways and neurotransmitter systems l Secondary effect of poisoning on CNS: hypoxaemia, hypoglycaemia, hyponatraemia, hypotension, seizures or cerebral oedema l 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 induction of anaesthesia and 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

SPECIFIC CONSIDERATIONS

2.4  COMA

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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 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):206–12. 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.

TABLE 2.4.1 Toxicological causes of coma

SPECIFIC CONSIDERATIONS

PRIMARY NEUROLOGICAL EFFECT

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Alcohols Ethanol Ethylene glycol Isopropyl alcohol Methanol Antipsychotic agents Amisulpride Chlorpromazine Clozapine Olanzapine Quetiapine Anticonvulsant agents Carbamazepine Lamotrigine Tiagabine Valproic acid Antidepressants Selective serotonin reuptake inhibitors Tricyclic antidepressants Antihistamines Diphenhydramine Antimalarial agents Chloroquine Hydroxychloroquine Quinine Baclofen Beta-adrenergic blockers Propranolol Centrally acting alpha2-agonists Clonidine Oxymetazoline

Cholinergic agents Carbamates Dementia acetylcholinesterase inhibitors (e.g. donepezil) Nicotine Organophosphates Hydrocarbons Eucalyptus oil Toluene Local anaesthetics Bupivacaine Cocaine Lignocaine Ropivicaine Mushrooms Gyromitra species Non-steroidal anti-inflammatory agents Ibuprofen Mefenamic acid Opioids Codeine Heroin Morphine Methadone Sedative-hypnotic agents Benzodiazepines Barbiturates 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 Selective noradrenaline reuptake inhibitors (e.g. venlafaxine) Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors

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: l Diagnose alternative non-toxicological causes of coma l Diagnose important complications of coma l Diagnose specific toxicities where specific interventions (enhanced decontamination 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

SPECIFIC CONSIDERATIONS

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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. This is ideally anticipated and prepared for on the basis of an early risk assessment. For example, the patient who presents conscious 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 dictates intubation at a Glasgow Coma Scale (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.

SPECIFIC CONSIDERATIONS

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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: l Pulmonary aspiration l Rhabdomyolysis l Acute renal failure l Compartment syndromes l Pressure areas l Hypoxic brain injury. Supportive care, monitoring and disposition

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: l Monitoring of conscious state and airway l Respiratory toilet and prophylaxis (mobilisation and/or physiotherapy) l Fluid monitoring and management l Bladder care (indwelling catheter) l Prevention of pressure areas l Thromboembolism prophylaxis l Mobilisation as mental status changes resolve. Investigations l Screening

(12-lead ECG 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 can not be determined l 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 l To detect and assess complications — Arterial blood gases, anion gap and lactate — Urea and electrolytes — Liver function tests — CK — Chest x-ray l To exclude or confirm important differential diagnoses — Arterial blood gases, anion gap and lactate — Urea and electrolytes — Liver function tests



Salicylate (severe poisoning only) Haemodialysis Toxic alcohols (ethylene glycol, methanol) Ethanol/fomepizole Haemodialysis Valproic acid Haemodialysis

— 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. 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).

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Carbamazepine Multi-dose activated charcoal Haemodialysis Isoniazid Pyridoxine Organophosphates Atropine Pralidoxime Phenobarbitone Multi-dose activated charcoal Haemodialysis

SPECIFIC CONSIDERATIONS

TABLE 2.4.2 Agents causing coma that may require specific intervention

SPECIFIC CONSIDERATIONS

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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 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: 1 Check cardiac rhythm and review a current 12-lead ECG. Commence continuous ECG monitoring until patient is stabilised and risk assessment is reviewed 2 Ensure adequate intravenous access 3 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) 4 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, colchicine, theophylline or salicylate intoxication fluid losses may be large and fluid resuscitation ongoing. In contrast, in calcium channel blocker intoxication excessive fluid resuscitation may lead to pulmonary oedema 5 Consider specific antidotes: l Digoxin-specific antibodies (digoxin) l Calcium (calcium channel blockers) 6 Consider atropine and pacing. Unfortunately, these rarely provide a definitive solution in the poisoned patient 7 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: l Noradrenaline (norepinephrine) l Adrenaline (epinephrine) l Dopamine 8 Commence central haemodynamic monitoring 9 Consider high-dose insulin therapy (see Chapter 4.15: Insulin (high dose)) 10 Consider extraordinary manoeuvres such as cardiopulmonary bypass. References 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):126–132.

TABLE 2.6.1 Toxicological causes of seizures Anticonvulsants Carbamazepine Topiramate Tiagabine Antidepressants Buproprion Citalopram Tricyclics Venlafaxine Antidysrhythmic agents Quinidine Antihistamines Antimalarial agents Chloroquine Hydroxychloroquine Quinine Antipsychotic agents Butyrophenones Phenothiazines Atypical antipsychotics Olanzapine Quetiapine Isoniazid Hypoglycaemic agents Insulin Sulfonylureas

Local anaesthetic agents Lignocaine Nicotine Non-steroidal anti-inflammatory agents Mefenamic acid Opioids Dextropropoxyphene Pethidine Tramadol Propranolol Salicylates Sympathomimetic agents Amphetamine and its derivatives Cocaine Theophylline Withdrawal syndromes Alcohol Barbiturates Benzodiazepines Non-benzodiazepine sedativehypnotic agents (e.g. gamma hydroxybutyrate)

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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. 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 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-toxicologic in origin. In either case, prompt further investigation is warranted.

SPECIFIC CONSIDERATIONS

2.6  APPROACH TO SEIZURES

SPECIFIC CONSIDERATIONS

MANAGEMENT

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See Chapter 1.2: Resuscitation 1 Attention to airway, breathing and circulation. If coma preceded onset of seizures (e.g. tricyclic antidepressant poisoning), proceed to rapid sequence intubation and ventilation as the steps below are taken 2 Administer oxygen 3 Check cardiac rhythm and output 4 Establish intravenous access 5 Check bedside blood glucose level and correct hypoglycaemia if present 6 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 7 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) 8 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.

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 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. TABLE 2.7.1 Diagnostic features of delirium (based on DSM-IV criteria) 1 Altered conscious state with impaired attention 2 Decreased cognition manifested by disorientation, memory deficits or abnormal speech 3 Acute onset (usually hours or days) and fluctuating course (distinct from dementia) 4 Evidence of an associated medical condition on history, examination or investigations 5 In broad terms, the associated medical condition may be nontoxicological, toxicological, due to drug withdrawal or multiple factors

TABLE 2.7.2 Toxicological causes of agitation and delirium Alcohol Anticholinergic syndrome Antidepressants Bupropion Monoamine oxidase inhibitors Venlafaxine Atypical antipsychotic agents Olanzapine 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 Theophylline Withdrawal syndromes

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

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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.

SPECIFIC CONSIDERATIONS

DUTY OF CARE

SPECIFIC CONSIDERATIONS

TABLE 2.7.4 Other conditions mimicking or contributing to agitation Acid–base disturbance Behavioural disturbance CNS infection (e.g. encephalitis) Dementia Electrolyte disturbance (e.g. hyponatraemia) Endocrine emergency (e.g. thyroid storm) 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)

MANAGEMENT 64 64 TOXICOLOGY HANDBOOK

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 core-temperature monitoring. A temperature >39.5°C is an emergency that requires prompt management to prevent multiple organ failure and neurological injury. 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 nontoxicological cause for delirium. 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: l Important complications of delirium (see Table 2.7.3) l Alternative (non-toxicological) causes (see Table 2.7.4) l Toxicities or syndromes where specific interventions (enhanced decontamination techniques or antidotes) are necessary to ensure a good outcome (see Table 2.7.5).

Agent

Possible interventions

Anticholinergic agents

Physostigmine (see Chapter 4.22: Physostigmine)

Neuroleptic malignant syndrome

Bromocriptine

Serotonin syndrome

Cyproheptadine (see Chapter 4.3: Cyproheptadine) Neuromuscular paralysis, intubation and ventilation

Salicylates

Urinary alkalinisation Haemodialysis

Theophylline

Multi-dose activated charcoal Haemodialysis

SPECIFIC CONSIDERATIONS

TABLE 2.7.5 Agents or syndromes associated with delirium and agitation that may require specific interventions

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The patient is managed in a calm environment to minimise external stimulation and crowding. Repeated reassurance and explanation are 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 firstline 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 second-line 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 arrhythmias 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.

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Supportive care and monitoring

SPECIFIC CONSIDERATIONS

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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 less 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 highdependency unit. Delirium may persist for days, depending on the cause. General supportive care as detailed in Chapter 1.4: Supportive care and monitoring includes: l Monitoring of conscious state and airway l Respiratory toilet and prophylaxis (mobilisation and/or chest physiotherapy) l Fluid monitoring and management l Bladder care (indwelling urinary catheter) l Prevention of pressure areas l Thromboembolism prophylaxis l 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 4.22: Physostigmine. Reference Carter LC, Dawson AH. Acute delirium. In: Dart RC, ed. Medical Toxicology. 3rd edn. Philadelphia: Lippincott Williams & Wilkins; 2004: Ch 15.

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

Apprehension Anxiety Agitation, psychomotor acceleration and delirium* Confusion

Autonomic stimulation

Neuromuscular excitation

Diarrhoea* Flushing Hypertension Hyperthermia† Mydriasis* Sweating* Tachycardia*

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

(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 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 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

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Mental status changes

SPECIFIC CONSIDERATIONS

TABLE 2.8.1 Clinical features of serotonin syndrome

FIGURE 2.8.1  Algorithm for diagnosis of serotonin syndrome

SPECIFIC CONSIDERATIONS

Serotonergic agent ingestion or overdose

68

Spontaneous clonus

yes

no

Inducible clonus OR Ocular clonus

yes

no

Tremor

Agitation OR Diaphoresis OR Hypertonia AND Pyrexia (>38oC)

yes

no yes

Hyperreflexia

yes

S E R O T O N I N T O X I C I T Y

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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.

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: l Introduction or increase in dose of a single serotonergic drug l Change in therapy from one serotonergic drug to another without an adequate intervening ‘washout’ period l Drug interaction between two serotonergic agents l Interaction between serotonergic drug and an illicit drug or herbal preparation l 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. 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). Life-threatening serotonin syndrome does not develop after ingestion of single SSRIs.

Selective serotonin reuptake inhibitors (SSRIs) Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Serotonin and noradrenaline reuptake inhibitors (SNRIs) Bupropion Venlafaxine Tryptophan

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.

MANAGEMENT Resuscitation l Attention

to airway, breathing and circulation. 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 l Administer oxygen l Establish intravenous access l Check bedside blood glucose level l 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 muscle-generated heat production, and severe hyperthermia leading to multiple organ failure, neurological injury and death l 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

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Analgesics and antitussives Dextromethorphan Fentanyl Pethidine Tramadol Antidepressants Tricyclic antidepressants Drugs of abuse Amphetamines Methylenedioxymethamphetamine (MDMA; ecstasy) Herbal preparations St John’s wort (Hypericum perforatum) Lithium Monoamine oxidase inhibitors (MAOIs) Moclobemide Phenelzine

SPECIFIC CONSIDERATIONS

TABLE 2.8.2 Agents implicated in development of serotonin syndrome

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SPECIFIC CONSIDERATIONS

TABLE 2.8.3 Differential diagnosis of serotonin syndrome Pupils

Skin

Bowel sounds

Neuromuscular tone

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

Depending on severity, further investigations may be required to exclude alternative diagnoses and detect significant complications. l Chest x-ray l 12-lead ECG l Full blood count l Renal function and electrolytes l Creatine kinase l Serum calcium and magnesium l Liver function tests l Arterial blood gases l Blood and urine cultures l Cranial CT l Lumbar puncture l MRI brain l Electroencephalogram. Supportive care l Cease

causative agent(s) patient l Administer intravenous fluids and institute fluid balance monitoring l Monitor temperature l In mild-to-moderate cases, supplemental benzodiazepine sedation may be indicated l Consider thromboembolism prophylaxis. l Reassure

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

SPECIFIC CONSIDERATIONS

Investigations

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muscle-generated heat production, and severe hyperthermia leading to multiple organ failure, neurological injury and death l Avoid any agent with dopamine antagonist effects l 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 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 l Hypertension and tachycardia may initially be treated with a parenteral vasodilator such as GTN or nitroprusside. Bromocriptine (see below) is indicated if there is significant autonomic instability.

SPECIFIC CONSIDERATIONS

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commences at 2.5 mg every 8 hours, increasing to 5 mg every 4 hours (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 conscious 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: l Severe NMS refractory to supportive care and antidote treatment l Severe NMS that is difficult to differentiate from acute lethal catatonia l Treatment of residual catatonic symptoms after NMS l 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. Neuroleptic malignant syndrome. In: Diagnostic and Statistical Manual of Mental Disorders. 4th edn. Washington DC: American Psychiatric Association; 1994: 739–742. 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.

2.12  ALCOHOL ABUSE, DEPENDENCE AND WITHDRAWAL BOX 2.12.1 Psychiatric definitions of substance abuse

Dependence Maladaptive pattern of substance use leading to clinically significant impairment or distress, manifested within a 12-month period by three or more of the following: l Tolerance (either increasing amounts or diminished effects with the same amounts) l Withdrawal (withdrawal symptoms or use to relieve or avoid symptoms) l Use of larger amounts over a period longer than intended l Persistent desire or unsuccessful attempts to cut down or control use l Great deal of time spent obtaining or using or recovering from use l Important social, occupational or recreational activities given up or reduced l Continued use despite knowledge of substance-related physical or psychological problems Adapted from Diagnostic and Statistical Manual of Mental Disorders. 4th edn. ­Washington DC: American Psychiatric Association; 1994.

Alcohol abuse and dependence along with other forms of substance abuse and dependence have formal psychiatric definitions (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 intoxication and abuse than from the consequences of long-term alcohol dependence (see Table 2.12.1). Upwards of 30% of all emergency department presentations are alcoholrelated. The incidence of alcohol-related problems is even higher in the population that presents to emergency departments with deliberate selfpoisoning 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.

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Abuse Maladaptive pattern of substance use leading to clinically significant impairment or distress, manifested within a 12-month period by one or more of the following: l Failure to fulfil role obligations at home, work or school l Recurrent use in physically hazardous situations l Substance-related legal problems l Continued use despite substance-related social or interpersonal problems l Symptoms have never met criteria for substance dependence

SPECIFIC CONSIDERATIONS

and dependence (DSM-IV)

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.

In most settings, physicians identify fewer than 50% of patients with alcohol-related problems. Factors associated with failure to identify these individuals include: l Inadequate training about substance abuse l Negative attitudes towards patients with substance abuse l Scepticism about effectiveness of treatments l Belief that alcohol problems are not in the realm of the generalist clinician l Excessive time required to perform formal screening procedures. 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).

BOX 2.12.2  The Alcohol Use Disorders Identification Test (AUDIT) Score (WHO 1992) Questions pertain to behaviour in the last year Score

0

1

2

3

4

How often do you have a drink containing alcohol?

Never

Monthly or less

Two to four times per month

Two to three times per week

Four or more times per week

How many drinks containing alcohol do you have on a typical day when you are drinking?

1 or 2

3 or 4

5, 6 or 7

8 or 9

10 or more

How often do you have 6 or more drinks on one occasion?

Never

Less than monthly

Monthly

Weekly

Daily or almost daily

How often during the last year have you found that you were not able to stop drinking once you had started?

Never

Less than monthly

Monthly

Weekly

Daily or almost daily

How often during the last year have you failed to do what was normally expected from you because of drinking?

Never

Less than monthly

Monthly

Weekly

Daily or almost daily

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

Less than monthly

Monthly

Weekly

Daily or almost daily

How often during the last year have you had a ­feeling of guilt or remorse after drinking?

Never

Less than monthly

Monthly

Weekly

Daily or almost daily

How often during the last year have you been unable to remember what happened the night before because you had been drinking?

Never

Less than monthly

Monthly

Weekly

Daily or almost daily Continued

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SPECIFIC CONSIDERATIONS

BOX 2.12.2  The Alcohol Use Disorders Identification Test (AUDIT) Score (WHO 1992)—cont’d Questions pertain to behaviour in the last year Score

0

1

2

3

4

Have you or someone else been injured as a result of your drinking?

No

Yes, but not in the last year

Yes, during the last year

Has a relative or friend or doctor or other health worker been concerned about your drinking or ­suggested you cut down?

No

Yes, but not in the last year

Yes, during the last year

Score >20

Hazardous alcohol usage. Help required

Score 16–19

Hazardous alcohol usage. Help urged

Score 8–15

Drinking exceeding safe levels

Score 0–7

Normal usage

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

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. Downregulation 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 l Occur



within hours of cessation and peak at 24–48 hours — Tremor — Anxiety and agitation

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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?

SPECIFIC CONSIDERATIONS

BOX 2.12.3  ‘CAGE’ questions

SPECIFIC CONSIDERATIONS



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— Sweating — Tachycardia — Hypertension — Nausea and vomiting — Hyperthermia

Neuro-excitation l Occur



within 12–48 hours of cessation — Hyperreflexia — Nightmares — Hallucinations (visual, tactile and occasionally auditory) — Generalised tonic–clonic seizures

Delirium tremens l Severe

form with mortality approaching 8% to 20% of patients admitted to urban hospitals with alcohol withdrawal l Associated with medical co-morbidities and delayed presentation — Hallucinations — Confusion, disorientation and clouding of consciousness — Autonomic hyperactivity — Respiratory and cardiovascular collapse — Death. l Up

CO-MORBIDITIES

A number of important co-morbidities should be considered, detected and managed in all patients with alcohol withdrawal: l Wernicke’s encephalopathy l Dehydration l Electrolyte abnormalities l Alcoholic gastritis and gastrointestinal bleeding l Pancreatitis l Alcoholic liver disease and hepatic encephalopathy l Subdural haemorrhage l 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: l History of severe alcohol withdrawal l Poor social support l Failure of unsupervised outpatient withdrawal

Resuscitation, supportive care and monitoring l 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 — Detect and treat hypoglycaemia l 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) l 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 l Give regular oral diazepam 5–20 mg PO as dictated by AWS to maintain adequate control of withdrawal l Give thiamine 100 mg IV or PO daily l Ensure adequate hydration, electrolyte balance and nutrition l Detect and treat co-morbidities l Note: Phenytoin is not indicated in the treatment or prevention of alcohol-related seizures. Investigations as indicated l EUC,

FBE, LFTs, coagulation profile, serum lipase.

Disposition and follow-up l Medical



admission is indicated if: — Large doses of diazepam are required to control withdrawal — Medical co-morbidities require care

SPECIFIC CONSIDERATIONS

MANAGEMENT APPROACH TO SEVERE ALCOHOL WITHDRAWAL IN HOSPITAL SETTING

91 TOXICOLOGY HANDBOOK

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: l Presentation with severe alcohol withdrawal — Abnormal vital signs after initial treatment — Hallucinations — Altered conscious state — Seizures l Presence of medical complications or co-morbidities (see above) l Presence of significant psychiatric co-morbidities.

BOX 2.12.5  Alcohol withdrawal score (AWS) Orientation

0—Orientated

SPECIFIC CONSIDERATIONS

1—Disorientated 2—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

Temperature

0—37.5°C or less 1—37.6°C to 38.5°C 2—>38.5°C

92 92 TOXICOLOGY HANDBOOK

= The patient is fully orientated in time, place and person = Disorientated but cooperative = Disorientated and uncooperative

2—At rest

Adapted with permission from the Alcohol Withdrawal Chart at Sir Charles Gairdner Hospital, Nedlands, Western Australia.

l Referral

to residential or home detoxification and rehabilitation services for assessment and psychosocial support is considered once acute withdrawal is controlled or resolving.

References 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? The 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. O’Connor PG, Schottenfeld RS. Patients with alcohol problems. New England Journal of Medicine 1998; 338(9):592–601. 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. 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.

2.13  AMPHETAMINE ABUSE, DEPENDENCE AND WITHDRAWAL

Amphetamine-related presentations represent a significant burden on emergency departments, accounting for over 1% of emergency department 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. 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. Definitions for amphetamine abuse and dependence are based on those for substance abuse and dependence in general and detailed in Box 2.12.1.

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 usually peak 2–4 days following cessation of use but may continue for 7–14 days.

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Medical Weight loss Cardiomyopathy (rare) Poor dentition Psychiatric Confusion Emotional lability Insomnia Memory loss Paranoia Paranoid psychosis Social Damage to social relationships Neglect of social, interpersonal and occupational responsibilities

SPECIFIC CONSIDERATIONS

TABLE 2.13.1 Effects of long-term amphetamine abuse

Amphetamine withdrawal in itself is rarely severe enough to warrant medical admission. Management consists of referral for appropriate psychosocial support.

SPECIFIC CONSIDERATIONS

References

94 94 TOXICOLOGY HANDBOOK

Romanelli F, Smith KM. Clinical effects and management of amphetamines. Pharmacotherapy 2006; 26(8):1148–1156. 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 DEPENDENCE AND 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. 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: l Anxiety, restlessness and dysphoria l Insomnia l Intense craving l Yawning

l Lacrimation l Salivation

l Rhinorrhoea l Anorexia,

nausea and vomiting cramps and diarrhoea

l Piloerection l Diaphoresis l Flushing l Myalgia

and arthralgia 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. l Hypertension

CO-MORBIDITIES

Co-morbidities that should be considered in patients with opioid withdrawal include: l Alcohol or sedative-hypnotic withdrawal syndrome l Dehydration l Electrolyte abnormalities l Infective complications of intravenous drug abuse l Psychiatric morbidities.

MANAGEMENT

Administration of opioids in sufficient dose will abolish all physiological manifestations of the withdrawal syndrome. Administration of opioids to 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 drugfree 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 non-judgmental way are vital to engage the patient in a realistic withdrawal treatment program. Admission to hospital may be required in the following circumstances: l Severe withdrawal syndrome (e.g. following administration of antagonist) l Significant complications (e.g. severe dehydration) l Significant intercurrent illness (e.g. sepsis) l Psychiatric co-morbidity. Pharmacologic treatment of opioid withdrawal is categorised into three types: opioid replacement therapy (e.g. methadone; buprenorphine), antagonist detoxification (e.g. naltrexone), and symptomatic treatment.

95 TOXICOLOGY HANDBOOK

l Mydriasis

SPECIFIC CONSIDERATIONS

l Abdominal

SPECIFIC CONSIDERATIONS

1 Opioid replacement therapy

96 96 TOXICOLOGY HANDBOOK

Methadone is used in opioid withdrawal and for maintenance in abstinence programs. Patients on methadone maintenance have markedly reduced mortality (25%) compared with those continuing illicit opioid use, due to decreased rates of heroin overdose or suicide. Methadone programs do not reduce mortality from non-heroin overdose, violence, trauma or natural causes. 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. Buprenorphine treatment is superior to clonidine and as effective as methadone in ameliorating withdrawal, treatment retention and treatment completion. Doses may start at 4–16 mg/day, and are also tapered over many weeks. 2 Detoxification

Rapid detoxification, using naltrexone, buprenorphine and clonidine in various combinations, or rapid tapering of methadone has been successful in selected patients. Efficacy depends on patient selection and TABLE 2.14.1 Symptomatic treatment of opioid withdrawal Dehydration Fluid resuscitation Nausea and vomiting Metoclopramide 10 mg or prochlorperazine 5 mg PO, 6 hourly as required Abdominal cramps and diarrhoea Hyoscine 20 mg PO every 6 hours or atropine–diphenoxylate (2.5 mg– 25 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 alpha2-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.

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.

SPECIFIC CONSIDERATIONS

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 remains unproven and controversial.

References

2.15  SEDATIVE-HYPNOTIC DEPENDENCE AND 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: l Benzodiazepines l Barbiturates l Non-benzodiazepine sedative-hypnotic agents (zolpidem, zopiclone) l Baclofen l Gamma-hydroxybutyrate (GHB) l Chloral hydrate l Paraldehyde.

PATHOPHYSIOLOGY

The sedative-hypnotic agents all modulate activity of the gamma aminobutyric acid (GABA) neurotransmitter complex. Abrupt withdrawal leads to symptoms of GABA excess.

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Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England Journal of Medicine 2003; 348:1786–1795. Olmedo R, Hoffman RS. Withdrawal syndromes. Emergency Medicine Clinics of North America 2000; 18(2):273–288. Tetrault JM, O’Connor PG. Substance abuse and withdrawal in the critical care setting. Critical Care Clinics 2008; 24:767–788. Webster IW (Chair of the Detoxification Guidelines Project Steering Committee). New South Wales Detoxification Guidelines. NSW Health Department 1999. State Health Publication Number (DTPU) 990049, May 1999.

SPECIFIC CONSIDERATIONS

CLINICAL FEATURES

98 TOXICOLOGY HANDBOOK

98

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. GBH) 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 dependence and withdrawal and Chapter 3.23: Cannabinoids (marijuana)). The commonly observed clinical features resemble those of alcohol withdrawal (see Chapter 2.12: Alcohol abuse, dependence and withdrawal), although psychomotor and autonomic nervous system signs may be more prominent: l Irritability and agitation l Anorexia l Inattention l Memory disturbances l Insomnia l Palpitations l Perceptual disturbances, including photophobia and hyperacusis l Hallucinations l Increased spasticity (baclofen).

CO-MORBIDITIES

Co-morbidities that should be considered in patients with sedativehypnotic withdrawal include: l Alcohol withdrawal syndrome l Dehydration l Electrolyte abnormalities l 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. Where the aim is to achieve permanent safe withdrawal or dose reduction then alternative management strategies are adopted. The usual

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: l History of severe withdrawal l Poor social support l Failure of unsupervised outpatient withdrawal. Inpatient sedative-hypnotic withdrawal is appropriate for a minority of patients in whom there is a significant risk of delirium or seizures: l Presentation in severe withdrawal l Abnormal vital signs after initial treatment l Hallucinations l Altered conscious state l Seizures l Presence of medical complications or co-morbidities l Presence of significant psychiatric co-morbidities. 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. McDonough M, Kennedy N, Glasper A et al. Clinical features of gamma-hydroxybutyrate (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.

SPECIFIC CONSIDERATIONS

DISPOSITION

99 TOXICOLOGY HANDBOOK

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 abuse, dependence and withdrawal). 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.

SPECIFIC CONSIDERATIONS

2.16  SOLVENT ABUSE, DEPENDENCE AND WITHDRAWAL

100 0

10 TOXICOLOGY HANDBOOK

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 TABLE 2.16.1 Chemicals used for inhalational abuse Aliphatic hydrocarbons Acetylene n-Butane Isobutane n-Hexane Propane Aromatic hydrocarbons Cyclopropane 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

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.

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.

SPECIFIC CONSIDERATIONS

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 purposes 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.

101

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.

MODES OF ABUSE

Solvent abusers always employ the inhalational route with the following methods described: l ‘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 l ‘Bagging’: the liquid is poured into a bag and the bag held over the head l ‘Sniffing’ or ‘snorting’: liquid is inhaled directly from the container.

CLINICAL FEATURES

The solvent abuser may present with acute solvent neurotoxicity or with the CNS, metabolic, behavioural and social complications associated with chronic abuse. Acute inhalational exposure

Acute inhalation predominantly affects the CNS, causing altered cognition that resembles ethanol intoxication. General impairment of psychomotor function, as measured by reaction time, manual dexterity,

TOXICOLOGY HANDBOOK

MECHANISM OF TOXICITY

SPECIFIC CONSIDERATIONS

102 2

10 TOXICOLOGY HANDBOOK

coordination and body balance occurs. 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 and throat. 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 (lipidrich 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 preexisting 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+ 30 also consider toxic alcohol intoxication and alcoholic ketoacidosis.

TABLE 2.19.2 Causes of a low anion gap (100 ms suggests blockade of cardiac fast sodium channels. In combination with right axis deviation of the terminal QRS, it is virtually pathognomonic (see Figure 2.20.3). Most studies examine ECG changes in TCA intoxication and are small or retrospective. However, the following appear to be associated with major toxicity: l QRS >100 ms (2.5 small squares) is associated with seizures l QRS >160 ms (4 small squares) is associated with ventricular dysrhythmias l Right axis deviation of the terminal QRS as defined by a Terminal R wave >3 mm in AVR b R/S ratio >0.7 in AVR.

SPECIFIC CONSIDERATIONS

5 D  etermine 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 pointes is more likely to occur where there is coexisting bradycardia. The arrhythmogenic risk for drug-induced QT prolongation is accurately predicted by the ‘QT nomogram’, which plots QT versus heart rate (see Figure 2.20.4). 6 Check for evidence of increased cardiac ectopy or automaticity 7 Check for evidence of hyperkalaemia 8 Check for evidence of myocardial ischaemia. FIGURE 2.20.4 QT interval nomogram for determining ‘at risk’ QT-HR pairs from a single 12-lead ECG

118 TOXICOLOGY HANDBOOK

8

11

QT interval (msec)

20

40

60

80

100

120

140

160

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 then 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.

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; 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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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: 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. Hypoxia, hypotension, hypoglycaemia and seizures in the mother are avoided where possible. If they occur they are promptly identified and corrected. 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: l Carbon monoxide l Methaemoglobin-inducing agents l Lead l Salicylates.

SPECIFIC CONSIDERATIONS

2.21  POISONING DURING PREGNANCY AND LACTATION

SPECIFIC CONSIDERATIONS

120 0

12 TOXICOLOGY HANDBOOK

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. 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.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l l





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 l 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 l Breath ethanol estimation provides a convenient bedside estimation of blood ethanol concentration but the result is influenced by minute ventilation.

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

l

SPECIFIC TOXINS

SI units (mmol/L)

131 TOXICOLOGY HANDBOOK

Ethanol dose (g/kg)

SPECIFIC TOXINS



l



l



l



l l



l



l



l

 asic resuscitative measures ensure the survival of the vast B majority of patients General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring Give thiamine 100 mg PO or IV 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 is not indicated Enhanced elimination Elimination of ethanol is enhanced by haemodialysis. However, as a good outcome is ensured with thorough supportive care, it is not routinely indicated Antidotes None available.

DISPOSITION AND FOLLOW-UP

132



TOXICOLOGY HANDBOOK

2

13

l

 atients with mild CNS depression are managed supportively in P a ward environment. When the patient is cooperative, clinically well, ambulant, passing urine, eating and drinking, discharge may occur l Patients with significant CNS depression require intubation and admission to an intensive care unit l Where appropriate, patients are counselled regarding ethanol abuse prior to discharge, as discussed in Chapter 2.12: Alcohol abuse, dependence and withdrawal.

HANDY TIPS



l

 serum ethanol concentration confirms the diagnosis of ethanol A intoxication but does not exclude other causes of CNS depression (e.g. co-ingestion, trauma, metabolic disorder) l Anticipate alcohol withdrawal during the observation period in patients with alcohol dependence.

PITFALLS

l l

 ailure to regard ethanol intoxication as potentially life threatening F Failure to detect and manage coexisting intoxications or other medical conditions in the ethanol intoxicated patient l Discharge of ethanol intoxicated patients before they are competent to make decisions about their own welfare and ensure their own safety.

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%

 ethylated spirits: 95% (Australia) M Mouth wash, food extracts and flavourings (e.g. vanilla extract 35% ethanol), cough and cold syrups, perfumes and cosmetics

References

3.2  ALCOHOL: ETHYLENE GLYCOL Ethylene glycol (EG) is a toxic alcohol. Deliberate self-poisoning is usually lethal without timely intervention.

SPECIFIC TOXINS

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.

RISK ASSESSMENT



l



l l l

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 1–4 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 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 17 hours, as EG has to be eliminated exclusively by the kidney. CLINICAL FEATURES

l

 he clinical course of EG intoxication is often described as T occurring in three stages (CNS, cardiopulmonary and renal), but these are artificial descriptions of a rapid clinical course

133 TOXICOLOGY HANDBOOK



Ingestion of >1 mL/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 l Co-ingestion of ethanol complicates risk assessment (see Investigations below) l Dermal and inhalation exposure does not lead to EG intoxication









SPECIFIC TOXINS





Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level

l

Specific investigations



4

13 TOXICOLOGY HANDBOOK

Initial clinical features develop within the first 1–2 hours and are similar to those of ethanol intoxication: — Euphoria, nystagmus, drowsiness, nausea and vomiting l 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 l Flank pain and oliguria indicate acute renal failure l Late cranial neuropathies (involving cranial nerves II, V, VII, VIII, IX, X and XII) are described up to 5–20 days later.

INVESTIGATIONS



134

l













l

 UC (including chloride), serum lactate, serum osmolality and E arterial blood gases — 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 — See Chapter 2.18: Osmolality and the osmolar gap and Chapter 2.19: Acid–base disorders for discussion of interpreting acid–base disturbances, anion and osmolar gaps l Breath or serum ethanol level — Required to determine whether there has been co-ingestion of ethanol, or to titrate ethanol treatment l Serum EG level — Not readily available at most locations in a clinically useful timeframe. Where available, it provides definitive confirmation of EG intoxication l Urine microscopy — Presence of calcium oxalate crystals in the urine is pathognomonic of ethylene intoxication but their absence does not exclude the diagnosis.

MANAGEMENT

Resuscitation, supportive care and monitoring l Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation l Patients with severe EG intoxication are acidaemic with a degree of respiratory compensation: — Intubation without maintaining hyperventilation exacerbates acidaemia and may result in an acute decompensation, and even death

l



l



l



l



l



l











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 l Lactate-free dialysates with added bicarbonate may assist correction of acidaemia l Indications for haemodialysis: — History of large EG ingestion with osmolar gap >10 — Acidaemia with pH 8 mmol/L (50 mg/dL) if available l 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.

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 43 hours, as methanol is eliminated exclusively by the kidney. CLINICAL FEATURES

l



l



l



l



l

 ild CNS depression similar to that of ethanol intoxication is M 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 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

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l



Specific investigations EUC (including chloride), serum lactate, serum osmolality and arterial 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: Osmolality and the osmolar gap and Chapter 2.19: Acid–base disorders for discussion of interpreting acid–base disturbances, anion and osmolar gaps

139 TOXICOLOGY HANDBOOK

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.

SPECIFIC TOXINS

Toxic mechanism









l

Breath or serum ethanol level — Required to determine whether there has been co-ingestion of ethanol, or to titrate ethanol treatment l Serum methanol levels — Not readily available in a clinically useful timeframe l Radiology — Brain CT scan demonstrates characteristic injury to the basal ganglia in patients with permanent neurological sequelae.

MANAGEMENT

SPECIFIC TOXINS



140





TOXICOLOGY HANDBOOK

0

14

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 l 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 x 50-g pellet packs in a 75-kg adult l Anticoagulation is usually associated with repeated ingestion. In this scenario, severe, prolonged (weeks to months) anticoagulation requiring massive doses of vitamin K is anticipated



l

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

l l

 atients are usually asymptomatic P Severe coagulopathy manifests as bruising, petechial or purpural rashes, gingival bleeding, epistaxis or haematuria l 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, BSL and paracetamol level



l



l









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 l Superwarfarin levels — Useful in cases where paediatric non-accidental injury or occult poisoning is suspected.

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. l 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 l

155 TOXICOLOGY HANDBOOK

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

l



l l



l



l

SPECIFIC TOXINS



156

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 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. CLINICAL FEATURES

l CNS depression l Anticholinergic syndrome

including delirium (see Chapter 2.9: Anticholinergic syndrome) l Seizures, hyperthermia and rhabdomyolysis are rare l Significant hypotension requiring inotropic support and cardiac conduction abnormalities secondary to fast sodium channel blockade (e.g. diphenhydramine) occur rarely after massive overdose.

INVESTIGATIONS

Screening tests in deliberate self-poisoning ECG, BSL and paracetamol level



l 12-lead



l Serial



Specific investigations as indicated 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 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

l Resuscitation



supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l Manage anticholinergic delirium as outlined in Chapter 2.9: Anticholinergic syndrome l Manage seizures along conventional lines, as outlined in Chapter 2.6: Approach to seizures l Hypotension usually responds to fluid administration. If not, an α1adrenergic agonist (noradrenaline) is second-line therapy l In the rare event of ventricular dysrhythmias, intubate, hyperventilate and give IV bolus sodium bicarbonate, as outlined in Chapter 4.25: Sodium bicarbonate Decontamination charcoal is not routinely indicated because the onset of sedation occurs in the first few hours and simple supportive care ensures a good outcome



l Activated



l Not



l Physostigmine

Enhanced elimination clinically useful Antidotes

administration is considered in patients with severe anticholinergic delirium not controlled with benzodiazepines (see Chapter 4.22: Physostigmine).

DISPOSITION AND FOLLOW-UP







l Patients

who remain asymptomatic and have a normal 12-lead ECG at 6 hours may be discharged. Discharge should not occur at night l 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 l Patients with significant agitation or delirium, and those requiring intubation, require admission to a high-dependency or intensive care unit l Ongoing cardiac monitoring is reserved for patients with abnormal ECGs, until changes resolve.

HANDY TIPS

l Antihistamines

properties.

may be abused for their anticholinergic

PITFALLS

l Failure

to recognise anticholinergic delirium because of concomitant sedative effects l Failure to detect and relieve urinary retention. This exacerbates agitation and prevents control with benzodiazepine sedation.

CONTROVERSIES

l Role

of physostigmine in the management of antihistamineinduced anticholinergic delirium.

SPECIFIC TOXINS



l General

163 TOXICOLOGY HANDBOOK



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)

SPECIFIC TOXINS

Ethanolamines

164

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

4

16

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

TOXICOLOGY HANDBOOK

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. 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.

3.14  ARSENIC 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



l Acute

or subacute ingestion of inorganic arsenic leads to a dosedependent sequential pattern of multiple organ failure: — Ingestion of >1 mg/kg is potentially lethal





— Ingestion of 10 years) drinking of contaminated artesian water l Children:

Any ingestion of arsenic insecticide should be regarded as potentially lethal.

Toxic mechanism

Toxicokinetics

Absorption occurs via dermal, respiratory and gastrointestinal routes. Elimination halflife 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.

SPECIFIC TOXINS

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.

CLINICAL FEATURES





Acute toxicity large ingestions there is rapid onset of severe watery diarrhoea (‘choleroid’ or ‘rice water diarrhoea’), vomiting and abdominal pain l Gastrointestinal haemorrhage may occur l Encephalopathy, seizures, and cardiovascular collapse develop within hours l Hypersalivation is characteristic, as is a garlic odour l Acute cardiomyopathy, ECG changes (prolonged QT) and cardiac dysrhythmias are described l Acute adult respiratory distress syndrome, renal failure and hepatic injury follow l Bone marrow depression develops within 24–72 hours in survivors, reaching a nadir in 2–3 weeks l Alopecia occurs in survivors of the initial phase l 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 l Initially manifests with gastrointestinal symptoms, leucopenia, deranged liver function and haematuria l Peripheral neuropathy develops after several weeks Chronic toxicity l 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. l Following

INVESTIGATIONS

Screening tests in deliberate self-poisoning ECG, BSL and paracetamol level

l 12-lead

165 TOXICOLOGY HANDBOOK









SPECIFIC TOXINS







166 6

16 TOXICOLOGY HANDBOOK

Specific investigations as indicated urinary arsenic (normal 1000 microgram/L (13 500 nmol/L) l 24–hour urinary arsenic excretion (normal 200 microgram/L or 2700 nmol/L) l Succimer is the agent of choice where oral administration is available (see Chapter 4.28: Succimer)





l 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) l 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

at 12 hours following acute ingestion of arsenic are not poisoned and may be discharged l Patients in whom clinical features develop following acute ingestion of inorganic arsenic require admission for observation, aggressive supportive care and chelation.

HANDY TIPS



l Chelation

therapy of acute arsenic intoxication is not delayed pending confirmatory levels l 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 l Patients should be instructed to avoid eating seafood or seaweed for 3–4 days prior to 24-hour urinary arsenic level l Cutting or burning pine impregnated with copper chrome arsenate preservative may cause symptoms of mucosal irritation from smoke or sawdust but does not cause arsenic poisoning. Elevated arsenic levels are associated with long-term occupational or domestic exposure to this compound.

PITFALLS

l Ordering

‘heavy metal screens’ on patients with non-specific symptoms without exposure assessment—these are rarely clinically useful.

CONTROVERSIES



l 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 l Analysis of hair for metals is frequently subject to artefacts and is not recommended l 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

SPECIFIC TOXINS



l Chronic intoxication can be managed on an outpatient basis l Patients who are clinically well without gastrointestinal symptoms

167 TOXICOLOGY HANDBOOK



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.

SPECIFIC TOXINS

3.15  BETA-BLOCKERS

168 8

16 TOXICOLOGY HANDBOOK

Atenolol, Bisoprolol, Carvedilol, Esmolol, Metoprolol, Oxprenolol, Pindolol, Propranolol, Sotalol 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





l Toxicity does l The following

not correlate well with ingested dose factors increase risk of severe toxicity: — Ingestion of propanolol/sotalol — Underlying heart or lung disease — Co-ingestion/regular treatment with calcium channel blocker or digoxin — Advanced age l The threshold dose for severe toxicity from propranolol may be as little as 1 g l Toxicity usually manifests within the first few hours, with the exception of overdose with controlled-release preparations or sotalol l PR interval prolongation even in the absence of bradycardia is an early sign of toxicity l 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 beta1 and beta2 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 arrhythmias 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 postingestion. 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 to around 60 beats/minute. More severe manifestations may also occur during this period following propranolol overdose or where there are other factors predisposing to severe effects.

Cardiovascular



sinus bradycardia, 1st to 3rd degree heart block, junctional or ventricular bradycardia l QRS widening is observed following propranolol overdose and the magnitude is a predictor of ventricular arrhythmias l QT prolongation is observed following sotalol overdose Central nervous system l Delirium, coma and seizures (propranolol) Other l Bronchospasm, pulmonary oedema l Hyperkalaemia l Hypo/hyperglycaemia.

INVESTIGATIONS

Screening tests in deliberate self-poisoning ECG, BSL and paracetamol level



l 12-lead



l EUC

Specific investigations as indicated

MANAGEMENT









Resuscitation, supportive care and monitoring l Acute beta-blocker poisoning is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation. l Resuscitation is most likely to be required following propranolol overdose. Prompt intubation and ventilation and administration of sodium bicarbonate are necessary to control ventricular arrhythmias (propanolol overdose is managed as a tricyclic antidepressant overdose) l 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 (peripheral vasodilation-beta2) – 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 l Close clinical observation and continuous ECG monitoring is mandatory for at least 4 hours l Invasive monitoring of haemodynamic parameters is very useful in sick patients

Decontamination l 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

SPECIFIC TOXINS



l Hypotension and bradycardia l Bradyarrhythmias observed include

169 TOXICOLOGY HANDBOOK



Enhanced elimination clinically useful



l Not



l None

Antidotes available.

DISPOSITION AND FOLLOW-UP

SPECIFIC TOXINS



who remain asymptomatic and have a normal ECG at 6 hours following the overdose may be medically cleared l Patients with clinical or ECG manifestations of toxicity require admission to an intensive care or high-dependency unit.

HANDY TIPS

l Approach

management of a propranolol overdose more like a tricyclic antidepressant or other Na-channel blocker overdose rather than a beta-blocker overdose

CONTROVERSIES

170 0

17 TOXICOLOGY HANDBOOK

l Patients





(see Chapter 4.12: Glucagon) has been regarded as a specific antidote to beta-blocker poisoning but it offers no advantages over standard inotropes and chronotropes. It can also be very difficult to source sufficient stocks and its use in betablocker poisoning is largely abandoned l 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 l 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). l Glucagon

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 self-poisoning with beta-blockers. Journal of Toxicology-Clinical Toxicology 1993; 31:531–551.

RISK ASSESSMENT



l Ingestions

>200 mg in adults are expected to cause significant CNS effects, including delirium, respiratory depression, coma and seizures l Ingestions of smaller doses cause relatively mild symptoms l 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. It is also mediates pre- and post-synaptic inhibition, causing paradoxical 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





l 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 – Hypertension – 1st degree heart block and QT prolongation (rare) l Delirium is most evident just prior to the onset of coma or upon awakening l Following large ingestions, coma may be profound. The patient may appear brain dead with fixed dilated pupils, absent brainstem (doll’s eyes, oculocephalic and corneal) reflexes and profound hypotonia l The duration of coma is usually between 24 and 48 hours.

171 TOXICOLOGY HANDBOOK

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.

SPECIFIC TOXINS

3.16  BACLOFEN

INVESTIGATIONS

Screening tests in deliberate self-poisoning ECG, BSL and paracetamol level

l 12-lead

MANAGEMENT

SPECIFIC TOXINS



172





Decontamination l Activated charcoal is avoided in the patient with an unprotected airway due to the risk of imminent coma and seizures



l Not



l None

2

17 TOXICOLOGY HANDBOOK

Resuscitation, supportive care and monitoring poisoning is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation l Respiratory depression and coma necessitate advanced airway management with early intubation and ventilation l Level of consciousness should be closely monitored during the first few hours l Seizures, should they occur, are managed with titrated doses of IV diazepam l Hypotension usually responds to fluid boluses. Inotropes are not usually required l Baclofen

Enhanced elimination clinically useful Antidotes available.

DISPOSITION AND FOLLOW-UP



l Following

baclofen overdose, all patients are closely observed for at least 4 hours l Patients who are asymptomatic at 4 hours following ingestion may be discharged. Discharge should never occur at night l Those manifesting minor CNS features such as delirium, require medical admission for ongoing supportive care until all clinical features resolve l Patients with significant CNS depression require intubation and are admitted to an intensive care unit.

HANDY TIPS





l 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 l 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 l Baclofen withdrawal syndrome occurs between 24 and 48 hours post cessation of baclofen and is manifested by seizures, hallucinations, dyskinesia and visual disturbances.

CONTROVERSIES



l 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 10 mg tablets (100) Baclofen 25 mg tablets (100)

Reference

Leung NY, Whyte IM, Isbister GK. Baclofen overdose: Defining the spectrum of toxicity. Emergency Medicine Australasia 2006; 18:77–82.

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 timely appropriate interventions will assure a good outcome. RISK ASSESSMENT

l Ingestion



l 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-amino butyric 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 interindividual variation (35–140 hours) and, as a result of saturable kinetics, may be prolonged even further after overdose.

173 TOXICOLOGY HANDBOOK



of >8 mg/kg is expected to produce toxic neurological symptoms in the non-tolerant individual. Multiples of this dose are expected to produce profound prolonged coma l 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

3.17  BARBITURATES

CLINICAL FEATURES



SPECIFIC TOXINS







174 TOXICOLOGY HANDBOOK

4

17





l Barbiturate

toxicity may develop with therapeutic administration of phenobarbitone or primidone. Symptoms are mild and neurological in nature; they resolve with cessation of administration l Barbiturate overdose is characterised by profound, prolonged and potentially fatal depression of the central nervous and cardiovascular systems l 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 neurologic 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 vasodilatation 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.

INVESTIGATIONS

Screening tests in deliberate self-poisoning ECG, BSL and paracetamol level



l 12-lead



l Serum





Specific investigations as indicated 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 3.17.1) — 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

TABLE 3.17.1  Correlation of serum phenobarbitone levels and clinical features

15–25 mg/L (65–108 micromol/L)

Usual therapeutic range

30–80 mg/L (130–350 micromol/L)

Increasing sedation

>80 mg/L (>345 micromol/L)

Coma requiring intubation

l 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 patients are managed in an area equipped for cardiopulmonary monitoring and resuscitation l Attention to airway, breathing and circulation are paramount. These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation l The need for intubation is anticipated and performed early in the patient with a declining level of consciousness l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l All

Decontamination charcoal 50 g is administered via a nasogastric tube to the unconscious patient only after the airway is secured by endotracheal intubation



l Activated



l The







SPECIFIC TOXINS



Clinical features

Enhanced elimination pharmacokinetics of phenobarbitone render it suitable for enhanced elimination techniques. The aim of instituting these interventions is to reduce duration of coma and length of ventilation in intensive care, which might otherwise amount to days or weeks l 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 l Haemodialysis, haemoperfusion and haemodiafiltration efficiently remove phenobarbitone. These invasive interventions are indicated for the patient with markedly elevated levels (>100 mg/L, >430 micromol/L) or where levels are rising or have plateaued despite MDAC, or where continued MDAC is not feasible due to ileus Antidotes l None available.

175 TOXICOLOGY HANDBOOK



Level

DISPOSITION AND FOLLOW-UP



SPECIFIC TOXINS



l 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 l 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 then further observation is not required l 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

l 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.

PITFALLS

176



6

17 TOXICOLOGY HANDBOOK

l Failure

to consider the diagnosis of barbiturate toxicity. Along with carbamazepine and valproate poisoning, it is an unusual but eminently treatable cause of coma.

CONTROVERSIES



l Urinary

alkalinisation has been shown to enhance elimination of phenobarbitone but it is inferior to MDAC and not recommended l Although MDAC effectively enhances phenobarbitone elimination, it has not been shown to reduce duration of coma or length of stay in intensive care l The indications for, method and timing of haemodialysis are not clearly defined. The decision involves clinical judgment of the patient’s clinical course and a risk–benefit analysis of the procedure.

Presentations

Pentobarbitone sodium: available as a veterinary preparation (used to euthanase animals) Phenobarbitone 15 mg/5 mL elixir (100 mL) Phenobarbitone 30 mg tablets (200) Phenobarbitone sodium 200 mg/1 mL ampoules Primidone 250 mg tablets (200) Thiopentone sodium 500 mg ampoules for reconstitution

References

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.

3.18  BENZODIAZEPINES Alprazolam, Bromazepam, Clobazam, Clonazepam, Diazepam, Flunitrazepam, Midazolam, Nitrazepam, Oxazepam, Temazepam, Triazolam Also covers the non-benzodiazepine sedative-hypnotics: Zolpidem, Zopiclone











l Isolated

benzodiazepine overdose usually causes only mild sedation, irrespective of the dose ingested, and can be easily managed with simple supportive care l Alprazolam overdose is associated with greater degree of CNS depression and is more likely to require intubation and ventilation l Zolpidem and zopiclone rarely cause severe CNS or respiratory depression when taken alone l Co-ingestion of other CNS depressants (e.g. alcohol, opioids, antidepressants) increases the risk of complications, prolonged length of stay and death l The elderly and patients with cardiorespiratory co-morbidities may suffer greater complications l Children:

Ingestion of one or two benzodiazepines usually manifests as mild sedation and ataxia within 2 hours.

Toxic mechanism

Benzodiazepines act by enhancing gamma-amino butyric acid (GABA) mediated neurotransmission. They bind to the GABAA receptor complex and increase the 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. CLINICAL FEATURES



l Onset

of symptoms occurs within 1–2 hours. Ataxia, lethargy, slurred speech and drowsiness are followed by decreased responsiveness. Profound coma is rare. Apnoea is a complication of airway obstruction. l 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.

177 TOXICOLOGY HANDBOOK

RISK ASSESSMENT

SPECIFIC TOXINS

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.

INVESTIGATIONS

Screening tests in deliberate self-poisoning ECG, BSL and paracetamol level.

l 12-lead

MANAGEMENT



SPECIFIC TOXINS



178



Decontamination l 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 clinically useful



l Not



l Flumazenil

Antidotes

8

17 TOXICOLOGY HANDBOOK

Resuscitation, supportive care and monitoring to airway, breathing and circulation are paramount. These priorities can usually be managed along conventional lines, as outlined in Chapter 1.2: Resuscitation l Basic resuscitative measures ensure the survival of the vast majority of patients l Monitor for urinary retention and place an indwelling catheter as required l Attention



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 l For further information on the indications, contraindications and administration see Chapter 4.9: Flumazenil.

DISPOSITION AND FOLLOW-UP





l 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 l Patients with mild sedation are managed supportively in a ward environment. They may be discharged when clinically well. Discharge should not occur at night l Patients with significant CNS depression requiring intubation or flumazenil infusion are admitted to a high-dependency or intensive care unit (rare).

HANDY TIPS

l Profound

coma, tachycardia or 12-lead ECG changes suggest a co-ingested agent and the need to revise the risk assessment l Flumazenil may be life saving in selected patients when the airway and breathing cannot be controlled by other means.

PITFALLS

l Administration

of flumazenil when contraindicated because of the risk of seizures.

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 10 mg tablets (7, 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.

3.19  BENZTROPINE Frequently prescribed to patients on antipsychotics to ameliorate dyskinesias, this is a potent anticholinergic agent in overdose. RISK ASSESSMENT

l Any

overdose of this agent is likely to precipitate anticholinergic symptoms and require medical care l Anticholinergic syndrome can also occur with excessive therapeutic doses.

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. CLINICAL FEATURES

l 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

SPECIFIC TOXINS

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) Bromazepam 6 mg tablets (30) Clobazam 10 mg tabletss (50) Clonazepam 0.5 mg tablets (100) Clonazepam 2 mg tablets (100) Clonazepam 2.5 mg/1 mL liquid Clonazepam 1 mg/1 mL ampoules Diazepam 2 mg tablets (30, 50, 90) Diazepam 5 mg tablets (30, 50) Diazepam 10 mg/10 mL liquid (100 mL) Diazepam for injection 10 mg/2 mL ampoules

179 TOXICOLOGY HANDBOOK

Presentations



l 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 ECG, BSL and paracetamol level



l 12-lead



l Other

Specific investigations as indicated tests including EUC, CT head and lumbar puncture are indicated if necessary to exclude important alternative diagnoses such as intracranial infection.

SPECIFIC TOXINS

MANAGEMENT



180 TOXICOLOGY HANDBOOK

0

18

Resuscitation, supportive care and monitoring is supportive and consists principally of sedation with benzodiazepines, intravenous fluids and insertion of an indwelling urinary catheter l Control of delirium can be challenging. Physical restraints are sometimes necessary l Once adequate sedation is attained, one-to-one nursing in a calm, closely monitored environment is essential to ensure patient safety l For a more detailed description of the management of anticholinergic syndrome see Chapter 2.9: Anticholinergic syndrome l Management



Decontamination l Activated charcoal may be useful if administered within 2 hours of ingestion l It is of little value, not to mention technically challenging, once delirium is established Enhanced elimination clinically useful



l Not



l Physostigmine

Antidote

is considered in cases where the delirium is not easily controlled with benzodiazepines (see Chapter 4.22: Physostigmine).

DISPOSITION AND FOLLOW-UP

l Once

initial control of delirium is attained, admission to a highdependency area with one-to-one nursing in a calm, reassuring environment is essential. Staff should be aware that the delirium might persist several days.

HANDY TIPS



l 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 l Excessive doses of benztropine, like other anticholinergic agents, are sometimes consumed for recreational purposes.

PITFALLS

l Failure

to distinguish anticholinergic delirium from psychosis or antisocial personality disorder.

CONTROVERSIES

l 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

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 lifethreatening cardiotoxicity occurs with very high doses. Supportive care and adequate benzodiazepine sedation usually ensure a good outcome.

SPECIFIC TOXINS

3.20  BUPROPION

RISK ASSESSMENT

l High risk of seizures following overdose of any amount l The first seizure is usually delayed 2–8 hours following ingestion



l Risk





but may be delayed up to 24 hours of seizures is increased if there is a preexistent lowered seizure threshold or co-ingestion of other centrally acting sympathomimetic or serotonergic agents l Severe cardiotoxicity, haemodynamic instability and cardiac deaths have occurred at doses >9 g l Children:

Any child suspected of ingesting >10 mg/kg requires assessment and observation in hospital.

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 arrhythmias. 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.

181 TOXICOLOGY HANDBOOK



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



SPECIFIC TOXINS



Screening tests in deliberate self-poisoning ECG, BSL and paracetamol level



l 12-lead



l Serial



2

18 TOXICOLOGY HANDBOOK

features develop progressively over 8 hours and include tachycardia, hypertension, tremors, GI disturbance, agitation, hallucinations, altered mental state and seizures l First seizure, heralded by neurological symptoms, usually occurs during this period but may be delayed up to 24 hours postingestion l Cardiovascular effects and ECG manifestations, including shock, QRS widening and tachydysrhythmias, are reported after massive overdose and manifest within 6 hours.

INVESTIGATIONS



182

l Clinical

Specific investigations as indicated ECGs — Perform a 12-lead ECG on all patients at presentation and at 6 hours post-ingestion — For ingestions >4.5 g, 12-lead ECGs should be reviewed every 2 hours (or if symptoms occur).

MANAGEMENT











Resuscitation, supportive care and monitoring overdose is a life-threatening emergency and is managed in an area equipped for cardiorespiratory monitoring and resuscitation l Early intubation and ventilation is indicated when the history and clinical progression suggest ingestion of >9 g l Clinical features that require immediate intervention include: — Seizures: give IV diazepam 5–10 mg and repeat if necessary as described in Chapter 2.6: Approach to seizures — Broad-complex tachycardias: manage aggressively with intubation, ventilation 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 l Control agitation and tachycardia with titrated doses of IV diazepam: give 2.5–5 mg every 2–5 minutes until gentle sedation achieved l Continue close monitoring for at least 12 hours following ingestions of >9 g l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring. l Bupropion

Decontamination charcoal or other attempts at decontamination are generally contraindicated because of the high risk of seizures l If >9 g is ingested and there is any evidence of toxicity, give activated charcoal 50 g via the nasogastric tube following endotracheal intubation l Activated

Enhanced elimination clinically useful



l Not



l None

Antidotes available.

DISPOSITION AND FOLLOW-UP







l 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 l Patients who are clinically well at 24 hours following ingestion do not require further medical observation. Discharge should never occur at night l Patients with cardiotoxicity or seizures are admitted for monitoring and supportive care until all clinical features of toxicity, including sinus tachycardia, resolve l Admission to ICU is indicated following massive ingestions (>9 g) and for patients manifesting signs of significant cardiotoxicity.

HANDY TIPS

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 pulse rate towards 100/minute.

SPECIFIC TOXINS



l It

183



l Failure

to anticipate and prepare for delayed onset of symptoms and seizures l Failure to administer benzodiazepines early and in sufficient dose l Administration of activated charcoal or initiation of whole bowel irrigation shortly before onset of seizures or cardiovascular toxicity.

CONTROVERSIES



l 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 l Intravenous lipid emulsion has been advocated in the management of severe bupropion toxicity but its role is as yet undefined.

Presentations

Bupropion hydrochloride 150 mg sustained-release tablets (30, 90)

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.

TOXICOLOGY HANDBOOK

PITFALLS

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. RISK ASSESSMENT

SPECIFIC TOXINS



184 4

18 TOXICOLOGY HANDBOOK



l

Ingested batteries of diameter 15 mm diameter (and usually >20 mm) may lodge in the oesophagus and cause severe local injury, including mucosal burns and strictures, oesophageal perforation, tracheooesophageal fistula and haemorrhage l Local injury may also occur after insertion of batteries into the aural or nasal cavities l Button batteries may contain manganese, silver, mercury, lithium or zinc but the quantities available for absorption are insufficient to cause systemic heavy metal toxicity.

Mechanism of injury

Local injury from ingested button batteries occurs as a result of direct pressure necrosis and leakage of alkali. Mucosal burns and strictures, oesophageal perforation, tracheooesophageal fistula and haemorrhage can develop. Elevated mercury levels are described after ingestion of mercuric oxide-containing batteries but severe toxicity is not reported. CLINICAL FEATURES



l

 he majority of patients are asymptomatic initially. They may T 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 l The most frequent symptoms of oesophageal lodgement are dysphagia and pain, although this may be delayed for several days. Many children also develop non-specific symptoms of cough or respiratory distress, irritability or fever if diagnosis is delayed.

INVESTIGATIONS



l

 istory of possible button battery ingestion mandates plain H anteroposterior (together with a lateral if an object is identified above the diaphragm) x-ray of the chest and abdomen to localise the object and guide further management l 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. l Delayed presentation may require resuscitation along standard protocols for cardiovascular collapse secondary to haemorrhage or sepsis from oesophageal perforation, or for respiratory distress from tracheo-oesophageal fistula l





Decontamination A button battery lodged in the oesophagus requires endoscopic removal, ideally within 6 hours of ingestion l 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 l A button battery located beyond the oesophagus in an asymptomatic child can be allowed to pass naturally l Batteries lodged in the nose or ears should be removed urgently. l

DISPOSITION AND FOLLOW-UP



l

 atients with a battery lodged in the oesophagus are referred for P urgent upper GI endoscopy and removal, ideally within 6 hours of ingestion l Patients 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. Repeat x-ray is only required if symptoms of perforation occur.

SPECIFIC TOXINS



HANDY TIPS



l

 atteries typically have a ‘double density’ shape on anteroposterior B view, and a ‘stepped’ appearance on lateral view radiography l A high index of suspicion is required for investigation of small children when a history of ingestion is not available.

PITFALLS

l l

 ailure to perform an x-ray F Mistaking a button battery for a coin on x-ray. Batteries have a distinctive appearance and lateral x-ray may help to identify the object l Delayed referral for endoscopic removal.

CONTROVERSIES



l

 iming of endoscopy. Removal of oesophageal button batteries is T recommended within 6 hours of ingestion; however, mucosal burns have been documented as early as 4 hours after ingestion and oesophageal perforation within 6 hours l Management of button batteries located in the stomach. Some authors recommend repeat x-ray at 48 hours 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.

Sources

Button batteries are commonly found in watches, cameras, electronic games and hearing aids. More recently manufactured devices tend to have smaller button batteries.

References

Alvi A, Bereliani A, Zahtz GD. Miniature disc battery in the nose: A dangerous foreign body. Clinical Paediatics 1997; 36(7):427–429. Sheikh A. Button battery ingestions in children. Paediatric Emergency Care 1993; 9(4):224–229. Yardeni D, Yardeni H, Coran AG et al. Severe esophageal damage due to button battery ingestion: can it be prevented? Paediatric Surgery International 2004; 20:496–501.

185 TOXICOLOGY HANDBOOK



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 not usually associated with severe toxicity.

SPECIFIC TOXINS

RISK ASSESSMENT

186

l



l l



l



l



l



l



l

TOXICOLOGY HANDBOOK

6

18



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) do not usually cause life-threatening toxicity, irrespective of dose 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 vasodilatation. The dihydropyridines chiefly cause the latter. Hypotension results from severe peripheral vasodilation, bradycardia and decreased contractility, associated with hyperglycaemia and lactic acidosis.

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. CLINICAL FEATURES

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 — Myocardial ischaemia, stroke or non-occlusive mesenteric ischaemia may occur l Central nervous system — Seizures and coma are rare — Coma usually indicates a co-ingested agent l Metabolic — Hyperglycaemia and lactic acidosis occur in severe intoxication. l

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



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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 — First, second and third degree heart block may occur l EUC l Serum calcium l Serum lactate and arterial blood gases l Chest x-ray l 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.







Resuscitation, supportive care and monitoring Acute CCB overdose is a time-critical emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation l Hypotension (SBP 10 tablets of verapamil XR or diltiazem XR Enhanced elimination Not clinically useful



l



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 arly invasive blood pressure monitoring is advised for evolving E shock. Inotropic and vasopressor therapy is best guided by pulmonary artery catheter measurements Graduated approach to hypotension: — Fluid resuscitation: give 10–20 mL/kg isotonic crystalloid — Calcium: (see Chapter 4.2: Calcium) – Give 60 mL calcium gluconate 10% (0.6–1.0 mL/kg in children) or calcium chloride 10% 20 mL (0.2 mL/kg) IV over 15 minutes – Although unlikely to be definitive treatment, calcium boluses can produce a temporary increase in heart rate and blood pressure and may be repeated up to three times while other therapies are started – Commence an infusion to maintain calcium level above 2.0 mEq/L Atropine — Administer 0.6 mg every 2 minutes up to 3 mg Catecholamine infusion — Titrate infusion of dopamine, adrenaline and/or noradrenaline High-dose insulin (see Chapter 4.15: Insulin (high dose)) Sodium bicarbonate — Administer 50–100 mEq sodium bicarbonate (0.5–1.0 mEq/kg in children) for metabolic acidosis Cardiac pacing — Ventricular pacing should be used to bypass AV block and rates should not exceed 60 beats/minute. Electrical capture is often difficult to achieve, and may not be associated with improved perfusion Cardiopulmonary bypass and intra-aortic balloon pump have been successfully used as extraordinary manoeuvres

Antidotes As discussed in Resuscitation, supportive care and monitoring above — Calcium (see Chapter 4.2: Calcium) — Atropine (see Chapter 4.1: Atropine) — High-dose insulin therapy (see Chapter 4.15: Insulin (high dose)).

DISPOSITION AND FOLLOW-UP



l

 atients who are clinically well with normal vital signs and 12P lead ECG at 4 hours following standard preparations or 16 hours following XR preparations may be discharged. Discharge should not occur at night l Patients with manifestations of intoxication are referred to an intensive care unit.

HANDY TIPS

 nce significant toxicity has manifested (e.g. SBP 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



 ollowing larger overdoses, anticholinergic effects may be F prominent prior to development of coma l 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 l 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.

193 TOXICOLOGY HANDBOOK

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.

SPECIFIC TOXINS

References

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-Daspartate central adenosine receptors.

Toxicokinetics

SPECIFIC TOXINS

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



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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 erratic absorption for several days frequently complicates large overdoses producing a fluctuating clinical course. l Mild–moderate CNS effects include nystagmus, dysarthria, ataxia, sedation, delirium, mydriasis, ophthalmoplegia and myoclonus l Anticholinergic effects, such as urinary retention, tachycardia and dry mouth, are common in the early stages l Coma requiring intubation and ventilation may be delayed until 8–12 hours post-ingestion. A fluctuating mental status with intermittent agitation may also occur l Large overdoses may be complicated by seizures, hypotension and cardiac conduction abnormalities. Cardiac dysrhythmias (VT, VF, asystole) are associated with massive overdoses.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



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Specific investigations as indicated Serum carbamazepine levels (see Table 3.24.2) Useful to confirm the diagnosis In mild–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





l

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















Decontamination Activated charcoal is considered for ingestions 30 mg/kg l Ingestion of >5 g of chloroquine in adults is usually fatal without intervention l The dose-related risk assessment is less well-defined for hydroxychloroquine, but appears to be similar to chloroquine l

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 Vd 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: l Non specific symptoms of dizziness, nausea and vomiting l Cardiovascular — Rapid onset of hypotension — Cardiac conduction defects (QRS widening, QT prolongation) — Cardiac arrest







Central nervous system — Depressed conscious state — Seizures l Metabolic — Hypokalaemia due to intracellular shift of potassium. l

INVESTIGATIONS



l





Specific investigations as indicated EUC — Detect and monitor hypokalaemia l Serial ECGs — Detect and monitor QRS and QT prolongation — Sinus arrest, varying degrees of heart block l Specific levels are not routinely available and do not assist in management. They may be useful retrospectively to confirm the diagnosis.

MANAGEMENT









Resuscitation, supportive care and monitoring Chloroquine or hydroxychloroquine overdose is a lifethreatening emergency and is managed in an area equipped for cardiorespiratory monitoring and resuscitation l 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 broad complex tachycardias aggressively with intubation, ventilation 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 are controlled with intravenous benzodiazepines l Ensure normokalaemia. Hypokalaemia should be anticipated, but avoid aggressive replacement, as total body potassium is not depleted l 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 l

Decontamination Administration of activated charcoal is withheld until the airway is protected



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Enhanced elimination Not clinically useful Antidote None available.

201 TOXICOLOGY HANDBOOK

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SPECIFIC TOXINS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



DISPOSITION AND FOLLOW-UP



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 ll children suspected of ingesting even one chloroquine or A hydroxychloroquine tablet must be assessed and observed in hospital l Patients who are asymptomatic at 6 hours following ingestion may be discharged. Discharge should never occur at night l Patients with signs of cardiotoxicity or seizures are admitted for observation and supportive care until all clinical features of toxicity including sinus tachycardia resolve l Admission to ICU is indicated following massive ingestions (>30 mg/kg) and for patients manifesting signs of significant cardiotoxicity.

HANDY TIPS

SPECIFIC TOXINS





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 nticipate catastrophic deterioration in any patient presenting early A following chloroquine overdose. Intubate and hyperventilate at the first sign of cardiotoxicity or clinical deterioration l 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.

CONTROVERSIES

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20

 he mechanism of action of high-dose diazepam infusion in T 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)

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. RISK ASSESSMENT

l

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.

CLINICAL FEATURES









Chloral hydrate overdose is characterised by rapid (20 microgram/kg, but large doses are sometimes tolerated with minor effects l Onset of clinical features is rapid, usually within 2 hours of ingestion and always within 6 hours l

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 used in the management of hypertension, migraine, withdrawal states, menopause and pain control. It acts as a sympathoplegic agent, decreasing central nervous sympathetic outflow. It also increases endothelial nitric oxide levels and decreases renin activity.

205 TOXICOLOGY HANDBOOK

Graham SR, Day RO, Lee R et al. Overdose with chloral hydrate: A pharmacological and therapeutic review. Medical Journal of Australia 1988; 149:686–688. Pershad J, Palmisano P, Nichols M. Chloral hydrate: the good and the bad. Pediatric Emergency Care 1999; 15:432–435. Sing K, Erickson T, Amitai Y et al. Chloral hydrate toxicity from oral and intravenous administration. Journal of Toxicology-Clinical Toxicology 1996; 34:101–106. Zahedi A, Grant MH, Wong DT. Successful treatment of chloral hydrate cardiac toxicity with propranolol. American Journal of Emergency Medicine 1999; 17(5):490–491.

Toxicokinetics

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

CLINICAL FEATURES

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 nset of toxicity is rapid. Transient early hypertension (not usually O 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, BSL and paracetamol level



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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 l Basic resuscitative measures ensure the survival of the vast majority of patients l Intubation and ventilation is only required in the most severe intoxications l 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 l Give 10–20 mL/kg of normal saline IV to patients with symptomatic hypotension l



Decontamination l Oral activated charcoal is contraindicated because of the risk of subsequent CNS depression



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Enhanced elimination Not clinically useful

Antidote Naloxone inconsistently provides transient reversal of the CNS and respiratory depression associated with clonidine intoxication l 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





l

 dminister repeated doses of 0.1 mg IV every 30–60 seconds while A supporting airway and ventilation, until adequate spontaneous respiration is re-established. Alternatively, 0.4 mg IM or SC can be administered if IV access cannot be established l For further information on the indications, contraindications and administration see Chapter 4.19: Naloxone.

DISPOSITION AND FOLLOW-UP







l

 aediatric patients should be observed in hospital following P potential accidental exposure l Patients who are clinically well without symptoms at 4 hours following ingestion may be discharged. Discharge should never occur at night l 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 l Patients with significant CNS depression requiring intubation require admission to an intensive care unit.

SPECIFIC TOXINS



HANDY TIPS



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 onsider the diagnosis of clonidine ingestion in any small child C who presents with lethargy, bradycardia and miosis l Bradycardia is frequently asymptomatic and specific management is not required l 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.

PITFALLS

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 ailure to recognise the potential lethality of accidental paediatric F ingestion of clonidine l Failure to recognise respiratory depression in children, especially at night l Iatrogenic anticholinergic delirium from excessive doses of atropine administered in response to bradycardia.

CONTROVERSIES

l

Role of naloxone.

Presentations

Clonidine 100 microgram tablets (100) Clonidine 150 microgram tablets (100) Clonidine 150 microgram/mL 1 mL ampoules

References

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.

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3.29  CLOZAPINE Deliberate self-poisoning with this atypical antipsychotic agent is unusual because its use is restricted and closely supervised. Care is supportive. RISK ASSESSMENT



 clear dose-response is not defined, but most poisonings follow a A relatively benign course l Coma requiring intubation is uncommon when clozapine is taken alone. It is more likely to develop in patients who do not normally take clozapine



l

SPECIFIC TOXINS



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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 be seen in the following days.

Toxic mechanism

Clozapine is a tricyclic dibenzodiazepine atypical antipsychotic. It is an antagonist at mesolimbic dopamine (D1 and D2), serotonin (5HT) 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 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

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 nset of intoxication is rapid, occurring within 4 hours of ingestion O Lethargy, confusion, sedation, tachycardia and orthostatic hypotension are common Anticholinergic effects, such as agitation, ileus or urinary retention, often occur Mydriasis and miosis are both described Hypersalivation is characteristic Seizures occur in approximately 5–10% of patients Extrapyramidal effects are more common in children Coma requiring intubation is uncommon QT prolongation is uncommon Toxicity usually resolves within 24 hours.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL 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.

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 l Basic resuscitative measures ensure a good outcome in the vast majority of patients l Treat seizures with benzodiazepines, as outlined in Chapter 2.6: Approach to seizures l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l Close clinical and physiological monitoring is indicated l Monitor fluid balance and urine output



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Decontamination Clozapine is rapidly absorbed and characterised by a benign clinical course; activated charcoal is not indicated Enhanced elimination Not clinically useful Antidotes None available.

SPECIFIC TOXINS



209



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 atients who are clinically well at 6 hours following ingestion are fit P for medical discharge l Patients who manifest clinical features of intoxication require admission for appropriate supportive care l Parents of small children who have ingested clozapine are advised that abnormal (extrapyramidal) movements might occur up to 7 days later.

HANDY TIPS



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 onsider the diagnosis of clozapine overdose in a sedated patient C with features of anticholinergic poisoning but small pupils and hypersalivation l Therapeutic use of clozapine is associated with agranulocytosis and myocarditis. These are not clinical features of acute poisoning.

PITFALLS

l

Failure to recognise and correct urinary retention.

Presentations

Clozapine 25 mg tablets (28, 100) Clozapine 50 mg tablets (100)

References

Clozapine 100 mg tablets (28, 100) Clozapine 200 mg tablets (100)

Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. 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. 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.

TOXICOLOGY HANDBOOK

DISPOSITION AND FOLLOW-UP

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-arrhythmic effects occur. RISK ASSESSMENT

SPECIFIC TOXINS



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 l The presence of hyperthermia, headache, cardiac conduction abnormalities, focal neurological signs or chest pain heralds potentially life-threatening complications 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

1g

Potentially lethal

Pregnancy: Cocaine is teratogenic and associated with an increased incidence of miscarriage and fetal demise l Lactation: Cocaine is excreted in breast milk and can result in infant intoxication l Children: Ingestion is potentially lethal. l

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: l Central nervous system — Euphoria — Anxiety, dysphoria, agitation and aggression









— Paranoid psychosis with visual and tactile hallucinations — Hyperthermia, rigidity and myoclonic movements — Seizures l Cardiovascular — Tachycardia and hypertension may be severe — Arrhythmias and cardiac conduction abnormalities — Acute coronary syndromes: vasospastic and/or coronary thrombotic — QT prolongation — Acute pulmonary oedema l Peripheral sympathomimetic — Hyperthermia — Muscle fasciculations — Mydriasis, sweating and tremor l 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



211

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



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Specific investigations as indicated EUC — Detect renal failure and hyponatraemia l 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 l Chest x-ray — Detect aortic dissection or pulmonary aspiration l CT head — Detect intracranial haemorrhage l Note: Decreased mental status or focal neurological signs prompts exclusion of hypoglycaemia, aortic dissection or intracranial haemorrhage l 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

l

TOXICOLOGY HANDBOOK

INVESTIGATIONS



SPECIFIC TOXINS



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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 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: Approach to 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



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Enhanced elimination Not clinically indicated Antidotes None available.

DISPOSITION AND FOLLOW-UP

l

 hildren with potential ingestions should be observed in hospital C for 4 hours. If they do not develop symptoms during that period they may then be safely discharged







l

 atients whose intoxication is adequately controlled with P 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 l Patients with significant alteration of conscious state, hyperthermia or ongoing chest pain are admitted to a high-dependency or intensive care unit l Cocaine body packers or stuffers must undergo gastrointestinal decontamination under medical supervision.

HANDY TIPS



 arly control of agitation with IV benzodiazepine sedation calms E the patient, improves tachycardia, hypertension and hyperthermia, and is safe l Administration of beta-adrenergic blockers is contraindicated in the management of cocaine intoxication because it causes unopposed alpha-receptor stimulation l Ongoing chest pain or headache requires further investigation l Acute coronary syndrome is managed according to normal protocols. CT brain should be performed prior to anticoagulation or angiography if headache is a feature.

PITFALLS

l l

 ailure to recognise and treat hyperthermia F Failure to adequately sedate the agitated patient with cocaine intoxication l Administration of beta-blockers.

CONTROVERSIES



l

 espite theoretical concerns, intravenous lignocaine does not D appear to cause cardiovascular or CNS toxicity when used to treat dysrhythmias in cocaine toxicity l 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. Hatsukami DK, Fischman MW. Crack cocaine and cocaine hydrochloride. Are the differences myth or reality? Journal of the American Medical Association 1996; 276:1580–1588. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. New England Journal of Medicine 2001; 345(5):351–358. Shih RD, Hollander JE, Burstein JL et al. Clinical safety of lidocaine in patients with cocaineassociated myocardial infarction. Annals of Emergency Medicine 1995; 26:702–706.

SPECIFIC TOXINS



l

213 TOXICOLOGY HANDBOOK



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. RISK ASSESSMENT

SPECIFIC TOXINS



l

 ny intentional ingestion of colchicine is considered potentially A 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

TABLE 3.31.1 Dose-related risk assessment: Colchicine Dose

Effect

0.8 mg/kg

Severe poisoning involving cardiovascular collapse, coagulopathy, acute renal failure. Approaching 100% mortality

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21

l

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. 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 40% 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).

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 arrhythmias and risk of sudden cardiac death

>7 days

Rebound leucocytosis and transient alopecia. Complete recovery is expected in patients who survive to this stage

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l l

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.

MANAGEMENT



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 l 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 l Early respiratory insufficiency and cardiac arrest is anticipated; airway protection and ventilatory assistance are implemented as necessary l Close clinical, physiological and laboratory monitoring is indicated l Patients with severe toxicity require invasive monitoring



l



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l

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.

215 TOXICOLOGY HANDBOOK

Time

SPECIFIC TOXINS

TABLE 3.31.2 Clinical progression of severe colchicine toxicity

DISPOSITION AND FOLLOW-UP

l

 ll adult cases of deliberate self-poisoning are admitted for A observation l Patients who do not develop gastrointestinal symptoms within 24 hours of ingestion are medically cleared l Patients with significant toxicity require admission to an intensive care unit.

HANDY TIPS

SPECIFIC TOXINS



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PITFALLS

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 dmit ALL colchicine overdoses. Arrange early transfer to intensive A care if more than 0.5 mg/kg is ingested or any symptoms develop.  ailure to identify ingestion of colchicine at presentation F Failure to anticipate the severity of colchicine poisoning.

CONTROVERSIES

l

 tility of granulocyte colony stimulating factor (GCSF) in the U treatment of severe leucopenia.

Presentations

Colchicine 500 microgram tablets (100)

TOXICOLOGY HANDBOOK

6

21 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 stratifies the risk for delayed sequelae in symptomatic patients. RISK ASSESSMENT



l

 eliberate or unintentional ingestion of concentrated sulfuric acid D (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 l Stridor, dyspnoea, dysphonia or throat pain indicate airway injury and an immediate threat to life l Significant gastro-oesophageal injury is indicated by any two of the following: stridor, drooling or vomiting





l

Ingestion of >60 mL of concentrated hydrochloric acid (HCl) leads to severe injury to the stomach and duodenum with necrosis and perforation, rapid onset of severe multi-organ failure and is usually fatal l Ingestion of 10 mmol/L for cyanide levels >40 micromol/L (0.1 mg/dL) are 87%, 94% and 95% respectively l Cyanide levels — These do not aid acute management but confirm diagnosis in retrospect — Take blood before antidotes are commenced (use a heparinised tube). TABLE 3.33.1 Correlation of blood levels and clinical effects: Cyanide Level

Effect

>20 micromol/L (0.05 mg/dL)

Symptomatic

>40 micromol/L (0.1 mg/dL)

Potentially toxic

>100 micromol/L (0.26 mg/dL)

Lethal

MANAGEMENT













Decontamination l Removal from the source of hydrogen cyanide gas exposure is vital l Remove clothes and wash skin with soap and water. Clothing should be bagged l 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 Enhanced elimination Not clinically useful

l

Antidotes l In a patient with suspected cyanide poisoning and serious clinical effects (altered mental status, seizures, hypotension, significant metabolic acidosis), administer a cyanide antidote l 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) l Under most circumstances, hydroxocobalamin is the preferred antidote if available.

DISPOSITION AND FOLLOW-UP





l l

 atients who are clinically well at 4 hours may be discharged P Patients managed supportively who show rapid clinical improvement, with normal mental status and vital signs, may be managed in a ward environment l Patients with objective evidence of cyanide intoxication require aggressive supportive care, intubation and ventilation and consideration for antidote treatment l Patients with severe cyanide intoxication and cardiovascular instability require management in an intensive care setting.

HANDY TIPS





l

 onsider the diagnosis of cyanide poisoning where a sustained C lactic acidosis is noted in the patient presenting following sudden collapse l Despite the presence of effective antidotes, early aggressive supportive care alone may be sufficient to achieve a good outcome in some cases l The decision to give antidote must be made before cyanide levels are available.

SPECIFIC TOXINS



Resuscitation, supportive care and monitoring Cyanide poisoning poses multiple immediate threats to life: coma, seizures, shock and profound lactic acidosis l Immediate intubation and ventilation with 100% oxygen is indicated in severe poisoning l Resuscitation proceeds along conventional lines, as outlined in Chapter 1.2: Resuscitation l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l

221 TOXICOLOGY HANDBOOK



PITFALLS

l l

 ailure to recognise cyanide intoxication F Inability to immediately access cyanide antidotes.

CONTROVERSIES

l

 he relative comparative efficacy between the antidotes for T cyanide poisoning in humans is not established.

SPECIFIC TOXINS

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 Natural Amygdalin (apple, apricot and peach pips) Foodstuffs (almonds, cabbage, spinach, tapioca, white lima beans) Iatrogenic Chemical warfare agent Sodium nitroprusside therapy

References

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22

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. Meredith TJ, Jacobsen D, Haines JA et al. IPCS/CEC evaluation of antidotes series. Volume 2. Antidotes for poisoning by cyanide. Cambridge University Press 1993. Also available online at http://www.inchem.org/documents/antidote/antidote/ant02.htm, accessed 16 May 2010.

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





l

 cute digoxin intoxication occurs if more than 10 times the daily A defined dose is ingested l 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 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 l

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









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: l Gastrointestinal — Nausea, vomiting and abdominal pain l 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 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



l

 atients with falling serial serum digoxin levels, normal serum P potassium, no gastrointestinal symptoms and no evidence of cardiotoxicity at 6 hours do not require further medical care or observation l Patients who have received digoxin immune Fab, have normal serum potassium, manifest no significant cardiac dysrhythmia and remain clinically well over the next 6 hours do not require further medical care or observation.

l



l



l



l



l



l



l

PITFALLS

l

 arly accurate risk assessment allows administration of digoxin E 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.

 ailure to stock sufficient digoxin immune Fab. In a large F overdose, antidote needs to be gathered from all available sources.

CONTROVERSIES

l

 ultiple-dose activated charcoal may be associated with improved M 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:

l l

 lants: foxglove, lily of the valley, oleander, rhododendron P Animals: toad (Bufo spp.) venom and body parts—used in some traditional Chinese medicines

225 TOXICOLOGY HANDBOOK



SPECIFIC TOXINS

HANDY TIPS

SPECIFIC TOXINS

References

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22 TOXICOLOGY HANDBOOK

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. 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 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.

3.35  DIGOXIN: CHRONIC POISONING See also 3.34: Digoxin: Acute overdose 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 comorbidities. Use of digoxin immune Fab reduces mortality and may reduce hospital length of stay and cost of care. RISK ASSESSMENT

l

 hronic digoxin poisoning, although variable in severity, is a lifeC threatening condition l Untreated, mortality within a week is 15–30% l 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%

 dapted from Abad-Santos F, Carca AJ, Ibanez C et al. Digoxin level A 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 extracellular potassium. Digoxin also enhances vagal tone leading to a decrease in sinoatrial and atrioventicular (AV) node conduction velocity.

Toxicokinetics











The clinical manifestations of chronic digoxin toxicity are nonspecific. 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: l Cardiovascular — Bradycardias – First, second or third degree AV block – AF with ventricular response 300 mL concentrate

Potentially fatal. Death usually from refractory shock

l

Children: Minor ingestions do not need hospital assessment unless symptoms develop.

TOXICOLOGY HANDBOOK

RISK ASSESSMENT

Toxic mechanism

Glyphosate is a phosphonoglycine compound structurally similar to glycine. It does not inhibit cholinesterase enzymes. Toxicity is thought to be predominantly due to the surfactant rather than glyphosate per se. The mechanism of toxicity may involve uncoupling of mitochondrial oxidative phosphorylation. Surfactant appears to cause significant direct myocardial depression and hypotension.

Toxicokinetics

Glyphosate is poorly absorbed following dermal and oral exposure. It is not metabolised, but eliminated unchanged by the kidneys. Prolonged elimination half-life occurs in renal impairment. CLINICAL FEATURES

SPECIFIC TOXINS



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l

l

l

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Gastrointestinal — Gastrointestinal irritation occurs early following ingestion — Nausea, vomiting, diarrhoea, abdominal pain — Oropharyngeal and oesophageal erosions Cardiovascular — Myocardial depression — Hypotension Respiratory — Upper respiratory tract irritation and drooling — Aspiration pneumonitis — Non-cardiogenic pulmonary oedema has been reported Patients may develop hepatic and renal dysfunction Multi-organ dysfunction secondary to myocardial depression and systemic acidosis can also occur.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l









Specific investigations as indicated Glyphosate levels are not readily available and not clinically useful l EUC, LFTs — Detect and monitor hepatic and renal dysfunction l Arterial blood gas, venous lactate — Detect and monitor metabolic acidosis l Chest x-ray — Detect aspiration pneumonitis, pulmonary oedema.

MANAGEMENT



Resuscitation, supportive care and monitoring Manage the patient in an area equipped for cardiorespiratory monitoring and resuscitation l Intubate and ventilate if any evidence of airway compromise from oropharyngeal corrosive injury l 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 l

Decontamination Not indicated and technically difficult due to vomiting

l

Enhanced elimination Haemodialysis enhances the elimination of glyphosate, but is not generally indicated. It is supportive in severe refractory shock and worsening metabolic acidosis



l



l

Antidotes None available.

DISPOSITION AND FOLLOW-UP







l

 atients who are clinically well after 4 hours of observation may be P discharged. Discharge should not occur at night l 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 l A patient known to have ingested >150 mL is admitted to a highdependency or intensive unit in anticipation of multiple organ effects within 24 hours l Adult patients with dermal occupational exposure do not require referral to hospital unless they are symptomatic.

SPECIFIC TOXINS



HANDY TIPS l

Intubate early if stridor develops.

237

PITFALLS

l

 ailure to appreciate potential for cardiovascular compromise F following large ingestions l Confusion between glyphosate and organophosphate poisoning. These are two distinct clinical entities.

CONTROVERSIES

l

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. 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.

3.39  HYDROCARBONS Aliphatic: Essential oils (includes eucalyptus oil), Kerosene, Petroleum distillates, Turpentine Aromatic: Benzene, Toluene, Xylene Halogenated: Carbon tetrachloride, Methylene chloride, Tetrachloroethylene, Trichloroethylene

TOXICOLOGY HANDBOOK



See also Chapter 2.16: Solvent abuse, dependence and withdrawal Hydrocarbons, whether ingested or inhaled, can cause rapid onset of CNS depression, seizures and (rarely) cardiac dysrhythmias. Aspiration can lead to chemical pneumonitis. Other end-organ effects are uncommon and usually associated with long-term occupational exposure.

SPECIFIC TOXINS

RISK ASSESSMENT

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23



 he major risks following acute ingestion are early CNS depression T 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 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 l Cardiovascular — Dysrhythmias occur early in poisoning (pre-hospital) l 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, dependence and withdrawal) l







Gastrointestinal — Nausea and vomiting l 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 occur in carbon tetrachloride (CCl4) poisoning — Toluene is nephrotoxic — Benzene is associated with haemolysis and leukaemia. l

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l



Specific investigations as indicated Serial ECGs and continuous cardiac monitoring if ectopy or bigeminy are noted at initial assessment l FBC, EUC, LFTs, arterial blood gases l Chest x-ray: Radiographic changes lag behind clinical features of pneumonitis l Chronic toluene abuse leads to a renal tubular acidosis characterised by hypokalaemic hyperchloraemic non-anion gap metabolic acidosis.

SPECIFIC TOXINS

INVESTIGATIONS

239









Resuscitation, supportive care and monitoring Resuscitation proceeds along conventional lines, as outlined in Chapter 1.2: Resuscitation l Close clinical and physiological monitoring is indicated l 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 l Manage seizures along conventional lines, as outlined in Chapter 2.6: Approach to seizures l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l 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 l Fever is common following significant aspiration with pneumonitis. Withhold antibiotics until there is objective evidence of pulmonary sepsis Decontamination l Remove patient from the exposure, remove clothing and wash skin l Activated charcoal does not bind hydrocarbons l Gastrointestinal decontamination of any kind is contraindicated following ingestion because induction of vomiting increases the risk of hydrocarbon aspiration l

TOXICOLOGY HANDBOOK

MANAGEMENT

Enhanced elimination Not clinically useful



l



l

Antidotes None available.

DISPOSITION AND FOLLOW-UP

SPECIFIC TOXINS





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PITFALLS

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24 TOXICOLOGY HANDBOOK

 hildren suspected of ingesting small amounts of hydrocarbons C may be observed at home providing they remain asymptomatic. Any respiratory symptoms beyond an initial cough mandates hospital assessment and observation l 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 l Patients with any symptoms or alteration in vital signs are admitted for observation and supportive care l Patients with high-pressure injection injuries require surgical referral for urgent debridement.

HANDY TIPS

240

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l

Coughing or gagging following ingestion suggests aspiration.  ailure to recognise dry cough as a symptom of evolving F pneumonitis.

CONTROVERSIES

l l

 echanisms of myocardial toxicity M 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. 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 lifethreatening systemic complications. Ingestion of HF is potentially lethal. RISK ASSESSMENT

l l

 ny dermal exposure may lead to delayed severe pain and tissue injury A Inhalational exposure can lead to pulmonary injury



l

 ystemic life-threatening fluorosis is associated with ingestion or S 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

l

Children: Any ingestion of a HF-containing product is potentially lethal.



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.

Toxicokinetics

Hydrofluoric acid is readily absorbed after ingestion or dermal contact. It penetrates deeply into tissues to release fluoride ions. 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 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



l

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, convulsions and cardiac arrest and sudden death within minutes may occur with larger ingestions of concentrated H2O2 (>10%) solutions













INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l l



Specific investigations as indicated EUC, FBE, ABGs Chest and abdominal x-rays may demonstrate perforation or oxygen gas embolism l Chest x-ray is also indicated if there is evidence of pulmonary irritation following inhalational exposure l Cerebral CT or MRI scanning is indicated if CNS effects develop and will demonstrate cerebral gas embolism and infarction l 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.

MANAGEMENT



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, tracheostomy may be required for life-threatening laryngeal oedema l The patient is initially managed in an area equipped for cardiorespiratory monitoring and resuscitation l High-flow oxygen via a tight-fitting mask is administered to all patients l Hyperbaric oxygen therapy is of value in treating cerebral gas embolism if suspected l

SPECIFIC TOXINS



— P  ainful 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 l 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 l Dermal — Inflammation, blistering and skin necrosis can occur, usually following exposure to concentrated solutions. Subcutaneous emphysema may be detected. l 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.

245 TOXICOLOGY HANDBOOK







SPECIFIC TOXINS



246



l

 lose cardiorespiratory monitoring is essential for any patient at C risk of gas embolism l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l Passage of a nasogastric tube may relieve the pain of gaseous gastric distension Decontamination Gastrointestinal decontamination is not indicated due to the rapid decomposition of H2O2 l Immediate eye irrigation with copious amounts of water or saline for at least 15 minutes is indicated after ophthalmic exposure l Clothing should be removed and the exposed skin washed with copious amounts of water following dermal exposure l

Enhanced elimination Not useful



l



l

Antidote None available.

DISPOSITION AND FOLLOW-UP l



l



l



l



l

TOXICOLOGY HANDBOOK

6

24



PITFALLS

l

 inor unintentional exposures to 3% solutions in either children M 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.

 remature discharge of a patient with vague neurological signs or P symptoms; this may indicate cerebral gas embolism.

CONTROVERSIES

l

 orticosteroids have been recommended for laryngeal and C pulmonary oedema, but their value is unproven.

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

References

Moon JM, Chun BJ, Min YI. Haemorrhagic gastritis and gas embolism after ingestion of 3% hydrogen peroxide. Journal of Emergency Medicine 2006; 30(4):403-406. Papafragkou S, Gasparyam A, Batista R et al. Treatment of portal venous gas embolism with hyperbaric oxygen after accidental ingestion of hydrogen peroxide: a case report and review of the literature. Journal of Emergency Medicine 2009 Oct 19 [Epub ahead of print]. Watt BE, Proudfoot AT, Vale JA. Hydrogen peroxide poisoning. Toxicological Reviews 2004; 23:51–57.

RISK ASSESSMENT





l

 eliberate self-poisoning with insulin by subcutaneous injection D causes life-threatening persistent hypoglycaemia with the risk of permanent neurological injury if not treated aggressively l Hypoglycaemia may last for days; patients require prolonged periods of close monitoring and treatment l The severity and duration of hypoglycaemia is unpredictable, is not dependent on the insulin preparation administered and correlates poorly with the dose injected l 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 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%). CLINICAL FEATURES





l

 he clinical features are those of hypoglycaemia. They usually T manifest within 2 hours after administration: l Autonomic symptoms — Nausea and vomiting — Diaphoresis — Tachycardia and palpitations l Central nervous system — Agitation and tremor — Confusion and visual disturbances

247 TOXICOLOGY HANDBOOK

Deliberate self-administered insulin overdose causes profound and prolonged hypoglycaemia that may result in life-threatening seizures, coma and permanent neurological injury.

SPECIFIC TOXINS

3.42  INSULIN



— Seizures — Hemiplegia — Coma l The hyperinsulinaemic state commonly persists for >3 days l Persistent, untreated hypoglycaemia may cause permanent neurologic injury and death.

SPECIFIC TOXINS

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l







248 TOXICOLOGY HANDBOOK

8

24

Specific investigations as indicated Serial blood glucose levels — Perform every 15 minutes during the resuscitation phase and every 1–2 hours during glucose infusion l EUC, serum phosphate and magnesium — Detect and monitor hypokalaemia, hypophosphataemia and hypomagnesaemia associated with insulin excess l 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 l If symptoms of hypoglycaemia occur or serum glucose is 120 mg/kg

Potentially lethal

l

Children: The dose ingested is usually trivial (90 micromol/L (500 microgram/ dL) are thought to be predictive of systemic toxicity l Arterial or venous blood gas — An anion gap metabolic acidosis is a useful marker of systemic toxicity l Abdominal x-ray — Useful in confirming ingestion, and planning and monitoring decontamination l Note: Hyperglycaemia and elevated white cell counts are frequently observed in iron poisoning, but do not correlate with toxicity.

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 l Ongoing fluid replacement is essential in the face of continuing gastrointestinal and third-space losses l

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) l Surgical or endoscopic removal may be considered in potentially lethal ingestions if WBI fails or is impractical l l

Enhanced elimination Not clinically useful



l



l

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 microg/dL) at 4–6 hours post ingestion. For further details see Chapter 4.4: Desferrioxamine.

SPECIFIC TOXINS



253







l

 hildren thought to have ingested 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





l

Initial symptoms are light-headedness, blurred vision, photophobia, nausea and vomiting l Physical examination may reveal tachycardia, dilated pupils, slurred speech, ataxia and hyperreflexia l If a sufficient dose is ingested, patients rapidly develop confusion, depressed level of consciousness, coma, status seizures, severe lactic acidosis and death l 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.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l







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 l 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 l Aggressive supportive care of airway, breathing and circulation is paramount until seizures are controlled and adequate doses of pyridoxine administered l The patient presenting unconscious or with seizures undergoes prompt rapid sequence induction of anaesthesia, intubation and ventilation l Seizures are controlled with high-dose intravenous diazepam while supplies of pyridoxine are secured and administered l EEG monitoring if available is useful in the intubated patient l

255 TOXICOLOGY HANDBOOK

CLINICAL FEATURES

SPECIFIC TOXINS

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.

SPECIFIC TOXINS

Decontamination Activated charcoal is only given once the airway is secured with endotracheal intubation and never takes precedence over resuscitation and supportive care



l



l



l



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) l Give 1 g for each gram of isoniazid ingested l If the ingested dose is unknown, give 5 g of pyridoxine and review response.

DISPOSITION AND FOLLOW-UP

256

l

 symptomatic patients can be observed for 6 hours and A discharged if no symptoms develop and no treatment is given l All patients who develop neurological toxicity should be admitted to an intensive care or high-dependency unit l Any patient who develops seizures is intubated and managed in intensive care.

TOXICOLOGY HANDBOOK

6

25 HANDY TIPS



l

 lways consider isoniazid overdose in the differential diagnosis of A status epilepticus, particularly if the patient or household member has a history of tuberculosis l Rapidly ascertain location of all available pyridoxine when confronted with a possible isoniazid overdose.

PITFALLS

l

Inability to secure adequate doses of IV pyridoxine.

CONTROVERSIES

l

 alue of prophylactic administration of pyridoxine to patients with a V history of ingestion of >1.5 g of isoniazid.

Presentations

Isoniazid 100 mg tablets (100)

Reference

Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and review of the literature. Intensive Care Medicine 1995; 21(8):641–644.

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





 cute or subacute severe lead intoxication occurs in the context A of ingestion or inhalational occupational exposure to lead. It is associated with encephalopathy, cerebral oedema and death l Chronic occupational or environmental exposure usually leads to a vague multi-system disorder with the potential for permanent neurological and neuropsychological sequelae l 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 l 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. l

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, 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 remobilise 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 preterminal conditions — Clinical effects generally correlate with levels although there is wide inter-individual variation (see Table 3.45.1) l 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. l

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level

l

SPECIFIC TOXINS



l

257 TOXICOLOGY HANDBOOK



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

258 TOXICOLOGY HANDBOOK

8

25











Specific investigations as indicated Whole blood lead level — Most useful indicator of lead exposure l FBC — Normochromic, normocytic anaemia with basophilic stippling of erythrocytes is classical but rarely seen l EUC, LFTs l 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 l Abdominal x-ray — Assists identification of ingested lead foreign bodies l Nerve conduction and psychomotor testing — May be useful in chronic exposures to demonstrate objective evidence of lead neurotoxicity. l

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 l Administer mannitol 1 g/kg and dexamethasone 10 mg (0.15 mg/kg in children) if cerebral oedema is present l l











 eizures are treated with benzodiazepines, as outlined in S Chapter 2.6: Approach to seizures l 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 x-rays every 24 hours to ensure 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) l Shrapnel or bullets adjacent to synovial tissue: — Surgical excision if feasible is indicated in the patient with symptoms or rising lead levels l

Enhanced elimination Not clinically useful



l



l





Antidotes Chelation therapy is indicated in symptomatic lead poisoning or if long-term neurological injury is anticipated l 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 4.26: Sodium calcium edetate l 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 4.28: Succimer.

HANDY TIPS





l

 iagnosis of chronic lead intoxication identifies an index case. D Other family members or colleagues should be screened and all potential exposures considered l Lead levels 10 microg/L (0.48 micromol/L) mandates strenuous efforts to identify the source and prevent further exposure, especially in children l Lead intoxication is a notifiable disease in most jurisdictions.

PITFALLS

l

 sing dicobalt edetate (antidote for cyanide) instead of sodium U calcium edetate (EDTA) l Failure to identify source of lead exposure in chronic poisoning, and prevent further exposure.

SPECIFIC TOXINS



l

259 TOXICOLOGY HANDBOOK



CONTROVERSIES



l

 hresholds for chelation in pregnant women, children and T asymptomatic adults remain controversial and are constantly under review l Value of chelation therapy for children with mild–moderate elevated lead levels (5 mmol/L occurring at 4–8 hours post ingestion are not unusual following acute overdose.

SPECIFIC TOXINS



l

261 TOXICOLOGY HANDBOOK



MANAGEMENT





SPECIFIC TOXINS



262



Decontamination l Activated charcoal does not effectively adsorb lithium and is not indicated



l



2

26 TOXICOLOGY HANDBOOK

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. l Maintain adequate hydration and sodium repletion with intravenous normal saline if necessary. Urine output is ideally >1 mL/kg/hour l Monitor fluid and electrolyte status, renal function, serum lithium and clinical features of neurotoxicity l Continuous cardiac monitoring is not required in the absence of co-ingestants l



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 l Haemodialysis is reserved for patients with established renal failure, particularly those who present late with clinical features of lithium neurotoxicity Antidotes None available.

l

DISPOSITION AND FOLLOW-UP

l

 atients with no clinical evidence of neurotoxicity and a serum P 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

l

 atients with chronic lithium toxicity always require admission. P Resolution of neurological symptoms may be very slow (weeks) and sometimes incomplete.

HANDY TIPS



l

 onsider the diagnosis of chronic lithium toxicity in any individual C on lithium who presents unwell, particularly if there is evidence of neurological dysfunction l Lithium neurotoxicity may persist long after serum lithium returns to therapeutic range.

PITFALLS

l

Failure to check a lithium level in the unwell patient on lithium therapy.

CONTROVERSIES

 he indications for haemodialysis are unproven and have not been T 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 l 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.

Presentations

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.

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

l



l



l l



l



l

 ost cases of LA toxicity arise from inadvertent intravascular M 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 in some circumstances 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 l 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 TIPS

l

 he development of any neurological symptoms during or shortly T after administration of a LA prompts close observation in an area equipped for cardiorespiratory monitoring and resuscitation.

CONTROVERSIES

l

 lthough currently recommended for cardiac arrest refractory A to standard resuscitation attempts, it may be appropriate to trial intravenous lipid emulsion in any patient with evidence of significant CNS or cardiovascular manifestations of LA toxicity.

SPECIFIC TOXINS



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. Immediate intubation and ventilation is indicated if there is evidence of cardiovascular toxicity l Ventricular dysrhythmias are treated with sodium bicarbonate 100 mEq (2 mEq/kg in children) IV repeated every 1–2 minutes until restoration of perfusing rhythm (see Chapter 4.25: Sodium bicarbonate) l Seizures are treated with benzodiazepines, as described in Chapter 2.6: Approach to seizures l Hypotension should be treated with administration of intravenous crystalloid 20 mL/kg followed by inotropic support if necessary l

267 TOXICOLOGY HANDBOOK



SPECIFIC TOXINS

Presentations

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8

26

Amethocaine HCl 0.5% eye drops Amethocaine HCl 1% eye drops Articaine HCl 40 mg/mL; adrenaline acid tartrate 1:100 000 vials (1.7 mL, 2.2 mL) Benzocaine topical oropharyngeal and otic preparations Bupivacaine HCl 0.25% ampoules (20 mL) Bupivacaine HCl 0.5% ampoules (10 mL, 20 mL) Bupivacaine HCl 5 mg/mL; adrenaline 12.5 microgram/mL cartridges (2.2 mL) Bupivacaine HCL 0.5% ampoules (4 mL) Bupivacaine HCl 1.25 mg; fentanyl citrate 5 microgram/mL ampoules (20 mL, 200 mL) Bupivacaine HCl 1.25 mg/1 mL polybags (100 mL, 200 mL) Bupivacaine HCl 2.5 mg/1 mL ampoules (20 mL) Bupivacaine HCl 2.5 mg/1 mL polybags (100 mL) Bupivacaine HCl 2.5 mg/1 mL; adrenaline 2.5 microgram/mL vials (20 mL) Bupivacaine HCl 3.75 mg/1 mL ampoules (20 mL) Bupivacaine 5 mg/1 mL ampoules (10 mL, 20 mL) Bupivacaine 5 mg/1 mL; adrenaline 5 microgram/mL vials (20 mL) Bupivacaine HCl 1.25 mg; fentanyl citrate 5 microgram/mL ampoules (20 mL) Bupivacaine HCl 1.25 mg; fentanyl citrate 5 microgram/mL polybags (200 mL) Levobupivacaine 25 mg/10 mL vials Levobupivacaine 50 mg/10 mL vials Levobupivacaine 75 mg/10 mL vials Levobupivacaine 62.5 mg/100 mL polybag Levobupivacaine 125 mg/100 mL polybag Levobupivacaine 125 mg/200 mL polybag Levobupivacaine 250 mg/200 mL polybag Lignocaine HCL 50 mg/1 mL; phenylephrine HCl 5 mg/mL nasal spray (15 mL, 50 mL) Lignocaine/prilocaine eutectic mixture 5% cream (5 g, 30 g) Lignocaine/prilocaine eutectic mixture 5% patches (1 g) Lignocaine HCL 2% gel (10 g, 20 g) Lignocaine HCl 2% gel urethral syringes (10 g) Lignocaine HCL 20 mg; chlorhexidine 0.5 mg urethral syringes (10 mL) Lignocaine HCl 1% ampoules (5 mL, 20 mL) Lignocaine HCl 2% ampoules (5 mL, 20 mL)

Lignocaine HCL 20 mg/mL; adrenaline 12.5 microgram/mL cartridges (2.2 mL) Lignocaine HCl 2% pre-filled syringe (5 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 5 mg/1 mL (5 mL) Lignocaine 10 mg/1 mL (2 mL, 5 mL) Lignocaine 20 mg/1 mL (2 mL 20 mL) Lignocaine HCl 20 mg/1 mL; adrenaline 1:80 000 ampoules (5 mL) Lignocaine HCl 10 mg/1 mL; adrenaline 1:100 000 ampoules (5 mL) Lignocaine HCl 5 mg/1 mL; adrenaline 1:200 000 ampoules (20 mL) Lignocaine HCl 10 mg/1 mL; adrenaline 1:200 000 ampoules (20 mL) Lignocaine HCl 20 mg/1 mL; adrenaline 1:200 000 ampoules (20 mL) Lignocaine 10 mg/0.1 mL pump spray (50 mL) Lignocaine 100 mg/1 g ointment (15 g) Lignocaine 20 mg/1 mL viscous solution (200 mL) Lignocaine 40 mg/1 mL topical solution (30 mL) Lignocaine 2% gel (30 g) Lignocaine HCl 20 mg/1 mL cartridges (2.2 mL) Lignocaine 20 mg/1 mL; adrenaline 1:80 000 cartridges (2.2 mL) Lignocaine 20 mg/1 mL; adrenaline 1:100 000 cartridges (2.2 mL) Lignocaine 5 g/100 g gel (50 g) Mepivacaine 2% cartridges (2.2 mL) Mepivacaine 3%; adrenaline 1:100 000 cartridges (1.8 mL, 2.2 mL) Prilocaine HCl 0.5% vials (50 mL) Prilocaine HCl 2% ampoules (5 mL) Prilocaine HCl 40 mg/1 mL cartridges (2.2 mL) Prilocaine HCl 30 mg/1 mL; adrenaline 1:300 000 cartridges (2.2 mL) Prilocaine HCl 30 mg/1 mL; felypressin 0.03 IU/mL cartridges (2.2 mL) Ropivacaine HCl 2 mg/1 mL ampoules (10 mL, 20 mL) Ropivacaine HCl 2 mg/1 mL polybags (100 mL, 200 mL) Ropivacaine HCl 7.5 mg/1 mL ampoules (10 mL, 20 mL) Ropivacaine HCl 7.5 mg/1 mL polybags (100 mL, 200 mL) Ropivacaine HCl 10 mg/1 mL ampoules (10 mL, 20 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. 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.

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 l 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 l 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 l

l

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.

269 TOXICOLOGY HANDBOOK

Elemental mercury, Inorganic mercury, Organic mercury

SPECIFIC TOXINS

3.49  MERCURY

Toxicokinetics

SPECIFIC TOXINS

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 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.

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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. l 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. l 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. l 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 l



— R  enal 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.



INVESTIGATIONS



l











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 l Urine mercury level: (normal: 100 microgram/L (500 nmol/L) is associated with neuropsychiatric disturbance l 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 l 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 l 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 l 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 l Ingestion of inorganic mercury requires aggressive fluid resuscitation and general supportive care measures for multiple organ failure l Exposure to organic mercury requires general supportive care measures, as outlined in Chapter 1.4: Supportive care and monitoring l

Decontamination l 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

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l

SPECIFIC TOXINS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



Remove contaminated clothing Remove mercury from skin 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

SPECIFIC TOXINS

l l



l



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Enhanced elimination Not clinically useful for elemental or inorganic mercury toxicity Administration of polythiol resin may interrupt enterohepatic circulation of organic mercury compounds





Antidotes Chelation therapy with dimercaprol, penicillamine or succimer (see Chapter 4.7: Dimercaprol, Chapter 4.21: Penicillamine and Chapter 4.28: 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.

DISPOSITION AND FOLLOW-UP



l

 atients exposed to mercury vapour or aerosol are counselled P regarding appropriate measures to cease exposure and clean up remnant environmental contamination l Symptomatic patients require admission for further management l Patients with potential ingestion of inorganic or organic mercury require admission for observation and aggressive management should clinical features develop.

HANDY TIPS

l

PITFALLS

l

 imercaprol is contraindicated following elemental mercury D exposure, as there is concern that it increases distribution of mercury to the brain.

 rdering ‘heavy metal screens’ on patients with non-specific O symptoms without exposure assessment—these are rarely clinically useful.

CONTROVERSIES

l

 he indications for chelation therapy. Dimercaprol does not T reduce symptoms of organic mercury intoxication. Succimer reduces mercury levels but has not been shown to alter prognosis



l

 alue of long-term chelation therapy following IV or SC injection of V mercury if decontamination cannot be adequately achieved l The literature does not support the routine replacement of mercury dental amalgams.

References

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 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









l

 actic acidosis in a patient on therapeutic metformin usually L occurs in the context of acute renal failure or severe sepsis and is associated with a mortality exceeding 50% l 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 l Lactic acidosis is more likely to develop following acute overdose if there is preexisting impairment of renal function or if cardiovascular toxicity of co-ingestants results in impaired renal perfusion l The prognosis for severe lactic acidosis from metformin overdose remains good provided there is early recognition and institution of haemodialysis l

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.

273 TOXICOLOGY HANDBOOK

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

SPECIFIC TOXINS

Sources

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

SPECIFIC TOXINS



l l

 cute metformin overdose is usually asymptomatic A 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 l Lactic acidosis may progress to coma, shock and death l Hypoglycaemia, if it develops at all, is usually minor and easily corrected by dextrose administration l 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 co-existing acute renal failure and/or sepsis.

INVESTIGATIONS

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Screening tests in deliberate self-poisoning 12-lead ECG, BSL 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 l General supportive care measures, as outlined in Chapter 1.4: Supportive care and monitoring ensure a good outcome in the majority of patients l Administration of sodium bicarbonate to control severe acidosis (see Chapter 4.25: Sodium bicarbonate) and control of hyperkalaemia help stabilise the severely unwell patient while awaiting haemodialysis l

Decontamination Administer oral activated charcoal to the co-operative patient who presents within 2 hours of deliberately self-poisoning with >10 g of metformin



l



l



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



— W  orsening lactic acidosis following acute overdose where signs of clinical instability are present or emerging l Haemodialysis may need to be prolonged >15 hours



l

Antidotes None available.

DISPOSITION AND FOLLOW-UP





l

 hildren who acutely ingest up to 1700 mg of metformin may be C safely observed at home l 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 l Patients who present with or develop lactic acidosis require critical care admission, monitoring and assessment for urgent haemodialysis.

HANDY TIPS

l

 onsider the diagnosis of lactic acidosis when confronted with any C unwell patient on metformin or any patient who becomes unwell following acute self-poisoning with metformin.

SPECIFIC TOXINS



275

PITFALLS



l

 reating metformin overdose as a sulfonylurea overdose—they are T both antidiabetic medications but belong to different classes and have different toxicities and risk assessments l Failure to consider the diagnosis of metformin-induced lactic acidosis.

CONTROVERSIES



l

 recise indications for initiating haemodialysis in metformin-related P 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 l Relative efficacy of various haemodialysis methods. Both intermittent and continuous haemodialysis techniques have been used successfully.

Presentations

Metformin hydrochloride 500 mg tablets (100) Metformin hydrochloride 850 mg tablets (60) Metformin hydrochloride 1000 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. 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; 34:1385–1358. Teale KFH, Devine A, Stewart H et al. The management of metformin overdose. Anaesthesia 1998; 53:698–701.

TOXICOLOGY HANDBOOK



3.51  METHOTREXATE 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. 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) l 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 l Intrathecal overdose — Potentially lethal



l



SPECIFIC TOXINS



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l

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

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.

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.

TABLE 3.51.1  Dose-related risk assessment: Acute methotrexate overdose Single dose 500 mg (5 mg/kg in children)

Toxic levels possible

CLINICAL FEATURES

l l

 ost patients remain asymptomatic after acute ingestion M 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.

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l



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 l EUC, FBC, liver function tests.

SPECIFIC TOXINS

INVESTIGATIONS

277













Resuscitation, supportive care and monitoring In patients presenting with established methotrexate toxicity l Attention to airway, breathing and circulation are paramount and managed along conventional lines, as outlined in Chapter 1.2: Resuscitation l Supportive care includes meticulous fluid resuscitation, management of sepsis, and administration of granulocyte colony stimulation factor (G-CSF) In patients presenting following acute overdose Ingestion 500 mg (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 l 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 l 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. l

TOXICOLOGY HANDBOOK

MANAGEMENT

SPECIFIC TOXINS

TABLE 3.51.2  Threshold blood levels for toxicity following a single acute overdose of methotrexate Methotrexate level (micromol/L)

6 hours 12 hours 24 hours

5 1 0.1

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



l



l



l

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Time since ingestion



Enhanced elimination Not clinically useful in the management of acute oral overdose in patients with normal renal function

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 methotrexate level is confirmed to be below threshold for toxicity (see Table 3.51.2) It is otherwise continued until the serum methotrexate is 2 mg/kg associated with toxicity – 4–6 mg/kg potentially fatal Tranylcypromine – >1 mg/kg associated with toxicity – 170 mg has caused a fatality





SPECIFIC TOXINS





— M  uscle 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 l 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.

INVESTIGATIONS

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Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level Specific investigations as indicated l 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 QTc is >500 ms, further monitoring is indicated l EUC, FBC, CK, troponin, arterial blood gases, chest x-ray, cranial CT scan, EEG. l

MANAGEMENT





Resuscitation, supportive care and monitoring A basic level of supportive care and monitoring is sufficient for pure moclobemide overdose l Serotonin syndrome and severe sympathomimetic toxicity are potentially life-threatening emergencies and managed in an area equipped for cardiorespiratory monitoring and resuscitation l Attention to airway, breathing and circulation are paramount (see Chapter 1.2: Resuscitation) l 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: Beta-adrenergic blockers are contraindicated as unopposed α-agonist stimulation may result l Seizures and agitated delirium may be managed with benzodiazepines, as outlined in Chapter 2.6: Approach to seizures and Chapter 2.7: Delirium and agitation l

l







l

Decontamination Moclobemide overdose has a good prognosis with standard supportive care. Decontamination is not indicated l 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 Enhanced elimination Not clinically useful



l



l

Antidotes A trial of cyproheptadine is indicated in patients with symptoms consistent with mild–moderate serotonin syndrome refractory to benzodiazepines (see Chapter 4.3: Cyproheptadine).

DISPOSITION AND FOLLOW-UP



l

 atients who are clinically well without features of serotonin toxicity P at 12 hours may be discharged. Discharge should not occur at night l 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 l Patients with severe serotonin syndrome or phenelzine/ tranylcypromine overdose usually require management in an intensive care unit.

HANDY TIPS

l

PITFALLS

l l

 yperthermia in the setting of MAOI toxicity requires rapid and H aggressive therapy.  ailure to recognise and treat hyperthermia F 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.

CONTROVERSIES

l

 he role of specific serotonin antagonists in the management of T MAOI toxicity.

SPECIFIC TOXINS





283 TOXICOLOGY HANDBOOK



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 and ventilation are indicated l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l Life-threatening serotonin syndrome requires specific care, including paralysis and intubation and ventilation to avoid fatalities (see Chapter 2.8: Serotonin syndrome) l Close clinical and physiological monitoring is indicated



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)

SPECIFIC TOXINS

References

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Downes MA, Whyte IM, Isbister GK. QTc abnormalities in deliberate self-poisoning with moclobemide. Internal Medicine Journal 2005; 35:388–391. 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  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





l

 verdose with these agents is generally benign, even following O large ingestions Dose-related risk assessment is best defined for ibuprofen (see Table 3.54.1) l Massive overdose is associated with severe multi-system organ dysfunction including shock, coma, seizure, acute renal failure and metabolic acidosis. Fatalities are reported. l Overdose with any amount of mefenamic acid is commonly associated with self-limiting seizures TABLE 3.54.1  Dose-related risk assessment: Ibuprofen



Dose

Effect

300 mg/kg

Risk of multi-system organ dysfunction

l

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, 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 5HT2), histamine (H1), muscarinic (M1) and peripheral alpha(α)-receptors.

SPECIFIC TOXINS

References

287 TOXICOLOGY HANDBOOK

Meloxicam 7.5 mg tablets (30) Meloxicam 15 mg tablets (30) Meloxicam 7.5 mg capsules (30) Meloxicam 15 mg capsules (30) Naproxen 250 mg tablets (50, 100) Naproxen 500 mg tablets (50) Naproxen 750 mg sustained-release tablets (28) Naproxen 1000 mg sustained-release tablets (28) Naproxen sodium 275 mg tablets (12, 20, 24) Naproxen sodium 550 mg tablets (50) Parecoxib sodium 40 mg vials and 2 mL diluent Piroxicam 10 mg tablets (50) Piroxicam 20 mg tablets (25) Piroxicam 10 mg capsules (50) Piroxicam 20 mg capsules (25) Piroxicam 125 mg/25 g gel Piroxicam 250 mg/50 g gel Sulindac 100 mg tablets (50, 100) Sulindac 200 mg tablets (50) Tiaprofenic acid 300 mg tablets (60)

SPECIFIC TOXINS

TABLE 3.55.1  Dose-related risk assessment: Olanzapine

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Dose (adult)

Effect

300 mg

Increasing sedation progressing to coma likely to require intubation Hypotension secondary to peripheral alpha blockade

Toxicokinetics

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. CLINICAL FEATURES

l l



l



l l



l l

 nset of clinical features of intoxication occurs within 2–4 hours O 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, BSL and paracetamol level



l



l



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 l Intubation and ventilation may be required if significant sedation occurs l



 eneral supportive care measures are indicated, as outlined in G Chapter 1.4: Supportive care and monitoring l Severe agitated delirium is managed, as outlined in Chapter 2.7: Delirium and agitation l Close clinical and physiological monitoring is indicated l Monitor for urinary retention and insert an indwelling urinary catheter if required Decontamination Oral activated charcoal is not indicated, because the onset of sedation and coma occurs early and supportive care ensures a good outcome



l



l



l

Enhanced elimination Not clinically useful Antidotes None available.

DISPOSITION AND FOLLOW-UP





l

 ll paediatric patients are observed in hospital following possible A 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 l 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 l 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.

HANDY TIPS

l

PITFALLS

l

 enzodiazepines are first-line agents for the management of B olanzapine-induced agitated delirium. However, subsequent fluctuations in mental status may mandate intubation and ventilation.

 ndetected urinary retention contributes to agitation and is U managed with an indwelling catheter.

CONTROVERSIES

l

 he role of physostigmine in the management of agitated T delirium. It is not clear that the delirium is entirely of anticholinergic origin.

Presentations

Olanzapine 2.5 mg tablets (28) Olanzapine 5 mg tablets (28) Olanzapine 7.5 mg tablets (28) Olanzapine 10 mg tablets (28) Olanzapine 5 mg wafers (28) Olanzapine 10 mg wafers (28)

Olanzapine 10 mg vials Olanzapine pamoate monohydrate 210 mg vials Olanzapine pamoate monohydrate 300 mg vials

SPECIFIC TOXINS



l

289 TOXICOLOGY HANDBOOK



References

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.

SPECIFIC TOXINS

3.56  OPIOIDS 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). RISK ASSESSMENT

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l

 ife-threatening CNS and respiratory depression frequently occur L just above the analgesic dose l Opioid use by naive 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 l Certain agents have specific risk assessments based on particular toxicities (see Table 3.56.1) l

Children: Opioid intoxication is the leading cause of death by poisoning in children. Ingestion of a single opioid tablet or a 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.

TABLE 3.56.1  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)

Pethidine

Repeated therapeutic doses are associated with seizures Implicated in serotonin syndrome

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.

Toxicokinetics

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.



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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 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 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 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, BSL and paracetamol level



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l



Specific investigations as indicated: Specific blood levels and urine screening do not assist clinical management l 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 l These priorities are managed along conventional lines, as outlined in Chapter 1.2: Resuscitation l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l Close clinical and physiological monitoring is indicated l 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 4.25: Sodium bicarbonate l

291 TOXICOLOGY HANDBOOK



SPECIFIC TOXINS

CLINICAL FEATURES



SPECIFIC TOXINS



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. l Oral activated charcoal may reduce length of stay if administered to patient presenting early after overdose with controlled-release morphine tablets l

Enhanced elimination Not clinically useful



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Antidotes Respiratory and CNS depression can be reversed with titrated doses of naloxone (see Chapter 4.19: Naloxone).

DISPOSITION AND FOLLOW-UP

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29

 he period of observation required to detect CNS depression varies T with the opioid. For most oral preparations 4 hours is sufficient A patient who ingests controlled-release morphine 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

TOXICOLOGY HANDBOOK



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

SPECIFIC TOXINS

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.

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CLINICAL FEATURES



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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, BSL and paracetamol level



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Specific investigations as indicated Arterial blood gases — Hypoxaemia and acidosis l Serial 12-lead ECGs — Increased ventricular ectopy may herald the onset of ventricular tachydysrhythmias l EUC, liver function tests — Hepatic and renal failure l Serum and fat organochlorine levels — Not readily available and do not assist management.

MANAGEMENT

Resuscitation, supportive care and monitoring Organochlorine poisoning is a potentially life-threatening emergency managed in an area equipped for cardiorespiratory monitoring and resuscitation

l







l

Potential life threats that require immediate intervention include: — Coma (see Chapter 2.4: Coma) — Seizures (see Chapter 2.6: Approach to seizures) — Ventricular dysrhythmias l Control agitation with carefully titrated doses of benzodiazepines l Institute general supportive care, as outlined in Chapter 1.4: Supportive care and monitoring Decontamination Resuscitation takes priority over decontamination and activated charcoal is not indicated until the airway is secured by endotracheal intubation l Following excessive dermal exposure, wash the skin with soap and water l

Enhanced elimination Not clinically useful



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l

Antidotes None available.

SPECIFIC TOXINS



DISPOSITION AND FOLLOW-UP





l

 hildren with potential ingestions should be observed in hospital C for 4 hours. If they do not develop symptoms during that period they may then be safely discharged. l Excessive dermal exposure only warrants referral to hospital if symptoms occur l 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 l Patients may be safely discharged once all symptoms resolve. Follow-up is not necessary if asymptomatic.

HANDY TIPS

l

 he seizures associated with acute intoxication are usually rapid in T onset, short duration and controlled with benzodiazepines. l Ventricular dysrhythmias associated with organochlorines are rare and may respond to IV beta-blockers (e.g. metoprolol or propranolol).

PITFALLS

l

 ailure to recognise the onset of acute toxicity, manifested by F vomiting, agitation or perioral paraesthesia.

CONTROVERSIES

l

 he chronic subclinical effect of the organochlorines, including T their carcinogenic potential.

Presentations

Most organochlorines are solid at room temperature and dissolved in hydrocarbon for ease of application.

297 TOXICOLOGY HANDBOOK



Industrial formulations: Aldrin, Chlordane, Dichlorodiphenyltrichloroethane (DDT), Dieldrin, Endosulfan, Endrin, Ethylan, Heptachlor, Hexachlorobenzene, Isobenzan, Lindane, Methoxychlor Medical formulations: Lindane 1% shampoo or lotion

References

SPECIFIC TOXINS

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.

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29 TOXICOLOGY HANDBOOK

3.58  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 (atropine and pralidoxime), is essential to achieve a good outcome. RISK ASSESSMENT

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 eliberate self-poisoning by ingestion of organophosphates almost D 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 Inadvertent or accidental occupational dermal or inhalation 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.

Toxic mechanism

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.

Toxicokinetics



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 iming of symptom onset depends on the agent, dose and route of T exposure. Symptoms may occur within minutes following ingestion of some agents (e.g. dimethoate, chlorpyrifos) or be delayed by many hours 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, bronchorrhea, bronchospasm, emesis, lacrimation, salivation (‘DUMBBELS’ mnemonic) – Bradycardia and hypotension — Nicotinic effects – Fasciculation, tremor, weakness, respiratory muscle paralysis – Tachycardia and hypertension – 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 Intermediate syndrome — Delayed paralysis (2–4 days) is associated with particular agents (e.g. fenthion, diazinon, malathion). The pathophysiology is not understood. Hypotheses include prolonged motor end-plate stimulation, delayed redistribution from lipid stores and inadequate early pralidoxime dosing Delayed — 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)

299 TOXICOLOGY HANDBOOK

CLINICAL FEATURES

SPECIFIC TOXINS

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 (paraoxomases). 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.

Chronic organophosphate-induced neuropsychiatric disorder — Long-term neuropsychiatric disorder, which may occur following acute intoxication or chronic low-level exposure.



INVESTIGATIONS l



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SPECIFIC TOXINS



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30 TOXICOLOGY HANDBOOK

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level





Specific investigations as indicated Red cell and plasma (butyryl-) 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 — Significant clinical features generally occur at levels 150 mg/kg (>10 g). 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 3.59.1 for a modified version of this nomogram). The probability of hepatotoxicity (defined as peak AST/ALT >1000 IU/L) is: — 1–2% if 4-hour level is 1980 micromol/L (300 mg/L) The risk of hepatic injury with NAC is determined primarily by time from overdose to commencement of NAC — Survival is 100% where NAC is commenced within 8 hours of ingestion (a small percentage of patients develop minor elevation of hepatic transaminases) — Benefit is reduced where NAC is commenced 8–24 hours following ingestion — Benefit is not established if NAC is commenced >24 hours following ingestion except in fulminant hepatic failure, where IV NAC decreases cerebral oedema, inotrope requirements and mortality Risk assessment is problematic if the time of ingestion is unknown or staggered. The nomogram may still be able applied using timeanchoring strategies (see Handy Tips below). Patients who present >8 hours after overdose with elevated hepatic transaminases are assumed to have early paracetamol-induced 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 Models that predict the risk at presentation of developing hepatotoxicity or fulminant hepatic failure have been developed by Silvalotti and Schiødt respectively Children: There are no reports of death following single acute nonintentional paracetamol exposure in children under 8 years of age. Ingestion of 100 seconds) and encephalopathy

Phase 4 (4 days–2 weeks)

Recovery phase during which hepatic structure and function return to normal

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG and BSL. The paracetamol level is not used as a screening test following known deliberate self-poisoning with paracetamol (see below).

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SPECIFIC TOXINS



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305 TOXICOLOGY HANDBOOK



Specific investigations as indicated A recommended approach to initial investigations is outlined in Table 3.59.2

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TABLE 3.59.2  Recommended initial investigations according to time from paracetamol ingestion to NAC treatment

SPECIFIC TOXINS

Time after paracetamol ingestion

306 TOXICOLOGY HANDBOOK

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Test

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.













l

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 — Serum paracetamol levels at 4 hours and again 8 hours after ingestion may be useful following ingestion of extended-release paracetamol preparations l Hepatic transaminases — If NAC is commenced later than 8 hours, baseline and serial hepatic transaminase levels are also taken to detect and monitor hepatic injury. The magnitude of elevation of ALT or AST is not, however, linked to outcome l Coagulation studies — Elevation of the INR is an important marker of hepatic injury l Platelet count, renal function and acid–base status — Useful to assess and monitor clinical status and prognosis of established hepatotoxicity.

MANAGEMENT









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 — It is never justified following acute ingestion of paracetamol by small children.

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Enhanced elimination l 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 l 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 l A management flow chart for acute paracetamol exposure with known time of ingestion is shown in Figure 3.59.2 l Note: See Chapter 4.18: N-acetylcysteine for full details on dosing and administration of NAC.

SPECIFIC TOXINS



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 l G eneral supportive care and monitoring measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l 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 l

307 TOXICOLOGY HANDBOOK



SPECIFIC TOXINS

FIGURE 3.59.2  Management flow chart for acute paracetamol ­exposure with known time of ingestion 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

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Measure serum paracetamol level & ALT

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

TOXICOLOGY HANDBOOK

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30

Plot serum paracetamol level on nomogram

yes

ALT normal

no

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.

DISPOSITION AND FOLLOW-UP

l

 atients in whom NAC is commenced within 8 hours of ingestion P do not require further investigation or follow-up. They are fit for medical discharge at the termination of the 20-hour infusion





l

 atients in whom NAC is commenced later than 8 hours P 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 l 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 a facility should occur if any of the following high-risk criteria develop: — INR >3.0 at 48 hours or >4.5 at any time — Oliguria or creatinine >200 micromol/L — Acidosis with pH 150 mg/kg of paracetamol is ingested and check serum paracetamol levels at 4 and 8 hours. If both levels fall below the treatment line, NAC may be discontinued.

Presentations

Paracetamol 500 mg/metoclopramide 5 mg tablets (8, 10, 24) Paracetamol 325 mg/dextropropoxyphene 32.5 mg capsules (20) Paracetamol 325 mg/dextropropoxyphene 32.5 mg tablets (20) Paracetamol 500 mg tablets (12, 24, 48, 50, 96, 100, 500) Paracetamol 500 mg capsules (24, 48, 96) Paracetamol 500 mg caplets (10, 12, 20, 24) Paracetamol 500 mg gel cap tablets (12, 24, 48) Paracetamol 250 mg soluble tablets (12) Paracetamol 500 mg soluble tablets (20) Paracetamol 500 mg gel tablets (12, 24) Paracetamol 120 mg chewable tablets (24) Paracetamol 160 mg chewable tablets (24) Paracetamol 665 mg modified-release tablets (96, 192) Paracetamol 665 mg extended-release tablets (18, 36) Paracetamol 1000 mg sachets (5, 10) Paracetamol 500 mg sachets (10) Paracetamol 125 mg suppositories (20) Paracetamol 250 mg suppositories (20) Paracetamol 500 mg suppositories (24) Paracetamol 10 mg/1mL vials (50, 100 mL) Paracetamol liquid 120 mg/5 mL (100, 200 mL) Paracetamol liquid 240 mg/5 mL (100, 200 mL) Paracetamol drops 100 mg/1 mL (20 mL) Paracetamol 160 mg/pseudoephedrine 15 mg/chlorpheniramine 1 mg per 5 mL liquid (100 mL, 200 mL) Paracetamol 120 mg/pseudoephedrine 20 mg/dextromethorphan 7.5 mg per 5 mL liquid (100, 200 mL) Paracetamol 500 mg/pseudoephedrine 30 mg tablets (24) Paracetamol 400 mg/pseudoephedrine 30 mg tablets (10, 30, 50) Paracetamol 1000 mg/pseudoephedrine 60 mg sachets (10) Paracetamol 500 mg/pseudoephedrine 30 mg/triprolidine 1.25 mg tablets (8, 16, 20, 24) Paracetamol 500 mg/pseudoephedrine 30 mg/codeine phosphate 9 mg tablets (24, 30, 48, 60) Paracetamol 500 mg/pseudoephedrine 30 mg/codeine phosphate 6 mg tablets (16, 24, 32, 48) Paracetamol 500 mg/pseudoephedrine 30 mg/dextromethorphan 10 mg capsules (18, 24) Paracetamol 300 mg/pseudoephedrine 30 mg/dextromethorphan 10 mg capsules (18, 24)

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. O’Grady JG. Acute liver failure. Postgraduate Medical Journal 2005; 81:148–154. Prescott LF. Paracetamol (acetaminophen). A Critical Bibliographic Review. 2nd edn. London: Taylor and Francis; 2001. Prescott LF, Illingworth RN, Critchley JA. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. British Medical Journal 1979; 2:1097. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. Journal of ToxicologyClinical Toxicology 2002; 40:3–20. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: 871–876.

SPECIFIC TOXINS

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Paracetamol 300 mg/pseudoephedrine 30 mg/dextromethorphan 10 mg/doxylamine 6.25 mg capsules (6, 16, 20) Paracetamol 500 mg/chlorpheniramine 2 mg/dextromethorphan 10 mg capsules (6) Paracetamol 500 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg tablets (18, 24, 36) Paracetamol 650 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg/chlorpheniramine 4 mg sachets (10) Paracetamol 325 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg tablets (18, 24, 48) Paracetamol 325 mg/dextromethorphan 15 mg/chlorpheniramine 2 mg tablets (6, 24) Paracetamol 325 mg/pseudoephedrine 30 mg/dextromethorphan 15 mg/chlorpheniramine 2 mg tablets (24) 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, 200 mL

Schiødt FV, Bondesen S, Tygstrup N et al. Prediction of hepatic encephalopathy in paracetamol overdose: a prospective and validated study. Scandinavian Journal of Gastroenterology 1999; 34(7):723–728. Silvalotti MCA, Yarema MC, Juurlink DN et al. A risk quantification instrument for acute acetaminophen overdose patient treatment with N-acetyl cysteine. Annals of Emergency Medicine 2005; 46(3):263–271.

SPECIFIC TOXINS

3.60  PARACETAMOL: REPEATED SUPRATHERAPEUTIC INGESTION

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31 TOXICOLOGY HANDBOOK

Acetaminophen, N-acetyl-p-aminophenol (APAP) See also Chapter 3.59: Paracetamol: Acute overdose 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







l l

 he Rumack-Matthew and Prescott nomograms are not useful T Risk assessment is based on dose history and biochemical testing l 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 l 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 l 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



l



Children: Patients 200 mg/kg over a single 24-hour period OR — >150 mg/kg/24 hours for the preceding 48 hours OR — >100 mg/kg/24 hours for the preceding 72 hours.

Toxic mechanism

See Chapter 3.59: Paracetamol: Acute overdose. CLINICAL FEATURES

l

 atients who go on to develop hepatic injury following P supratherapeutic paracetamol overdose encounter the same four clinical phases as for acute paracetamol poisoning (see Table 3.59.1).

INVESTIGATIONS





l

Serum paracetamol level and hepatic transaminase levels (ALT/AST) — Determine the risk of hepatotoxicity and requirement for NAC l Liver function tests, urea and electrolytes, prothrombin time-INR, acid–base status and blood sugar — Monitor the clinical course of those patients with hepatic injury (see Chapter 3.59: 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 l General supportive care and monitoring measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l 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 l

Decontamination Gastrointestinal decontamination is not indicated



l



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l

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)

313 TOXICOLOGY HANDBOOK

Toxicokinetics

SPECIFIC TOXINS

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.





SPECIFIC TOXINS



l

Intravenous NAC is continued for at least 8 hours. Serum ALT or AST measurement is repeated after that time. A rapid rise in 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 l Note: For a detailed description of NAC and its administration see Chapter 4.18: N-acetylcysteine l A management flow chart for repeated therapeutic ingestion of paracetamol exposure is shown in Figure 3.60.1.

FIGURE 3.60.1  Management flow chart for repeated supratherapeutic paracetamol ingestion Does the patient meet the criteria for repeated supratherapeutic ingestion?

314 TOXICOLOGY HANDBOOK

4

31 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 5 g



l

 ardiac dysrhythmias are very uncommon, with the exception of C thioridazine in large doses l Seizures are uncommon after any dose l Children: Lethargy, coma, agitation, tachycardia and extrapyramidal effects may occur after small ingestions. Ingestion of even one tablet warrants hospital observation. Delayed extrapyramidal effects sometimes occur over the next few days.

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 receptor systems, including histaminic (H1), GABAA, muscarinic (M1), α1- and α2-adrenergic and serotonergic (5HT) receptors. Cardiotoxicity is secondary to sodium and potassium channel blocking effects. The butyrophenones are a separate class of drug, but have similar pharmacologic and pharmacokinetic properties.

Toxicokinetics

The antipsychotics are rapidly absorbed following oral administration at therapeutic doses and undergo extensive first-pass metabolism. As a result, bioavailability is relatively low and can be variable. 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).

SPECIFIC TOXINS

Toxic mechanism

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 nset of clinical features of intoxication occurs within 2–4 hours of O 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

l

Children: Ingestion of one or two 100 mg tablets is insufficient to cause symptoms and does not require referral for medical assessment or observation.

Toxic mechanism

Phenytoin blocks sodium channels and suppresses membrane post-tetanic potentiation and hyperexcitability.

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

323 TOXICOLOGY HANDBOOK

Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: A systematic review. Drug Safety 2005; 26(11):1029–1044. James LP, Abel K, Wilkinson J et al. Phenothiazine, butyrophenone, and other psychotropic medication poisonings in children and adolescents. Clinical Toxicology 2000; 38(6):615–623. Strachan EM, Kelly CA, Bateman DN. Electrocardiographic and cardiovascular changes in thioridiazine and chlorpromazine poisoning. European Journal of Clinical Pharmacology 2004; 60:541–545.

SPECIFIC TOXINS

References

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.

SPECIFIC TOXINS

CLINICAL FEATURES

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32

 hronic toxicity usually presents with gradual onset of ataxia. C 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 arrhythmias and asystole.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l



Specific investigations as indicated Serum phenytoin levels — Useful to confirm the diagnosis — 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 (130–160 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.

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 l General supportive care as outlined in Chapter 1.4: Supportive care and monitoring ensure a good outcome in the majority of patients l Bed rails should be raised at all times and ambulation should be initially only attempted with supervision l



l



l



l

Enhanced elimination Multiple-dose activated charcoal enhances elimination but there is no evidence that outcome is improved; this intervention is not routine l Charcoal haemoperfusion and plasmapheresis have been used in severe phenytoin intoxication and may enhance elimination, but are not routine Antidotes None available.

l

DISPOSITION AND FOLLOW-UP



l

 hildren may be observed at home following unintentional C exposures. Hospital assessment is only indicated if significant ataxia or drowsiness develops l Patients with nystagmus, ataxia or drowsiness are managed supportively in a ward environment l Patients with coma requiring intubation or seizures require admission to the intensive care unit l Patients are medically fit for discharge as soon as they are able to walk safely.

HANDY TIPS

l

 onsider the diagnosis of phenytoin toxicity in any patient on C chronic therapy who presents with difficulty walking l It may take several days for phenytoin toxicity to resolve l Coma is rare in isolated phenytoin overdose. Other causes should be considered and excluded.

PITFALLS

l

 ailure to order a phenytoin level in the patient on chronic therapy F who presents with ataxia or non-specific symptoms l Allowing a patient with phenytoin toxicity to fall during unsupervised attempts at mobilisation.

CONTROVERSIES

l

 tility of techniques of enhanced elimination. These techniques U have not been demonstrated to provide any clinical benefit.

Presentations

Phenytoin sodium 30 mg tablets (200) Phenytoin sodium 100 mg tablets (200) Phenytoin 50 mg infatabs (200) Phenytoin 30 mg/5 mL suspension (500 mL) Phenytoin sodium 100 mg/2 mL ampoules (contain propylene glycol diluent) Phenytoin sodium 250 mg/5 mL ampoules (contain propylene glycol diluent)

SPECIFIC TOXINS



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

325 TOXICOLOGY HANDBOOK



 CG monitoring is not necessary following oral phenytoin overdose E or for chronic phenytoin toxicity

References

SPECIFIC TOXINS

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. Wyte CD, Berk WA. Severe oral phenytoin overdose does not cause cardiovascular morbidity. Annals of Emergency Medicine 1991; 20(5):510–512.

326

3.64  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 l



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 mall ingestions are usually benign in patients with normal renal S 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 The lethal dose of KCl tablets (each containing 8 mmol KCl) in an adult is not well defined Massive ingestion (>40 x 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. CLINICAL FEATURES

l

 ollowing overdose of potassium salts, GI symptoms including F abdominal pain, nausea and vomiting are common and occur early. Ileus and mucosal perforation may occur



l

 s hyperkalaemia progresses (serum potassium 6–8 mmol/L), A lethargy, confusion, weakness, paraesthesia and hyporeflexia develop l Paralysis and bradycardia herald cardiac arrest (serum K >8 mmol/L).

INVESTIGATIONS l



l

MANAGEMENT









Resuscitation, supportive care and monitoring Attention to airway, breathing and circulation are paramount. Refer to Chapter 1.2: Resuscitation l Initial efforts are directed at detecting a rising serum potassium and acting to achieve temporary control while arrangements are made for urgent haemodialysis l 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) l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l

Decontamination Activated charcoal does not bind potassium chloride and is not indicated l 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 l

Enhanced elimination Haemodialysis is the definitive treatment of hyperkalaemia following massive potassium chloride overdose. Initiation of haemodialysis provides immediate control of hyperkalaemia. Haemodialyis must be started before hyperkalaemic cardiac arrest occurs

l

327 TOXICOLOGY HANDBOOK



Specific investigations as indicated Serial 12-lead ECGs demonstrate a progression of abnormalities as serum potassium rises: peaked T waves (plasma K >5.5–6.0 mmol/L), PR prolongation, loss of P waves with atrial paralysis, widening of QRS, QT prolongation, sine wave appearance and finally asystole l EUC with serial potassium concentrations l 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.

SPECIFIC TOXINS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level







SPECIFIC TOXINS





l

 lanning for haemodialysis begins at the risk assessment stage P and is indicated if: — Ingested dose >40 x 600 mg KCl tablets confirmed on x-ray — Renal impairment — Cardiovascular instability — Serum potassium >8.0 mmol/L — Rapidly rising serum potassium l Haemodialysis continues until decontamination of the gastrointestinal tract with WBI is confirmed on x-ray l 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).

l

DISPOSITION AND FOLLOW-UP



328

l

 atients demonstrating toxicity or having ingested a toxic dose are P managed in a high-dependency or intensive care area with dialysis facilities l Patients are medically fit for discharge once decontamination is complete and serum potassium is stable off haemodialysis.

TOXICOLOGY HANDBOOK

8

32 HANDY TIPS



l l

 low-release potassium chloride tablets are radio-opaque S 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 l Resonium A (cation exchange resin) 20–50g (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.

CONTROVERSIES

l

Indications for haemodialysis and WBI.

Presentations

Potassium chloride 600 mg (8 mmol KCl) slow-release tablets (100)

Reference

Su M, Stork C, Ravuri S et al. Sustained-release potassium chloride overdose. Clinical Toxicology 2001; 39(6):641–648.

3.65  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

 uetiapine intoxication is associated with predictable doseQ dependent CNS depression ranging from sedation to coma and a characteristic brisk tachycardia (see Table 3.65.1) l Mild hypotension is sometimes observed. It may be profound with massive ingestion l Minor QT prolongation may occur but there are no reports of torsades de pointes l C o-ingestion of ethanol or other sedative–hypnotic agents increases the risk of coma and loss of airway protective reflexes



l



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.

TABLE 3.65.1  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

Toxic mechanism

Quetiapine is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5HT2A), histaminic (H1), muscarinic (M1) and peripheral alpha (α1) receptors.

Toxicokinetics

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

l



l l l l



l

 nset of clinical features of intoxication occurs within 2–4 hours O 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, they may be discharged. Parents are advised that abnormal (extrapyramidal) movements might occur up to 3 days after ingestion l Patients who have ingested 3 g, or manifest clinical features of intoxication, require admission for appropriate supportive care.

HANDY TIPS

l

 inus tachycardia exceeding 120 beats/minute is usual. No specific S intervention is required l 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.

CONTROVERSIES

l

 he agitated delirium associated with quetiapine intoxication is T likely to be of central anticholinergic origin; however, the role of physostigmine is yet to be determined.

Presentations

Quetiapine 25 mg tablets (60) Quetiapine 100 mg tablets (90) Quetiapine 200 mg tablets (60) Quetiapine 300 mg tablets (60) Quetiapine 50 mg modified-release tablets (60) Quetiapine 150 mg modified-release tablets (60)

Quetiapine 200 mg modified-release tablets (60) Quetiapine 300 mg modified-release tablets (60, 100) Quetiapine 400 mg modified-release tablets (60)

3.66  QUININE 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



 ll cases of deliberate self-poisoning should be regarded as having A the potential to cause cardiotoxicity and delayed visual disturbance l Ingestion of >1 g usually produces some degree of cinchonism l Cardiotoxicity, CNS disturbances and blindness are more commonly observed when the ingested dose is >5 g and almost universal if >10 g



l



l

Children: Ingestion of 600 mg (two tablets) by a child 24 hours in overdose. Elimination is largely via hydroxylation with about 20% being excreted unchanged in the urine. Quinine does not undergo enterohepatic circulation.

331 TOXICOLOGY HANDBOOK

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. 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

References

CLINICAL FEATURES





SPECIFIC TOXINS



332







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33

Cinchonism — Characterised by nausea, vomiting, alterations in hearing, tinnitus, and vertigo — Occurs early following overdose and resolves as blood quinine concentration falls l Cardiovascular — Hypotension, sinus tachycardia, QRS widening and prolongation of the QT and PR intervals — Wide-complex tachycardia and torsades de pointes are reported — These effects usually occur relatively early (within 8 hours) and resolve as blood quinine concentration falls l Central nervous system — Drowsiness and confusion are observed with larger ingestions — Coma and seizures are rare l Eyes — Onset of visual disturbance is delayed and usually not apparent until 6–8 hours post ingestion. It is often not detected until the next morning when the patient wakes up — Manifestations include blurring, disturbances in colour perception, pupillary dilatation and visual field constriction. Complete blindness develops in severe cases — Recovery of visual disturbance usually occurs over days to weeks, although permanent residual deficits do occur. These are more likely in patients who develop complete blindness during the acute phase. l

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l l l

Specific investigations as indicated Serial 12-lead ECGs EUC, BSL, 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 l 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 is indicated (see Chapter 4.25: Sodium bicarbonate for details on administration) l



Decontamination Administer 50 g activated charcoal to all overdose patients who are awake and able to drink the charcoal slurry themselves. Antiemetics may aid administration. If there is significant CNS depression or seizures then activated charcoal is only administered by nasogastric tube after the airway is secured by endotracheal intubation



l



l



l

Enhanced elimination Multiple-dose activated charcoal is demonstrated to substantially enhance the elimination of quinine. This intervention is indicated in any patient who has ingested >5 g of quinine or who has any degree of visual disturbance Antidotes None available.

DISPOSITION AND FOLLOW-UP

l



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 ll children who are suspected of ingesting 600 mg or more A 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

HANDY TIPS

l

 onsider quinine overdose in any patient with deliberate C self-poisoning who complains of visual disturbance l 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.

SPECIFIC TOXINS



— T  orsades 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 1 mg is associated with clinical features of toxicity including lethargy, sedation, tachycardia, postural hypotension and extrapyramidal effects.

Toxic mechanism

Risperidone is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5HT2A), 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.

l



l l l l l l l

 he onset of clinical features of intoxication is rapid and usually T occurs within 4 hours Lethargy, confusion, mild sedation and tachycardia are common Mild hypertension or hypotension sometimes occurs Miosis and mydriasis are reported Extrapyramidal movements may be seen QT prolongation may occur but torsades de pointes is not reported Anticholinergic features and coma are rare Clinical features resolve within 24 hours.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l



Screening tests in deliberate self-poisoning Serial ECGs — Perform an ECG is 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 l Basic resuscitative measures ensure a good outcome in the vast majority of patients l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l Close clinical and physiological monitoring is indicated l Monitor fluid balance and urine output



l



l



l





l

Decontamination Activated charcoal is not routinely indicated Enhanced elimination Not clinically useful Antidotes None available.

DISPOSITION AND FOLLOW-UP

l

 ll symptomatic children and those thought to have ingested A >1 mg should be referred for hospital assessment and observation l Patients who are clinically well, not sedated and have a normal 12-lead ECG at 4 hours may be medically cleared

335 TOXICOLOGY HANDBOOK



SPECIFIC TOXINS

CLINICAL FEATURES



l

 ymptomatic patients are admitted for supportive care until all S clinical features of toxicity resolve l Cardiac monitoring is not indicated beyond 4 hours post ingestion unless the QT interval is prolonged l At discharge parents should be advised that abnormal (extrapyramidal) movements might occur up to 3 days after ingestion.

HANDY TIPS

SPECIFIC TOXINS



336 6

33 TOXICOLOGY HANDBOOK

l

PITFALLS

l

 oma, seizures or significant alteration in vital signs prompt C consideration of alternative diagnoses and revision of the risk assessment.  ailure to warn parents of the possibility of delayed abnormal F (extrapyramidal) movements after unintentional paediatric exposure.

Presentations

Risperidone 0.5 mg tablets (20, 60) Risperidone 1 mg tablets (60) Risperidone 2 mg tablets (60) Risperidone 3 mg tablets (60) Risperidone 4 mg tablets (60) Risperidone 0.5 mg orally disintegrating tablets (28) Risperidone 1 mg orally disintegrating tablets (28) Risperidone 2 mg orally disintegrating tablets (28) Risperidone 1 mg/mL solution (30 mL, 100 mL) Risperidone 25 mg extended-release microspheres with 2 mL solvent pre-filled syringe Risperidone 37.5 mg extended-release microspheres with 2 mL solvent pre-filled syringe Risperidone 50 mg extended-release microspheres with 2 mL solvent pre-filled syringe

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. 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.

3.68  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.

RISK ASSESSMENT l

 he severity of clinical features following acute aspirin overdose is T dose-related (see Table 3.68.1) and progresses over hours l Chronic poisoning has an increased risk of an adverse outcome l 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)



Effect

300 mg/kg

Severe intoxication. Metabolic acidosis, altered mental state, seizures

>500 mg/kg

Potentially lethal

l

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.

l



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 l 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) 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) – Chronic poisoning >4.4 mmol/L (>60 mg/dL) — The threshold to dialyse is lower in the elderly (>60 mg/dL)



l





l

Antidotes None available.

SPECIFIC TOXINS



DISPOSITION AND FOLLOW-UP





l

 ll children suspected of ingesting methyl salicylate products A should be observed in hospital for signs of salicylate toxicity for at least 6 hours l 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) and the clinical features and acid–base abnormalities have resolved l Patients with significant toxicity are admitted to an intensive care or high-dependency unit.

HANDY TIPS



l

 rgent haemodialysis is indicated in any patient who requires U intubation for salicylate poisoning (but not if intubated because of co-ingestants) l Consider salicylate toxicity and order a serum salicylate level in any elderly patient with altered mental status and metabolic acidosis.

PITFALLS



l

 ailure to appreciate the potential for ongoing delayed absorption F from the gastrointestinal tract l Failure to maintain alkalaemia after intubation and ventilation, leading to catastrophic clinical deterioration due to rapid redistribution of salicylate to the CNS l Failure to diagnose chronic aspirin poisoning l Confusion between standard and SI units for salicylate concentration.

Presentations

Aspirin 100 mg tablets (112) Aspirin 300 mg tablets (24, 42, 60) Aspirin 320 mg tablets (20)

339 TOXICOLOGY HANDBOOK



Aspirin 500 mg tablets (16, 120) Aspirin 650 mg tablets (100) Methyl salicylate is found in oil of wintergreen (98% methyl salicylate) and various products marketed for topical application, including certain Asian herbal remedies.

References

SPECIFIC TOXINS

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.

340

3.69  SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline

TOXICOLOGY HANDBOOK

0

34

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 dose-dependent QT interval prolongation. RISK ASSESSMENT



l l

 verdose with SSRIs is usually benign, irrespective of dose O Mild symptoms of serotonin toxicity occur in less than 20% of patients and usually last 440 ms and 12% >500 ms in one series. QT prolongation is also described with escitalopram intoxication — Following citalopram overdose of >600 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 QT nomogram against heart rate, resolves (see Figure 2.20.4) — If >1000 mg citalopram is ingested, continue ECG monitoring until 13 hours post ingestion, prior to a decision based on a 12-lead ECG performed at that time.

MANAGEMENT





Resuscitation, supportive care and monitoring Attention to airway, breathing and circulation are paramount. Refer to Chapter 1.2: Resuscitation l Seizures and agitation are managed with benzodiazepines, as outlined in Chapter 2.6: Approach to seizures and Chapter 2.7: Delirium and agitation l Management of serotonin syndrome is discussed in Chapter 2.8: Serotonin syndrome l General supportive care measures are indicated, as outlined in Chapter 1.4: Supportive care and monitoring l 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 pulse rate falls towards 100 beats/minute l Continuous cardiac monitoring continues for 8 hours following ingestion of >600 mg citalopram, and 13 hours following ingestion of >1000 mg of citalopram. If the QT suggests no risk of torsades de pointes at that time, monitoring may cease l

SPECIFIC TOXINS



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341 TOXICOLOGY HANDBOOK





SPECIFIC TOXINS



342

Decontamination Alert and cooperative patients who have ingested >600 mg citalopram may drink 50 g of activated charcoal if it can be administered within 4 hours l Overdose with other SSRIs has an excellent outcome with minimal supportive care; activated charcoal is not indicated unless warranted by co-ingestants l

Enhanced elimination Not clinically useful



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Antidotes None available.

DISPOSITION AND FOLLOW-UP l



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 aediatric patients may be observed at home following possible P 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 and 13 hours after ingestion of >1000 mg of citalopram. Monitoring should continue if significant abnormalities are detected (see Chapter 2.20: The 12lead 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.

HANDY TIPS



l

 oma indicates co-ingestion or complication and is not secondary C to SSRI intoxication l 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 if >600 mg is ingested l Although the thresholds for risk of significant QT prolongation with escitalopram are less defined than with citalopram, a similar approach to monitoring is suggested.

PITFALLS

l

 ailure to administer prophylactic benzodiazepines to patients with F increasing anxiety, sweating, tremor, tachycardia and mydriasis.

CONTROVERSIES

l

 ctivated charcoal reduces citalopram absorption and decreases A maximal QT prolongation. However, given that torsades de pointes is extremely rare following citalopram overdose, the number needed to treat with activated charcoal to prevent dysrhythmia is not known.

References

Hayes BD, Klein-Schwartz W, Clark RF et al. Comparison of toxicity of acute overdose with citalopram and escitalopram. Journal of Emergency Medicine 2008; Dec 10 (Epub ahead of print). 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. 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, Whyte IM, Isbister GK. Clinical and ECG effects of escitalopram overdose. Annals of Emergency Medicine 2009: 54(3):404–408.

3.70  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. RISK ASSESSMENT



l

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 l Any deliberate ingestion is likely to be rapidly lethal without early intervention l Sublethal doses lead to painful generalised muscle spasms and stiffness precipitated by external stimuli l

Children: An accidental taste is potentially lethal in a small child.

Toxic mechanism

Strychnine is a competitive glycine antagonist at brainstem and spinal post-synaptic 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.

343 TOXICOLOGY HANDBOOK

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 tables (30) Sertraline hydrochloride 50 mg tablets (30) Sertraline hydrochloride 100 mg tablets (30)

SPECIFIC TOXINS

Presentations

Toxicokinetics

Strychnin e 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.

SPECIFIC TOXINS

CLINICAL FEATURES

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INVESTIGATIONS

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34 TOXICOLOGY HANDBOOK

 nset of nausea, agitation, twitching and muscle spasms occurs O 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 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.

Screening tests in deliberate self-poisoning 12-lead ECG, BSL 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 l EUC, CK, arterial blood gases, lactate and troponin.

MANAGEMENT





Resuscitation, supportive care and monitoring Strychnine intoxication is a time-critical life-threatening emergency l Potential early life threats that require immediate intervention include: — Generalised muscle rigidity — Respiratory paralysis l Prompt neuromuscular paralysis, intubation and ventilation are life saving l Resuscitation proceeds along conventional lines, as outlined in Chapter 1.2: Resuscitation l The patient is not unconscious and it is essential to ensure adequate sedation l 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 l

Decontamination Resuscitation takes priority over decontamination. Activated charcoal is not indicated until the airway is secured

l

Enhanced elimination Not clinically useful



l



l

Antidotes None available.

DISPOSITION AND FOLLOW-UP

 xposed patients who are clinically well without twitching or E muscle spasm at 4 hours post ingestion are not poisoned and are cleared for medical discharge. Discharge should not occur at night l 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 rigidity have resolved, provided secondary complications of spasm or hypoxia do not complicate clinical progress.

HANDY TIPS

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 atients with mild symptoms must be observed very carefully for P any signs of progression l Muscle spasm heralds the imminent onset of lethal muscle rigidity—prepare for immediate paralysis, intubation and ventilation.

PITFALLS

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 ollowing deliberate self-poisoning, many patients do not reach F hospital alive l Failure to institute prompt paralysis and intubation leading to secondary complications, including hyperthermia, lactic acidosis, rhabdomyolysis and hypoxic brain injury.

CONTROVERSIES

l

 orced diuresis, dialysis and urinary acidification have been F 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 up to 5% 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, 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.

SPECIFIC TOXINS



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3.71  SULFONYLUREAS Glibenclamide, Gliclazide, Glimepiride, Glipizide

SPECIFIC TOXINS

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.

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RISK ASSESSMENT l



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 cute poisoning with sulfonylureas can result in profound A hypoglycaemia Ingestion of just one tablet can produce hypoglycaemia in the nondiabetic patient Sulfonylurea-induced hypoglycaemia is likely to be prolonged and relapse is common following initial resolution that follows glucose administration 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. 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 4–6 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 may be more prolonged following overdose. CLINICAL FEATURES



l

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



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Specific investigations as indicated Serial blood glucose levels Insulin levels may have some application if available.

MANAGEMENT





Decontamination l Oral activated charcoal can be given where the patient presents within 1 hour of acute overdose, providing mental state permits. Activated charcoal could be considered up to 4 hours following ingestion of a modified-release preparation Enhanced elimination Not clinically useful



l



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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 l See Chapter 4.20: Octreotide for further details.

DISPOSITION AND FOLLOW-UP

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 ll children with suspected sulfonylurea ingestion require A observation in hospital and monitoring of blood sugar levels with bedside testing for at least 8 hours All patients with definite or suspected sulfonylurea overdose require observation for clinical features of hypoglycaemia and monitoring of blood sugar levels with bedside testing for at least 8 hours from the time of the overdose Patients who remain asymptomatic, euglycaemic and clinically well after 8 hours 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 6 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 blood sugar level, treatment of intercurrent medical conditions and re-evaluation of diabetic therapy.

HANDY TIPS

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 arly institution of octreotide therapy can completely avoid the E need for hypertonic dextrose infusions and central venous access

SPECIFIC TOXINS



Resuscitation, supportive care and monitoring Administer concentrated IV glucose solutions as part of the initial resuscitation of the already hypoglycaemic patient l Give adults 50 mL of 50% glucose as an IV bolus and children 5 mL/kg of 10% glucose IV l Maintain euglycaemia by continued administration of concentrated glucose solution until octreotide can be started l Blood sugar levels 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 l

347 TOXICOLOGY HANDBOOK







l

 o not ignore blood glucose level 50 mg/kg is expected to lead to life-threatening toxicity, manifested by tachyarrhythmias and seizures (see Table 3.72.1)







Effect

5–10 mg/kg

Therapeutic loading dose

>10 mg/kg

Potential for toxicity

>50 mg/kg

Life-threatening

l

 atients with chronic toxicity have a poor prognosis. This is P frequently compounded by failure to make the diagnosis or appreciate the severity of the condition l Elderly patients with coexisting medical illnesses tolerate theophylline toxicity poorly and are more likely to have a poor outcome l Serum theophylline levels, when available, further refine risk assessment (see Investigations below). l

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



l

 arly manifestations of toxicity in acute overdose include anxiety, E vomiting, tremor and tachycardia l Severe poisoning is associated with: — Cardiac dysrhythmias: – Supraventricular tachycardia – Atrial fibrillation and flutter – Ventricular tachycardia — Refractory hypotension — Seizures

349 TOXICOLOGY HANDBOOK



Dose

SPECIFIC TOXINS

TABLE 3.72.1  Dose-related risk assessment: Acute theophylline overdose



SPECIFIC TOXINS



350

— M  etabolic abnormalities: – Hypokalaemia (severe, refractory) – Hypophosphataemia, hypomagnesaemia – Hyperglycaemia – Metabolic acidosis l Cardiac dysrhythmias and seizures occur late and indicate an extremely poor prognosis l 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.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



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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 3.72.2) 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). TABLE 3.72.2  Correlation of serum levels and toxicity: Acute theophylline overdose Level (micromol/L)

Level (mg/L)

Toxicity

55–110 110–220 220–440 >440 >550

10–20 20–40 40–80 >80 >100

Therapeutic Minor toxicity Moderate toxicity Severe toxicity 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 l Potential immediate life-threats include: — Hypotension — Seizures — Ventricular and supraventricular tachycardia (SVT) l 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 l















 ypotension usually responds to fluid administration, although H 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) l Treat seizures with benzodiazepines, as outlined in Chapter 2.6: Approach to seizures l 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 rate of 0.05 mg/kg/ minute (20 mL/hour in 70-kg adult) and titrated to response l Metabolic disturbances do not generally require specific therapy, although severe hypokalaemia, if present, should be corrected with potassium supplementation 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

l

Enhanced elimination l Haemodialysis is the definitive life-saving intervention in severe theophylline poisoning and highly effective in achieving good clinical outcome if commenced early l 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: arrhythmia, hypotension or seizures l Multiple-dose activated charcoal enhances the elimination of activated charcoal, but use of this modality delays effective treatment with haemodialysis Antidotes None available.

l

DISPOSITION AND FOLLOW-UP

l

 atients who have acutely ingested theophylline syrup and are P asymptomatic at 6 hours may be medically cleared l Overdose of modified-release tablets requires observation for 12 hours although serial levels may hasten medical clearance l 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.

SPECIFIC TOXINS



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351 TOXICOLOGY HANDBOOK



HANDY TIPS

l

 atients at risk of death should be identified and dialysed before P clinical deterioration l Most theophylline overdoses are of sustained-release preparations and clinical deterioration is delayed many hours l 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

SPECIFIC TOXINS





 ailure to identify high-risk cases early based on dosing history. F This delays arrangements for haemodialysis until patient is clinically unstable l Failure to closely observe and follow theophylline levels.

CONTROVERSIES



352 2

35 TOXICOLOGY HANDBOOK

l

l

 eta-blocker use in asthmatic patients with theophylline toxicity. If B beta-blockers are used, short-acting agents such as esmolol given by titrated infusion are preferred l 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 250 mg/10 mL ampoules Theophylline 200 mg modified-release tablets (100) Theophylline 250 mg modified-release tablets (100) Theophylline 300 mg modified-release tablets (100) Theophylline 133 mg/25 mL syrup (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.

3.73  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



l

 he majority of patients with acute thyroxine overdose remain T asymptomatic or experience only mild to moderate symptoms of hyperthyroidism some 2–7 days later l Symptoms are not expected unless >10 mg of thyroxine is ingested l The elderly and patients with cardiovascular co-morbidities are at increased risk of complications should hyperthyroid symptoms occur



l

 evere toxicity is more likely to occur following chronic abuse of S thyroid hormones



l

Children: Ingestion of up to 5 mg is associated with minimal symptoms. Clinically significant thyrotoxicosis is not reported after unintentional paediatric ingestion of thyroxine.

Toxic mechanism

Thyroxine (T4) is converted to triiodothyronine (T3) in the liver and kidney. T3 binds to the nucleus and influences multiple metabolic processes (cardiovascular, metabolic, growth and development).

CLINICAL FEATURES





l l

 ollowing acute ingestion, most patients remain asymptomatic F Where symptoms do develop, they are not usually apparent until >24 hours following the ingestion but may then last more than 1 week l Signs and symptoms when they do occur are those of adrenergic stimulation and include fever, agitation, sweating, tachycardia, hypertension, headache, diarrhoea and vomiting l 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, BSL and paracetamol level



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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.

MANAGEMENT





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 l 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 l 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 l Close clinical and physiological monitoring is indicated for patients with severe symptoms. l l

353 TOXICOLOGY HANDBOOK

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.

SPECIFIC TOXINS

Toxicokinetics



Decontamination Give oral activated charcoal 50 g to cooperative patients who present within 1 hour of ingesting >10 mg of thyroxine l Oral activated charcoal is not indicated in children following unintentional ingestion l

Enhanced elimination Not clinically useful



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Antidotes None available.

SPECIFIC TOXINS

DISPOSITION AND FOLLOW-UP

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 hildren suspected of ingesting up to 5 mg of thyroxine may be C observed at home provided they remain asymptomatic l 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 betablockers is indicated, usually for a period of 1 week. Thyroxine may be restarted after a week if indicated.

HANDY TIPS l

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PITFALLS

l l

 any patients remain asymptomatic. If symptoms occur, onset is M usually delayed >24 hours post ingestion.  nnecessary admission for prolonged medical observation U Failure to anticipate or recognise the delayed onset of symptoms following large overdoses.

Presentations

Thyroxine 50 microgram tablets (40, 200) Thyroxine 100 microgram tablets (40, 200) Thyroxine 200 microgram tablets (40, 200)

References

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: 298–289. 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.

3.74  TRAMADOL Tramadol is a centrally acting synthetic analgesic. In overdose, it frequently causes delayed-onset seizures. It may also cause mild sedation and respiratory depression.

RISK ASSESSMENT



l

 pioid effects (sedation and respiratory depression) are usually O mild and rarely require intervention l 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 l Serotonin syndrome may develop if there is co-ingestion of other serotonergically active agents l Children: CNS depression and seizures can occur with ingestion of >10 mg/kg.

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 3–5 hours after ingestion of extended-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.

SPECIFIC TOXINS

Toxic mechanism

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 pioid agonist effects are not prominent and consist of mild O sedation, mild respiratory depression and miosis Coma requiring intubation is unusual except in the presence of coingestants, especially ethanol or benzodiazepines 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 sustainedrelease preparation), of short duration and easily controlled with benzodiazepines Serotonin syndrome may develop, especially if there is coingestion of other serotonergically active drugs (see Chapter 2.8: Serotonin syndrome).

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



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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 l The need for intubation is anticipated and performed early in the patient with a declining level of consciousness l

TOXICOLOGY HANDBOOK

CLINICAL FEATURES





SPECIFIC TOXINS



356





 eizures are treated with titrated doses of IV benzodiazepines, as S outlined in Chapter 2.6: Approach to seizures l Increasing agitation, tachycardia, tremor and myoclonic jerks herald onset of seizures and these symptoms are controlled with titrated IV doses of diazepam: give 5 mg every 2–5 minutes until gentle sedation is achieved and the heart rate falls towards 100 beats/minute l Serotonin syndrome, if it develops, should be identified and managed as described in Chapter 2.8: Serotonin syndrome l 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 l The potential for seizures must be considered when making a risk– benefit analysis of the value of administering activated charcoal l In the patient who is intubated, activated charcoal may be safely administered via a nasogastric tube l

Enhanced elimination Not clinically useful



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35 TOXICOLOGY HANDBOOK

l

Antidotes Naloxone may reverse CNS and respiratory depression secondary to μ opioid agonist activity (see Chapter 4.19: Naloxone). However, this is rarely a clinically significant problem with pure tramadol overdose and naloxone is rarely useful.

DISPOSITION AND FOLLOW-UP







l

 hildren suspected of ingesting >10 mg/kg of sustained-release C tramadol must be assessed and observed in hospital for at least 12 hours. Discharge should not occur at night l Because of the risk of seizures, all adult patients who have ingested >1.5 g must be observed with IV access in place for a minimum of 12 hours and until symptom free l 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 l Patients who require intubation for coma or severe serotonin syndrome are admitted to intensive care.

HANDY TIPS

l

PITFALLS

l l

 rophylactic administration of intravenous benzodiazepines P to patients with clinical features of toxicity such as agitation, tachycardia, tremor or myoclonic jerking will usually prevent seizures.

 ailure to anticipate and prepare for delayed symptoms or seizures F Administration of activated charcoal shortly before onset of seizures.

Presentations

Tramadol hydrochloride 50 mg capsules (20) Tramadol hydrochloride 50 mg sustained-release tablets (20) Tramadol hydrochloride 100 mg sustained-release tablets (10, 20) Tramadol hydrochloride 150 mg sustained-release tablets (20) Tramadol hydrochloride 200 mg sustained-release tablets (10, 20) Tramadol hydrochloride 300 mg sustained-release tablets (10) Tramadol hydrochloride 100 mg/1 mL oral drops (10 mL) Tramadol 100 mg/2 mL ampoules

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.

SPECIFIC TOXINS

References

3.75  TRICYCLIC ANTIDEPRESSANTS (TCAs)

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

Ingestion of >10 mg/kg is potentially life threatening (see Table 3.75.1) l Onset of severe toxicity usually occurs within 2 hours of ingestion l Seizures and myoclonus are more common with dothiepin l

TABLE 3.75.1  : Dose-related risk assessments: Tricyclic antidepressants Dose

Effect

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

357 TOXICOLOGY HANDBOOK

Amitriptyline, Clomipramine, Dothiepin, Doxepin, Imipramine, Nortriptyline, Trimipramine



l

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 observation.

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.

SPECIFIC TOXINS

Toxicokinetics

358 8

35 TOXICOLOGY HANDBOOK

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









l

 evere toxicity is characterised by rapid deterioration in clinical S status within 1–2 hours of ingestion. Patients may present alert and orientated, only to rapidly develop coma, seizures, hypotension and cardiac dysrhythmias l Central nervous system — Sedation and coma usually precede cardiovascular signs — Seizures — Delirium secondary to anticholinergic effects is often obscured by coma l 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 l 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.

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l



Specific investigations as indicated Serial ECGs — Vital tool in the management of TCA intoxication — Diagnostic features include: – Prolongation of PR and QRS intervals – 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



— Q  RS widening reflects degree of fast sodium channel blockade — QRS >100 ms is predictive of seizures — QRS >160 ms is predictive of ventricular tachycardia.

MANAGEMENT













Decontamination l Activated charcoal is not indicated for ingestions 1 g/kg is potentially lethal

SPECIFIC TOXINS

3.76  VALPROIC ACID (sodium valproate)

361



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

l

Children: Unintentional ingestions of 400 mg/kg is suspected, serum valproate levels are repeated every 4–6 hours until they decrease l In the comatose patient, valproate levels are essential to determining the risk of life-threatening multi-system valproate toxicity and need for haemodialysis l Serial EUC, acid–base status and full blood counts are followed in all comatose patients to detect and manage multi-system toxicity. TABLE 3.76.2  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













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 l Haemodialysis is ideally performed before multi-system organ dysfunction is evident Antidotes None available.

l

DISPOSITION AND FOLLOW-UP



l

 atients 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 be not feasible; early haemodialysis is highly effective and a more appropriate intervention in this life-threatening situation l Carnitine has been suggested as an antidote for valproate-induced 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 l The benefit of haemodialysis has not been validated with controlled trials.

Presentations

Sodium valproate 100 mg tablets (100) Sodium valproate 200 mg enteric-coated tablets (100, 200) Sodium valproate 500 mg enteric-coated tablets (100, 200) Sodium valproate 200 mg/5 mL liquid (300 mL) Sodium valproate 400 mg and 4 mL solvent vials

References

Isbister GK, Balit CR, Whyte IM et al. Valproate overdose: a comparative cohort study of self-poisonings. British Journal of Clinical Pharmacology 2003; 55:398–404. Spiller HA, Krenzelok EP, Klein-Schwartz W et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. Clinical Toxicology 2000; 38(7):755–760. Sztajnkrycer MD. Valproic acid toxicity: Overview and management. Journal of ToxicologyClinical Toxicology 2002; 40(6):789–801. Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clinical Toxicology 2009; 47(7):609–616.

3.77  VENLAFAXINE AND DESVENLAFAXINE Venlafaxine and desvenlafaxine are potent selective serotonin and noradrenaline reuptake inhibitors. Venlafaxine overdose is potentially life threatening; it frequently causes seizures and in very large ingestions, cardiovascular toxicity. Supportive care and adequate benzodiazepine sedation usually ensure a good outcome. There is less clinical experience with desvenlafaxine, but it is likely that the clinical features of overdose are similar to those of venlafaxine.

RISK ASSESSMENT



l l



l



l



l

 4% of patients have seizures but the incidence is dose dependent 1 (see Table 3.77.1) 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 up to 2–3 tablets is not associated with significant symptoms. Referral to hospital is not required unless symptoms occur.

TABLE 3.77.1  Dose-related risk assessment: Venlafaxine Dose

Effect

4.5 g

Risk of seizures approaches 100% Hypotension Minor QRS and QT prolongation on 12-lead ECG

>7 g

Hypotension and cardiac dysrhythmias

Toxic mechanism

Venlafaxine and its metabolite O-desmethylvenlafaxine (desvenlafaxine) are potent selective serotonin and noradrenaline reuptake inhibitors (SNRIs). They also exhibit ratedependent sodium channel blocking activity. They have only weak dopamine reuptake activity and no activity at muscarinic, histamine (H1), or α1-adrenegic receptors. They do not inhibit monoamine oxidase (MAO).

Toxicokinetics

Venlafaxine is well absorbed and undergoes extensive first pass metabolism, resulting in bioavailability of only 50%. All currently available preparations are modified-release and peak plasma levels occur at 6–8 hours. The volume of distribution of venlafaxine is 5–7 L/kg. The apparent elimination half-life following therapeutic doses of modified-release preparations is 15 hours. Desvenlafaxine is also well absorbed, but does not undergo extensive first-pass metabolism and has a bioavailability of 80%. The volume of distribution is 3–4 L/kg. Up to 45% of an ingested dose is excreted unchanged in the urine, with the rest predominantly undergoing glucuronide conjugation. The elimination half-life is approximately 11 hours. CLINICAL FEATURES

l

 nset of significant clinical features of toxicity may be delayed up O to 6–12 hours following overdose l Dysphoria, anxiety, mydriasis, sweating, tremor, clonus, tachycardia (up to 160 beats/minute) and hypertension are common, and may herald the onset of seizures

SPECIFIC TOXINS

l

365 TOXICOLOGY HANDBOOK



SPECIFIC TOXINS

366



l



l l



l



l



l



l

INVESTIGATIONS

Screening tests in deliberate self-poisoning 12-lead ECG, BSL and paracetamol level



l



l



6

36 TOXICOLOGY HANDBOOK

 eizures are generalised, short duration and terminated with S benzodiazepines. The first seizure may be delayed up to 16 hours Coma is not a feature of venlafaxine intoxication Although some clinical features of intoxication may be serotonergic in origin, severe serotonin syndrome develops only where there is co-ingestion of other serotonergically active drugs, especially MAO inhibitors Hypotension occurs following very large ingestions and again, onset may be delayed up to 12 hours Minor dose-dependent QRS and QT prolongation may occur with venlafaxine intoxication but is unlikely to be associated with dysrhythmias, except perhaps following massive overdose Rhabdomyolysis, occasionally severe, is reported infrequently following large overdose of venlafaxine Venlafaxine intoxication usually resolves within 24 hours.





Specific investigations as indicated Serial ECGs — Perform a 12-lead ECG on all patients at presentation and 6 hours post ingestion, repeat at 12 hours if >4.5 g ingested l Creatine kinase — Detect and monitor rhabdomyolysis.

MANAGEMENT









Resuscitation, supportive care and monitoring Venlafaxine overdose is a life-threatening emergency and managed in an area equipped for cardiorespiratory monitoring and resuscitation l Early intubation and ventilation is indicated when the history and clinical progression suggest ingestion of >7g l Clinical features that require immediate intervention include: — Seizures: treat with benzodiazepines, as outlined in Chapter 2.6: Approach to seizures — Broad complex tachydysrhythmias: 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 l Increasing agitation, tachycardia and tremor herald onset of seizures and are controlled with titrated doses of IV diazepam: give 5 mg every 2–5 minutes until gentle sedation is achieved and the heart rate falls towards 100 beats/minute l Hyperthermia is a feature of severe serotonin syndrome and must be immediately controlled. Temperature >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 l General supportive care measures as outlined in Chapter 1.4: Supportive care and monitoring are indicated l



Enhanced elimination Not clinically useful



l



l

Antidotes None available.

DISPOSITION AND FOLLOW-UP







l

 ecause of the risk of seizures following venlafaxine or B desvenlafaxine overdose, all patients must be observed with IV access in place for a minimum of 16 hours and until symptom free l 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 l Patients with severe venlafaxine intoxication or serotonin syndrome require management in an intensive care unit.

HANDY TIPS



l

 arly prophylactic doses of intravenous benzodiazepines will E usually prevent seizures. The dose is titrated to achieve a calm patient and a fall in the pulse rate towards 100 beats/minute l Coma is not secondary to venlafaxine intoxication and indicates co-ingestion or complication.

PITFALLS

l

 ailure to anticipate and prepare for delayed onset of symptoms F and seizures l Failure to administer benzodiazepines early and in sufficient dose l Administration of activated charcoal or initiation of whole bowel irrigation (WBI) shortly before onset of seizures or cardiovascular toxicity.

CONTROVERSIES



l

 oth single-dose oral activated charcoal and WBI reduce venlafaxine B 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 l 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 becomes available.

SPECIFIC TOXINS



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 l Activated charcoal is contraindicated in the awake patient with more delayed presentation or symptoms, due to the risk of seizures l If >7 g venlafaxine is ingested and seizures, hypotension or altered mental status occur, give activated charcoal 50 g via the nasogastric tube only after endotracheal intubation l

367 TOXICOLOGY HANDBOOK



Presentations

Desvenlafaxine succinate 50 mg (7, 28) Desvenlafaxine succinate 100 mg (28) Venlafaxine modified-release tablets 37.5 mg (28) Venlafaxine modified-release tablets 75 mg (28) Venlafaxine modified-release tablets 150 mg (28)

SPECIFIC TOXINS

References

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.

3.78  WARFARIN 368 TOXICOLOGY HANDBOOK

8

36

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







l

 herapeutic over-anticoagulation presents as an asymptomatic T patient with an elevated INR or with active bleeding; the risk of bleeding increases progressively as the INR rises above 5 l In patients not on therapeutic warfarin who overdose: — Acute ingestion 2 mg/kg can produce a significant increase in INR within 72 hours l Active bleeding constitutes an emergency and requires urgent combination therapy (see below) l

Children: Single acute unintentional ingestion of 9.

HANDY TIPS

l

PITFALLS

l

 arfarin levels may be useful in cases where paediatric W non-accidental injury or occult poisoning is suspected.  ailure to carefully titrate vitamin K dose in patients requiring F therapeutic anticoagulation.

Presentations

Warfarin 1 mg tablets (50) Warfarin 2 mg tablets (50) Warfarin 3 mg tablets (50) Warfarin 5 mg tablets (50)

References

Baker RI, Coughlin PB, Gallus AS et al. The Warfarin Reversal Consensus Group Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Medical Journal of Australia 2004: 181(9):494–497. Isbister GK, Hackett LP, Whyte, IM. Intentional warfarin overdose. Therapeutic Drug Monitoring 2003; 25(6):715–722.

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 Glucagon 4.13 Glucose 4.14 Hydroxocobalamin 4.15 Insulin (high-dose) 4.16 Intravenous lipid emulsion 4.17 Methylene blue 4.18 N-acetylcysteine 4.19 Naloxone 4.20 Octreotide 4.21 Penicillamine 4.22 Physostigmine 4.23 Pralidoxime 4.24 Pyridoxine 4.25 Sodium bicarbonate 4.26 Sodium calcium edetate 4.27 Sodium thiosulfate 4.28 Succimer 4.29 Vitamin K

372 373 376 377 379 381 383 385 387 389 391 392 394 396 398 400 401 403 406 408 410 411 413 415 417 420 422 424 426

4.1  ATROPINE Atropine is a competitive muscarinic antagonist, used to treat druginduced bradycardia and poisoning by acetylcholinesterase inhibitors. Presentations

Atropine sulfate 0.6 mg/mL ampoules Atropine sulfate 1.2 mg/mL ampoules TOXICOLOGICAL INDICATIONS

l Poisoning

by agents that impair AV conduction such as cardiac glycosides, beta-blockers and calcium channel blockers l Organophosphate and carbamate poisoning.

CONTRAINDICATIONS

ANTIDOTES



372 2

37 TOXICOLOGY HANDBOOK



l 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





l Place

the patient in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care Organophosphate and carbamate poisoning l Administer an initial IV bolus of 1.2 mg l Further doses are given every 2–3 minutes, doubling the dose each time until drying of respiratory secretions is achieved l 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 l Administer an IV bolus of 0.6 mg l Repeat doses of 0.6 mg are given as required up to a maximum of 1.8 mg.

THERAPEUTIC END POINTS

l Drying of respiratory secretions in organophosphate poisoning l Note: The development of anticholinergic features indicates

excessive dosing.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT

l 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 retention.



SPECIFIC CONSIDERATIONS

Pregnancy: No restriction on use Paediatric: Initial paediatric dose is 20 microgram/kg.

HANDY TIPS

l Very

large doses of atropine may be required to treat organophosphate poisoning—anticipate this need and procure sufficient stocks as soon as possible.

PITFALLS

to administer sufficient doses of atropine in organophosphate or carbamate poisoning l 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 gluconate 1 g/10 mL vials (0.22 mmol calcium ions/mL) Calcium gluconate 5 g/50 mL vials (0.22 mmol calcium ions/mL) Calcium chloride 0.74 g/5 mL ampoules (1.01 mmol calcium ions/mL) Calcium chloride 1 g/10 mL ampoules (0.68 mmol calcium ions/mL) Calcium chloride 1 g/10 mL single-use syringe (0.68 mmol calcium ions/mL) TOXICOLOGICAL INDICATIONS

l Calcium channel blocker poisoning l Hydrofluoric acid skin exposure l Hypocalcaemia of systemic fluorosis

secondary to ingestion of, or extensive skin exposure to, hydrofluoric acid l Hypocalcaemia secondary to ethylene glycol poisoning l Iatrogenic hypermagnesaemia l Hyperkalaemia.

CONTRAINDICATIONS

l Hypercalcaemia l Digoxin toxicity.

ANTIDOTES



l Failure

373 TOXICOLOGY HANDBOOK



Mechanism of action

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.

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. ADMINISTRATION

ANTIDOTES





374 TOXICOLOGY HANDBOOK

4

37













l Place

the patient in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care l Cardiac monitoring is mandatory during infusion of calcium salts Hypocalcaemia/hyperkalaemia/hypermagnesaemia l 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. Repeat every 10–15 minutes as required l Further administration of calcium salts is guided by serum calcium concentrations, which should not exceed the normal range Calcium channel blocker poisoning l 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. l Commence patients who respond to calcium on a continuous infusion of 1 g/hour of calcium chloride l Serum calcium concentrations are monitored during an infusion. An ionised serum calcium concentration of 2 mmol/L has been suggested as optimal Hydrofluoric acid skin exposure l Topical 2.5% calcium gel — Minor burns — For burns to hand, put gel in glove and place hand in glove l 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 l 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 proximally 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 l Intraarterial infusion





— Insert arterial line into radial, brachial or femoral artery of affected limb — Dilute 1g (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 l Give nebulised 2.5% calcium gluconate solution.

THERAPEUTIC END POINTS

l Hypocalcaemia/hypermagnesaemia/hyperkalaemia:

normalisation of serum calcium l Calcium channel blocker poisoning: haemodynamic improvement l Hydrofluoric acid skin exposure: resolution of pain.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT





l Transient

hypercalcaemia manifested by tetany and seizures — Interrupt calcium salt administration and check serum calcium concentration l Vasodilatation, hypotension, dysrhythmias, syncope or cardiac arrest due to over-rapid administration — Interrupt calcium salt administration — Institute advanced cardiac life support as appropriate l 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









l QT

duration and clinical features of hypocalcaemia may be a more useful guide to calcium requirements than serum calcium concentrations l 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 l 2.5% calcium gluconate gel for treatment of skin exposure to hydrofluoric acid can be prepared by mixing 10 mL of 10% 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 l Do not use calcium salt solution to irrigate the eye after ocular hydrofluoric acid exposure as it may cause corrosive injury l Pain refractory to calcium administration in late-presentation hydrofluoric acid burns may indicate established tissue damage rather than therapeutic failure l Very large doses of calcium chloride may be required to maintain eucalcaemia following hydrofluoric acid ingestion.

CONTROVERSIES

l Efficacy

and optimal dosing of calcium salts in calcium channel blocker poisoning l Most effective route of administration of calcium salts for hydrofluoric acid skin exposures.

ANTIDOTES



375 TOXICOLOGY HANDBOOK



References

Albertson TE, Dawson AH, de Latorre F et al. TOX-ACLS: toxicologic-oriented advanced cardiac life support. Annals of Emergency Medicine 2001; 37:S78–S90. 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 Cyproheptadine is a histamine and serotonin antagonist with anticholinergic properties. It has been advocated for control of symptoms in mild to moderate serotonin syndrome. ANTIDOTES

Presentations

Cyproheptadine 4 mg tablets (50, 100) TOXICOLOGICAL INDICATION

l Mild

to moderate serotonin syndrome.

CONTRAINDICATIONS

376 TOXICOLOGY HANDBOOK

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37



l Known hypersensitivity l Acute asthma l Closed angle glaucoma l Bladder neck obstruction,

including prostatism.

Mechanism of action

Cyproheptadine acts as a competitive antagonist at histamine H1 and serotonin 5HT1a and 5HT2 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. ADMINISTRATION

l Administer

an initial dose of 8 mg orally and observe for clinical response l If a response is observed, continue treatment with 8 mg every 8 hours for 24 hours l Therapy should not be required beyond 24 hours, provided agents that may precipitate serotonin syndrome are withheld l A longer duration of therapy may be required to treat serotonin syndrome associated with an irreversible MAO inhibitor.

THERAPEUTIC END POINTS

l 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

l Insignificant

adverse effects at therapeutic doses.

SPECIFIC CONSIDERATIONS

Pregnancy: No restriction on use Paediatric: Paediatric dose is not well established. For 7–14-year-olds an initial dose of 4 mg followed by 4 mg every 8 hours for 24 hours is suggested.

HANDY TIPS

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 l 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

l Failure to assess clinical response to initial dose l Reliance on cyproheptadine to the detriment of good

care in the management of serotonin syndrome.

supportive

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) TOXICOLOGICAL INDICATIONS





l 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 l Chronic iron overload.

CONTRAINDICATIONS

l None.

Mechanism of action

Desferrioxamine (DFO) binds avidly with free ferric ion in the plasma to form ferrioxamine. This stable complex is highly water-soluble and is readily excreted in the urine.

ANTIDOTES



l Cyproheptadine

377 TOXICOLOGY HANDBOOK



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.

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. ADMINISTRATION

l Cardiac monitoring is mandatory during DFO administration l Reconstitute 500 mg of powder with 5 mL sterile water and dilute



l Commence IV infusion at an initial dose of 15 mg/kg/hour l Reduce the infusion rate if hypotension develops l The rate may be increased in life-threatening toxicity up to

ANTIDOTES

in 100 mL normal saline or 5% dextrose



40 mg/kg/hour, providing significant hypotension does not supervene l Continue the infusion until therapeutic end points have been achieved, but avoid infusions prolonged >24 hours.

THERAPEUTIC END POINTS

378

l Patient clinically stable l Serum iron 24 hours) l Toxic retinopathy l Secondary infections including Yersinia sepsis and mucormycosis: ferrioxamine complex acts as a siderophore promoting growth of these organisms.

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 as for adults.

HANDY TIPS

l DFO

is ideally administered before iron moves intracellularly and systemic toxicity develops l Intramuscular DFO administration is not indicated in acute iron poisoning l Although urine may change to the classical vin rosé colour during DFO administration, this is an unreliable sign of effective chelation



l Six

hours of DFO chelation is usually sufficient and it is extremely rare to require therapy beyond 24 hours.

PITFALLS

l Administration of DFO when not clinically indicated l Excessive duration of DFO administration.

CONTROVERSIES



l There

are no controlled trials or dose–response studies to support the efficacy of DFO chelation for human iron poisoning l The optimal indications, dose, route of administration and end points for therapy are not well defined.

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.

ANTIDOTES

References

4.5  DICOBALT EDETATE 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

l Unequivocal

acute cyanide poisoning.

CONTRAINDICATIONS

l Suspected

cyanide poisoning without definite signs of poisoning, such as impairment or loss of consciousness.

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

l This

antidote is only administered to critically ill patients in a monitored area where equipment, drugs and personnel are

379 TOXICOLOGY HANDBOOK

Cobalt edetate, Cobalt EDTA, Cobalt tetracemate





available to provide full resuscitative care. Cardiac monitoring is mandatory l Administer 300 mg (1 ampoule) IV over 1 minute, followed immediately with 50 mL of 50% dextrose IV to protect against toxicity l A repeat second or third dose of 1 ampoule is given if an immediate clinical response is not observed.

THERAPEUTIC END POINTS

l Improvement in conscious state l Haemodynamic stability l Improvement in metabolic acidosis.

ADVERSE DRUG REACTIONS

ANTIDOTES





l Significant

adverse reactions have been reported, usually when it is inappropriately administered in the absence of cyanide poisoning l These reactions are due to direct toxicity of the cobalt salt and include convulsions, 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).

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HANDY TIPS



l Never

give dicobalt edetate to a patient without clinical features of definite severe cyanide poisoning including impaired level of consciousness l The occurrence of adverse outcomes is minimised by adhering to strict clinical criteria for giving the antidote.

PITFALLS



l Administration

of dicobalt edetate to a patient without cyanide poisoning or one displaying only minor clinical manifestations of cyanide poisoning l Inadvertent or mistaken administration of sodium calcium edetate (EDTA), an antidote used in the treatment of lead poisoning.

CONTROVERSIES

l 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. Meredith TJ, Jacobsen D, Haines JA, Berger J-C. IPCS/CEC evaluation of antidotes series. Volume 2. Antidotes for poisoning by cyanide. Cambridge University Press 1993. Also available at http://www.inchem.org/documents/antidote/ant02.htm# SubSectionNumber:5.12.2, accessed13 April 2010.

4.6  DIGOXIN IMMUNE FAB These antibody fragments promptly and safely reverse the toxicity of digoxin and other cardiac glycosides. Presentations

Digoxin-specific immune antigen binding fragments as lyophilised powder 38 mg ampoules







CONTRAINDICATIONS

l None.

Mechanism of action

Digoxin immune Fab is created by papain cleaving 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.

Pharmacokinetics

The elimination half-life of Fab fragments is about 12 hours and predominantly non-renal. Digoxin bound to Fab fragments is excreted in the urine, with an elimination half-life of 16–30 hours. ADMINISTRATION



l 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 l Calculate the dose required (see below), dilute in 100 mL normal saline and administer over 30 minutes

381 TOXICOLOGY HANDBOOK



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: l 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 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–severe gastrointestinal symptoms — Any symptoms in presence of impaired renal function l Other cardiac glycoside poisoning — Oleander — Bufotoxin (cane toad).

ANTIDOTES

TOXICOLOGICAL INDICATIONS



l Dose

is calculated on the presumption that one ampoule of Fab binds 0.5 mg of digoxin.

CALCULATION OF DOSE



l Acute

digoxin overdose — Known digoxin dose – Number of ampoules = Ingested dose (mg) x 0.8 (bioavailability) x 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 l 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 l 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.

ANTIDOTES

—







382 TOXICOLOGY HANDBOOK

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38



DURATION OF TREATMENT

l A single dose given over 30 minutes is usually sufficient l Following an adequate dose, a response is normally apparent

20 minutes and maximal by 4 hours.

THERAPEUTIC END POINTS

l Restoration of normal cardiac rhythm and l Resolution of gastrointestinal symptoms.

by

conduction

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: l Hypokalaemia l Allergy (extremely rare) l Exacerbation of underlying cardiac failure l Loss of rate control of preexisting atrial fibrillation. SPECIFIC CONSIDERATIONS

Pregnancy: No restriction on use Paediatric: No restriction on use.

HANDY TIPS

l 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 l Digoxin levels following treatment may appear very high. This is because most serum digoxin assays measure both free and Fabbound digoxin. Some laboratories are able to assay free digoxin l Hyperkalaemia due to acute digoxin poisoning is treated with Fab, not intravenous calcium, as digoxin causes elevation in intracellular myocardial calcium levels l 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 l Administration of digoxin immune Fab to patients with non-life threatening chronic digoxin toxicity is shown to significantly reduce length-of-stay in hospital.

PITFALLS



l Unavailability

of sufficient digoxin immune Fab to treat lifethreatening poisoning l 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.

ANTIDOTES



CONTROVERSIES



l It

may be pharmacokinetically more appropriate to give smaller initial doses of digoxin immune Fab and follow up with repeat doses or an infusion l 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. 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 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 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.

383 TOXICOLOGY HANDBOOK



Presentations

Dimercaprol 300 mg, benzyl benzoate 600 mg, peanut oil 2100 mg/3 mL ampoules TOXICOLOGICAL INDICATIONS



l Arsenic poisoning l Inorganic mercury poisoning l Gold intoxication l Severe lead poisoning or lead l Other heavy metal poisoning

encephalopathy (adjunct to EDTA)

— Dimercaprol has been used to chelate bismuth, antimony, chromium, nickel, tungsten and zinc, but clinical experience is limited.

CONTRAINDICATIONS

ANTIDOTES



384

l Peanut allergy l G6PD deficiency.

Pharmacodynamics

Dimercaprol binds metal ions to form stable dimercaptides, which can then be excreted in the urine.

Pharmacokinetics

TOXICOLOGY HANDBOOK

4

38

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





l Therapy

is always commenced in an intensive care setting due to severity of underlying condition and adverse effects l 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 l Give 3 mg/kg IM every 4 hours for 48 hours then l Give 3 mg/kg IM every 12 hours for 7–10 days depending on clinical response Lead encephalopathy l Commence dimercaprol 4 hours before commencing EDTA l Give 4 mg/kg every 4 hours for 5 days l See Chapter 4.26: Sodium calcium edetate for further information.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT



Dimercaprol is associated with an extremely high incidence (about 50%) of adverse effects at therapeutic dose. These include: l Pain and sterile abscess formation at injection sites l Fever (especially children) and myalgia l Chest pain, hypertension and tachycardia l Headache, nausea and vomiting l Peripheral paraesthesias; burning sensation of lips, mouth, throat and eyes



l Lacrimation, rhinorrhoea and excessive salivation l Risk of intravascular haemolysis in patients with G6PD



l Nephrotoxicity

deficiency



secondary to the dissociation of dimercaprol–metal complexes in acid urine l 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.

SPECIFIC CONSIDERATIONS



l Never give intravenously l Dimercaprol is most effective

when administered shortly after the exposure l Never give more than 4 mg/kg as a single dose due to high incidence of adverse effects l If the patient is well enough, chelation with the orally-active analogue of dimercaprol (succimer) is always preferable.

PITFALLS

l Failure

to access supplies promptly—dimercaprol is difficult to obtain and stocked by relatively few hospitals.

CONTROVERSIES

l 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.

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%

385 TOXICOLOGY HANDBOOK

HANDY TIPS

ANTIDOTES

Pregnancy: Safety not established. Administration should not be withheld if clinically indicated Lactation: Safety not established Paediatric: Dose and administration as for adults.

TOXICOLOGICAL INDICATIONS

l Methanol poisoning (confirmed or suspected) l Ethylene glycol poisoning (confirmed or suspected).

CONTRAINDICATIONS

l 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 20x) for ethanol than for ethylene glycol or methanol. Alcohol 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).

ANTIDOTES

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

386 TOXICOLOGY HANDBOOK

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38









l 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 l Ethanol may be administered by the oral, nasogastric or intravenous route to maintain a blood ethanol concentration of 100–150 mg/dL (22–44 mmol/L) Oral or nasogastric administration l Loading dose: 1.8 mL/kg of 43% ethanol, or 3 x 40 mL shots of vodka in a 70-kg adult l Note: Omit the loading dose of ethanol in the already ethanolintoxicated patient l Maintenance: 0.2–0.4 mL/kg/hour of 43% ethanol, or 40-mL shot each hour Intravenous administration l Loading dose: 8 mL/kg of 10% ethanol l Maintenance infusion rate: 1–2 mL/kg/hour of 10% ethanol l Note: A 10% ethanol solution is prepared by adding 100 mL of 100% ethanol to 900 mL of 5% dextrose in water l 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 l Continue maintenance ethanol therapy until the toxic alcohol poisoning has been definitively treated with haemodialysis.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT

l Local phlebitis from intravenous solutions l Ethanol intoxication l Reduce rate of ethanol administration if blood

ethanol concentration exceeds 150 mg/dL (44 mmol/L) l Hypoglycaemia in children.

SPECIFIC CONSIDERATIONS

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.

HANDY TIPS

l Ethanol

for intravenous therapy is difficult to procure—alcoholic spirits suitable for oral administration are ubiquitous l Administration of ethanol may be delayed in the patient who already has a high ethanol level l Breath ethanol estimations may be substituted for repeated blood ethanol levels during maintenance therapy. l Delay in starting therapy l Failure to monitor blood ethanol

levels closely resulting in sub- or supratherapeutic concentrations.

CONTROVERSIES



l Relative

merits of fomepizole over ethanol in the management of toxic alcohol poisoning l Clinical efficacy of ethanol in the treatment of poisoning with other toxic alcohols, including glycol ethers, diethylene glycol, triethylene glycol, propylene glycol and butanediol l Necessity to continue to maintain ethanol levels after commencement of 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. 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

Flumazenil 0.5 mg/5 mL ampoules TOXICOLOGICAL INDICATIONS



l 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)

387 TOXICOLOGY HANDBOOK



ANTIDOTES

PITFALLS





— Note: Isolated benzodiazepine overdose rarely causes CNS depression sufficient to warrant intervention l To confirm diagnosis of benzodiazepine intoxication — Useful if it avoids invasive or expensive further investigation to exclude alternative diagnoses l Reversal of benzodiazepine conscious sedation.

CONTRAINDICATIONS

l Known seizure disorder l Known or suspected co-ingestion of pro-convulsant drugs l Known benzodiazepine dependence l QRS prolongation on ECG (suggests co-ingestion of tricyclic

antidepressant).

ANTIDOTES

Mechanism of action

388

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.

8

38

ADMINISTRATION

TOXICOLOGY HANDBOOK







l Flumazenil

should only be administered in an environment where equipment and personnel are available to manage a seizure l Give an initial dose of 0.1–0.2 mg IV and repeat every minute until reversal of sedation is achieved l Maximal response should be observed with a dose not exceeding 2 mg l 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 l Note: Patients must be observed for re-sedation for several hours following the last dose of flumazenil.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT

Benzodiazepine withdrawal syndrome







l Manifests as agitation, tachycardia and seizures l Mild benzodiazepine withdrawal will be short-lived

and does not require specific management l Severe withdrawal syndrome requires administration of benzodiazepines in titrated doses Seizures l Most commonly occur in patients with benzodiazepine dependence, co-ingestion of pro-convulsant drugs or an underlying seizure disorder l Withhold further flumazenil l Repeated or prolonged seizures require administration of benzodiazepines in titrated doses.

SPECIFIC CONSIDERATIONS

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 unlikely to be benzodiazepine-dependent.

HANDY TIPS

l Flumazenil

may be life-saving if personnel and equipment for definitive airway control are not available.

PITFALLS

administration to patients with mild benzodiazepine poisoning l Administration when contraindicated due to risk of seizures l Failure to observe for re-sedation.

References

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 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 oncologic practice. Its applications in clinical toxicology are rather more limited. Presentations

Calcium folinate 15 mg tablets (10) Calcium folinate 15 mg/2 mL ampoules Calcium folinate 50 mg/5 mL plastic vials Calcium folinate 50 mg/5 mL ampoules Calcium folinate 100 mg/10 mL plastic vials Calcium folinate 100 mg/10 mL ampoules TOXICOLOGICAL INDICATIONS





l 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 l Single acute oral methotrexate overdose — Methotrexate toxicity has never been reported in this scenario

ANTIDOTES



l Unnecessary

389 TOXICOLOGY HANDBOOK







— 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 l Adjunct treatment for methanol poisoning l Massive pyrimethamine and trimethoprim poisoning.

CONTRAINDICATIONS

l Known

hypersensitivity.

Mechanism of action

ANTIDOTES

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 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.

390

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 halflife of 35 minutes. Elimination is predominantly by metabolism to an active metabolite, 5-methyl tetrahydrofolate, which has a volume of distribution of 40 L and an elimination half-life of over 400 minutes. ADMINISTRATION

TOXICOLOGY HANDBOOK

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39

Methotrexate overdose







l Give 15 mg PO, IM or IV every 6 hours l 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 7 mg/kg) secondary to a direct oxidative effect on haemoglobin l Acute haemolytic anaemia may occur in G6PD-deficient individuals and with very large doses of methylene blue (>15 mg/kg).

SPECIFIC CONSIDERATIONS

Pregnancy: No restrictions on use Lactation: No restrictions on use Paediatric: Initial paediatric dose is 1 mg/kg.

HANDY TIPS







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% l Pulse oximetry is unreliable, as MetHb and methylene blue interfere with the readings l 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 l 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 l If methylene blue fails to control methaemoglobinaemia, consider exchange transfusion or hyperbaric oxygen therapy.

CONTROVERSIES

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.

l Whether

Reference

Clifton J, Leiken JB. Methylene blue. American Journal of Therapeutics 2003; 10:289–91.

4.18  N-ACETYLCYSTEINE N-acetylcysteine (NAC) is the most widely used sulfhydryl donor in the treatment of paracetamol poisoning. Standard therapy consists of a 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 2 g/10 mL ampoules TOXICOLOGICAL INDICATIONS

ANTIDOTES



l Patients

l Acute paracetamol overdose l Repeated supratherapeutic paracetamol ingestion l Paracetamol-induced fulminant hepatic failure l 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 3.59: Paracetamol: Acute overdose

403 TOXICOLOGY HANDBOOK







l 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 l Prevention of contrast-induced nephrotoxicity.

CONTRAINDICATIONS

l None.

ANTIDOTES

Mechanism of action

404

NAC prevents N-acetyl-p-benzoquinoneimine (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.

TOXICOLOGY HANDBOOK

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40 ADMINISTRATION









l Patients

are carefully monitored for anaphylactoid reaction during and after the initial dose of NAC. Cardiac monitoring is not required after that time l Give 150 mg/kg NAC diluted in 200 mL of 5% dextrose IV over 15 minutes followed by l 50 mg/kg NAC diluted in 500 mL of 5% dextrose IV over 4 hours followed by l 100 mg/kg NAC diluted in 1000 mL of 5% dextrose IV over 16 hours l The standard treatment duration is 20 hours; however, it may be interrupted before this time where risk of hepatotoxicity is excluded l 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

l Absent

or resolving hepatotoxicity as determined by transaminases.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT

l Mild

anaphylactoid reactions (incidence of 10–50%), including mild hypotension, mild flushing, rash and angioedema l These usually occur during or shortly after the initial dose and can be treated with promethazine 12.5 mg IV l 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.





HANDY TIPS

l 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.

PITFALLS

l Failure

to initiate NAC empirically in the patient who presents more than 8 hours following a paracetamol overdose of >200 mg/kg l Failure to warn patient and staff of the high likelihood of a mild anaphylactoid reaction occurring early in treatment.

CONTROVERSIES



l 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 l The value of NAC in patients who present more than 24 hours post overdose with elevated transaminases, but who are otherwise well.

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 clinical toxicologists consulting to the Australasian poisons information centres. Medical Journal of Australia 2008; 188:296–301.

405 TOXICOLOGY HANDBOOK



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: l 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.

ANTIDOTES

SPECIFIC CONSIDERATIONS

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.

4.19  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 (‘mini-jet’) Naloxone hydrochloride 2 mg/5 mL pre-filled syringe (‘mini-jet’)

ANTIDOTES

TOXICOLOGICAL INDICATIONS

6

40 TOXICOLOGY HANDBOOK

of CNS and respiratory depression caused by opioid intoxication l Empiric treatment for coma thought to be secondary to opioids.

CONTRAINDICATIONS

406

l Reversal



l Avoid

in the opioid-dependent individual unless: — Significant respiratory depression (respiratory rate 140 ms) — Commence an infusion of 100 mmol sodium bicarbonate diluted in 1000 mL normal saline at 250 mL/hour — 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 — Given 1–2 mmol/kg sodium bicarbonate IV bolus — Commence infusion of 100 mmol sodium bicarbonate in 1000 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.

ADVERSE DRUG REACTIONS

l Alkalosis (serum pH >7.6 is detrimental to cardiovascular l Hypernatraemia and hyperosmolarity l Fluid overload and acute pulmonary oedema l Hypokalaemia l Local tissue inflammation secondary to extravasation.

function)

419 TOXICOLOGY HANDBOOK



ANTIDOTES

ADMINISTRATION

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



l 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 l The frail elderly patient or patient with underlying cardiac disease may not tolerate the fluid and osmotic load associated with sodium bicarbonate administration.

PITFALLS

ANTIDOTES



l Insufficient

doses of sodium bicarbonate when attempting resuscitation of severe tricyclic antidepressant poisoning l Failure to correct hypokalaemia when attempting urinary alkalinisation l Failure to recognise and rapidly treat acidaemia in the patient with severe salicylate poisoning.

CONTROVERSIES

420

l Utility and indications for urinary alkalinisation in toxic rhabdomyolysis l Value and indications for prophylactic serum alkalinisation in



l Relative

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tricyclic antidepressant poisoning efficacy of hyperventilation versus administration of sodium bicarbonate in the management of tricyclic antidepressant toxicity l 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.

4.26  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

l Lead encephalopathy l Severely symptomatic

lead poisoning without encephalopathy



l Asymptomatic

or mildly symptomatic lead poisoning (lead level >70 microgram/dL or 6.72 micromol/L) l Second-line chelating agent when succimer is either not available or not tolerated by the patient l Other heavy metal poisoning (efficacy unknown).

CONTRAINDICATIONS

l Relative

contraindication: anuric renal failure.

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.

ADMINISTRATION











l 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 l 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 l 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 l In the setting of encephalopathy, EDTA (and dimercaprol) should be continued until the patient is clinically stable l Once clinically improved, chelation may be switched to oral succimer if tolerated.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT





l Local

pain and thrombophlebitis due to rapid IV administration. Local phlebitis may be minimised by: — Infusing dilute solution (4 hours l General systemic — Malaise, fatigue, thirst, chills, fever, myalgias, dermatitis, headache, anorexia, urinary frequency, sneezing, nasal

421 TOXICOLOGY HANDBOOK

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.

ANTIDOTES

Pharmacokinetics





congestion, lacrimation, glycosuria, hypotension, transaminase elevations and ECG changes l 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 — Limit daily dose to 2 g (1 g in children) — Continuous therapy for no longer than 5 days — Daily monitoring of renal function.

SPECIFIC CONSIDERATIONS

ANTIDOTES

Pregnancy: Safety 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.

HANDY TIPS

l The

asymptomatic patient or minimally symptomatic patient, able to tolerate oral therapy, should be treated with oral succimer rather than EDTA.

PITFALLS

422



l Inadvertent

TOXICOLOGY HANDBOOK

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or mistaken administration of dicobalt edetate, an antidote used in the treatment of cyanide poisoning.

CONTROVERSIES



l 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 l Ability of EDTA chelation to reverse the neurobehavioural effects of lead poisoning is unknown l Utility of diagnostic EDTA chelation lead mobilisation test to evaluate total body lead burden.

References

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.

4.27  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 vial

TOXICOLOGICAL INDICATIONS



l Reasonable suspicion of cyanide poisoning l May also be useful in poisoning from other agents

— Chlorate — Cisplatin — Bromate — Bromine — Iodine — Mustard gas — Nitrogen mustard.

including:

CONTRAINDICATIONS

l None:

sodium thiosulfate has little toxicity at the recommended doses.

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.

ANTIDOTES

Mechanism of action

Pharmacokinetics

ADMINISTRATION

l Place

the patient in a monitored area where equipment, drugs and personnel are available to provide full resuscitative care l Administer 12.5 g sodium thiosulfate (50 mL of 25% solution) IV over 10 minutes or 200 mg/kg IV over 10 minutes l Repeat after 30 minutes if clinical features of cyanide toxicity persist.

THERAPEUTIC END POINTS

l Improvement in conscious state l Haemodynamic stability l Improvement in metabolic acidosis.

ADVERSE DRUG REACTIONS

l Adverse

effects are mild and of minor importance compared with the risks associated with cyanide poisoning l Rapid injection may be associated with nausea and vomiting l Other minor adverse effects associated with thiocyanate production are hypotension, nausea, headache, abdominal pain and disorientation.

SPECIFIC CONSIDERATIONS

Pregnancy: Safety not established. Administration should not be withheld if clinically indicated

423 TOXICOLOGY HANDBOOK

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.

Paediatric: The recommended dose of 400 mg/kg is relatively higher than for adults. HANDY TIPS





l Collect blood for l The combination

cyanide level before antidote administration of sodium thiosulfate, oxygen and supportive therapy is probably sufficient to treat mild to moderately severe cases of cyanide toxicity l Sodium thiosulfate is valuable in doubtful cases of poisoning, such as smoke inhalation, where it may have both therapeutic and diagnostic value l In severe poisoning sodium thiosulfate should be given together with other antidotes, with which it acts synergistically.

CONTROVERSIES

ANTIDOTES



424

l 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

Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for empiric treatment of cyanide poisoning? Annals of Emergency Medicine 2007; 49:806–813. Meredith TJ, Jacobsen D, Haines JA, Berger J-C. IPCS/CEC evaluation of antidotes series. Volume 2. Antidotes for poisoning by cyanide. Cambridge University Press 1993. Also available at http://www.inchem.org/documents/antidote/ant02.htm# SubSectionNumber:5.12.2, accessed 15 April 2010.

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4.28  SUCCIMER 2,3-Dimercaptosuccinic acid (DMSA) This orally active metal chelator is used to treat lead and other heavy metal poisoning. Presentations

Succimer 100 mg tablets (100), obtained under special access scheme in Australia TOXICOLOGICAL INDICATIONS







l Adult

lead poisoning — Symptomatic — Asymptomatic with blood lead level >60 microgram/dL (>2.9 micromol/L) l Paediatric lead poisoning — Symptomatic — Asymptomatic with blood lead level >45 microgram/dL (2.17 micromol/L) l Other heavy metal poisoning — Has been used to chelate mercury, arsenic, bismuth, antimony and copper, but clinical experience is limited.

CONTRAINDICATIONS

l Known hypersensitivity l 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. ADMINISTRATION







l 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 4.26: Sodium calcium edetate) l Other heavy metal poisoning — In the absence of any guidelines, administration is the same as for lead poisoning.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT



l Hypersensitivity reactions l Gastrointestinal upset is very

common with this foul-smelling drug — Symptomatic care for gastrointestinal symptoms — Converting to parenteral therapy may occasionally be necessary l Transient liver function test abnormalities (occurs in up to 60% of patients) l Reversible neutropenia (rare).

SPECIFIC CONSIDERATIONS

Pregnancy: Safety 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



l The

asymptomatic patient or minimally symptomatic patient, able to tolerate oral therapy, should be treated with oral succimer rather than sodium calcium edetate l Succimer can be given on an outpatient basis to compliant patients.

PITFALLS

l It

may be difficult to obtain succimer—it is only available in Australia under the special access scheme.

ANTIDOTES



425 TOXICOLOGY HANDBOOK



CONTROVERSIES

l The

threshold blood 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.

References

ANTIDOTES

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.

4.29  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.

426 TOXICOLOGY HANDBOOK

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42

Presentations

Phytomenadione 10 mg tablets (100) Phytomenadione 2 mg/0.2 mL ampoules Phytomenadione 10 mg/1 mL ampoules TOXICOLOGICAL INDICATIONS



l Significant

coumadin-induced coagulopathy: — Therapeutic over-warfarinisation — Intentional warfarin overdose — Ingestion of long-acting anticoagulant rodenticides (e.g. brodifacoum).

CONTRAINDICATIONS

l 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.

ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT



l Minor

facial flushing, chest tightness, dyspnoea or dizziness with IV administration l Anaphylaxis following IV administration (rare) l 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

l Never l When

give vitamin K by the intramuscular route giving vitamin K for warfarin reversal it is preferable to give the injectable formulation orally rather than use tablets. This formulation is well absorbed orally and allows more flexible dosing

427 TOXICOLOGY HANDBOOK

The approach and dosing of Vitamin K varies according to the clinical indication and relative need to maintain anticoagulation. Therapeutic over-warfarinisation l See Appendix 5: Therapeutic over-warfarinisation Warfarin overdose l No therapeutic requirement for warfarin anticoagulation (patient took someone else’s warfarin) — Single dose 10–20 mg vitamin K PO or IV — INR can be checked at 48 hours as an outpatient l 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 or returns to >5 — Start heparin if INR falls 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.

ANTIDOTES

ADMINISTRATION



l 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



l 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 l Administration of vitamin K prior to demonstration of anticoagulant effectinadultswhoself-poisonwithlong-actinganticoagulantrodenticides.

CONTROVERSIES

ANTIDOTES



428 8

42 TOXICOLOGY HANDBOOK

l The

threshold INR for vitamin K administration following therapeutic over-warfarinisation or warfarin overdose.

References

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, McMeeding et al. 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 and Whyte IM. Intentional warfarin overdose. Therapeutic Drug Monitoring 2003; 25(6):715–722.

CHAPTER 5

ENVENOMINGS 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 5.16

 lack snake B Brown snake Death adder Tiger snake Taipan Sea snake Australian scorpions Bluebottle jellyfish (Physalia species) Stonefish Box jellyfish (Chironex fleckeri) Irukandji syndrome Blue-ringed octopus Redback spider Funnel-web (big black) spider White-tailed spider Ticks

430 433 436 439 442 445 447 449 450 452 454 457 459 461 463 465

5.1  BLACK SNAKE l l l l l

ENVENOMINGS

l

430

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 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 south-eastern coastal areas and the envenoming is not usually lethal, even without treatment.

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

0

43 TOXICOLOGY HANDBOOK

TOXINS

Mulga snake venom contains myotoxins, neurotoxins and anticoagulant toxins. It has no procoagulant toxins. Red-bellied and blue-bellied black snake venoms have less potent toxins, which cause minor myolysis only.

CLINICAL PRESENTATION AND COURSE





Bourke

Wilcannia Gladstone

Mulga snake, Collett’s snake, Butler’s snake and Papuan black snake l These snakes characteristically inflict a large, painful bite leading to extensive local tissue swelling. Regional lymphadenitis occurs in 60% of cases l S ystemic 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. Features of mild paralysis, such as blurred vision, ptosis or diplopia, occur in 15% of envenomings



l



l



 yoglobinuria and renal failure may occur secondary to M rhabdomyolysis. Clinical features of anticoagulation, such as bleeding gums, are rare

Red-bellied and blue-bellied black snakes Bites by the red-bellied or blue-bellied black snake usually cause local pain and discomfort, but patients rarely develop systemic features of envenoming. Minor myolysis may occur, but features of paralysis or coagulopathy do not l 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.

MANAGEMENT











Pre-hospital Apply a pressure immobilisation bandage (PIB) Transport to a hospital capable of providing definitive care

l l

Hospital  esuscitation and supportive care R l 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 l Watch for evidence of rhabdomyolysis and deteriorating renal function Antivenom l Systemic envenoming by black snakes is defined by gastrointestinal symptoms refractory to supportive care, or objective evidence of evolving rhabdomyolysis (e.g. CK rise above 5000 IU/L). It is treated with an initial dose of 1 ampoule of either monovalent Black Snake or Tiger Snake Antivenom l CSL monovalent Black Snake Antivenom (see Chapter 6.1) is the definitive treatment of systemic envenoming by mulga, Collett’s, Butler’s and Papuan black snakes 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.

INVESTIGATIONS



l

 he diagnosis of envenoming is based on the correlation of history, T clinical features and laboratory data l 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) l CK is usually abnormal at the time of presentation if envenoming has occurred. 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

431 TOXICOLOGY HANDBOOK



ENVENOMINGS

See Chapter 2.1: Approach to snakebite for a guide to the principles of snakebite management.





l

 he anticoagulant coagulopathy of black snake envenoming is T characterised by: — Elevated APTT and INR (usually mild) — Normal fibrinogen — Normal d-dimer and fibrin degradation products — Normal platelet count l 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

ENVENOMINGS



 levation of the CK may also be observed in taipan and tiger snake E envenoming l 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 fibrinogen level normal l 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 rhabdomyolysis and coagulation defects do not occur.

DISPOSITION AND FOLLOW-UP

432 2

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TOXICOLOGY HANDBOOK

l

l

 ll patients must be admitted for observation to a hospital capable of A providing definitive care (see Chapter 2.1: Approach to snakebite) l Patients who have no clinical features and no laboratory evidence of rhabdomyolysis at 12 hours are not envenomed and may be discharged. Discharge should not occur at night l 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





l

 he mulga snake is sometimes referred to as the king brown T snake, however it is not a brown snake and envenoming will not resolve with Brown Snake Antivenom l Envenoming by the red-bellied black snake or blue-bellied black snake is usually mild and rarely requires antivenom. If antivenom is indicated, Tiger Snake Antivenom may be used as an alternative to Black Snake Antivenom l 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.

PITFALLS



l

 ailure to recognise that snakebite may have occurred, institute F early PIB or to manage the patient in a hospital setting for an appropriate duration l Inaccurate snake identification l Misinterpretation of a SVDK result l Administration of antivenom to a patient who is not envenomed.

CONTROVERSIES l

 he point at which slowly evolving rhabdomyolysis is treated with T antivenom. Antivenom prevents progression of muscle injury, but does not reverse injury that has already occurred. Most experienced clinicians treat with antivenom if CK exceeds 5000 IU/L. A much lower threshold is used if the patient is symptomatic l The indications for antivenom administration following red-bellied black snake envenoming and the antivenom of choice (Tiger or Black Snake Antivenom).





References

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. White J. Snakebite and spiderbite management guidelines for South Australia 2005. Adelaide: Department of Health; South Australia.

l l l l l l

Pseudonaja affinis: dugite Pseudonaja guttata: spotted brown snake Pseudonaja inframacula: peninsula brown snake Pseudonaja ingrami: Ingram’s brown snake Pseudonaja mengendi: western brown snake or gwardar Pseudonaja modesta: ringed brown snake Pseudonaja nuchalis: tropical brown snake Pseudonaja textilis: eastern brown snake

ENVENOMINGS

l l

Distribution of brown snakes

433 Rottnest Island

Brown snake envenoming is the most common cause of death from snakebite in Australia. The most important manifestation of severe envenoming is venom-induced consumptive coagulopathy (VICC). TOXINS

The venom contains procoagulants, cardiotoxins and a potent presynaptic neurotoxin (textilotoxin).

CLINICAL PRESENTATION AND COURSE

l l

 atients may present asymptomatic with no obvious bite site P Non-specific features of envenoming include headache, nausea, vomiting and abdominal pain l Systemic envenoming may be heralded by pre-syncope or sudden collapse l Early death occurs rarely, probably secondary to direct cardiotoxicity l 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

TOXICOLOGY HANDBOOK

5.2  BROWN SNAKE





l

 hrombotic microangiopathy, characterised by thrombocytopenia, T microangiopathic haemolytic anaemia (MAHA) and acute renal failure occur in about 10% of brown snake envenomings. Oliguria may be present from the time of envenoming l Rhabdomyolysis 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.



ENVENOMINGS



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4 43 TOXICOLOGY HANDBOOK







Pre-hospital Apply a pressure immobilisation bandage (PIB) Transport to a hospital capable of providing definitive care

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Hospital Resuscitation and supportive care l Brown snake envenoming is a potentially life-threatening emergency and patients should be managed in an area capable of cardiorespiratory monitoring and resuscitation l Potential early life threats that require immediate intervention include: — Hypotension — VICC with uncontrolled haemorrhage l 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 definitive treatment of envenoming. A dose of 2 ampoules (2 x 1000 units) is indicated for systemic envenoming, as evidenced by collapse or objective evidence of coagulopathy.

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 he diagnosis of envenoming is based on the correlation of history, T 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) VICC is characterised by: — Elevated INR (at least >3 but usually unrecordable) — Undetectable fibrinogen — Elevated d-dimer (10 x normal) and fibrin degradation products Recovery from VICC (INR returning to