Deliberate self-poisoning is one of the commonest reasons for general hospital admission in the UK ¹ and accounts for 1–5% of all public hospital admissions in Australia.^2,³ The bulk of the medical management of cases presenting to hospital is carried out in the emergency department (ED), and the emergency physician is expected to be expert in the field. Although the management must vary considerably according to the nature and severity of the poisoning, some general principles apply.

Above all, it must be remembered that the acute overdose presentation is only a discrete time-limited event in the course of the underlying condition, which is usually psychiatric or social in origin.

Pathophysiology and clinical features

The effects of ingestion of pharmaceuticals or illicit drugs range from the non-toxic to the life-threatening and may involve any system. Poisoning is a dynamic presentation and the patient may present at varying points in the time course of the poisoning. Consequently, rapid clinical deterioration or improvement may be observed after the initial presentation and assessment.

Acute morbidity and mortality from poisoning is usually a consequence of the cardiovascular, respiratory or central nervous system (CNS) complications of the poisoning. Less commonly, hepatic, renal or metabolic effects are potentially life-threatening.

The most frequent life-threatening respiratory complication of poisoning is ventilatory failure, which is usually a consequence of CNS depression. Less commonly, it is secondary to ventilatory muscle paralysis. The frequency and depth of respirations are reduced. Respiratory failure may also be caused by direct pulmonary toxicity, or complications such as pulmonary aspiration or non-cardiogenic pulmonary oedema (Table 29.1.1).

Table 29.1.1 Toxic causes of respiratory failure

Cardiovascular manifestations of poisoning include tachycardia, bradycardia, hypertension, hypotension, conduction defects and arrhythmias (Table 29.1.2). Bradycardia is relatively rarely observed and is associated with a number of potentially life-threatening ingestions. Tachycardia is commonly observed and is usually benign. It may be due to intrinsic sympathomimetic or anticholinergic effects of a drug, or a reflex response to hypotension or hypoxia. Hypotension is also commonly observed and may be due to a number of different causes (Table 29.1.2). Hypertension is unusual. Severe hypertension is usually associated with illicit drug use and is important because it may produce complications such as intracerebral haemorrhage.

Table 29.1.2 Cardiovascular effects of poisoning

Tachycardia

• Tricyclic antidepressants

Reflex response to hypotension

Bradycardia (includes AV block)

β-Blockers

Calcium channel blockers

Clonidine

Digoxin

Hypotension

Fluid loss/third spacing

Myocardial depressants

• β-Blockers

• Calcium channel blockers

Peripheral vasodilators

Hypertension

Rhythm/ECG abnormalities

QRS prolongation (fast sodium channel blockade)

• Class 1a and 1c antiarrhythmics

• Thioridazine

• Tricyclic antidepressants

• Propranolol

QT prolongation/torsades de pointes

• Tricyclic antidepressants

Ventricular tachycardia/fibrillation

• Tricyclic antidepressants

Ischaemia/infarction

Cocaine

Complication of hypoxia or hypotension

CNS manifestations of poisoning include decreased level of consciousness, agitation or delirium, seizures and disordered temperature regulation. A decreased level of consciousness is a common presentation of poisoning and is associated with many drugs, some of which are listed in Table 29.1.1. Although usually a direct drug effect, CNS depression is occasionally secondary to hypoglycaemia, hypoxia or hypotension. Common causes of agitation or delirium following overdose are listed in Table 29.1.3. Toxic seizures are potentially life-threatening, and important causes are listed in Table 29.1.4.

Table 29.1.3 Toxic causes of agitation or delirium

Alcohol

Anticholinergic syndrome

Antidepressants

• Bupropion

• Venlafaxine

Atypical antipsychotic agents

• Olanzapine

Benzodiazepines and other sedative-hypnotics

Cannabis

Hallucinogenic agents

Serotonin syndrome

Sympathomimetic syndrome

Table 29.1.4 Toxic causes of seizures

Tricyclic antidepressants

Venlafaxine

Hypothermia is usually a complication of environmental exposure secondary to a decreased level of consciousness or altered behaviour. Hyperthermia is a direct toxic effect and causes are listed in Table 29.1.5. Severe hyperthermia is rapidly lethal if not corrected.

Table 29.1.5 Toxic causes of hyperthermia

Metabolic and other manifestations of poisoning include hyper- and hypoglycaemia, hyper- and hyponatraemia, acidosis and alkalosis and hepatic failure.

Acute poisoning is distinguished from many other forms of acute illness in that, given appropriate supportive care over a relatively short period, a full recovery can usually be expected. A small number of potentially fatal poisonings may demonstrate progressive toxicity despite full supportive care. These are the so-called cellular toxins, and include colchicine, iron, salicylate, cyanide, paracetamol, theophylline and digoxin. In some of these cases early aggressive gastrointestinal decontamination, timely administration of antidotes or the institution of techniques of enhanced elimination may be life saving.

Mortality or morbidity may also result from specific complications of a poisoning. These include trauma, pulmonary aspiration, adult respiratory distress syndrome, rhabdomyolysis, renal failure and hypoxic encephalopathy. These complications usually occur prior to arrival in the ED.

Pulmonary aspiration frequently complicates a period of decreased level of consciousness or a seizure. It is a leading cause of in-hospital morbidity and mortality following overdose. This complication is characterized by rapid onset of dyspnoea, cough, fever, wheeze and cyanosis.

Rhabdomyolysis occurs as a direct toxic effect (rare) or secondary to excessive muscular hyperactivity, seizures, hyperthermia or prolonged coma with direct muscle compression. The urine is dark and acute renal failure can develop secondary to tubular deposition of myoglobin.

Assessment

Risk assessment

A risk assessment should be made as soon as possible in the management of the poisoned patient. Only resuscitation is a greater priority (see Table 29.1.6). Risk assessment is a distinct quantitative cognitive step through which the clinician attempts to predict the likely clinical course and potential complications for the individual patient at that particular presentation.⁴ An accurate risk assessment allows informed decision-making in regard to all subsequent management steps including duration and intensity of supportive care and monitoring, screening and specialized testing, decontamination, enhanced elimination, antidotes and disposition. Factors that are taken into account when formulating this risk assessment include: the agent(s), the dose, the time since ingestion, the clinical features present and patient factors (Table 29.1.6). Specialized testing may refine risk assessment. Access to specialized poisons information in the form of a poisons information centre or in-house databases is often necessary to formulate an accurate risk assessment.

Table 29.1.6 Risk assessment-based approach to poisoning

• Correct hypoglycaemia

• Correct hyperthermia

• Consider resuscitation antidotes

Risk assessment

• Agent

• Dose

• Time since ingestion

• Clinical features and course

• Patient factors

Supportive care and monitoring

Investigations

• Screening: 12-lead ECG, paracetamol

Reproduced from Toxicology Handbook. Murray L, Daly F, Little M, Cadogan M. Elsevier, Sydney 2007.

History

Every effort should be made to obtain information as to the type and dose of drug ingested, the time of ingestion and the progression of symptoms since ingestion. History provided by the patient, if they are awake, is usually reliable and should not be dismissed.

Physical examination

The focused physical examination of the poisoned patient aims to:

• identify any immediate threats to life and the need for intervention

• establish a baseline clinical status

• corroborate the history

• identify intoxication syndromes

• identify possible alternative diagnoses

• identify any complications of the poisoning.

The initial physical examination of the overdose patient in many ways parallels the primary survey of the trauma patient. The airway, breathing and circulation are assessed and stabilized as necessary. The level of consciousness should be assessed, the presence of seizure activity noted and the blood glucose and temperature measured.

A more complete examination is carried out when the patient is stable. This should include a full neurological examination, including assessment of the level of consciousness and mental status, pupil size, muscle tone and movements and the presence or absence of focal neurological signs. Poisoning normally causes global CNS depression, and focal signs suggest an alternative diagnosis or a CNS complication such as cerebral haemorrhage.

Other features that should be specifically sought are any evidence of associated trauma, the state of hydration, the condition of the skin, in particular the presence of pressure areas, the presence or absence of bowel sounds and the condition of the urine.

Several toxic autonomic syndromes, or ‘toxidromes’, have been described in relation to poisoning. The principal ones are listed in Table 29.1.7. Identification of these syndromes may narrow the differential diagnosis in cases of unknown poisoning.⁵

Table 29.1.7 Toxic autonomic syndromes or ‘toxidromes’

Toxidrome	Features	Common causes
Anticholinergic	Agitated delirium	Antihistamines
	Tachycardia	Benztropine
	Hyperthermia	Carbamazepine
	Dilated pupils	Phenothiazines
	Dry flushed skin	Plant poisonings
	Urinary retention	Tricyclic antidepressants
	Ileus
Mixed cholinergic	Brady- or tachycardia	Organophosphates
	Hypo- or hypertension	Carbamates
	Miosis or mydriasis
	Sweating
	Increased bronchial secretion
	Gastrointestinal hyperactivity
	Muscle weakness
	Fasciculations
Mixed α- and β-adrenergic	Hypertension	Amphetamines
	Tachycardia	Cocaine
	Mydriasis
	Agitation
β-Adrenergic	Hypotension	Caffeine
	Tachycardia	Salbutamol
	Hypokalaemia	Theophylline
	Hyperglycaemia
Serotonin	Altered mental status	Amphetamines
	Autonomic dysfunction	Antihistamines
	Fever	Monoamine oxidase inhibitors
	Hypertension	NSSRIs
	Sweating	SSRIs
	Tachycardia	Tricyclic antidepressants (Usually combined overdose)
	Motor dysfunction
	Hyperreflexia
	Hypertonia (esp. lower limbs)
	Myoclonus

NSSRI, non-selective serotonin re-uptake inhibitor; SSRI, selective serotonin re-uptake inhibitor.

Poisons information

Information on the clinical course and toxic doses of specific pharmaceutical and non-pharmaceutical poisons is available on a 24 h basis throughout Australia by telephoning 131126. The poison information centres are staffed by pharmacists and are also able to refer cases to clinical toxicologists for consultation.

Treatment

The management of poisoning should be approached in a systematic way. Following initial resuscitation, further treatment is informed by the risk assessment (Table 29.1.6).

Resuscitation, supportive care and monitoring

Supportive care is the key element in the management of poisoning. The vast majority of poisonings result in temporary dysfunction of one or more of the body systems. If appropriate support of the system in question is instituted in a timely fashion and continued until the toxic substance is metabolized or excreted, a good outcome can be anticipated. In severe poisonings supportive care may be very aggressive, and possible interventions are listed in Table 29.1.8.

Table 29.1.8 Supportive care measures for the poisoned patient

Airway	Endotracheal intubation
Breathing	Supplemental oxygen
Breathing	Ventilation
Circulation	Intravenous fluids
	Inotropes
	Antihypertensives
	Antiarrhythmics
	Defibrillation/cardioversion
	Cardiac pacing
	Cardiopulmonary bypass
Metabolic	Hypertonic dextrose
	Hypertonic saline
	Insulin/dextrose
	Calcium salts
	Sodium bicarbonate
Agitation/delirium	Benzodiazepines
Agitation/delirium	Butyrophenones
Seizures	Benzodiazepines
Seizures	Barbiturates
Body temperature	External rewarming
Body temperature	External cooling
Impaired renal function	Rehydration
Impaired renal function	Haemodialysis

The specific supportive management of a number of manifestations or complications of poisoning warrants further mention insofar as it may differ from the standard management of such conditions with other aetiologies.

Cardiopulmonary arrest from poisoning should be aggressively resuscitated. Direct current cardioversion is rarely successful in terminating toxic arrhythmias and should not take precedence over establishing adequate ventilation and oxygenation, cardiac compressions, correction of acidosis or hypovolaemia and the administration of specific antidotes. Resuscitative efforts should be continued beyond the usual timeframe. In cardiac arrest due to drugs with direct cardiac toxicity, the use of cardiopulmonary bypass or extracorporeal membrane oxygenation (ECMO) until the drug is metabolized may be life-saving.

In general, intravenous benzodiazepines are the drugs of choice for control of toxic seizures. Large doses may be required. Hypoxia and hypoglycaemia must be corrected if they are contributory factors. Patients with toxic seizures do not generally need long-term anticonvulsant therapy. Isoniazid-induced seizures are not controlled without administration of an adequate dose of the specific antidote, pyridoxine.

The management of pulmonary aspiration is essentially supportive, with supplemental oxygenation and intubation and mechanical ventilation if necessary. Neither prophylactic antibiotics nor corticosteroids have been shown to be helpful in the management of this condition, which is essentially a chemical pneumonitis.

Toxic hypertension rarely requires specific therapy. Most cases are mild and simple observation is sufficient. Agitation or delirium is a feature of many intoxications associated with hypertension, and adequate sedation with benzodiazepines usually lowers the blood pressure. Severe toxic hypertension is most likely in toxicity from cocaine or amphetamine-type drugs, and treatment may be indicated to avoid complications such as cardiac failure or intracerebral haemorrhage. The drug of choice in this situation is sodium nitroprusside by intravenous infusion. The extremely short duration of action of this vasodilator allows accurate control of hypertension during the toxic phase, and avoids the development of hypotension once toxicity begins to wear off.

Management of rhabdomyolysis consists of treatment of the causative factors, fluid resuscitation and careful monitoring of fluids and electrolytes. The role of mannitol and urinary alkalinization in reducing the risk of renal failure is not clear. Established acute renal failure requires haemodialysis, often for up to 6 weeks.

Decontamination

The aim of decontamination of the gastrointestinal tract is to bind or remove ingested material before it is absorbed into the circulation and able to exert its toxic effects. This is a very attractive concept and has long been considered one of the fundamental interventions in management of the overdose patient.

However, gastrointestinal decontamination should not be regarded as a routine procedure in the management of the patient presenting to the ED following an overdose. The decision to perform gastrointestinal decontamination and the choice of method should be based on an assessment of the likely benefit, the likely risk and the resources required. Gastrointestinal decontamination should only be considered where there is likely to be a significant amount of a significantly toxic material remaining in the gut. It is never indicated when the risk assessment predicts a benign course. Efforts at decontamination technique should never take precedence over the institution of appropriate supportive care.

Three basic approaches to gastrointestinal decontamination are available: gastric emptying, administration of an adsorbent and catharsis.

Gastric emptying can be attempted by the administration of an emetic, most commonly syrup of ipecac, or by gastric lavage. In volunteer studies both of these techniques removed highly variable amounts of marker substances from the stomach even if performed immediately after ingestion, and the effect diminished rapidly with time to the point of being negligible after one hour.^6,⁷ Clinical outcome trials have failed to demonstrate improved outcome as a result of routine gastric emptying in addition to administration of activated charcoal, except, perhaps, in patients presenting unconscious within 1 h of ingestion.⁸^–¹⁰

The principal adsorbent available to clinicians is activated charcoal (AC), which effectively binds most pharmaceuticals and chemicals, and is currently the decontamination method of choice for most poisonings. Materials that do not bind well to charcoal are listed in Table 29.1.9.

Table 29.1.9 Materials that do not bind well to activated charcoal

Metals and their salts

Charcoal is ‘activated’ by treatment in acid and steam at high temperature. This process removes impurities and greatly increases the surface area available for binding. Activated charcoal is packaged as a 50 g dose premixed with water or sorbitol, which is likely to be sufficient for the majority of ingestions. Adult patients are usually able to drink AC slurry from a cup. If the level of consciousness is too impaired to allow this, they should be intubated first. Administration of AC is absolutely contraindicated unless the patient has an intact or protected airway.

Volunteer studies demonstrate that the effect of AC diminishes rapidly with time and that the greatest benefit occurs if it is administered within 1 h. There is as yet no evidence that AC improves clinical outcome.¹¹

There is no evidence to suggest that the addition of a cathartic such as sorbitol to AC improves clinical outcome.^12,¹³

Apart from rarely employed endoscopic and surgical techniques, whole-bowel irrigation (WBI) is the most aggressive form of gastrointestinal decontamination. Polyethylene glycol solution (Golytely™) is administered via a nasogastric tube at a rate of 2 L/h until a clear rectal effluent is produced. This usually takes about 6 h and requires one-to-one nursing. In volunteer studies, this technique reduced the absorption of slow-release pharmaceuticals and so may be of benefit in life-threatening overdoses of these agents.^13,¹⁴ Again, clinical benefit has not yet been conclusively demonstrated.¹⁵ The use of WBI has also been reported in the management of potentially toxic ingestions of iron, lead and packets of illicit drugs. Whole-bowel irrigation is contraindicated if there is evidence of ileus or bowel obstruction, and in patients who have an unprotected airway or haemodynamic compromise.¹⁶

Enhanced elimination

A number of techniques are available to enhance the elimination of toxins from the body. Their use is rarely indicated, as only a very few drugs capable of causing severe poisoning have pharmacokinetic parameters that render them amenable to these techniques (Table 29.1.10).

Table 29.1.10 Techniques of enhanced elimination

Technique	Suitable toxin
Repeat-dose activated charcoal	Carbamazepine
	Dapsone
	Phenobarbitone
	Phenytoin
	Salicylate
	Theophylline
Urinary alkalinization	Phenobarbitone
Urinary alkalinization	Salicylate
Haemodialysis	Ethylene glycol
	Lithium
	Methanol
	Salicylate
	Theophylline
Haemoperfusion	Theophylline

Repeat-dose AC (25–50 g every 3–4 h) may enhance drug elimination by interrupting the enterohepatic circulation or by ‘gastrointestinal dialysis’. Gastrointestinal dialysis is the movement of a toxin across the gastrointestinal wall from the circulation into the gut down a concentration gradient that is maintained by charcoal binding. For this technique to be effective, a drug must undergo considerable enterohepatic circulation or, in the case of ‘gastrointestinal dialysis’, have a small volume of distribution, small molecular weight, low protein binding, slow endogenous elimination and bind to charcoal.^16,¹⁷ The advantages of this technique are that it is non-invasive and simple to carry out.

Alkalinization of the urine enhances urinary excretion of drugs that are filtered at the glomerulus and are unable to be reabsorbed across the tubular epithelium when in an ionized form at alkaline pH. For elimination to be effectively enhanced by this method, the drug must be predominantly eliminated by the kidneys in the unchanged form, have a low pKa, be distributed mainly to the extracellular fluid compartment and be minimally protein bound.¹⁸

Haemodialysis (HD) and haemoperfusion (HP) are both very invasive techniques and for that reason are reserved for potentially life-threatening intoxications. Only a small number of drugs that have small volumes of distribution, slow endogenous clearance rates, small molecular weights (HD) and bind to charcoal (HP) will have their rates of elimination significantly enhanced by these procedures.

Antidotes

Very few drugs have effective antidotes. Occasionally, however, timely use of an antidote may be life saving or substantially reduce morbidity, time in hospital or resource requirements. Antidotes that may be indicated in the ED setting are listed in Table 29.1.11. However, it must be remembered that antidotes are also drugs, and are frequently associated with adverse effects of their own. An antidote should only be used where a specific indication exists, and then only at the correct dose, by the correct route, and with appropriate monitoring. Because many antidotes are so infrequently used, obtaining sufficient supplies when the need arises can be difficult. Every ED must review its stocking of antidotes and have a plan for obtaining further supplies should the need arise.

Table 29.1.11 Useful emergency antidotes

Poisoning	Antidote
Atropine	Physostigmine
Benzodiazepines	Flumazenil
Cyanide	Dicobalt edetate, hydroxocobalamin
Digoxin	Digoxin-specific Fab fragments
Insulin	Dextrose
Iron	Desferoxamine
Isoniazid	Pyridoxine
Methaemoglobinaemia	Methylene blue
Methanol and ethylene glycol	Ethanol, fomepizole
Organophosphates and carbamates	Atropine, oximes
Opioids	Naloxone
Paracetamol	N-acetyl cysteine
Sulphonylureas	Dextrose, octreotide
Tricyclic antidepressants	Sodium bicarbonate
Warfarin, brodifacoum	Vitamin K

Differential diagnosis

It is essential to exclude important non-toxic diagnoses in the patient presenting with coma or altered mental status presumed to be due to drug overdose. These diagnoses include head injury, intracerebral haemorrhage or infarction, CNS infection, hyponatraemia, hypoglycaemia, hypo- or hyperthermia, post-ictal states and psychiatric disorders.

Clinical investigation

Investigations should only be performed if they are likely to affect the management of the patient. They are employed as either screening tests or for specific purposes.

In poisoning, screening tests aim to identify occult toxic ingestions for which early specific treatment might improve outcome. The recommended screening tests for acute poisoning are the 12-lead ECG and the serum paracetamol level. The ECG is used to exclude conduction defects, which may predict potentially life-threatening cardiotoxicity. The serum paracetamol is useful to ensure that paracetamol poisoning is diagnosed within the time available for effective antidotal treatment.

Other specific investigations may be indicated to exclude important differential diagnoses, confirm a specific poisoning for which significant complications might be anticipated, assess the severity of intoxication, assess response to treatment or assess the need for a specific antidote or enhanced elimination technique.

The patient with only minor manifestations of poisoning may require no other blood tests apart from a screening paracetamol level. Pregnancy should be excluded in women of childbearing age by serum or urine β-HCG if necessary. More seriously ill patients may require electrolyte, renal and liver function tests and a full blood count, creatine kinase and arterial blood gases. Urinalysis reveals myoglobinuria in significant rhabdomyolysis.

Routine qualitative drug screening of urine or blood in the overdose patient is rarely useful in planning management.

Measurement of serum drug concentrations is only useful if this provides important diagnostic or prognostic information, or assists in planning management. Some drug levels that may be useful are listed in Table 29.1.12. For most cases, drug overdose management is guided by clinical findings and not by drug levels. Some drugs commonly taken in overdose for which serum concentrations are of no value in planning management are listed in Table 29.1.13.

Table 29.1.12 Drug levels that may be helpful in the management of selected cases of overdose

Table 29.1.13 Drug levels that are not helpful in the management of overdose

CNS drugs	Cardiovascular drugs
Antidepressants	ACE inhibitors
Benzodiazepines	Beta-blockers
Benztropine	Calcium channel blockers
Cocaine	Clonidine
Newer antipsychotics
Opiates
Phenothiazines

Radiology has a limited role in the management of overdose. A chest X-ray is indicated in any patient with a significantly decreased level of consciousness, seizures or hypoxia. It may show evidence of pulmonary aspiration. A computerized tomography scan of the head may be indicated to exclude other intracranial pathology in the patient with an altered mental status. The abdominal X-ray is useful in evaluating overdose of radio-opaque metals including iron, lithium, potassium, lead and arsenic.

Disposition

Both the medical and the psychiatric disposition of the overdose patient must be considered. A good risk assessment is essential to determining timely and safe disposition.

The majority of overdose patients who remain stable at 4–6 h after the ingestion do not need further close monitoring and may be admitted to a non-monitored bed until manifestations of toxicity completely resolve. An emergency observation ward is ideal for this purpose.

Any patient who develops clinical manifestations of intoxication severe enough to require the institution of specific supportive care measures requires admission to an intensive care environment. A few patients will require admission for prolonged monitoring based on the history of the ingestion. For example, anyone with a history of ingestion of colchicine, organophosphates, slow-release theophylline or slow-release calcium channel blockers requires admission because of the possibility of delayed onset of severe toxicity.

Psychiatric evaluation of deliberate self-poisoning cases is indicated as soon as the patient’s medical condition permits. All such patients must be continuously supervised until the psychiatric evaluation has taken place.

Controversies

1 The role of, choice of method, and indications for gastric decontamination remain controversial. These procedures are no longer regarded as routine, but there are likely to be subgroups of overdose patients who may derive clinical benefit from gastrointestinal decontamination. These groups have not yet been precisely identified.

2 The clinical and economic utility of establishing specialized toxicology treatment centres.^19,²⁰

References

1 Hawton K, Fagg J. Trends in deliberate self-poisoning and self-injury in Oxford. British Medical Journal. 1992;304:1409-1411.

2 McGrath J. A survey of deliberate self-poisoning. Medical Journal of Australia. 1989;150:317-322.

3 Pond SM. Prescription for poisoning. Medical Journal of Australia. 1995;162:174-175.

4 Murray L, Daly F, Little M, Cadogan M, editors. Toxicology handbook. Sydney: Elsevier, 2007.

5 Kulig K. Initial management of ingestion of toxic substances. New England Journal of Medicine. 1992;326:1677.

6 Krenzelok EP, McGuigan M, Lheureux P. Position statement: ipecac syrup. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):699-709.

7 Vale JA. Position statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):711-719.

8 Kulig K, Bar-Or D, Kantrill SV, et al. Management of acutely poisoned patients without gastric emptying. Annals of Emergency Medicine. 1990;14:562-567.

9 Merigian KS, Woodard M, Hedges JR, et al. Prospective evaluation of gastric emptying in the self-poisoned patient. American Journal of Emergency Medicine. 1990;8:479-483.

10 Pond SM, Lewis-Driver DJ, Williams G, et al. Gastric emptying in acute overdose: a prospective randomised controlled trial. Medical Journal of Australia. 1995;163:345-349.

11 Chyka PA, Seger D. Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):721-741.

12 Barceloux D, McGuigan M, Hartigan-Go K. Position statement: cathartics. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):743-752.

13 Kirshenbaum LA, Mathew SC, Sitar DS, et al. Whole-bowel irrigation versus activated charcoal in sorbitol for the ingestion of modified-release pharmaceuticals. Clinical Pharmacology Therapy. 1989;46:264-271.

14 Smith SW, Ling LJ, Halstenson CE. Whole-bowel irrigation as a treatment for acute lithium overdose. Annals of Emergency Medicine. 1991;20:536-539.

15 Tenenbein M. Position statement: whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology – Clinical Toxicology. 1997;35(7):753-756.

16 Pond SM. Role of repeated oral doses of activated charcoal in clinical toxicology. Medical Toxicology. 1986;1:3-11.

17 Chyka PA. Multiple-dose activated charcoal and enhancement of systemic drug clearance: summary of studies in animals and human volunteers. Clinical Toxicology. 1995;33:399-405.

18 Winchester JF. Active methods for detoxification. In Haddad LM, Shannon MW, Winchester JF, editors: Clinical management of poisoning and drug overdose, 3rd edn, Philadelphia: WB Saunders, 1998.

19 Whyte IM, Dawson AH, Buckley NA, et al. A model for the management of self-poisoning. Medical Journal of Australia. 1997;167:142-146.

20 Lee V, Kerr JF, Braitberg G, et al. Impact of a toxicology service on a metropolitan teaching hospital. Emergency Medicine. 2001;13:37-42.

29.2 Cardiovascular drugs

Betty Chan, Lindsay Murray

Essentials

1 Many cardiovascular medications, including the calcium channel blockers, the β-blockers and digoxin, are associated with potentially life-threatening toxicity.

2 The key to the management of calcium channel blocker and β-blocker toxicity rests with aggressive supportive care of the circulation including early use of hyperinsulinaemia euglycaemia therapy.

3 The onset of toxicity following overdose with slow-release formulations of calcium channel blockers may be delayed.

4 Early aggressive decontamination with whole-bowel irrigation is important in the management of slow-release calcium channel blocker overdose.

5 Early identification of patients presenting with potentially severe digoxin toxicity and appropriate use of the specific Fab fragment antibody is life saving.

6 The management of clonidine poisoning is largely supportive.

Calcium channel blockers and β-blockers

Introduction

The calcium channel blockers (CCBs) and β-blockers are widely prescribed in the community. In overdose, they present with similar clinical pictures of potentially life-threatening impairment of cardiac function. The management of both types of overdose is similar and they are discussed together.

Pharmacokinetics

Standard CCB preparations are rapidly absorbed from the gastrointestinal tract, with onset of action occurring within 30 min.¹ Pharmacokinetic parameters are shown in Table 29.2.1. Verapamil and diltiazem undergo significant first-pass hepatic clearance. Verapamil is metabolized to norverapamil, which possesses 15–20% of verapamil’s pharmacological activity and is renally excreted. Diltiazem is metabolized to deacetyldiltiazem, which has half the potency of the parent compound and undergoes biliary excretion. The elimination half-lives of all CCBs may be prolonged following massive overdose. Amlodipine has a longer plasma half-life (30–50 h) than other CCBs.

Table 29.2.1 Pharmacological profiles of the calcium channel blockers

Importantly, slow-release preparations of both verapamil and diltiazem are widely prescribed and are associated with much longer times to peak plasma concentration and clinical effect.

Absorption of β-blockers is rapid, with peak clinical effects occurring within 1–4 h. Pharmacokinetic parameters of the principal β-blockers are detailed in Table 29.2.2. Agents with high lipid solubility, such as propranolol, penetrate the blood–brain barrier better than the water-soluble agents, and hence cause greater central nervous system (CNS) toxicity.

Table 29.2.2 Pharmacological profiles of the β-blockers

Pathophysiology

CCBs antagonize the entry of extracellular calcium into cardiac and smooth muscle, but not skeletal muscle. Upon entry into cells, calcium participates in mechanical, electrical and biochemical reactions. It is involved in excitation–contraction of cardiac and smooth muscles, as well as phase 0 depolarization in the sinus and atrioventricular (AV) nodes by calcium influx through channels.² CCBs affect myocardial contractility and slow conduction through the sinus and AV nodes. Contraction of smooth muscle is mediated by calcium influx, which is inhibited by CCBs. This results in vasodilatation and secondary reflex tachycardia from an increase in sympathetic activity.

The different classes of CCB have somewhat different pharmacological and toxic effects, as a consequence of their different binding characteristics to the dihydropyridine (DHP) receptors. Verapamil, a phenylalkylamine, produces more profound cardiac conduction defects and equal reductions in systemic vascular resistance when compared with other CCBs on a mg/kg basis.¹ Verapamil is more likely to produce symptomatic decreases in blood pressure, heart rate and cardiac output than diltiazem, a benzothiazepine. The DHPs, which include amlodipine, felodipine, lercanidipine and nifedipine preferentially bind to vascular smooth muscle and predominantly decrease systemic and coronary vascular resistance. With the exception of felodipine, they also produce a reflex tachycardia by the unloading of baroreceptors.

β-blockers prevent the binding of catecholamines to β receptors (β₁, β₂). β₁ receptors are located in the myocardium, kidney and eye, and β₂ receptors in adipose tissue, pancreas, liver and both smooth and skeletal muscle. β₁ stimulation produces increased chronotropy and inotropy in the heart, increased renin secretion in the kidney and increased aqueous humor production. β₂ stimulation relaxes smooth muscle in the blood vessels, bronchial tree, intestinal tract and uterus.

Blockade of β receptors results in increased intracellular cAMP concentrations, with a resultant blunting of the metabolic, chronotropic and inotropic effects of catecholamines. Some β-blockers, especially propranolol, may also impede sodium entry via myocardial fast inward sodium channels, thus slowing phase 0 of the action potential. This results in a prolonged QRS duration on the electrocardiogram and produces cardiotoxicity in overdose more like that of the tricyclic antidepressants.

The different β-blockers have slightly differing pharmacological properties, including selectivity for β adrenoreceptors, intrinsic sympathomimetic activity and membrane-stabilizing activity. The relative affinity for β adrenoreceptors may influence expression of toxicity. Atenolol, esmolol and metoprolol are β₁-selective agents, and therapeutic use of these drugs is less likely to produce the peripheral vasoconstriction, bronchospasm and disturbances in glucose homoeostasis that result from β₂ inhibition. However, pharmacological specificity decreases with increasing dose.³ Several β-blockers have partial agonist activity such that, although they block the β receptor to catecholamines, they also weakly stimulate the receptor. This partial agonist activity may have a protective effect in overdose.

Clinical features

Calcium channel blockers

The severity of toxicity is determined by a number of factors, including the amount and characteristics of the drug ingested, the underlying health of the patient, co-ingestants and delay until treatment. The majority of serious cases result from the ingestion of verapamil or diltiazem, the most toxic of the CCBs. Elderly patients and those with congestive cardiac failure are more prone to develop CCB poisoning. The principal clinical features are shown in Table 29.2.3. Ingestion of toxic amounts of standard preparations typically produces symptoms within 2 h, although maximal toxicity may not occur for up to 6–8 h. The slow-release preparations can produce significant toxicity, with onset of symptoms more than 6 h post ingestion. The major threats to life are myocardial depression and hypotension. Nifedipine produces tachycardia with normal blood pressure during the first 30 min, followed later by hypotension and bradycardia in large ingestions (>10 mg/kg). With verapamil and diltiazem poisoning, nausea, vomiting, hyperglycaemia and metabolic acidosis can develop. All CCBs can cause symptoms of cerebral hypoperfusion, such as syncope, lethargy, lightheadedness, dizziness, altered mental status, seizures and coma.

Table 29.2.3 Clinical features of CCB overdose

Central nervous system

• Lethargy, slurred speech, confusion, coma

• Bradycardia and other arrhythmias

• Sinus bradycardia

• Accelerated AV nodal rhythm

• 2° AV block

• 3° AV block with AV nodal or ventricular escape rhythm

• Sinus arrest with AV nodal escape rhythm

β-blockers

In one large series of patients with β-blocker overdose, 30–40% of patients remained asymptomatic and only 20% developed severe toxicity.⁴ Toxicity is more likely to develop after ingestion of propranolol, in patients with pre-existing cardiac disease or where there is co-ingestion of other drugs with effects on the cardiovascular system, especially CCBs and cyclic antidepressants.^4,⁵ If β-blocker toxicity is to develop, it is usually observed within 6 h of ingestion.^5,⁶

Sinus node suppression and conduction abnormalities and decreased contractility are typical. First-degree AV block, AV dissociation, right bundle branch block and intraventricular conduction delay have been reported.

Propranol overdose is characterized by cardiotoxicity including prolongation of the QRS interval and ventricular arrhythmias that more closely resemble tricyclic antidepressant overdose; a consequence of the sodium channel blocking effects.

Sotalol has both β-blocker activity and class III antiarrhythmic properties. Class III drugs lengthen the duration of the QT interval owing to prolongation of the action potential in His-Purkinje tissue. Therefore, ventricular arrhythmias are more common with sotalol.

Hypotension occurs as a result of negative inotropic effect. In addition, CNS effects, such as depressed conscious level and seizures, can occur, especially with the more lipid-soluble and membrane-depressant agents such as propranolol. Hypoglycaemia is reported following atenolol overdose.

Clinical investigation

The ECG is essential in evaluating and monitoring toxic conduction defects. Serum drug levels are unhelpful in management. Patients with severe toxicity require monitoring of serum electrolytes and glucose. Serum calcium must be closely monitored if calcium salts are administered therapeutically.

Treatment

The primary aim in both β-blocker and CCB toxicity is to restore perfusion to vital organs by increasing cardiac output, and the methods used are similar.

Supportive management may include airway and ventilatory support, intravenous fluid administration, transcutaneous or transvenous pacing and administration of inotropes. Severe cases may require placement of a Swan–Ganz catheter and invasive blood pressure monitoring.

Oral-activated charcoal should be administered as soon as practicable to all patients presenting within 2–4 h of ingestion, and to all those presenting after ingestion of slow-release preparations. More aggressive decontamination, with whole-bowel irrigation, is indicated following overdose with slow-release CCBs.⁷

A number of drugs play a role in the management of significant CCB or β-blocker poisoning, although none is a completely effective antidote. Suggested doses are shown in Table 29.2.4.

Table 29.2.4 Useful drugs in the management of CCB and β-blocker toxicity

	CCBs	β-Blockers
Calcium	0.5–1 g (5–10 mLs) calcium chloride or 1–2 g (10–20 mLs) calcium gluconate i.v. over 5–10 minutes. Repeat every 10–15 minutes as required. Further administration guided by serum calcium concentrations.
Catecholamines	Adrenaline (epinephrine) infusion started at 1 μg/kg/min and titrate to maintain organ perfusion.	Isoprenaline or adrenaline (epinephrine) infusion titrated to maintain organ perfusion.
Glucagon	A bolus dose of 5–10 mg followed by an infusion of 1–5 mg/h.	A bolus dose of 5–10 mg followed by an infusion of 1–5 mg/h.
Hyperinsulinaemia euglycaemia	Actrapid 1 U/kg i.v. bolus followed by 0.5–1 U/kg/hr infusion. Give with 50% dextrose 50 mL followed by infusion to maintain euglycaemia.	Actrapid 1 U/kg i.v. bolus followed by 0.5–1 U/kg/hr infusion. Give with 50% dextrose 50 mL followed by infusion to maintain euglycaemia.

Calcium, an inotropic agent, is the initial drug of choice for CCB toxicity. Administration must be closely monitored, with ionized calcium measured 30 min after commencing the infusion, and then second-hourly.⁸ Catecholamines are useful in attempting to restore adequate tissue perfusion.

Glucagon, a polypeptide hormone of pancreatic origin, enhances myocardial performance by increasing intracellular cAMP concentrations. This increase in cAMP triggers the release of cAMP-dependent protein kinase, which activates the calcium channels, causing an increase in heart rate and myocardial contractility. It works independently from that of the β-adrenoreceptor stimulation of the heart. Use of glucagon is supported only by case reports and some animal studies. There are no clinical trials supporting its efficacy in either calcium channel or beta-blocker poisoning and its role in management of these poisoning is questioned.⁹ It is frequently difficult to source adequate stocks of glucagon for use as an inotropic agent.

Hyperinsulinaemic euglycaemia therapy (HIET) is increasingly advocated as therapy for hypotension unresponsive to fluids, calcium salts and inotropes. This therapy is supported by animal work ^10,¹¹ and promising initial human case reports¹² but again clinical trials are lacking. Insulin administration switches cardiac cell metabolism from fatty acids to carbohydrates. It restores calcium fluxes and improves myocardial contractility. The recommended initial dose of actrapid is 1 U/kg i.v. followed by an infusion of 0.5–1 U/kg/h. This should be accompanied by an initial bolus dose of 50 mL 50% dextrose followed by an infusion to maintain euglycaemia.¹³

Severe propranolol toxicity is usually due to sodium channel blockade and treatment as for tricyclic antidepressant poisoning, including intubation, ventilation and sodium bicarbonate, is appropriate.

There are no clinically effective methods of enhancing the elimination of CCBs or β-blockers.

Disposition

Following overdose of β-blockers or standard CCBs, patients should be observed in a monitored environment for at least 6 h. Overdoses of slow-release CCBs require monitoring for at least 16 h from the time of ingestion. All symptomatic patients should be admitted to a monitored environment until toxicity resolves.

Digoxin

Introduction

Both chronic and acute digoxin toxicity are potentially life-threatening presentations to the emergency department (ED). Early recognition and administration of the specific Fab fragment antidote, if indicated, usually results in a good outcome.

Pharmacokinetics

Digoxin is moderately well absorbed following oral administration, with a bioavailability in the range of 50–80%. The initial volume of distribution is relatively small, but it is then slowly redistributed, predominantly to skeletal muscle, to give a relatively large volume of distribution of approximately 8 L/kg. Digoxin is excreted predominantly unchanged by the kidney, with an elimination half-life of about 36 h.

Pathophysiology

At a subcellular level digoxin inhibits the function of Na-K ATPase, which leads to intracellular depletion of potassium and accumulation of sodium and calcium ions. Alteration of ionic fluxes affects cell membrane conduction. At toxic concentrations of digoxin, the effects on the cardiac conducting system produce decreased conduction velocity throughout the system, increased refractoriness at the AV node and enhanced automaticity of the Purkinje fibres. Vagal tone is also enhanced. In acute digoxin poisoning the sudden loss of Na-K ATPase function produces hyperkalaemia.

Clinical features

Two distinct clinical presentations of digoxin toxicity are observed: acute and chronic. Both are characterized by cardiac arrhythmias, and virtually all types of arrhythmia have been reported in the context of digoxin toxicity.¹⁴

Acute digoxin overdose in adults is usually intentional. The therapeutic margin for digoxin is relatively narrow, and any ingestion with suicidal intent is regarded as potentially life-threatening.

The non-cardiac manifestations of toxicity are nausea and vomiting and hypokalaemia. Nausea and vomiting occur early and may be the presenting complaint. The most common cardiac manifestations are sinus bradycardia, sinoatrial node arrest and first-, second- or third-degree heart block. Ventricular tachycardia and fibrillation may occur. In significant acute overdose progressive worsening of the conduction disturbance over a period of hours is usually observed.

Chronic digoxin toxicity may be precipitated by therapeutic errors, intercurrent illnesses that decrease renal elimination of digoxin or by drug interactions. Common drug interactions include those with quinidine, CCBs, amiodarone and indometacin. The patient is commonly elderly. Reduced muscle mass and reduced renal function in the elderly mean that both the volume of distribution and rate of elimination of digoxin may be substantially reduced.

Nausea and vomiting are also common manifestations of chronic digoxin toxicity and are frequent presenting symptoms. Neurological manifestations are characteristic of chronic toxicity and include visual disturbances, weakness and fatigue. The most common cardiovascular manifestations of chronic digoxin toxicity are arrhythmias, and these may be sinus bradycardia, atrial fibrillation with slowed ventricular response or a junctional escape rhythm, atrial tachycardia with block and ventricular tachycardia and fibrillation.

Death from digoxin toxicity results from pump failure, severe cardiac conduction impairment or ventricular arrhythmia.

Clinical investigation

The most important investigations are the ECG, serum electrolytes and creatinine and serum digoxin concentration.

The ECG is invaluable in documenting the type and severity of any cardiac conduction defect. Serial ECGs may demonstrate worsening of the cardiac conduction defects as toxicity progresses.

In acute poisoning the serum potassium rises as Na-K ATPase function is progressively impaired. Hyperkalaemia denotes significant acute digoxin toxicity. Prior to the availability of a specific antidote for digoxin poisoning, a serum potassium concentration >5.5 mEq/L was associated with a high probability of lethal outcome.¹⁶ Hyperkalaemia is not usually observed in chronic digoxin toxicity. In fact, these patients are frequently hypokalaemic and hypomagnesaemic secondary to chronic diuretic use. Both these electrolyte disorders are important as they exacerbate digoxin toxicity.

Serum digoxin concentrations are extremely useful in assessing and confirming toxicity, but must be carefully interpreted in the context of the clinical presentation. They do not accurately correlate with clinical toxicity. Therapeutic concentrations are usually quoted as 0.6–2.3 nmol/L (0.5–1.8 μµg/L). Significant chronic toxicity may be associated with relatively minor elevations of the serum digoxin concentration. This is particularly the case in the presence of pre-existing cardiac disease, hypokalaemia or hypomagnesaemia. Following acute overdose the serum digoxin concentration is relatively high compared to tissue concentrations, until distribution is completed by 6–12 h post ingestion. However, early concentrations greater than 15 nmol/L indicate serious poisoning.

Treatment

The best outcome is associated with early recognition of digoxin toxicity.

For chronic toxicity with minimal symptoms, management may involve no more than observation, cessation of digoxin administration, correction of hypokalaemia and hypomagnesaemia and appropriate management of any factors that contributed to the development of toxicity. However, presence of any cardiovascular system effects, particularly in elderly patients, is an indication for the administration of Fab fragments of digoxin-specific antibodies. The potential lethality of chronic digoxin poisoning is often underestimated with the result that digoxin antibody fragments are inappropriately withheld.¹⁶ From a purely economic view, the reduction in length of stay as a result of treatment with digoxin-specific antibodies outweighs the expense of the therapy.¹⁷

Following acute overdose the patient should be initially managed in a monitored area with full resuscitative equipment available. Immediate attention to the airway, breathing and circulation may be required. Intravenous access should be established and blood sent for urgent electrolytes and serum digoxin concentration. Although digoxin is well bound by charcoal, administration is usually difficult because of repetitive vomiting, and attempts should not detract from other interventions.

The specific antidote to digoxin poisoning is Fab fragments of digoxin-specific antibodies, which should be administered as soon as possible in any potentially life-threatening digoxin intoxication. Commonly accepted indications for the administration of Fab fragments are listed in Table 29.2.5.

Table 29.2.5 Indications for administration of Fab fragments of digoxin-specific antibodies following acute overdose

Hyperkalaemia (K > 5.0 mmol/L) associated with digoxin toxicity

History of ingestion of more than 10 mg of digoxin

Haemodynamically unstable cardiac arrhythmia

Cardiac arrest from digoxin toxicity

Serum digoxin concentration greater than 15 nmol/L

Fab fragments of digoxin-specific antibodies

These are derived from IgG antidigoxin antibodies produced in sheep. Removal of the Fc fragments of the antibodies greatly reduces the potential for hypersensitivity reactions and contributes to the remarkable safety profile of the product. Intravenously administered Fab fragments bind digoxin in the intravascular space on a mole-for-mole basis. As binding continues, digoxin moves down a concentration gradient from the tissue compartments to the intravascular compartment. Bound digoxin is inactive. A clinical response is usually observed within 20–30 min of administration. The Fab–digoxin complexes are excreted in the urine.

The extraordinary clinical efficacy of digoxin-specific fragments has been well documented in a multi-centre study.¹⁷ The same study also demonstrated the safety of the product, with the only adverse reactions reported being hypokalaemia (4% incidence) and worsening of congestive cardiac failure (3%).

The correct dose of Fab fragments may be calculated on the basis that 40 mg (one vial) will bind 0.6 mg of digoxin. If the dose ingested is unknown and/or a steady-state serum digoxin concentration is not available, dosing of Fab fragments must be empiric. Following acute overdose a reasonable approach to empiric dosing is to give five vials initially and then repeat until a clinical response is observed. Smaller doses (two vials) are usually sufficient to reverse the effects of chronic toxicity.

It is important that ED staff are aware of the amount and location of supplies of Fab fragments within their own institution, and know the most rapid way to acquire further stocks should the need arise.

Serum digoxin concentrations will be extremely high following the administration of Fab fragments because most assays measure both bound and unbound digoxin.

Only gold members can continue reading. Log In or Register to continue