Assessment

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:

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’

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).

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

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

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

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.

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

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

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

Disposition

Patients with mild, chronic digoxin toxicity (gastrointestinal symptoms only) may be discharged after cessation of digoxin therapy provided there are no significant electrolyte disturbances, renal failure or other precipitating medical conditions. Following administration of Fab fragments, cases of chronic toxicity with conduction defects usually require medical admission for observation and treatment of intercurrent illness.

Acute overdoses require close observation for at least 12 h. Those that develop toxicity require admission and an appropriate level of monitoring. Following successful administration of digoxin-specific Fab fragments, patients must be carefully monitored for hypokalaemia and worsening of any underlying medical conditions for which digoxin may have been prescribed therapeutically. All intentional ingestions require psychiatric evaluation prior to medical discharge.

Clonidine

Pharmacokinetics

Clonidine is well absorbed with a bioavailability of almost 100%. The peak concentration in plasma and effect is observed within 1–3 h. The elimination half-life is 6–24 h with a mean half-life of 12 h. Half of the administered dose is excreted unchanged by the kidney.¹⁹

Pathophysiology

Clonidine activates central α₂ receptors. This results in a reduction in CNS sympathetic outflow at the vasomotor centre in the medulla oblongata. Clonidine is thought to reduce blood pressure through a reduction in cardiac output as well as its weak peripheral alpha adrenergic antagonist properties. Clonidine also stimulates parasympathetic outflow and this may contribute to the slowing of heart rate as a consequence of increased vagal tone. Paradoxically, clonidine overdose can result in an initial hypertension from its partial α₁ adrenergic agonist effect. It is suggested that clonidine’s inhibition of sympathetic outflow is mediated through endogenous opiate release.

Clinical features

Clonidine can cause transient hypertension from initial vasoconstriction with parenteral administration followed by hypotension. In addition to bradycardia and conduction defects, it can cause a central chlorpromazine-like effect with sedation. Other CNS symptoms include coma, seizure, miosis, reduced respiration and hypothermia.²⁰ The median onset of symptoms following clonidine ingestion is 30 min and patients are usually symptomatic on arrival at the ED.²⁰ Symptoms usually resolve by 24 h.²¹

Investigations

The ECG is essential in evaluating and monitoring for bradycardia and conduction defects.

Treatment

The management of clonidine poisoning is primarily supportive. Hypotension usually responds to intravenous fluids. Atropine has been shown to abolish bradycardia in some case reports. Occasionally inotropes may be required to maintain haemodynamic stability. Hypertension is usually short-lived and rarely requires treatment. Patients are usually symptomatic on arrival and the benefits of administering activated charcoal are unlikely to outweigh the risk of aspiration.

Disposition

Patients should be observed in hospital until they are asymptomatic and bradycardia has resolved. They do not require ongoing cardiac monitoring for a stable sinus bradycardia.

Pharmacology

SSRIs raise synaptic concentrations of serotonin by inhibiting serotonin uptake into presynaptic neurons. In addition, serotonin release from neurons, like other biogenic amines, is subject to autoregulation by presynaptic serotonin receptors that mediate negative feedback. SSRIs desensitize presynaptic serotonin autoreceptors, resulting in increased serotonin release. The rise in synaptic serotonin concentration and resultant stimulation of serotonin receptors (at least 14 different receptors discovered to date) is thought to explain SSRIs’ antidepressant activity.⁶⁹

The atypical antidepressants have other effects apart from those on serotonin neurotransmission and these are listed in Table 29.3.5. The SSRIs and atypical antidepressants are generally rapidly and well absorbed after oral administration. Importantly, an extended release formulation of venlafaxine is widely prescribed. These drugs display diverse elimination patterns and have numerous active metabolites, which results in an extended therapeutic effect but also prolongs the time during which drug interactions and adverse effects can occur.

Clinical features

Symptoms usually begin shortly after the commencement of a serotoninergic drug, or the administration of two different classes of drugs that increase serotonin levels synergistically, for example lithium and fluoxetine. In addition, potential drug interaction may arise when the appropriate ‘change-over’ period between drugs is not observed.⁷⁷ A severe form of the syndrome may develop some hours following overdose with an SSRI or, more commonly, following overdose with multiple serotonergically active drugs.^78–80

The diagnosis of serotonin syndrome is clinical and based upon the presence of the triad of alteration in behaviour-cognitive ability, autonomic function and neuromuscular activity. A grading system has been proposed.⁸¹ In its most benign form the patient experiences anxiety and apprehension, but altered sensorium with confusion occurs in 50% of reported cases.⁶⁹ Seizures may occur.⁷⁹ Abnormal neuromuscular activity, caused by increased brainstem and spinal-cord serotonin levels, manifests as increased rigidity (more in the lower than the upper limbs), hyperreflexia, involuntary jerks and resting extremity tremor. Hyperthermia, secondary to increased muscle activity is a common feature and may lead to confusion with NMS. Diaphoresis, diarrhoea and rigors are common. Cardiovascular instability may occur. Although most patients recover, fatalities are reported.^79,80 There is no correlation with drug levels, and serotonin syndrome remains a clinical diagnosis.⁶⁹ The differential diagnosis includes NMS, acute dystonia, hyperadrenergic states (e.g. cocaine toxicity), anticholinergic syndrome and malignant hyperthermia. Decision algorithms have been developed to help the clinician distinguish serotonin syndrome from other conditions.⁸²

Treatment

The management of most SSRI and atypical antidepressant overdose is supportive. This usually consists of simple observation, particularly for clinical evidence of serotonin syndrome. Venlafaxine overdose may require more aggressive intervention to ensure control of seizures and cardiotoxicity. Overdose of extended-release preparations of venlafaxine mandates observation for at least 12 h and until symptom-free.

Management of the serotonin syndrome is directed towards withdrawal of the causative agent and the administration of benzodiazepines to decrease muscular rigidity. Benzodiazepines have been reported to non-specifically inhibit serotonin neurotransmission. If hyperthermia is severe more aggressive treatment may be warranted, including neuromuscular paralysis. Seizures should be treated with benzodiazepines or barbiturates.

Non-specific 5-HT₁ and 5-HT₂ antagonists such as propranolol, cyproheptadine, chlorpromazine and olanzapine have been tried.^83–85 There are no controlled trials using these agents, but anecdotally cyproheptadine appears to be effective without the adverse effects of the other drugs.⁵⁸ A dose of 4–8 mg 8-hourly is recommended.

Anticonvulsants

Anticonvulsants are frequently taken in deliberate self-poisoning. Toxicity resulting in ED attendance also results as a consequence of therapeutic administration. The benzodiazepines and phenobarbitone are discussed earlier in this chapter. This section discusses the traditional anticonvulsants, carbamazepine, phenytoin and sodium valproate – all of which have important toxic syndromes, and the newer anticonvulsants.

Carbamazepine

Phenytoin

Valproic acid

L-carnitine

L-carnitine is an amino acid carrier molecule used to transport long-chain fatty acids across to mitochondria. It is synthetized chiefly in liver and kidney. It is available in oral and intravenous forms and appears to have an acceptable safety profile.¹⁰⁰ It is postulated that L-carnitine could provide benefit in patients with concomitant hyperammonemia encephalopathy and/or hepatotoxicity as there is some evidence that it reduces ammonia concentrations in acute valproate overdose.^101,102 While L-carnitine has been used in a number of case reports definitive evidence of efficacy is lacking.

Newer antiepileptic drugs

A number of new antiepileptic drugs with differing pharmacokinetic properties and mechanisms of action have been introduced into clinical practice over the last decade. These include oxcarbazepine, gabapentin, felbamate, vigabatrin, topiramate and tiagabine. The toxicity profiles of these drugs in overdose are not yet well established. Gabapentin, felbamate and lamotrigine are reported to cause only minor CNS effects in overdose.^99–103 Vigabatrin overdose has resulted in severe agitation.¹⁰⁴

Pharmacodynamics and pharmacokinetics

The H₁-antagonists are a diverse group of agents that reversibly block the action of histamine at H₁ receptors. High lipid solubility results in central nervous system (CNS) penetration and sedation. The first generation agents also block muscarinic, α-adrenergic and serotonergic receptors. Local anaesthetic effects due to sodium channel blockade may mimic the antiarrhythmic properties of class 1A antiarrhythmic agents.¹¹ Diphenhydramine, dimenhydrinate and cyproheptadine, in particular, may prolong the cardiac muscle cell action potential duration by this mechanism.^12,13

The second generation H₁-antagonists (fexofenadine, loratadine) have much less CNS penetration and are more histamine receptor specific with little or no effect at other receptor subtypes.¹¹

All the H₁-antagonists are well absorbed orally with peak serum concentrations occurring within 2 to 4 h. Absorption may be delayed in overdose due to anticholinergic effects seen with the first-generation agents. Bioavailability is limited by significant first-pass metabolism. Some agents may be converted to active metabolites (e.g. hydroxyzine). Volume of distribution and protein binding are generally high. Elimination half-lives for the first generation agents are between 2 and 6 h.¹¹ The second generation agents generally have longer half-lives (e.g. loratadine 8.3 h).¹¹

The H₂-antagonist agents are generally well tolerated with few side effects with therapeutic dosing. Cimetidine inhibits hepatic microsomal enzyme metabolism and reduces the metabolism of drugs eliminated by this pathway. This may result in increased serum concentrations and clinical effects of co-ingested medications.

All drugs with anticholinergic side effects have the potential to slow gastric emptying and produce gastrointestinal ileus when taken in overdose. As a result, absorption of these agents may be slowed and result in the potential for prolonged toxicity.

Clinical features

The anticholinergic toxidrome is usually manifest by a combination of peripheral and central muscarinic, cholinergic receptor blockade. Peripheral effects may include sinus tachycardia, cutaneous vasodilatation and flushing, low-grade temperature, warm dry skin with an absence of axillary sweat, dry mucous membranes, gastrointestinal ileus and urinary retention. CNS effects include mydriasis with blurred vision due to the inhibition of visual accommodation, delirium, confusion, visual hallucinations, incoherent speech, agitation, combativeness, aggression and coma.¹⁴ Patients presenting with anticholinergic syndrome will often have an impaired perception of their environment. This may result in behaviour that could injure the patient. Anticholinergic symptoms and signs may be prominent with ingestion of first-generation antihistamines.^15–17 Even therapeutic doses of some of the H₁-antagonist agents may be sufficient to produce an anticholinergic delirium in susceptible individuals (especially the elderly and children). Topical use of these agents, particularly on broken skin surfaces, may also result in anticholinergic delirium.^18,19

In patients who present to hospital several hours following poisoning with an anticholinergic agent, the peripheral features of the toxidrome may be absent.^20–22 This may also occur in elderly people with mild-to-moderate anticholinergic delirium resulting from the side effects of therapeutic drug administration.²²

Other manifestations of H₁-antagonist toxicity may include CNS and cardiovascular effects, and rhabdomyolysis. Overdose of first-generation agents commonly produces drowsiness, sedation, confusion, agitation and ataxia. Large ingestions may result in coma.^23,24 Seizures may also occur. Pheniramine, a commonly abused antihistamine in Australia, appears to be more proconvulsant than other agents following overdose, with a reported incidence of seizures of 30%.¹⁷ Seizures have been reported with other first-generation H₁-antagonists, such as diphenhydramine, in doses as small as 150 mg in children.^23,25 Fatal doses of diphenhydramine in adults range from 20 to 40 mg/kg.²⁶ Doxylamine poisoning may result in non-traumatic rhabdomyolysis.^27,28 Hypotension, due to α-receptor blockade, can occur following large ingestions of first-generation agents. Conduction defects are infrequent following poisoning with first-generation H₁-antagonists. Diphenhydramine and dimenhydrinate poisoning can result in QRS-interval prolongation, broad-complex tachycardia and ventricular arrhythmias similar to that seen in cyclic antidepressant poisoning.^12,13 This effect has not been reported with other first-generation H₁-antagonists.

Overdose with H₂-antagonists, such as cimetidine, usually results in little or no evidence of toxicity. Doses of up to 15 g have failed to produce clinical toxicity.²⁹

Clinical investigation

A 12-lead electrocardiograph should be performed to check for the presence of sinus tachycardia, QRS and QT-interval duration. Bedside blood glucose testing is indicated in all patients with altered mental status. Blood for serum electrolytes and paracetamol level should be collected. In patients with mental status changes not easily explained by drug intoxication, other organic causes for cognitive impairment should be ruled out. Serum antihistamine levels are not readily available and do not influence patient management. Standard ‘drugs-of-abuse’ urine screens do not detect antihistamines or most other agents with anticholinergic toxicity.

Treatment

The mainstay of therapy for poisoning with anticholinergic agents is supportive care in a safe environment. Comatose or hypoventilating patients should have appropriate airway intervention and ventilatory support. Hypotension should be treated initially with intravenous crystalloid boluses. Hypotension refractory to fluids may necessitate the use of pressor agents such as noradrenaline. Agitation and seizures can be controlled using parenteral benzodiazepines in the first instance. Barbiturates (thiopentone, phenobarbitone) may be considered in refractory cases.

Gastrointestinal decontamination, if indicated, should be performed with a single-dose of oral activated charcoal. The benefit of activated charcoal in patients presenting with minimal or no signs of toxicity more than 2 h following ingestion is doubtful. Methods of enhancing elimination of antihistamines are ineffective because of their large volumes of distribution and high protein binding.

The reversible acetylcholinesterase inhibitor physostigmine has been used in the management and diagnosis of anticholinergic agitation and delirium.^30–32 Physostigmine rapidly reverses the effects of anticholinergic delirium and may prevent the need for escalating doses of benzodiazepines to control agitation. Physostigmine may decrease the need for other interventions such as cerebral computerized tomography scanning and lumbar puncture in patients with suspected anticholinergic delirium.³¹

When using physostigmine, an initial test dose 0.5 mg i.v. is followed by 1.0–2.0 mg over the following 3–5 min in an adult. A partial response may necessitate further 0.5–1.0 mg boluses. Clinical effects may last from 30 to 120 min. Caution should be exercised in using physostigmine in patients with suspected acute cyclic antidepressant poisoning or ECG evidence of cardiac conduction delay because of the risk of precipitating cardiac asystole.^33,34

Broad-complex tachycardia resulting from severe poisoning with diphenhydramine or dimenhydrinate should be treated with serum alkalinization with intravenous sodium bicarbonate boluses (0.5–1.0 mmol/kg) as for severe cyclic antidepressant poisoning.^12,13 Symptomatic bradycardia and high degree atrioventricular block should be initially treated with atropine. Unresponsive cases may need cardiac pacing or inotropic support. Class-1a, -1c or -3 anti-arrhythmic agents should be avoided in cases of antihistamine-induced arrhythmias.

Disposition

Patients who present with minimal or no signs of toxicity require 4–6 h of observation and monitoring. They may be medically cleared if, at the end of this period, they are alert and awake with a normal ECG. Patients with persistent mental status changes require further observation but, if the ECG is normal, do not require further cardiac monitoring. The duration of anticholinergic delirium may be from 12 h to several days depending on the agent and dose ingested. Severe toxicity, if it is to develop, will be evident within 2–3 h of ingestion. Those patients with poisoning complicated by coma, seizures or CVS toxicity require admission and observation in an intensive-care or high-dependency setting.

All patients with intentional ingestions or suspicion of self-harm require psychiatric assessment prior to discharge.