29.1 Approach to the poisoned patient

Treatment

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

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 time frame. 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 difficult to control 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 1 hour [4,5]. 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 [6–8].

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.

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 (AC) 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 [9].

There is no evidence to suggest that the addition of a cathartic, such as sorbitol, to AC improves clinical outcome [10].

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. Again, clinical benefit has not yet been conclusively demonstrated [11]. 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.

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).

Multiple-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 [12]. 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.

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.

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 investigations

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.

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 computed 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 radiopaque 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.

29.2 Cardiovascular drugs

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, early implemenation of hyperinsulinaemia euglycaemic therapy and administration of inotropes. Transcutaneous or transvenous pacing may be tried in cases with profound bradycardia, but often is of limited benefit. Severe cases may require studies on cardiac output and peripheral vascular resistance using either Swan–Ganz catheter or pulse contour cardiac output monitoring (PiCCO) and invasive blood pressure monitoring.

If safe to do so, oral-activated charcoal should be administered as soon as practicable to all those presenting after ingestion of slow-release preparations and may be considered for other β-blocker ingestions. More aggressive decontamination, with whole-bowel irrigation, is indicated following overdose with slow-release CCBs.

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.

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

Hyperinsulinaemic euglycaemia therapy (HIET) is increasingly advocated as therapy for hypotension unresponsive to fluids and calcium salts, with many toxicologists using HIET early in the management of these poisonings if inotropes are being considered. This therapy is supported by animal work and multiple human case reports, but a randomized controlled trial is 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 IV followed by an infusion commencing at 1 U/kg/h. Although the optimal dose is still to be determined, there are some human case reports suggesting increasing doses up to 10 U/kg/h. This should be accompanied by an initial bolus dose of 50 mL 50% dextrose followed by an infusion of dextrose to maintain euglycaemia. Case reports often describe patients needing no more than 25 g/h of dextrose while poisoned (i.e. 50 mL/h of 50% dextrose).

The 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 β-blocker poisoning. Due to the significant doses often required, it is frequently difficult to source adequate stocks of glucagon for use as an inotropic agent. As such, its use in the treatment of calcium channel or β-blocker poisoning is not routinely recommended.

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

There are no clinically effective methods of enhancing the elimination of CCBs or β-blockers. When all else fails, extra-corporeal life support has been shown to allow organ perfusion until reversal of cardiac dysfunction and elimination of the drugs.

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 acute and chronic 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 7 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.

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 hyperkalaemia. Nausea and vomiting occur early and may be the presenting complaint. The most common cardiac manifestations are sinus bradycardia, increased ventricular ectopy, 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 indomethacin. 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 investigations

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. Hyperkalaemia seldom occurs in chronic digoxin poisoning, unless patient has acute renal failure. 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 levels taken at 6 hours post ingestion are 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 0.6–1.0 nmol/L (0.5–0.8 mcg/L). Significant chronic toxicity may be associated with 0.6–1.0 nmol/L (0.5–0.8 mcg/L) 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, the presence of any cardiovascular system effects, particularly in elderly patients, is an indication for the administration of Fab fragments of digoxin-specific antibodies. Apart from brady-tachy arrhythmias that are associated with haemodynamic instability, patients who have increased automaticies with cardiac or gastrointestinal symptoms may be considered for digoxin specific antibody. This is especially for patients who have renal failure with a Creatinine clearance <30 ml/min. From an economic viewpoint, the potential reduction in length of stay of 1-2 days as a result of treatment with digoxin specific antibody needs to take into consieration of the increase in the cost of 1 vial of digoxin Fab to A$850 per 40 mg vial.

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.

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 few multicentre studies. These studies demonstrated the safety of the product, with the adverse reactions reported being hypokalaemia (4%), rapid atrial fibrillation or worsening of congestive cardiac failure (3%) and allergic reaction (0.8%).

The correct dose of Fab fragments may be calculated on the basis that 40 mg (one vial) will bind 0.5 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. A reasonable empiric dosing is to give 2 vials initially and then check for a clinical response. Further digoxin specific antibody may be given to neutralise half of the body burden once digoxin concentration is available. If the digoxin ingested dose or serum concentration is known, give half of the equimolar dose is adequate to stablise patient with severe digoxin toxiicty. In cardiac arrest, give a bolus dose (5 vials), and this dose can be repeated after 30 to 60 minutes if there has been no clinical response. 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.

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

Introduction

Clonidine, an imidazoline derivative, is a central α₂-adrenergic agonist. It was first developed in the 1960s as a nasal decongestant. It is currently used for the management of hypertension, attention deficit hyperactivity disorder (ADHD) as well as withdrawal symptoms from drug and alcohol addiction, tobacco withdrawal and Tourette’s syndrome. Clonidine toxicity often mimics that of opioids.

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.

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 α-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. The median onset of symptoms following clonidine ingestion is 30 min and patients are usually symptomatic on arrival at the ED. Symptoms usually resolve by 24 h.

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.

Class 1c Antiarrhythmics

Introduction

Apart from the class one antiarrhythmics, many drugs in overdose cause sodium channel blockade. Drugs highly associated with sodium channel blockade and QRS widening are shown in Table 29.2.6. Overdose with class 1c antiarrhythmic drugs is among the most serious ingestions and is associated with a high morbidity and mortality. Overdoses with these agents are rare but they may be rapidly lethal with profound cardiovascular collapse. Drugs in this class include flecainide and propafenone; they are used for the treatment of SVT and ventricular arrhythmias. Class 1c antiarrhythmics block the fast inward sodium channel during phase 0 of the action potential. They have slow offset kinetics and cause complete blockade of sodium channel for a much longer duration than class 1a and 1b antiarrhythmics.

Pharmacokinetics

Flecainide has a high oral bioavailability and a rapid onset of action of 30 to 60 min. It has a long elimination half-life of 7–23 h. In adults, ingestions of 800 mg or more should be considered as life threatening. Similarly, propafenone has a long elimination half-life.

Clinical Features

In overdose, they have a rapid onset of clinical symptoms, typically with 30 min to 2 h. Overdose symptoms include nausea, vomiting, hypotension, bradycardia, varying degrees of atrioventricular block and tachyarrhythmia. In severe cases, coma and seizures may occur. Severe intoxication is frequently fatal because of the rapid onset of hypotension and ventricular arrhythmias.

Investigations

The ECG is essential in evaluating and monitoring the QRS duration, conduction defects and QT interval. The most common and important ECG change in overdose is QRS widening (more than 120 ms). Although QT prolongation occurs in flecainide overdose, torsades de pointes is rare.

Treatment

The mainstay of management of class 1c overdose is good supportive care including inotropic support, gastrointestinal decontamination and early and repeated doses of sodium bicarbonate to treat any broad complex arrhythmias and hypotension. Treatment is similar to other sodium channel blocking agents, such as the tricyclic antidepressants and includes plasma alkalinization to a pH of 7.5 with hyperventilation and repeated boluses of sodium bicarbonate. The use of antiarrhythmic drugs is problematic and are generally contraindicated and sufficient amounts of sodium bicarbonate should be used first.

Disposition

Asymptomatic patients with a normal ECG 4 h after ingestion of flecainide are unlikely to develop toxicity. Patients who are symptomatic should be admitted to a monitored area.

Cardiac arrest due to cardiovascularly active drugs

It is important for clinicians to be aware that cardiac arrest due to overdose of cardiovascularly active drugs may necessitate prolonged CPR and resuscitative manoeuvres and consideration of heroic measures, such as cardiopulmonary bypass (Fig. 29.2.1). Consultation with a clinical toxicologist is always recommended prior to cessation of resuscitative efforts in these cases.

29.3 Antipsychotic drugs

Overdose

Following overdose of antipsychotics, the most common and significant manifestations involve the CNS and cardiovascular system.

Dose-dependent CNS depression occurs, ranging from lethargy and somnolence to coma and seizures. Airway protective reflexes may be impaired, requiring intensive care. Many of the agents can cause significant anticholinergic delirium with associated peripheral effects, such as urinary retention, flushed skin and reduction in sweat and saliva secretion.

The most common cardiovascular effects are tachycardia and hypotension. Tachycardia may be due to anticholinergic effects and also as a response to hypotension. Hypotension often occurs as a result of peripheral α₁-receptor blockade, leading to vasodilatation.

ECG changes are often present after overdose and can include QRS prolongation and QT interval prolongation. Significant arrhythmias are uncommon, apart from following overdose with amisulpride, which can cause torsades des pointes.

Some of the specific clinical features following overdose of individual agents are described below.

Amisulpride

Overdose of amisulpride commonly causes QT prolongation, bradycardia and hypotension. Episodes of torsades de pointes have been reported and so amisulpride is considered to be particularly cardiotoxic. Onset of cardiotoxicity may be delayed for greater than 12 hours and QT prolongation can persist for many hours, with the potential to develop torsades de pointes abruptly. Ingestions greater than 4 g have been associated with development of prolonged QT and ingestions greater than 8 g can cause significant sedation and hypotension.

Chlorpromazine

Ingestions of greater than 15 mg/kg of chlorpromazine in children are associated with significant toxicity. Large overdoses>5 g, especially in drug-naïve patients, may lead to significant CNS depression, which may require intubation and intensive care due to loss of airway protective reflexes. Significant hypotension also occurs following overdose.

Clozapine

Acute overdose of clozapine leads to CNS depression, which is more pronounced in clozapine-naïve patients, who may require intubation. Seizures are reported in overdose. Despite the known anticholinergic properties of clozapine, hypersalivation is common. Miosis is classically described, but mydriasis can also occur. Agranulocytosis does not occur after a single overdose.

Haloperidol

Sedation and EPS are common following overdose of haloperidol. Haloperidol has also been associated with QT prolongation and arrhythmias following large ingestions or intravenous administration.

Olanzapine

Onset of clinical features following overdose is within 6 hours. Sedation and anticholinergic effects are the most common manifestations, leading to a combination of agitation and drowsiness, which may require intubation. Miosis may be noted. Tachycardia is common, but significant ECG abnormalities are rare.

Quetiapine

Quetiapine is available in immediate and extended release preparations. Overdose causes dose-related CNS depression and tachycardia. Hypotension and seizures are also reported after larger ingestions. Ingested doses of greater than 3 g are associated with increased length of stay and ICU admission. QTc prolongation is often reported, although the clinical significance of this is unclear, as there have been no reported cases of torsades de pointes. It may be that the prolongation of the QTc is as a result of overcorrection for tachycardia rather than intrinsic cardiotoxicity.

Risperidone

Risperidone is relatively benign following overdose, with tachycardia and dystonia being the most common effects. Onset of dystonia may be delayed and may recur after treatment.

Ziprasidone

Ziprasidone is associated with QT prolongation, both with therapeutic use and following overdose. Torsades de pointes has been reported after ziprasidone overdose with co-ingestants, but not in isolation.

Investigations

Antipsychotic toxicity is primarily diagnosed on history and examination for typical clinical features. Serum drug concentrations are not usually available in a clinically useful time frame or helpful in the management of acute overdose. In the case of patients on clozapine who present unwell to hospital, then a clozapine concentration can be measured. For these patients, a WCC is helpful when looking for agranulocytosis and troponin may be elevated in cases of clozapine-induced myocarditis. If this is suspected, then ECG and echocardiography may also be required.

Initial ECG evaluation should occur for all patients following antipsychotic overdose and any abnormality of the QRS or QT intervals warrants continuous cardiac monitoring. If initial ECG is normal, then it should be repeated after 6 hours in asymptomatic patients. More prolonged cardiac monitoring is required for patients following overdose with amisulpride or ziprasidone.

Treatment

The management of antipsychotic toxicity is primarily supportive. Attention to initial resuscitation should occur initially. Mild sedation requires no specific treatment. Patients with significantly decreased conscious state with loss of airway protective reflexes will require intubation, ventilation and intensive care.

Decontamination with activated charcoal can be considered if the presentation is within an hour and there is no clinical sign of CNS depression. Otherwise, administration of activated charcoal should be delayed until after the airway has been secured with intubation. There is no evidence for any benefit from enhanced elimination techniques, either with multidose activated charcoal or extracorporeal techniques and so they are not indicated.

Hypotension should initially be treated with an appropriate bolus of crystalloid solution. If there is no response to initial fluid bolus, then vasopressors may be required. There have been reports of worsening hypotension following the administration of adrenaline to patients who are hypotensive following quetiapine overdose, so noradrenaline is the preferred initial vasopressor. Patients with ventricular arrhythmias or with prolonged QRS should be managed with sodium bicarbonate in a similar fashion to patients with significant tricyclic antidepressant (TCA) toxicity. Intravenous bicarbonate 8.4% (1 mL=1 mmol) 1–2 mmol/kg boluses should be administered to obtain an arterial pH of 7.50–7.55. The pH may then be maintained in this range using hyperventilation in intubated patients. QT prolongation requires no specific management other than cardiac monitoring and correction of any potential contributing electrolyte abnormalities, such as hypokalaemia or hypomagnesaemia. Should torsades de pointes develop, it should be treated in the first instance with IV magnesium sulphate 50% 2–4 mL (1–2 g or 4–8 mmol) infusion over 10 minutes. Chemical or electrical overdrive pacing may also be required to avoid further instances.

Seizures are often self-limiting and require no treatment. However, should intervention be necessary, benzodiazepines should be used first line. Barbiturates and/or general anaesthesia are used for refractory seizures or status. There is no role for other anticonvulsants, such as phenytoin, in the management of drug-induced seizures.

Anticholinergic delirium should be managed initially with non-pharmacological measures, such as nursing in a quiet area and limiting stimulation. Urinary retention should be sought and relieved with a urinary catheter, as the distress caused by this may contribute to any agitation. Should medication be required, titrated doses of benzodiazepines (e.g. diazepam) should be used, although it must be appreciated that benzodiazepines may contribute to any CNS depressant effects of the ingested antipsychotic.

Acute dystonia is managed with an anticholinergic agent, such as benztropine (1–2 mg given IV or IM). Benzodiazepines may also be used. Repeat dosing may be required as the dystonia can recur.

Disposition

Patients should be observed for 6 hours after overdose of most antipsychotics. If they remain asymptomatic and have a normal ECG at this time, then they can be medically cleared for discharge. This observation period should be extended for 12 hours following significant ingestion of extended release preparations of quetiapine, ingestions of>4 g amisulpride and ingestions of ziprasidone.

Patients with significant symptoms should be admitted for observation until symptoms are resolving. Intensive care admission is required for patients requiring intubation and ventilation. In the event of any concerning ECG abnormalities, such as QT prolongation, then admission for cardiac monitoring is recommended until these changes are resolving.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a rare, idiosyncratic, potentially life-threatening adverse reaction that has been reported to occur with all the antipsychotics. There is a large variation in reported incidence, but recent pooled data suggest an incidence of 0.01–0.2%. The pathophysiology of NMS is not completely understood, but is thought to be due to central dopamine blockade, especially in the nigrostriatal and hypothalamic pathways. Risk factors for the development of NMS include male gender, young age, use of high potency antipsychotics, recent increase in dose, parenteral administration, dehydration and organic brain disease.

Clinical features

The onset of NMS occurs typically over 1–3 days. The typical clinical features are a combination of altered mental status, hyperthermia (temperature>38°C), autonomic dysfunction and muscular rigidity (‘lead pipe’ rigidity). The altered mental status ranges from delirium and confusion to stupor and coma. Autonomic dysfunction can manifest as tachycardia, cardiac arrhythmias, respiratory irregularities and hypo- or hypertension. The muscular rigidity is classically described as ‘lead-pipe’ rigidity, with increased tone and resistance to passive movement. There may be superimposed tremor leading to cogwheeling. Other neuromuscular abnormalities include bradykinesia, dystonia, mutism and dysarthria.

Differential diagnosis

There have been numerous diagnostic criteria proposed for NMS, but none are universally accepted. Alternate diagnoses must be considered and excluded, particularly CNS infection. Other conditions to be considered in the differential include heatstroke, thyrotoxicosis, serotonin toxicity, anticholinergic syndrome, malignant catatonia, non-convulsive status epilepticus, phaeochromocytoma and drug intoxication (MAOIs, sympathomimetics).

However, NMS must be considered in any patient on antipsychotic medication who is unwell, particularly when there is altered mental status, fever or muscle rigidity, especially if there has been a recent change in the antipsychotic regimen.

Investigations

There is no diagnostic test for NMS, although there are characteristic laboratory abnormalities in some cases. Increased muscle enzymes (CK, LDH, AST) are often present in cases of NMS. Leucocytosis is also frequently observed. There may be other electrolyte disturbance, metabolic acidosis and coagulation abnormalities.

Investigations to rule out alternate diagnoses need to be carried out, including CT scan of the brain and lumbar puncture to rule out CNS infection.

Treatment

Once NMS is diagnosed, it is essential to institute aggressive supportive care. The offending drug must be immediately withdrawn. Patients are often dehydrated, so fluid resuscitation should be commenced. Hyperthermia must be managed aggressively with passive and active cooling. If the temperature is>39.5°C, then intubation and neuromuscular paralysis should be considered. There is increased risk of thromboembolism, so prophylaxis should be commenced.

Benzodiazepines are often used early in the treatment of NMS and they may be effective in ameliorating symptoms in milder cases. Bromocriptine is a centrally acting dopamine agonist that can only be administered orally or via NG tube. The starting dose is 2.5 mg three times daily, increased to a daily maximum of 40 mg. It needs to be continued for 1–2 weeks, as premature discontinuation can lead to rebound symptoms. Potential adverse effects include vomiting and worsening of psychosis.

Dantrolene interferes with calcium release in skeletal muscle cells and therefore reduces skeletal muscle activity. It may be useful in cases of NMS with prominent hyperthermia and muscle rigidity. It can be given by IV infusion at 2–3 mg/kg/day. However, there are conflicting reports regarding the efficacy and outcome benefit of dantrolene in the management of NMS. Electroconvulsive therapy (ECT) has been advocated for cases of NMS refractory to pharmacological treatments, although its efficacy is unclear.

29.4 Antidepressant drugs

Bupropion

Pharmacology

Bupropion is a drug with a unicyclic structure used as a smoking cessation aid in Australia and as an antidepressant in a number of other countries. It has a structure similar to amphetamine and inhibits reuptake of dopamine, with a lesser effect on noradrenaline and serotonin. Bupropion is licensed for use as an antidepressant in some countries. It is only available as an extended release preparation in Australia. Bupropion and its active metabolite hydroxyl-bupropion have half-lives of approximately 20 hours. Both are relatively highly protein bound (84% and 77%). Bupropion has a volume of distribution of 2000 L. Mild anticholinergic properties may be evident following OD. Bupropion OD is characterized by a high risk of seizures; studies suggest hydroxyl-bupropion is responsible, although the exact mechanism is unclear.

Clinical features

Bupropion is only available as a modified release preparation in Australia. In therapeutic doses, bupropion may cause mild hypertension, postural hypotension in sporadic cases, headache, agitation, seizures and gastrointestinal irritation. Cardiac conduction abnormalities are not reported in therapeutic dosing.

Tachycardia, hypertension, nausea, vomiting, tremor and hallucinations may be observed following bupropion OD; however, severe agitation and seizures are the most significant clinical features; seizures are typically delayed up to 6–8 hours (in some cases up 16 hours) post-exposure and are dose dependent. In a series of 59 patients presenting following OD of modified release bupropion, seizures occurred in 30% of those ingesting<4.5 g, 50% with 4.5–9 g ingested and 100% of individuals who ingested>9 g.

QT and QRS prolongation, arrhythmias and hypotension have been reported following ingestions of>9 g of bupropion. QT prolongation is likely to be related to coexisting tachycardia. A QT nomogram should be utilized in the risk assessment of any measured QT prolongation related to bupropion toxicity. Deaths have been reported following massive ingestions.

Treatment

Provision of meticulous supportive care is the mainstay of management following bupropion OD. Patients should be managed in a monitored area with resuscitation facilities available in case of seizures or cardiovascular deteriorations. Activated charcoal should be considered in patients who are cooperative and not agitated within 4 hours of ingestion. Intravenous benzodiazepines should be administered in incremental doses to control agitation at an early stage as they may increase the threshold for seizure activity. Resistant agitation may require sedation and intubation. Seizures are managed using benzodiazepines.

Hypotension is initially treated with intravenous crystalloid. QRS prolongation is treated with intravenous sodium bicarbonate (see tricyclic antidepressant section).

Disposition

Patients who are well with a normal ECG and no agitation or seizures 16 hours post-bupropion exposure are safe for medial discharge. Patients with significant agitation, ongoing seizures, or CVS instability require admission to a critical care environment.

Monoamine oxidase inhibitors

Pharmacology

Monoamine oxidase inhibitors (MAOIs) either reversibly or irreversibly inhibit function of the enzymes monoamine oxidase A and B (MAO-A, MAO-B), leading to increased CNS concentrations of adrenaline, noradrenaline, serotonin and dopamine. The pharmacodynamic effects of non-selective irreversible MAOIs (including phenelzine and tranylcypromine) are not overcome until MAO is resynthesized, resulting in dose-dependent toxicity that may last for days. Moclobemide, a selective reversible inhibitor of MAO-A is more benign in OD, but may cause severe serotonin toxicity when combined with other serotonergic agents.

The MAOIs are well absorbed orally, undergo extensive first-pass metabolism, readily cross the blood–brain barrier and have moderate volumes of distribution. Peak concentrations occur within 2 or 3 hours of ingestion. Metabolites are renally eliminated.

Clinical features

Overdose of irreversible MAOIs is characterized initially by peripheral sympathomimetic stimulation and central nervous system excitation. Symptoms do not usually manifest until 6–12 hours post-overdose. Initial symptoms include tachycardia, agitation, restlessness, hyperreflexia and voluntary movements. As toxicity progresses, there is progressive muscle rigidity, respiratory failure, decreasing conscious state, hyperthermia, rhabdomyolysis, coma and cardiovascular collapse. Clinical toxicity may last for days.

Lone overdose of the reversible selective MAOI moclobemide generally produces only mild symptoms including tachycardia, nausea and anxiety. Overdose of moclobemide with another serotonergic agent may lead to significant serotonin toxicity.

MAOI adverse effects in therapeutic doses include the development of serotonin toxicity when combined with other serotonergic agents. The tyramine reaction may occur following ingestion of tyramine-containing foods. Tyramine is an indirect acting sympathomimetic. MAOI inhibition of tyramine metabolism can lead to a hyperadrenergic crisis with severe hypertension, intracranial haemorrhage, renal failure, disseminated intravascular coagulopathy (DIC) and rhabdomyolysis.

Treatment

Management of MAOI toxicity is primarily supportive. Asymptomatic patients presenting within 2 hours of ingestion of tranylcypromine or phenelzine may benefit from administration of activated charcoal. Patients with evidence of severe toxicity are managed in a resuscitation area with particular attention to supporting organ function and limiting complications. Hypertension is initially treated using titrated doses of intravenous benzodiazepines. Refractory hypotension requires treatment with intravenous nitrates, sodium nitroprusside or phentolamine. Beta-adrenergic blockers are contraindicated; unopposed α-receptor stimulation may worsen toxicity. Hypothermia unresponsive to sedation with benzodiazepines must be treated aggressively along conventional lines. Serotonin toxicity requires specific care as outlined below. Moclobemide toxicity usually only requires basic supportive care.

Disposition

Patients who remain clinically well 6 hours post-ingestion of moclobemide or 12 hours post-ingestion of phenelzine or tranylcypromine are safe for medical discharge. Patients who are symptomatic following overdose of an irreversible MAOI require admission to an intensive care unit.

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SRRIs) are associated with fewer adverse effects both in therapeutic use and OD compared to TCAs. They are utilized in treating depression, obsessive–compulsive disorder, panic/anxiety disorders, eating disorders and chronic pain syndromes. Table 29.4.3 lists SSRIs available in Australia.

Combined serotonin and noradrenaline reuptake inhibitors

Duloxetine, reboxetine, venlafaxine and desvenlafaxine are the combined selective serotonin and noradrenaline reuptake inhibitor antidepressants available in Australia.

Pharmacology

Selective serotonin and noradrenaline reuptake inhibitor (SNRIs) inhibit both serotonin and noradrenaline reuptake in the CNS. Rapid downregulation of β-adrenergic receptors may increase the speed of onset of therapeutic effect compared to SSRIs.

SNRIs are rapidly absorbed after oral administration and are hepatically metabolized. Desvenlafaxine and venlafaxine are only available in Australia in modified release formulations.

Clinical features

Overdose produces a noradrenergic mediated sympathomimetic toxidrome characterized by tachycardia, tremor, nausea, vomiting, dizziness and agitation. Venlafaxine is associated with seizures following ingestions of>5 g. Increasing agitation may herald onset of seizures. Hyperthermia and rhabdomyolysis may occur with large ingestions. Cardiovascular toxicity may occur following ingestions of>8 g of venlafaxine. QRS prolongation, QT prolongation, ventricular arrhythmias and hypotension have been reported. Desvenlafaxine is more potent than venlafaxine therapeutically (50 mg desvenlafaxine is equivalent to 75 mg venlafaxine) and therefore thresholds for toxic effects are likely to be lower with desvenlafaxine.

Treatment

Following large ingestions of SNRIs, patients should be managed in an area equipped with cardiac monitoring and facilities to manage seizures. Activated charcoal may be beneficial if administered within an hour of a large ingestion. Intubation and administration of activated charcoal within 4 hours of ingestion of>5 g of venlafaxine should be considered.

Agitation should be controlled using incremental doses of benzodiazepines. Seizures are normally self-limiting, but may require treatment with intravenous benzodiazepines.

Hypotension is treated initially with intravenous fluid. Arrhythmias associated with QRS prolongation should be treated with sodium bicarbonate (see TCA section).

Disposition

Patients should be observed for at least 6 hours post-ingestion of standard release preparations and 16 hours post-ingestion of modified release preparations or until clinically well. Cardiac monitoring is indicated following large ingestions (>5 g venlafaxine). Ingestion of>5 g of venlafaxine mandates 24 hours of observation due to the risk of delayed seizures.

Mirtazapine

Mirtazapine is a unique antidepressant; in addition to blocking the reuptake of serotonin, mirtazapine is a centrally acting α₂-antagonist (increasing concentrations of serotonin and noradrenaline) and serotonin receptor (5-HT2 and 5-HT3) agonist.

Overdose of mirtazapine typically only causes minor effects including minor sedation. Tachycardia, more significant CNS sedation and seizures have been reported following large ingestions. Treatment is supportive.

Serotonin toxicity

Pharmacology

Serotonin toxicity (traditionally described as serotonin syndrome) is a consequence of excess serotonin acting at CNS and peripheral receptor sites. Table 29.4.4 lists drugs associated with serotonin toxicity. Although the exact pathophysiological mechanism is not fully elucidated, 5-HT1A and 5-HT2A receptors appear to be predominantly involved.

Although serotonin toxicity may occur following lone therapeutic or excess exposure to a serotonergic agent, it most commonly occurs in the context of combination use of serotonergic drugs or in instances where there has been an inadequate ‘wash-out’ time between substitution of one serotonergic agent for another.

Clinical features

Serotonin toxicity normally develops within hours of exposure to the offending agent or agents. A number of diagnostic criteria have been suggested, but none widely validated. Most commonly, the diagnosis has been defined as the presence of clinical findings affecting three distinct systems (in the context of exposure to a serotonergic agent):

Toxicity is seen along a spectrum and varies from subclinical non-specific feelings of anxiety and apprehension, through to life-threatening hyperthermia, autonomic instability, cardiovascular dysfunction, multiorgan failure, seizures and rigidity. Most patients recover, but deaths have been reported. The variety and variable severity of symptoms may make the diagnosis challenging and it is not uncommon for the differential diagnosis to include neuromuscular malignant syndrome (NMS). Distinguishing features include the slower onset of NMS and the typical associated ‘bradykinetic’ clinical picture and severe muscle rigidity. Serotonergic toxicity is characterized by hyperexcitability with hyperreflexia and clonus. Other differential diagnoses include CNS infection, anticholinergic syndrome, sympathomimetic syndrome, acute dystonia, malignant hyperthermia and non-convulsive seizures. Blood concentrations of serotonergic drugs do not correlate with clinical toxicity.

Treatment

Cessation of the serotonergic agents implicated in toxicity and avoidance of further serotonergic agents are mandatory in all cases. Benzodiazepines are first-line treatment to reduce muscle rigidity or to treat seizures. Cases of severe hyperthermia or muscle rigidity should be treated aggressively: sedation with neuromuscular paralysis and admission to a critical care environment.

The use of a number of antidotes known to antagonize 5-HT1 and 5-HT2 receptors has been reported. No clinical trials have examined the safety or efficacy of these drugs. They include cyproheptadine, olanzapine, chlorpromazine and propranolol. Of these, cyproheptadine appears to be the most widely utilized. The dose is 12 mg orally (via a nasogastric tube in the intubated patient) as a single dose followed by 4–8 mg orally 8-hourly. Chlorpromazine may be useful in cases where additional sedation is required, but the possibility of dehydration may combine with the peripheral vasodilating effects of chlorpromazine to produce significant hypotension.

29.5 Lithium