10 Poisoning, overdose, antidotes
Deliberate overdose with drugs is a common clinical problem. Poisoning may also occur as a result of accidental ingestion, occupational exposure and in the context of recreational substance use. The effective management of poisoning is based upon the use of general supportive measures, reduction of drug absorption or increase in elimination and the use of specific pharmacological agents (‘antidotes’). This chapter will examine:
Introduction
The UK has one of the highest rates of deliberate self-harm in Europe. Deliberate self-harm involves intentional self-poisoning or self-injury irrespective of the intended purpose of that act. Self-poisoning is the commonest form of deliberate self-harm after self-mutilation. Poisoning, usually by medicines taken in overdose, is currently responsible for over 150 000 hospital attendances per annum in England and Wales (population 54 million). Prescribed drugs are involved in more than 75% of episodes, but teenagers tend to favour non-prescribed analgesics available by direct sale. In particular, over half of these involve ingestion of paracetamol, with the associated risk of serious toxicity. In order to address this problem the pack size of paracetamol was reduced to 8 g for non-prescription purchase and 16 g for prescription in the UK in 1998. Evidence suggests that this has not so far been effective in reducing paracetamol-related deaths but the mortality rate of self-poisoning overall is very low (less than 1% of acute hospital admissions with poisoning). The total number of deaths related to drug poisoning in England and Wales increased each year from 1993 to a peak in 1999, and then began to decline.
Most patients who die from deliberate ingestion of drugs do so before reaching medical assistance; overall only 11–28% of those who die following the deliberate ingestion of drugs reach hospital alive. The drugs most frequently implicated in hospital deaths of such individuals in the UK are paracetamol, tricyclic antidepressants and benzodiazepines. In India, deliberate self harm is seen with similar prescribed agents, together with frequent deliberate self harm with the antimalarial chloroquine and accidental or deliberate injury from pesticides such as the organophosphates or aluminium phosphide. In Sri Lanka deliberate pesticide ingestion is also a serious public health issue.
Accidental self-poisoning, causing admission to hospital, occurs predominantly among children under 5 years of age, usually from medicines left within their reach or with commonly available domestic chemicals, e.g. bleach, detergents.
Initial assessment
It is important to obtain information on the poison that has been taken. The key pieces of information are:
• The identity of the substance(s) taken.
• The time that has elapsed since ingestion.
• Whether alcohol was also taken.
Adults may be sufficiently conscious to give some indication of the poison or may have referred to it in a suicide note, or there may be other circumstantial evidence e.g. knowledge of the prescribed drugs that the patient had access to, empty drug containers in pocket or at the scene. The ambulance crew attending to the patient at home may have very valuable information and should be questioned for any clues to the ingested drug. Any family or friends attending with the patient should be similarly questioned.
The response to a specific antidote may provide a diagnosis, e.g. dilatation of constricted pupils and increased respiratory rate after intravenous naloxone (opioid poisoning) or arousal from unconsciousness in response to intravenous flumazenil (benzodiazepine poisoning).
Many substances used in accidental or self-poisoning produce recognisable symptoms and signs. Some arise from dysfunction of the central or autonomic nervous systems; other agents produce individual effects. They can be useful diagnostically and provide characteristic toxic syndromes or ‘toxidromes’ (Table 10.1).
Table 10.1 Characteristic drug ‘toxidromes’
| Toxidrome | Clinical features | Causative agents |
|---|---|---|
| Antimuscarinic | TachycardiaDilated pupilsDry, flushed skinUrinary retentionDecreased bowel soundsMild increase in body temperatureConfusionCardiac arrhythmiasSeizures | AntipsychoticsTricyclic antidepressantsAntihistaminesAntispasmodicsMany plant toxins |
| Muscarinic | SalivationLachrymationAbdominal crampsUrinary and faecal incontinenceVomitingSweatingMiosisMuscle fasciculation and weaknessBradycardiaPulmonary oedemaConfusionCNS depressionSeizures | AnticholinesterasesOrganophosphorus insecticidesCarbamate insecticidesGalantamineDonepezil |
| Sympathomimetic | TachycardiaHypertensionHyperthermiaSweatingMydriasisHyperreflexiaAgitationDelusionsParanoiaSeizuresCardiac arrhythmias |
In addition, sedatives, opioids and ethanol cause signs that may include respiratory depression, miosis, hyporeflexia, coma, hypotension and hypothermia. Other drugs and non-drug chemicals that produce characteristic effects include: salicylates, methanol and ethylene glycol, iron, selective serotonin reuptake inhibitors. Effects of overdose (and treatment) with other individual drugs or drug groups appear in the relevant accounts throughout the book.
Resuscitation
In concert with attempts to define the nature of the overdose it is essential to carry out standard resuscitation methods. Maintenance of an adequate oxygen supply is the first priority and the airway must be sucked clear of oropharyngeal secretions or regurgitated matter. Shock in acute poisoning is usually due to expansion of the venous capacitance bed and placing the patient in the head-down position to encourage venous return to the heart, or a colloid plasma expander administered intravenously restores blood pressure. External cardiac compression may be necessary and should be continued until the cardiac output is self-sustaining, which may be a long time when the patient is hypothermic or poisoned with a cardiodepressant drug, e.g. tricyclic antidepressant, β-adrenoceptor blocker.
External cardiac compression may be required for prolonged periods of cardiac arrest, up to several hours. In young patients the heart is anatomically and physiologically normal and will recover when the poison has been eliminated from the body.
Investigations may include arterial blood gas analysis and examination of plasma for specific substances that would require treatment with an antidote, e.g. with paracetamol, iron and digoxin.
Plasma concentration measurement is also used to quantify the risk. Particular treatments such as haemodialysis or urine alkalinisation may be indicated for overdose with salicylate, lithium and some sedative drugs, e.g. trichloroethanol derivatives, phenobarbital.
Rapid biochemical ‘screens’ of urine are widely available in hospital emergency departments and will detect a range of drugs (Table 10.2).
Table 10.2 Drugs that can be readily tested for and detected in urine in the emergency department
| Drugs detectable on rapid urine testing |
Supportive treatment
The majority of patients admitted to hospital will require only observation combined with medical and nursing supportive measures while they metabolise and eliminate the poison. Some will require specific measures to reduce absorption or to increase elimination. A few will require administration of a specific antidote. A very few will need intensive care facilities. In the event of serious overdose, always obtain the latest advice on management.
In the UK, regional medicines information centres provide specialist advice and information over the telephone throughout the day and night (0870 600 6266).
TOXBASE, the primary clinical toxicology database of the UK National Poisons Information Service, is available on the internet to registered users at: http://www.toxbase.org
The most efficient eliminating mechanisms are the patient’s own physiological processes, which, given time, will inactivate and eliminate all the poison. Most patients recover from acute poisonings provided they are adequately oxygenated, hydrated and perfused.
Special problems introduced by poisoning are as follows:
• Airway maintenance is essential; some patients require a cuffed endotracheal tube but seldom for more than 24 h.
• Ventilation: a mixed respiratory and metabolic acidosis is common; the inspired air is supplemented with oxygen to correct the hypoxia. Mechanical ventilation is necessary if adequate oxygenation cannot be obtained or hypercapnia ensues.
• Hypotension: this is common in poisoning and, in addition to the resuscitative measures indicated above, conventional inotropic support may be required.
• In addition: there is recent interest in the use of high dose insulin infusions with euglycaemic clamping as a positive inotrope in the context of overdose with myocardial depressant agents. The very high insulin doses given (0.5–2 units/kg/h) have so far deterred physicians from the routine use of such therapy. There are, however, a number of case reports that support such an approach. Many of these are in the context of overdosage with non-dihydropyridine calcium channel blockers that are often resistant to conventional inotropic agents.
• Convulsions should be treated if they are persistent or protracted. Intravenous benzodiazepine (diazepam or lorazepam) is the first choice.
• Cardiac arrhythmia frequently accompanies poisoning, e.g. with tricyclic antidepressants, theophylline, β-adrenoceptor blockers.
• Acidosis, hypoxia and electrolyte disturbance are often important contributory factors and it is preferable to observe the effect of correcting these before considering resort to an antiarrhythmic drug. If arrhythmia does lead to persistent peripheral circulatory failure, an appropriate drug may be cautiously justified, e.g. a β-adrenoceptor blocker for poisoning with a sympathomimetic drug.
• Hypothermia may occur if CNS depression impairs temperature regulation. A low-reading rectal thermometer is used to monitor core temperature and the patient is nursed in a heat-retaining ‘space blanket’.
• Immobility may lead to pressure lesions of peripheral nerves, cutaneous blisters, necrosis over bony prominences, and increased risk of thromboembolism warrants prophylaxis.
• Rhabdomyolysis may result from prolonged pressure on muscles from agents that cause muscle spasm or convulsions (phencyclidine, theophylline); may be aggravated by hyperthermia due to muscle contraction, e.g. with MDMA (‘ecstasy’). Aggressive volume repletion and correction of acid–base abnormality are needed; urine alkalinisation and/or diuretic therapy may be helpful in preventing acute tubular necrosis but evidence is not conclusive.
Preventing further absorption of the poison
From the environment
When a poison has been inhaled or absorbed through the skin, the patient should be taken from the toxic environment, the contaminated clothing removed and the skin cleansed.
From the alimentary tract (‘gut decontamination’)1
Emesis using syrup of ipecacuanha is no longer practised in hospital, as there is no clinical trial evidence that the procedure improves outcome.
Oral adsorbents
Activated charcoal (Carbomix) consists of a very fine black powder prepared from vegetable matter, e.g. wood pulp, coconut shell, which is ‘activated’ by an oxidising gas flow at high temperature to create a network of small (10–20 nm) pores with an enormous surface area in relation to weight (1000 m2/g). This binds to, and thus inactivates, a wide variety of compounds in the gut. Indeed, activated charcoal comes nearest to fulfilling the long-sought notion of a ‘universal antidote’.2 Thus it is simpler to list the exceptions, i.e. substances that are poorly adsorbed by charcoal:
• Metal salts (iron, lithium).
• Alcohols (ethanol, methanol, ethylene glycol).
• Clofenotane (dicophane, DDT).
To be most effective, five to ten times as much charcoal as poison, weight for weight, is needed. In the adult an initial dose of 50 g is usual, repeated if necessary. If the patient is vomiting, give the charcoal through a nasogastric tube. Unless a patient has an intact or protected airway its administration is contraindicated.
Activated charcoal is most effective when given soon after ingestion of a potentially toxic amount of a poison and while a significant amount remains yet unabsorbed. Volunteer studies suggest that administration within 1 h can be expected to prevent up to 40–50% of absorption. There are no satisfactorily designed clinical trials in patients to assess the benefit of single dose activated charcoal. Benefit after 1 h cannot be excluded and may be sometimes be indicated. Charcoal in repeated doses accelerates the elimination of poison that has been absorbed (see later). Activated charcoal, although unpalatable, appears to be relatively safe but constipation or mechanical bowel obstruction may follow repeated use. In the drowsy or comatose patient there is particular risk of aspiration into the lungs causing hypoxia through obstruction and arteriovenous shunting. Methionine, used orally for paracetamol poisoning, is adsorbed by the charcoal.
Other oral adsorbents have specific uses. Fuller’s earth (a natural form of aluminium silicate) binds and inactivates the herbicides paraquat (activated charcoal is superior) and diquat; colestyramine and colestipol will adsorb warfarin.
Whole-bowel irrigation3
Whole bowel irrigation should be used with special care in patients who are debilitated or who have significant concurrent medical conditions. The effectiveness of activated charcoal may be reduced by co-administration with whole bowel irrigation.
Cathartics have no routine role in gut decontamination, but a single dose of an osmotic agent (sorbitol, magnesium sulphate) may be justified on occasion.
Accelerating elimination of the poison
Techniques for eliminating absorbed poisons have a role that is limited, but important when applicable. Each method depends, directly or indirectly, on removing drug from the circulation and successful use requires that:
• The poison should be present in high concentration in the plasma relative to that in the rest of the body, i.e. it should have a small volume of distribution.
• The poison should dissociate readily from any plasma protein binding sites.
• The effects of the poison should relate to its plasma concentration.
Methods used are:
Repeated doses of activated charcoal
Activated charcoal by mouth not only adsorbs ingested drug in the gut, preventing absorption into the body (see above), it also adsorbs drug that diffuses from the blood into the gut lumen when the concentration there is lower. As binding is irreversible, the concentration gradient is maintained and drug is continuously removed; this has been called ‘intestinal dialysis’. Charcoal may also adsorb drugs that secrete into the bile, i.e. by interrupting an enterohepatic cycle. The procedure is effective for overdose of carbamazepine, dapsone, phenobarbital, quinine, salicylate and theophylline.
Repeated-dose activated charcoal is increasingly preferred to alkalinisation of urine (below) for phenobarbital and salicylate poisoning. In adults, activated charcoal 50 g is given initially, then 50 g every 4 h. Vomiting should be treated with an antiemetic drug because it reduces the efficacy of charcoal treatment. Where there is intolerance, the dose may be reduced and the frequency increased, e.g. 25 g every 2 h or 12.5 g every hour, but efficacy may be compromised.
Alteration of urine pH and diuresis
It is useful to alter the pH of the glomerular filtrate such that a drug that is a weak electrolyte will ionise, become less lipid soluble, remain in the renal tubular fluid, and leave the body in the urine (see p. 80).
The objective is to maintain a urine pH of 7.5–8.5 by an intravenous infusion of sodium bicarbonate. Available preparations of sodium bicarbonate vary between 1.2% and 8.4% (1 mL of the 8.4% preparation contains 1 mmol sodium bicarbonate) and the concentration given will depend on the patient’s fluid needs.
Alkalinisation4 may be used for: salicylate (> 500 mg/L + metabolic acidosis, or in any case > 750 mg/L) phenobarbital (75–150 mg/L); phenoxy herbicides, e.g. 2,4-D, mecoprop, dichlorprop; moderately severe salicylate poisoning that does not meet the criteria for haemodialysis.
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