9 Poisoning, overdose, antidotes SYNOPSIS Deliberate and accidental self-poisoning Principles of treatment Poison-specific measures General measures Specific poisonings: cyanide, methanol, ethylene glycol, hydrocarbons, volatile solvents, heavy metals, herbicides and pesticides, biological substances (overdose of medicinal drugs is dealt with under individual agents) Incapacitating agents: drugs used for torture drugs, and psychotropic drugs is increasing. Re- peated episodes are not rare. 1 Prescribed drugs are used in over 75% of episodes but teenagers tend to favour nonprescribed analgesics available by direct sale, e.g. paracetamol, which is important bearing in mind its potentially serious toxicity. The mortality rate of self-poisoning is very low (less than 1% of acute hospital admissions), but 'completed' suicides by poisoning still number 3500 per annum in England and Wales. Accidental self-poisoning causing admission to hospital occurs predominantly amongst children under 5 years, usually with medicines left within their reach or with domestic chemicals, e.g. bleach, detergents. Self-poisoning Deliberate self-poisoning. A curious by-product of the modern 'drug and prescribing explosion' is the rise in the incidence of nonfatal deliberate self-harm. The majority of people who do this lack serious suicidal intent and are therefore termed parasuicides. In over 90% of instances in the UK, poisoning is the means chosen, usually by medi- cines taken in overdose and these amount to at least 70 000 hospital admissions per annum in England and Wales (population 51 million). Two or more drugs are taken in over 30% of episodes, not including alcohol which is also taken in over 50% of the instances; the use of hypnotic and sedative Principles of treatment Successful treatment of acute poisoning depends on a combination of speed and common sense, as well as on the nature of the poison, the amount taken and the time which has since elapsed. The majority of those admitted to hospital require only observa- tion and medical and nursing supportive measures 1 An extreme example is that of a young man who, over a period of 6 years, was admitted to hospital following 82 episodes of self-poisoning, 31 employing paracetamol; he had had a disturbed, unhappy upbringing and had been expelled from both the Danish Navy and the British Army. Prescott L F et al 1978 British Medical Journal 2: 1399. 151 9 POISONING, OVERDOSE, ANTIDOTES while they metabolise and eliminate the poison. Some require a specific antidote or a specific measure to increase elimination. Intensive care facilities are needed by only a few. In the UK the centres of the National Poisons Information Service provide information and advice over the telephone throughout the day and night. 2 Poison-specific measures IDENTIFICATION OF THE POISON(S) The key pieces of information are: • the identity of the substance(s) taken • the dose(s) • the time that has since elapsed. 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. Rapid (1-2 h) biochemical 'screens' of plasma or urine are available but are best reserved for seriously ill or unconscious patients in whom the cause of coma is unknown. Analysis of plasma for specific substances is essential in suspected cases of paracetamol or iron poisoning, to indicate which patients should receive antidotes; it is also required for salicylate, lithium and some sedative drugs, e.g. trichloroethanol derivatives, phenobarbitone, when a decision is needed about using urine alkalinisation, haemodialysis or haemoperfusion. Response to a specific antidote may provide a diagnosis, e.g. dilatation of constricted pupils and increased respiratory rate after i.v. naloxone (opioid poisoning) or arousal from unconsciousness in response to i.v. flumazenil (benzodiazepine poisoning). PREVENTION OF 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 2 Telephone numbers are to be found in the British National Formulary (BNF). the toxic environment, the contaminated clothing removed and the skin cleansed. From the gut Oral adsorbents. Activated charcoal (Carbomix, Medicoal) reduces drug absorption better than syrup of ipecacuanha or gastric lavage, is easiest to administer and has fewest adverse effects. It 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 fine (10-20-nm) pores to give it an enormous surface area in relation to weight (1000 m 2 /g). This binds to, and thus inactivates, a wide variety of compounds in the gut. Thus it is simpler to list the exceptions, i.e. substances that are not adsorbed by charcoal which are: iron, lithium, cyanide, strong acids and alkalis, and organic solvents and corrosive agents. Indeed, activated charcoal comes nearest to fulfilling the long-sought notion of a 'universal antidote'. 3 It should be given as soon as possible after a potentially toxic amount of a poison has been ingested, and whilst a significant amount remains yet unabsorbed (thus ideally within 1 h). To be most effective, 5-10 times as much charcoal as poison, weight for weight, is needed; in the adult an initial dose of 50-100 g is usual. If the patient is vomiting, the charcoal should be given through a nasogastric tube. Activated charcoal also accelerates elimination of poison that has been absorbed (see p. 155). Activated charcoal, although unpalatable, appears to be relatively safe but constipation or mechanical bowel obstruction may be caused by repeated use. Aspiration of charcoal into the lungs can cause hypoxia through obstruction and arteriovenous shunting. Charcoal adsorbs and thus inactivates 3 For centuries it was supposed not only that there could be, but that there actually was, a single antidote to all poisons. This was Theriaca Andromachi, a formulation of 72 (a magical number) ingredients amongst which particular importance was attached to the flesh of a snake (viper). The antidote was devised by Andromachus whose son was physician to the Roman Emperor, Nero (AD 37-68). 152 9 ipecacuanha but may be used after successful emesis if this method has been deemed necessary; methionine, used orally for paracetamol poisoning, is also adsorbed. Other oral adsorbents have specific uses. Fuller's earth and bentonite (both natural forms of alumi- nium silicate) bind and inactivate the herbicides, paraquat (activated charcoal is superior) and diquat; cholestyramine and colestipol will adsorb warfarin. Gastric lavage incurs dangers as well as benefits; it is best confined to the hospitalised adult who is believed to have taken a potentially life-threatening amount of a poison within 1 h (or longer in the case of drugs that delay gastric emptying, e.g. aspirin, tricyclic antidepressants, sympathomimetics, theo- phylline, opioids). Lavage is probably worth under- taking in any unconscious patient who is believed to have ingested poison, and provided the airways are protected by a cuffed endotracheal tube. Para- doxically, lavage may wash an ingested substance into the small intestine, enhancing its absorption. Leaving activated charcoal in the stomach after lavage is appropriate to lessen this risk. Neverthe- less, patients who have ingested tricyclic anti- depressants or centrally depressant drugs must be subject to continued monitoring after the lavage. The passing of a gastric tube, naturally, takes second place to emergency resuscitative measures, institution of controlled respiration or suppression of convulsions. Nothing is gained by aspirating the stomach of a corpse. Emesis has been used for children and also for adults who refuse activated charcoal or gastric lavage, or if the poison is not absorbed by activated charcoal. Its routine use in emergency departments has been abandoned, as there is no clinical trial evidence that the procedure improves outcome for poisoned patients. Emesis is induced, in fully conscious patients only, by Ipecacuanha Emetic Mixture, Pediatric (BNF), 10 ml for a child 6-18 months, 15 ml for an older child and 30 ml for an adult, i.e. all ages may receive the same preparation but in a different dose, which is followed by a tumblerful of water (250 ml). The active constituent of ipecacuanha is emetine; it can cause prolonged vomiting, diarrhoea and drowsiness that may be confused with effects of the ingested poison. Even POISON-SPECIFIC MEASURES fully conscious patients may develop aspiration pneumonia after ipecacuanha. Both emesis and lavage are contraindicated for corrosive poisons, because there is a risk of perfora- tion of the gut, and for petroleum distillates, as the danger of causing inhalational chemical pneumonia outweighs that of leaving the substance in the stomach. Cathartics or whole-bowel irrigation 4 have been used for the removal of sustained-release formula- tions, e.g. theophylline, iron, aspirin. Evidence of benefit is conflicting. Activated charcoal in repeated (10 g) doses is generally preferred. Sustained- release formulations are now common, and patients have died from failure to recognise the danger of continued release of drug from such products, after apparently successful gastric lavage. SPECIFIC ANTIDOTES 5 Specific antidotes reduce or abolish the effects of poisons through a variety of mechanisms, which may be categorised as follows: • receptors, which may be activated, blocked or bypassed • enzymes, which may be inhibited or reactivated • displacement from tissue binding sites • exchanging with the poison • replenishment of an essential substance • binding to the poison (including chelation). 4 Irrigation with large volumes of a polyethylene glycol- electrolyte solution, e.g. Klean-Prep, by mouth causes minimal fluid and electrolyte disturbance (it was developed for preparation for colonoscopy). Magnesium sulphate may also be used. 5 Mithridates the Great (7132-63 BC) king of Pontus (in Asia Minor) was noted for 'ambition, cruelty and artifice'. 'He murdered his own mother and fortified his constitution by drinking antidotes' to the poisons with which his domestic enemies sought to kill him (Lempriere). When his son also sought to kill him, Mithridates was so disappointed that he compelled his wife to poison herself. He then tried to poison himself, but in vain; the frequent antidotes which he had taken in the early part of his life had so strengthened his constitution that he was immune. He was obliged to stab himself, but had to seek the help of a slave to complete his task. Modern physicians have to be content with less comprehensively effective antidotes, some of which are listed in Table 9.1. 153 9 POISONING, OVERDOSE, ANTI DOTES TABLE 9.1 Some specific antidotes, indications and modes of action (see Index for a fuller account of individual drugs) Antidote Indication Mode of action acetylcysteine atropine benzatropine calcium gluconate desferrioxamine dicobalt edetate digoxin-specific antibody fragments (FAB) dimercaprol (BAL) ethanol flumazenil folinic acid glucagon isoprenaline methionine naloxone neostigmine oxygen penicillamine phenoxybenzamine phentolamine phytomenadione (vitamine K 1 ) pralidoxime propranolol protamine Prussian blue (potassium ferric hexacyanoferrate) sodium calciumedetate unithiol paracetamol, chloroform, carbon tetrachloride cholinesterase inhibitors, e.g. organophosphorus insecticides p-blocker poisoning drug-induced movement disorders hydrofluoric acid, fluorides iron cyanide and derivatives, e.g. acrylonitrile digitalis glycosides arsenic, copper, gold, lead, inorganic mercury ethylene glycol, methanol benzodiazepines folic acid antagonists e.g. methotrexate, trimethoprim P-adrenoceptor antagonists p-adrenoceptor antagonists paracetamol opioids antimuscarinic drugs carbon monoxide copper, gold, lead, elemental mercury (vapour), zinc hypertension due to oc-adrenoceptor agonists, e.g. with MAOI, clonidine, ergotamine as above coumarin (warfarin) and indandione anticoagulants cholinesterase inhibitors, e.g. organophosphorus insecticides P-adrenoceptor agonists, ephedrine, theophylline, thyroxine heparin thallium (in rodenticides) lead lead, elemental and organic mercury Replenishes depleted glutathione stores Blocks muscarinic cholinoceptors Vagal block accelerates heart rate Blocks muscarinic cholinoceptors Binds or precipitates fluoride ions Chelates ferrous ions Chelates to form nontoxic cobalti-and cobalto-cyanides Binds free glycoside in plasma, complex excreted in urine Chelates metal ions Competes for alcohol and acetaldehyde dehydrogenases, preventing formation of toxic metabolites Competes for benzodiazepine receptors Bypasses block in folate metabolism Bypasses blockade of the B-adrenoceptor; stimulates cyclic AMP formation with positive cardiac inotropic effect Competes for p-adrenoceptors Replenishes depleted glutathione stores Competes for opioid receptors Inhibits acetylcholinesterase, causing acetylcholine to accumulate at cholinoceptors Competitively displaces carbonmonoxide from binding sites on haemoglobin Chelates metal ions Competes for oc-adrenoceptors (long-acting) Competes for oc-adrenoceptors (short-acting) Replenishes vitamin K Competitively reactivates cholinesterase Blocks P-adrenoceptors Binds ionically to neutralise Potassium exchanges for thallium Chelates lead ions Chelates metal ions Table 9.1 illustrates these mechanisms with antidotes that are of therapeutic value. CHELATING AGENTS Chelating agents are used for poisoning with heavy metals. They incorporate the metal ions into an inner ring structure in the molecule (Greek: chele, claw) by means of structural groups called ligands (Latin: ligare, to bind); effective agents form stable, biolog- ically inert complexes that are excreted in the urine. Dimercaprol (British Anti-Lewisite, BAL). Arsenic and other metal ions are toxic in low concentration because they combine with the SH groups of essential enzymes, thus inactivating them. Dimer- caprol provides SH groups which combine with the metal ions to form relatively harmless ring compounds which are excreted, mainly in the urine. As dimercaprol, itself, is oxidised in the body and renally excreted, repeated administration is necessary to ensure that an excess is available until all the metal has been eliminated. 154 9 Dimercaprol may be used in cases of poisoning by antimony, arsenic, bismuth, gold and mercury (inorganic, e.g. HgCl 2 ). Adverse effects are common, particularly with larger doses, and include nausea and vomiting, lachrymation and salivation, paraesthesiae, muscu- lar aches and pains, urticarial rashes, tachycardia and a raised blood pressure. Gross overdosage may cause overbreathing, muscular tremors, convul- sions and coma. Unithiol (dimercaptopropanesulphonate, DMPS) effectively chelates lead and mercury; it is well tolerated. Sodium calciumedetate is the calcium chelate of the disodium salt of ethylenediaminetetra-acetic acid (calcium EDTA). It is effective in acute lead poisoning because of its capacity to exchange calcium for lead: the lead chelate is excreted in the urine, leaving behind a harmless amount of calcium. Dimercaprol may usefully be combined with sodium calciumedetate when lead poisoning is severe, e.g. with encephalopathy. Adverse effects are fairly common, and include hypotension, lachrymation, nasal stuffiness, sneez- ing, muscle pains and chills. Renal damage can occur. Dicobalt edetate. Cobalt forms stable, nontoxic complexes with cyanide. It is toxic (especially if the wrong diagnosis is made and no cyanide is present), causing hypertension, tachycardia and chest pain; consequent cobalt poisoning is treated by giving sodium calcium edetate and i.v. glucose. Penicillamine (dimethylcysteine) is a metabolite of penicillin that contains SH groups; it may be used to chelate lead and also copper (see Hepatolenticular degeneration). Its principal use is for rheumatoid arthritis (see Index). Desferrioxamine: see Iron. ACCELERATION OF ELIMINATION OF THE POISON Techniques for eliminating poisons have a role that is limited, but important when applicable. POISON-SPECIFIC MEASURES 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 distribution volume • 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; because binding is irreversible the concentration gradient is main- tained and drug is continuously removed; this has been called 'intestinal dialysis'. Charcoal may also adsorb drugs that are secreted into the bile, i.e. by interrupting an enterohepatic cycle. Evidence shows that activated charcoal in repeated doses effectively adsorbs (shortens t 1 / 2 of) phenobarbital (phenobarbitone), carbamazepine, theophylline, quinine, dapsone and salicylate. 6 Repeated-dose activated charcoal is increasingly preferred to alkalinisation of urine (below) for phenobarbitone and salicylate poisoning. Activated charcoal in an initial dose of 50-100 g should be followed by not less than 12.5 g/h; the regular hourly administra- tion is more effective than larger amounts less often. Alteration of urine pH and diuresis By manipulation of the pH of the glomerular filtrate, a drug can be made to ionise, become less lipid-soluble, remain in the renal tubular fluid, and so be eliminated in the urine (see p. 97). Mainte- nance of a good urine flow (e.g. 100 ml/h) helps this process but it is the alteration of tubular fluid pH that is all important. The practice of forcing 6 Bradberry S M, Vale A J 1995 Journal of Toxicology: Clinical Toxicology 33(5): 407-416. 155 9 POISONING, OVERDOSE, ANTIDOTES diuresis with frusemide (furosemide) and large volumes of i.v. fluid does not add significantly to drug clearance but may cause fluid overload; it is obsolete. Alkalinisation may be used for salicylate (>500mg/l + metabolic acidosis, or in any case > 750 mg/1), phenobarbital (75-150 mg/1) or phenoxy herbicides, e.g. 2,4-D, mecoprop, dichlorprop. The objective is to maintain a urine pH of 7.5-8.5 by an i.v. 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 of sodium bicarbonate) and the con- centration given will depend on the patient's fluid needs. Acidification may be used for severe, acute amphetamine, dexfenfluramine or phencyclidine poisoning. The objective is to maintain a urine pH of 5.5-6.5 by giving i.v. infusion of arginine hydro- chloride (10 g) over 30 min, followed by ammonium chloride (4 g) 2-hourly by mouth. It is rarely necessary. Phenoxybenzamine should be adequate for amphetamine-like drugs (a-adrenoceptor block). Such artificial methods of removing poison from the body are invasive, demand skill and experience on the part of the operator and are expensive in manpower. Their use should therefore be confined to cases of severe, prolonged or progressive clinical intoxication, when high plasma concentration indi- cates a dangerous degree of poisoning, and when removal by haemoperfusion or dialysis constitutes a significant addition to natural methods of elimination. • Haemodialysis is effective for: salicylate (> 750 mg/1 + renal failure, or in any case > 900 mg/1), isopropanol (present in aftershave lotions and window-cleaning solutions), lithium and methanol. • Haemoperfusion is effective for: phenobarbitone (> 100-150 mg/1, but repeat-dose activated charcoal by mouth appears to be as effective, see above) and other barbiturates, ethchlorvynol, glutethimide, meprobamate, methaqualone, theophylline, trichloroethanol derivatives. Peritoneal dialysis Peritoneal dialysis involves instilling appropriate fluid into the peritoneal cavity. Poison in the blood diffuses into the dialysis fluid down the concen- tration gradient. The fluid is then drained and replaced. The technique requires little equipment but is one-half to one-third as effective as haemo- dialysis; it may be worth using for lithium and methanol poisoning. Haemodialysis and haemoperfusion A temporary extracorporeal circulation is established, usually from an artery to a vein in the arm. In hae- modialysis, a semipermeable membrane separates blood from dialysis fluid and the poison passes passively from the blood, where it is present in high concentration. The principle of haemoperfusion is that blood flows over activated charcoal or an appropriate ion-exchange resin which adsorbs the poison. Loss of blood cells and activation of the clotting mechanism are largely overcome by coating the charcoal with an acrylic hydrogel which does not reduce adsorbing capacity, though the patient must be anticoagulated with heparin. General measures INITIAL ASSESSMENT AND RESUSCITATION The initial clinical review should include a search for known consequences of poisoning, which include: impaired consciousness with flaccidity (benzodiazepines, alcohol, trichloroethanol) or with hypertonia (tricyclic antidepressants, antimuscarinic agents), hypotension, shock, cardiac arrhythmia, evidence of convulsions, behavioural disturbances (psychotropic drugs), hypothermia, aspiration pneu- monia and cutaneous blisters, burns in the mouth (corrosives). Maintenance of an adequate oxygen supply is the first priority. A systolic blood pressure of 80 mmHg can be tolerated in a young person but a level below 90 mmHg will imperil the brain or kidney of the elderly. Expansion of the venous capacitance bed is the usual cause of shock in acute poisoning and blood pressure may be restored by placing the patient in the head-down position to encourage venous return to the heart, or by the use of a colloid 156 9 plasma expander such as gelatin or etherified starch. 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 cardio- depressant drugs, e.g. tricyclic antidepressants, (3- adrenoceptor blockers. The airway must be sucked clear of oropharyngeal secretions or regurgitated matter. Supportive treatment The salient fact is that patients recover from most poisonings provided they are adequately oxy- genated, hydrated and perfused, for, in the majority of cases, the most efficient mechanisms are the patients' own and, given time, they will inactivate and eliminate all the poison. Patients require the standard care of the unconscious, with special attention to the problems introduced by poisoning which are outlined below. Airway maintenance is essential; some patients require a cuffed endotracheal tube but seldom for more than 24 h. Ventilation needs should be assessed, if necessary supported by blood gas analysis. A mixed respira- tory and metabolic acidosis is common. Hypoxia may be corrected by supplementing the inspired air with oxygen but mechanical ventilation is necessary if the PaCO 2 exceeds 6.5 kPa. Hypotension is common and in addition to the resuscitative measures indicated above, infusion of a combination of dopamine and dobutamine in low dose may be required to maintain renal perfusion. Convulsions should be treated if they are persistent or protracted. Diazepam i.v. is the first choice. Cardiac arrhythmia frequently accompanies poison- ing, e.g. with tricyclic antidepressants, theophylline, B-adrenoceptor blockers. Acidosis, hypoxia and electrolyte disturbance are often important contri- butory factors; the emphasis of therapy should be to correct these and to resist the temptation to resort to an antiarrhythmic drug. If arrhythmia leads SOME POISONINGS to persistent peripheral circulatory failure, then an appropriate drug ought to be used, e.g. a p-adrenoceptor blocker for poisoning with a sympathomimetic drug. Hypothermia may occur if temperature regulation is impaired by CNS depression. Core temperature must be monitored by a low-reading rectal ther- mometer, while the patient is nursed in a heat retain- ing 'space blanket'. Immobility may lead to pressure lesions of periph- eral nerves, cutaneous blisters and necrosis over bony prominences. Rhabdomyolysis may result from prolonged press- ure on muscles, from agents that cause muscle spasm or convulsions (phencyclidine, theophylline) or be aggravated by hyperthermia due to muscle contraction, e.g. with MDMA ('ecstasy'). Aggressive volume repletion and correction of acid-base abnor- mality may be needed, and urine alkalinisation may prevent acute tubular necrosis. PSYCHIATRIC AND SOCIAL ASSESSMENT Most cases of self-poisoning are precipitated by interpersonal or social problems, which should be addressed. Major psychiatric illness ought to be identified and treated. 'There are said to be occasions when a wise man chooses suicide—but generally speaking it is not in an excess of reasonableness that people kill themselves. Most men and women die defeated .' 7 Some poisonings (for medicines: see individual drugs) Common toxic syndromes 8 Many substances used in accidental or self- 7 Voltaire (pseudonym of Francios-Marie Arouet, French writer, 1694-1778). 8 Based on Kulig K1992 New England Journal of Medicine 326:1677-1681. 157 9 POISONING, OVERDOSE, ANTI DOTES poisoning cause dysfunction of the central or auto- nomic nervous systems and produce a variety of effects which may be usefully grouped to aid the identification of the agent(s) responsible. Antimuscarinic syndromes consist of tachycardia, dilated pupils, dry, flushed skin, urinary retention, decreased bowel sounds, mild elevation of body temperature, confusion, cardiac arrhythmias and seizures. They are commonly caused by antipsych- otics, tricyclic antidepressants, antihistamines, anti- spasmodics and many plants (see p. 160). Cholinergic (muscarinic) syndromes comprise sali- vation, lachrymation, abdominal cramps, urinary and faecal incontinence, vomiting, sweating, miosis, muscle fasciculation and weakness, bradycardia, pulmonary oedema, confusion, CNS depression and fitting. Common causes include organophos- phorus and carbamate insecticides, neostigmine and other anticholinesterase drugs, and some fungi (mushrooms). Sympathomimetic syndromes include tachycardia, hypertension, hyperthermia, sweating, mydriasis, hyperreflexia, agitation, delusions, paranoia, seizures and cardiac arrhythmias. These are commonly caused by amphetamine and its derivatives, cocaine, proprietary decongestants, e.g. ephedrine, and theophylline (in the latter case, excluding psych- iatric effects). Sedatives, opioids and ethanol cause signs that may include respiratory depression, miosis, hypo- reflexia, coma, hypotension and hypothermia. Poisonings by (nondrug) chemicals Cyanide causes tissue anoxia by chelating the ferric part of the intracellular respiratory enzyme, cytochrome oxidase. Poisoning may occur as a result of self-administration of hydrocyanic (prussic) acid, by accidental exposure in industry, through inhaling smoke from burning polyurethane foams in furniture, through ingesting amygdalin which is present in the kernels of several fruits including apricots, almonds and peaches (constituents of the unlicensed anticancer agent, laetrile), or from excessive use of sodium nitroprusside for severe hypertension. 9 The symptoms of acute poisoning are due to tissue anoxia, with dizziness, palpita- tions, a feeling of chest constriction and anxiety; characteristically the breath smells of bitter almonds. In more severe cases there is acidosis and coma. Inhaled hydrogen cyanide may lead to death within minutes but when it is ingested as the salt several hours may elapse before the patient is seriously ill. Chronic exposure damages the nervous system causing peripheral neuropathy, optic atrophy and nerve deafness. The principles of specific therapy are as follows: • Dicobalt edetate to chelate the cyanide is the treatment of choice when the diagnosis is certain (see p. 155). The dose is 300 mg given i.v. over one minute (5 min if condition is less serious), followed immediately by a 50 ml i.v. infusion of glucose 50%; a further 300 mg of dicobalt edetate should be given if recovery is not evident within one minute. • Alternatively, a two-stage procedure may be followed by i.v. administration of: (1) sodium nitrite, which rapidly converts haemoglobin to methaemoglobin, the ferric ion of which takes up cyanide as cyanmethaemoglobin (up to 40% methaemoglobin can be tolerated); (2) sodium thiosulphate, which more slowly detoxifies the cyanide by permitting the formation of thiocyanate. When the diagnosis is uncertain, administration of thiosulphate plus oxygen is a safe course. There is evidence that oxygen, especially if at high pressure (hyperbaric), overcomes the cellular 9 Or in other more bizarre ways. 'A 23-year-old medical student saw his dog (a puppy) suddenly collapse. He started external cardiac massage and a mouth-to-nose ventilation effort. Moments later the dog died, and the student felt nauseated, vomited and lost consciousness. On the victim's arrival at hospital, an alert medical officer detected a bitter almonds odour on his breath and administered the accepted treatment for cyanide poisoning after which he recovered. It turned out that the dog had accidentally swallowed cyanide, and the poison eliminated through the lungs had been inhaled by the master during the mouth-to-nose resuscitation/ Journal of the American Medical Association 1983 249: 353. 158 9 anoxia in cyanide poisoning; the mechanism is uncertain, but oxygen should be administered. Carbon monoxide (CO) is formed when substances containing carbon and hydrogen are incompletely combusted; poisoning results from inhalation. Oxygen transport to cells is impaired and myo- cardial and neurological injury result; delayed (2-4 weeks) neurological sequelae include parkinsonism and cerebellar signs. The concentration of CO in the blood may confirm exposure (cigarette smoking alone may account for up to 10%) but is no guide to the severity of poisoning. Patients with signs of cardiac ischaemia or neurological defect may be treated with hyperbaric oxygen, although the evi- dence for its efficacy is conflicting and transport to hyperbaric chambers may present logistic problems. Lead poisoning arises from a variety of occupa- tional (such as house renovation and stripping old paint), and recreational sources. Environmental exposure had been a matter of great concern, as witness the protective legislation introduced by many countries to reduce pollution, e.g. by removing lead from petrol. Lead in the body comprises a rapidly exchange- able component in blood (2%, biological t 1 /, 35 d) and a stable pool in dentine and the skeleton (95%, biological t 1 / 2 25 y). In severe lead poisoning sodium calciumedetate is commonly used to initiate lead excretion. It chelates lead from bone and the extracellular space and urinary lead excretion of diminishes over 5 days thereafter as the extracellular store is exhausted. Subsequently symptoms (colic and encephalopathy) may worsen and this has been attributed to redistri- bution of lead from bone to brain. Dimercaprol is more effective than sodium calciumedetate at chelating lead from the soft tissues such as brain, which is the rationale for combined therapy with sodium calciumedetate. More recently succimer (2,3- dimercaptosuccinic acid, DMSA), a water-soluble analogue of dimercaprol, has been increasingly used instead. Succimer has a high affinity for lead, is suitable for administration by mouth and is better tolerated (has a wider therapeutic index) than dimercaprol. It is licenced for such use in the USA but not the UK. SOME POISONINGS Methanol is widely available as a solvent and in paints and antifreezes, and may be consumed as a cheap substitute for ethanol. As little as 10 ml may cause permanent blindness and 30 ml may kill, through its toxic metabolites. Methanol, like ethanol, is metabolised by zero-order processes that involve the hepatic alcohol and aldehyde dehydrogenases, but whereas ethanol forms acetaldehyde and acetic acid which are partly responsible for the unpleasant effects of 'hangover', methanol forms formaldehyde and formic acid. Blindness may occur because aldehyde dehydrogenase present in the retina (for the interconversion of retinol and retinene) allows the local formation of formaldehyde. Acidosis is due to the formic acid, which itself enhances pH- dependent hepatic lactate production, so that lactic acidosis is added. The clinical features are severe malaise, vomiting, abdominal pain and tachypnoea (due to the acidosis). Loss of visual acuity and scotomata indicate ocular damage and, if the pupils are dilated and non- reactive, permanent loss of sight is probable. Coma and circulatory collapse may follow. Therapy is directed at: • Correcting the acidosis. Achieving this largely determines the outcome; sodium bicarbonate is given i.v. in doses up to 2 mol in a few hours, carrying an excess of sodium which must be managed. Methanol is metabolised slowly and the patient may relapse if bicarbonate administration is discontinued too soon. • Inhibiting methanol metabolism. Ethanol, which occupies the dehydrogenase enzymes in preference to methanol, competitively prevents metabolism of methanol to its toxic products. A single oral dose of ethanol 1 ml/kg (as a 50% solution or as the equivalent in gin or whisky) is followed by 0.25 ml/kg/h orally or i.v., aiming to maintain the blood ethanol at about 100 mg/100 ml until no methanol is detectable in the blood. Fomepizole (4-methylpyrazole), also a competitive inhibitor of alcohol dehydrognase, has proved effective in severe methanol poisoning and is less likely to cause cerebral depression. • Eliminating methanol and its metabolites by dialysis. Haemodialysis is 2-3 times more effective than is peritoneal dialysis. Folinic 159 9 POISONING, OVERDOSE, ANTI DOTES acid 30 mg i.v. 6-hourly may protect against retinal damage by enhancing formate metabolism. Ethylene glycol is readily accessible as a consti- tuent of antifreezes for car radiators. It has been used criminally to give 'body' and sweetness to white table wines. Metabolism to glycolate and oxalate causes acidosis and renal damage, and usually the sit- uation is further complicated by lactic acidosis. In the first 12 hours after ingestion the patient appears as though intoxicated with alcohol but does not smell of that; subsequently there is increasing acidosis, pulmonary oedema and cardiac failure, and in 2-3 days renal pain and tubular necrosis develop because calcium oxalate crystals form in the urine. Acidosis is corrected with i.v. sodium bicarbonate and hypocalcaemia with calcium gluco- nate. As with methanol (above), ethanol or fome- pizole is given competitively to inhibit the meta- bolism of ethylene glycol and haemodialysis is used to eliminate the poison. Hydrocarbons, e.g. paraffin oil (kerosene), petrol (gasoline), benzene, chiefly cause CNS depression and pulmonary damage from inhalation. It is vital to avoid aspiration into the lungs during attempts to remove the poison or in spontaneous vomiting. Gastric aspiration should be performed only if a cuffed endotracheal tube is effectively in place, if necessary after anaesthetising the subject. Volatile solvent abuse or 'glue sniffing', is common among teenagers, especially males. The success of the modern chemical industry provides easy access to these substances as adhesives, dry cleaners, air fresheners, deodorants, aerosols and other products. Various techniques of administration are employed: viscous products may be inhaled from a plastic bag, liquids from a handkerchief or plastic bottle. The immediate euphoriant and excitatory effects are replaced by confusion, hallucinations and delusions as the dose is increased. Chronic abusers, notably of toluene, develop peripheral neuropathy, cerebellar disease and dementia; damage to the kidney, liver, heart and lungs also occurs with solvents. Over 50% of deaths from the practice follow cardiac arrhyth- mia, probably caused by sensitisation of the myo- cardium to catecholamines and by vagal inhibition from laryngeal stimulation when aerosol propellants are sprayed into the throat. Standard cardiorespiratory resuscitation and antiarrhythmia treatment are used for acute solvent poisoning. Toxicity from carbon tetrachloride and chloroform involves the generation of phosgene (a 1914-18 war gas) which is inactivated by cysteine, and by glutathione which is formed from cysteine; treatment with N-acetylcysteine, as for poisoning with paracetamol, is therefore recommended. Poisoning by herbicides and pesticides Organophosphorus pesticides are anticholineste- rases; poisoning and its management are described on page 437. Organic carbamates are similar. Dinitro-compounds. Dinitro-orthocresol (DNOC) and dinitrobutylphenol (DNBP) are used as selective weed killers and insecticides, and cases of poison- ing occur accidentally, e.g. when safety precautions are ignored. These substances can be absorbed through the skin and the hands, face or hair are usually stained yellow. Symptoms and signs indi- cate a very high metabolic rate (due to uncoupling of oxidative phosphorylation); copious sweating and thirst proceed to dehydration and vomiting, weakness, restlessness, tachycardia and deep, rapid breathing, convulsions and coma. Treatment is urgent and consists of cooling the patient and attention to fluid and electrolyte balance. It is essential to differentiate this type of poisoning from that due to anticholinesterases because atropine given to patients poisoned with dinitro-compound will stop sweating and may cause death from hyperthermia. Phenoxy herbicides (2,4-D, mecoprop, dichlorprop) are used to control broad-leaved weeds. Ingestion causes nausea, vomiting, pyrexia (due to uncoupl- ing of oxidative phosphorylation), hyperventilation, hypoxia and coma. Their elimination is enhanced by urine alkalinisation. Organochlorine pesticides, e.g. dicophane (DDT), may cause convulsions in acute overdose. Treat as for status epilepticus. Rodenticides include warfarin and thallium (see Table 9.1); for strychnine, which causes convulsions, give diazepam. 160 [...]... execution, e.g combinations of thiopentone, potassium, curare, given intravenously GUIDETO FURTHER READING Dawson A H, Whyte IM 1999 Therapeutic drug monitoring in drug overdose British Journal of Clinical Pharmacology 48: 278-283 Ernst A, Zibrak J D 1998 Carbon monoxide poisoning New England Journal of Medicine 339:1603-1608 Evison D, Hinsley D, Rice P 2002 Chemical weapons British Medical Journal... innocent, bedridden invalid should a projectile enter a window CS (chlorobenzylidene malononitrile, a tear 'gas') is a favoured substance at present This is a solid that is disseminated as an aerosol (particles of 1 micron diameter) by including it in a pyrotechnic mixture The spectacle of its dissemination has been rendered familiar by television It is not a gas, it is an aerosol or smoke The particles... substances and no further important information is readily available This brief account has been included, because, in addition to helping victims, even the most well-conducted and tractable students and doctors 11 10 Health aspects of chemical and biological weapons 1970 WHO Geneva 162 Home Office Report (1971) of the enquiry into the medical and toxicological aspects of CS pt II HMSO, London: Cmnd 4775... can devise When the definition of criminal activity becomes perverted to include activities in defence of human liberty, the employment of drugs offers inducement to inhuman behaviour Such use, and any doctors or others who engage in it, or who misguidedly allow themselves to believe that it can be in the interest of victims to monitor the activity by others, must surely be outlawed It might be urged... (tularaemia), Yersinia pestis (plague), and variola virus (smallpox) Drugs used for the treatment and prophylaxis of some of 161 9 POISONING, OVERDOSE, ANTI DOTES the bacterial infections appear in Table 11.1 (p 211) Vaccines are kept in special centres to immunise against anthrax, plague and smallpox, and an antitoxin for botulism That it has been thought necessary even to make reference to the subject of bioterrorism . Therapeutic drug monitoring in drug overdose. British Journal of Clinical Pharmacology 48: 278-283 Ernst A, Zibrak J D 1998 Carbon monoxide . of forcing 6 Bradberry S M, Vale A J 1995 Journal of Toxicology: Clinical Toxicology 33(5): 407-416. 155 9 POISONING, OVERDOSE, ANTIDOTES diuresis