Q J Med 2001; 94: 117-120
© 2001 Association of Physicians
Editorial |
Our poisoned patients
West Midlands Centre for Adverse Drug Reaction Reporting City Hospital Birmingham B18 7QH
Patients poison themselves, sometimes deliberately, sometimes unintentionally; or they are poisoned by others, who may or may not mean to do them harm. Self-poisoning is still a major problem throughout the world.1 The balance in England and Wales has changed over the last 25 years. In 1978, 4085 deaths from poisoning were recorded, of which 1265 (31%) were from barbiturate poisoning, and 22 (0.5%) from opiate poisoning.2 By 1998, when 3328 people died from poisoning, barbiturates accounted for 23 (0.7%) and opiates for 483 (15%)—and many more if deaths due to addiction are included.3
The principles of management of acute poisoning are well established: separate the poison and the patient (‘decontaminate’); institute general supportive measures; and administer specific antidotes if they are appropriate. The enthusiasm for aggressive decontamination by gastric lavage has waned in recent years. The dangers of aspiration pneumonia, paradoxically increased absorption, and mechanical trauma can no longer be justified, because experimental studies in volunteers, and endoscopy of real patients, show that in most cases only trivial amounts of poison are recovered.4–6 The efficacy of gastric lavage diminishes rapidly as time passes after ingestion, and its routine use should now be abandoned.7,8
Ipecacuanha, given to induce vomiting, has even less merit than gastric lavage. Experimental studies show that it has little benefit,4 and the symptoms induced by the emetic are often more unpleasant than any likely symptoms from the poison.9
The efficacy of adsorbents was demonstrated in a dramatic, but anecdotal, fashion by the pharmacist Touéry, who took ten times the lethal dose of strychnine with activated charcoal before describing its benefits to the Academie de Medicine in Paris.10 Later studies have confirmed the efficacy of activated charcoal in reducing absorption, though there is little direct evidence of clinical benefit. Some substances, notably salts of iron and lithium, are not adsorbed on to charcoal. Aspiration of charcoal into the lungs is sometimes fatal.11–13 Nonetheless, in patients whose protective reflexes are intact, or whose airway is guarded by a cuffed endotracheal tube, activated charcoal is the preferred option for gut decontamination.7,14
Deliberate self-poisoning in England and Wales is most often due to acetaminophen (paracetamol). Management has evolved over the last decade. The mechanism by which acetaminophen damages the liver, and more rarely the kidney, was elucidated by Prescott and colleagues in Edinburgh. Therapeutic doses are mainly eliminated as water-soluble conjugates of sulphuric or glucuronic acid. These pathways are saturated in overdose, and then an alternative pathway by oxidation to the reactive species N-acetyl-p-benzoquinoneimine (NABQI) becomes important. NABQI can react with glutathione to form inactive conjugates, but when glutathione is depleted, NABQI reacts with sulfhydryl residues in cellular proteins, and cell death results. Treatment of overdose depends on providing sulfhydryl residues before cellular proteins are irreversibly damaged.15,16
There is controversy over the use of oral preparations containing sulfhydryl groups.17 Methionine and acetylcysteine are rather unpalatable, and, coupled with the nausea that commonly accompanies acetaminophen poisoning, cause vomiting, and in consequence reduce the amount of antidote taken. Intravenous infusion regimens for acetylcysteine are complex,18 but demonstrably effective.19 Efficacy falls if the antidote is given more than 8 h after overdose, but acetylcysteine infusion still gives some benefit even if its administration is delayed. A group of ten patients treated between 15 and 24 h did no worse than a group treated between 12 and 15 h, and neither group developed liver damage as severe as predicted from prior experience.20 That trial was not randomized, and there were no contemporaneous controls. A randomized trial has compared acetylcysteine with placebo in patients who developed fulminant hepatic failure from acetaminophen poisoning.21 Infusion of acetylcysteine was continued until recovery or death. Survival in the patients receiving placebo was 20%; absolute survival rates were 28% [95%CI 3–53%] higher in those treated with acetylcysteine. This study justifies the continued infusion of acetylcysteine in patients who present ‘late’ with significant acetaminophen poisoning until they recover, die, or undergo hepatic transplantation.22
A second important change in routine management has come from the identification of a group of patients in whom the risk of fulminant hepatic failure is high even at plasma concentrations of acetaminophen that were previously considered unlikely to be dangerous. They include patients with anorexia nervosa or other cause of malnourishment, and patients taking drugs likely to induce liver enzymes.23 A cautious approach, treating patients at high risk where plasma concentrations are above 50% of the usually accepted boundary for treatment, may obviate this problem.24–26 Patients who chronically abuse alcohol could also be at high risk of liver damage, but this is not proven.27,28
Unintentional poisoning by drugs of abuse, deliberately taken for ‘pleasure’, is now commonplace. Opiate poisoning is frequent in this context, and sometimes difficult to manage. The features of opioid poisoning are characteristic: pin-point pupils, depression of the rate and depth of respiration, and depression of consciousness. The stigmata of addiction include ‘needle tracks’—sites of old injections; emaciation, which is a consequence of opioid-induced anorexia; and possession of ‘gear’—the impedimenta of rubber tourniquet, syringes, spoons, and cigarette lighters and filters necessary to dissolve impure street heroin in lemon juice or vinegar, filter out gross particulate contaminants, and inject it intravenously. The effects of most opioids can be reversed at once by the injection of a sufficient quantity of the specific opioid antagonist naloxone, which is itself devoid of any agonist activity. It is best not to give it unless there are symptoms and signs of opioid intoxication.29 If patients are physically dependent, too much antidote can precipitate withdrawal reactions within minutes. These can be unpleasant both for the patient and for the medical staff, and are best avoided by careful dose titration from a small initial dose.
The effects of naloxone, a competitive antagonist, soon wear off as the drug is broken down, and the patient may relapse into a sedated state, the risk increasing with the dose of opioid and its duration of action. This risk can be mitigated by monitoring of patients for several hours after naloxone administration, and treated by infusion of naloxone at a rate sufficient to maintain adequate respiration. The required rate is usually about two-thirds of the ‘wake-up’ dose per hour.30
The management of opiate withdrawal outside specialist units is difficult. Addicted patients often deceive themselves and others. Unfortunately, kindness and credulity can be a lethal combination, if the result is prescription of methadone. This has probably been responsible for many deaths, although the toxicological evidence is not quite certain.31–33 There are two important dangers in prescribing or represcribing methadone outside a specialist environment. First, systemic absorption of this orally active agent is slow, and the peak concentration can be reached several hours after administration, so that patients who appear well can become sedated, then lapse into coma, aspirate stomach contents or develop respiratory depression, and die. This is particularly a problem for doctors who treat prisoners in custody, but can occur in general medical wards.34 Secondly, the half-life is about 18 h on average, but can vary by a factor of four between one individual and the next. Cumulative toxicity is therefore a real but unpredictable danger. It is safest not to prescribe methadone at all in the context of an acute medical ward. The drug's long half-life means that, if treatment is stopped, symptoms of opiate withdrawal are mild, and can be managed with benzodiazepine hypnotics, antidiarrhoeal agents such as loperamide, and simple analgesics. If methadone is to be prescribed, then the initial dose should not exceed 20 mg/day even in patients who insist they have been in the habit of taking more.
There is a widespread fear of being poisoned by others, deliberately or accidentally. The perceived hazards of synthetic chemicals, and the perceived safety of ‘natural’ products, reflect this, and lead to concerns out of proportion to likely risks. Failure to find clear scientific evidence of harm has, paradoxically, increased the anxiety of activists, and claimants, that real harmful effects are being hidden. The issue illustrates the refinements in society, as many overtly poisonous substances are removed from the environment, and the fear of subtle, chronic, or undetected harm becomes magnified.
The difficulties are illustrated by the case of organophosphorus compounds used as pesticides. The possible chronic effects of low-level exposure have recently been examined by the Committee on Toxicity.35
The issue is complex, since there is no doubt that some organophosphorus compounds, for example those used as nerve agents in warfare, are extremely potent acute poisons, and others, notably tri-ortho-cresyl phosphate, can cause chronic neurological damage without severe symptoms of cholinergic excess, which is the classical manifestation of nerve agent poisoning. Tri-ortho-cresyl phosphate, a contaminant of ‘Ginger Jake’, an alcoholic extract of Jamaican ginger much drunk in the United States during Prohibition, caused an irreversible axonal peripheral neuropathy. The earliest effects occurred about one week to 1 month after exposure and progressed for up to 6 months, during which the subject suffered weakness and changes in sensation culminating in paralysis, particularly of the lower limbs; sensory symptoms disappeared within a month or so, leaving the patient with motor damage that might improve, or remain for many years.36 Since Johnson and others developed a test based on observation that the hen is much more susceptible than the human to organophosphorus-induced delayed neuropathy,37 this gross form of the disease has been avoided. If neuropathy occurs after chronic low-level exposure, it is likely to be subclinical.35
There remains a concern that organophosphorus compounds might have neuropsychiatric adverse effects, but the epidemiological studies of possible late neuropsychiatric effects after severe acute poisoning have not produced consistent or strong evidence of deficit. Studies of chronic exposure have been beset by difficulties in defining suitable control subjects.38 On balance, it seems very unlikely that there is a general risk of clinically detectable neuropsychiatric damage from exposure insufficient to cause severe poisoning.
Hospital patients risk being poisoned by medication errors.39 Little attempt to understand or prevent the phenomenon has been made until recently. This has changed with the publication of a report by the Institute of Medicine in the US entitled ‘To err is human ...’, and by suggestions that in the US up to 100 000 people a year die from errors.40,41
The everyday experience of misdated cheques, forgotten wedding anniversaries, and wrong turnings should be enough to show that we all make errors without intending to, and that however hard we try we cannot avoid errors.42 They have, though, previously been ascribed to indolence, incompetence, or stupidity. Only now are we beginning to realize that systems have to be built to withstand human error, rather than ignoring it or putting the onus on the human to avoid it. The railway system is struggling with similar difficulties over ‘signals passed at danger’. How systems can be devised to avoid ten-fold dosing errors, prevent serious drug interactions, and stop the confusion between one drug and another with a similar name but different effects, is unclear. Computers must have some role,43,44 although they will not be a panacea.45 The most important change will be from a punitive environment where errors are hidden and their importance minimized to one of openness where all dangerous occurrences are recorded, analysed, and used to improve the process.
Deliberate criminal poisoning is rare, or rarely detected. Serial murder by poisoning is exceedingly rare, but the last decade has seen two cases of medical staff convicted. The nurse Beverley Allitt murdered four children and injured many more. This was discovered when a non-diabetic boy became hypoglycaemic, was transferred from Grantham and Kesteven Hospital to the regional paediatric unit in Nottingham, and was found to have an enormously high serum insulin concentration in the absence of C-peptide—this being characteristic of the injection of exogenous insulin. Beverley Allitt also used potassium chloride, and suffocation. This heterodox approach is unusual, and may have prevented earlier recognition of the reason for the 28 cardiac arrest calls that occurred when she was on duty.
Dr Harold Shipman adopted a more uniform method of working, using opiates to kill (mainly elderly) patients. He was convicted of fifteen murders. Traces of diamorphine were found in the exhumed bodies of nine of his victims, demonstrating that they had received the drug, although there was no therapeutic indication. Nicola Davies QC appealed memorably but vainly to the jury, arguing that: ‘The prosecution case is built on one foundation stone and that is toxicology. Without it there would be no case. Toxicology is a new science and untested by proven scientific methods.’ Mead, Orfila, and Christison, the great eighteenth and nineteenth century founders of scientific toxicology, would have been surprised. And the advances of the last decade illustrate that progress in the science of clinical toxicology continues.
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