Clinical Toxicology: Clinical Science to Public Health

Clinical and Experimental Pharmacology and Physiology (2005) 32, 995–998 Annual Scientific Meeting of ASCEPT 2004 CLINICAL TOXICOLOGY: CLINICAL SCIENCE TO PUBLIC HEALTH DN Bateman NPIS Edinburgh, Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh, Edinburgh, UK SUMMARY 1. The aims of the present paper are to: (i) review progress in clinical toxicology over the past 40 years and to place it in the context of modern health care by describing its development; and (ii) illustrate the use of clinical toxicology data from Scotland, in particular, as a tool for informing clinical care and public health policy with respect to drugs. 2. A historical literature review was conducted with amalgamation and comparison of a series of published and unpublished clinical toxicology datasets from NPIS Edinburgh and other sources. 3. Clinical databases within poisons treatment centres offer an important method of collecting data on the clinical effects of drugs in overdose. These data can be used to increase knowledge on drug toxicity mechanisms that inform licensing decisions, contribute to evidence-based care and clinical management. Combination of this material with national morbidity datasets provides another valuable approach that can inform public health prevention strategies. 4. In conclusion, clinical toxicology datasets offer clinical pharmacologists a new study area. Clinical toxicology treatment units and poisons information services offer an important health resource. Key words: clinical science, clinical toxicology, poisons information, public health, review. INTRODUCTION The history of poisoning and its treatment goes into prehistory. Therapies for poisoning were developed by the ancient Greeks and their physicians to the Roman emperors developed a complex ‘universal antidote’. The concept of the universal antidote lasts into the latter half of the 20th century. Understanding of the basic mechanisms of toxicity is a key to determining treatment strategy. The growth of the chemical and pharmaceutical industries from the end of the 19th century has created a wide variety of new potential Correspondence: Dr DN Bateman, NPIS Edinburgh, Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK. Email: Nick.bateman@luht.scot.nhs.uk Presented at the 38th Annual Scientific Meeting for the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Brisbane, 1–6 August 2004. Received 17 February 2005; revision 7 July 2005; accepted 17 July 2005. © 2005 Blackwell Publishing Asia Pty Ltd toxins. After the Second World War, there was an upsurge of hospital admissions relating to poisoning, of which the majority were noted to be deliberate. The clinical disorder of deliberate selfharm has widely become recognized and, in a proportion of patients where suicide occurs, this is an accidental event relating to drug ingestion in crisis. A relatively small proportion of patients presenting with self-harm have pre-existing extensive suicidal ideation. The practice of clinical toxicology developed from the need to manage the poisoning epidemic that evolved in developed countries between 1945 and the 1970s. Key developments are listed in Table 1 and include the demonstration that patients fared better if treated in one hospital area (an idea subsequently adapted by other disciplines) and, equally importantly, if they had less unnecessary and unproven interventions. Today, clinical toxicology faces four challenges, as given in Table 2. The present paper will illustrate key developments in clinical toxicology and parallel these with those in clinical pharmacology from the perspective of a clinical toxicology unit sited within a major UK teaching hospital, the Royal Infirmary of Edinburgh. DEVELOPMENTS IN CLINICAL SCIENCE Placing of patients with self-harm into one clinical area permits a detailed case study of patients with acute poisoning. It provides a unique insight into the clinical pharmacology of drugs taken at doses far higher than are normally permitted in clinical trials or that occur during routine clinical use. This approach has been used in a variety of settings and is considerably aided by detailed case data collection onto computer databases (e.g. in Newcastle, Australia).1 However, the difficulties of performing clinical trials in this patient group are considerable, partly because of the frequent co-ingestion of products and also because of ethical issues that constrain informed consent in a self-harming population. Two examples will be used to illustrate this. Dextropropoxyphene In the UK, dextropropoxyphene is marketed as the product coproxamol (a combination of paracetamol 325 mg and dextropropoxyphene 32.5 mg). It is widely prescribed and has the highest incidence of death associated with it of any pharmaceutical in the UK.2 Death frequently occurs before patients reach hospital, but the cause has remained unclear. By examining electrocardiogram (ECG) changes in a cohort of 15 patients poisoned with coproxamol and comparing them with 15 cases who ingested other opioid–paracetamol combination products, we have shown that 996 DN Bateman co-proxamol ingestion is associated with widening of the QRS complex on the ECG.3 This phenomenon is usually attributed to sodium channel blockade and, as such, if sufficiently wide, is a risk factor for cardiac arrhythmia. This action is separate from the opioid antagonist action associated with dextropropoxyphene. We have also shown a relationship between length of QRS and ingested dose, as reflected by plasma paracetamol concentration,3 further emphasising the dose dependency of this change. The hypothesis advanced as a result of these findings is that dextropropoxypheneassociated death is secondary to a complication of the opioid and electrophysiological actions. These are likely to be synergistic in contributing to toxicity because respiratory depression will cause hypoxia and acidosis that exacerbates the ECG effects. Antipsychotics Prolongation of the QT interval is another known risk factor for ventricular arrhythmias (torsade de pointes). This abnormality is caused by many drugs,4 but the likelihood of torsade de pointes in a clinical toxicology environment appears to be different with different agents. We have recently studied a large case series retrospectively in which we examined the relationship between stated dose ingested (by the patient) and cardiovascular effects (blood pressure, pulse, ECG) following overdose. We compared 36 cases of thioridazine poisoning and 96 of chlorpromazine poisoning.5 These data demonstrated a dose-related effect for thioridazine on QTc (Bazett’s correction), but not with chlorpromazine. Both drugs had dose-related effects on pulse rate and chlorpromazine, which has significant -adrenoceptor antagonist action, also lowered blood pressure in a dose-dependent manner. This study Table 1 Key developments in clinical toxicology Centralization of treatment Avoidance of unnecessary treatment Development of poisons information centres Clinical trials in patients with poisoning Fig. 1 Annual proportions of admissions in Edinburgh for seven main drug categories over the period 1981–2001 in females. (-----), paracetamol; (– – – – –), benzodiazepines; (••••••), antidepressants; (– • – • – • –), nonopioids; (–––––), opiates; (– •• – •• –), salicylates; (– ••• – ••• –), antipsychotics. illustrates the possibility of obtaining information on the wider profile of drug toxicity in overdose and potentially exploring the clinical pharmacology of drugs at doses outside the therapeutic range. It also highlights the possibility of using self-harm patients as a potential source of drug safety information, particularly for new drugs. Further work is on-going on new antipsychotics, an increasingly frequent cause of presentation with overdose. EVIDENCE-BASED MEDICINE AND PROGRESS IN CLINICAL PRACTICE Over the past 30 years, a number of key antidotal regimens has been developed as biochemical and pharmacological knowledge and techniques have advanced. These include the introduction of N-acetylcysteine in the treatment of paracetamol poisoning6,7 and the development of treatment lines for paracetamol overdose management that followed a better understanding of the biochemistry of paracetamol toxicity.6 Other important developments followed increasing knowledge of basic pharmacology, as illustrated by the development of naloxone.8 In contrast, other treatments that have previously been accepted as effective, such as forced alkaline diuresis, were studied in more detail in the carefully controlled environment of a clinical toxicology unit and found to be ineffective.9 The whole approach to gastric decontamination has changed, in part in response to Susan Pond’s work10 and position statements published by the largest American and European societies of Clinical Toxicology.11–15 Table 2 Challenges in clinical toxicology Further development of evidence-based practice: Expansion of pharmaceutical products and chemicals Social phenomena: Self harm and drugs of abuse Public concerns: Environmental pollutants Deliberate release Fig. 2 Annual proportions of admissions in Edinburgh for seven main drug categories over the period 1981–2001 in males. (-----), paracetamol; (– – – – –), benzodiazepines; (••••••), antidepressants; (– • – • – • –), nonopioids; (–––––), opiates; (– •• – •• –), salicylates; (– ••• – ••• –), antipsychotics. © 2005 Blackwell Publishing Asia Pty Ltd Clinical toxicology: Science to public health Regrettably, work in this area has often been driven by academics rather than the larger pharmaceutical companies, as is illustrated by the development of fomepizole as an antidote to ethanol and ethylene glycol poisoning.16 PUBLIC HEALTH AND CLINICAL TOXICOLOGY The increase in the frequency of self-harm as a presentation within acute medical units has raised the profile of this condition and made it a target for governments, including that in the UK, keen to improve the management of patients with mental health disorders.17 Therefore, studying patterns of behaviour in self-harm may be useful in determining potential actions to reduce the epidemic. We have recently examined the trends in admissions for self-harm between 1981 and 2001 in Edinburgh (Figs 1,2) and shown that, over this 20 year period, the proportion of patients ingesting paracetamol has increased approximately fourfold and now accounts for over 40% of all admissions. In contrast, benzodiazepine poisoning has fallen from 30% in women and 20% in men in 1981 to less than 15% in both men and women in 2001. Major increases have been seen in antipsychotic poisoning and in overdoses involving opioids. Because paracetamol poisoning is such an important component of drug admissions in Scotland and the UK as a whole, legislation 997 was introduced in the 1990s to reduce the available pack size of paracetamol in an attempt to reduce the number of deaths. Mortality statistics and hospital discharge statistics are difficult to study because paracetamol may be a component of a multioverdose mixture. Nevertheless, Figs 3,4 demonstrate that there has been no significant trend over the period 1995–2002 either in paracetamol poisoning overall or as a proportion of total poisonings (Fig. 3) or in mortality either overall or in hospital (Fig. 4). The in-hospital deaths more likely reflect the true effect of paracetamol because many of the hospital deaths are associated with co-proxamol or other co-ingested agents and the speed of death suggests that paracetamol cannot be responsible. POISONS INFORMATION SERVICES Fig. 3 Hospital deaths and discharges involving poisonings/100 000 population, Scotland 1995–2002. (), paracetamol poisonings; (), other poisonings. Before the 1950s, information on the management of poisoning was mostly found in medical textbooks. The expansion in marketed pharmaceuticals and chemicals after 1945 meant that the need for up-to-date authoritative advice increased markedly and poisons centres were established, initially in Chicago and subsequently around the world. These centres provided information to clinicians and, subsequently, members of the public and these centres were often combined with clinical treatment units where expert physicians could also learn, first hand, the clinical effects of overdose. The poisons information service has developed in the UK over 40 years and an on-line service, TOXBASE (http://www.spib. axl.co.uk), now provides information as the first-line database.18 Its introduction on the internet in late 1999 has led to a marked increase in use, with an associated fall in telephone enquiries relating to low-level enquiries (Fig. 5). Numbers of remote consultant referrals for advice have remained relatively stable. Poisons information data also allows the study of the epidemiology of patterns of self-harm and, when provided on-line, allows rapid assessment of changes in behaviour. Thus, we were able to demonstrate that the rapid fall in the prescribing of thioridazine that followed a change to its UK licence advising limitation of use owing to risk of arrhythmia was also followed in the same timeframe by a significant decrease in poisons enquiries, a reflection of hospital case load.19 Internet services also allow the ability to rapidly update large groups of heath professionals, particularly in case of counter-terror alerts, because they allow access to up-to-the-minute data to groups Fig. 4 Paracetamol-related deaths. In-hospital () and total () deaths in Scotland, 1995–2002. Fig. 5 UK TOXBASE (http://www.spib.axl.co.uk) sessions () and telephone enquiries (), 2000–2003. © 2005 Blackwell Publishing Asia Pty Ltd 998 DN Bateman of health professionals, particularly those in accident departments, without the need for large numbers of telephone enquiry lines and their consequent costs. CONCLUSIONS Clinical toxicology units offer the enquiring physician an opportunity to establish and investigate the clinical effects of drugs and chemicals in humans. In the present report, I have illustrated the potential of managing such patients in environments that permit data collection and clinical monitoring to be collated. Challenges remain, particularly in mounting large-scale clinical trials for the management of clinical poisoning. Nevertheless, the speciality of clinical toxicology, with its many parallels to clinical pharmacology practice, can provide information both to basic scientists, clinicians and public health specialists. All of this should contribute to increased patient safety and a better understanding of the clinical pharmacology and clinical toxicology of drugs and chemicals exposure in humans. ACKNOWLEDGEMENTS This paper is based on a keynote lecture given at the 7th World Congress of Clinical Pharmacology and Therapeutics, Brisbane 2004, supported by the British Toxicological Society and the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists. REFERENCES 1. Whyte IM, Buckley NA, Dawson AH. Data collection in clinical toxicology: Are there too many variables? J. Toxicol. Clin. Toxicol. 2002; 40: 223–30. 2. Hawton K, Simkin S, Deeks J. Co-proxamol and suicide: A study of national mortality statistics and local non-fatal self poisonings. BMJ 2003; 326: 1006–8. 3. Afshari R, Maxwell SRJ, Dawson AH, Bateman DN. ECG abnormalities in co-proxamol (paracetamol/dextropropoxyphene) poisoning. J. Toxicol. Clin. Toxicol. 2005; 43: 255–9. 4. Roden DM. 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Br. J. Clin. Pharmacol. 2002; 54: 3–9. 19. Bateman DN, Good AM, Afshari R, Kelly CA. Effects of licence change on prescribing and poisons enquiries for antipsychotic agents in England and Scotland. Br. J. Clin. Pharmacol. 2003; 5: 596–603. © 2005 Blackwell Publishing Asia Pty Ltd