- Email: [email protected]
Evidence-based medicine in toxicology: where is the evidence?
Evidence-based medicine in toxicology: where is the evidence?
Nicholas A
Buckley, Anthony J Smith
described the clinical effects of antihistamine We found that one particular antihistamine, poisoning.’ pheniramine, not only was taken in deliberate overdose ten times more commonly than any other antihistamine, but also that patients who took pheniramine were far more likely than those taking other drugs to have seizures (adjusted odds ratio for seizures 36 [95% CI 4-299], p=0-001). If this analysis is extended to include all the 197 cases of antihistamine poisoning that presented in Newcastle, NSW, Australia, during the past 8-5 years, the proportion with seizures was 16 of 53 (30%) for pheniramine compared with 1 of 144 (less than 1%) for all other antihistamines combined (unadjusted odds ratio 61-8 [8-8-2610], p<0-001). The high risk of seizures in overdose with pheniramine had not previously been documented. Antihistamine poisoning is not an uncommon problem. Pond2 estimated that there are between 30 000 and 150 000 hospital admissions for poisoning each year in Australia alone, accounting for 1-5% of total admissions. Our local experience is that 6% of poisoning episodes involve antihistamines,3this is consistent with studies from other countries.4-6 Since antihistamine drugs have been available and widely used worldwide for longer than 50 years we were surprised that a previously unsuspected finding of this magnitude could be made by collecting data from one Australian centre over 6 years. At the same time as these findings came to light we were seeking to establish a poisoning review group as part of the Cochrane collaboration. The focus of this collaboration was systematically to identify and collate data from randomised clinical trials.7 There are few controlled clinical trials and yet many articles published on poisoning and there is no shortage of citations in the many lengthy texts on poisoning. Our response to the question of what our review group could do was that we should examine and summarise the quality of this evidence to identify how such a large difference in toxicity between drugs in the antihistamine group could have been missed. We also considered what alternative approaches could be used to gather and collate information on poisoning. We therefore had to identify the information that would be useful, to examine the available data, and to compare them with data presented in some of the major texts on poisoning.8-12 The management of antihistamine poisoning falls within the domain of several groups: regulatory In 1994
we
authorities, public-health physicians,
epidemiologists,
Faculty of Medicine, Discipline of Clinical Pharmacology, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia (NA Buckley FRACP, Prof A J Smith FRCP) Correspondence to:
Dr Nicholas A
Buckley
clinicians, and forensic pathologists. All of these require different data to apply an evidence-based approach to their specific aspects of antihistamine poisoning (table).13 The burden of any disease in the community needs to be assessed so that any community-based strategy to tackle it can be developed, monitored, and evaluated. Clinicians need to know about the spectrum of clinical effects, the usefulness of investigations, and the safety and efficacy of treatments. The data required by forensic pathologists to find out whether these drugs have contributed to the death of a person are the ranges of concentrations found in tissue or plasma, or both, during therapeutic use and in poisoning, fatal or non-fatal. We looked for published data from the past 30 years, which had the potential to answer our questions, in both bibliographies of review articles and textbooks as well as in Medline and Excerpta Medica databases. We examined the data to decide what evidence relating to our questions could be found; this information was then compared with that presented in standard texts on poisoning. Ignoring review articles, we identified 155 primary papers which referred human antihistamine poisoning (full reference list available on request). These included 135 single case reports, most reporting seizures, arrhythmias, deaths, or a combination. There were also 20 case series (reporting 2-136 poisonings). Only seven of these described more than seven patients 5,6,14-18 and only one was predominantly a series of non-referred patients, although in that study patients were selected for coingestion of pethidine. 14 There were no randomised or non-randomised clinical trials of interventions or management. Publications detailing the clinical effects in overdose were available for only 19 of the antihistamine
compounds. Six of the seven larger series described experience with cyclizine," cyproheptadine,16 doxylamine,5 diphenhydramine6,15 (two series, one in combination with methaqualone) and tripelennamine [with pethidine] .14 The seventh series included 15 cases of methapyrilene use among 155 poisonings with over-the-counter sedatives, but did not give sufficient information for us to separate the pertinent data.’8 All but one of the series were derived from referrals and telephone calls to a poison information centre, which indicates a major potential for selection bias in favour of more serious cases. However, these larger series provide the best available published data with which to address the clinical and epidemiological concerns, and data were limited to these five antihistamines only. Most deaths were reported as single cases. The largest forensic series was of five methapyrilene deaths.19 All the textbooks we examined 11-12 described clinical syndromes and recommended investigations and treatment. However, the way this information is presented in toxicology texts is diverse and much of what is written in some textbooks must be based largely on the author’s 1167
RCT=randomised controlled trial.
Table: Clinical data
required for evidence-based medicine in toxicology according to possible primary data
unpublished experience. Norman,9 for example provides a very comprehensive text with 97 references. However, these references include only one of the case series and the text does not discuss the quality of the papers (almost entirely single case reports) referenced. Ellenhorn and Barceloux,8 by contrast, present very little information on antihistamine poisoning in general, and only a small section on diphenhydramine, the antihistamine for which there are the most published data. Vicellio" provides predominantly unreferenced discussion, the references (all case reports) given only for the range of symptoms. GoldfrankJO refers to only one of the case series in quite a lengthy chapter. Perhaps this apparent neglect of a common poisoning simply reflects the lack of available knowledge. Baselt and Cravey, 12 in their book to aid forensic pathologists in finding out cause of death, give data on lethal drug concentrations in the blood for only 11 own
antihistamines. The median number of cases for which data are available for each antihistamine is three (range 1-14) and many of the cases have not been described
elsewhere. In 1951 Wyngaarden and Seevers20 reviewed antihistamine poisoning, by collecting together published and unpublished case reports. They described a range of toxicity, including trivial effects, seizures, and death and
suggested
some
untested
treatments.
45
later of data and years
textbooks have essentially the same quality conclusions and many still cite that review. Which of the areas identified (table) as requiring data could be addressed from published reports? Single case reports contribute very little because, by definition, they are subject to selection bias. They are, at best, a hypothesis-generating exercise, or represent a point in an undefined range. Interpretation of case series relies on their size and adequate documentation. If, as in our series,’ the patients have taken various antihistamines, data for individual antihistamines rely on the possibility that the clinical effects can be correlated with the drug ingested. Judgments made from small case series are unreliable. For example, the 95% CI around a clinical observation made in 2 of 7 (28%) patients is 4% to 71%. In most cases this degree of uncertainty limits any generalisations of findings derived from any such small series.
1168
sources
Are the data adequate to allow judgments to be made even about poisoning with the antihistamines for which have large series?5,6,14-18 There were no defined we populations from which these centres gathered their cases, no data on drug availability, no data about the spectrum of poisoning from which the cases were selected, and no data on deaths occurring in the same areas over the time series were collected. We conclude that the best-quality evidence on antihistamine poisoning deals with only six such drugs and provides data only on the symptoms at presentation to medical care that were deemed, for whatever reason, to be severe enough to warrant contact with a poison information centre. Thus, in 30 years, the published data on antihistamines have all been subject to selection bias and reported experience in only 600-700 patients. This figure is much less than 1 % of all the antihistamine poisonings likely to be occurring each year worldwide. Expert opinion, derived from personal experience and understanding of mechanisms, rather than evidence is used as a foundation for many decisions in medicine. Although in some specialties of medicine there is a lack of published descriptive data for quite common disorders, it is unusual for statements in textbooks to be described in terms such as "it is my experience", or "extrapolating from animal data", or "it seems logical based on my understanding". The lack of empirical evidence behind statements is rarely defined and yet an attempt is made to appear objective. If it is important to have empirical evidence, the lack of it also needs to be identified. One approach might be to do systematic reviews and incorporate them into a structured textbook of evidence. What constitutes adequate evidence would be defined in advance. An example, for chlorpheniramine poisoning, is shown in the panel. Those advocating evidence-based medicine caution against the tendency towards therapeutic nihilism.13 However, we believe a means to identify areas of missing evidence is needed otherwise the quality of information will remain the same as that in 1951.=° The editors of conventional textbooks will conclude that this approach does not make for good reading or provide much assistance in managing the condition. However, to aid those performing research to fill the gaps in the clinical knowledge of poisoning we need to start to shift the
Panel: Evidence
on
chlorpheniramine poisoning
Epidemiology incidence-unknown Risk factors-unknown
Reported symptoms
and
signs
Ataxia, sedation, delirium, adult respiratory distress syndrome, heart block, death.
Likely frequency-unknown Proposed investigations
Electrocardiography Sensitivity, specificity, predictive value-unknown Proposed specific treatments Physostigmine, diazepam, alkalinisation None tested in clinical trials
Potentially lethal drug concentrations Unknown
The current focus of evidence-based medicine is to collect and collate the best evidence for treatments (ie, randomised clinical trials). The identification of areas where evidence is lacking has a low priority and systematic reviews of the evidence for treatments that have no evidence are unlikely to be published. Thus the resources and effort of the Cochrane collaboration and the evidence-based medicine movement are being led by the evidence down a well-trodden path of well-funded research. It is perhaps an uncomfortable irony for evidence-based that the medicine overwhelming to predilection publish positive systematic reviews (ie, reviewing subjects that have been extensively studied) is apparently a further example of unwitting publication bias. We thank Andrew Dawson and Ian advice.
Whyte for helpful
comments
and
References
balance away from expert opinon and towards evidence. There are several features of poisoning by drugs that facilitate collection of good descriptive data. Admission or death after drug poisoning has no alternative cause. There are legal requirements to report to the coroner any deaths that are a result of poisoning, and most patients with nonfatal poisoning present to hospital. The difficulties in most case series, such as bias related to selection of cases (and controls) and the need to take into account confounding variables that may have also caused the condition, rarely arise. A much better estimate of incidence can be made than is usual with a registry of cases, so allowing an absolute as well a relative risk to be estimated. The reason that data are not being collected may be a lack of interested people or of funding to do the research, but is not due to difficulties inherent in the condition being studied. The descriptive data could be collected by any clinician working in this specialty. We have facilitated this process in our region with a preformatted admission form outlining the data we wished to collect. These data are then entered on a computer database. Information is gathered on all patients who present to hospitals within the area as well as on deaths caused by poisoning as reported to the coroner. This simple approach requires few resources but much organisation and motivation. Within only a few years it has been possible to identify several previously unrecognised associations.1,2,2H3 If expert opinion is justified largely on the basis of case reports there is little incentive to collect better-quality data. Perhaps if this lack of evidence were publicised, clinicians and pathologists might be stimulated to document and collate their clinical experience. This action would lead, ideally, to national or international collaboration to collect data on poisonings by similar methods. Regional variation could then be examined and poisoning with some of the less common toxins could be studied in detail. Does the lack of evidence affect only this somewhat specialised area of medicine? It seems unlikely. Perhaps people working and researching in some of the less glamorous areas of medicine might be able to tell us how much evidence has been collected on the natural course and management of several
practice (eg,
common
general (eg, hernias), or
Dawson AH, Whyte IM, Cruickshank DA. Pheniramine: much abused drug. Med J Aust 1994; 160: 188-92. Pond SM. Prescription for poisoning. Med J Aust 1995; 162: 174-75. Buckley NA, Dawson AH, Whyte IM, McManus P, Ferguson N. Six years of self-poisoning in Newcastle: 1987-1992. Med J Aust 1995; 162: 190-93. Jacobsen D, Freiderichson PS, Knutsen KM, et al. A prospective study of 1212 cases of acute poisoning: general epidemiology. Hum Toxicol 1984; 3: 93-106. Koppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases. Hum Toxicol 1987; 6: 355-59. Koppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine overdose: an evalation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol 1987; 25: 53-70. Chalmers I, Haynes B. Reporting, updating and correcting systematic reviews of the effects of health care. BMJ 1994; 309: 862-65. Ellenhorn MJ, Barceloux DG. Medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier, 1988. Normann S. Antihistamine (management treatment protocol). In: Rumack BH, Hess AJ, Gelmen CR, eds. Poisindex (R) system. Vol 86: text written 1988, revised 1992. Englewood: Micromedex, Inc:
Buckley NA, a
2
3
4
5
6
7
8 9
(edition current to 31/12/95). 10 Weissman RS, Goldfrank LR. Antihistamines. In: Goldfrank LR, ed. Goldfrank’s Toxicologic emergencies, 5th edn. Appleton and Lange: East Norwalk, 1994. 11 Fisher WL, Viccellio P. Antihistamines. In: Vicellio P, ed. Handbook of medical toxicology, 1st edn. Boston: Little Brown & Co, 1993. 12 Baselt RC, Cravey RH. Disposition of toxic drugs and chemicals in man, 3rd edn. Chicago: Year Book Medical Publishers Inc, 1989. 13 Sackett DL, Haines RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine, 2nd edn. Boston: Little Brown & Co, 1989. 14 De Bard ML, Jagger JA. "T’s and B’s"-midwestern heroin substitute. Clin Toxicol 1981; 18: 1117-23. 15 Matthew H, Proudfoot AT, Brown SS, Smith AC. Mandrax poisoning: conservative management of 116 patients. BMJ 1968; ii: 101-02. 16 von Muhlendahl KE, Kreinke EG. Zur Toxizitat von Cyproheptadin (Nuran): Nebenwirkungen und akzientielle Intoxikationen. Monatsschr Kinderheilkd 1978; 126: 123-26. 17 Resch F, Bachner I, Hruby K, Lenz K. Die Intoxikation mit Cyclizin im Kindes- und Erwachsenenalter (Erfahrungen einer Vergiftungsinformationszentrale). Klin Padiatr 1982; 194: 42-45. 18 Hooper RG, Conner CS, Rumack BH. Acute poisoning from overthe-counter sleep preparations. J Am Coll Emerg Phys 1979; 8: 98-100. 19 Winek CL, Fochtman FW, Trogus WJ Jr, Fusia EP, Shanor SP. Methapyrilene toxicity. Clin Toxicol 1977; 11: 287-94. 20 Wyngaarden JB, Seevers MH. The toxic effects of antihistaminic drugs. JAMA 1951; 145: 277-82. 21 Buckley NA, Whyte IM, Dawson AH. Thioridazine has greater cardiotoxicity in overdose than other neuroleptics. J Toxicol Clin Toxicol
1995; 33: 199-204. 22
Buckley NA, Dawson AH, Whyte IM, Henry DA. Greater toxicity of dothiepin overdose than of other tricyclic antidepressants. Lancet
23
Buckley NA, Whyte IM, Dawson AH, O’Connell D. The relative toxicity of benzodiazepines in overdose. BMJ 1995; 310: 219-21.
disorders in
infections), surgery psychiatry (eg, tardive dyskinesia). ear
1
1994; 343: 159-62.
1169
Nicholas A
Buckley, Anthony J Smith
described the clinical effects of antihistamine We found that one particular antihistamine, poisoning.’ pheniramine, not only was taken in deliberate overdose ten times more commonly than any other antihistamine, but also that patients who took pheniramine were far more likely than those taking other drugs to have seizures (adjusted odds ratio for seizures 36 [95% CI 4-299], p=0-001). If this analysis is extended to include all the 197 cases of antihistamine poisoning that presented in Newcastle, NSW, Australia, during the past 8-5 years, the proportion with seizures was 16 of 53 (30%) for pheniramine compared with 1 of 144 (less than 1%) for all other antihistamines combined (unadjusted odds ratio 61-8 [8-8-2610], p<0-001). The high risk of seizures in overdose with pheniramine had not previously been documented. Antihistamine poisoning is not an uncommon problem. Pond2 estimated that there are between 30 000 and 150 000 hospital admissions for poisoning each year in Australia alone, accounting for 1-5% of total admissions. Our local experience is that 6% of poisoning episodes involve antihistamines,3this is consistent with studies from other countries.4-6 Since antihistamine drugs have been available and widely used worldwide for longer than 50 years we were surprised that a previously unsuspected finding of this magnitude could be made by collecting data from one Australian centre over 6 years. At the same time as these findings came to light we were seeking to establish a poisoning review group as part of the Cochrane collaboration. The focus of this collaboration was systematically to identify and collate data from randomised clinical trials.7 There are few controlled clinical trials and yet many articles published on poisoning and there is no shortage of citations in the many lengthy texts on poisoning. Our response to the question of what our review group could do was that we should examine and summarise the quality of this evidence to identify how such a large difference in toxicity between drugs in the antihistamine group could have been missed. We also considered what alternative approaches could be used to gather and collate information on poisoning. We therefore had to identify the information that would be useful, to examine the available data, and to compare them with data presented in some of the major texts on poisoning.8-12 The management of antihistamine poisoning falls within the domain of several groups: regulatory In 1994
we
authorities, public-health physicians,
epidemiologists,
Faculty of Medicine, Discipline of Clinical Pharmacology, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia (NA Buckley FRACP, Prof A J Smith FRCP) Correspondence to:
Dr Nicholas A
Buckley
clinicians, and forensic pathologists. All of these require different data to apply an evidence-based approach to their specific aspects of antihistamine poisoning (table).13 The burden of any disease in the community needs to be assessed so that any community-based strategy to tackle it can be developed, monitored, and evaluated. Clinicians need to know about the spectrum of clinical effects, the usefulness of investigations, and the safety and efficacy of treatments. The data required by forensic pathologists to find out whether these drugs have contributed to the death of a person are the ranges of concentrations found in tissue or plasma, or both, during therapeutic use and in poisoning, fatal or non-fatal. We looked for published data from the past 30 years, which had the potential to answer our questions, in both bibliographies of review articles and textbooks as well as in Medline and Excerpta Medica databases. We examined the data to decide what evidence relating to our questions could be found; this information was then compared with that presented in standard texts on poisoning. Ignoring review articles, we identified 155 primary papers which referred human antihistamine poisoning (full reference list available on request). These included 135 single case reports, most reporting seizures, arrhythmias, deaths, or a combination. There were also 20 case series (reporting 2-136 poisonings). Only seven of these described more than seven patients 5,6,14-18 and only one was predominantly a series of non-referred patients, although in that study patients were selected for coingestion of pethidine. 14 There were no randomised or non-randomised clinical trials of interventions or management. Publications detailing the clinical effects in overdose were available for only 19 of the antihistamine
compounds. Six of the seven larger series described experience with cyclizine," cyproheptadine,16 doxylamine,5 diphenhydramine6,15 (two series, one in combination with methaqualone) and tripelennamine [with pethidine] .14 The seventh series included 15 cases of methapyrilene use among 155 poisonings with over-the-counter sedatives, but did not give sufficient information for us to separate the pertinent data.’8 All but one of the series were derived from referrals and telephone calls to a poison information centre, which indicates a major potential for selection bias in favour of more serious cases. However, these larger series provide the best available published data with which to address the clinical and epidemiological concerns, and data were limited to these five antihistamines only. Most deaths were reported as single cases. The largest forensic series was of five methapyrilene deaths.19 All the textbooks we examined 11-12 described clinical syndromes and recommended investigations and treatment. However, the way this information is presented in toxicology texts is diverse and much of what is written in some textbooks must be based largely on the author’s 1167
RCT=randomised controlled trial.
Table: Clinical data
required for evidence-based medicine in toxicology according to possible primary data
unpublished experience. Norman,9 for example provides a very comprehensive text with 97 references. However, these references include only one of the case series and the text does not discuss the quality of the papers (almost entirely single case reports) referenced. Ellenhorn and Barceloux,8 by contrast, present very little information on antihistamine poisoning in general, and only a small section on diphenhydramine, the antihistamine for which there are the most published data. Vicellio" provides predominantly unreferenced discussion, the references (all case reports) given only for the range of symptoms. GoldfrankJO refers to only one of the case series in quite a lengthy chapter. Perhaps this apparent neglect of a common poisoning simply reflects the lack of available knowledge. Baselt and Cravey, 12 in their book to aid forensic pathologists in finding out cause of death, give data on lethal drug concentrations in the blood for only 11 own
antihistamines. The median number of cases for which data are available for each antihistamine is three (range 1-14) and many of the cases have not been described
elsewhere. In 1951 Wyngaarden and Seevers20 reviewed antihistamine poisoning, by collecting together published and unpublished case reports. They described a range of toxicity, including trivial effects, seizures, and death and
suggested
some
untested
treatments.
45
later of data and years
textbooks have essentially the same quality conclusions and many still cite that review. Which of the areas identified (table) as requiring data could be addressed from published reports? Single case reports contribute very little because, by definition, they are subject to selection bias. They are, at best, a hypothesis-generating exercise, or represent a point in an undefined range. Interpretation of case series relies on their size and adequate documentation. If, as in our series,’ the patients have taken various antihistamines, data for individual antihistamines rely on the possibility that the clinical effects can be correlated with the drug ingested. Judgments made from small case series are unreliable. For example, the 95% CI around a clinical observation made in 2 of 7 (28%) patients is 4% to 71%. In most cases this degree of uncertainty limits any generalisations of findings derived from any such small series.
1168
sources
Are the data adequate to allow judgments to be made even about poisoning with the antihistamines for which have large series?5,6,14-18 There were no defined we populations from which these centres gathered their cases, no data on drug availability, no data about the spectrum of poisoning from which the cases were selected, and no data on deaths occurring in the same areas over the time series were collected. We conclude that the best-quality evidence on antihistamine poisoning deals with only six such drugs and provides data only on the symptoms at presentation to medical care that were deemed, for whatever reason, to be severe enough to warrant contact with a poison information centre. Thus, in 30 years, the published data on antihistamines have all been subject to selection bias and reported experience in only 600-700 patients. This figure is much less than 1 % of all the antihistamine poisonings likely to be occurring each year worldwide. Expert opinion, derived from personal experience and understanding of mechanisms, rather than evidence is used as a foundation for many decisions in medicine. Although in some specialties of medicine there is a lack of published descriptive data for quite common disorders, it is unusual for statements in textbooks to be described in terms such as "it is my experience", or "extrapolating from animal data", or "it seems logical based on my understanding". The lack of empirical evidence behind statements is rarely defined and yet an attempt is made to appear objective. If it is important to have empirical evidence, the lack of it also needs to be identified. One approach might be to do systematic reviews and incorporate them into a structured textbook of evidence. What constitutes adequate evidence would be defined in advance. An example, for chlorpheniramine poisoning, is shown in the panel. Those advocating evidence-based medicine caution against the tendency towards therapeutic nihilism.13 However, we believe a means to identify areas of missing evidence is needed otherwise the quality of information will remain the same as that in 1951.=° The editors of conventional textbooks will conclude that this approach does not make for good reading or provide much assistance in managing the condition. However, to aid those performing research to fill the gaps in the clinical knowledge of poisoning we need to start to shift the
Panel: Evidence
on
chlorpheniramine poisoning
Epidemiology incidence-unknown Risk factors-unknown
Reported symptoms
and
signs
Ataxia, sedation, delirium, adult respiratory distress syndrome, heart block, death.
Likely frequency-unknown Proposed investigations
Electrocardiography Sensitivity, specificity, predictive value-unknown Proposed specific treatments Physostigmine, diazepam, alkalinisation None tested in clinical trials
Potentially lethal drug concentrations Unknown
The current focus of evidence-based medicine is to collect and collate the best evidence for treatments (ie, randomised clinical trials). The identification of areas where evidence is lacking has a low priority and systematic reviews of the evidence for treatments that have no evidence are unlikely to be published. Thus the resources and effort of the Cochrane collaboration and the evidence-based medicine movement are being led by the evidence down a well-trodden path of well-funded research. It is perhaps an uncomfortable irony for evidence-based that the medicine overwhelming to predilection publish positive systematic reviews (ie, reviewing subjects that have been extensively studied) is apparently a further example of unwitting publication bias. We thank Andrew Dawson and Ian advice.
Whyte for helpful
comments
and
References
balance away from expert opinon and towards evidence. There are several features of poisoning by drugs that facilitate collection of good descriptive data. Admission or death after drug poisoning has no alternative cause. There are legal requirements to report to the coroner any deaths that are a result of poisoning, and most patients with nonfatal poisoning present to hospital. The difficulties in most case series, such as bias related to selection of cases (and controls) and the need to take into account confounding variables that may have also caused the condition, rarely arise. A much better estimate of incidence can be made than is usual with a registry of cases, so allowing an absolute as well a relative risk to be estimated. The reason that data are not being collected may be a lack of interested people or of funding to do the research, but is not due to difficulties inherent in the condition being studied. The descriptive data could be collected by any clinician working in this specialty. We have facilitated this process in our region with a preformatted admission form outlining the data we wished to collect. These data are then entered on a computer database. Information is gathered on all patients who present to hospitals within the area as well as on deaths caused by poisoning as reported to the coroner. This simple approach requires few resources but much organisation and motivation. Within only a few years it has been possible to identify several previously unrecognised associations.1,2,2H3 If expert opinion is justified largely on the basis of case reports there is little incentive to collect better-quality data. Perhaps if this lack of evidence were publicised, clinicians and pathologists might be stimulated to document and collate their clinical experience. This action would lead, ideally, to national or international collaboration to collect data on poisonings by similar methods. Regional variation could then be examined and poisoning with some of the less common toxins could be studied in detail. Does the lack of evidence affect only this somewhat specialised area of medicine? It seems unlikely. Perhaps people working and researching in some of the less glamorous areas of medicine might be able to tell us how much evidence has been collected on the natural course and management of several
practice (eg,
common
general (eg, hernias), or
Dawson AH, Whyte IM, Cruickshank DA. Pheniramine: much abused drug. Med J Aust 1994; 160: 188-92. Pond SM. Prescription for poisoning. Med J Aust 1995; 162: 174-75. Buckley NA, Dawson AH, Whyte IM, McManus P, Ferguson N. Six years of self-poisoning in Newcastle: 1987-1992. Med J Aust 1995; 162: 190-93. Jacobsen D, Freiderichson PS, Knutsen KM, et al. A prospective study of 1212 cases of acute poisoning: general epidemiology. Hum Toxicol 1984; 3: 93-106. Koppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases. Hum Toxicol 1987; 6: 355-59. Koppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine overdose: an evalation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol 1987; 25: 53-70. Chalmers I, Haynes B. Reporting, updating and correcting systematic reviews of the effects of health care. BMJ 1994; 309: 862-65. Ellenhorn MJ, Barceloux DG. Medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier, 1988. Normann S. Antihistamine (management treatment protocol). In: Rumack BH, Hess AJ, Gelmen CR, eds. Poisindex (R) system. Vol 86: text written 1988, revised 1992. Englewood: Micromedex, Inc:
Buckley NA, a
2
3
4
5
6
7
8 9
(edition current to 31/12/95). 10 Weissman RS, Goldfrank LR. Antihistamines. In: Goldfrank LR, ed. Goldfrank’s Toxicologic emergencies, 5th edn. Appleton and Lange: East Norwalk, 1994. 11 Fisher WL, Viccellio P. Antihistamines. In: Vicellio P, ed. Handbook of medical toxicology, 1st edn. Boston: Little Brown & Co, 1993. 12 Baselt RC, Cravey RH. Disposition of toxic drugs and chemicals in man, 3rd edn. Chicago: Year Book Medical Publishers Inc, 1989. 13 Sackett DL, Haines RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine, 2nd edn. Boston: Little Brown & Co, 1989. 14 De Bard ML, Jagger JA. "T’s and B’s"-midwestern heroin substitute. Clin Toxicol 1981; 18: 1117-23. 15 Matthew H, Proudfoot AT, Brown SS, Smith AC. Mandrax poisoning: conservative management of 116 patients. BMJ 1968; ii: 101-02. 16 von Muhlendahl KE, Kreinke EG. Zur Toxizitat von Cyproheptadin (Nuran): Nebenwirkungen und akzientielle Intoxikationen. Monatsschr Kinderheilkd 1978; 126: 123-26. 17 Resch F, Bachner I, Hruby K, Lenz K. Die Intoxikation mit Cyclizin im Kindes- und Erwachsenenalter (Erfahrungen einer Vergiftungsinformationszentrale). Klin Padiatr 1982; 194: 42-45. 18 Hooper RG, Conner CS, Rumack BH. Acute poisoning from overthe-counter sleep preparations. J Am Coll Emerg Phys 1979; 8: 98-100. 19 Winek CL, Fochtman FW, Trogus WJ Jr, Fusia EP, Shanor SP. Methapyrilene toxicity. Clin Toxicol 1977; 11: 287-94. 20 Wyngaarden JB, Seevers MH. The toxic effects of antihistaminic drugs. JAMA 1951; 145: 277-82. 21 Buckley NA, Whyte IM, Dawson AH. Thioridazine has greater cardiotoxicity in overdose than other neuroleptics. J Toxicol Clin Toxicol
1995; 33: 199-204. 22
Buckley NA, Dawson AH, Whyte IM, Henry DA. Greater toxicity of dothiepin overdose than of other tricyclic antidepressants. Lancet
23
Buckley NA, Whyte IM, Dawson AH, O’Connell D. The relative toxicity of benzodiazepines in overdose. BMJ 1995; 310: 219-21.
disorders in
infections), surgery psychiatry (eg, tardive dyskinesia). ear
1
1994; 343: 159-62.
1169