Toxicology

Re: “Parallel infusion of hydrocortisone ± chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites”, by Gawarammana I B, et al in the 5 January issue of the Journal (Med J Aust 2004; 180: 20-23). As a result of a programming error, the confidence intervals in Box 3 of the article were incorrect. Box 3 should be as follows. 3: Reactions to antivenom and time from antivenom infusion to reaction Reaction Treatment A (n = 10) Treatment B (n = 21) Treatment C (n = 16) Mean time (min) Patients Mean time (min) Patients Mean time (min) Patients No. % (95% CI) No. % (95% CI) No. % (95% CI) Hypotension (< 120/80 mmHg) 43 5 33% (15%–58%) 26 8 38% (21%–59%) 22 9 56% (33%–77%) Tachycardia (> 80/min) 42 5 33% (15%–58%) 18 7 33% (17%–55%) 16 10 63% (39%–82%) Rigors 90 1 7% (1%–30%) 38 6 29% (14%–50%) 16 3 19% (7%–43%) Itching 25 10 67% (42%–85%) 16 10 48% (28%–68%) 13 10 63% (39%–82%) Urticaria 32 10 67% (42%–85%) 19 8 38% (21%–59%) 15 12 75% (51%–90%) Dyspnoea 15 2 13% (4%–38%) — 0 — — 16 5 31% (14%–56%) Treatments: A, hydrocortisone and placebo; B, hydrocortisone and chlorpheniramine; C, placebo and placebo. The html and pdf versions of the article appearing in the eMJA were corrected on 19 April 2004.

S Abeysingha M Kularatne MB BS, MD, MRCP(UK) · Indika B Gawarammana MB BS, MD

Simon G A Brown Emergency Physician, Fremantle Hospital & Health Service, and Clinical Senior Lecturer in Emergency Medicine, University of Western Australia, Department of Emergency Medicine, Fremantle Hospital, Alma Street, Fremantle, WA 6160. simon.brownAThealth.wa.gov.au To the Editor: Gawarammana et al present an interesting study of premedication to prevent adverse reactions to snake antivenom,1 but I have concerns with the data presentation and analysis. The 95% confidence intervals presented in Box 3 of their article are impossibly narrow. For example, recalculation of the first cell (hypotension rate for treatment A) by the binomial method gives a 95% confidence interval of 12%–62%, not 30%–36% as presented. Also, my analysis of the aggregate endpoint differs. Using the Fisher exact test to compare reaction rates in the hydrocortisone + antihistamine group (11/21) with placebo (13/16), for the difference in proportions of 0.29 I obtain a 95% confidence interval of 2 0.04 to 0.58. This has a P value of 0.14 using a 2-tailed test, according to the program Analyse-it.2 This comes as no surprise given that steroids take hours to work, and that histamine is just one of many mediators released during anaphylaxis, rising early and only transiently during severe and protracted anaphylactic reactions.3 Although antihistamines reverse the effects of histamine infusions which mimic anaphylaxis, animal studies indicate that they are ineffective for treating anaphylaxis mediated by mast-cell degranulation.4,5 Human studies have shown that H1 blockade is useful in preventing mild reactions to immunotherapy that are confined to the skin, but do not appear to prevent severe reactions.6,7 One human study has compared H1 + H2 blockade with H1-only blockade for the management of mild allergic reactions, finding a small benefit of combined H1 + H2 blockade.8 However, a confounder was that adrenaline was administered more frequently in the combined H1 + H2 antihistamine treatment group. A study of reactions to immunotherapy has failed to show any benefit from H1 + H2 blockade.7 I suspect that, instead of proceeding to study combination prophylaxis with antihistamines, steroids and adrenaline, it might be better to examine the preparation for and management of allergic reactions to antivenom. Many doctors fear intravenous adrenaline infusions, but in our experience this approach to managing anaphylaxis is safe, well tolerated and immediately effective, without the unpredictable, unpleasant, and (in the setting of venom-induced coagulopathy) potentially dangerous side effects sometimes seen with intramuscular, subcutaneous and intravenous bolus injections.9 Perhaps it is time for a trial of premedication with subcutaneous adrenaline versus an “as required” approach using a carefully titrated intravenous infusion.

Simon G A Brown

S Abeysingha M Kularatne,* Indika B Gawarammana† * Senior Lecturer, † Lecturer, Department of Medicine, Peradeniya University, Sri Lanka. samkulATsitnet.lk In reply: Brown has pointed out some interesting observations about antihistamines and mediators such as histamine, released during anaphylactic reactions. First, we must address the statistical issues. We are grateful to Brown for detecting an important error in Box 3 of our article.1 When we were asked to calculate confidence intervals for the percentages, we used a formula recommended by Spiegel.2 As this formula was not available in our software packages, we programmed it ourselves. We made an error in our programming and we apologise for this. (See Correction, page 428.) For the difference in reaction rates for the treatment regimens, we used the following calculation. The difference P1 – P2 = − 0.2887 To calculate the confidence interval, we calculated the standard error (SE) of the difference by the following formula. This interval does not include 0, so Brown’s P value of 0.14 is not reasonable. We do accept that the statistical significance is marginal. We agree that antihistamine is ineffective as a prophylactic agent in anaphylaxis. This was observed in studies in Sri Lanka and Brazil, where chlorpheniramine and promethazine, respectively, were used to prevent reactions to antivenom.3,4 However, we defended the observed reduction of mild to moderate acute reactions to antivenom in our study by highlighting the counter-effect of antihistamine on released histamine after mast-cell degranulation.1 Our study was to test the usefulness of an established practice in Sri Lanka, where steroid infusion is used to counter reactions to antivenom. The crux of the problem is the highly antigenic antivenom preparations used in Sri Lanka, despite ever-increasing reaction rates, because of the lack of facilities for developing purified antivenom. The proposal of using intravenous adrenaline infusion to reduce allergic reactions is novel and exciting. This should be tested by randomised controlled trials.

Indika B Gawarammana

Val J Gebski Principal Research Fellow, NHMRC Clinical Trials Centre, Level 5, Building MO5, Mallett Street Campus, University of Sydney, NSW 2006. valATctc.usyd.edu.au Comment: Kularatne and Gawarammana compared the proportion of side-effects given in their table above using the well-known (and easily understood) test of the difference between two proportions using the normal distribution. However, as each of these proportions follows a binomial distribution (13 “successes” out of 16 trials and 11 “successes” out of 21 trials), the normal approximation is only useful if the number of trials is greater than 30. Because of the small sample sizes, “exact” methods better reflect the true difference (in terms of P values and confidence intervals) between the two proportions. The more complicated methods (different formulations of the exact test) and the resulting confidence intervals provide a clearer indication of whether the proportions are indeed different (statistically). In this instance, the evidence is not sufficient to declare the two proportions statistically different.

Val J Gebski

Lyndon E Llewellyn,* Cedric E Robillot,† Andrew P Negri‡ * Principal Research Scientist, Bioactive Molecule Discovery; † Senior Research Specialist, Bioinnovation; ‡ Senior Research Scientist, Bioinnovation, Australian Institute of Marine Science, PMB 3, Townsville, QLD 4810. L. LlewellynATaims.gov.au To the Editor: Seafood is not only consumed as food, but also as dietary supplements and complementary medicines. Examples are capsules of freeze-dried oysters and mussels, or freeze-dried extract of shellfish meat, sold as reputed antihypertensives, cardioprotectants, and anti-inflammatories, among other medical claims. However, oysters and mussels can become dangerously toxic after they ingest poisonous microscopic algae. If these molluscs are sold as food in Australia, they are subject to the Food Standards Code,1 under which their sale is prohibited if biotoxin levels per kilogram of wet shellfish meat exceed 800 g of paralytic shellfish poisons, 200 mouse units of neurotoxic shellfish poisons, 200 g of diarrhoetic shellfish poisons, or 20 mg of amnesic shellfish poisons. Shellfish capsules can be simply manufactured by milling dried meat and encapsulating the powder, a process unlikely to degrade shellfish biotoxins, which are stable to heat, pressure and freeze-drying. 2,3 Such capsules may then become subject to regulation by the Australian Therapeutic Goods Administration (TGA), which distinguishes therapeutics from food, on the basis of whether there is a “tradition of use as a food in the form presented”, especially if there is an associated health claim. Such complementary medicines can be either “registered” or “listed”. Registered medicines require extensive safety, quality and efficacy data. Listed medicines are considered to pose a lower risk than registered medicines, and regulations allow product sponsors to “self-assess” products. Listing is a route commonly taken for complementary medicines. A pertinent example is the TGA listing of therapeutic goods containing dried green-lipped mussel (Perna canaliculus).4 Where manufacturers of shellfish capsules have undertaken the responsibility of ensuring product safety, they invariably adopt existing biotoxin testing protocols developed for food safety. However, as the allowable biotoxin level is based on wet weight, and the dry weight of bivalve shellfish is only 10%–15% of the wet weight,5 safety limits for shellfish meat as food are incorrect by an order of magnitude, and potentially more for capsules containing extracts of shellfish meat. While important for acute exposure to these toxins, this may be even more relevant in chronic exposure. Okadaic acid, the cause of diarrhoetic shellfish poisoning, is a tumour promoter,6 and epidemiological studies suggest that rates of cancer have increased in regions with regular dietary exposure to low levels of this toxin.7 Capsules are available that contain 500 mg of dried shellfish meat, which may equate to 5 g of wet shellfish meat.5 Unlike a shellfish meal, which may be considered equivalent to a single acute exposure, recommended doses for shellfish capsules can be as many as five capsules a day for many weeks, if not months, therefore magnifying the risk of chronic exposure. It is known that different classes of biotoxins can co-occur in shellfish, adding to the potential hazard outlined here.8 Further complications arise because some shellfish capsules include other natural extracts (such as ginseng) or pharmaceutical formulations that might affect toxin uptake. While this situation needs to be subjected to risk assessment, testing products in accordance with an inappropriate standard can make them seem safe when they might not be. This is especially so for products which are usually self-prescribed, and where patients can exceed recommended doses in the belief that more is better. For products such as shellfish capsules that straddle the food/therapeutic divide, it is better for manufacturers to test the final consumer product and not the raw supply.

Lyndon E Llewellyn · Cedric E Robillot · Andrew P Negri

Improving safety is important, but in many regions antivenoms are not available Although snakebite has been a subject of medical interest since antiquity, and despite it continuing to affect millions of people annually,1,2 it remains one of the neglected health problems of the tropics.1-3 Today, almost lost amidst the preoccupation with shortages of vaccines and antiretroviral medication in the developing world, there is a crisis in antivenom availability in the very same nations.3 In response, the World Health Organization recently held its first antivenom workshop in more than 20 years, to discuss the global supply and quality of antivenoms.4 However, perhaps more importantly, a growing community of physicians from the regions with the greatest snakebite burden have become more active in seeking solutions to at least some part of this ancient problem. The study by Gawarammana and colleagues in Sri Lanka (page 20) is one example of such scholarship.5 It is a welcome addition to the relatively scant clinical trial literature examining the management of snakebite. In a well conducted but underpowered study, the authors document a reduction in mild-to-moderate acute reactions to antivenom with an antihistamine bolus in conjunction with a hydrocortisone infusion. However, in the clinically important endpoints of moderate and severe reactions, there was insufficient power to confirm a trend toward fewer reactions in the hydrocortisone-containing regimens. This study is in contrast to a previous study from Brazil that failed to demonstrate any difference in early antivenom reactions with prophylactic promethazine alone.6 Most notable in this and an earlier Sri Lankan study,7 which assessed subcutaneous adrenaline as prophylaxis against acute antivenom reactions, was the extremely high rate of such reactions — in this study, almost half the patients had moderate or severe reactions sufficient to require adrenaline. This differs considerably from the rates in Australia (reported as 10% in the absence of premedication8 and 4.6% with premedication9). Snake antivenom is derived from antibodies of immunised animals; the rates of reactions appear to vary with the species of antibody origin, the extent of pepsin digestion, the presence of molecular aggregates and the total protein content of the product.4,10 It has been presumed that most acute reactions relate to the extent of complement activation from Fc receptor binding,10,11 with improvements in quality having largely resulted from enhancements in antivenom processing.4 However, the recent WHO workshop called for a re-examination of old assumptions concerning such reactions and, consequently, what constitutes “best practice” for antivenom manufacture and administration.4 Although Sutherland attributed the low reaction rate to Australian snake antivenoms to a series of refinements in the recommendations from the former Commonwealth Serum Laboratories concerning antivenom administration, including the practice of prophylactic use of adrenaline and hydrocortisone,9 current national reaction rates and associated clinical practice remain unclear.12 It is intended that recently introduced refinements to the Australian coding standards for ICD-10-AM (third edition)13 will assist in closing this gap in the national toxinology evidence base. However, because of the inherent delays in the collation of national statistics, and as current methods are far from complete,12 it would seem appropriate to mandate reporting of adverse antivenom reactions to facilitate appropriate follow-up. Such a system is in place in Brazil.14 Meanwhile, there is a dichotomy in current premedication recommendations for reducing acute reactions to snake antivenoms in Australia. In Australia’s toxinology textbook,15 Sutherland and Tibballs considered the evidence available up to 2001 and concluded that “premedication with subcutaneous adrenaline is recommended (0.25 mg for an adult, 0.005 mg/kg for a child) before antivenom therapy”. By contrast, a recent review by Currie concluded: “with the very low rate of severe reactions to antivenom seen in Australia . . . and the ability of emergency medicine physicians to adequately manage reactions that may occur, a policy of withholding premedication but always having adrenaline drawn up and ready is now recommended by many authorities and is policy in the Northern Territory”.16 In the middle is Australia’s antivenom manufacturer, CSL Limited: “Some authorities have advocated premedication with subcutaneous adrenaline and intravenous antihistamine, particularly in those patients who are known to be at risk, but such use is controversial”.17 Readers should consult the references for further details of the respective arguments and the history and evolution of the manufacturer’s recommendations.8,9 Although it is likely that well staffed major hospitals can, if it is recognised early, readily and rapidly manage antivenom reactions, such events can be severe, progressive and are not necessarily remediable.18 Therefore, it is the small rural centres, with more limited staffing and facilities, that may benefit most from the apparent efficacy of adrenaline premedication.7,9,15 If premedication is to be given, currently the best evidence is that it should be subcutaneous adrenaline.7 However, it is notable that Sutherland himself was agreeable to some “alternative but equally effective replacement for adrenaline”.9 And so we return to the search in Sri Lanka for such a replacement (or adjunct). The apparent benefit from the combination of an H1 antagonist and hydrocortisone described here suggests that a combination of H1 and H2 blockers may bring additional benefit, as has been proven for the treatment of acute allergic syndromes.19 However, the applicability of this study, in which a poor-quality antivenom resulted in extreme reaction rates, to the situation in Australia (where low reaction rates are reported) is uncertain. Interestingly, the antivenom used (the Haffine polyvalent snake antivenom) appears to be an equine Fab2 product,20 the same as that used in Australia.17 The Indian antivenom that was used in Sri Lanka, however, is a lyophilised preparation5, whereas the Australian antivenom is a liquid product. Therefore, aside from the premedication issue, there are clearly opportunities to improve the reaction rate by improved processing of this Indian product.4 Unfortunately, these debates are irrelevant for most people affected by snakebite, predominantly in the rural tropics. For example, in Papua New Guinea the high cost of Australian antivenoms puts adequate supplies beyond the reach of the health budget.2 For people in countries where the available antivenoms are of poorer quality, studies such as these, even if they only demonstrate reductions in reaction rates from 80% to 50%, are applauded; more are sorely needed. But for most countries where antivenoms are unavailable or unaffordable, there is little to do but measure smoke from the burning house while praying for rain.

Allen C Cheng MB BS, FRACP, GradDipClinEpid · Ken D Winkel BMedSci, PhD, FACTM

Objective: To investigate the efficacy of continuous infusion of hydrocortisone with or without chlorpheniramine bolus against early adverse reactions to polyspecific antivenom.Design and setting: Prospective, double-blind, randomised, placebo-controlled trial at General Hospital, Anuradhapura, Sri Lanka.Subjects: 52 patients with snake envenoming were randomised to receive infusion of hydrocortisone (Group A), hydrocortisone with chlorpheniramine bolus (Group B) or placebo (Group C) during the administration of antivenom.Intervention: Hydrocortisone 1000 mg in 300 mL of normal saline infusion was started 5 min before and continued for 30 min after antivenom. Chlorpheniramine 10 mg intravenous bolus dose was given 5 min after commencement of antivenom.Main outcome measures: Occurrence and severity of adverse reactions to antivenom.Results: Adverse reactions were observed in 80% (12/15) of Group A, 52% (11/21) of Group B, and 81% (13/16) of Group C. Reactions were mild or moderate except in two patients. A significant reduction in the number of adverse reactions was seen in Group B compared with the placebo group (difference, 29 percentage points; 95% CI, 0.2 to 58 percentage points). There was no significant difference between Group A and the placebo group.Conclusion: Prophylaxis with a parallel hydrocortisone infusion alone is ineffective in reducing the occurrence of acute adverse reaction to antivenom serum, but combining it with chlorpheniramine seems efficacious.

Indika Bandara Gawarammana MB BS · S Abeysingha M Kularatne MB BS, MD, FRCP(UK) · Ranjith P V Kumarasiri MB BS, MSc, MD · Nimal Senanayake PhD, DSc, FRCP · Wasantha P Dissanayake MB BS, DCH, MD · H Ariyasena MB BS, MD, MRCP

Necrotising arachnidism should be a diagnosis of last resort The article by Isbister and Gray (page 199),1 documenting 130 confirmed cases of bites by white-tail spiders, will, we hope, become one of the last acts in a prolonged and sad medical fable in Australia, regrettably now exported beyond our shores.2 In 1982, a paper on possible spider bite necrosis in Australia was presented at the International Society on Toxinology World Congress in Brisbane,3 and followed by an editorial in the MJA in 1983.4 In 1987, Spring reported a case of severe skin damage following a presumed spider bite;5 the article and the associated editorial6 mentioned the white-tail spider. Speculation about the causative spider continued, with two “likely” candidates charged with the crime by the non-medical media,7 supported by a few in the medical community. These spiders were the wolf spider and the white-tail spider. The former was suspected partly because of evidence from Brazil, subsequently debunked, implicating these spiders in causing skin necrosis. The actual cause in Brazil has since been shown to be recluse spiders (loxoscelism).8 However, it was the white-tail spider, Lampona cylindrata, that was the principal focus of attention. Within a short time, at least a few doctors were diagnosing necrotising arachnidism caused by these spiders, and within about five years the popular association of these spiders with skin necrosis was well established. The lack of strong evidence to support this association seemed to be a triviality to be ignored. Research projects were proposed and funded to examine white-tail spider venom to understand its necrotic potential. Calls were made for governments to fund development of an antivenom. General practitioners regularly and confidently diagnosed skin lesions as “white-tail spider bite”. A few voices called “foul”. Where was the evidence to support the veracity of this new venomous scourge of urban Australia? Some confirmed bites by white-tail spiders were published, with no evidence of skin damage.9 Early research on the venom found no necrotic activity.10 The spider is native to Australia, yet most people ignored questions about the absence of cases of necrotising arachnidism in the 200 years before Spring’s article. Arachnologists questioning the validity of white-tail spider bite necrosis were also dismissed. In both the general and the medical community, the era of “white-tail spider bite necrosis” had arrived. But the evidence cast ever stronger doubt about the veracity of white-tail spider bite necrosis, despite occasional published “cases”. What was needed was a large number of cases of confirmed white-tail spider bite to clearly show the true range of its effects. Isbister and Gray’s article defines a clear and consistent pattern of clinical effects, based on a large series, with no evidence of necrosis. As the authors point out, the inappropriate diagnosis of spider bite in cases of skin damage is not isolated to Australia or the white-tail spider, but our episode is particularly disturbing, because there was never any strong evidence to link this spider with necrosis. Publication of Isbister and Gray’s article should herald the demise of the spurious diagnosis of white-tail spider bite necrosis. This will, we hope, bring an end to conditions such as basal cell carcinoma being misdiagnosed as spider bite, and to cases of feigned white-tail spider bite necrosis (where the patient inflicts skin damage with chemicals, then claims a spider bite). This does not mean spider bite never causes necrosis. Recluse spiders have clearly been shown to cause necrosis in some parts of the world, including two cases in Australia,11 where the spiders have been introduced. However, there is no evidence recluse spiders are widespread in Australia, and it would be erroneous to now label skin damage of uncertain origin as “loxoscelism” instead of “white-tail spider bite”. When presented with skin damage of initially uncertain origin, medical practitioners must look for all the many and varied non-spider-bite causes for such damage, leaving necrotising arachnidism as a diagnosis of last resort and uncertain validity after all other possibilities are excluded. Any future research into necrotising arachnidism in Australia should focus on accurately determining the cause.

Julian White MB BS, MD, FACTM

Corrine R Balit,* Geoffrey K Isbister,† Andrew H Dawson,‡ Frank F Daly,§ Ian M Whyte‡ * Research Pharmacist, NSW Poisons Information Centre, The Children's Hospital, Locked Bag 4001, Westmead, NSW 2145; † Lecturer and Clinical Toxicologist, ‡ Associate Professor, Newcastle Mater Misericordiae Hospital and the University of Newcastle, Newcastle, NSW; § Clinical Toxicologist, Royal Perth Hospital and University of Western Australia, Perth, WA. corrinebalitATaol.com To the Editor: Paracetamol availability is an important public health issue. Kisely et al have further investigated the impact of two paracetamol recall periods on analgesic poisoning using a dataset derived from hospital admissions.1 We are concerned about the robustness of data that uses ICD codes, because of significant coding problems that occur with poisoning admissions. The aim of their study was as a follow-up to our own,2 to look at the impact of removing paracetamol tablets from the shelf during a recall period. Availability is reported to be the most common reason for patients choosing to take paracetamol in overdose3 and, as such, has the potential to affect acute deliberate self-poisoning. However, Kisely et al recognised that it was difficult for them to distinguish between intentional and unintentional ingestions because of the limitations of their dataset1 and hence they considered both of these together. This is inappropriate if the aim is to assess the effect of availability on paracetamol deliberate self-poisoning. For example, there is no evidence that presentations with therapeutic errors in dosing are related to availability and these should be excluded. This is not possible by using ICD codes and was therefore not done by Kisely et al.1 In addition, it is only relevant to include accidental ingestions of tablet formulations of paracetamol, because only these were affected by the recall. There are significant numbers of presentations of children, who accidentally ingest liquid formulations of paracetamol (hence not related to the recall period), that are coded as paracetamol admissions. This introduces a further significant potential bias in the Kisely study. A more concerning problem is the reliability of ICD coding in separating out different analgesics. Poisoning with prescription products such as paracetamol-codeine combination analgesics, which were not affected by the recall period, are also likely to be included in the study being coded as T39.1 (paracetamol overdoses).1 There are significant limitations in using ICD codes, resulting in the dataset analysed not being a true reflection of the impact of the recall of paracetamol tablets. Our study took into account only tablet formulations of the paracetamol alone compounds.2 Paracetamol ingestions following therapeutic error were excluded and accidental ingestions of only tablet formulations were included. While the numbers in the study were small for the hospital presentations, the data set for the NSW Poisons Information Centre was much larger and showed significant increases in intentional and accidental ingestions of ibuprofen, the next most available analgesic.2 In an environment where paracetamol restriction is a hotly debated topic, particularly in light of recent coroners’ cases, it is vital to consider the impact of paracetamol restriction on all types of deliberate self-poisoning by using an appropriate dataset that reflects the measures taken to reduce availability. The challenge for state and federal health departments is to fund appropriate postmarketing toxicovigilance for accidental and intentional self-poisoning in order to clarify these important public health issues.

Corrine R Balit · Geoffrey K Isbister · Andrew H Dawson · Frank F Daly · Ian M Whyte

Elizabeth A Hender,* Jeremy Raftos† * Scientific Officer, Hazardous Substances Section, Department of Human Services, PO Box 6, Rundle Mall, Adelaide, SA 5000; † Director, Paediatric Emergency Department, Women’s and Children’s Hospital, Adelaide, SA. Elizabeth. HenderATdhs.sa.gov.au To the Editor: We read with interest the study of Kisely et al,1 which showed a decrease in admissions for poisoning with paracetamol, but no coincident increase in use of other agents, as a result of the paracetamol recalls. We had noticed there was an unusually high number of presentations (18) to the Paediatric Emergency Department at the Women’s and Children’s Hospital, Adelaide (WCH), for poisoning with aspirin in 2000, compared with one presentation in 2001 and one in 2002. We wondered if the presentations in 2000 were temporally associated with the paracetamol recalls. We extracted all WCH presentations with a primary diagnosis of paracetamol poisoning (ICD-9 code 965.4), aspirin poisoning (965.1), nonsteroidal anti-inflammatory drugs (965.6) and poisoning with all other drugs (960–979.9) for the two recall periods (16 March 2000 to 21 May 2000; 6 June 2000 to 23 August 2000)2 and the same periods in 2001 and 2002. It could not be determined whether an over-the-counter preparation of a nonsteroidal anti-inflammatory drug had been taken. The results are shown in the Box. Presentations (P) and admissions (A) for poisoning with paracetamol, aspirin, NSAIDs and other drugs at the Women’s and Children’s Hospital, Adelaide 2000 restricted 2001 available 2002 available P A P A P A Aspirin 15 13 1 0 0 0 Paracetamol 23 6 34 13 34 14 NSAID 3 1 0 0 1 0 Other drugs 86 43 89 35 60 23 NSAID = non-steroidal anti-inflammatory drug. These data show that the number of paracetamol poisoning presentations and admissions was lower during the recalls than in the same period in subsequent years, but there was a higher number of presentations and admissions for poisoning with aspirin. All the aspirin poisoning presentations and admissions during the period when paracetamol was recalled were during the second recall (affecting SmithKline Beecham products). The other three aspirin poisoning presentations in 2000 occurred within 10 days of the end of the second recall. All but one of the 18 patients with aspirin poisoning who presented during 2000 were adolescents (17 females). Most of these exposures were likely to be due to intentional self-poisoning. Although it is not possible to reach any definite conclusion from these observations, we share the concerns of Balit et al2 that limiting the availability of paracetamol could result in an increase in poisonings with potentially more acutely dangerous agents such as aspirin, particularly for adolescents. There needs to be further consideration of the motivation of patients in choosing paracetamol and the source of the drug when taken for intentional self-poisoning before measures are taken to restrict access to paracetamol.

Elizabeth A Hender · Jeremy Raftos

Stephen R Kisely,* David Lawrence,† Neil J Preston‡ * Professor of Health Outcomes, Department of Psychiatry, Dalhousie University, Canada; † Post-doctoral Fellow, Institute for Child Health Research, Perth, WA; ‡ Research Psychologist, Fremantle Hospital and Health Service, Fremantle, WA. stephen.kiselyATcdha.nshealth.ca In reply: Balit et al raise the problem of distinguishing between intentional and unintentional ingestions. As stated in our article, we did look at deliberate and accidental poisonings separately, but space restrictions, not limitations of our dataset, prevented us from presenting the results.1 Of 2266 paracetamol poisonings, 1731 (76%) were coded as deliberate, 433 (19%) were accidental and in 103 (4.5%) the intention could not be determined. Restricting the analysis to the deliberate cases yields almost identical results. Our dataset may have contained poisonings with liquid or combination formulations of paracetamol that were not recalled. This factor would have operated before, during and after the recall and would only serve to reduce the magnitude of any effect, rather than accentuating it. We considered 2663 admissions for over-the-counter analgesic poisoning,1 as opposed to 143 in the NSW study.2 We did not look at telephone calls, as reliance on data from calls to a poisons information centre raises far more concerns about data quality than hospital statistics do. How reliable was the informant? How serious was the poisoning? Do telephone data contain less serious cases that do not require admission? Hender et al report the findings of an observational study restricted to a single paediatric emergency department attached to the Women’s and Children’s Hospital, Adelaide. Unfortunately, data for only three years are presented, with no information for the years before the recall. Neither do we know how many were intentional or unintentional. By definition, their data exclude adults. As they state themselves, it is not possible to reach any definite conclusions from their observations. We should not prematurely dismiss the possible benefits of restrictions on the availability of paracetamol. If there are concerns that restricting the availability of paracetamol might increase the use of other over-the-counter analgesics in poisonings, we should be investigating the effectiveness of restrictions on the availability of these as well. Who precisely benefits from continued sales of over-the-counter analgesics in catering pack sizes?

Stephen R Kisely · David Lawrence · Neil J Preston

We report a 44-year-old Western Australian man who suffered a cardiac arrest several hours after a bite by a brown snake. He was successfully resuscitated after bolus administration of undiluted brown snake antivenom. We suggest that an initial bolus dose of at least five ampoules (5000 units) of undiluted brown snake antivenom should be given as primary therapy for cardiac arrest following brown snake envenomation in Western Australia. (MJA 2002; 177: 646-649) Brown snakes are the leading cause of both snakebites and snakebite fatalities in Australia.1,2 The characteristic feature of significant envenomation by brown snakes is defibrination coagulopathy caused by potent procoagulants in the venom. However, the cause of cardiac arrest after this envenomation is unclear. One hypothesis, derived from animal models, is that early massive thrombosis results in collapse, cardiac arrest and death. The brief thrombotic phase of envenomation occurs before the development of defibrination. It is hypothesised that coronary vessels become temporarily occluded, resulting in hypotension, collapse and cardiac arrest.3,4 We report a patient who was successfully resuscitated after cardiac arrest following brown snake envenomation. The clinical and laboratory evidence appears to support the above hypothesis. Western brown snake (Pseudonaja nuchalis). Illustration copyright Dr Julian White, Head of Toxinology, Women's and Children's Hospital, North Adelaide, SA (Clinical toxinology resources <www.toxinology.com>) Clinical recordA 44-year-old man found a snake (later identified as Pseudonaja nuchalis, also known as a gwardar) in his house in Toodyay (85 km east of Perth). He attempted to catch it and was bitten on the middle finger of the left hand. He was alone and placed a single compression bandage on his left upper limb extending from the fingers to the elbow. He then drove to his general practitioner, a journey of 15 km, taking about 10 minutes. The GP observed no symptoms or signs of envenomation and referred the patient to Royal Perth Hospital by ambulance. In transit, several minutes from Swan District Hospital, the patient complained of feeling unwell with chest tightness, and rapidly became unresponsive. It was decided to seek medical attention at Swan District Hospital. 02:15 hours after the bite: On arrival at the hospital, the patient was in a tonic–clonic state and unresponsive. Electrocardiography (ECG) revealed a narrow complex rhythm with no cardiac output (ie, pulseless electrical activity). Standard advanced life support measures were commenced, including cardiopulmonary resuscitation, intubation, and administration of two 0.5 mg doses of adrenalin and one litre of normal saline. In addition, undiluted snake antivenom was given as an intravenous bolus, comprising one ampoule of polyvalent antivenom and two ampoules each of brown snake antivenom (2000 units) and tiger snake antivenom (6000 units). The situation was discussed with the on-call toxicologist at the local poisons information centre. Once further antivenom supplies were obtained, another ampoule of polyvalent antivenom and three ampoules of brown snake antivenom (3000 units) were administered. Spontaneous circulation resumed within one minute of administration of these three ampoules. Total cardiopulmonary resuscitation time was 11 minutes. When the patient's condition was stabilised, he was transferred to Royal Perth Hospital. En route, the first signs of coagulopathy appeared, with bleeding lips and gingivae (Box 1). Results of laboratory investigations are shown in Box 2. 03:10 hours after the bite: On arrival at Royal Perth Hospital, the patient's heart rate was 105 bpm, blood pressure was 135/60 mm Hg, and pupils were equal at 4 mm diameter and briskly reactive. Examination revealed bleeding gingivae and nose, suffusion petechiae around the eyes, oozing from venepuncture sites, and rosé-coloured urine. ECG findings are shown in Box 3. Initial management involved reinforcing the compression bandage and extending it to include the whole of the left upper limb, and infusion of 10 ampoules of brown snake antivenom in 100 mL 0.9% saline over 15 minutes. Following this infusion, no further oozing of blood was noted. The compression bandage was then removed. The patient's clinical condition remained stable. Cranial computed tomography revealed no evidence of intracranial haemorrhage, nor early evidence of arterial thrombosis or ischaemia. 05:00 hours after the bite: The patient was transferred to the intensive care unit, where his condition remained stable. Repeat coagulation studies at 05:53 hours after the bite revealed a plasma fibrinogen level still below 0.3 g/L (Box 2). A further five ampoules of brown snake antivenom were infused. 11:38 hours after the bite: Coagulation studies demonstrated the return of measurable clotting activity, with a fibrinogen titre < 0.3 g/L, but an international normalised ratio (INR) of 2.7, and an activated partial thromboplastin time (APTT) of 64.4 s. No further antivenom was given. 14:49 hours after the bite: Repeat coagulation studies revealed a rising fibrinogen titre of 0.5 g/L, INR of 1.8, and an APTT of 44.7 s. The patient was subsequently extubated, neurologically normal. No additional blood products, such as fresh frozen plasma or cryoprecipitate, were administered at any stage. In view of the high antivenom load given to the patient and the consequent risk of serum sickness, the patient was commenced on a five-day course of oral prednisone (50 mg/day). Day 2: The patient was transferred to the cardiology unit for investigation of the chest pain, collapse and subsequent rise in plasma troponin I level. He had no risk factors or previous history of cardiac disease, and experienced no further episodes of chest pain. An angiogram four days after envenomation revealed normal left ventricular function and normal coronary arteries. There were no abnormal neurological findings, and he was discharged after the angiogram. At follow-up a month later: The patient was well but reported a mild flu-like illness with rash and sore joints between days 17 and 21 after envenomation. DiscussionDeaths after brown snake envenomation tend to be either early (within hours) or delayed (days after the bite). Early deaths have been thought to result from a primary cardiotoxic effect, anaphylaxis, or early massive thrombosis.3,4 Delayed deaths appear to result from secondary complications, such as intracranial haemorrhage.5,6 Our patient described chest tightness immediately before his sudden collapse, and the post-resuscitation ECG was non-specific, possibly consistent with diffuse myocardial ischaemia. These changes could be associated with short-lived coronary vessel occlusion by thrombi generated by venom procoagulants.3,4 The rise in serum troponin I level was consistent with the effects of cardiopulmonary resuscitation, but could also represent ischaemic injury to the myocardium.7 An in-vitro study showed that the venoms of three Pseudonaja spp. have strong coagulant activity.8 There is strong prothrombin activator activity (Factor Xa-like) converting prothrombin to thrombin, with no dependence on Factor V and little dependence on calcium and phospholipid. Intravenous injection of venom in dogs showed the potential for early thrombosis, resulting in hypotension, cardiac arrest and death.3,4 There have been previous reports of survival of patients in extremis after brown snake envenomation. In 1975, Sutherland described a 42-year-old woman who suddenly collapsed about 20 minutes after envenomation. She was said to be pulseless, but her condition improved within 30 seconds of receiving antivenom.9 In another report, a 52-year-old man became unconscious within 15 minutes of a bite by Pseudonaja textilis. He received 1000 units of brown snake antivenom intravenously 30 minutes after the bite, and his condition stabilised.10 However, in neither case did the patient require external cardiac compression or advanced life support measures, such as intubation and adrenalin. We believe that the more severe nature of our patient's condition makes this case notable. Antivenom dosing is controversial and to some extent arbitrary. However, as a result of this case, we propose that cardiac arrest due to massive brown snake envenomation in Western Australia should be treated with an initial minimum bolus of at least five ampoules (5000 units) of undiluted brown snake antivenom. This contrasts with the usual slow infusion of diluted antivenom. Even higher doses of antivenom may be required. A study in dogs found that the dose required to prevent cardiovascular depression and coagulopathy induced by P. textilis was 25 times the current recommended dose for clinical use.11 Other authors have also stated that the necessary dose of antivenom may be greater than current recommendations.5 In addition, the venom of the western brown snake (P. nuchalis, or gwardar) may be more potent than that of the eastern brown snake (P. textilis),12 while antivenom raised against P. textilis may be less effective in neutralising the venom components of Western Australia's P. nuchalis.13 It should be noted that antivenom is an increasingly scarce resource, and that stocks in many hospitals are limited. Some clinicians might have considered administering adjuvant therapies, such as fresh frozen plasma, to our patient. However, our approach was consistent with the guidelines of the antivenom manufacturer, which state that fresh frozen plasma "is usually not needed and is contraindicated until all circulating venom has been neutralised with adequate antivenom, except if there is severe, life threatening haemorrhage".14 Our patient had acceptable INR and APTT readings within two hours of the last antivenom dose, and his fibrinogen level had returned to levels associated with haemostasis within five hours. He remained clinically stable, with no evidence of active haemorrhage.15 During the initial resuscitation, we chose a smaller than standard dose of adrenalin (0.5 mg v 1 mg) to avoid further increasing the risk of intracranial haemorrhage.6 As the cardiac arrest was witnessed, with only a short interval before resuscitation began, and as the cause was known, it was decided that a lower dose would provide the optimum balance between benefit and risk. Our patient also illustrates the need to emphasise the public health message for the community — early application of appropriate first aid is effective in brown snake envenomation.16 Correct first aid comprises pressure immobilisation bandaging of the entire limb, keeping the patient still, splinting the limb and seeking medical attention. In many fatal cases, there has been a failure to apply correct first aid.17 Despite the development of antivenom, pressure immobilisation bandages and venom detection kits, brown snake envenomation still causes deaths, so consultation with an expert is always appropriate. 1: Coagulopathy after brown snake envenomation The first signs of coagulopathy were bleeding lips and gingivae, which became apparent three hours after the snakebite. 2: Results of laboratory investigations in a 44-year-old man with brown snake envenomation Hours after bite Platelets (x 109/L) INR APTT (s) Plasma fibrinogen (g/L) Fibrinogen degradation products (μg/mL) Serum creatinine (μmol/L) ALT (U/L) Creatine kinase (U/L) Troponin I (μg/L) Reference range 150–400 0.9–1.3 29.5–40.5 2.1–4.0 < 0.4 60–105 < 41 < 190 < 0.10 02:15 33 > 10 > 180 < 0.3 > 20 108 113 143 < 0.4 Treatment with 2 ampoules of polyvalent, 5 of brown snake and 2 of tiger snake antivenom 03:40 111 > 10 > 180 < 0.3 > 20 131 201 164 < 0.4 Treatment with 10 ampoules of brown snake antivenom* 05:53 214 > 10 > 180 < 0.3 > 20 133 277 259 2.8 Treatment with 5 ampoules of brown snake antivenom (infusion completed at 09:30) 09:34 161 > 10 > 180 < 0.3 > 20 127 243 366 10.4 11:38 167 2.7 64.4 < 0.3 131 238 14:49 148 1.8 44.7 0.5 > 20 134 223 462 6.8 20 133 1.3 38.4 1 > 20 123 197 518 4.8 45 129 1.1 30.6 2.7 119 148 381 93 151 1 31.4 3 98 77 INR = international normalised ratio. APTT = activated partial thromboplastin time. ALT = alanine transaminase. * Results of Venom Detection Kit testing of the bite site taken at 03:24 hours after the bite were strongly positive for brown snake venom. 3: Electrocardiogram after brown snake envenomation Electrocardiogram 03:10 hours after the snakebite revealed sinus tachycardia, with a mild intraventricular conduction disturbance with a (pre-existing) right bundle branch block pattern (A), and mild generalised ST-segment depression (B).

Michelle A Johnston FACEM · Daniel M Fatovich FACEM · Andrew D Haig FACEM · Frank F S Daly FACEM

Puffer fish poisoning has been documented rarely in Australia. It results from ingesting tetrodoxtoxin found in the liver, ovaries, intestines and skin of the fish. Over a recent 16-month period, 11 cases of puffer fish poisoning were reported to the NSW Poisons Information Centre. Symptoms of poisoning may include paralysis, respiratory failure, numbness, paraesthesia, nausea and ataxia. Health professionals should be aware of the condition so as to institute early and appropriate management. (MJA 2002; 177: 650-653) Tetrodotoxin (TTX) is present in high concentrations in the liver, ovaries, intestines and skin of puffer fish (Box 1).1 Although TTX poisoning caused by ingestion of the fish is common in some parts of the world, it occurs only sporadically in Australia, with only 16 published cases reported over the past 200 years.2-7 (This figure does not include the 11 cases described here.) One of the earliest descriptions of puffer fish poisoning in this region can be found in Captain James Cook's journal from his second voyage in 1774 (see Time Capsule, page 653).3 The majority of reported cases have occurred in southeastern Asia,1,8-10 particularly Japan, where puffer fish is considered a delicacy.1,11 Although improved legislation governing marketing and preparation of the fish has reduced the incidence of puffer fish poisoning in Japan, it remains the most common cause of fatal food poisoning, as there are still some unlicensed cooks and untrained workers involved in preparing the fish.1,11 Before 1950, all reported cases in Australia were fatal,5 and in Japan up to 100 deaths a year were reported.11 We describe 11 patients with puffer fish poisoning, four of whom underwent comprehensive neurophysiological testing. Clinical findingsFor the period 1 January 2001 to 13 April 2002, records of 149 453 calls to the NSW Poisons Information Centre were searched for instances of puffer fish poisoning. The Centre covers New South Wales and Tasmania 24 hours a day and the rest of Australia overnight. Of 195 calls coded as food or fish poisoning, there were five calls regarding puffer fish. Two were minor cases involving people who had been squirted with fluid from puffer fish. The three remaining calls were from hospitals: a total of 11 affected people (described here) were involved. Patient 1A 33-year-old woman presented to a semi-rural hospital with nausea and vomiting, perioral paraesthesia, dysarthria, ataxia and hyperventilation after ingesting seven puffer fish several hours earlier (see Box 1). Her vital signs were stable and the FEV1 (forced expiratory volume in one second) was 2.2 litres (normal range, 3.3–4.0 L). However, an hour after presentation she became more dysarthric and developed limb paresis with hyporeflexia. In view of progressive lethargy, dyspnoea and a fall in FEV1 to 1.5 L, she was intubated and ventilated, then transferred to the intensive care unit of a metropolitan teaching hospital. On arrival, the patient was haemodynamically stable but her pupils were dilated and non-reactive to light. Investigations, including a lumbar puncture and cranial computed tomography scan, were normal. With a presumptive diagnosis of tetrodotoxin poisoning, the patient was managed with supportive care. Over the next two days, her condition improved, deep tendon and pupillary reflexes returned, and she was extubated on Day 2. The other symptoms gradually resolved, and she was discharged on Day 5 after full neurological recovery. Patient 2A 40-year-old man presented to a metropolitan teaching hospital (see Box 2). He stated that he had eaten 10 small toadfish eight hours earlier, together with drinking a significant quantity of alcohol. Following ingestion of the toadfish he had collapsed a number of times and felt tingling of his hands and feet and around his mouth. With each collapse, he experienced generalised weakness, but did not lose consciousness. He had no relevant past medical history. On examination he was afebrile, with a pulse rate of 110 beats/minute, blood pressure of 140/80 mmHg, respiratory rate of 16 breaths/minute and oxygen saturation of 96%. A neurological examination was entirely normal. After uneventful overnight observation, he was discharged. Patients 3–11Seven adults and two children ate a soup made from about 30 puffer fish, gutted with heads intact and boiled in fresh water. The cook referred to the fish as puffer fish, and one of us (J U) identified one of the fish as a puffer fish. All nine patients had been previously well, not taking medication, and with no known allergies. The patients' clinical features are shown in Box 2. One child was completely asymptomatic, and the other had mild symptoms of perioral numbness and dysaesthesia of the extremities for five hours. Both were discharged from the emergency department. Most of the seven adults presented to hospital with nausea, perioral and lingual numbness, dysaesthesia of the extremities, dizziness and gait ataxia. Several patients had vomiting and one was experiencing respiratory distress. Neurological examination revealed marked ataxia in all seven patients and limb weakness in two patients (more marked in the upper than lower limbs). One patient had decreased sensation in the hands and feet. Most symptoms resolved over 48 hours, but slight weakness and ataxia of the lower limbs remained. These resolved completely over the following week. Neurophysiological investigation was undertaken in four of the adult patients (see Box 3) within 24 hours of ingestion. DiscussionAlthough puffer fish poisoning is rare in Australia, our report highlights the seriousness of TTX poisoning and its potential to be life-threatening.11 However, early recognition of the condition and supportive care in a modern intensive care unit should ensure a safe outcome. The clinical effects of TTX poisoning have been graded by the severity of neurological and cardiovascular involvement (Box 2).11 In this series, one patient had Grade 3 poisoning, and most others Grade 2 poisoning. Most of the patients exhibited typical neurological features, including perioral numbness and/or paraesthesia, distal limb numbness/paraesthesia and ataxia — symptoms similar to those seen in previous case series.1-10 Gastrointestinal features were also typical, with nausea, occasional vomiting, but no diarrhoea. Cardiovascular effects (not present in this series) occur only in the most severe (Grade 4) cases. The onset of symptoms in TTX poisoning is usually rapid, but is dependent on the severity of poisoning. In the moderately severe cases in this series, symptoms had all occurred within 90 minutes. In reported fatal cases and severe poisoning, symptoms have almost always developed within 1–2 hours.10 The majority of moderate to severe cases in this series resolved within five days, consistent with previous reports,3,6 although this also depends on the severity. In minor cases the duration of symptoms may only be a few hours. The relatively mild symptoms experienced by patients 3–11 probably reflect the relatively low dose of TTX ingested. TTX is present in high concentrations in the viscera of puffer fish, particularly the liver and intestines (Box 4). These organs were removed before cooking the fish soup, and the amount of TTX was subsequently diluted by adding fresh water to the soup and possibly by subsequent boiling. With higher levels of TTX, paralysis and respiratory failure are inevitable, although consciousness is not lost except in extreme cases (Box 2). Of interest, such a process has been implicated in the phenomenon of "zombification" in Haiti.22,23 Nerve conduction studies revealed clear abnormalities. Nerves in the patients tested were of high threshold, and exhibited slow conduction and reduced-amplitude compound potentials, indicating that some axons were unable to conduct at all. This effect was greater in sensory than motor axons, correlating well with the greater prominence of sensory symptoms (dysaesthesiae and numbness) relative to motor symptoms (weakness) in these patients. Voltage-dependent Na+ channels underlie action potential generation and are the chief determinants of membrane excitability in human nerves.24,25 Tetrodotoxin blocks Na+ channels at very low concentrations, affecting action potential generation and impulse conduction. It is important that health professionals are aware of TTX poisoning because of the potential for severe and life-threatening effects. All but the mildest cases (Grade 1) should be admitted to hospital for observation until the peak of the clinical effects has passed. After 24 hours it is extremely unlikely that life-threatening effects will occur in patients who have not already developed severe effects. Early diagnosis by recognition of the combination of clinical effects in people ingesting puffer fish is essential to management. 1: The common toadfish (Tetractenos hamiltoni) The fish pictured here is approximately 10 cm in length. Photo courtesy of Erik Schlogl. 2: Description of 11 patients presenting with puffer fish poisoning Patient Sex, age Onset (minutes) Gastrointestinal features Neurological features Duration of symptoms Severity grade* 1 F, 33 NR Nausea, vomiting Perioral paraesthesia, dysarthria, ataxia, limb weakness, hyporeflexia and ophthalmoplegia. Decreased FEV1, with respiratory failure. 5 days 3 2 M, 40 60 Nil Perioral and extremity paraesthesia, dizziness. 18 hours 2 3 F, 5 NA Nil Nil. NA NA 4 F, 12 NR Nil Perioral and extremity paraesthesia. < 6 hours 2 5† M, 33 30 Nausea, vomiting Perioral and lingual numbness, dysaesthesia of extremities, dizziness and gait ataxia. 5 days 2 6† F, 47 NR Nausea, vomiting Perioral and extremity paraesthesia, dizziness and gait ataxia. 5 days 2 7 M, 39 60 Vomiting Perioral and lingual numbness, dysaesthesia of extremities, dizziness and gait ataxia. Mildly reduced power in upper and lower limbs. 5 days 2 8† M, 41 60 Nil Perioral numbness, dysaesthesia of extremities, dizziness and gait ataxia. Decreased sensation in hands and feet ("glove-and-stocking" distribution). 5 days 2 9 F, 35 60 Vomiting; simultaneous incomplete miscarriage Perioral and lingual numbness, dysaesthesia of extremities, slight dizziness and gait ataxia. Normal power and sensation. Respiratory distress. 5 days 2 10† M, 47 30 Nausea Perioral and lingual numbness, dysaesthesia of extremities, dizziness and gait ataxia. Mildly reduced power in upper and lower limbs. 5 days 2 11 M, 50 90 Nausea Perioral numbness, dizziness and gait ataxia. Normal power and sensation. 5 days 2 NA = not applicable. NR = not recorded. * Clinical grading system for tetrodotoxin poisoning based on symptoms and signs present (after Fukuda and Tani12): Grade 1: perioral numbness and paraesthesia, with or without gastrointestinal symptoms (mainly nausea). Grade 2: numbness of tongue, face and other areas (distal); early motor paralysis and incoordination; slurred speech; normal reflexes. Grade 3: generalised flaccid paralysis, respiratory failure (dyspnoea), aphonia and fixed/dilated pupils; patient still conscious. Grade 4: severe respiratory failure and hypoxia; hypotension, bradycardia and cardiac dysrhythmias; unconsciousness may occur. † Neurophysiological testing was done on these patients (see Box 3). 3: Neurophysiological investigation of patients with puffer fish poisoning Neurophysiological investigation* was performed in four adult patients (numbered 5, 6, 8 and 10 in Box 2) within 24 hours of puffer fish ingestion. None of the patients studied had a history of medical conditions known to affect nerve function, and none were taking any regular prescribed medication. Results of motor (Figures A1–A3) and sensory (Figures B1–B3) nerve conduction studies of the median nerve in patients with puffer fish poisoning and control subjects are compared. (Results are expressed as mean ± standard error of the mean and compared using an unpaired two-tailed t-test.) Stimulus–response curves showed that the stimulus current (threshold) required to generate compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) was significantly higher in patients with puffer fish poisoning than control subjects, suggesting an overall reduction in axonal membrane excitability (Figures A1, B1).13 Compound potentials were smaller in amplitude (Figures A2, B2) and of longer latency (Figures A3, B3) in affected patients compared with controls. These parameters are dependent on Na+ channel function and suggest reduction both in the number of conducting axons and in the conduction velocity of those axons still available for impulse transmission. Overall, these findings indicate a reduction in Na+ conductance in the nerves of affected patients, consistent with direct blockade of axonal Na+ channels by tetrodotoxin. *Method: Motor and sensory nerve conduction studies of the median nerve were performed using surface electrodes. Results were compared with established normative data using previously described standard techniques.14,15 The median nerve was stimulated at the wrist, with the evoked orthodromic compound muscle action potential (CMAP) recorded from thenar muscles and antidromic sensory nerve action potential (SNAP) recorded using ring electrodes around the index finger. Latency was measured to peak response. Skin temperature was recorded at the site of stimulation in each patient throughout the study, and individual measurements were compensated for temperature using the relationship found in normal subjects.16,17 4: Puffer fish poisoning Tetrodotoxin (TTX) is present in high concentrations in the liver of puffer fish, with progressively decreasing amounts in the ovaries, intestines and skin.1 TTX poisoning can occur from ingestion of a wide range of bony fish from families in the order Tetraodontiformes, most importantly the family Tetraodontidae (puffer fish).11 While none of our cases were confirmed by expert identification of the fish, the description by the patients suggested puffer fish (sometimes called "toadfish" in Australia), and the clinical features were consistent with TTX poisoning. Although ciguatera is also caused by ingestion of fish, the clinical effects differ, and tropical reef fish are mainly implicated.18 The fish ingested by patients 2–11 were from the Georges River, in southern Sydney. While 35 species from the family Tetraodontidae occur in New South Wales, the species in the cases described here were most likely Tetractenos hamiltoni (common toadfish), T. glaber (smooth toadfish), or Torquigener pleurogramma (weeping or banded toadfish), all of which are common and have been recorded in the Georges River and Botany Bay (Doug Hoese and Mark McGrouther, Fish Section, Australian Museum, personal communication). The common toadfish is a sandy to whitish colour, with small brown spots over most of the back and upper sides. The lower sides often have brown bars and blotches (Box 1). It occurs from southern New South Wales to northern Queensland in shallow coastal waters and estuaries. The smooth toadfish looks similar to the common toadfish, but has larger spots and distinct body spines. With other species of puffer fish found in tropical waters, the potential for TTX poisoning exists in many coastal regions of Australia. The in-vitro effects of TTX are well characterised. It is a selective blocker of voltage-sensitive sodium channels and prevents conduction in motor and sensory nerves by blocking sodium channels at the nodes of Ranvier.11,19 Less is known about the in-vivo effects in humans. Nerve conduction studies have been limited,20,21 and demonstrate effects on muscle and sensory action potential amplitudes.20

Geoffrey K Isbister BSc, MB BS, FACEM · Julie Son MB BS · Josef Ujma MB BS · Brendon Smith DipRACOG, DA, FACEM · D G Milder MB BS, MD, FRACP · Frank Wang BSc(Med), MB BS · Catriona J Maclean MB BS · Cindy S-Y Lin MEngSc, PhD · Matthew C Kiernan PhD, FRACP · Corrine R Balit BPharm

Objective: To determine the effect of temperature on lethality of venom from Chironex fleckeri (the potentially fatal box jellyfish).Design: Venom extracted from nematocysts of mature Chironex fleckeri specimens was exposed to temperatures between 4°C and 58°C for periods of two, five or 20 minutes, and then injected into freshwater crayfish (Cherax quadricarinatus) to assess lethality.Main outcome measure: Venom lethality, assessed as time to cardiac standstill in crayfish after intramuscular injection.Results: Venom lethality was significantly affected by both temperature (F7,34 = 21915; P < 0.0001) and time of exposure (F2,34 = 9907; P < 0.0001). No significant loss of lethality was seen after exposure to temperatures ≤ 39°C, even after 20 minutes' exposure. At temperatures ≥ 43°C, venom lost its lethality more rapidly the longer the exposure time. Venom was non-lethal after exposure to 48°C for 20 minutes, 53°C for five minutes, and 58°C for two minutes.Conclusion: Exposure to heat dramatically reduces the lethality of extracted C. fleckeri venom. Although heat application may be of limited use in treating C. fleckeri envenoming because of the speed of symptom onset, its use in other box-jellyfish envenomings, such as Irukandji syndrome, requires investigation.

Teresa J Carrette MSc · Jamie E Seymour PhD · Paul Cullen FACEM · Peter L Peiera FACEM · Mark Little FACEM, MPHTM

Six patients presented with clinical, biochemical and histological evidence of severe hepatitis after taking herbal remedies. One patient required urgent liver transplantation for fulminant hepatic failure after the brief use of black cohosh. Five patients took a combination of herbs and presented with jaundice, fatigue and pruritus. Healthcare providers and members of the public should be aware of the potential adverse effects of these remedies. (MJA 2002; 177: 432-435) There has been a steady rise in the use of complementary medicine throughout the world. In 1997 it was estimated that 57% of Australians used complementary medicines, with an annual expenditure of $621 million.1,2 Self-medication is common, with 62%–72% of patients not disclosing the use of herbal preparations to their family doctors.3 This reluctance may be due to a perceived conflict between practitioners of conventional and alternative medicine. Although there have been trials on the efficacy of several herbal remedies, most information is based on anecdotal evidence and reputation. Information documenting adverse reactions is based on case reports and literature reviews, as there have been few prospective trials to date.4-7 As a result, the data available may not highlight potential adverse effects. In 1999 the Office of Complementary Medicine was created as part of the Therapeutic Goods Administration (TGA) in an attempt to regulate alternative medicine in Australia. The constituents of a herbal remedy must undergo pre-market evaluation for safety and quality before being listed on the Australian Register of Therapeutic Goods. Manufacturers of herbal products must now be licensed and need to adhere to the Therapeutic Goods Advertising Code. If a complementary medicine claims to "cure/manage or prevent" a disorder it requires high-level evidence to be registered, but if it claims to be for "symptom relief/health maintenance or health enhancement" then the product does not need formal evaluation. With the expanding use of these remedies, the risk of serious drug interactions increases. There is some information available on common interactions,7,8 but continued vigilance is required with the introduction of new medications. We describe six patients with hepatotoxicity from a variety of herbal remedies. The patients were reviewed by a gastroenterologist in Queensland (P K) between 1996 and 2001. Data were collected when the patient presented and subsequent telephone inquiry clarified any other details. The individual herbal products were not analysed for their constituents. Clinical recordsClinical records for the six patients are summarised in Box 1. One woman used black cohosh (Cimicifuga racemosa) alone for one week, and the other five patients were taking various combinations of herbs for 6–18 weeks before the onset of symptoms. Four patients disclosed the use of the herbal product to their general practitioner before referral. Patient 1 was taking the herbal remedy for relief of symptoms of menopause, Patient 5 as a "liver tonic", and Patient 6 to lose weight. The others took the remedies for general health promotion. The doses varied and were not reported to exceed the dosage recommended on the package. None of the patients had a history of excessive alcohol intake, injecting drug use, prior blood transfusion, family history of liver disease, or past history of liver or biliary tract disease. Patient 3 was taking temazepam, and Patient 4 had been taking long term low dose aspirin. No other concurrent medication was reported. Two patients had notable comorbidities: Patient 3 suffered from Huntington's chorea, and Patient 2 was diagnosed with ovarian adenocarcinoma shortly after presenting with hepatitis, but had no evidence of metastatic involvement of the liver on biopsy, computed tomography scan or at laparotomy. All patients developed jaundice, and the pattern of liver enzyme abnormality was predominantly hepatocellular (serum alanine aminotransferase level > 1000 U/L in each), with moderate elevations in the cholestatic enzymes. Pruritus was present in three patients. The international normalised ratio [INR] was elevated in two subjects (Patient 1: INR, 4.6; Patient 2: INR, 2.4). Peripheral blood eosino-philia was not present in any of the patients. No causes for liver disease other than the herbal remedies were found. Serology for hepatitis A (IgM, anti-HAV), hepatitis B (HBsAg) and hepatitis C (anti-HCV) was negative in each of the patients. The antinuclear antibody was positive in a titre of 1: 40 in Patients 2 and 3. The smooth-muscle antibody and antimitochondrial antibody titres were negative for all patients tested (1–3, 5, 6). The iron and copper profiles were in keeping with an acute phase response. The alpha-1-antitrypsin level was normal in all patients. An endoscopic retrograde cholangiopancreatogram demonstrated a normal biliary tree in two patients with jaundice and cholestatic features. All patients had normal imaging of the liver by upper abdominal ultrasound or computed tomography examination. Percutaneous liver biopsy was performed in five subjects with severe hepatitis, and the liver removed at transplantation (Patient 1) was available for study (Box 2). The biopsies were processed routinely, three sections were stained with haematoxylin–eosin, and additional sections were stained with haematoxylin–van Gieson. In all biopsies there was moderate to marked portal and lobular hepatitis. The limiting plates showed moderate to severe interface hepatitis (piecemeal necrosis). In addition, there was confluent zone 3 dropout and linkage of portal tracts and central veins. Eosinophils were present in five of the six cases but were not a conspicuous feature. All the biopsies were typical of acute hepatitis such as that seen in severe viral hepatitis. These changes are typically found in severe immunological reactions and are not the changes of direct toxic injury. Three patients with persistent jaundice and severe pruritus were treated with oral prednisone, resulting in immediate improvement in the symptoms of pruritus and jaundice. DiscussionHerbal remedies, like conventional medications, carry a risk of adverse reactions. There are many factors contributing to the potential toxicity of herbs. These include misidentification of the plant, variability in the time and place of collecting the plant, use of the wrong part of the plant, incorrect storage, contamination during preparation, and inconsistency in nomenclature and labelling of the final product.10 Adulterants such as corticosteroids have been added to some preparations.11 The remedies may have multiple ingredients, creating difficulty determining the causative agent and possible mechanism of injury. The identification of a herbal remedy as being responsible for hepatotoxicity often depends on demonstrating a temporal relationship between consumption of the product and development of the illness and improvement after discontinuation, after excluding other causes of liver disease. Some herbal agents used as medicinal products which are known to cause liver disease are listed in Box 3. We have identified six patients who developed abnormal liver function tests after taking herbal remedies. Other causes of liver disease were excluded. One patient required urgent liver transplantation, and the others recovered after stopping the herbal remedy. For ethical reasons, challenge experiments were not performed. Liver biopsies were characteristic of an idiosyncratic, immunological reaction24,25 and were very similar to the changes seen in acute viral hepatitis. In particular, there was prominent hepatocyte apoptosis, acinar zone 3 dropout, and at least focal bridging "necrosis" in all cases. This pattern of injury has been noted with skullcap and valerian,19 but differs from the liver injury described with chaparral12 and germander,14 where true coagulative necrosis rather than apoptosis is observed (suggesting toxic injury and not an immunological reaction). The most serious illness occurred in a 47-year-old woman (Patient 1) who was taking black cohosh for symptoms related to the menopause. Histological examination of her explant liver confirmed severe hepatitis and multiacinar dropout. The large number of synonyms for black cohosh highlights the problems with nomenclature, with up to 20 names used in North Carolina and South Carolina alone.11 It is widely used, particularly in Europe, for its putative beneficial influence on perimenopausal symptoms.26 In the United States, the Food and Drug Administration (FDA) lists it as a "herb of undefined safety".27 There are no restrictions on the use of black cohosh in Australia. It contains a mixture of alkaloids, tannins and terpenoids, and has not previously been reported to have hepatotoxic effects. Diterpenoids have been shown in animal models to result in liver injury, either by reactive metabolites or by an auto-immune mechanism.7 Previous studies have incriminated mixtures of skullcap and valerian as causing hepatitis,13,19 with jaundice and marked elevation in serum bilirubin and alanine amino-transferase levels being features. In our series, two patients (2 and 3) were using this combination and a further patient (4) used skullcap without valerian. In addition, the mixture Patient 2 took also contained black cohosh. Patient 5 was taking a combination of herbs that included chaparral. Chaparral, when taken in capsule or tablet form, can cause subacute hepatitis, but no deaths have been reported.12 In 1992, the FDA issued a warning about the potential danger of its use. There are no reported cases of the other herbs being hepatotoxic. Patient 6 was taking a preparation containing a mixture of herbs advertised as a fat metaboliser and a fluid retention remedy. Greater celandine (Chelidonium majus) has been associated with acute hepatitis characterised by marked cholestasis.15 Buchus leaf contains pulegone, a volatile oil also found in pennyroyal oil. Pulegone has been reported to be hepatotoxic,28 either directly or via a reactive intermediate.29 The true incidence of hepatic damage caused by herbal medications remains unknown owing to a lack of prospective studies. The incidence of hepatotoxicity from Chinese herbal remedies has been estimated at between 0.2% and 1%.30 With the increasing use of herbal remedies, medical practitioners need to be aware of the potential adverse effects and should routinely ask patients about all medications, including herbal mixtures. Labelling and advertising should include the known adverse effects, and a public education program is needed so that consumers are more aware of potential risks. The establishment of the Office of Complementary Medicine should address some of these issues. Finally, toxicity testing for plants and herbs used therapeutically should be undertaken as for manufactured drugs. 1: Summary of clinical and laboratory data for six patients who developed hepatitis after taking herbal remedies Patient (sex, age) Herbal remedy Time on herbs (weeks) Time to symptoms (weeks) Symptoms Peak value Time from diagnosis to normal laboratory results (weeks) Treatment Symptom Duration(weeks) Bilirubin† (μmol/L) ALP‡ (U/L) AST§ (U/L) ALT¶ (U/L) GGT** (U/L) 1(F, 47) Black cohosh 1 1 Jaundice 2 335 158 3182 2295 163 Not applicable Liver transplant 2(F, 43) Skullcap;* valerian;* black cohosh; passionflower; Angelicia sinensis; hops; Avema sativa; chasteberry N/A N/A Jaundice; nausea; vomiting; diarrhoea 18 284 80 1140 1500 N/A N/A Nil 3(F, 75) Skullcap; valerian;* hops 6 6 Jaundice 4 169 219 933 1470 330 20 Nil 4(M, 55) Skullcap; Ginkgo biloba 14 18 Jaundice; pruritus 5 181 150 1018 1293 373 7 Prednisone 5(M, 25) Chaparral;* dandelion; Withania somnifera; horsetail; echinacea 6 8 Jaundice; pruritus; fatigue 4 684 159 3910 3104 318 7 Prednisone 6(F, 23) Greater celandine;* buchus leaf; Uva ursi; juniper; parsley piert; choline bitartrate; dandelion 12 12 Jaundice; pruritus; fatigue 5 1073 134 2092 3764 81 25 Prednisone * Herbal remedies reported as hepatotoxic (see Box 3). † Bilirubin normal range < 20 μmol/L. ‡ Alkaline phosphatase (ALP) normal range 40–250 U/L. § Aspartate aminotransferase (AST) normal range < 35 U/L. ¶ Alanine aminotransferase (ALT) normal range < 40 U/L. ** Gamma glutamyltransferase (GGT) normal range < 50 U/L. N/A = not available. Botanical names: Black cohosh, Cimicifuga racemosa; Skullcap, Scutellaria lateriflora; Valerian, Valeriana officinalis; Passionflower, Passiflora incarnata; Hops, Humulus lupulus; Chasteberry, Vitex agnus-castus; Chaparral, Larrea tridentata; Dandelion, Taraxacum officinale; Horsetail, Equisetum arvense; Greater celandine, Chelidonium majus; Juniper, Juniperus communis. 2: Liver histology for the six patients* Patient Interface hepatitis (0–4) Portal inflammation (0–4) Zone 3 hepatocyte loss (0–4) Bridging necrosis (0–2) Lobular inflammation (0–4) Eosinophils (0–2) Bile duct damage Fibrosis (0–6) 1 ++ ++ ++++ ++ ++ ++ 0 Early 2 ++++ ++++ +++ focal ++++ ++ 0 0 3 +++ ++ ++++ + ++++ + 0 Early 4 +++ ++ +++ focal +++ 0 0 0 5 +++ +++ +++ focal ++++ ++ 0 0 6 +++ +++ ++++ + ++++ + 0 0 * Scoring system adapted from Ishak et al.9 Eosinophils 0 = none; 1 = 1–4 per portal tract; 2 = > 4 per portal tract. 3: Common herbal remedies suspected of being hepatotoxic Common name Botanical name Potential toxic constituents Indications Hepatic disease References Chaparral Larrea tridentata Nordihydroguaiaretic acid Free radical scavengerDelays aging Hepatitis Gordon et al (1995)12 Comfrey Symphytum officinale Pyrrolizidine alkaloids Herbal teaPoultice Veno-occlusive diseaseHepatic adenomas Miskelly et al (1992)13 Germander Teucrium chamaedrys Furano neoclerodaneFlavonoids Antipyretic Weight control Hepatitis Larrey et al (1992)14 Greater celandine Chelidonium majus Unknown Gallstones Dyspepsia Hepatitis Benninger et al (1999)15 Jin Bu Huan Lycopodium serratum Unknown Sedative Analgesic Hepatitis Graham-Brown (1992)16 Kombucha tea Kombucha "mushroom" Unknown Arthritis Cancer cure Hepatitis Perran et al (1995)17 Mistletoe Viscum album Unknown Antihypertensive Sedative Hepatitis Harvey and Colin-Jones (1981)18 Mixtures of valerian and skullcap Valeriana officinalis Scutellaria lateriflora Alkylating agents Crystalline glycoside and a volatile oil Sedative Sedative Hepatitis Hepatitis MacGregor et al (1989)19 Miskelly et al (1992)13 Pennyroyal oil (squawmint oil) Labiatae spp. Pulegone Abortifacient Menstrual complaints Hepatic necrosis Anderson et al (1996)20 Sassafras Sassafras albidum Safrole Arthritis Hepatitis Hepatocarcinogen Segelman et al (1976)21 Senna Cassia angustfolia Sennosides Laxative Hepatitis Beuers et al (1991)22 White chameleon Atractylis gummifera Potassium atractylate Gummiferin Antipyretic Purgative Hepatitis Georgiou et al (1988)23

Peter W Whiting MB BCh, BAO, FRACP · Andrew Clouston MB BS, PhD, FRCPA · Paul Kerlin BA, MD, FRACP

To the Editor: Thalidomide (N-α-phthalimidoglutarimide) was first marketed as a sedative-hypnotic in 1957. It was withdrawn from the market in 1961 as it was found to cause congenital malformations.1 Infant mortality statistics in Germany for the years 1959 to 1963 show that about 40% of thalidomide-affected babies died in the neonatal period.2 The main causes of death were atresia of the bowel, renal dysgenesis and heart malformations. As a result of extensive studies on the pathogenesis of the malformations, it was found that thalidomide is an immunosuppressant.3 The use of two different 14C-labelled thalidomide preparations showed that a portion or the whole of the glutarimide molecule binds to the DNA of rabbit embryos.4 In Britain and Ireland, 480 thalidomide-affected infants survived. Of these, 25 died before reaching the age of 40 years. The causes of death were cancer (4), heart disease (4), diabetes (3), hypertension and renal failure (3), motor accidents (3), and substance misuse or suicide (8) (M Johnson, Director, the Thalidomide Trust [United Kingdom], personal communication). Four deaths from cancer before the age of 40 years in a cohort of 480 is an incidence of 0.83%. The death rate from cancer in England and Wales before the age of 40 is 9.4 per 100 000 population, or 0.0084%.5 Thus, the thalidomide-affected individuals had a 99-fold increase in the age-related cancer death rate. Another of the cohort died aged 41 years of round-cell sarcoma. The high incidence of malignancy, together with the knowledge that a portion of the thalidomide molecule binds with the DNA of laboratory animals, suggest a possible mutational change in some of the cells of thalidomide-affected people. Thalidomide is currently being used to treat a variety of diseases, some because of its immunosuppressant properties. These diseases include graft-versus-host disease, leprosy, AIDS, Behçet's syndrome, tuberculosis, multiple myeloma and many dermatoses. It is also being used for treating some cancers. Its chemotherapeutic value probably results from the ability of the glutarimide component of the thalidomide molecule to bind with the DNA of rapidly dividing cells. However, if the genetic injury is not accurately repaired, it may result in mutations or even cell death. Although thalidomide is now proving to be a useful therapeutic agent, its ability to bind with DNA makes it dangerous, not only when taken by pregnant women, but also potentially when taken by men, whose sperm might be affected.6

William McBride

To the Editor: In their case report entitled "Dangerous bodies", Nocera and colleagues described a case of poisoning with aluminium phosphide tablets,1 which generate the fumigant gas phosphine when exposed to moisture.2 The foul odour emanating from the patient alarmed hospital staff, leading to evacuation of the emergency department. After the patient died, they sealed his body in an impervious suit and bin. It was buried, without autopsy, using earth-moving equipment — it being considered too dangerous to do this by hand. The burial was filmed for television. The article sought to highlight risks to hospital staff from poisoned patients and indicated that phosphine gas emanating from this patient could be toxic before it was able to be smelt. Despite stated fears of extreme toxicity, no air samples were collected for analysis, and the sole symptom among staff was nausea (not unexpected given the smell). In parts of India, where wheat is commonly stored in the home before being ground into flour, aluminium phosphide tablets are widely available for household use to stem insect attack on the grain.3,4 Ingestion of these tablets is a common way to attempt suicide, with perhaps as many as 15 000 cases per year, two-thirds of which are fatal. The hospital in the city of Chandigarh, in northern India, treats about 50 cases per year. The breath of patients who have ingested aluminium phosphide has a characteristic garlic-like odour. Diagnosis is based on history and a positive result (blackening) on tests of the patient's breath with paper moistened with fresh silver nitrate solution. Hospital staff take no special precautions during resuscitation, and surviving patients are managed with routine supportive care. Autopsies are routine. No threat is perceived by hospital staff. Metal phosphides have been safely used by trained people in Australia for decades. They are Schedule 7 poisons and so require an expensive permit for purchase. Consequently, their use for suicide is rare. Nocera and colleagues understandably reacted with caution to an unusual situation. However, we consider that, in documenting their experience, they overstated the risk. Because of the legal and ethical issues involved in patient care in a situation of alleged risk, we consider that risk estimates should, when possible, be based on available evidence rather than theoretical possibilities. In general, apart from a few highly toxic, mainly anticholinesterase compounds that can be absorbed through the skin (eg, sarin and tabun), there are no known poisons that will seriously endanger hospital staff routinely caring for patients in an emergency department. Competing interests: The authors have no association with companies that manufacture or market aluminium phosphide, and had no financial support for preparation of this letter. In reply: In our article, we clearly stated that the emergency department was evacuated on the instructions of officers from the New South Wales Fire Brigades.1 The officers then placed the patient's body within a fire brigade hazardous materials encapsulated suit and, when that began to distend with phosphine gas emissions from the body, into a hazardous materials recovery bin. In contrast, Christophers and colleagues state that staff at the hospital in Chandigarh, India, take no special precautions in antemortem or postmortem care of patients who have taken aluminium phosphide tablets. I am disappointed that they provide no data on air sampling for phosphine gas during this care to justify this practice. Our case highlights the problems confronting emergency department staff with a critically ill patient and an unknown chemical hazard. In this case, the chemical hazard was not correctly identified for over 30 minutes. The risk cannot be estimated, as suggested by Christophers and colleagues, until the chemical agent and its vapour concentration are correctly identified. Retrospective determinations cannot be used to guide the immediate emergency department response, or to determine what personal protective equipment is needed by staff during the initial confusion of a hazardous materials incident. In addition to organophosphates, over 30 chemical agents have the potential to be used as chemical weapons. Furthermore, the toxicity profiles of many industrial chemicals are unknown or incomplete. We do not believe that any hospital or emergency department staff should be exposed to avoidable danger during antemortem or postmortem care of patients, or that healthcare institutions should be exempt from their statutory obligations under occupational health and safety legislation.

Allen J Christophers · Surjit Singh · David G Goddard · Antony Nocera FACEM, MSc (Emergency Planning and Disaster Management)

To the Editor: We report two episodes of serotonin toxicity (or serotonin syndrome) caused by drug interaction in one individual chronically treated with dexamphetamine. The interacting drugs were venlafaxine, then later citalopram. We are not aware of any previous reports of serotonin toxicity caused by dexamphetamine in combination with either venlafaxine or any selective serotonin reuptake inhibitor (SSRI). A 32-year-old man presented after two days of marked agitation, anxiety, shivering and tremor. He was being treated with dexamphetamine, 5 mg three times daily, for adult attention deficit hyperactivity disorder. He had started venlafaxine (75 mg daily) two weeks previously, and this had been increased to 150 mg daily after a week. On examination, he was alert and oriented, but diaphoretic, shivering and had fine motor tremor. His heart rate was 140 bpm, blood pressure was 142/93 mmHg and temperature 37.3°C. Pupils were 3 mm diameter and reactive, with no nystagmus or ocular clonus. There was generalised hypertonia, hyperreflexia, 1–2 beats of inducible ankle clonus, frequent myoclonic jerking and tonic spasm of the right side of his orbicularis oris muscle. His abdomen was tense, but non-tender, with normal bowel sounds. An electrocardiogram showed sinus tachycardia with a baseline tremor, but no other abnormality. Therapy with dexamphetamine and venlafaxine was ceased, and cyproheptadine (8 mg doses up to a total of 32 mg over three hours) was given. The patient had a stepwise reduction in heart rate, with complete resolution of his symptoms, and was discharged the next morning. Dexamphetamine therapy was restarted three days later and citalopram therapy was commenced one week after discharge. Two weeks after discharge, he reported similar symptoms, and ceased citalopram. Three days later he was still agitated, with nausea, diarrhoea and teeth clenching. There was no rigidity, tremor or diaphoresis, and his heart rate was 76 bpm. He was given two 8 mg doses of cyproheptadine and was asymptomatic two days later. Some of this patient's symptoms could be attributed to noradrenaline excess. However, the combination of neuromuscular and autonomic features is more consistent with serotonin toxicity. The fact the symptoms resolved after administration of cyproheptadine (a 5-HT2-receptor antagonist) supports this hypothesis. There is no theoretical reason why the interaction of citalopram (a pure SSRI) and dexamphetamine should cause catecholamine excess, and again the more likely explanation is serotonin toxicity. Dexamphetamine causes psychostimulation and increased peripheral sympathomimetic activity. Centrally it causes presynaptic release of serotonin,1 and dopamine and catecholamine release.2 Venlafaxine and its metabolite, O-desmethylvenlafaxine, inhibit both neuronal 5-HT reuptake and noradrenaline reuptake,3 whereas citalopram, an SSRI, has little effect on noradrenaline reuptake.4 The combination of serotonin reuptake blockade and either presynaptic release of serotonin or monoamine oxidase inhibition by dexamphetamine will cause increased serotonin levels in the central nervous system, and is the likely mechanism of toxicity in this patient. This is consistent with the mechanism for other reports of serotonin toxicity.5 Increased awareness and cautious monitoring is advised when using a combination of dexamphetamine and either venlafaxine or an SSRI. This is particularly important in people using amphetamines recreationally and in children taking dexamphetamine for attention deficit hyperactivity disorder.

Felicity H Prior BPharm, GradDipEpi · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson MB BS, FRCP, FRACP · Ian M Whyte MB BS, FRACP FRCP

To the Editor: From 1 February to 30 June 2001, 277 602 prescriptions for the smoking cessation drug bupropion hydrochloride (Zyban, GlaxoSmithKline) were processed. The Health Insurance Commission approved 343 737 prescriptions for bupropion between 1 February and 30 June.1 Comparing this figure with the 277 602 processed scripts, some 66 135 (19.2%) scripts went unfilled. One reason for this may have been extensive publicity given to reports of deaths and numerous adverse reactions following bupropion use. The website of the Australian Drug Reactions Advisory Committee (ADRAC) reports that, as at 22 June, there had been 18 reports of deaths in patients aged from 30 years to 69 years who were using or who had recently stopped using bupropion.2 ADRAC summarised intelligence on these deaths thus: ... there were a variety of reported causes of death and not a single consistent mode of death. In addition to being smokers, several patients had other existing risk factors for unexpected death such as alcohol abuse, diabetes or cardiomyopathy. Eleven of the 18 patients had an alternative explanation for death that was at least as plausible as a possible effect of bupropion. In four reports, the available information was very limited and it was not possible to assess the cause of death. Further information is being sought on three cases to aid assessment of the cause of death.2 Smokers are at 3.1 times greater risk of dying (from any cause) than non-smokers and twice as likely to die from coronary disease and stroke.3 People with depression are three times as likely to be daily smokers4 and have double the suicide rate of non-smokers.5 In Australia, sudden coronary fatalities occur at a rate of about 450 per million people aged under 65,6 perhaps at a rate of 355 per million in non-smokers and about double that in smokers. In three months (the period of recommended bupropion use), one would expect 180 deaths per million smoker-users. Thus, among 277 602 Australian smokers, 50 might die during any given three-month period without any added risk from bupropion. This estimate helps to place the 18 fatalities reported to ADRAC in context. The 277 602 scripts represent about 9.5% of Australia's 2.9 million regular smokers. These people, their families and doctors deserve to have their anxieties about the risks of using bupropion addressed. We would urge the government to commission urgently a case–control study of morbidity and mortality among smokers and their relationships to use or non-use of bupropion.

Simon C Chapman · Konrad Jamrozik

Although responsibility for health is national, the means to fulfil that responsibility are increasingly global. MJA 2001; 175: 648-651 3 AM. The phone falls to the floor as I grope around in the dark. "We have another one for you, boss", the voice says, with the schadenfreude that the night doctors feel when summoning the on-call staff. "What, another snakebite ?" I wonder what the poor man was doing getting bitten at that hour. It has been a tough night for the emergency doctors. Patients look up hopefully at the first sign of a doctor, while others complain to triage. There is some blood on the floor in the main room; the smell of sweat hangs thick in the air. The interns gesture tiredly in the direction of the resuscitation room. "There is a transfer letter somewhere," they tell me. It is a pithy statement of fact, even for Papua New Guinea. "Thank you for taking K, who is 12 years old. He was bitten by a snake at 6 PM. We have no tet tox or penicillin. We have no antivenom. Yours truly." I'm not sure if they mean to tell me that they have thought of these things, or they are hoping we will provide some for them. Although Australian snakebite mortality rates have fallen more than tenfold since the introduction of the first antivenom 70 years ago1(see Box 1), our nearest neighbour, Papua New Guinea (PNG), has not been so fortunate. Not only do they share with us snakes that are among the most toxic known, but in some areas the snakebite rate is one of the highest in the world.2 Moreover, the consequences of snakebite in PNG are particularly severe; 36% of envenomed patients seen at Port Moresby General Hospital (PMGH) will require ventilation3(see Box 2). In an ironic twist, Gajdusek, whose work on kuru among the Fore people underlies contemporary understanding of "mad cow disease" (which has received much funding and international attention), also reported that snakebite was the commonest cause of death in some of these villages.4 At the same time, the cost of a single ampoule of Australian polyvalent antivenom (CSL Limited), the type most frequently used in PNG,5 at over A$1200, represents approximately half the per capita annual gross domestic product (Anna Leina, Officer in Charge, Pharmacy Department, Port Moresby General Hospital, personal communication). Consequently, even the nation's premier medical institution, Port Moresby General Hospital (PMGH), is frequently without antivenom.6 This situation, unthinkable in Australia, has forced some healthcare centres into managing death adder bites with prolonged pressure bandaging to save scarce antivenom supplies.7The child is not well. Held up by his tired parents, his eyes are heavy from fatigue and from the neurotoxin that is taking over. He is still breathing, with some effort. He does not care that saliva spills from his chin onto his T-shirt. He will need to be ventilated soon, but not yet. His blood does not clot. I have learned not to ask the lab to tell me how long it takes; once I called for missing results only to be told that they couldn't give me a clotting time, as they were still waiting. It has been a steep learning curve for me. The refrigerator in the emergency department has contained two ampoules of sea snake antivenom for a few years now. No-one at the hospital has ever heard of anyone being bitten by a sea snake. The paediatric ward staff tell me they do not have any polyvalent antivenom, but I run across to make sure. It would not be the first time they have tried to save some antivenom. Pharmacy is locked, but I checked there earlier in the day. The nurses in intensive care eye me suspiciously. "We are full, boss." It has been just over a hundred years since Calmette successfully developed the first antivenom, using cobra venom from Indo-China, now Vietnam.8Unfortunately, little has changed regarding antivenom availability for snakebite victims in this region during the past century. The global burden of this eminently treatable condition is estimated at approximately 100 000 deaths each year,9 about a tenth the mortality attributable to malaria. Most of these deaths are concentrated in the Indo-Pacific region,10 where the poor (or absent) access to antivenom for most people results in snakebite mortality orders of magnitude greater than that in Australia (see Box 3). Indeed, tragically, although the burden of snakebite on the local people stimulated Calmette's original studies at the Vaccine Institute in Saigon (now Ho Chi Minh City),11 no snake antivenom was made in Vietnam for the next 100 years. There were five snakebites today and two yesterday — unusual even here. There are over 100 snakebite victims seen each year at Port Moresby General Hospital and we had received 20 ampoules of antivenom in the year 2000. There are seven ventilators. I try again to wrest an ampoule of antivenom from the intensive care ward by telling the staff that this patient might not need to come up to their ward if he had some. They honestly do not have any. I try all the tricks. Neostigmine sometimes helps if the snake was a death adder. I know that over 90% of bites are from taipans, but it is worth a try. I wonder if the scientists who theorised about cholinergic neurotoxins ever thought that it would come to this. It has been said that as the horses used to produce antivenoms for other snake venoms were the same ones used for the taipan antivenom, the antivenoms might have some activity against other snakes. Perhaps the sea snake antivenom might yet be useful. . . We recently proposed a global strategy for snakebite control and procurement of funding to overcome the inequality of antivenom supply.12 This comes amid an acute crisis in antivenom availability for Africa13 and a long-standing undersupply in the Asia-Pacific region14-16(see Box 3). Echoing Nossal's call to awaken the global conscience to the resource constraints facing childhood vaccination,17 we note that the greatest barrier to the widespread availability of antivenoms is not technical, but rather the mobilisation of enough resources. Fortunately for childhood vaccination, the establishment of the Global Fund for Childhood Vaccines by the William H Gates Foundation represents an unprecedented opportunity for infectious disease control by a systematic change in vaccine procurement methods.18 This change recognises that while "responsibility for health is national . . . the determinants of health and the means to fulfil that responsibility are increasingly global".18,19 A similarly coordinated international strategy is required to tackle the neglected issue of snakebite. We propose a comprehensive program that builds on the resources and relationships acquired by the Children's Vaccine Initiative20 and on World Health Organization (WHO) policy initiatives towards securing global access to essential drugs.21 It would employ strategies such as that adopted by the Pan American Health Organization's revolving fund, which emphasises sustainability by long-term government commitment before donor-supported expansion.22 This International Snakebite Initiative (ISI) would recognise that antivenoms are, like vaccines, international public commodities usually manufactured by the same companies facing the same pressures of economics.18 This is already recognised implicitly by the inclusion of antivenoms in the WHO's essential drug list.23 The ISI would require an interdisciplinary and multisectoral partnership maintaining national responsibility and aiming, where possible, for antivenom self-sufficiency. In addition to procurement, it would facilitate the development of new antivenom technology and adjuvant therapies. It would also encourage sustained primary-prevention programs, sponsor research and implement appropriate first-aid methods, ongoing snakebite injury surveillance and improved clinical education tools such as regional snakebite management guidelines. I intubate the boy, leave the intern with the bag, and go back to intensive care and give the staff the bad news. They tell me again that there are no ventilators. I ask which patients' wantoks (relatives) are staying with them. I tell them that we need the ventilator for a child and that they will have to help. I disconnect a patient's ventilator and attach the bag to his tube, explaining to his relatives,"This is how you breathe for him. If you stop, he does not breathe." The lesson is easily understood. We transfer the boy from emergency to intensive care and the other patients' relatives look at us impassively. As highlighted by the reduction in Australian snakebite mortality over the past century, dedicated venom and antivenom research and production saves lives and alleviates suffering. Unfortunately, the global tendency to privatise government-owned antivenom manufacturers,13,24 unleashing free market forces in countries with poor pharmaceutical regulation, threatens the humanitarian task of international snakebite control.13,14,16,25 For example, fake antivenoms are widely sold in Nigeria, and in many countries only charlatans or traditional healers are available to manage snakebite.13,14 These difficulties, combined with the cessation or reduction in antivenom production by traditional manufacturers, such as Aventis Pasteur, have precipitated escalating snakebite mortality in Africa.13Locally, efforts to enhance antivenom availability in PNG through calls for direct or indirect price subsidies16,25 have been ineffective.12,16,25,26 This reflects the general difficulty of facilitating access to essential drugs by appeals to charity or corporate social responsibility.21 Commercial disinterest in this class of pharmaceuticals is clearly evident in the apparent recent withdrawal of the incumbent snake antivenom manufacturer from the United States market.27 This has handed a monopoly to the new producer, which is now selling the most expensive antivenom in the world.14 We therefore argue that a new and more sustainable approach to antivenom procurement is required. Our proposal places antivenoms within global initiatives to secure access to essential drugs, particularly immunotherapeutics, in partnership with donors, the public sector and the pharmaceutical industry.21 Despite these challenges there is room for optimism. The chosen theme of PNG's 25th anniversary of Independence last September was "Walking together", or Raka hebou in Motu and Wokabaut wantaim in Tok Pigin. This theme resonates strongly with our aspirations for regional and global partnerships for snakebite control. Australia, with its distinguished record in antivenom research and development as well as in the Children's Vaccine Initiative, has the potential to play a leading role in the ISI. Countries with a high burden of snakebite, such as PNG and Vietnam, have well-organised national health systems effectively participating in global vaccination programs and disease eradication.28 Australian medical staff assist with snakebite management in regular regional toxinology teaching workshops and courses,29 and by international hospital-based, exchanges, sponsored by Australian institutions.30 Indeed, in the very week of PNG's Silver Jubilee celebrations, two such snakebite workshops were held at PMGH by one of us (K D W). Nevertheless, the need for global snakebite control is urgent and "action plans express no outrage".31 Unless affluent nations like Australia rise to this challenge, variations on our tragic scene will be replayed daily throughout the Asia-Pacific region for want of a 19th-century therapy. Acknowledgements We thank Professor Emeritus Sir Gustav Nossal, Professor Graham Brown and Dr Gabrielle Hawdon of the University of Melbourne, Dr Gertrude Didei of the Port Moresby General Hospital, Dr John Reeder of the Papua New Guinea Institute of Medical Research, and Professor David Warrell, University of Oxford, for their critical review of the manuscript. We are grateful to Dr Forbes McGain for the use of his photograph. Thanks also to CSL Limited and Boucher and Muir for sponsoring K W's trip to Port Moresby and to the ongoing Medical Officer, Nursing and Allied Health Training Project, for its support of A C's part in the registrar exchange program with PMGH. We acknowledge the continuing support of the Victorian Department of Human Services for the work of the Australian Venom Research Unit. Competing interests None declared. The preparation of this article received no specific funding from any organisation. References Winkel KD. Strychine, ammonia and gunpowder for snake bite — the end of an era. Med J Aust 2001; 174: 607. Lalloo DG, Trevett AJ, Saweri A, et al. The epidemiology of snake bite in the Central Province and National Capital District, Papua New Guinea. Trans R Soc Trop Med Hyg 1995; 89: 178-182. Warrell DA, Lalloo DG. Snake bite and its treatment in Papua New Guinea. In: O'Shea M, editor. A guide to the snakes of Papua New Guinea. Madang, Papua New Guinea: Christensen Research Institute, 1996. Gajdusek DC. Urgent opportunistic observations: the study of changing, transient and disappearing phenomena of interest in disrupted primitive human communities. In: Ciba Foundation Symposium 49 (new series), editors. Health and diseases in tribal societies. Amsterdam: Elsevier, 1977. Trevett AJ, Lalloo DG, Nwokolo NC, et al. Venom detection kits in the management of snakebite in Central Province, Papua New Guinea. Toxicon 1995; 33: 703-705. Dyke T. In the tail of the taipan. A personal view of snakebite and serum sickness. Med J Aust 1995; 163: 614-615. Oakley J. Managing death adder bite with prolonged pressure bandaging. In: Handbook, Millennium 2000, the 36th PNG Medical Society Symposium. Port Moresby, Papua New Guinea: PNG Medical Society, 2000: 24. Calmette A. Propriétés du sérum des animaux immunisés contre le venin des serpents; thérapeutique de l'envenimation. C r hebd Seanc Acad Sci Paris 1894; 118: 720-722. Chippaux J-P. Snake bites: appraisal of the global situation. Bull World Health Organ 1998; 76: 515-524. WHO/SEARO guidelines for the clinical management of snake bites in the Southeast Asian region. Southeast Asian J Trop Med Public Health 1999; 30 (Suppl 1): 1-85. Calmette A. étude éxperimentale du venin de Naja tripudians or cobra capel. Ann l'Institute Pasteur 1892; 6: 160-183. Cheng AC, Winkel KD. Call for global snakebite control and procurement funding [letter]. Lancet 2001; 357:1132. Theakston RD, Warrell DA. Crisis in snake antivenom supply for Africa [letter]. Lancet 2000; 356: 2104. McNamee D. Tackling venomous snake bites worldwide [news]. Lancet 2001; 357: 1680. Currie B, Vince J, Naraqi S. Snake bite in Papua New Guinea. PNG Med J 1988; 31: 195-198. Currie B. Medicine in tropical Australia: the quality and price of snake antivenoms [letter]. Med J Aust 1993; 159: 284. Nossal GJV. Awakening the global conscience: Who will benefit from new vaccines in the 21st century? Immunol Cell Biol 1997; 75: 584-586. Mahoney RT, Ramachandran S, Xu Z-Y. The introduction of new vaccines into developing countries II. Vaccine financing. Vaccine 2000; 18: 2625-2635. Jamison DT, Frenk J, Knaul F. International collective action in health: objectives, functions and rationale. Lancet 1998; 351: 514-517. Muraskin WA. The politics of international health. Albany: State University of New York, 1998. Scholtz M. WHO's role in ensuring access to essential drugs. WHO Drug Infor 1999; 13: 217-220. Freeman P. The PAHO revolving fund: history, operations and contribution to speeding vaccine introductions. Geneva: Children's Vaccine Initiative, 1999. Essential drugs: WHO Model list, 11th revision. WHO Drug Infor 1999; 13: 245-258. Sutherland SK. The sale of Commonwealth Serum Laboratories: wither antivenom research? Med J Aust 1992; 157: 731-732. Cheng AC, Ratcliff A, Adhikari P. Snake anti-venom in Papua New Guinea. Fellowship Affairs 2000; 19: 26. Sutherland SK. Medicine in tropical Australia: the quality and price of snake antivenoms. Med J Aust 1993; 159: 284. Galli R. The antivenin is safe, but its future is uncertain. West J Med 2001; 175: 91-92. Temu P. Health Secretary's message to the 2000 medical symposium. In: Handbook, Millennium 2000, the 36th PNG Medical Society Symposium. Port Moresby, Papua New Guinea: PNG Medical Society, 2000: 6-9. White J, editor. Clinical toxinology short course. 2001 handbook. Adelaide: University of Adelaide Faculty of Health Sciences, 2001. AusAID. Papua New Guinea program profiles, 1999-2000. Canberra: Australian Agency for International Development, 2001. Einternz EM. International aid and medical practice in the less-developed world: doing it right. Lancet 2001; 357: 1524-1525.(Received 19 Jul, accepted 1 Nov, 2001) Authors' details Duke University Medical Center, Durham, NC, USA. Allen C Cheng, MB BS, Fellow in Infectious Diseases. Department of Pharmacology, University of Melbourne, VIC. Kenneth D Winkel, MB BS, PhD, Director, Australian Venom Research Unit. Reprints: Dr K D Winkel, AVRU, Department of Pharmacology, University of Melbourne, VIC 3010. kdwATunimelb.edu.au Make a comment 1: Snakebite fatalities in Austrlia, 1910-1989 Back to text 2: A young snakebite victim requiring assisted ventilation in the Intensive Care Unit, Port Moresby General Hospital, in September 2001. This patient recovered after receiving two ampoules of Australia-New Guinea polyvalent snake antivenom (CSL Limited). Photograph by Dr Forbes McGain, Fellow, Australian Venom Research Unit. Back to text 3: Reported or derived snakebite mortality rates and the quality and status of antivenom supply, by country, in the Asia-Pacific region, excluding the Indian subcontinent9,10 Country Estimated snakebite mortality* Antivenom quality and supply Burma 100 Reasonable quality, limited supply Vietnam 80 Good quality, very limited supply Papua New Guinea 20 Imported high quality, limited supply Taiwan 2.5 Good quality, uncertain supply Australia 0.2 High quality, excellent supply Thailand 0.2 Good quality, excellent supply Japan No data Good quality, good supply East Timor No data Imported reasonable quality, little supply Malaysia No data Imported from Thailand China No data Quality and supply uncertain Indonesia No data Low quality, very limited supply Philippines No data Low quality, uncertain supply * Per million population per year. No data available for Cambodia and Laos. Many of the data reflect historic patterns and are subject to significant reporting bias. Where it is likely that the rate is an underestimate, such as for Myanmar (Burma), the figures presented here incorporate appropriate adjustments. The comparative assessment of quality combines measures of potency, clinical efficacy, pyrogenicity and acute allergic reaction rates. Back to text

Allen C Cheng · Kenneth D Winkel

Bites and stings Prospective study of jellyfish stings from tropical Australia, including the major box jellyfish Chironex fleckeri Gerard M O'Reilly, Geoffrey K Isbister, Paula M Lawrie, Greg T Treston and Bart J Currie MJA 2001; 175: 652-655 Abstract - Methods - Results - Discussion - Acknowledgements - Conflict of interest - Reference - Authors' details - - More articles on Insects, bites and stings Abstract Objective: To determine the immediate and delayed effects of jellyfish stings, and correlate these with microscopic identification of jellyfish nematocysts. Design: Prospective study of patients presenting with jellyfish stings. Participants and setting: 40 people presenting with jellyfish stings to the emergency department of a teaching hospital in tropical Australia between 1 August 1999 and 31 July 2000. Main outcome measures: Clinical diagnosis (sting by Chironex fleckeri, "Darwin carybdeid" or other jellyfish, or "Irukandji" syndrome); clinical severity; delayed hypersensitivity; and sticky-tape sampling and microscopic identification of nematocysts. Results: Patients were aged 2-50 years, with eight aged under 15 years; 23 were male. Presentations were consistent with C. fleckeri sting in 28 cases, Darwin carybdeid sting in five, and Irukandji syndrome in four. Sticky-tape sampling was done in 39 patients and was positive for C. fleckeri nematocysts in 23 and for non-C. fleckeri nematocysts in six, with nematocysts not detected in 10 (including all four with Irukandji syndrome). All microscopically confirmed C. fleckeri stings had typical clinical presentations. None of the stings were life-threatening, and no antivenom was given. Delayed hypersensitivity reactions were seen in 11 of the 19 patients (58%) followed up after stings positive for C. fleckeri nematocysts. Conclusions: Although most jellyfish stings presenting to Royal Darwin Hospital were caused by C. fleckeri, severe envenomation was rare. There was a strong association between clinical features and sticky-tape identification of nematocysts. Delayed hypersensitivity was common after C. fleckeri stings. Box jellyfish stings have historically been an important cause of mortality and morbidity in coastal tropical Australia.1-3 The most common cause of sting presentations to the Royal Darwin Hospital (NT) is the major box jellyfish Chironex fleckeri (Class Cubozoa; Order Chirodropidae)4-6(Box 1A). It is responsible for most severe cases of jellyfish envenomation.1-4 Clinical manifestations include immediate local pain with visible linear tentacle marks and, in severe stings, systemic effects with cardiorespiratory arrest possible within minutes.1-4,6-8 However, fatalities are rare, and the clinical spectrum is not evident from published case reports, which mostly present fatal or near-fatal cases. In addition, it is not clear whether delayed hypersensitivity, which has been reported after other jellyfish stings, is a feature of C. fleckeri stings.1The "Irukandji" syndrome has been associated with stings by Carukia barnesi (Class Cubozoa; Order Carybdeidae)9,10 (Box 1C), although other jellyfish may cause a similar syndrome.11C. barnesi has rarely been found in the Northern Territory (P Alderslade, Curator of Coelenterates, Museum and Art Gallery of the Northern Territory, Darwin, NT, personal communication), and the Irukandji syndrome is less common than in far north Queensland.10,11 Other jellyfish species appear to cause some stings in the Darwin region.1,4 These include the "Darwin carybdeid",1 a four-tentacled jellyfish larger than C. barnesi, which appears to cause less severe skin damage than C. fleckeri. We conducted a prospective study of all jellyfish-sting presentations to Royal Darwin Hospital over 12 months in 1999 and 2000. Our aim was to determine the immediate and delayed effects of all marine stings, and to correlate these with microscopic identification of jellyfish nematocysts using the sticky-tape sampling technique.6 Methods The study included all patients who presented to the Royal Darwin Hospital after a jellyfish sting between 1 August 1999 and 31 July 2000. The study was approved by the Joint Institutional Ethics Committee of the Royal Darwin Hospital and the Menzies School of Health Research. Patients were assessed and treated in the Emergency Department according to the Royal Darwin Hospital protocol12(Box 2). Clinical and demographic details were entered prospectively, along with details of hospital management, on a standardised form. Details included investigations (eg, electrocardiography [ECG]), type and effect of analgesia (topical [ice], oral [eg, aspirin or codeine], or parenteral [morphine or pethidine]) and whether C. fleckeri antivenom was administered. The clinical diagnosis was classified as typical or not typical of C. fleckeri sting according to known features (immediate and persistent local pain, linear sting marks and absence of generalised pain, which is seen in Irukandji syndrome).1,3,11 Sticky-tape sampling During the initial presentation, the sting site was sampled for nematocysts using the sticky-tape technique developed in Darwin.6 Transparent sticky tape was applied to the site and then transferred to a microscope slide for examination at x 100 to x 400 magnification. This allows nematocysts of C. fleckeri to be distinguished from those of other jellyfish on the basis of morphology (Box 1B and 1D). Presence of C. fleckeri or other jellyfish nematocysts was determined by one of the authors (P M L) and verified by another (B J C). Follow-up We telephoned patients about three weeks after initial presentation to ask about persistent or delayed effects, especially emergence of a pruritic rash at the site of the initial sting. Results Forty patients presented to Royal Darwin Hospital with jellyfish stings in the 12-month study period. They were aged two to 50 years (median, 21 years), with eight aged under 15 years; 23 were male. Seasonal variation in stings is shown in Box 3. Of the 40 stings, 28 (70%) were clinically typical of C. fleckeri, and 12 (30%) were not typical. Four of the latter were consistent with Irukandji syndrome (minimal local erythema, and delayed systemic symptoms, especially pain), and five with Darwin carybdeid sting (less severe skin pain and markings, with some "overlap" Irukandji features, such as abdominal pain). A typical C. fleckeri sting is shown in Box 4A. Sticky-tape sampling Sticky-tape sampling was done in 39 patients and was positive for nematocysts in 29 — C. fleckeri in 23 and carybdeid-appearing nematocysts in six. Sampling was negative for nematocysts in 10 patients, including all four with Irukandji syndrome. Correlation between microscopic findings and clinical presentation is shown in Box 5. All microscopically confirmed C. fleckeri stings had typical clinical presentations. Of the six patients with carybdeid-appearing nematocysts, five had presentations consistent with Darwin carybdeid envenomation, while one was more consistent with C. fleckeri. Management None of the 40 patients had documented arrhythmias on ECG, or pulmonary oedema. None was treated with pressure-immobilisation bandages or C. fleckeri antivenom, and there were no deaths. Of the 23 patients with stings positive for C. fleckeri nematocysts, one required parenteral analgesia and nine oral analgesia. In five, pain responded to topical ice alone, and eight required no pain relief. None of these patients required admission. Maximum length of tentacle marks was 5 m, followed by 4 m; both patients had severe local pain. Three of the patients with Irukandji syndrome and one stung by an unidentified jellyfish (no nematocysts detected on sticky-tape sampling) required admission for analgesia. Follow-up Twenty-nine patients were followed up, including 19 whose stings were positive for C. fleckeri nematocysts. Of these 19, 11 (58%) had delayed hypersensitivity reactions. These comprised an itchy red maculopapular rash dotted along the initial tentacle contact points consistent with papular urticaria, occurring 7-14 days after first presentation (Box 4B). These reactions resolved spontaneously in seven patients and after treatment with oral antihistamine and topical corticosteroid cream in four. Discussion This is the largest prospective study of C. fleckeri stings to date. Most previously published cases describe fatal or near-fatal stings, and some authors quote mortality rates up to 20%.13 Our study does not support this high mortality rate and showed that most stings were not severe, consistent with previous Northern Territory findings.5-7Although most C. fleckeri stings are minor and not life-threatening, the potential exists for severe systemic envenomation and even death. It is a concern that, despite considerable public education, eight of our cases were in children. The last 10 deaths from C. fleckeri envenomation in the Northern Territory were all of children, most recently a three-year-old girl from a remote Aboriginal community in February 1996.4 In January 2000, a five-year-old boy died soon after a jellyfish sting near Yarrabah, in north Queensland, presumed to be from C. fleckeri.14 In the past, considerable attention has focused on the use of antivenom in C. fleckeri envenomation.3,8,15-17 Indications have been cardiac arrest and arrhythmias, analgesia or cosmesis, although evidence supporting the efficacy of antivenom remains limited.7 None of our patients received antivenom, as none had cardiac toxicity, and severe local pain was controlled with appropriate analgesia. Nevertheless, it is crucial that antivenom is available for early use in life-threatening situations with arrhythmias or cardiorespiratory arrest. None of our patients had pressure-immobilisation bandages applied. These bandages are not recommended in the Northern Territory, as they potentially increase nematocyst discharge and are unlikely on theoretical grounds to prevent venom absorption.7,12,18 Delayed skin eruptions have been reported after jellyfish stings, although C. fleckeri has not been specifically implicated.19-21 These eruptions typically occurred at the site of the original sting after five days or more, and were pruritic and painless.1 Their histological features were generally consistent with delayed (type IV) hypersensitivity reactions.20 They are likely to be a response to retained foreign material, such as nematocyst thread or other cellular substances injected into the dermis, but specific antigens have not been identified. In our study, over half the patients followed up after stings positive for C. fleckeri nematocysts had delayed skin eruptions clinically resembling papular urticaria, similar to those reported after other jellyfish stings.19-21 This confirms that delayed cutaneous hypersensitivity reactions are common after C. fleckeri stings. Corticosteroid cream, with or without systemic antihistamines, may help relieve symptoms of delayed reactions.1,7 Correlation of sticky-tape sampling with clinical presentation suggests that there were no false-positive identifications of C. fleckeri nematocysts. The false-negative rate is unknown. However, as the test was negative for nematocysts in only three cases that appeared clinically typical of C. fleckeri envenomation, correlation with clinical findings appears good. While all the non-C. fleckeri nematocysts detected were carybdeid in appearance, degenerate C. fleckeri nematocysts may sometimes appear similar. Further description and classification is needed of the Darwin carybdeid and other local jellyfish yet to be identified. Clinical features of most of the carybdeid nematocyst-positive stings differed from those of both C. fleckeri stings and the Irukandji syndrome. The Darwin carybdeid appears to cause local pain from tentacle marks, but this pain is less severe than in C. fleckeri stings. The Darwin carybdeid also causes some "overlap" systemic symptoms, similar to those of a mild Irukandji syndrome. Two earlier stings with these features were confirmed to be caused by the Darwin carybdeid through capture and examination of the jellyfish, as well as microscopic identification of nematocysts1 (Currie BJ, unpublished data). Finally, although life-threatening envenomation is uncommon, we should continue to pursue public education and prevention policies vigorously. Deaths from severe C. fleckeri envenomation will inevitably occur while people, especially children without protective clothing, enter tropical waters in Australia. Acknowledgements We would like to acknowledge support from the Cooperative Research Centre for Aboriginal and Tropical Health; from the National Health and Medical Research Council Centre of Clinical Excellence grant to the Northern Territory Clinical School, Royal Darwin Hospital; and the staff of the Emergency Department, Royal Darwin Hospital, particularly Carole Mansfield and Marg St Leone. We would also like to acknowledge Phil Alderslade (Northern Territory Museum, Darwin) for assistance and for the photograph of the Darwin carybdeid. Conflict of interest There was no specific funding for this study and no conflict of interest. References Williamson JA, Fenner PJ, Burnett JW, Rifikin JF. Venomous and poisonous marine animals. 1st ed. Sydney: University of New South Wales Press, 1996. Williamson JA, Callanan VI, Hartwick RF. Serious envenomation by the northern Australian box-jellyfish (Chironex fleckeri). Med J Aust 1980; 1: 13-15. Williamson JA, Le Ray LE, Wohlfahrt M, Fenner PJ. Acute management of serious envenomation by box-jellyfish (Chironex fleckeri). Med J Aust 1984; 141: 851-853. Currie BJ. Clinical toxicology: a tropical Australian perspective. Ther Drug Monit 2000; 22: 73-78. Currie BJ, Khanh DM, Alderslade P, et al. Jellyfish envenomation in the Northern Terrritory of Australia. Toxicon 1992; 30: 501. Currie BJ, Wood YK. Identification of Chironex fleckeri envenomation by nematocyst recovery from skin. Med J Aust 1995; 162: 478-480. Currie B. Clinical implications of research on the box-jellyfish Chironex fleckeri. Toxicon 1994; 32: 1305-1313. Lumley J, Williamson JA, Fenner PJ, et al. Fatal envenomation by Chironex fleckeri, the north Australian box jellyfish: the continuing search for lethal mechanisms. Med J Aust 1988; 148: 527-534. Barnes JH. Cause and effect in Irukandji stingings. Med J Aust 1964; 1: 897-904. Little M, Mulcahy RF. A year's experience of Irukandji envenomation in far north Queensland. Med J Aust 1998; 169: 638-641. Fenner PJ, Williamson JA, Callanan VI, Audley I. Further understanding of, and a new treatment for, "Irukandji" (Carukia barnesi) stings. Med J Aust 1986; 145: 569-574. Currie B. Box-jellyfish in the Northern Territory. N T Dis Control Bull 1998; 5: 12-14. Guenin DG, Auerbach PS. Trauma and envenomations from marine fauna. In: Tintinalli JE, Ruiz E, Krome RL, editors. Emergency medicine — a comprehensive study guide. 4th ed. New York: McGraw-Hill, 1996: 868-873. Lill J. Fatal sting. Box jellyfish kills boy, 5. The Cairns Post 2000 Jan 25: 1. King GK. Acute analgesia and cosmetic benefits of box-jellyfish antivenom. Med J Aust 1991; 154: 365-366. Beadnell CE, Rider TA, Williamson JA, Fenner PJ. Management of a major box jellyfish (Chironex fleckeri) sting. Lessons from the first minutes and hours. Med J Aust 1992; 156: 655-658. Holmes JL. Marine stingers in far north Queensland. Australas J Dermatol 1996; 37 Suppl 1: S23-S26. Pereira PL, Carrette T, Cullen P, et al. Pressure immobilisation bandages in first-aid treatment of jellyfish envenomation: current recommendations reconsidered. Med J Aust 2000; 173: 650-652. Reed KM, Bronstein BR, Baden HP. Delayed and persistent cutaneous reactions to coelenterates. J Am Acad Dermatol 1984; 10: 462-465. Pierard GE, Letot B, Pierard F. Histologic study of delayed reactions to coelenterates. J Am Acad Dermatol 1990; 22: 599-601. Burnett JW, Cobbs CS, Kelman SN, Calton GJ. Studies on the serologic response to jellyfish envenomation. J Am Acad Dermatol 1983; 9: 229-231.(Received 20 Apr, accepted 13 Aug, 2001) Authors' details Royal Darwin Hospital, Darwin, NT. Gerard M O'Reilly, MB BS, Emergency Registrar; currently, Emergency Registrar, Alfred Hospital, Melbourne, VIC. Geoffrey K Isbister, BSc, MB BS, Emergency Registrar; currently, Toxicology Registrar, Department of Clinical Toxicology and Pharmacology, Newcastle Mater Hospital, Newcastle, NSW. Greg T Treston, DTMH, DIMCRCS, FACEM, Director of Emergency Department; currently Consultant, Emergency Department, John Flynn Hospital, Tugun, QLD. Menzies School of Health Research, Darwin, NT. Paula M Lawrie, BSc, Technical Officer. Bart J Currie, FRACP, FAFPHM, DTMH, Head of Tropical Medicine and International Health Unit; and Professor in Medicine, NT Clinical School, Darwin, NT. Reprints will not be available from the authors. Correspondence: Professor B J Currie, Tropical Medicine and International Health Unit, Menzies School of Health Research, PO Box 41096, Casuarina, NT 0811. bartATmenzies.edu.au Make a comment 1: Common Northern Territory jellyfish and their nematocysts Chironex fleckeri A. B. Nematocysts from C. fleckeri (original magnification, x 400; sticky-tape preparation; no stain). "Darwin carybdeid" C. D. "Darwin carybdeid" nematocyst (original magnification, x 1000; eosin stain). Nematocysts from C. fleckeri are usually elongated ellipses (cigar-shaped), while those from carybdeid (four-tentacled box-jellyfish) species are usually less elongated and more lemon-shaped or round. Back to text 2: Protocol for hospital treatment of Chironex fleckeri stings in the Northern Territory 1. If necessary, attend to airway, breathing and circulation and give oxygen. 2. Apply vinegar to the stings for at least 30 seconds to inactivate remaining nematocysts. 3. If patient is unconscious or has life-threatening cardiac or respiratory decompensation or significant arrhythmia, administer at least one ampoule of antivenom intravenously (20 000 units per ampoule, diluted 1:10 with an isotonic crystalloid solution such as Hartmann's solution or isotonic saline, given over 5-10 minutes). In a life-threatening situation where response remains inadequate, up to three ampoules may be given consecutively. 4. Cardiopulmonary resuscitation should be continued in a patient with ongoing cardiac arrest until after further therapy with antivenom (at least six ampoules total dose if available) and consideration of cardioactive drugs. 5. For non-life-threatening stings (no cardiac or respiratory decompensation), use ice-packs for initial pain relief, together with oral or parenteral analgesia if necessary (pethidine, 1 mg/kg up to 50 mg adult dose initially, or morphine, 0.1 mg/kg up to 5 mg initially, but can be repeated). For pain not relieved by ice-packs and narcotic analgesia, administer one ampoule of antivenom intravenously as above. Back to text 3: Jellyfish sting presentations to Royal Darwin Hospital, 1999-2000 Back to text 4: Chironex fleckeri stings A. Severe sting on Day 2. B. Hypersensitivity reaction seen 10 days after a sting. Back to text 5: Correlation between clinical presentation and nematocyst identification in 39* jellyfish stings Nematocyst appearance Presentation Chironex fleckeri Other jellyfish† Not detected Typical of C. fleckeri (n = 27)* 23 1 3 Not typical 0 5 7 "Irukandji" syndrome (n = 4) 0 0 4 Other (n = 8) 0 5 3 * Nematocyst sampling was not performed in one patient with a typical C. fleckeri presentation. † All non-C. fleckeri-appearing nematocysts were consistent with carybdeid nematocysts, although degenerate C. fleckeri nematocysts may sometimes look similar. Back to text

Gerard M O'Reilly · Geoffrey K Isbister · Paula M Lawrie · Greg T Treston · Bart J Currie

Notable Cases Caffeine-induced cardiac arrhythmia: an unrecognised danger of healthfood products We describe a 25-year-old woman with pre-existing mitral valve prolapse who developed intractable ventricular fibrillation after consuming a "natural energy" guarana health drink containing a high concentration of caffeine. This case highlights the need for adequate labelling and regulation of such products. Marianne E Cannon, Clive T Cooke and James S McCarthy MJA 2001; 174: 520-521 Clinical record - Discussion - References - Authors' details - - More articles on Toxicology While caffeine is widely used in most Western societies, caffeine toxicity is rare, and certainly rarely diagnosed. Case reports of death from caffeine toxicity number approximately 20 in the medical literature.1-3 We report a case of sudden death in a young woman which was associated with ingestion of caffeine present in guarana, a widely available health supplement marketed as a "natural" source of energy, and targeted to young people in advertising. Clinical record A 25-year-old woman had been working at a bar where she was seen to collapse. Police at the scene started cardiopulmonary resuscitation shortly afterwards. An ambulance arrived several minutes later and she was defibrillated according to ambulance protocol, with a total of 12 defibrillation attempts. She arrived at the emergency department in ventricular fibrillation and was resuscitated according to advanced cardiac life support guidelines for a further 20 minutes. At no stage did she regain a spontaneous cardiac output. Further history (which became available later) indicated that the patient had been diagnosed with mitral valve prolapse. She had been referred to a cardiologist because of palpitations. He had raised the issue of caffeine intake, and she had agreed to limit this to a cup of tea daily. Her previously recorded resting electrocardiogram was normal, with no evidence of QT prolongation. On the day of her death she had been given a 55 mL squirt bottle of "Race 2005 Energy Blast with Guarana and Ginseng", which she had nearly emptied. Other staff working at the bar had also been given bottles of Race 2005. She had not consumed other caffeine-containing substances. At autopsy, the patient was found to have sclerosis and myxoid change of the mitral valve leaflets. A toxicological screen for all common prescribed and non-prescribed drugs (including opiates, cannabis, amphetamines, and cocaine metabolites) was performed. Assay methods included gas chromatography and mass specrometry (GC-MS) and immunoassay. Caffeine was detected by GC-MS; the toxicology screen was negative for other substances. High pressure liquid chromatography revealed a caffeine concentration of 19 mg/L (non-preserved) in aortic blood. The caffeine concentration in the bottle of Race 2005 Energy Blast was assayed at the Chemistry Centre of Western Australia and yielded a level of 10 g/L, which is more than 60 times the concentration of caffeine in cola beverages (see Box).4 A similar bottle was later shown to have a caffeine concentration of 19 g/L. Discussion The wide availability and toxicology of "natural" tonics and remedies and the regulation of such substances has been the subject of vigorous debate in both the lay press and the medical literature.6-10Guarana is produced from the seeds of the guarana plant (Paullina cupana), a creeping Amazonian shrub. The seeds are black "like an eye" and contain 3.6%-5.8% caffeine.11 The substance is named after the Guarani Amazonian tribe, who originally used the seeds to brew a drink.11 In Brazil, guarana is commonly used as an astringent, a flavouring, and as a stimulant, and it is increasingly being used in similar products internationally. Such products are widely available at pharmacies and natural food outlets, and are marketed as natural sources of energy. Caffeine is a natural alkaloid methylxanthine. Ninety-nine per cent is absorbed after oral ingestion, the blood concentration peaks 1-1.5 hours after ingestion, and its half-life in adults is 3-6 hours. Caffeine is metabolised by the P450 hepatic enzyme system.12 The pharmacodynamic profile of caffeine is similar to that of theophylline, another methylxanthine, in that it inhibits the adenosine receptor and acts as a phosphodiesterase inhibitor.12 At high serum levels, enzyme saturation occurs, and elimination follows zero-order kinetics, with constant elimination regardless of serum level.12 Caffeine increases intracellular calcium concentrations, causes noradrenaline release and sensitises dopamine receptors. The pharmacological effects of caffeine include central nervous system (CNS) and cardiac stimulation, as well as coronary vasodilatation. It relaxes smooth muscle, stimulates skeletal muscle, has a weak diuretic action, and its metabolic effects include hypoglycaemia. While toxicity generally occurs at serum levels over 25 mg/L, the correlation between concentration and clinical effects is poor.4 The measured concentration of 19 mg/L in our patient may reflect postmortem changes in drug level, or an enhanced sensitivity to caffeine toxicity in this patient. The measured concentration is the equivalent of what would result from drinking approximately 15-20 cups of coffee.4 The toxic effects of caffeine include vomiting and abdominal pain followed by CNS symptoms, including agitation, altered conscious state, rigidity and seizures.4 Cardiovascular effects include supraventricular and ventricular tachyarrhythmias, and significant metabolic disturbances may occur, including hypokalaemia and hyperglycaemia. Suggested management for caffeine toxicity, in addition to general supportive measures, includes multidose charcoal therapy, and extracorporeal elimination by charcoal haemoperfusion.13 One proposed mechanism for the seizures and cardiac arrhythmias is the blockade of adenosine receptors.12 Thus, there is a theoretical rationale for the use of adenosine in this setting, particularly if seizures are refractory to benzodiazepine agents.14 Likewise, as there is adrenergic stimulation, parenteral -blocker therapy (propranolol or esmolol) should be considered for treating ventricular arrhythmias.15 Most deaths associated with caffeine intoxication have occurred after overdose with diet pills and stimulants, and most have occurred in young patients without known underlying heart disease or variant of normal, such as mitral valve prolapse. At least two case reports document sudden death in patients who "walked" into an emergency department.14 After the death of our patient, the Western Australian Coroner recommended that Race 2005 Energy Blast be removed from the local market, and the product was recalled nationally by letter to distributors in August 1999. However, many other products containing guarana (eg, "energy" tablets containing 35 mg of caffeine each, as well as a variety of energy drinks) remain available Australia-wide. With the growing use of guarana-based products containing high levels of caffeine, there is an obvious potential for lethal overdose. Our patient had a relatively common cardiac abnormality, present in 2.4% of the population.16 While mitral valve prolapse has been associated with sudden death, the risk of this is low.17 Malignant arrhythmias may occur in the absence of cardiac stimulants, but the association of arrhythmia with drugs that increase cardiac irritability is well known. The role of caffeine in this woman's death is supported by her history of palpitations associated with caffeine ingestion, a history that had prompted her cardiologist to advise her to limit her caffeine intake. In this patient's case the Coroner found that the high level of caffeine was associated with the development of an intractable arrhythmia. This case highlights the need for more careful regulation of "natural" products, including warnings for patients with underlying health problems, and clear labelling to document the presence of any constituents with potentially toxic effects. It also shows the need for medical practitioners to be familiar with the more widely used "natural"-remedy substances, and their toxicological profile. Acknowledgements: We thank Dr Julian Stella and Dr Peter Sprivulis for their assistance in the preparation of this manuscript. Disclosure: We did not receive any financial or other support for this work, and have no financial or professional relationships that may pose a conflict of interest. References Garriott JC, Simmons LM, Poklis A, Mackell MA. Five cases of fatal overdose from caffeine-containing "look-alike" drugs. J Anal Toxicol 1985; 9: 141-143. Mrvos RM, Reilly PE, Dean BS, Krenzelok EP. Massive caffeine ingestion resulting in death. Vet Hum Toxicol 1989; 31: 571-572. Walsh I, Wasserman GS, Mestad P, Lanman RC. Near-fatal caffeine intoxication treated with peritoneal dialysis. Pediatr Emerg Care 1987; 3: 244-249. Lewin NA. Caffeine. In: Goldfrank LR, editor. Goldfrank's toxicologic emergencies. 6th ed. Stamford: Appleton & Lange, 1998: 555-562. Abbott PJ. Caffeine: a toxicological overview. Med J Aust 1986; 145: 518-521. Angell M, Kassirer JP. Alternative medicine — the risks of untested and unregulated remedies. N Engl J Med 1998; 339: 839-841. De Smet PA. Should herbal medicine-like products be licensed as medicines? BMJ 1995; 310: 1023-1024. Ernst E. Harmless herbs? A review of the recent literature. Am J Med 1998; 104: 170-178. Shaw D. Risks or remedies? Safety aspects of herbal remedies in the UK. J R Soc Med 1998; 91: 294-296. Kessler DA. Cancer and herbs. N Engl J Med 2000; 342: 1742-1743. Duke JA. CRC Handbook of medicinal herbs. Boca Raton: CRC Press, 1985. Serafin WE. Drugs used in the treatment of asthma. In: Hardman JG, Limbird LE, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996. Nagesh RV, Murphy KA. Caffeine poisoning treated by hemoperfusion. Am J Kidney Dis 1988; 4: 316-318. Shum S, Seale C, Hathaway D, et al. Acute caffeine ingestion fatalities: management issues. Vet Hum Toxicol 1997; 39: 228-230. Pentel P. Toxicity of over-the-counter stimulants. JAMA 1984; 252: 1898-1903. Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 1999; 341: 1-7. Duren DR, Becker AE, Dunning AJ. Long-term follow-up of idiopathic mitral valve prolapse in 300 patients: a prospective study. J Am Coll Cardiol 1988; 11: 42-47. (Received 5 Oct 2000, accepted 13 Mar 2001) Authors' details Department of Emergency Medicine, Fremantle Hospital, Fremantle, WA. Marianne E Cannon, MB BS, FACEM, Emergency Medicine Staff Specialist. PathCentre, QEII Medical Centre, Nedlands, WA. Clive T Cooke, BMedSci, FRCPA, Forensic Pathologist. University of Western Australia, Department of Medicine, Fremantle Hospital, Fremantle, WA. James S McCarthy, MB BS, FRACP, Senior Lecturer. Reprints will not be available from the authors. Correspondence: Dr M E Cannon, Department of Emergency Medicine, Fremantle Hospital, Fremantle, WA 6959. mariannecannonAThotmail.com Make a comment Caffeine content of various food, drinks and medicines Substance Defined dose* Concentration Tea 40mg per cup (approx.) 0.16g/L Coffee 100mg per cup (approx.) 0.4-1.6g/L Chocolate (30g) 4mg Cola 0.15g/L Diet pills 75-200mg Race 2005 (30mL "dose") 300-570mg 10-19g/L *After Lewin4 and Abbott.5 Back to text

Marianne E Cannon · Clive T Cooke · James S McCarthy

Bites and Stings Pressure immobilisation bandages in first-aid treatment of jellyfish envenomation: current recommendations reconsidered Peter L Pereira, Teresa Carrette, Paul Cullen, Richard F Mulcahy, Mark Little and Jamie Seymour MJA 2000; 173: 650-652 Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Emergency medicine Abstract Objective: To evaluate whether applying pressure equivalent to that of pressure immobilisation bandages (PIB) causes release of additional venom from discharged jellyfish nematocysts. Design: In-vitro experiment -- the venom beads released from electrically activated Chiropsalmus sp. nematocysts were viewed under direct microscopy before and after applying 40 mmHg pressure (replicating the pressure of PIB); and saline washings of discharged nematocysts before and after applying pressure were tested for toxicity (time to ventricular standstill after injecting into live prawns). Results: Applying 40 mmHg pressure caused the venom beads to visibly increase in size, consistent with pressure expressing further venom from the discharged nematocysts. First washings of the nematocyst shafts before compression produced ventricular standstill in prawns within 60 seconds (n = 3); second washings did not produce standstill during 540 seconds of observation (n = 3); and washings after applying 40 mmHg pressure showed a return of toxicity, with ventricular standstill in all prawns within 180 seconds (n = 3). Conclusion: Discharged nematocysts are by no means empty and harmless. Applying pressure results in further release of nematocyst venom. The currently recommended practice of applying PIB in the initial treatment of patients stung by a jellyfish may exacerbate the envenomation, and thus should not be recommended. Introduction The application of pressure immobilisation bandages (PIB) in the first-aid treatment of jellyfish envenomation remains controversial. It is currently recommended by the Australian Resuscitation Council,1 by the Queensland Surf Life Saving Association2 and the Queensland Ambulance Service,3 but not by authorities in the Northern Territory.4,5 The evidence to support the use of PIB is anecdotal,6 and its use is a direct extrapolation of PIB use in elapid snakebite. In snakebite, its beneficial effects have been proposed7 and supported by published case reports.8,9The effect of PIB is to retard the dissipation of snake venom into the circulation by impeding lymphatic flow. This protects target tissues by confining the toxin to the affected limb until the patient is treated with antivenom. In snakebite, the venom is released into the tissues and the delivery apparatus (the snake's fangs) does not remain at the bite site. By contrast, in jellyfish stings, the venom is delivered by specialised cells (nematocysts) which have barbed shafts that adhere to the skin. Unless the nematocysts have entirely discharged their venom, applying pressure (as with PIB) has the potential to worsen the envenomation. Our anecdotal experience is that patients with jellyfish stings whose first aid includes PIB have more severe and prolonged symptoms. Furthermore, no scientific evidence supports the use of PIB in the treatment of box jellyfish stings.10 We designed an experiment to test the hypothesis that applying direct pressure to discharged nematocysts releases further venom. Methods Tentacles from live Chiropsalmus sp. (a closely related species to the box jellyfish Chironex fleckeri) were collected and placed on human amniotic membrane, which in turn was placed over the open end of a glass cylinder (4.5 cm in diameter and 5.5 cm in depth). To cause the nematocysts to discharge, we applied a 6 volt, 3 ampere direct current charge across the tentacles for two seconds. Such electrical augmentation is currently used to collect venom from jellyfish for antivenom production.11 After removal of the tentacles, the membrane was inverted, leaving the nematocyst bodies lying within the cylinder and their penetrating shafts directed externally through the membrane. An aneroid sphygmomanometer (bladder removed) was then attached to the other end of the cylinder (Box 1) to apply pressure to the discharged nematocysts. We used a pressure of 40 mmHg, as pressures of between 40 and 70 mmHg from PIB have been found to obstruct lymphatic flow in simulated snake envenomation.12 Through a dissecting microscope (x 100 magnification) small beads of clear fluid were noted on the tips of the shafts (Box 2). With constant visualisation of these beads, 40 mmHg pressure was applied, and a subjective estimate was made as to whether the pressure altered the size of the beads. To confirm the nature of these beads, the shafts from the discharged nematocysts were washed repeatedly with 2 mL of isotonic saline. The first washing was after activation of the nematocysts (A); the second (B) further cleaned the nematocysts; and the final washing (C) occurred after pressure was applied (and released). Live adult prawns (Penaeus mergenensus) were then injected with one of the three washes (0.2 mL intramuscular injection into the second abdominal segment) and their heart rate was observed every 30 seconds for a period of 10 minutes. The time to ventricular standstill was recorded as a measurement of toxicity. Each solution was administered to three prawns. Statistical analysis Statistical analysis was performed using SPSS.13 Differences in the mean time to cardiac death for prawns in each of the three treatments were determined using a balanced one-way analysis of variance with type I sums of squares. Differences between the means of the treatments were determined using least significant difference (LSD) post-hoc analysis. Results The venom beads, viewed under direct microscopy, visibly increased in size on applying 40 mmHg pressure. The heart rates of the nine prawns at time zero (before injection of the washings from the nematocyst shafts) were not statistically different (F2,6 = 1.895; P = 0.230), but there were significant differences between time from injection of the washings to ventricular standstill for the three different washings (F20,65 = 8.53; P < 0.001) (Box 3). Solution A: In the three prawns administered the first washing, ventricular standstill occurred within 60 seconds of injection. Solution B: All three prawns administered the second washing were unaffected by this inoculum during 540 seconds of observation, apart from a minor reduction in heart rate at 60 seconds for one prawn. Solution C: The third washing (after applying pressure), although not as potent as the first washing, caused ventricular standstill within 180 seconds in all three prawns. Discussion Our experiment shows clearly that further venom is expressed by applying pressure (equivalent to that of PIB) to discharged nematocysts. Furthermore, direct visual examination revealed an increase in bead size related to the amount of pressure being applied. This suggests that our simulated PIB caused mechanical expression of nematocyst contents rather than nematocyst reactivation, in which a triggered quantum of venom would be expected. We showed that Solution A (with venom from initially activated nematocysts) produced the anticipated ventricular standstill when injected into prawns. The relatively innocuous nature of Solution B, which did not produce any ventricular standstill, shows that Solution A had effectively cleaned the nematocyst of any substantial amount of venom. Solution C showed a return of toxicity after 40 mmHg pressure was applied. Thus, pressure applied to discharged nematocysts of Chiropsalmus sp. results in further venom being released. Vinegar, presumably through a chemical process, is a potent inactivator of nematocysts' firing mechanism. Not discounting this important function, its role in first aid is limited to inactivating undischarged nematocysts. Any inference that it has a continuing protective effect with discharged nematocysts is probably incorrect, as further expression of venom from discharged nematocysts appears to be mechanical rather than triggered. Given that the physical processes behind nematocyst discharge in all jellyfish are similar, and that nematocyst discharge operates similarly, there is sufficient reason to believe that the use of PIB on any jellyfish sting site may exacerbate the envenomation, irrespective of whether vinegar has been applied. Until evidence to the contrary is available, we recommend that applying PIB is not part of the management of this life-threatening condition. An amended first-aid protocol for jellyfish stings is given in Box 4. References Envenomation -- jellyfish stings. Australian Resuscitation Council. Policy Statement No 8.9.6. Melbourne: Australian Resuscitation Council, July 1996. Fenner P. The marine stinger guide -- dangerous jellyfish and other sea creatures in Australia. Identification and treatment. Brisbane: The Surf Life Saving Association of Australia, Queensland State Centre Inc, 1985. Case management guidelines for poisoning, envenomation, cuboidal jellyfish. Revised May 1998. Queensland Ambulance Service -- clinical practice manual. AL 10, Guideline A 12-6. Brisbane: Queensland Ambulance Service, May 1998. Currie B. Box-jellyfish in the Northern Territory. Northern Territory Disease Control Bulletin, Sept 1998; 5(3): 12-14. Currie B. Clinical implications of research on the box-jellyfish Chironex fleckeri. Toxicon 1994; 32: 1305-1313. Williamson J, Fenner P, Burnett J. Principles of patient care in marine envenomations and poisonings. In: Williamson JA, Fenner PJ, Burnett JW, Rifkin JF, editors. Venomous and poisonous marine animals -- a medical and biological handbook. Sydney: University of New South Wales Press, 1996. 98-118. Sutherland SK, Coulter AR, Harris RD. Rationalisation of first-aid measures for elapid snakebite. Lancet 1979; 1: 183-185. Sutherland SK, Leonard RL. Snakebite deaths in Australia 1992-1994 and a management update. Med J Aust 1995; 163: 616-618. Currie B, Fitzmaurice M, Oakley J. Resolution of neurotoxicity with anticholinesterase therapy in death adder envenomation. Med J Aust 1988; 148: 522-525. Little M, Mulcahy RF. A year's experience of Irukandji envenomation in far north Queensland. Med J Aust 1998; 169: 638-641. Barnes JH. Extraction of Cnidaria venom from living tentacle. In: Russell FE, Saunders PR, editors. Animal toxins. London: Pergamon Press, 1967: 115-129. Howarth DM, Southee AE, Whyte IM. Lymphatic flow rates and first-aid in simulated peripheral snake or spider envenomation. Med J Aust 1994; 161: 695-700. SPSS [computer program], version 9. Chicago, Ill: SPSS Inc, 1999. (Received 3 Jul, accepted 19 Sep, 2000) Authors' details Department of Emergency Medicine, Cairns Base Hospital, Cairns, QLD. Peter L Pereira, MB BS, FACEM, Director of Emergency Medicine, and Director of C-Airmed; Paul Cullen, BMed, FACEM, Staff Specialist; Richard F Mulcahy, MB BS, Staff Specialist; Mark Little, DTM&H, FACEM, MPH&TM, Staff Specialist. School of Tropical Biology, James Cook University, Cairns, QLD. Teresa Carrette, BSc, Senior Researcher; Jamie Seymour, BSc(Hons), PhD, Lecturer. Reprints will not be available from the authors. Correspondence: Dr P L Pereira, Department of Emergency Medicine, Cairns Base Hospital, PO Box 902, Cairns, QLD 4870. peter_pereiraAThealth.qld.gov.au 1: The experiment Pressure of 40mmHg applied to discharged nematocysts across an amniotic membrane to simulate pressure immobilisation bandages applied to jellyfish stings. Return to text 2: The discharged nematocysts Beads of clear fluid on the shafts of the nematocysts (original magnification x 100) after applying pressure. Return to text 3: Heart rate v time after injection Effect of the three injected solutions on the heart rate of prawns, showing time to ventricular standstill. Solution A = first washings of discharged nematocysts; Solution B = second washings; Solution C = washings after applying 40 mmHg pressure to the discharged nematocysts. Return to text 4: Proposed first-aid management of cuboidal jellyfish stings (including species of Chironex, Chiropsalmus, Carukia and any jellyfish causing "Irukandji" syndrome) Ensure rescuer safety Resuscitate patient as necessary Apply vinegar concomitantly (pour onto the site for at least 30 seconds) Gently apply a vinegar-soaked dressing Do not apply pressure immobilisation bandages Transport patient to the nearest medical facility Provide supportive management as required Return to text

Peter L Pereira · Teresa Carrette · Paul Cullen · Richard F Mulcahy · Mark Little · Jamie Seymour

Notable Cases Poisoning by Amanita phalloides ("deathcap") mushrooms in the Australian Capital Territory Amanita phalloides ("deathcap") mushrooms are widespread in south-eastern Australia. Seven patients presented to hospital in the Australian Capital Territory with poisoning by this mushroom between 1988 and 1998. Three developed hepatoxicity and one died. Because A. phalloides is becoming more widespread, increased community and medical awareness is needed to reduce the frequency and morbidity of poisoning. Amanita phalloides mushrooms growing under an oak tree on the western shores of Lake Burley Griffin, Canberra. MJA 1999; 171: 247-249 Geoffrey M Trim, Heino Lepp, Matthew J Hall, Robin V McKeown, Geoffrey W McCaughan, Geoffrey G Duggin and David G Le Couteur Introduction - Clinical records - Discussion - Acknowledgements - References - Authors' details - - More articles on Toxicology Introduction The "deathcap" mushroom, Amanita phalloides, accounts for most deaths after mushroom ingestion.1,2 There are four clinical phases of poisoning: an initial asymptomatic latent phase, a gastrointestinal phase characterised by watery diarrhoea, a honeymoon period when symptoms temporarily resolve, and a final hepatic phase characterised by hepatic and renal failure. In an adult, death may ensue within 7-10 days of ingestion of a single cap.1,2 We report seven cases of poisoning by A. phalloides mushrooms that occurred in the Australian Capital Territory (ACT) between 1988 and 1998. The only other Australian reports have been from Victoria,3,4 and there is now concern that the mushroom may be becoming more widespread in Australia. Clinical records The seven cases are summarised in the Box. Patients comprised six adults aged 20-46 years and a seven-year-old child. All patients had eaten cooked mushrooms that they had picked in gardens or streets of Canberra, except the child, who had eaten part of a raw mushroom she had picked in her schoolyard. Three Laotians were poisoned at the same time when they mistook A. phalloides for the superficially similar-appearing paddy straw mushroom (Volvariella volvacea), common in South-East Asia. The dose ranged from a quarter to eight mushrooms. All patients presented after one to two days with diarrhoea and, in most cases, vomiting, except the child, who vomited within two hours and was brought for medical attention immediately. The diagnosis was made on initial presentation in only this child and the other 1998 patient (Patient 2). Three patients developed significant hepatic dysfunction, and two were transferred to a liver transplant unit, one of whom died. Details of the two who were transferred follow. Patient 1 In 1995, a 46-year-old man ate eight mushrooms which he had picked in a north Canberra suburb. He presented with vomiting and diarrhoea the next day, but, as he was confident that the mushrooms were not A. phalloides, he was discharged home after receiving intravenous rehydration. He presented again two days later with hepatic and renal failure. Initial investigations revealed the following serum levels: alanine aminotransferase (ALT) > 10 000 U/L (reference range [RR], 5-55 U/L); bilirubin, 114 µmol/L (RR, 3-20 µmol/L); creatinine, 535 µmol/L (RR, 40-90 µmol/L); and prothrombin time - international normalised ratio (PT-INR) > 10. A mycologist identified A. phalloides growing in the street where the patient had picked the mushrooms and also identified the mushroom stalks that he had discarded in a rubbish bin. The patient was transferred to a liver transplant unit but died from hepatic failure six days after mushroom ingestion. Postmortem examination of his liver revealed complete necrosis of parenchyma, with one residual island of intensely vacuolated hepatocytes with severe intracanalicular biliary stasis. No viable hepatocytes were seen. Patient 2 In 1998, a 39-year-old man ate three mushrooms picked from his back garden in an inner Canberra suburb. The mushrooms were cooked as a pasta sauce. He had been previously well but had been taking griseofulvin for six months to treat a fungal toenail infection. Eighteen hours after ingestion, he developed watery diarrhoea. He presented to hospital with dehydration and epigastric discomfort 36 hours after ingestion. Initial investigations revealed the following serum levels: ALT, 914 U/L; bilirubin, 24 µmol/L; and creatinine, 102 µmol/L. He had evidence of metabolic acidosis, with pH of 7.30 (RR, 7.34-7.44) and bicarbonate level of 18.6 mmol/L (RR, 22-26 mmol/L). The mushrooms were identified as A. phalloides by a mycologist. The patient was transferred to a liver transplant unit and treated with intravenous fluids, high dose penicillin and N-acetylcysteine. Three days after mushroom ingestion, his serum ALT level peaked at 8199 U/L, and PT-INR at 4.7, but he did not develop encephalopathy. He subsequently made an uneventful recovery. Discussion Our seven patients poisoned by A. phalloides mushrooms in the ACT is the only series reported in Australia. In five of our seven patients, the diagnosis was not made on initial presentation, and in one it was not suspected at all, despite a history of mushroom ingestion and characteristic clinical picture. Three patients developed significant hepatic dysfunction, two were transferred to a liver transplant unit and one died. There have been only two other reports of poisoning by A. phalloides mushrooms in Australia,3,4 both in Victoria. Neither case was diagnosed on initial presentation, and one was fatal.3A. phalloides is a mycorrhizal fungus (ie, it grows in a symbiotic association with the roots of trees, primarily oak trees). It produces a range of toxins (amatoxins). The major toxin, a cyclic peptide, amanitin, inhibits RNA polymerase II and is not inactivated by cooking, freezing or drying. The lethal dose is about 0.1 mg/kg, which may be contained in as little as one mushroom.5 Amanitin is usually cleared rapidly, mainly by renal excretion.6 Recommended treatment of A. phalloides poisoning includes vigorous gastrointestinal decontamination.7 Early and aggressive decontamination may have prevented toxicity in the seven-year-old child. Supportive care, including intravenous rehydration, is thought responsible for most of the improvement in mortality, from well over 50% early this century to 20%-30% in recent decades.1 Many specific antidotes have been used, although no prospective-trial evidence is available. Retrospective clinical studies and animal studies support the use of high dose penicillin (0.5-1 million units/kg per day) and parenteral silibinin, an extract of milk thistle available only in Europe. Both are thought to act by inhibiting amatoxin uptake into hepatocytes and by interfering with its enterohepatic circulation.1,7 Cimetidine, a hepatic enzyme inhibitor, may be harmful.8 We speculate that, in Patient 1, long-term use of griseofulvin (a hepatic enzyme inducer) before poisoning may have increased the rate of detoxification of amatoxin and thereby contributed to survival. Liver transplantation may be used in cases that fail to respond to more conservative measures. It has been performed successfully for this indication in the United States since 1985,9 but has not been attempted for this indication in Australia. A. phalloides mushrooms have been described in many regions of south-eastern Australia. Collections have been made in several Melbourne suburbs,4,10,11 and the Victorian country centres of Riddells Creek, Morwell and Walhalla.11 The National Herbarium of Victoria and the State Herbarium in Adelaide hold collections of A. phalloides or very similar species from New South Wales, Tasmania and Victoria. A. phalloides mushrooms were first reported in Canberra in 19614 and are now widespread in the ACT. Although A. phalloides is found primarily in association with oak trees, there is concern among mycologists and toxicologists that it may develop the ability to grow in association with other trees, particularly Australian natives, and thereby spread dramatically. Associations between Eucalyptus spp. and Amanita spp. other than A. phalloides have been reported in other countries,12 and between Eucalyptus spp. and A. phalloides itself in Africa.13,14 There is anecdotal evidence of A. phalloides forming mycorrhizae with Eucalyptus spp. in Canberra (Richard Windsor, consultant botanist, Canberra, ACT, personal communication). A. phalloides is not the only mushroom to contain amatoxins. In the northern hemisphere, these toxins are found in other Amanita species and in species within the genera Conocybe, Galerina and Lepiota,1 which also occur in Australia. Four cases of Lepiota helviola poisoning have been reported from Adelaide. In each, hepatotoxicity occurred and amatoxins were identified.4,15 A. phalloides is now widely distributed in south-eastern Australia, and may become more widespread if it develops the ability to grow in association with eucalyptus trees. Increased community and clinician awareness is needed to reduce the incidence of poisoning and to improve outcomes. Wild mushrooms should not be eaten unless definitely identified as non-poisonous. Clinicians should consider A. phalloides poisoning in patients with vomiting, diarrhoea or abnormal liver function. Acknowledgements We thank Graham Bell (State Herbarium, Adelaide) and Tom May (National Herbarium of Victoria) for information about Amanita phalloides collections in their herbaria, and Richard Windsor (Canberra, ACT) for his comments about A. phalloides and Eucalyptus spp. in Canberra. References Benjamin DR. Amatoxin syndrome. Mushrooms: poisons and panaceas -- a handbook for naturalists, mycologists and physicians. New York: W H Freeman and Company, 1995: 198-241. Pond SM, Olson KR, Woo OF, et al. Amatoxin poisoning in northern California, 1982-1983. West J Med 1986; 145: 204-209. Nicholson FB, Korman MG. Death from Amanita poisoning. Aust N Z J Med 1997; 27: 448-449. Southcott RV. Notes on some poisonings and other clinical effects following ingestion of Australian fungi. S Aust Clin 1974; 6: 442-478. Weiland T. Poisonous principles of mushrooms of the genus Amanita. Science 1968; 159: 946-952. Jaeger A, Jehl F, Flesch F, et al. Kinetics of amatoxins in human poisoning: therapeutic implications. J Toxicol Clin Toxicol 1993; 31: 63-80. Floersheim GL. Treatment of human amatoxin mushroom poisoning: myths and advances in therapy. Med Toxicol 1987; 2: 1-9. Schneider SM, Vanscoy G, Michelson EA. Failure of cimetidine to affect phalloidin toxicity. Vet Hum Toxicol 1991; 33: 17-18. Klein AS, Hart J, Brems JJ, et al. Amanita poisoning: treatment and the role of liver transplantation. Am J Med 1989; 86: 187-193. Reid DA. A monograph of the Australian species of Amanita Pers. ex Hook (Fungi). Aust J Bot Supplementary Series No. 8, 1980: 48. Cole FM. Amanita phalloides in Victoria. Med J Aust 1993; 158: 849-850. May TW, Wood AE. Extra-Australian species associated with Eucalyptus. Fungi of Australia. Volume 2A. Canberra: Australian Biological Resources Study and CSIRO, CSIRO, 1997: 239-240. Malencon G, Bertault R. Flore des champignons supérieurs du Maroc. Tome I. Rabat, Morocco: Faculté des Sciences, 1970: 75. Pegler DN. Amanitaceae. A preliminary agaric flora of East Africa. London: HMSO, 1977: 296-297. Lloyd C, White J, Downes S, et al. Amatoxin poisoning following ingestion of Lepiota helviola. Report of two cases with hepatotoxicity. Abstracts of the 10th World Congress on Animal, Plant and Microbial Toxins. Singapore; 1991 3-8 Nov. 1991: 345. (Received 11 Feb, accepted 24 Jun, 1999) Authors' details Canberra Hospital, Canberra, ACT. Geoffrey M Trim, MB BS, Clinical Pharmacology Registrar; Robin V McKeown, PhC, Poisons Information Service; David G Le Couteur, FRACP, PhD, Associate Professor, The Canberra Clinical School of the University of Sydney. Australian National Herbarium, Centre for Plant Biodiversity Research, Canberra, ACT. Heino Lepp, BSc(Hons), Scientific Associate. Royal Prince Alfred Hospital, Sydney, NSW. Matthew J Hall, MB BS, Gastroenterology Registrar; Geoffrey W McCaughan, FRACP, PhD, Physician-in-Charge, Australian National Liver Transplant Unit; Geoffrey G Duggin, FRACP, Head, Toxicology Unit. Reprints will not be available from the authors. Correspondence: Associate Professor D G Le Couteur, Department of Clinical Pharmacology, The Canberra Hospital, Yamba Drive, Garran, ACT 2605. Email: david_lecouteurATdpa.act.gov.au Amanita phalloides mushrooms at different stages of the lifecycle. A mature "deathcap" typically has a greenish-brown to white cap, white gills on the underside of the cap, a white frill-like ring on a white to pale yellow-green stem, and a white underground cup. The deathcap may be mistaken by those unfamiliar with fungi for mushrooms of the genus Agaricus, the type most commonly grown for consumption. The deathcap also superficially resembles the edible paddy straw mushroom (Volvariella volvacea). Seven cases of poisoning by Amanita phalloides in the Australian Capital Territory, 1988-1998 YearAge (years) sexMushrooms ingested (identified*)SymptomsResults of liver function testsTreatmentOutcome 198820, M† Several (yes)Diarrhoea after 1-2 daysNormalNilRecovered 20, M† Several (yes)Diarrhoea after 1-2 daysNormalNilRecovered 20, F† Several (yes)Diarrhoea, vomiting after 1-2 daysNormal Intravenous fluidsRecovered 199546, M‡8 (yes)Diarrhoea, vomiting after 1-2 daysALT > 10 000 U/L; PT-INR > 10; creatinine 535 µmol/LTransferred to transplant unit, intravenous fluids, high dose penicillin, N-acetylcysteineDied 199745, MSeveral (no)Diarrhoea, vomiting after 2 daysALT, 2938 U/L; PT, 19 s; creatinine, 216 µmol/LIntravenous fluidsRecovered 199839, M§3 (yes)Vomiting, diarrhoea after 1-2 daysALT, 8199 U/L; PT-INR, 4.7Transferred to transplant unit, intravenous fluids, high dose penicillin, N-acetylcysteineRecovered 7, F1/4 (yes)Vomiting within 2 hoursNormalIntravenous fluids, whole bowel irrigation, multiple dose activated charcoal, high dose penicillinRecovered ALT = serum alanine aminotransferase level (reference range [RR], 5-55 U/L). PT-INR = prothrombin time, international normalised ratio. PT = prothrombin time (RR, 8-14 s). Creatinine = serum creatinine level (RR, 40-90 µmol/L). * Identity confirmed by a mycologist. † These three people from Laos were poisoned at the same time when they ate mushrooms picked from a Canberra street. ‡ Patient 1. § Patient 2.

Geoffrey M Trim · Heino Lepp · Matthew J Hall · Robin V McKeown · Geoffrey W McCaughan · Geoffrey G Duggin · David G Le Couteur

Notable Cases Echinacea-associated anaphylaxis Raymond J Mullins A woman with atopy experienced anaphylaxis after taking, among other dietary supplements, a commercial extract of echinacea. Hypersensitivity was confirmed by skinprick and RAST testing. Regular ingestion of echinacea by up to 5% of surveyed patients with atopy, combined with detection of echinacea-binding IgE in atopic subjects (19% by skin testing; 20% with moderate to strong reactivity by RAST testing), raises the possibility of severe allergic reactions, even with first-time use, due to cross-reactivity with other structurally similar allergens. Patients with atopy should be cautioned about the risk of developing life-threatening reactions to complementary medicines, including echinacea. MJA 1998; 168: 170-171 For the full text of this article, see the pdf version

Raymond J Mullins