Pharmacology

Antiplatelet drugs protect against myocardial infarction, stroke, cardiovascular death and other serious vascular events in patients with a history of previous vascular events or known risk factors for cardiovascular disease. Aspirin reduces the risk of serious vascular events in patients at high risk of such an event by about a quarter and is recommended as the first-line antiplatelet drug. Clopidogrel reduces the risk ...

Graeme J Hankey MD, FRACP · John W Eikelboom MB BS, FRACP

Differences in kava extraction methods may affect hepatotoxicity In this issue of the Journal, Gow and colleagues (page 442) report the first Australian case of fulminant hepatic failure attributed to a herbal product containing kava,1 while Moulds and Malani (page 451) note the cultural and economic importance of kava for Pacific island nations, and provide a balanced overview on kava safety and availability.2 For centuries kava has been widely consumed in Pacific island countries as a ceremonial beverage and for its mood-altering and stress-relieving properties. It is prepared as an aqueous emulsion of the crushed fresh or dried roots or lower stems of the kava shrub Piper methysticum ("intoxicating pepper").3 Pharmacological properties, such as anxiolytic activity, are attributed to a poorly characterised group of compounds termed kavalactones.3,4 In 1982, kava was introduced to some Arnhem Land Aboriginal communities from Pacific island countries, in part to reduce the harmful effects of alcohol.5 Kava use continued to rise during the 1980s and 1990s, supplied by a lucrative black market. Concerns about adverse health, social and economic effects of widespread heavy consumption resulted in the Northern Territory Kava Management Act in May 1998, which made the possession of more than 2 kg of kava illegal unless in accordance with a licence. However, an illegal trade continued, with profiteering by those distributing kava imported from several Pacific island countries. In October 2000, the Kava Management Act was amended to incorporate harm reduction objectives and a system of licensed kava supply, controlled by local Aboriginal community organisations. Over the last decade, there has been an expanding global market for herbal preparations made in Western countries and containing kava extracts.4 These products have been marketed for the treatment of anxiety, insomnia, premenstrual syndrome and stress, and sold over the counter as complementary medicines or dietary supplements.6 Since 1999, cases of severe hepatic toxicity in people using kava-containing herbal products have been reported from Europe and the United States.6,7 Subsequently, kava-based herbal products have been banned in some European countries, including the United Kingdom. In Australia, a practitioner alert and consumer advice were issued in February 2002 by the Therapeutic Goods Administration (TGA) concerning hepatotoxicity possibly related to kava-containing products. By late 2002, eight cases of liver transplantation after hepatic failure associated with use of kava-containing products had been reported from Europe, and two from the United States.6 The patient reported by Gow et al died soon after liver transplantation.1 As a result of this case, the TGA initiated a voluntary recall of all complementary medicines containing kava extracts on 15 August 2002.8 The TGA has 87 products containing kava on its Australian Register of Therapeutic Goods.8 Although details are sketchy for many of the at least 68 cases of suspected kava hepatotoxicity,4 with the herbal products sometimes containing additional ingredients, the increasing number of well documented cases1,6,7 make it likely that kava extracts are responsible for occasional severe progressive hepatotoxicity. However, the mechanism of this toxicity remains to be determined. Histological examination has shown portal inflammation with lymphocytes and eosinophils,6,7,9 and an idiosyncratic immune response to a reactive metabolite has been suggested as a possible cause.9 In two patients, phenotyping of the activity of cytochrome P450 isoform CYP2D6 showed that they were "poor metabolisers", and it was postulated that genetic differences in liver metabolism of kavalactones may be important.9 Moulds and Malani discuss the paradox that fulminant hepatic failure has not been documented with traditional kava use in Pacific countries.2 Kavalactones in herbal products are usually extracted with ethanol or acetone,6 and may differ critically from the aqueously extracted kavalactones used in Pacific countries and Aboriginal communities. Of note is an early study of the health effects of kava use in Aboriginal communities, which documented consistent abnormalities in liver function tests in heavy kava drinkers.5 A recent study in Arnhem Land has confirmed these findings, with abnormal serum levels of γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) in 61% and 50% of kava users, respectively.10 However, serum levels of alanine aminotransferase (ALT) were not raised in any kava drinkers. Furthermore, the abnormalities in liver function usually return to normal within 1–2 months of stopping kava use.10 The raised GGT and ALP levels combined with normal ALT levels in Aboriginal kava users do not suggest acute inflammation and are not consistent with the changes documented in the cases of hepatotoxicity associated with herbal products, where aminotransferase levels are especially high.1,6,7 Clinical surveillance in the Northern Territory over 20 years has not documented any cases of fulminant hepatic failure attributable to kava use. This is despite Aboriginal kava drinkers consuming kavalactones in doses estimated to be 10–50 times the recommended therapeutic doses for herbal products.3 However, the recent study confirmed adverse effects of kava, such as kava dermopathy and lymphocytopenia,10 which were documented in the 1980s.5 Although a rigorous systematic review found kava to be an effective symptomatic treatment option for anxiety,4 herbal preparations should not be used until the mechanism for hepatic toxicity is clearly ascertained. The abnormal but reversible GGT and ALP levels seen in heavy kava drinkers does not reflect the same pathological process. Whether the apparently idiosyncratic fulminant hepatic failure documented with herbal kava preparations can also occur with traditional aqueous extracts requires further surveillance. Close monitoring for this and other potential adverse effects of kava use in Aboriginal communities and Pacific countries is recommended, in addition to initiatives encouraging moderation in consumption.

Bart J Currie FRACP, DTMTH · Alan R Clough MSc

Pharmacological treatment remains the mainstay of the management of schizophrenia. Older, "typical" antipsychotics carry a significant burden of side effects, notably extrapyramidal and neurocognitive side effects. Newer, "atypical" agents carry a lower risk of extrapyramidal side effects. They appear to have added benefit for treating negative and cognitive symptoms of schizophrenia, and hence can enhance the quality of life of some patients. The choice of particular agents for individual patients requires a balancing of efficacy and side effects. Medication is only one element of what should be an individualised comprehensive treatment plan for people with schizophrenia.

Timothy J R Lambert BSc, MB BS, FRANZCP · David J Castle MD, MRCPsych, FRANZCP

Patients who fail to respond adequately to pharmacological treatment present an ongoing therapeutic challenge. The term "incomplete recovery" (IR) is preferred to the current term "treatment resistance" to describe these patients. IR should be considered from a multidimensional perspective that includes a broad range of symptoms and functional disabilities that are relevant to schizophrenia. The approach to the incompletely recovered patient needs to be systematic, with consideration given to the factors that may hamper recovery. "Atypical" (second-generation) antipsychotic drugs target various domains of symptoms relevant to IR. Adjunctive treatment strategies (eg, mood stabilisers, antidepressants, combinations of antipsychotics) may be useful, but should be undertaken in specialist psychiatric settings. Although pharmacological treatment is a necessary first step in managing incompletely recovered patients, adjunctive psychosocial interventions are needed to optimise treatment success.

Christos Pantelis MB BS, MRCPsych, FRANZCP · Timothy J R Lambert BSc, MB BS, FRANZCP

Objective: To achieve sustained improvement in use of cefotaxime and ceftriaxone (CEFX) in a major teaching hospital, as measured against national antibiotic guidelines.Design and setting: Pre- and post-intervention survey of CEFX use in the Royal Melbourne Hospital, a tertiary hospital in Melbourne, Victoria.Intervention: Web-based antimicrobial approval system linked to national antibiotic guidelines was developed by a multidisciplinary team and implemented in March 2001.Main outcome measures: Change in rate of CEFX use (defined daily doses [DDDs] per 1000 acute occupied bed days) over 8 months pre- and 15 months post-intervention; concordance of indication for CEFX with national antibiotic guidelines pre- and post-intervention.Results: CEFX use decreased from a mean of 38.3 DDDs/1000 bed days pre-intervention to 15.9, 18.7 and 21.2 DDDs/1000 bed days at 1, 4 and 15 months post-intervention. Concordance with national antibiotic guidelines rose from 25% of courses pre-intervention to 51% within 5 months post-intervention (P < 0.002). Gentamicin use also increased, from a mean of 30.0 to 48.3 DDDs/1000 bed days (P = 0.0001).Conclusion: The web-based antimicrobial approval system achieved a sustained reduction in CEFX use over 15 months as well as increased prescribing concordance with antibiotic guidelines. It has potential for linking to electronic prescribing and for wider use for other drugs, as well as for research into the epidemiology of antibiotic use.

Michael J Richards FRACP · Lyn-Li Lim MB BS · Marion B Robertson BPharm, MSc · Nicholas R Jones BPharm, Grad Dip Clinical Pharmacy · Simone E Taylor PharmD, Grad Cert CRM · Margarida M Duarte BA (CompSci), BEng (partial) · Dale A Kerr BBus (Information Systems) · Graham J Stanton · Peter D Ritchie MPubHlth, FACEM · Jonathan G A Dartnell BPharm, PhD

To the Editor: This is the first report of the use of magnesium sulfate to treat Irukandji syndrome. A previously well 26-year-old commercial diver was stung on the neck by a jellyfish while collecting sea cucumbers in Barrier Reef waters off Townsville in February 2003. As is typical for an Irukandji syndrome, he was asymptomatic for about 30 minutes, after which he developed back and abdominal pain, nausea and headache. He was retrieved from the scene by helicopter and arrived in the emergency department (ED) two hours after the onset of symptoms. On retrieval he had a blood pressure of 150/90 mmHg, agitation, marked diaphoresis, piloerection and some dyspnoea. A typical carybdeid jellyfish sting mark was present on the neck. The cardiac troponin I level was elevated from the time of admission. En route and in the ED he was treated with intravenous morphine and diazepam. Skin scrapings were taken for nematocyst identification. After he had received 27.5 mg of morphine and 15 mg of diazepam, his pain settled somewhat, but abdominal discomfort, agitation and profuse diaphoresis persisted. Despite the dyspnoea, he showed no other overt clinical signs of cardiac failure. Concern with the patient's increasing hypertension (170/100 mmHg five hours after envenomation) led to his being transferred to the high dependency unit (HDU) six hours after envenomation. It was decided to try a therapeutic trial of magnesium sulfate for this patient in an attempt to control the hypertension. This decision was taken on the basis of: the unsatisfactory results of measures taken thus far, the postulated hyperadrenergic basis of hypertension in Irukandji syndrome, the known 20%–30% fall in systemic vascular resistance associated with magnesium administration in hyperadrenergic states,1 and considerable experience within the HDU with managing severe pre-eclampsia. Intravenous magnesium sulfate was administered as a loading dose of 10 mmol followed by an infusion of 5 mmol per hour. Sympathetic features and agitation resolved, and pain nearly completely resolved towards the end of the loading dose. Of note, an early reduction in the rate of magnesium sulfate infusion resulted in recrudescence of hypertension, back pain and piloerection. The infusion was uneventfully reduced to 3 mmol per hour at 11 hours after envenomation, and discontinued at 20 hours after envenomation. No adverse effects related to the magnesium infusion were noted. The patient subsequently remained well. The troponin I level rose to a peak of 6.4 μg/L, and an echocardiogram was normal at 20 hours after envenomation. Irukandji syndrome is produced by carybdeid jellyfish envenomation2 and has been shown (in animals) to be associated with dramatically elevated serum noradrenaline levels.3 Severe hypertension in Irukandji syndrome can be difficult to treat and has been associated with two deaths from intracranial haemorrhage. The origin of the extensive, severe pain associated with the syndrome is unknown. Postulated mechanisms include ischaemia from widespread small vessel vasoconstriction resulting from a hyperadrenergic state, and sodium channel opening in afferent pain fibres. Other mechanisms are equally likely. Induced catecholamine release or direct toxicity have been proposed as the cause of myocardial injury. This may produce overt, and occasionally severe, cardiac failure. Magnesium decreases both catecholamine release and sympathetic terminal receptivity to catecholamines1 via multiple sites of action, including most calcium channel subtypes (both at the cell membrane and intracellularly), as well as modifying other cation fluxes. It reduces catecholamine-induced myocardial necrosis in phaeochromocytoma (Professor M James, Department of Anaesthesia, University of Cape Town, personal communication) and is widely used in other hyperadrenergic states, such as phaeochromocytoma and pre-eclampsia.1 The apparent efficacy of intravenous magnesium in our patient suggests the need to further investigate this therapy. A larger case series, a multicentre randomised trial of magnesium sulfate administration in Irukandji syndrome and a dose-finding study are under way.

Michael A Corkeron

To the Editor: McBride reports that there were four deaths from cancer before the age of 40 years in a group of 480 thalidomide-affected people in the United Kingdom, an approximate cumulative mortality rate of 0.83%.1 He compares this with the annual death rate in the under-40-years age group, and concludes that the rate is increased almost 100 times in those affected by thalidomide. The correct comparison is with the cumulative mortality rate in the general population from birth to age 40. From 1999 UK statistics,2 this is about 0.31% — that is, we would expect 1.48 deaths among 480 people. While the observed number of four is greater than this, it is only slightly greater, and the difference is not statistically significant (the mortality ratio is 2.7, with exact 95% confidence limits of 0.7 to 6.9, based on a Poisson distribution). McBride's conclusion is based on an inappropriate comparison. A full analysis would use population death rates over the 40-year period and take account of censoring, but that is unlikely to affect the result substantially.

J Mark Elwood

To the Editor: In a valuable review of low-molecular-weight heparins (LMWH), Eikelboom and Hankey1 stray off the beaten path into the unwelcoming area of obstetric therapeutics — a notoriously hostile environment replete with traps and hazards. Their statement that "low-molecular-weight heparins are being used increasingly in pregnant women with prosthetic heart valves and for the prevention and treatment of venous thromboembolism" is contentious and requires considerable qualification. The Journal has already published a position statement concerning the use of these heparins in pregnancy.2 It clearly stated that the initial treatment for pulmonary embolism in pregnancy remains intravenous unfractionated heparin, because so far there are no trials of LMWH in pulmonary embolism in pregnancy. The guidelines of the American College of Chest Physicians do endorse the use of LMWH for this indication,3 but base that view on data in non-pregnant patients. We believe that, as yet, there is insufficient evidence to recommend LMWH for the initial management of pulmonary embolism in pregnancy, although, on theoretical grounds, the treatment seems attractive. In anticoagulation therapy for artificial heart valves in pregnancy, there are serious problems. Unfortunately, the conscientious adviser must be very circumspect in counselling women with these prostheses. Pregnancy for these women presents significant risks. None of the heparins, unfractionated or low molecular weight, has been shown to protect reliably against embolism from, or thrombosis of, these valves in pregnancy. Whether LMWH is better than unfractionated heparin has not been established and awaits appropriate trials. Warfarin, which crosses the placenta, remains a valid, but worrying, choice in pregnancy for antico-agulation in patients with prosthetic heart valves. This drug provides optimal protection from valve thrombosis, but with the potential for teratogenicity in the first trimester and fetal (and maternal) haemorrhage later in pregnancy. Many experts use heparin and warfarin sequentially in this situation.3 Thus, anticoagulation therapy for pregnant women with serious medical problems remains, as always, perplexing, difficult and dangerous. While LMWH offer considerable promise and have undoubted utility in several areas, there are very compelling caveats about their current use for pulmonary embolism and prosthetic heart valves in pregnant women. For these reasons and others, women with prosthetic heart valves planning pregnancy, as well as those already pregnant, should be counselled about these problems by a physician experienced in managing medical problems in pregnancy.

Barry NJ Walters · Dorothy Graham

To the Editor: The recent "New Drugs, Old Drugs" review of low molecular weight heparins (LMWH) and heparinoids1 provides a timely reminder of the limitations of studies that support the use of these agents in preventing venous thromboembolism (VTE), particularly in orthopaedic surgery. A new class of anticoagulants has recently been released in Australia and is being promoted as being more effective than LMWH in preventing VTE. However, while several randomised controlled trials suggest that fondaparinux reduces the risk of asymptomatic deep vein thrombosis (DVT) in patients undergoing hip and knee replacement surgery,2,3 there is currently no evidence to suggest that it reduces the risk of symptomatic VTE. Fondaparinux is a synthetic penta-saccharide that selectively binds to antithrombin III, enhancing the neutralisation of factor Xa and inhibiting generation of thrombin and subsequent clot formation.2 Unlike LMWH, fondaparinux does not appear to affect platelet function, thus potentially reducing bleeding tendencies and avoiding the risk of immune-mediated thrombocytopenia. The main problem facing researchers who study VTE prophylaxis in patients undergoing orthopaedic surgery is that, while asymptomatic DVT is common, symptomatic VTE is rare. The rate of fatal pulmonary embolism in patients undergoing hip replacement surgery is 0.1%–0.2% in those who receive no prophylaxis.4 Trials to demonstrate a reduction in symptomatic VTE are not performed because huge sample sizes are required to show a statistically significant difference in outcome (50 000 patients would need to be enrolled in a trial to show a reduction in the rate of fatal pulmonary embolism from 0.2% to 0.1% with 80% power). If such a difference could be shown, it would probably be clinically irrelevant to an orthopaedic surgeon performing 50 joint replacements a year. Although asymptomatic DVT is used as a surrogate endpoint for trials that support VTE prophylaxis, the natural history of asymptomatic DVT is poorly documented. There is some evidence to suggest that asymptomatic DVT is not associated with an increased risk of subsequent chronic venous insufficiency,5 and the association between asymptomatic DVT and subsequent clot propagation and embolisation is not well established. Further information on the natural history of asymptomatic DVT must be obtained before the clinical relevance of results from current studies of VTE prophylaxis can be determined. Until then, the clinical relevance of studies comparing the use of "new drugs" with "old drugs" in preventing VTE in orthopaedic surgery cannot be assessed.

Owen D Williamson · Alison M. Street

In reply: Walters and Graham question the role of low-molecular-weight heparin (LMWH) as a replacement for unfractionated heparin during pregnancy, and cite the lack of randomised comparisons to support their view that the standard initial treatment for pulmonary embolism during pregnancy remains intravenous unfractionated heparin. We do not deny the lack of clinical trials of LMWH in pregnancy; we were simply referring to the increased use of LMWH.1,2 However, the lack of evidence of effectiveness does not equate with evidence of lack of effectiveness of LMWH in pregnancy. Clinical trials are needed to determine optimal anticoagulant strategies during pregnancy, particularly in patients with prosthetic heart valves. While awaiting the results of these trials, we believe that the major pharmaco-kinetic and safety advantages of LMWH over unfractionated heparin, coupled with an extensive body of evidence demonstrating their efficacy and safety in non-pregnant patients, should not be ignored in our pursuit of optimal anticoagulation therapies. Williamson and Street question the validity of asymptomatic deep vein thrombosis as a surrogate for symptomatic venous thromboembolism in patients undergoing major orthopaedic surgery. Further, they cite a 0.1%–0.2% incidence of pulmonary embolism in patients undergoing hip replacement surgery without prophylaxis3 to support the conclusion that any effect of thromboprophylaxis on reducing symptomatic events is likely to be irrelevant for individual orthopaedic surgeons. We believe that their argument is seriously flawed. Firstly, the "meta-analysis" they cite3 had major methodological limitations, as elegantly highlighted by "Sherlock Holmes" in his critical appraisal of systematic reviews of surgical thromboprophylaxis.4 Secondly, rigorously conducted randomised trials and meta-analyses of randomised trials have demonstrated the efficacy of antithrombotic therapy for the prevention of both symptomatic and fatal venous thromboembolism in high-risk surgical patients, including lower-limb orthopaedic surgery.5,6 Thirdly, the clear correlation between reduction in asymptomatic and symptomatic venous thromboembolism in patients undergoing elective joint replacement surgery7 suggests that asymptomatic thrombosis detected by screening venography is a valid surrogate for symptomatic events. Fourthly, we agree that an individual orthopaedic surgeon performing 50 joint replacements per year may remain unaware of a small reduction in fatal pulmonary emboli in his or her own practice (eg, a 0.1% absolute risk reduction would be equivalent to preventing one death in 20 years of practice). Yet, on a population basis, even a 0.1% absolute reduction (which is likely to be an underestimate — the PEP study showed a 0.3% absolute reduction in fatal pulmonary embolism with aspirin5) equates to 50 preventable deaths per year in Australia alone8 and many thousands worldwide. There is now overwhelming evidence of the efficacy of thromboprophylaxis for preventing venous thromboembolism, including symptomatic and fatal pulmonary embolism, in high-risk surgical patients. With the rapid ageing of the Australian population and the expected increase in joint replacement surgery in coming years,9 the failure to use effective thromboprophylaxis in orthopaedic patients will likely result in a growing burden of preventable morbidity and mortality from venous thromboembolism.

John W Eikelboom · Graeme J Hankey

Clinical record A 65-year-old woman had recurrent generalised tonic–clonic seizures. She was being treated with peritoneal dialysis for chronic renal failure caused by a combination of agenesis of the left kidney and focal sclerosing glomerulonephritis. Other medical problems included mixed connective tissue disease, ischaemic heart disease, Raynaud's phenomenon, anaemia of chronic disease, asthma, hypertension and chronic bilateral serous otitis media (treated with tympanostomy tubes). Her regular medications included atorvastatin, alendronate, perindopril, aspirin, allopurinol, ranitidine, doxepin, controlled release morphine sulfate, ferrous sulfate, calcium carbonate, frusemide, prednisolone, and diltiazem. Intermittently she had been given erythropoietin (a seizure precipitant)1 for her anaemia. She developed a rash when taking cephalosporins, and had a sister who had primary generalised epilepsy. The seizures continued despite cessation of the erythropoietin therapy and administration of sodium valproate. Magnetic resonance imaging of the brain and electroencephalography gave normal results. Meticulous medication review eventually revealed the coincidence of seizures with the intermittent prescription of ciprofloxacin eardrops. Eight of the nine seizures occurred while taking Ciproxin HC Ear Drops (ciprofloxacin 2 mg, hydrocortisone 10 mg; Alcon Laboratories, Sydney) for otitis media (Box). The ciprofloxacin eardrops were neither recorded on admission nor listed by the patient on direct questioning about medications she was taking. She has had a seizure-free period of 9 months after cessation of the eardrops, despite tapering of the dose of sodium valproate. The ciprofloxacin eardrops are considered the probable cause of the seizures in this case, according to the Naranjo algorithm for estimating causality of an adverse drug reaction (score, 8).2 Polypharmacy in complex medical patients frequently causes adverse effects.3 Up to 26% of prescription drugs are not recorded at the time of hospital admission,4 and eardrops are a common omission from medication lists. Ciprofloxacin is a fluoroquinolone antibiotic that inhibits bacterial replication. It is thought to lower seizure threshold by reducing γ-aminobutyric acid (GABA) transmission. Ciprofloxacin is excreted renally and has a half-life of 2.9–4.3 hours, which doubles in end-stage renal failure. Dose reduction is advised when patients not receiving dialysis have a creatinine clearance of less than 30 mL/min.5 There are reports of seizures after enteral and intravenous administration of ciprofloxacin,6 but, to our knowledge, this is the first report of seizures with ciprofloxacin eardrops. The recurrent seizures were believed to be due to the combination of an epileptogenic predisposition, renal failure, and intermittent ciprofloxacin use, with absorption facilitated by the bilateral tympanostomy tubes. Topical medications can produce systemic effects and this should be considered, particularly when other factors favour systemic absorption. A thorough drug history is necessary in assessing patients with complex medical problems taking multiple medications. Lessons from practice Topical medications can produce systemic effects. Fluoroquinolones may trigger seizures by any route of administration. A thorough drug history is necessary in assessing patients with complex medical problems. Eardrops are a frequent omission from medication histories. Chronological sequence of seizures and medication The period during which the patient had seizures () related to receiving ciprofloxacin eardrops (dropper), erythropoietin (EPO) for anaemia in chronic renal failure, and increasing doses of sodium valproate. (We thank Heidi Cartwright for preparing the diagram.)

Carolyn F Orr MRCP · Dominic B Rowe PhD, FRACP

To the Editor: The article by Mant et al1 and the letters following its publication focus attention on a long-standing problem that, despite concerted efforts by governments, healthcare providers and other stakeholders to address it, remains a major obstacle to effective and appropriate continuity of pharmacotherapy following discharge from hospital. There is little doubt that many of the difficulties arise as a result of poor communication between hospitals and general practitioners. This is further exacerbated by a lack of standard protocols for the preparation and dissemination of discharge summaries. Nowhere is this more evident than in the case of residents of aged-care facilities returning from hospital with radically changed medication regimens. To establish appropriate communication channels, Mant et al mention hospital GP liaison officers.1 New canvasses the potential problems and suggests sensible solutions, including the involvement of community pharmacists.2 However, every hospital has a readymade resource that requires only a set of formal protocols and procedures to make it function — clinical pharmacists. Clinical pharmacists view every patient's chart at least once every day. The chart not only provides information for dispensing, but also gives pharmacists an opportunity to monitor Quality Use of Medicines and communicate with hospital doctors regarding existing or potential problems. By the time the "prescription" is processed and the medication dispensed, quality issues have been addressed and a detailed record created. From the dispensing record, a "medication profile" could be generated. This can provide the patient with consumer information regarding each drug, its dose, frequency of administration and mode of action, and can act as an accurate and up-to-date discharge summary. In addition, a clear, legible copy can be faxed, mailed or electronically transmitted to the patient's GP, pharmacist, specialist, allied healthcare professional, rehabilitation hospital or aged-care facility. Our organisation provides medication management services to a large number of aged-care facilities as well as to public and private hospitals, and correctional facilities. Quality Use of Medicines monitoring constitutes a vital part of our clinical pharmacists' duties. It provides an effective, accurate and timely method of communicating detailed discharge summaries (which have undergone thorough Quality Use of Medicines screening) to GPs and other interested parties. By including hospital clinical pharmacists in the Quality Use of Medicines monitoring and evaluation process, meaningful information can be obtained, appropriate judgements made, effective communication conducted and optimum pharmacotherapy outcomes achieved.

Joseph J Gelb

In reply: Gelb points out that clinical pharmacists can, and in some cases do, provide useful communication to general practitioners following hospitalisation, as well as for their patients in aged care facilities. Regrettably, clinical pharmacists are in short supply, even in teaching hospitals; thus, in practice, their expertise often cannot be fully utilised.1 Attention to this shortage is clearly warranted to safeguard patient care. We agree that clinical pharmacists (hospital and community based) should be included in the Quality Use of Medicines monitoring and evaluation process. In addition, we urge all healthcare providers to take responsibility for careful and timely communication to ensure continuity of patient care.

Karen I Kaye · Andrea Mant · Linda Kehoe · Wendy C Rotem

To the Editor: The publication of the main results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), and the accompanying editorial, triumph the role of thiazide diuretics as first-line management for hypertension.1,2 It brought to mind the lines from the nursery rhyme Old Mother Hubbard — "And when she went there, the cupboard was bare." Simple frequency analysis of diuretic antihypertensive medications listed in the Australian Medicines Handbook (1998 and 2003) revealed that the total number of thiazide diuretics available as monotherapy in 1998 was six (bendrofluazide chlorothiazide, chlorthalidone, hydrochlorothiazide, methyclothiazide and indapamide), and in 2003 three (bendrofluazide, chlorthalidone and indapamide).3,4

Mark R Nelson

We have the tools to improve prescribing — the challenge is to use them Australia's place among the world leaders in the quality use of medicines is exemplified by its National Medicines Policy, the framework of which was put in place over 10 years ago.1 At the centre of the policy is the goal that medicines are used wisely — the Quality Use of Medicines (QUM) acronym has since become somewhat hackneyed and maybe the time is ripe to replace it by a less pretentious label. This issue of the Journal contains three reports that address issues related to QUM. Liaw and colleagues (page 203) examined doctors' perceptions of the Authority Prescribing system of the Pharmaceutical Benefits Scheme (PBS) and found (among other things) that doctors generally do not perceive the system as promoting QUM.2 South et al (page 207) describe how the use of laminated cards, which list guidelines for prescribing antibiotics for infections commonly seen in a paediatric hospital, significantly improved prescribing.3 Newby et al (page 210) found that computer-generated prescriptions for antibiotics in general practice are more likely than handwritten prescriptions to contain repeats, many of which are probably unnecessary.4 Each of these reports shows that, even a decade after the introduction of the National Medicines Policy, aspects of prescribing in Australia can be improved. Thus, it is timely to reflect on what we have been doing right, what we have not been doing right, and where there is still room for improvement. We have developed robust structures to promote QUM in Australia. For instance, Australian Prescriber commenced publication in 1975, and, despite a rather stormy career, continues to provide independent information on issues related to drug therapy. The first edition of Antibiotic Guidelines was published in 1978, and the Therapeutic Guidelines series now covers all the major therapeutic areas. The Australian medicines handbook was first published in 1998. An important initiative was the establishment in 1991 of the Pharmaceutical Health and Rational Use of Medicines (PHARM) Working Party (later Committee),5 which used its modest budget largely to fund projects studying QUM. This committee has been an important stimulus for QUM projects, rather like an "NHMRC" of drug prescribing. However, the committee did not have a mandate to fund ongoing programs. More recently, the National Prescribing Service (NPS) has been established. One of its major mandates is to put in place ongoing programs to improve prescribing, particularly of drugs listed on the PBS. Its continued funding depends on the demonstration of savings to the PBS. To date, the NPS appears to have largely managed to combine quality use with cheaper use, although it is the latter on which its survival depends. It has also managed its recent assimilation of Australian Prescriber in a mature manner. However, the NPS might have increasing difficulty in the future combining its cost-saving mandate with QUM, as this is not necessarily synonymous with cheaper use of medicines. There is also still an element of being "the new (rich) kid on the block", and the NPS has yet to define fully its relationship with established organisations involved with QUM in Australia, such as Therapeutic Guidelines (centred in Victoria), the Australian medicines handbook and the Drug and Therapeutic Information Service (DATIS) group (centred in South Australia), and State groups such as the NSW Therapeutic Assessment Group and the Victorian Drug Usage Advisory Committee. These have been some of the QUM successes, but what are the failures? Undoubtedly one has been the concentration of the Authority system of the PBS on cost saving rather than QUM. This was probably inevitable given that the accelerating expenditure on the PBS cannot be offset by savings elsewhere in healthcare. However, it is a failed opportunity as far as QUM is concerned. Another failure has been the continuing secrecy of the data submitted by pharmaceutical companies to the relevant advisory committees (such as the Pharmaceutical Benefits Advisory Committee [PBAC]) and on which the decisions on registration of drugs, their scheduling, and subsidisation by the PBS are based. Most of this information is not in the public domain, yet would greatly assist doctors and organisations in making good decisions about whether or when a drug should be used. In short, there is no good justification for this bureaucratic secrecy, and it undoubtedly hinders QUM in Australia. The recent putative moves to open PBAC deliberations to public scrutiny are to be welcomed. Another failure is the dependence of our drug evaluation system on fees paid by the pharmaceutical company applicants. It is a tribute to the professionalism of the evaluators that they appear to have largely retained their independence (but the secrecy surrounding the system does not allow for a definitive judgement). However, no regulatory system dependent on fees can ignore the interests of its payers, which are not necessarily the same as those of the Australian public, whom the regulatory system is supposed to serve. A further failure has been our inability to grasp the opportunities presented for QUM by the introduction of computerised prescribing. Unfortunately, this strategy seems to be following the same path as the introduction of computing into hospitals, where it was introduced very much as a management tool and not as a means of improving the quality of clinical care. So, where do we go next? First, the process to make bureaucracy more transparent should be vigorously pursued. Second, we should develop a national forum, for QUM issues. The NPS cannot provide that forum, as it has an overt cost-saving agenda, and its survival depends on it "blowing its own trumpet", sometimes at the expense of other bodies. Perhaps all the different organisations involved with QUM should form a QUM Society, and have national meetings to share results and experiences. Not only would that encourage cooperation rather than competition, it would also promote better recognition of the work of individuals involved in QUM. Most are in academic institutions, and QUM tends not to attract the research grants and publications that academia use to judge success. Third, we must quickly grasp the opportunities presented by computerised prescribing. Advertising must not be allowed to intrude into the prescribing process, automatic repeats for antibiotic prescriptions should not be allowed, and suitable incentives should be provided to ensure that decision support systems are embedded into prescribing software. Last, and most important, we should not rest on our laurels. Australia has done well, but QUM is a fragile flower, easily crushed by other forces, such as the economic imperative to support the pharmaceutical industry. My recent new experience in a country with far fewer resources than Australia has already taught me that much can be achieved with the wise use of resources (such as an essential drug list) I would previously have considered totally inadequate. We should not be in the thrall of the new — we already have the tools, and the challenge is to use them to maximum effect.

Robert F W Moulds PhD, FRACP

Objective: To examine doctors' perceptions and attitudes to prescribing within the Authority Prescribing System (APS).Design and setting: Questionnaire survey of Australian doctors' responses to a number of statements and factorial vignettes, conducted between 1 May and 30 June 2001.Participants: A national random sample of 1200 doctors, stratified according to specialist/generalist, rural/urban and high/low prescriber: 669 (56%) responded.Main outcome measures: Self-reported perceptions of the APS and attitudes to prescribing within the APS.Results: 72% of doctors agreed that the APS makes effective medications available to the socioeconomically disadvantaged members of the Australian public and 50% agreed that it compromises patient privacy. Fewer agreed that authority indicators were based on the highest quality of evidence quality (40%) or medication safety (12%). Doctors placed more emphasis on the doctor–patient relationship than on the criteria for authority prescribing in their decisions about prescribing APS medications. Doctors who used computers to prescribe were more likely to agree that computers can improve the authority prescribing process.Conclusions: This study suggests that authority-required prescribing is not achieving the stated aims of the National Medicines Policy in reducing variability in prescribing. Strategies to improve the quality of prescribing must consider the professional and ethical conundrum associated with prescribing outside of PBS/APS approved use for clinical and patient-centred reasons.

Siaw-Teng Liaw PhD, FRACGP · Christopher M Pearce FRACGP, FACRRM, MFM · Patty Chondros MSc · Leone Piggford MB BS, FRACGP · Kay Jones MSW, PhD · Barry P McGrath PhD, MB BS

Objective: To evaluate changes in prescribing behaviour after distribution of antibiotic guidelines printed on a 9 × 6 cm laminated card suitable for clipping to a hospital identification badge.Intervention: Guidelines for appropriate antibiotic prescribing for 20 common and important paediatric infections were printed on a laminated 9 × 6 cm card suitable to clip to a hospital identification badge and distributed to all medical staff.Design: We collected data from medical records for three marker conditions (tonsillitis, pneumonia, and orbital/periorbital cellulitis) on samples of patients from the six-month periods either side of the month in which the cards were distributed. Prescribers were unaware of the study and investigators analysed the prescriptions without knowledge of the period in which they were written. Prescriptions were rated for appropriate choice of antibiotic and appropriate dose. Data were also collected on antibiotic costs.Main outcome measures: Proportion of cases in which antibiotic choice was appropriate; proportion of cases in which antibiotic dose was appropriate; annualised costs of third-generation cephalosporins.Results: For tonsillitis there was little change in prescribing practice after the cards were introduced. For pneumonia, cases with appropriate choice increased from 77% to 92% (P = 0.028) and cases with appropriate dose increased from 48% to 81% (P = 0.001). For orbital/periorbital cellulitis, cases with appropriate choice increased from 19% to 78% (P < 0.001) and cases with appropriate dose increased from 30% to 51% (P = 0.11). Annualised costs of third-generation cephalosporins were $193 245 pre-cards and $89 814 post-cards.Conclusion: The cards appeared to have a beneficial effect on prescribing practice for the three marker conditions. This simple intervention is likely to be cost-effective and useful in reducing inappropriate use of antibiotics.

Michael South FRACP, MD · Jenny Royle FRACP, MD · Michael Starr FRACP

Objectives: To examine whether the use of current prescribing software systems might raise rates of repeat prescribing, with a consequent increase in use of antibiotics in the community.Design and setting: A prospective audit of consecutive prescriptions for amoxycillin, cefaclor, roxithromycin and amoxycillin/clavulanate presented to community pharmacies in the Hunter region of New South Wales and a follow-up survey of people who received a repeat prescription, October to November 2000.Main outcome measures: The frequency of repeat prescription ordering on computer-generated and handwritten prescriptions; the proportion of people who filled their repeat prescription.Results: Data were collected for 1667 prescriptions presented to 35 pharmacies; 126 people who received repeat prescriptions completed the survey. The rate of repeat prescription ordering on computer-generated prescriptions was 69%, compared with 40% for handwritten prescriptions (odds ratio, 3.3; 95% CI, 2.6–4.2). Computer-generated repeat prescriptions were as likely to be filled as hand-written prescriptions (61% and 69%, respectively).Conclusions: The default settings on computerised prescribing packages result in a significant increase in the use of antibiotics. We estimate these settings result in about 500 000 additional prescriptions being filled annually in Australia for the four antibiotics in the study.

David A Newby BPharm, PhD · Jayne L Fryer BMath, GradDipMedStats · David A Henry MB ChB, FRCP

Three children presented with adrenal crises, manifested by vomiting and hypoglycaemia, after protracted courses of high-dose inhaled corticosteroids for asthma. Significant dose reduction was possible in all three without loss of asthma control, emphasising the importance of back-titration to minimise dose. Parents of children taking high doses of inhaled corticosteroids should be alerted to the clinical features of adrenal insufficiency. If suspected, prompt medical assessment should be arranged, including serum glucose and cortisol measurement. The effectiveness of prophylactic inhaled corticosteroids (ICS) in childhood asthma is well established1 and these drugs are recommended as a safe, first-line preventive therapy.2-4 Dose-dependent biochemical adrenal suppression with ICS has been well documented,3-5 although, until recently, reports of frank adrenal insufficiency in children have been rare.6-9 We present the first documented Australian report of three children who presented with adrenal crises while being treated with ICS for asthma. Each had a history of an intercurrent illness during which they were unable to mount a stress-response rise in cortisol level. Clinical recordsPatient 1Presentation: A seven-year-old boy presented with hypoglycaemia associated with vomiting, abdominal pain and drowsiness preceded by two days of fever, rhinorrhoea and fatigue. He had had a previous episode of hyponatraemia and vomiting, but his blood glucose level was not documented at the time. Although he had been noted to have a cushingoid appearance in the past, he was normal on physical examination, his height and weight were on the 3rd percentile, and his growth velocity was normal. He was found to be hypoglycaemic and hyponatraemic, with a low serum cortisol level (Box 1). A short Synacthen test confirmed adrenal insufficiency (Box 2). Asthma history: The patient had a history of "poorly controlled" asthma, but his wheeze was minimal and not associated with increased work of breathing. He undertook normal physical activity and was rarely absent from school. Spirometry findings in the past had been normal. Medications: He was taking fluticasone propionate (1500 μg daily), nebulised budesonide (1000 μg daily till three weeks before presentation), salmeterol (50 μg twice daily), nebulised salbutamol (5 mg four times daily) and ipratropium (250 μg four times daily) and montelukast (5 mg daily). From the age of two years his ICS doses had been progressively increased and had been at these levels for 10 months before this presentation. He had received frequent doses of oral prednisolone from the age of four years, but had had none for the past eight months. Treatment and clinical course: Immediate treatment included a glucose bolus, fluid replacement and hydrocortisone. Ongoing treatment involved giving regular hydrocortisone while reducing the dose of ICS, with no deterioration of asthma control. Four months after his presentation he was taking 500 μg fluticasone daily and being weaned off hydrocortisone. Patient 2Presentation: A four-year-old boy was referred for investigation of two episodes of hypoglycaemia associated with vomiting and lethargy. There was a third episode of vomiting and lethargy; his blood glucose level was normal on this occasion (his mother had treated him with glucose before presentation at hospital). The patient was normal on physical examination, with height and weight between the 10th and 25th percentiles and with normal growth velocity. He was not cushingoid in appearance and had no abnormal pigmentation. Results of available baseline investigations during the hypoglycaemic episodes are shown in Box 1. A short Synacthen test confirmed secondary adrenal insufficiency (Box 2). Asthma history: The patient had had a history of episodic cough and wheeze since the age of four months, but had good exercise tolerance and minimal nocturnal symptoms between episodes. Past spirometry findings were normal. He had started taking ICS at 18 months of age, with progressively increasing doses in an attempt to control acute episodes. Medications: His medications were 1–2 puffs of 250 μg fluticasone propionate with 25 μg salmeterol (Seretide 250/25; Allen & Hanburys) twice daily (giving a daily fluticasone dose of 500–1000 μg), and salbutamol and ipratropium as required. He had never previously required oral steroids. Treatment and clinical course: With each hypoglycaemic episode he was treated with intravenous fluids, with good clinical response, but on one occasion he also received a short course of prednisolone for a "mild exacerbation of asthma". With the normoglycaemic episode he was treated with intravenous fluids and hydrocortisone for two days. After adrenal insufficiency was confirmed (Box 2), therapy with replacement hydrocortisone was commenced and he was weaned from his ICS dose. He currently takes 100 μg fluticasone and 4 mg montelukast daily, with no significant symptoms. He takes hydrocortisone as needed in times of stress, such as during infections. The patient was also subsequently found to have normal spirometry results, even during acute episodes of asthma. Patient 3Presentation: A 10-year-old boy presented after a hypoglycaemic seizure preceded by 24 hours of vomiting. He was normal on physical examination. His height was on the 90th percentile, weight between the 25th and 50th percentiles, and his growth velocity was normal. He was not of cushingoid appearance and had no abnormal pigmentation. He was found to have hypoglycaemia (Box 1), and hyponatraemia was also detected, but was possibly dilutional, as it was collected from the same intravenous cannula through which the dextrose bolus was given. A short Synacthen test confirmed secondary adrenal insufficiency (Box 2). Asthma history: The patient had a history of frequent episodic wheeze and breathlessness during early childhood, and had been admitted to a rural intensive care unit for asthma exacerbation at the age of five years. Past spirometry findings had been normal. He had been taking his current ICS dose for the previous two years, despite having no acute episodes of asthma or interval symptoms. Medications: He was taking Seretide 500/50 twice daily (giving 1000 μg fluticasone propionate daily) and salbutamol as needed. Treatment and clinical course: Therapy with replacement hydrocortisone was begun while the ICS dose was gradually decreased to two puffs of Seretide 50/25 twice daily (giving 200 μg fluticasone daily); hydrocortisone therapy was continued for four months and is now taken as stress cover for intercurrent illness. DiscussionOur case series further highlights the potential for the systemic activity of ICS to manifest as an acute adrenal crisis. These children, as well as patients in previously reported cases,6-9 all had biochemical evidence of adrenal insufficiency in the absence of other causes (normal long-chain fatty acids, excluding adrenoleukodystrophy, and normal adrenal antibodies, excluding autoimmune adrenalitis [Box 2]). The vomiting associated with hypoglycaemia seen in the three children has been previously described,6-9 as have seizures7-9 seen in our Patient 3. The hyponatraemia found in two of our patients is an unexpected feature, but mild hyponatraemia with normokalaemia has been documented in secondary adrenal insufficiency and postulated to be the result of inappropriate vasopressin secretion10 or subnormal aldosterone secretion in response to severe sodium restriction.11 Hydrocortisone has some mineralocorticoid action, and its use as sole replacement therapy was sufficient to restore electrolyte balance in these instances. While growth suppression was noted in one case series,6 and has been reported in association with asymptomatic adrenal suppression,12,13 it was not a feature in our patients, or in other reports.7,8 This suggests that adrenal suppression may manifest differently, perhaps related to differing patient susceptibility, or dose or duration of ICS use. Our patients and most children in previous reports6-9,12,13 were taking high doses of fluticasone. This may reflect current prescribing habits. While fluticasone may be more likely to cause severe adrenal suppression owing to its higher potency compared with other ICSs,7-9,12,13 all ICS medications have been shown to produce dose-dependent adrenal suppression in children.3-5 The low doses used in some reported cases6 again suggest varying patient susceptibility. Screening for asymptomatic adrenal insufficiency in children receiving high doses of ICS is problematic, particularly as abnormal results do not accurately predict clinically meaningful adrenal-axis suppression.4 Clinical indicators of systemic effects, such as poor growth or cushingoid features, were not seen in our patients or in previously reported cases.6-9 Results of tests such as 24-hour urinary free cortisol excretion and random serum or salivary cortisol levels are often indeterminate.14 Early-morning levels of serum or salivary cortisol which are at the high end of the normal range reassure that there is no serious adrenal suppression, but lower levels can be indeterminate.15 "Gold standard" tests, such as insulin-induced hypoglycaemia or metyrapone suppression, carry significant risks and are difficult to justify in this situation. The standard dose (250 μg) short Synacthen test is generally reliable, but may give false normal results in some instances where central hypothalamic–pituitary–adrenal-axis suppression predominates. The low-dose (0.5 μg/1.73 m2) short synacthen test has been proposed as being less prone to such errors,14 but abnormal test results do not always have clinical significance. A more pragmatic approach would be to warn the parents of children taking high dose ICS of the potential for adrenal suppression so that they seek medical advice during an intercurrent illness associated with unexpected lethargy, vomiting, abdominal pains or seizures. Such "non-respiratory" presentations warrant urgent assessment and tests for baseline blood glucose level (for hypoglycaemia) and serum cortisol level (which may be inappropriately low). Prompt recognition and treatment with hydrocortisone and intravenous fluids containing glucose may be life saving in the event of an adrenal crisis. In less acute presentations, suspected adrenal suppression warrants referral for endocrine assessment and adrenal testing, although there is considerable debate as to the best method for doing this.16,17 If significant adrenal suppression is evident by either a low cortisol level at the time of hypoglycaemia or an extremely low response to cortisol stimulation, then maintenance hydrocortisone should be used in the short term to facilitate safe weaning of the child from ICS. However, it is important to remember that some degree of adrenal suppression and risk of adrenal crisis may persist in such children if any steroid therapy continues, or for up to 12 months after steroid therapy is ceased. Two other important messages arise out of these case reports. Firstly, it is important to ensure that ICS therapy is appropriate for the child. The United Kingdom national survey indicated that around 20% of patients presenting with adrenal crisis were later shown not to have asthma.9 Other areas where ICS have no proven benefit are children presenting with recurrent cough18 or episodic viral wheeze.19 Secondly, in children with asthma receiving ICS therapy, it is important to minimise the dose by "back-titration" or by adding long-acting β-agonists (or both), as highlighted in recent guidelines.2,3 All our patients were taking more than 500 μg per day of fluticasone, which is currently the upper limit of the recommended dose for children.2 Further, significant dose reduction was possible without loss of asthma control, suggesting that these children were being overtreated. This report also serves to reinforce the recent guideline recommendation for specialist referral for children requiring high doses of ICS.2,3 1: Baseline investigations Daily dose of fluticasone propionate Blood glucose level (normal, > 3.5 mmol/L) Sodium level (normal, 135–145 mmol/L) Urinary sodium concentration (normal, < 20 mmol/L) Patient 1 1500 μg 1.3 mmol/L 130 mmol/L* 88 mmol/L Patient 2 (two episodes) 500–1000 μg 2.2 mmol/L < 1.2 mmol/L Not available 135 mmol/L Not available Not available Patient 3 1000 μg < 1.0 mmol/L 126 mmol/L† Not available * Specimen collected before glucose bolus. † Specimen collected after glucose bolus. 2: Adrenal investigations Stimulated cortisol level (normal, > 600 nmol/L) Adrenocorticotropic hormone level (normal, 2–10 pmol/L) Adrenal antibodies (normal, negative) Very long chain fatty acids (normal, negative) Patient 1 108 nmol/L* Not available Negative Negative Patient 2 44 nmol/L† < 1 pmol/L Negative Negative Patient 3 129 nmol/L† < 1 pmol/L Negative Negative * At time of presentation with hypoglycaemia (blood glucose level, 1.3 mmol/L). † During short Synacthen test (60 minutes after an injection of 250 μg Synacthen).

Joseph S Macdessi MB BS, DCH · Peter P van Asperen MD, FRACP · Tabitha L Randell MB ChB, MRCP, MRCPCH · Kim C Donaghue MB BS, PhD, FRACP · Geoffrey R Ambler MD, FRACP · Craig M Mellis MD, MPH, FRACP

To the Editor: Kuchar et al1 describe a patient who received an implantable defibrillator discharge after a single ingestion of loratadine. We are concerned that their conclusion — that this patient "probably" had drug-induced torsade de pointes — is incorrect. Review of the intracardiac electrograms from this patient (shown in Box 2 of their article) with known monomorphic ventricular tachycardia (VT; shown in their Box 1) shows a relatively fixed rate of the VT without the large variations in cycle length consistent with torsade de pointes. While there are no established guidelines for determining torsade de pointes based on intracardiac electrograms, it is clear that during monomorphic VT electrocardiograms can show variability in amplitude and orientation. Consistent with the early stages of monomorphic VT,2 the first three electrograms have a different orientation compared with the remaining electrograms, which are largely similar. Unfortunately, as the transition from supraventricular rhythm to tachycardia was not shown, it cannot be ascertained whether the tachycardia began with a pause-dependent mechanism, an important criterion to help diagnose torsade de pointes.3 Given that this patient's implantable defibrillator intracardiac electrograms do not show a continually changing electrogram pattern, that the cycle length is relatively constant, and that there is a lack of documented QT prolongation, there is no evidence of the patient's arrhythmia being torsade de pointes. Incidentally, it is unclear whether these electrograms were recorded before (as specified in the discussion) or after defibrillator discharge (title of Box 2). It is well documented that a defibrillator discharge can have significant effects on the recording of intraventricular electrograms. Most likely, this patient, with documented pre-existing monomorphic VT (their Box 1[b]), had an episode of VT (not torsade de pointes) appropriately treated by the implanted defibrillator, probably having no direct relationship with loratadine. Notably, their Box 3 shows torsade de pointes in another patient, not receiving loratadine. In summary, Kuchar et al1 correctly state that there have been no documented episodes of torsade de pointes after ingestion of loratadine. Similarly, their report does not appear to document an episode of torsade de pointes.

Philip T Sager · Enrico P Veltri

In reply: We agree that there are no guidelines defining torsade de pointes based on intracardiac electrograms, but there are several reasons why the likelihood of torsade de pointes (as opposed to any other arrhythmia) in our patient is high. The electrogram shows the arrhythmia just before delivery of direct current shock, this being about 30 minutes after the patient took her first ever dose of loratadine. There are marked variations in electrogram morphology, despite minimal variation in RR interval, in a short strip of recording in this patient with documented QT prolongation. Further, she had no history of monomorphic ventricular tachycardia, no inducible monomorphic ventricular tachycardia at electrophysiologic examination, and no evidence of structural heart disease. Neither was a mechanism for supraventricular arrhythmia identified. The absence of initiating beats showing pause-dependence is unfortunate, but this is not provided by the generation of device implanted in this patient. Hence, we believe the word "probable" is an apt description for the observation made.

Dennis L Kuchar · Bruce D Walker · Charles W Thorburn

To the Editor: Our recent study of patients' priorities for asthma care1,2 provides additional evidence supporting the concerns of Wilson and Robertson in their editorial questioning the possible overuse of inhaled corticosteroids.3 We have reported a qualitative study of 62 individuals who presented to an emergency department at either a central city, suburban or rural hospital, in which we explored individuals' perceptions about their asthma, its care and the impact of asthma on their lives.1,2 We also asked participants to complete a questionnaire on the use of medications and sought to amplify this information by further probing the use of medications in our qualitative data collection. Of the 82% of participants in our study currently using inhaled corticosteroid medication (51), 30% (16) were taking 1000 μg of fluticasone or equivalent daily and another 19% (10) were taking more than 1500 μg or equivalent. Current product information for fluticasone suggests a maximum dose of 1000 μg twice daily, whereas National Asthma Council (NACA) guidelines recommend that 500 μg fluticasone or equivalent daily may be the upper limit of useful effect.4,5 We also asked patients how long their medication lasted. Eleven (18%) stated that inhaled corticosteroid devices lasted three weeks or less. Use above recommended doses did not only occur for inhaled corticosteroids, but also for symptom controller medications. Twenty-four (35%) of the 31 (50%) patients receiving this medication reported that a device lasted three weeks or less, indicating use above usual recommended doses. Most patients in our study voiced concerns about the cost of asthma and drug side effects; some adjusted their medication use to manage these issues.1 In such individuals, high use or overuse of preventive and controller medication would increase both costs and side effects, partly explaining these patients' concerns. Doctors may be overprescribing inhaled corticosteroid medication because there is a discrepancy between dosages recorded in published drug information and newer recommendations for optimal inhaled corticosteroid dose.4,5 Our findings show that, in some patients, the risks associated with the use of inhaled corticosteroids are likely to be compounded by using them at higher doses than those recommended. Doctors need to be aware of this in managing patients with asthma who have severe symptoms, in whom overuse, rather than underuse, is likely to be a problem.

Dianne P Goeman · Susan M Sawyer · Michael J Abramson · Kay Stewart · Francis C K Thien · Rosalie A Aroni · Jo A Douglass

In reply: We agree with Johnson and Lassere about the value of longitudinal studies, especially clinical trials, in assessing healthcare benefits and costs. They are critical to informing clinical practice and health policy. If it were possible to conduct these studies across a wide variety of settings, representing the range of "real life" practice, then there would be little need for epidemiological modelling. However, this is not possible. Clinical trials (with or without cost components) will only ever be conducted over relatively short durations, on circumscribed populations and under tightly controlled conditions. A key, but often overlooked, issue is whether the results of studies are externally valid (generalisable). Indeed, the evidence base that dictates clinical practice and health policy should comprise data that are both internally and externally valid. We do not suggest that epidemiological modelling replace longitudinal studies (in fact, modelling depends critically on robust prospective data); rather, it complements these studies by providing a means to assess their external validity. We are also mindful of the limitations of epidemiological modelling, as outlined in our article,1 and acknowledge the importance of ensuring rigour in the methods. Our article dealt with generating the data needed for sound economic evaluation, by taking into account the long-term benefits, risks and costs of treatment strategies, and "real-life" health service conditions. This is distinct from the issue of whether "conditional listing" on the Pharmaceutical Benefits Scheme should be implemented for drugs that are yet to be proven cost-effective.

Danny Liew · John J McNeil · Anna Peeters · Stephen S Lim · Theo Vos

To the Editor: In their Notable Case on jellyfish envenomation causing Irukandji syndrome,1 Fenner and Hadok suggest that similar deaths may have occurred in the past, with the relationship to Irukandji syndrome not being recognised. However, their call for urgent research into developing an antivenom needs to be based on a clear understanding about the risk of death. Unfortunately, they have not presented data that clearly establish causation or support their conclusions about treatment and the need for further research. While they reported a history that supports envenomation, there was no confirmation by detection of nematocysts or autopsy to examine for other causes of death. An alternative explanation could be that the patient was overcoagulated and died from complications of an intracerebral haemorrhage. While it is clear that blood pressure must be monitored, to suggest that it must be treated with phentolamine is not supported by this case report. Clearly, supportive management and, in particular, the optimal treatment of cardiovascular complications needs to be defined and may obviate the need for antivenom.

Andrew H Dawson

Objective: To investigate the toxicity of bupropion hydrochloride in deliberate self-poisoning in adults and accidental ingestion by children.Design and setting: Prospective study of cases identified from calls to the New South Wales Poisons Information Centre (NSW PIC), with follow-up through hospital medical records.Participants: Patients with bupropion poisoning managed in hospital, about whom the NSW PIC was contacted for advice, from 1 November 2000 to 31 July 2001 (59 adults and 10 children).Main outcome measures: Clinical effects, adverse outcomes (including seizures and death) and treatment.Results: 45 of the 59 adults were followed up (76%), 19 of whom had taken bupropion alone. Major clinical effects of bupropion included sinus tachycardia (83%), hypertension (56%), seizures (37%), gastrointestinal symptoms (37%) and agitation (32%). Seizures were dose-dependent, with those having seizures ingesting a significantly higher median dose (P = 0.02). All seizures were brief and self-limiting. 29 patients received decontamination therapy. 10 patients required pharmacological sedation, 10 were admitted to intensive care and six were intubated. None died. Eight of 10 accidental ingestions by children were followed up (80%); one child had symptoms (vomiting and hallucinations).Conclusions: Bupropion overdose caused significant clinical effects in adults, but few in children.

Corrine R Balit BPharm · Christa N Lynch BPharm · Geoffrey K Isbister BSc, MB BS FACEM