Volume 179 Issue 8

Burden-of-disease and cost-effectiveness studies will help us realise better population health Over the past decade or so, there has been increasing demand for greater clarity about the major causes of disease and injury, how these differentially affect populations, and how they are changing. In part, this demand has been motivated by resource constraints and a realisation that better health is possible with more informed allocation of resources. At the same time, there has been a change in the way population health and its determinants are quantified, with a much closer integration of the quantitative population sciences (such as epidemiology, demography and health economics) to strengthen and broaden the evidence base for healthcare policy. As demand for healthcare grows, decisions about resource allocation and priorities for the healthcare sector will fall under increasing scrutiny. The first coordinated efforts to provide more relevant and comprehensive data on the health (as opposed to survival) of populations and on specific strategies for disease control were led by the World Bank, culminating in two seminal reports in 1993 on the state of global health and priorities for improving it.1,2 These reports have subsequently had a great influence on debates about health sector priorities and healthcare research needs. A fundamental outcome of this World Bank research has been a change in the paradigm for health accounting, from measuring death to measuring population health, using a single summary index that simultaneously incorporates information about age at death and the incidence and prevalence of disease and injury. A time-based metric, the disability-adjusted life-year (DALY), was used to capture both fatal and non-fatal health outcomes affecting populations. DALYs for over 100 specific diseases and injuries have been assessed within a “burden-of-disease” framework which constrains individual estimates and preserves epidemiological plausibility.3,4 The burden-of-disease approach gives estimates of DALYs from risk factors (eg, smoking) as well as diseases caused by known risk factors (eg, ischaemic heart disease related to smoking) and from other, unrelated conditions (eg, road traffic accidents, which have nothing to do with smoking).5 Thus, a single metric (the DALY) can be used to compare disease burden across a range of diseases, injuries and risk factors. Certainly, the data and information requirements for adequate measurements of the burden of disease in a population are not inconsiderable. They need information on age at death and cause of death, the age-specific incidence of disease and injury, the typical duration of life lived with the sequelae of diseases and injuries, and some quantification of the severity of disability assessed according to a commonly agreed framework. The ethical, philosophical and conceptual issues involved in quantifying states of health other than perfect health are still very much a matter of debate, and rightly so.6 However, the reliability, and hence the utility, of burden-of-disease studies for public policy depend much more strongly on the quality and availability of the underlying epidemiological data. A principal advantage of the burden-of-disease approach is that it entails a data “audit”, whereby the completeness, reliability and consistency of routinely collected data are assessed, and critical gaps in health data collection are identified. One implication is that periodic quality assessments of, say, routine cause-of-death data ought to be carried out to ensure their continued relevance and reliability for public policy. Another might be the need for a more rational assessment of priority data for the healthcare sector, placing greater emphasis on data collection and data linkage to facilitate burden-of-disease studies, rather than on routine collection of statistics of limited public health relevance. The burden-of-disease framework, based on the estimated epidemiological path of incident cases, would benefit greatly from wider availability of linked data sets on health outcomes and further research into health-state transition probabilities (ie, the probability that patients with a given illness or disability will get better or worse, and the severity of their current compared with their previous health state) from longitudinal studies.7 In parallel with the increased emphasis on more reliable and comprehensive assessment of population health, there has been a rapid expansion in knowledge about the cost-effectiveness of interventions for reducing the burden of disease. Packages of interventions to optimise health in populations at different levels of development were among the major research outcomes of the World development report 1993.1 Subsequent work by the World Health Organization identified evidence of cost-effectiveness as a key health research priority worldwide.8 The findings of a large international study of the cost-effectiveness of 170 interventions, primarily to reduce health hazards from unsafe water and hygiene, childhood undernutrition, tobacco use, unsafe sex, and high blood pressure and blood lipid levels were recently reported by WHO.9 The evidence base for setting health priorities is thus rapidly expanding. Yet, as the WHO report points out, there is still a large potential for realising better health through more informed and systematic application of this knowledge.9 As demand for healthcare grows, decisions about resource allocation and priorities for the healthcare sector will fall under increasing scrutiny. This is likely to lead to demands for more reliable and useful evidence about population health problems, and for affordable and effective measures to address them. Australian researchers have been at the forefront of these international developments, and have carried out local burden-of-disease studies that have been used to support policy development by the federal and state governments, particularly in Victoria.10,11 Australia is also well placed to provide technical support to neighbouring countries that are undertaking burden-of-disease and cost-effectiveness research to improve the efficiency of their healthcare systems. More than 5 years have now passed since the first Australian burden-of-disease study was undertaken, and much could be gained from a renewed appraisal of Australian healthcare information based on the methodological advances in burden-of-disease measurement in the interim. The School of Population Health at the University of Queensland has established a Centre for Burden of Disease and Global Health Research which has a mission to provide the technical and strategic leadership for priority-setting research in Australia and the entire Asia–Pacific region. Strong links to WHO, the World Bank, the National Institutes of Health in the United States, and other leading health research institutions worldwide, will ensure that efforts to improve the evidence base for healthcare reflect global advances in health research and development.

Alan D Lopez PhD

Manufacturers’ claims in well funded marketing campaigns cannot replace the test of time Declaring war and prescribing drugs are decisions dependent on information, and the consequences can be calamitous if that information is incomplete or inaccurate. The calamity which threatened the sustainability of the Pharmaceutical Benefits Scheme (PBS) in 2000 and 2001 was the volume of prescriptions for cyclooxygenase (COX)-2 inhibitors. Celecoxib was listed on the PBS on 1 August 2000, and by the end of December 2000 over 1.5 million prescriptions had been written, costing the government more than $76 million.1 By the end of June 2001, the cost had exceeded $160 million.2 In this issue of the Journal (page 403), Kerr and colleagues confirm the rapid rise in prescriptions for celecoxib and rofecoxib.3 However, their research cannot explain why the general practitioners in their study were so enthusiastic about the new drugs. The doctors’ decisions to prescribe would have been based on the available information. At the time the drugs were launched in Australia, most of that information would have been supplied directly or indirectly by the manufacturers. There was little independent information, and the major randomised trials of celecoxib (CLASS4) and rofecoxib (VIGOR5) were only published in late 2000. The information from the manufacturers emphasised the relative safety of the new drugs. Compared with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), the new drugs caused fewer peptic ulcers. This was an important message, as doctors are often warned about the serious gastrointestinal complications of NSAIDs. There is evidence that some patients were prescribed the new drugs because they had suffered adverse effects from NSAIDs.6 However, this did not result in a fall in the prescribing of NSAIDs. The availability of celecoxib and rofecoxib increased the number of people being treated for musculoskeletal disorders,3 suggesting the new drugs were being prescribed for conditions beyond the restrictions of the PBS. Such conditions include non-specific back pain, sprains and sports injuries.3,6 Some general practitioners believe that COX-2 inhibitors are more effective than NSAIDs.6 This belief is not confirmed by the clinical trials, and now even the evidence of their improved safety is being questioned.7 The published results of VIGOR5 and CLASS4 did not include all the data submitted to the United States Food and Drug Administration (FDA).7,8 The favourable results of CLASS were based on only the first 6 months of the trial. Analysis of the 12 months’ data that was available to the FDA suggests that celecoxib was associated with a similar number of ulcer complications as were diclofenac and ibuprofen.7,9 Similarly, analysis of the complete data for rofecoxib suggests it may be associated with an increased risk of cardiovascular events10 and that serious adverse effects may be more frequent than with naproxen.8 The Therapeutic Goods Administration (TGA) probably had access to the complete data when it evaluated the drugs for use in Australia. However, unlike the FDA data, which are published on its website,8,10 the TGA’s evaluations are kept secret. Would publication of the TGA’s evaluations have alerted Australians to the possible problems with COX-2 inhibitors? Concerns about the drugs only arose months after they were marketed. Even if they had been aired earlier, they are likely to have been lost in the excitement surrounding the launch of the drugs. Even the Minister for Health and Aged Care put out a press release listing some of the benefits of celecoxib and describing it as a “major breakthrough in arthritis therapy”.11 Enthusiasm for the COX-2 inhibitors waned slightly with experience. In Kerr and colleagues’ study, rofecoxib was not embraced to the same extent as celecoxib. Nearly a third of the patients prescribed rofecoxib had previously been prescribed celecoxib, suggesting they had been disappointed by the response.3 Initial enthusiasm followed by a slower increase or plateau in prescribing is a common pattern with new drugs. If the new drugs are not as good as they were thought to be, can they justify being twice the price of other NSAIDs? What coaxes doctors to expose their patients to new products when so little information is available? I believe that manufacturers’ marketing strategies play on doctors’ desire to give their patients the best possible care. Much of the variation in the prescribing of new drugs depends on the personality of the doctors, and probably on their susceptibility to these marketing techniques.12 The prospect of reduced adverse effects is likely to have a strong influence on prescribing practice. If adopting new drugs quickly actually puts patients at risk, prescribers must be presented with information to balance the claims of the drug companies. Achieving this balance is difficult, partly because independent information (such as Therapeutic guidelines and the Australian medicines handbook) sometimes comes at a cost, while drug company information — supported by massive advertising budgets — is free. In 2000, the amount spent on promoting rofecoxib to Americans (US$160 million) exceeded the advertising budgets for Pepsi and Budweiser beer.13 In view of the popularity of the new drugs in the United States, perhaps Australia should have been prepared for the demand. If the TGA had been able to provide its evaluations to publishers of independent information, they could have prepared prescribing guidelines before the drugs were marketed. The National Prescribing Service has recently received funding to provide doctors with independent information about new additions to the PBS. To ensure advertising does not swamp these messages, perhaps there should be limits on promotional activities around the date of PBS listing. While governments are unlikely to ban advertising, they could at least mandate that it provides quantitative information about the outcomes for patients.14 Another approach to new drugs is not to use them. This will spare patients from the serious adverse effects which sometimes only emerge after marketing. The Health Research Group in the US now recommends waiting 7 years before using a new drug that provides no clear advantage over current therapies.15 While this may be an extreme position, there is no need to feel pressured into immediately prescribing the latest drug. New is not always better.

John S Dowden MRCGP, FRACGP

Treating substance misuse might not significantly reduce the number of offenders According to recent estimates, crime costs the community $32 billion annually. Of this, $1960 million is directly attributable to drugs, and, if indirect costs were included, the proportion attributable to drugs would be higher.1 Clearly, interventions that target potential risk factors for crime, such as drugs and mental health problems, will have significant payoffs for individuals and the wider community. However, the relationship between drugs and crime is complex. Policy development in this regard needs to take into account the multifaceted nature of the problem. In this issue of the Journal (page 408), Heffernan et al present the first Australian publication that seeks to clinically assess the level of substance-use disorders and psychological distress among police arrestees.2 This article makes a constructive contribution to the evidence base. The study highlights that the overwhelming majority of arrestees suffer from clinical substance-use disorders and psychological distress, and that they are a population who may be in need of treatment. Replication of these findings is important to furthering our understanding of the need for treatment among this group. In Australia, evidence is emerging (building on overseas research) that criminal behaviours among arrestee and prison populations vary widely, from minor disorderly conduct through to homicide, with different factors contributing to these behaviours. Illegal drug use is just one of many risk factors, but there is no doubt that it is significant in the behaviour of a subset of offenders. Recent analyses of police detainees and the incarcerated adult male population estimate that this is the case for between 34% and 52% of offenders.3,4 This clearly suggests that effective treatment interventions could significantly reduce crime rates. Criminological studies that track when people start, persist with and desist from drug use and offending demonstrate that most offenders become involved in minor crime before experimenting with and using illegal drugs.5,6 For example, the onset of crime preceded regular heroin use in 69% of one sample of offenders.5 Illegal drug use seems to compound a pre-existing problem, and so produces higher levels of offending.7 Thus, treating substance misuse among offenders, although an essential public health measure, might not necessarily result in significant reductions in the number of offenders. This is because crime and drug use may be caused more by factors external to the individual, such as early-childhood experiences and development, access to labour markets, access to local drug markets and their supply routes, the social and cultural environment, lifestyle choices, and other determinants that are not easily amenable to treatment.8 The links between drug use and crime and the policy implications that flow from this will be affected by the nature of the local drug market. The Australian Institute of Criminology’s Drug Use Monitoring in Australia project has conclusively shown that police detainees’ drug use patterns vary across the country. Higher rates of amphetamine use have been detected in Queensland, Western Australia and South Australian sites; while higher rates of heroin use have been detected in New South Wales sites.9 Furthermore, breakdowns by offence type indicate that users of amphetamines are arrested for a range of offences, not just violence, and similarly heroin users are arrested for a range of offences, not just property. The links between drugs and offending types appear more variable than is often thought. Changing human behaviour is difficult. Some people take drugs because they like the effects, some because they are risk takers, and some to self-medicate for past and current painful situations and events; others take them because they are addicted and simply cannot stop. Not everybody who is defined as dependent will want or seek treatment. In this complex environment, public policy responses, such as drug courts and court diversion systems, need to be cognizant of what drives behaviours and develop appropriate responsive systems (of which levels of dependency will be only one factor). Recent evaluations of the south-east Queensland and NSW drug courts10,11 have shown that, even with a 12-month, structured, supervised program, some people continue to be criminally active and use illegal drugs. Estimates from the early stages of the Queensland study suggest about a third of graduates reoffended within the follow-up period after graduating from the court. Similarly, police diversion schemes need careful targeting, as good longitudinal research shows that, after a “first” contact with the criminal justice system, many young offenders (upwards of 60%) do not come back into contact with the juvenile system again.12-15 Because of the intersection between illegal drug use and crime, the criminal justice systems in Australia have developed a range of policy innovations to divert offenders into treatment and other programs. These include early police diversion programs, court-based initiatives to divert offenders into treatment, and formal drug courts for serious offenders. There have also been attempts to provide treatment programs within prisons. However, opportunities for diversion could be strengthened in other areas. The first area is at the “end” of the criminal justice system, by providing postrelease support programs for prisoners leaving custody. Given that some 58% of prisoners have been imprisoned previously and 22% of police detainees have been imprisoned in the past 12 months, interventions to break the cycle of reoffending would have a significant beneficial effect on both the individual and the wider community — drug treatment is clearly one of those interventions. The second opportunity to improve diversion to treatment is in the gap between police diversion and the drug court: targeting people who are arrested and processed but whose offence is not sufficiently serious to meet the criteria for a formal drug court program. The study by Heffernan et al includes a significant number of these people, providing support for “arrest drug referral” schemes, as undertaken in the United Kingdom.16 However, there could be very large numbers of people suitable for such schemes. Policymakers first need to know how many of those people would avail themselves of treatment. In addition, treatment options must exist — at present, there is a range of effective treatments for heroin, but options for other illegal drugs are extremely limited. Reducing crime requires a multipronged approach that goes beyond criminal justice and treatment responses, to include a whole-of-government approach. Building the evidence base with valuable contributions such as that by Heffernan et al is vital to ensuring our interventions are successful.

Toni Makkai PhD

We should do all we can to ensure that every baby benefits from this important preventive activity Newborn screening is a wonderful example of preventive medicine. Pioneered by Dr Robert Guthrie in the early 1960s, the blood-testing of newborns for treatable disorders has become almost universal in developed countries. From the first programs for phenylketonuria testing, the scope has widened to include disorders such as hypothyroidism and cystic fibrosis. More recently, analysis by tandem mass spectrometry, which can detect over 30 rare inborn errors of protein and fatty-acid metabolism, has been introduced.1 Soon all babies in Australia will be able to be tested by tandem mass spectrometry. A simple heelprick is all that is needed. More than one baby in every 1000 (over 250 babies a year in Australia) will have a detectable disorder needing treatment. Without early detection, some of these babies would develop intellectual disability, some would develop acute life-threatening illness, and a few avoidable deaths would result. Screening for phenylketonuria alone, with subsequent treatment, has saved over 700 Australian children from moderate to severe disability since screening began. The consequences of not having a screening test might seem trivial to an individual family — only about one chance in 1000 that anything threatening would be missed. But, for every 1% of babies in Australia that are not tested, two or three babies per year with a treatable disorder could die or suffer permanent damage. In this issue of the Journal, Metz and colleagues (page 412) report the results of a systematic investigation of the coverage of newborn screening in South Australia for the year 1999.2 The team not only examined coverage, but carefully analysed who it was that missed out on screening. Some of the results are not surprising, but some are. Being Aboriginal, having a home birth, being in hospital for less than three days, or suffering neonatal death were all risk factors for missed screening, as were having a gestational age of less than 32 weeks, being in intensive care, having a congenital anomaly, or having a mother who normally lived in another state. (Being a twin or triplet, however, was protective — they rarely missed being screened.) Metz and colleagues concluded that, overall, about 2% of babies did not get a screening test. The methodology used was thorough, matching newborn screening data with the SA perinatal data collection using sophisticated software. Of course, data matching is never perfect. Baby’s-surname changes are common soon after birth (even the mother’s indicated surname can change), and babies are sometimes transferred from one hospital to another. In the end, there were 413 births to which Guthrie screening cards could not be matched, and 44 unmatched cards. Even if the unmatched cards represented babies who were born interstate then transferred to South Australia, as was suspected, this would not have materially altered the finding that about 1 in every 50 babies born was not screened in 1999. This should sound a warning note to those who oversee other screening programs, many of whom have assumed a greater than 99% coverage without adequate supporting data. There has indeed been little published on newborn screening coverage, although a recent survey from London did suggest an enviable coverage of 99.9%.3 Newborns are an ideal population to screen, being “captive” for the crucial time, but the problem of early discharge is threatening this, just as screening is poised to expand into new fields. Newborn hearing screening is becoming universal in Australia, and for this, too, it will be important to ensure a very high coverage.4 Biochemical screening by means of the routine dried blood spot is also very likely to expand as new possibilities, supported by new technology, are being explored.5 The lessons from the SA study are clear. To achieve close to 100% coverage, strategies must especially target groups at high risk of not being screened, and healthcare providers need to be reminded and re-reminded about the importance of the test. In relation to the SA study, it would have been interesting to know whether some birth units had particularly high rates of missed tests — if that were the case, such units could be targeted for kindly reminders. As the authors point out, it is also important to collect a sample from newborns who die. Now that expanded testing by tandem mass spectrometry is available, firm diagnoses can sometimes be made from dried blood samples of babies who have died. In New South Wales, over a 4-year period, we have diagnosed fatty-acid-oxidation disorders in this way in three children who died 2–3 days after birth. Achieving a diagnosis makes possible either prenatal diagnosis in a future pregnancy, if desired, or early management of a subsequent baby to avoid clinical problems. For better coverage, perhaps screening should become mandatory in Australia, as it largely is in the United States. In Australia, we have felt that parents have a right to refuse neonatal screening on behalf of their baby. But should parents be able to refuse a procedure that carries such a tiny risk and has an obvious potential benefit, and would this not infringe on the baby’s right to have what ethicists call an “open future”?6 This is a difficult question, but one that is growing in importance as the potential for well targeted newborn screening increases. At present, in our experience, only a very small number of parents refuse newborn screening, for a variety of reasons. If we feel that newborn screening tests are valuable, then we need to ensure that every baby has a chance to benefit. Few preventive medicine programs are so effective.

Bridget M Wilcken AM, FRACP

Objective: To assess trends in the first two years of prescribing of COX-2-selective non-steroidal anti-inflammatory drugs (C2SNs) by Australian general practitioners.Design: Retrospective analysis of deidentified electronic patient records from GPs enrolled in the General Practice Research Network (GPRN).Setting and participants: Overall prescription rates for C2SNs and NSAIDs were assessed for all GPRN participants (437 GPs) between 1 September 1999 and 30 September 2002. Also, three cohorts of patients, with at least 12 months of prescription data, who received their first prescription for celecoxib between August and October 2000 (Cohort 1, 2366 patients), celecoxib between February and April 2001 (Cohort 2, 640 patients), and rofecoxib between February and April 2001 (Cohort 3, 608 patients) were selected for further analysis.Main outcome measures: Age and sex of patients; reason for prescription; previously prescribed pain medications and concomitant use of medications that could predispose to an adverse renal or bleeding event.Results: Prescriptions for C2SNs increased dramatically after they were listed on the Pharmaceutical Benefits Scheme (PBS). C2SN prescriptions for patients aged less than 65 years accounted for 52.6%, 59.5% and 50.7% of those in Cohorts 1, 2 and 3, respectively; large numbers of patients in the study cohort had reasons recorded for prescription that did not comply with PBS restrictions, and between 36.7% and 61.3% of patients in the three cohorts had not received a prescription for any pain medication in the year before being prescribed a C2SN. Between 4.7% and 7.9% were coprescribed drugs that could cause renal complications.Conclusions: Rapid, early adoption of C2SNs by Australian GPs has resulted in prescribing and drug use patterns that were not in accord with quality use of medicine (QUM) principles.

Stephen J Kerr BPharm, PhD · Andrea Mant MD, MA · Fiona E Horn BSc, MPH · Kevin McGeechan BSc · Geoffrey P Sayer BSc(Psychol), MCH

Objectives: To determine the 12-month prevalence of substance-use disorders and psychological morbidity in an Australian arrestee population.Design: Cross-sectional descriptive study.Participants and setting: 288 police arrestees at the Brisbane City Police Watch House in February and March 2001.Outcome measures: Prevalence of drug and alcohol disorders; psychological “caseness” according to the 28-item General Health Questionnaire; demographics and index offences.Results: 86% of the arrestees had at least one substance-use disorder; most had multiple disorders. More than 80% were substance dependent. The predominant substances used were amphetamines, marijuana, opioids and alcohol. 82% of the men and 94% of the women were suffering significant psychological distress.Conclusions: Development of services for detoxification and treatment of this population is a pressing need. The findings provide crucial information for the planning and implementation of drug courts and court diversion systems.

Edward B Heffernan BSc(Hons), FRANZCP · John B Saunders FRACP, FAFPHM, FRCP · Gerard Byrne PhD, FRANZCP · Joe Finn BN

Objective: To determine the biochemical screening rate of newborns in South Australia and the factors associated with babies not being screened.Design: Matching of data in the SA Newborn Screening Centre database (acquired from Guthrie cards) with the SA perinatal data collection (compiled from supplementary birth records) to determine how many newborns missed screening. Risk factors for missed screening were identified from sociodemographic and clinical variables recorded in the perinatal data collection and analysed by multivariable unconditional logistic regression analysis.Patients and setting: All live births (n = 18 426) in South Australia in 1999, in the 63 hospitals assisting deliveries or in the home.Main outcome measures: Rates of biochemical screening and missed screening in all newborns and among various subgroups; adjusted odds ratios (after multivariable logistic regression analysis) for risk factors for missed screening.Results: The newborn screening rate in South Australia in 1999 was 97.8%. Babies born at home, born to an Aboriginal mother, or born to a mother who normally resided in another state were at higher risk of missed screening. Other factors associated with missed screening were having fewer than seven antenatal visits, prematurity (gestational age at birth < 32 weeks), congenital abnormality in the baby, use of paediatric intensive care, early discharge from hospital before 3 days (but especially after less than 1 day), and death of the baby during the neonatal period.Conclusion: In South Australia, while 2.2% of all newborns missed screening in 1999, in certain high-risk groups the proportions of unscreened babies were significantly higher. With a 2% missed screening rate, one might expect one newborn with a screening-detectable disorder to elude detection every other year in South Australia.

Michael P Metz MD, MAACB · Enzo Ranieri BSc(Hons), MSc · Rosemarie L Gerace BSc · Kevin R Priest BSc · Colin G Luke MPH, FAFPHM · Annabelle Chan DPH, FAFPHM

Objectives: To examine the complexity of activities undertaken in general practice in relation to degree of rurality of the practice.Design and setting: National mail questionnaire survey across non-metropolitan Australia in July 2002.Participants: 1498 respondents out of 4406 GPs providing at least 375 Medicare-rebatable consultations in rural and remote locations during January–March 2002 (response rate, 35%).Main outcome measures: Responses to five sentinel measures of practice complexity.Results: In general, the proportion of GPs providing complex services increases with increasing rurality or remoteness. Isolated rural and remote GPs manage myocardial infarctions to a higher level than GPs in larger rural and regional centres, are more likely to administer cytotoxic drugs, perform forensic examinations, stabilise injured patients pending retrieval, and coordinate discharge planning more often.Conclusions: The more rural or remote the area, the more likely a GP is to be regularly engaged in complex care. These findings have implications for the workload, responsibility, vocational satisfaction, need for professional education and support, and costs and remuneration of practice.

John S Humphreys BA(Hons), PhD · Judith A Jones BA(Hons), MSPD · Michael P Jones BSc(Hons), PhD · David Mildenhall DANZCOG, DCH, FACRRM · Paul R Mara DipRACOG, FRACGP, FACRRM · Bruce Chater FACRRM, FRACGP, DRANZCOG(Advanced) · David R Rosenthal DipRACOG, FAMA, FACRRM · Nola M Maxfield MB BS, DipRACOG, FACRRM · Michael A Adena PhD, Astat, MACS

Heart failure prevalence is increasing because of the ageing of the population and the longer survival of people experiencing myocardial infarction and heart failure. The lifetime risk of developing heart failure in Western countries is about 20%. The increasing prevalence of overweight, obesity and diabetes is likely to accelerate heart failure incidence. While there have been major advances in treating heart failure, a preventive approach promises greater benefit to a larger proportion of the community. The medical strategy for heart failure prevention, based on calculation of individual risk, is focused on the minority of individuals who exceed an arbitrary risk threshold. A public health strategy targeting the whole population offers a greater prospect of reducing the incidence of heart failure and other cardiovascular disease. A multitiered approach, encompassing environmental determinants of lifestyle, legislation, and education about healthy lifestyles throughout life, in addition to aggressive control of risk factors in high-risk individuals, is likely to have the greatest impact.

Duncan J Campbell FRACP, PhD

Regulatory and ethical guidelines require clinical trial sponsors to disseminate clinical trial adverse event reports to involved investigators and human research ethics committees. Compliance with these guidelines has resulted in a major administrative burden for ethics committees. This burden does not necessarily contribute to the protection of clinical trial participants. Rationalisation of the adverse event reporting might allow better use of the data and might benefit human research ethics committees.

Winston S Liauw MMedSci, FRACP · Richard O Day AM, MD, FRACP

Clinical record In 2001, a young man was admitted to hospital with a 3-day history of gradual-onset headache, nausea, vomiting, neck stiffness and photophobia. Three weeks earlier he had experienced a gastrointestinal illness (nausea, abdominal cramps, diarrhoea, myalgia and fever) that persisted for 1 week. On examination, he had a low-grade fever and meningism. A cerebral computed tomography scan showed no abnormality. Peripheral blood eosinophilia (1.6 x 109/L; reference range [RR], < 0.44 x 109/L) was noted, and examination of cerebrospinal fluid (CSF) showed 530 x 106/L monocytes (RR, < 5 x 106/L), 22 x 106/L red cells (RR, < 1 x 106/L), no eosinophils on routine staining, a raised protein level of 1.07 g/L (RR, < 0.45 g/L) and a normal glucose level. He was treated with intravenous aciclovir for 6 days. A CSF polymerase chain reaction test for herpes simplex virus-1 (HSV-1) and HSV-2 subsequently gave negative results. Serological tests for Strongyloides and Angiostrongylus were negative. CSF and blood cultures showed no growth. Twelve days after admission, he was discharged from hospital with resolving meningism. Five days later, increasing headache and drowsiness prompted his admission to another hospital. He was afebrile, drowsy and irritable, with gross bilateral papilloedema. He described mild paraesthesiae in both hands. He had peripheral blood eosinophilia (3.1 x 109/L). Magnetic resonance imaging of the brain with gadolinium contrast showed multiple focal enhancing lesions in the deep white matter of both cerebral hemispheres, including the corpus callosum (Figure A). CSF from cisternal puncture was cloudy, under high pressure and, on routine toluidine blue staining, had 1008 x 106/L polymorphonuclear cells (RR, < 5 x 106/L), 186 x 106/L monocytes and 21 x 106/L red cells. Further staining to detect eosinophils was requested, and 90% of the polymorphonuclear cells were found to be eosinophils (Figure B). His CSF protein level was elevated at 0.8 g/L and glucose level 2.6 mmol/L (50% serum glucose). India ink, Ziehl–Neelsen and Gram stains were negative. Repeated questioning revealed that the patient had ingested, 5 weeks earlier, for a dare, two slugs from a garden in a Sydney suburb. Repeat Angiostrongylus immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), tested in parallel with the first specimen, was positive, confirming seroconversion. Several leopard slugs, Limax maximus (Figure C), taken from the Sydney garden were dissected without finding larvae (Figure D), but no rats from the vicinity were examined for this infection. Treatment comprised measures to reduce intracranial pressure with repeated CSF drainage, acetazolamide and dexamethasone, initially given intravenously, and then orally. CSF drainage consisted of one cisterna magna puncture and two lumbar punctures. Specific anthelmintic agents were not given. No ocular larvae were seen on regular formal ophthalmological review. He improved gradually and, after 17 days in hospital, was discharged with instructions to take a reducing dose of dexamethasone over 4 weeks. His final lumbar puncture 1 month after admission showed an almost normal CSF protein level (0.5 g/L) and a reduction in CSF white cell count (107 x 106/L; 8% eosinophils). After 5 months, he successfully returned to full-time studies and competitive sport. A: Magnetic resonance image of the brain, showing multiple focal enhancing lesions in the deep white matter (arrows). B: Spun-down cerebrospinal fluid cells (Romanowsky stain: original magnification x400). C: Limax maximus, the leopard slug, an intermediate host for Angiostrongylus cantonensis. D: Adult female Angiostrongylus cantonensis from the lungs of Rattus norvegicus. This is the first reported case of human eosinophilic meningitis due to Angiostrongylus cantonensis acquired in Sydney. The first A. cantonensis infection in humans reported in Australia was from Brisbane in 1971.1 More recently, a fatal case occurred in a child who ingested molluscs in a suburban Brisbane garden.2 Over the past 10 years, Angiostrongylus has been isolated from dogs, flying foxes, marsupials and zoo primates in Sydney.3 Angiostrongylus cantonensis, also known as Parastrongylus cantonensis, is the commonest infectious cause of eosinophilic meningitis worldwide and is endemic in South-East Asia and the Pacific Basin.4 The other, rarer parasitic causes of eosinophilic meningitis are not endemic to Australia.5 Non-infectious causes of eosinophilic meningitis include haematological malignancies, antibiotics (ciprofloxacin, intraventricular gentamicin or vancomycin) and idiopathic hypereosinophilic syndrome.6 The lifecycle of the parasite from the adult stage in the definitive rat host through the intermediate mollusc host has been described previously.2 Humans become accidental hosts when they ingest the larval stage in raw or undercooked molluscs or crustaceans or in fresh vegetables contaminated by infected molluscs.5 The diagnosis of angiostrongyliasis in a patient with acute eosinophilic meningoencephalitis is supported by a history of mollusc ingestion, but eliciting this may require specific questioning. Symptoms occur 2–45 days after ingestion.7 The most common symptom is headache. Paraesthesiae are frequently reported.6 In our patient, the acute febrile gastrointestinal illness 6 days after consuming the slugs may have been caused by invasion of the parasite through the intestinal wall. Initial entry into the meninges, and subsequent migration through brain parenchyma, caused the clinical picture of meningitis followed by encephalitis. Seizures or other focal neurological symptoms may occur. Peripheral blood and CSF eosinophilia strongly support a diagnosis of Angiostrongylus meningoencephalitis, but may appear only later in the course of the illness, or, in a minority of cases, not at all.4,7,8 It is important to emphasise that eosinophils may not easily be differentiated from neutrophils on routine microbiological staining, such as with toluidine blue wet films. In aseptic meningitis, particularly associated with peripheral eosinophilia, specific Romanowsky stains, such as May–Grünwald–Giemsa or Wright stains, should be performed. An ELISA measuring total IgG can be diagnostic. The ELISA used to demonstrate seroconversion in this case utilised somatic antigens from adult A. cantonensis. The ELISA can be performed on serum or CSF. The Institute for Clinical Pathology and Medical Research at Westmead Hospital is the only centre in New South Wales performing the assay. As parasitologically proven cases are rare, it is difficult to determine the sensitivity and specificity of this assay. Angiostrongylus meningitis is usually mild and resolves spontaneously over 6 weeks. Occasionally, cases are severe and may have chronic sequelae.5,6,8 No randomised controlled studies have assessed optimal management, but repeated CSF drainage may give symptomatic relief.8,9 Steroid treatment appears to be beneficial, presumably reducing CSF pressure and inflammatory response. Regimens reportedly of benefit include prednisolone 30–60 mg/day for 5 days,8 prednisolone 40–60 mg/day with weaning over a few weeks,9 and prednisolone 60 mg/day for 2 weeks.10 The use of anthelmintic agents is controversial. Generally, avoidance of anthelmintic agents has been recommended on the (theoretical) basis of their potential for harm owing to the inflammatory response provoked by antigen release after parasite death.4,8 A. cantonensis should be considered as a cause of aseptic meningitis in patients with paraesthesiae and peripheral eosinophilia, and a history of exposure to undercooked molluscs or crustaceans. This report highlights the wider distribution of this parasite in Australia and, in particular, its close proximity to urban populations. Lessons from practice Angiostrongylus cantonensis should be considered as a cause of aseptic meningitis in patients with paraesthesiae and peripheral eosinophilia, and a history of exposure to undercooked molluscs or crustaceans. It is important to specifically request tests for eosinophils in cerebrospinal fluid (CSF) when their presence is suspected, particularly if there is peripheral eosinophilia. Eosinophilia in peripheral blood and CSF supports a diagnosis of Angiostrongylus meningoencephalitis, but absence of eosinophilia does not exclude it, particularly early in the course of the illness.

Don S Pryor MD, FRACP · Pam Konecny MD, DTM · Sanjaya N Senanayake MB BS(Hons) · John Walker PhD

A recent editorial in the New York Times makes disturbing reading. It says, in part: . . . the number of Americans without insurance . . . stood at 39 million even at the end of the booming 1990s . . . more than 2 million Americans lost their insurance last year. The soaring costs are driven, in part, by the biomedical revolution of the past decade, which has produced an array of expensive new treatments for an ageing population, from drugs to fight osteoporosis to high-tech heart pumps. The result is a health care system filled with great promise and inequity — such as wonder drugs that many of the nation’s elderly must struggle to afford. Dr Janelle Walhout sees the paradox every day at the community clinic in Seattle where she works. “I’ve been thinking lately about the mismatch,” Dr Walhout said, “between how very high-tech medicine has become, with all these genetic tests for everything, mixing your medicines like fine cocktails, and our patients, who can’t afford them, can’t understand it, can’t get interpreters to explain it and are just not accessing those things.”1 This is a newspaper editorial from the world’s wealthiest country — the country that is the paradigm for development in the Western world. If the United States leads, can we be far behind? I have been asked to speak broadly about the ethics of healthcare, as a background to a discourse of healthcare reform. There seem to be good grounds to pursue reform; and yet there’s been so much that is good that has happened in the last 50 years. To take but one example, cancer survival overall has risen from 30% to 50%. Some malignancies, such as Hodgkin’s disease and some kinds of testicular cancer, are curable, even when they’re quite advanced. Prevention and early detection have changed the whole history of malignant melanoma, that most Australian of cancers. The genetic basis of a few cancers has been determined, and that may lead to preventive or even curative approaches. However, there is an obdurate residue that we cannot shift. Advanced bowel cancer is common and generally unresponsive. Lung cancer still has a poor outlook. We will all die of something, and strokes, heart disease and cancer remain the three most common causes. These are the sad facts that govern our lives, but my concern here is to talk about the social and political systems in which healthcare is embedded, and why progress in science and technology masks deep social and ethical problems. My view of the future for Western health and medicine is bleak. The gaps between rich and poor, between their health, wealth, welfare, access to justice, education and pleasure, will widen. The burgeoning technology that promises so much will prove to be of inestimable benefit to those who can afford it, and who, in many ways, need it least. Commercial interests will prevail increasingly over moral commitments, and multinational companies will continue their course to replace nation states as the centres of political and economic power. Global issues, such as pollution, environmental destruction and global warming, will be endlessly discussed, and endlessly dismissed. Spiritual and aesthetic issues will decline in importance still further, and money will become almost the sole criterion of worth. Universities, healthcare systems, churches and cults will be judged, and will appraise themselves, by their capacity to make profits rather than prophets. All these things will happen in Australia and in most of the Western world. Indeed, this pattern of development is seen to be the criterion of successful development. Those countries that can’t make it in such an environment will be marginalised, and seen as “opportunities for investment” or as “sources of cheap labour”. These things are happening now, and I see nothing that is likely to change this progression. At its root are two closely linked things — the science of economics (if it is a science) and the colonisation of values by money.2,3 Economics defines itself as the branch of knowledge that deals with the distribution of wealth on one hand, and (in its more idealistic moments) as “the study of how men [sic] and society end up choosing, with or without the use of money, to employ scarce productive resources . . . It analyses the costs and benefits of improving patterns of resource allocation”.4 Unfortunately, these definitions represent conflicting priorities. The distribution of wealth ties economics to money, to a utilitarian calculus, and to commercial values. The domain of scarce resources is communitarian and socially oriented. The dominant paradigm, however, is that of handling wealth and managing the monetary economy, a “neo-classical” model. It is economists of this persuasion who advise and influence heads of state, who determine whether interest rates will inflict “necessary pain” in order to adjust the national inflation figures or “limit the blow-out in the balance of trade”. There are, of course, economists of the communitarian or socially conscious persuasion,5-8 but they work for social change at the margins of both mainstream politics and mainstream economics. They have their apparent victories, as John Deeble did with Medicare in Australia. However, at the end of the day, some form of “economic rationalism” dominates, because it is money management that influences politicians. And it is money that is the problem. Money presumably began life as a convenience, as a portable means of trading that put an exchange medium in the place of barter. It began life as a symbol of value, but has become an abstraction against which value is measured. Money thus colonises our moral space. It has also colonised political space almost completely. In Australia, for example, there’s effectively only one viable political party. We might call it the Economic Realist Party. Like the recognised parties, it has its factions. Just to the left of centre is a faction which insists on emphasising a (heavily qualified) social awareness. To the right, a counterfaction espouses a (qualified) free-market philosophy. Both factions woo the corporate sector; both make gestures toward social welfare. Both temper their ideals with appeals to the central reality of economic restraints. Inevitably, this determines policy for all public services, whether they be in education, transport, housing, roads, defence or health. Levels of services are determined by what we can afford rather than what we can transact between each other. It’s scarcely realistic to suggest going back to some kind of barter system in any westernised country — although Argentina’s recent social credit experiment suggests that the idea isn’t dead — but we do need to understand how money alienates us from the sustaining, foundational values which underlie the provision of any services. The effective colonisation of morals and politics by money and commerce has far-reaching consequences. Commercial values and the notion of the legally binding contract have replaced trust in many relationships, including those between patients and their families, and doctors. The ideal of service has been replaced by the legally nuanced “duty of care”. Our adversarial legal system has entered the space of health services more and more intrusively, so that “defensive medicine” is now an established (and very expensive) part of healthcare practice.9,10 The costs of healthcare services have inevitably demanded that commercial and economic ideas, such as “best practice”, “efficiency”, “cost-effectiveness”, “outcomes”, and “evidence-based medicine” have become more important than human relationships and the nature of the processes of healthcare. Compassion and time to talk return no dollars that can be easily identified on a balance sheet, yet they’re as fundamentally important in healthcare as any technology. Healthcare services are essentially moral endeavours. Western governments and other agencies are obliged to provide them because people generally value human life in both quantity and quality.11 Each person wants to be protected from illness, and, when illness strikes, to be looked after. Each wants some sort of bulwark against the risks and sufferings that illness threatens. This is the value that underpins the ethics of healthcare. If we didn’t value human life to a significant extent, societies wouldn’t permit the expenditure that governments put into healthcare services. Huge amounts of money are committed. Individuals and corporations can become immensely wealthy by supplying goods and services within the healthcare sector. Science and technology continually promise more and better ways to diagnose and cure disease. Life expectancy in Australia was 78.2 years in 1997.12 It has increased by more than 20 years in the US in the last 100 years.13 The last gains have been the hardest and the most expensive, and that’s a common pattern of technological advance.14 It’s time to recognise that we are in the phase of diminishing returns,13 and to re-examine what more we can achieve. Although we are told by some that economics is the science of distributing scarce resources, it’s not really the resources which are scarce in themselves. It’s the scarcity of money that is the problem. If there were more money, we could train and employ any number of doctors, buy computed tomography scanners for every town, and have oncology services and palliative care distributed widely. We could provide sophisticated services for outback towns, public health programs for Indigenous communities, and we could endlessly fund molecular and genetic research in cancer. Whether this increased expenditure would translate into better public health is another question. It would probably make little difference. The public health parameters for Australia, the United Kingdom and the US are very similar, despite differences in expenditure from more than 14% of gross domestic product in the US to about 7% in the UK.12 Speaking ethically, it’s quite likely we could achieve greater health gains by concentrating on improving the health of those with the greatest health needs — the poor, the elderly, the unemployed, Indigenous groups — but it is far more likely that medical research will continue to be funded for the advancement of “high-end” technology, such as molecular genetics and gene therapy. These technological wonders may produce some benefits, but it is extremely unlikely that they will produce the revolutions confidently predicted by scientists at the start of the Human Genome Project. Further, we must ask ourselves who might reap those benefits — the already wealthy (and statistically more healthy), or the poor and needy? As the medical technology corporations inevitably think in terms of profit rather than public service or morality, each advance will come at a price that will be beyond the reach of the disadvantaged, and beyond the reach of most governments to subsidise. Healthcare, then, is underpinned by two imperatives — the relief of suffering and the prevention of death. The massive expenditure of effort and money that Western societies commit to prolonging life has become a defining characteristic of our culture and our times. We fear death, and no amount of stoical rationality can remove that intuitive fear.15,16 When our lives are threatened, we struggle to survive. It’s not surprising, therefore, that our community wants access to healthcare that defends us and our loved ones against the reality and inevitability of death. Medical technology, health systems, medical research — all are sustained and justified, in major part, by our intuitive desire to oppose death and dying with systems that ensure our security and hold out hopes for our flourishing. This is all perfectly good and appropriate — up to a point, but there are some awkward consequences, and we are already in the midst of some of them: It seems unlikely that death can ever be entirely eliminated. That means that, somewhere along the line, we’ll all have to accept that there is a stopping point, a point at which we must call a halt. There is an old law of technological development that says that the last gains are the hardest.14 In other words, we must enter a phase of diminishing returns, waiting for a paradigm shift that moves us away from the established models. In watchmaking, for example, the invention of the quartz movement suddenly made accuracy cheap. No such paradigm shift is on the horizon for medicine. The genetic revolution is immensely expensive, and genetic interventions — exciting though they promise to be — are not likely to be available at bargain prices nor free of patents. Further prolongation of life, beyond, say, an average of 80 years or so, will be increasingly costly. In a global context, the endless prolongation of average life-span is irrelevant. Most of the world’s populations live in what the Western world defines as poverty, with health statistics that are unthinkable in “advanced” countries. Even within wealthy nations — like Australia — there are subpopulations of the Indigenous, the poor, the handicapped, whose health is poor and whose deaths occur at significantly younger ages. World health, in which we are all involved whether we like it or not, doesn’t depend on cutting-edge technological advances, but on moral awareness and political commitment. The indefinite prolongation of life raises practical and moral issues of great complexity and profound significance. Say that scientists find ways to prolong average life span to 100 years. In Western cultures, the 80 years of average life causes problems enough. We’ve scarcely begun to manage the problems of the ageing population. We lack facilities, personnel and funds to care for the aged. Those same scientists will have to find ways to reduce the impact of ageing, so that less care is needed for the elderly. And then, should they succeed in that endeavour, they create another problem. Fit, mentally active people aged 70–80 years will need some way to occupy their time, not just playing bingo or lawn bowls, but working and using their skills and their great experience. How will we achieve this while remaining fair towards younger people wanting to secure and advance their own careers? And how will we manage the population pressures? If the mean duration of life increases, populations will increase, unless birth rates fall even further. And what will a further fall in birth rate do to the balance of ages within our community, to the rights of younger people, to their capacity to earn? Medical research is a wonderful thing, and it does much to increase the sense of security we all feel in our societies, but perhaps it addresses too much the ambition of endless prolongation of life. Perhaps it should turn more to an understanding of suffering,17 to ways of making the average life-span more enjoyable, more secure. Maybe we should do more qualitative research, which is relatively cheap to fund and produces insights that can help healthcare deliverers, educators and policy makers. In our knowledgeable, paternalistic way, we seem to be always prescribing “appropriate” or “sustainable” technology for the Third World. Perhaps we need to listen to our own advice, to curb our ambitions for immortality. Perhaps we need to decide, as a community, how much we’re prepared to spend on healthcare and medicine, and then determine — as they did in the state of Oregon in the US18,19 — just what priorities consumers want. We need, in other words, to decide what it is appropriate for us to do. Community consultation is a part of Danish life. We’ve even done it in Australia at the Constitutional Convention and the Community Jury on Genetically Modified Food. Recently, Gabbay and colleagues in Southampton described the formation and successful function of facilitated groups called Communities of Practice, which assemble stakeholders to examine available evidence and formulate policy suggestions.20 It is not impossible to consult communities, and it sometime produces results that surprise us all. Medical research and the advance of technology will continue, as indeed they should, but we must stop seeing research and technology as ends in themselves, or as directed solely toward the conquest of death. Healthcare is justified just as much by its capacity to limit suffering. If the thrilling advances of cutting-edge science are available only to the few who can afford them, we face some real moral dilemmas. They’re dilemmas which should prompt us to think about the values we might want for ourselves and our children. There are limits to growth, and limits to what we can afford. Here, then, is the message from ethics; a call for action rather than an appeal to theory. It’s time to look at the society in which we live, and to ask ourselves “Is this a society in which there’s real justice? Is this a society where I and my loved ones, in our time of trouble, can be sure to access care which is compassionate, thoughtful and appropriate?” I don’t know what conclusions you’ll reach in this Summit, but I do know that you’ll have wasted your time, and failed the constituency of the ill, if you fail to think deeply about these questions, and to suggest plans of action which will let us answer “yes” to both.

J Miles Little MD, FRACS

QuestionIs early surgical referral for children with persistent otitis media with effusion (OME) appropriate? Trial details Design: Randomised, assessor-blinded, controlled trial. Setting: Two hospitals and six private paediatric group practices from the Pittsburgh region in the United States. Participants: 429 children aged less than 3 years who had otitis media with effusion (OME) that had persisted despite treatment with antimicrobial drugs for the equivalent of: 90 days in the case of bilateral effusion; or 135 days in the case of unilateral effusion. Interventions: Children assigned to the early treatment group were scheduled to have ventilation tubes (grommets) inserted as soon as possible. Children assigned to the late treatment group were scheduled to undergo the operation 6 months later if bilateral effusion persisted (or 9 months later if unilateral effusion persisted). Children in the late treatment group could receive grommets earlier if their parents requested the operation. Main outcome measures: Standardised assessment of cognitive ability, receptive language ability, expressive language ability, parenting stress, and child behaviour at 3 years of age. Main results: 169 children in the early treatment group (82%) and 66 children in the late treatment group (34%) had had ventilation tubes (grommets) inserted by 3 years of age. There were no significant differences (mean ± standard deviation) for early treatment versus late treatment in the General Cognitive Index of McCarthy's Scales of Children's Abilities (99 ± 14 v 101 ± 13); Peabody Picture Vocabulary Test–Revised (92 ± 13 v 92 ± 14), Number of Different Words Test (124 ± 32 v 126 ± 30), Percentage of Consonants Correct–Revised Test (85 ± 7 v 86 ± 7), Total Parenting Stress Index, Short-form–Total Stress (66 ± 18 v 68 ± 21), and Child Behaviour Checklist–Total Problems (50 ± 10 v 49 ± 10). Conclusion: In young children with persistent OME, prompt insertion of ventilation tubes (grommets) does not measurably improve developmental outcomes by 3 years of age. CommentaryRationale for the trialOtitis media with effusion (OME) is the most prevalent form of middle ear disease in young children. It is defined as the presence of fluid behind the tympanic membrane without the symptoms or signs of acute otitis media (AOM).1 It is usually associated with some hearing loss. OME with persistent hearing loss may contribute to delays in speech and language development.2 Recommended interventions include the use of antibiotics and the insertion of ventilation tubes (grommets).2-4 There have been concerns about the overuse of grommet surgery. Substantial variation in rates of this procedure have been documented.5,6 Clinical practice guidelines have recommended that grommets are an option for children who have bilateral OME associated with a hearing loss of > 20 decibels for at least 3 months.2-4 The intervention is most likely to benefit younger children (during the most critical phase of language development) and those with most hearing loss. Trial methodsThis trial was part of the largest otitis media cohort study ever conducted.7 The study was generally well designed and well reported.8,9 A total of 6350 healthy infants were enrolled in their first 2 months of life and were evaluated monthly for otitis media; 588 of these children had persistent or very frequent OME. They were regarded as typical of children who might receive surgery in the United States. The aim of the study was to determine the benefits of early referral for surgery compared with delayed referral (where “watchful waiting” continued for an additional 6 months). Random assignment was made by designated non-clinical staff using separate, computer-generated lists of random numbers. Children were stratified according to site, age (in 6-month categories), and whether the eligibility criteria were met on the basis of bilateral or unilateral effusion. Assignment within each of the predetermined strata occurred in permuted blocks of four. This ensured that the allocation was balanced after every four new children (in a stratum) were randomly allocated. Children underwent developmental assessment as soon as possible after their third birthday (and always within 2 months). Standardised assessment tools were used. Assessors were unaware of the child’s medical history, health insurance status, and mother’s level of education. The investigators proposed that a difference of 0.33 standard deviations between groups on any outcome measure could be clinically important. Follow-up of participants over a prolonged period was reasonably good (95% and 92% of the early- and late-treatment groups, respectively). All analyses were based on the intention-to-treat principle (although children who were not assessed could not be included in the analysis). Any weaknesses in the methods and the quality of reporting were relatively minor. Ideally, the authors should have also described (i) how random allocation was concealed from the investigators, (ii) how block size was concealed from investigators (so they couldn’t guess which intervention would be allocated next), (iii) the adequacy of blinding, (iv) the primary outcome for the study, and (v) an assessment of adverse outcomes. The choice of a 0.33-standard- deviation difference between the groups in any of the assessments as the minimal clinically important difference was controversial. While this approach should be able to identify reasonably small statistical differences attributable to the intervention, the clinical importance of such a difference is not easily understood. In the end, because there were no statistically significant differences in any of the outcome measures, this issue did not arise. New informationThis is the largest randomised trial to evaluate ventilation tubes in children with persistent OME. Previous studies had shown that surgery improved hearing by around 12 dB at 6 months and 6 dB at 12 months.5 Most of these studies involved older children and did not include an assessment of speech and language (which is generally regarded as the most important outcome). The results of this study are consistent with those of previous studies in demonstrating that grommet surgery will substantially reduce the amount of time that a child has OME, and modestly improve hearing. However, by 3 years of age, early referral for surgery had no beneficial effect on development or behaviour. The consistent lack of effect for a range of outcome measurements was striking. These findings were not changed by the subsequent subgroup analyses.10 The results of this study are unlikely to be explained by a biased estimate of effect or by chance. Similar results have also been documented in other recent well designed studies in different populations.11-13 Implications for clinical practiceIdentifying young children with persistent OME is a common problem for general practitioners in Australia. For children who are otherwise well, this study shows that early referral for surgery does not improve developmental outcomes at 3 years of age. For individual families affected by long waiting times or preferring to avoid an operation, parents can be reassured that the child will not be disadvantaged by delaying the decision about surgery. The duration of “watchful waiting” can be extended to 9–12 months without serious consequences. Although hearing loss will persist longer, many episodes of persistent OME will resolve and potential complications of surgery (otorrhoea, chronic perforation) will be avoided. It is still possible that the insertion of ventilation tubes will improve developmental outcomes in some children. The results of this study are not applicable to: children with established speech and language delay (or conditions known to be associated with speech and language delay); children with bilateral OME that persists longer than 9–12 months; and children with more substantial conductive hearing loss. Parents of these more severely affected children can be advised that this simple and safe operation will improve their child’s hearing. However, whether it will improve their speech and language development is still uncertain. Further trials targeting these specific subgroups should be supported.

Peter S Morris FRACP, PhD · Amanda J Leach PhD

Determining the sample of participants to be analysed is a crucial step in reporting clinical trials. For such analyses, the gold standard is the “intention-to-treat” principle. The question of which participants are included in the analysis appears as Item 16 of the CONSORT statement (Box 1).1 Intention-to-treat (ITT)Analysis by ITT is a strategy that compares the study groups in terms of the treatment to which they were randomly allocated, irrespective of the treatment they actually received or other trial outcomes. Regardless of protocol deviations and participant compliance or withdrawal, analysis is performed according to the assigned treatment group.2,3 Random allocation aims to ensure that trial participants’ risk factors that may affect the outcome under investigation are balanced between the allocated treatments. This is to ensure that any differences in outcomes observed between groups are actually a result of the trial interventions. Importantly, there can be no guarantee that participants from each group who do not comply with the allocated treatment have the same risk-factor profile. Any analysis other than an ITT analysis (eg, one that excludes non-compliant participants) will potentially compromise the balance of these factors and introduce bias into the treatment comparisons. Thus, the ITT strategy generally gives a conservative estimate of the treatment effect compared with what would be expected if there was full compliance. By accepting that non-compliance and protocol deviations are likely to occur in actual clinical practice,3,4 ITT essentially tests a treatment policy or strategy, and avoids overoptimistic estimates of the efficacy of an intervention resulting from the removal of non-compliers. Ensuring ITT produces meaningful answersThe reality of conducting clinical trials means that the ITT principle is not usually fully met, especially when outcome data are missing for some participants. However, clinical trial researchers should consider this principle an ideal, and steps to achieve it should be considered in both the design and conduct of a trial. Firstly, eligibility errors can be avoided by careful scrutiny before random allocation. Indeed, allocation of ineligible patients should be the exception, unless eligibility cannot be assessed quickly. Secondly, all efforts should be pursued to ensure minimal dropouts from treatment, crossover of participants between groups and losses to follow-up. An active run-in phase may be feasible to identify patients who are likely to drop out. A thorough consent process for participants and education of investigators will also minimise the number of dropouts. During the trial, adequate warning of the potential side effects of treatment, together with ongoing clinical support and reassurance, should be available to all participants. When a proportion of participants are expected to receive a treatment different from the assigned one, a dilution effect generally results. The subsequent potential loss of study power can be accounted for by increasing the planned sample size.5 Box 2 details the advantages and limitations of ITT analyses. Alternatives to ITT analysisPer-protocol (PP) analysisThere is a view that only patients who sufficiently complied with the trial’s protocol should be considered in the analysis.6 Compliance covers exposure to treatment, availability of measurements, and absence of major protocol violations. Such an analysis is often referred to as a “per-protocol” or “on treatment” analysis. The main issue arising from this approach is that it might introduce bias related to excluding participants from analysis. Therefore, the ITT analysis should always be considered as the ideal primary analysis, possibly supplemented by a secondary analysis using the PP approach. However, if investigators decide differently, their choice must be justified and should be subject to strict rules.7-9 Treatment-received (TR) analysisAnother approach is to analyse all participants according to the treatment they actually received, regardless of what treatment they were originally allocated. While this may have some initial appeal, once again the effect of random allocation is compromised, making the interpretation of the results difficult. The impact of various approaches is illustrated in Box 3. When ITT requirements are not fully metA number of strategies can be adopted if the assumptions underpinning ITT are not satisfied. If the crossover/non-compliance rates are small, then an ITT analysis should be the principal method of analysis. There is still some debate about whether ineligible subjects can legitimately be omitted from the final analysis.2 For instance, in a study involving a potentially life-threatening condition, such as severe acute respiratory syndrome, treatment may be routinely commenced before laboratory confirmation of the diagnosis. If the patients subsequently are not diagnosed with the condition, there may be a case for excluding them from the ITT population. In these instances, a “modified” or “quasi” ITT population may be defined, allowing for such exclusions. The following principles should be followed to allow participants to be excluded from such an analysis: the criteria for exclusion from the analysis should be pre-specified in the protocol, be objective and clearly defined;7,8 and, to remain unbiased, decisions to exclude participants need to be made (i) by researchers blinded to treatment allocation, and (ii) on the basis of information not related to either the allocated treatment or to events or outcomes that occur after random allocation. In all circumstances, all patients randomly allocated to a study arm should be followed up, as exposure to study treatment may still influence their safety and place them at risk of serious adverse events. All efforts must be made to ensure maximum compliance and that patients continue to take their allocated treatments, and that all patients are accounted for in the trial report.9 The modified or quasi ITT population may also be useful when outcomes are not assessed in all participants. For example, outcomes requiring colonoscopic follow-up can result in no information for patients who, for any reason, did not undergo colonoscopy during the study, requiring an analysis based on a subset of the patient population.10 In such a case, modifying the ITT population allows some clinical interpretation of the results. A more extreme example is a study evaluating hip protectors, in which only around 50% of those in the intervention arm were wearing a hip protector at the time of their fracture.11 In this situation, neither an ITT or per-protocol analysis would necessarily provide reliable information about the value of hip protectors when actually worn. There has been debate about the appropriateness of imputing missing values.4 If missing data are imputed, it is recommended that some sensitivity analysis be performed to ensure that study conclusions are not misleading.4,12 ConclusionITT analysis gives unbiased and consistent estimates of a treatment policy, and should, wherever possible, be the analysis of choice. Deviations from this principle compromise the balance between groups that is achieved by random allocation, and are rarely justifiable as a principal analysis. 1: CONSORT checklist of items to include when reporting a trial Selection and topic Item no. Descriptor Numbers analysed 16 Number of participants (denominator) in each group included in each analysis, and whether the analysis was by “intention to treat”. State results in absolute numbers (eg, 10/20, not 50%). 2: Advantages and limitations of an intention-to-treat (ITT) analysis Advantages Retains balance in prognostic factors arising from the original random treatment allocation Gives an unbiased estimate of treatment effect Admits non-compliance and protocol deviations, thus reflecting a real clinical situation Limitations Estimate of treatment effect is generally conservative because of dilution due to non-compliance In equivalence trials (attempting to prove that two treatments do not differ by more than a certain amount), this analysis will favour equality of treatments Interpretation becomes difficult if a large proportion of participants cross over to opposite treatment arms Requirements for an ideal ITT analysis Full compliance with randomised treatment No missing responses Follow-up on all participants ITT analysis is highly desirable unless: there is overwhelming justification for a different analysis policy (eg, an unacceptably high proportion of ineligible participants — those without the disease under study, for whom there is no potential benefit from the intervention. In these circumstances a “quasi” ITT approach (in which ineligible patients are excluded) is more appropriate. 3: Example illustrating the impact of intention-to-treat, per-protocol and treatment-received analyses in a placebo-controlled trial* Treatment group (n = 1000) Control group (n = 1000) Compliers Non-compliers (drop-outs) Compliers Non-compliers (drop-ins)‡ Compliance 80%†‡ 800† 200† 800‡ 200‡ Untreated baseline risk 10% 10% 7.5% 20% Number of events without any treatment 80 20 60 40 Overall event rate 100/1000 = 10% 100/1000 = 10% Expected number of events Expected benefit (relative risk reduction) Full compliance 80 100 20% benefit (1 – [80/100]) Intention-to-treat analysis 64 20 60 32 9% benefit (1 – [84/92]) Per-protocol analysis 64 — 60 — 7% detriment (1 – [64/60]) Treatment-received analysis 80 20 60 32 40% detriment (1 – [112/80]§) Trial assumptions * The average risk of each group is 10% over the long term trial duration, and active treatment, when taken, reduces the risk by 20%. † 20% of those allocated to receive the active drug do not take it because of early side-effects unrelated to the study outcome. ‡ 20% of those allocated to receive the matching placebo medication are prescribed the active therapy because of early clinical deterioration of their condition directly related to their risk of study outcome (these participants are a high-risk subset and have double the average risk [ie, 20%]). § This comprises expected events in those taking the active drug (treatment group compliers and control group non-compliers) divided by those not taking the active drug (control group compliers and treatment group non-compliers). A simple adjustment factor to obtain a better estimate of what might happen with full compliance (100%) compared with observed compliance (80% for each group) can be applied to the ITT benefit (ie, 9% x 100/80 x 100/80 = 13% benefit).

Stephane R Heritier PhD · Val J Gebski BA, MStat · Anthony C Keech MScEpid FRACP

As suboptimal blood glucose control has a lasting harmful effect even if control improves later, intensive insulin therapy to minimise hyperglycaemia is now recommended for all patients with type 1 diabetes. The new rapid- and long-acting insulin analogues offer more physiological insulin profiles than traditional insulin preparations. Continuous insulin infusion (“pump therapy”) may provide a solution for some patients with frequent hypoglycaemia or hypoglycaemic unawareness. Continuous blood glucose monitoring reveals postprandial hyperglycaemia and asymptomatic nocturnal hypoglycaemia and may be especially useful for programming overnight basal insulin rates for pump therapy. In type 2 diabetes, management should change with disease progression; introduction of insulin should not be delayed if metabolic control becomes suboptimal. More individualised and physiological therapy is now possible

Jennifer J Couper MD, FRACP · Johannes B Prins PhD, FRACP

A 17-year-old man presented with a history of several months of constant, throbbing headaches. He had always had long hair, concealing an obvious skull deformity that had not previously been noticed. Examination revealed a visible occipital deformity of the skull (Box, A). He had chronic papilloedema, with a visual acuity of 6/60 within markedly contracted visual fields. There were no other neurological abnormalities. ImagingX-rays, computed tomography and magnetic resonance imaging further delineated the anatomy of the lesion (Box, B,C). Volume estimation1 yielded a total volume of 1094 cm3, making this one of the largest meningiomas ever reported. ManagementThe patient was given high-dose corticosteroids, and surgical excision was undertaken in two stages. At the first operation, the extracranial component and most of the hyperostotic bone were removed (Box, D). A week later, the remainder of the tumour was removed and the involved (and occluded) superior sagittal sinus resected. The postoperative period was complicated by a cerebrospinal fluid (CSF) leak and meningitis, requiring replacement of the artificial dural graft with fascia lata and CSF diversion with a lumbar drain. Histopathological examination of the tissue revealed a meningothelial meningioma with no atypical features. As a Simpson grade II removal (complete resection of macroscopic tumour with diathermy of the dural origin)2 had been achieved, no adjuvant treatment was given. Six months later, an acrylic cranioplasty was performed, and at 2-year follow-up the patient was well. His visual acuity had returned to 6/36 and his visual fields had expanded. DiscussionMeningiomas account for about 20% of all intracranial tumours3 and, as slow-growing tumours that display benign behaviour, can escape notice. Hyperostosis is often palpable through the scalp, but this patient had an unusually large extracranial volume of tumour (more commonly associated with malignant meningiomas,4 which often lack a significant intracranial component). Complete surgical excision of meningiomas has been shown to offer the best long-term outcome compared with subtotal excision with or without radiotherapy.5 However, even with optimum surgical excision, recurrence rates of up to 20% can be expected over a 20-year period.6

Rodney S Allan MB BS(Hons) · Peter J Spittaler FRACS · Lindsay J Rowe FRANZCR

Ian G Jacobs,* James Tibballs,† Peter T Morley,† Jennifer Dennett,‡ Jeff Wassertheil,§ Vic Callanan,¶ John Hall** (ARC executive committee on behalf of the Australian Resuscitation Council) * Chairman, Australian Resuscitation Council, C/- Royal Australasian College of Surgeons, Spring Street, Melbourne, VIC 3000; † Physician, Intensive Care Unit, Royal Children’s Hospital, Melbourne, VIC; ‡ Nurse Unit Manager, Central Gippsland Health Service, Sale, VIC; § Director of Emergency Medicine, Peninsula Health, Frankston, VIC; ¶ Head, Anaesthesia, Townsville Hospital, Townsville, QLD; ** Superintendent, Divisional Office, Ambulance Service of NSW, Hurstville, NSW. ijacobsATcyllene.uwa.edu.au To the Editor: With the increasing availability of biphasic defibrillators for use in both the manual and shock-advisory modes, considerable confusion has developed as to the appropriate energy levels to be used with these devices. This confusion has arisen partly because of differing recommendations from manufacturers, partly as a result of limited clinical evidence and partly because of the clinical availability of both monophasic and biphasic defibrillators. The differences between these waveforms are the way energy is delivered. Biphasic energy is delivered in two directions, whereas monophasic energies are delivered in one direction. Recommendations of the International Liaison Committee on Resuscitation state that biphasic energies less than or equal to 200 J are as efficacious as escalating higher-energy monophasic shocks.1 Lower-energy biphasic shocks cause less myocardial injury and postresuscitation myocardial dysfunction, and so potentially improve the likelihood of survival.2 Faced with the lack of data with respect to biphasic energy levels, the Australian Resuscitation Council makes the following recommendations: 1. When using manual biphasic defibrillators, energy levels of 150 J should be used for defibrillating ventricular fibrillation and pulseless ventricular tachycardia in adults. The basis of this recommendation is as follows: one randomised controlled trial in people in out-of-hospital ventricular fibrillation compared monophasic and biphasic shocks delivered by automated external defibrillators (AEDs).3,4 This study showed that 150 J biphasic shocks achieved higher rates of defibrillation and return of spontaneous circulation than higher-energy (200 J/200 J/360 J) escalating monophasic shocks. No differences were observed in the proportion of patients discharged from hospital. As clinical superiority of one particular biphasic waveform over another has yet to be demonstrated, it is appropriate to recommend this single energy level to achieve a consistent approach. 2. Biphasic energy levels of 1–2 J/kg should be used for defibrillating ventricular fibrillation and pulseless ventricular tachycardia in children. The basis of this recommendation is as follows: extrapolation from adult data, supported by studies in “child” and “infant” animal models, suggests that the dose for biphasic shocks in children should be 1–2 J/kg (about half the monophasic dose). Higher doses (up to 4 J/kg) are not likely to be harmful and are more efficacious than equivalent monophasic shocks.5 Biphasic shocks may be delivered in a fixed dose of 50 J by an AED. The use of AEDs in children less than 1 year of age is not recommended, as in this situation these devices are unable to differentiate between shock-able and non-shockable rhythms (eg, ventricular fibrillation v pulseless electrical activity). Energy levels for AEDs when used in automatic mode have been pre-set by the manufacturer, and do not require an energy level to be set by the user.

Ian G Jacobs · James Tibballs · Peter T Morley · Jennifer Dennett · Jeff Wassertheil · Vic Callanan · John Hall

Judy A Seal,* Eric M Johnson,† Zelda Doyle,‡ Kelly Shaw§ * State Nutrition Officer, † State Food Officer, § Public Health Registrar, Public and Environmental Health, Department of Health and Human Services, GPO Box 125, Hobart, TAS 7001; ‡ Field Officer, Broad Street Consultants, Tasmanian Iodine Monitoring Program, Lauderdale, TAS. judy.sealATdhhs.tas.gov.au To the Editor: Tasmania has been recognised for many years as an area of endemic iodine deficiency.1 According to the World Health Organization, populations are considered iodine sufficient if population median urinary iodine (UI) levels exceed 100 μg/L, with less than 10% of the UI levels below 50 μg/L.2 Two random surveys (1998–99 and 2000–01) of Tasmanian school children aged 4–14 years suggest mild iodine deficiency. Median UI levels were 75 μg/L and 77 μg/L, with 13% and 21%, respectively, of the UI levels below 50 μg/L.3 In response to these findings, an iodine supplementation program was introduced in October 2001. Tasmanian bakeries were encouraged to switch to using iodised salt in place of regular salt. The program is voluntary, with participating bakeries asked to sign a memorandum of understanding. Industry advice suggests that bakeries that have signed the memorandum produce about 80% of the bread available for consumption in Tasmania. The Tasmanian Iodine Monitoring Program commenced in July 2002. Its objectives are to determine the effect of iodine supplementation of bread on the general population and on high-risk groups, and to identify any negative health effects associated with the program. Preliminary results from the monitoring are encouraging. Children were selected using a random cluster sampling approach. The sampling frame included all Grade 4 classes in all government, Catholic and independent schools in Tasmania. To date, 148 urine samples have been collected, with results from 124 available (test completion rate, 84%). The median UI level from the preliminary results is 97 μg/L (95% CI, 90–109 μg/L), with 10.5% below 50 μg/L. Ongoing monitoring will provide a more rigorous evaluation of the effects of the iodine supplementation program. Early indications suggest the supplementation program may be achieving its goal of improving the iodine status of the Tasmanian population. The monitoring program will continue for the next 4 years, with regular surveys to detect any changes in the population’s iodine status. It will be challenging to retain the ongoing participation of the bread industry if, in the future, there is increased reliance on premixed and ready-to-bake products from outside Tasmania. Maintaining bread supplementation in Tasmania would then require cooperation from interstate suppliers to ensure iodine supplemention of these premixes and ready-to-bake products. Given that recent research has shown mild iodine deficiency in other parts of Australia and New Zealand, perhaps it is time for a bi-national solution to the problem.4,5

Judy A Seal · Eric M Johnson · Zelda Doyle · Kelly Shaw

Donna B Mak,* Eleanor M Platt,† Christopher H Heath‡ * Public Health Medical Officer (currently, Adjunct Research Fellow, School of Population Health, University of Western Australia, Nedlands, WA 6009); † Senior Public Health Nurse, Kimberley Public Health Unit, Derby, WA; ‡ Infectious Diseases Physician and Clinical Microbiologist, Royal Perth Hospital, Perth, WA, and Clinical Senior Lecturer in Medicine, University of Western Australia. makhoATbigpond.com To the Editor: The World Health Organization has established the Global Alliance for the Elimination of Leprosy, which aims to eliminate leprosy from every country by 2005.1 Elimination is defined as reducing the disease prevalence to below one case per 10 000 population. Australia has met this goal. Nevertheless, leprosy transmission still occurs in parts of Australia. Between 1986 and 2002, 28 new cases of leprosy were notified to the Kimberley Public Health Unit (KPHU). All patients except one were Indigenous. At diagnosis their ages ranged from 8 to 63 years. In several recent cases, diagnosis was delayed despite multiple presentations to primary healthcare staff and medical specialists. Eleven patients (39%), including the most recently diagnosed case, had multibacillary disease (WHO classifies leprosy as paucibacillary [< 6 skin lesions with no bacilli on skin smears] or multibacillary [≥ 6 skin lesions and/or positive skin smears]2). People with multibacillary leprosy can transmit the disease. This epidemiological pattern is also seen in Australia’s Northern Territory, where a third of the 236 new cases of leprosy between 1970 and 1997 were multibacillary.3 In leprosy-endemic countries, the proportion of cases that are multibacillary ranges from 32% in Guinea to 84% in Egypt.4 The long incubation period of leprosy (usually 2–5 years, but possibly decades) makes it likely that new cases will occur in Australia over the next few decades. Management of patients in the Kimberley region is challenging, not only because of remoteness, patient mobility and the prolonged treatment and follow-up required, but because adverse reactions to leprosy treatment are common, and may occur weeks to months after starting therapy with antileprotic agents. With all presentations of leprosy, the KPHU informs patients and relevant health professionals about these reactions, including how to recognise them and where to seek specialist advice. The region’s frequent turnover of healthcare professionals and its increasing reliance on short-term and overseas-trained doctors makes this a time-consuming undertaking. With increasing movement of people into and out of leprosy-endemic areas like the Kimberley, or leprosy-endemic countries, Indigenous Australians who have not yet been exposed to leprosy may now be at greater risk of encountering and acquiring the disease. In addition, Indigenous Australians from leprosy-endemic areas may develop symptoms of leprosy when they are no longer in leprosy-endemic areas, and may attend health professionals unfamiliar with leprosy, resulting in delayed diagnosis.5 In the 21st century, the medical community still needs to be alert to the possibility of leprosy in patients with chronic dermatological or neurological conditions, and needs to enquire about exposure to leprosy (eg, living in a leprosy-endemic area, history of leprosy in relatives — both by blood and by marriage). Otherwise, we will fail to diagnose and appropriately manage this disease, risking further outbreaks of leprosy in Indigenous Australian populations.

Donna B Mak · Eleanor M Platt · Christopher H Heath

Michael South Paediatrician, General Medicine, Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052. mike.southATrch.org.au To the Editor: The recent study by Wilson,1 and its accompanying editorial by Walters and colleagues,2 highlight a number of issues about written asthma action plans (AAPs). The utility of AAPs is controversial. However, a number of points are more certain: AAPs will achieve nothing unless they are part of a comprehensive program of therapy, patient education and review. AAPs must be individualised, and must cover several aspects of self-management, including ongoing maintenance therapy and future acute episode treatment (including the current episode if this has triggered the patient’s attendance). AAPs cannot improve patient care if doctors don’t take the time and effort to write them, and if patients don’t have them available at the time of need, particularly during acute episodes. AAPs are a useful communication tool, and an aid in consistency of care, provided patients and all their doctors have up-to-date copies of the same plan. To help with the complex and time-consuming task of producing customised AAPs, we developed a computerised AAP generator which runs in a standard web browser. Individualised AAPs are produced with minimal typing and a few mouse clicks in less than 45 seconds. All plans have sections for future acute episodes. Sections for preventer medications and the current episode only appear when selected. All asthma medications currently available in Australia are selectable from drop-down menus, and these lists are updated regularly. There are several prompts to encourage best-practice care. Enough copies are produced for the family, school, kindergarten, child minder, grandparents, general practitioner, and hospital notes. The AAP generator was made available on the Royal Children’s Hospital intranet in July 1999. This intranet version logs, in detail, all use of the plan and the recommended therapies, without any patient identification. About 19 500 plans have been generated since. We have not formally evaluated this system, but we do know, from informal feedback and from our records showing that many of them have used it hundreds of times each, that our staff find it useful. AAPs are only a part of the “education package” required for patients with asthma. If it is quick and easy to generate good AAPs, it is to be hoped this will encourage doctors to produce them, while also giving them more time to concentrate on the explanation and discussion of care. The AAP generator is available for free download from our website (www.rch.org.au/clinicalguide/asthmaPlanRequest.php).

Michael South

Milton G Roxanas Psychiatrist, The Epping Clinic, PO Box 288, Eastwood, NSW 2122. mroxanasATbigpond.net.au To the Editor: I wish to report hyponatraemia in a patient commencing therapy with mirtazapine — this is the first such report from Australia. An 86-year-old widow with depression had had a previous episode of hyponatraemia while taking venlafaxine. Anticipating the possibility of further hyponatraemia, I prescribed mirtazapine 15 mg nightly — half the recommended starting dose. At this time, she was also taking amiodarone, gliclazide, l-thyroxine, irbesartan with hydrochlorothiazide, alendronate, omeprazole, atorvastatin and zolpidem. Her baseline serum sodium level was 135 mmol/L (normal range [NR], 135–149 mmol/L), but 4 days later it had fallen to 130 mmol/L, with serum osmolality of 294 mosmol/kg (NR, 280–295 mosmol/kg), urine osmolality of 398 mosmol/kg (NR, 50–1200 mosmol/kg), spot urine sodium concentration of 42 mmol/L, and plasma antidiuretic hormone (ADH) level of 0.7 pmol/L (NR, 0.1–7.0 pmol/L). Mirtazapine therapy was stopped after a further 2 days, and 10 days later her serum sodium level was 134 mmol/L, serum osmolality 296 mosmol/kg, urine osmolality 419 mosmol/kg and spot urine sodium concentration 27 mmol/L. Her plasma glucose level varied from 7.4 mmol/L to 9.2 mmol/L (NR, 3.4–5.4 mmol/L). Her condition was subsequently stabilised on mianserin (20 mg nightly) without electrolyte abnormalities. There are 12 reports worldwide of hyponatraemia due to mirtazapine (manufacturer’s data “on file”). This antidepressant inhibits α2 auto- and heteroreceptors, blocks 5-HT2 and 5-HT3 receptors, and acts via noradrenergic and 5-HT1A receptors. The mechanism of hyponatraemia is thought to be via α1 or serotonergic stimulation of ADH, but other possible causes include increased osmoreceptor sensitivity, reduced renal ability to conserve salt and water in the elderly, enhanced renal action of ADH1 and reduced metabolism of the antidepressant. There is no known interaction between mirtazapine and amiodarone or irbesartan or thiazides to account for hyponatraemia. This patient had risk factors — she was elderly, female, was taking diuretics and had had hyponatraemia with another antidepressant medication. As in previously reported cases the ADH level was not elevated, although the syndrome of inappropriate ADH secretion (SIADH) is not always accompanied by raised ADH levels.2 Hyponatraemia is seen more often these days because of greater awareness, the increasing proportion of elderly people in the population and the trend towards polypharmacy in the elderly. Many drugs have the potential to produce SIADH; one report has indicated that almost all antidepressants are implicated.3 Amitriptyline-induced hyponatraemia was first described in 1974, and a recent retrospective study of elderly patients found an incidence of 32% with selective serotonin reuptake inhibitors and an unusually high 71% with venlafaxine.4 In the face of an increasingly common phenomenon, I recommend that patients aged over 65 years should have baseline measurements of electrolyte levels before starting therapy with an antidepressant, and that these should be repeated 2–7 days later to detect possible hyponatraemia and initiate treatment.

Milton G Roxanas

John F Kerin Professor, Reproductive Medicine Unit, University of Adelaide, and Adelaide Fertility and Gyn-Endoscopy Centre, “Timara”, 154 Barton Terrace West, North Adelaide, SA 5006. kerinjfATsenet.com.au To the Editor: In a recent article by Foran,1 information provided on the new Essure (Conceptus, Inc) permanent birth control or sterilisation method was inaccurate in several respects. Firstly, Foran stated, incorrectly, that the Essure method is performed laparoscopically (it is actually a hysteroscopic method). This is a significant error, as one of the unique advantages of this method is the avoidance of incisional surgery, particularly laparoscopy and a general anaesthetic. This hysteroscopic procedure is well tolerated and can be performed with minimal or no sedation, followed by a rapid postprocedure recovery and early return to normal activity.2,3 Secondly, the failure rate in terms of postprocedure pregnancy is much less than the 0.6% quoted by Foran. To date, no pregnancies have been recorded in Phase II2 or Phase III3 multicentre, prospective, single-arm clinical trials conducted according to US Food and Drug Administration guidelines between 1998 and 2003. To date, no pregnancies have occurred in women relying on this intratubal microinsert during a combined 15 635 women-months of follow-up. The effectiveness rate for pregnancy prevention after 2 years of follow-up is 100% (95% CI, 99.5%–100%). Thirdly, it is not a titanium insert. The metal used in the outer dynamic coil is a nickel–titanium alloy commonly known by the trade name Nitinol. Fourthly, the adverse effects claimed (infection, bleeding) are misleading and incorrect. No infections within the uterus, tubes or pelvis have been recorded, and abnormal bleeding is not a feature of this form of sterilisation.2,3 Essure is the first hysteroscopic method of female sterilisation to gain regulatory approval for clinical use (in November 2002). This method of sterilisation offers women the choice of a less invasive, safe and reliable choice of sterilisation in the future.

John F Kerin

Therese M Foran Medical Director, FPA Health, 328–336 Liverpool Road, Ashfield, NSW 2131. terrifashATfpahealth.org.au In reply: Mea culpa! Essure is, of course, a hysteroscopic rather than a laparoscopic method of female sterilisation and is described so in the text of the article. I apologise for not picking up this error while checking the proofs. Kerin is also correct in pointing out that Essure is made not from pure titanium but from a titanium alloy. The possible adverse effects, though rare, are listed among a number of others in the manufacturer’s information brochure.1 I am always extremely wary of ascribing a 100% effectiveness rate to any contraceptive method. Since Essure has been used so far on only small numbers of women, the figure I quoted was the upper limit of the failure rate in world literature for female sterilisation procedures.2 Although initial experience indicates that the eventual success rate should be very close to 100%, Kerin’s quoted 95% CI suggests that, at present, we can only promise potential Essure users a better than 99.5% effectiveness rate (ie, a failure rate quite close to the figure I used). I consider Essure to be an excellent new method of permanent contraception, and apologise if my article gave any other impression. I am certain that Australian women and their doctors will increasingly consider it an option in the future.

Therese M Foran

David H Eizenberg Obstetrician and Gynaecologist, Macquarie Chambers, 183 Macquarie Street, Sydney, NSW 2000 To the Editor: In their recent article on treatment of menstrual disorders, Hickey and Farquhar described three case scenarios to highlight alternative treatments for menstrual disorders.1 In Patient 1, a 39-year-old woman with dysfunctional uterine bleeding, the authors preferentially treated the patient with the levonorgestrel-releasing intrauterine system (20 μg per 24 h). Unfortunately, this device is available through the Pharmaceutical Benefits Scheme only for contraception, not treatment of menorrhagia. It would be difficult to explain to the government its use in this woman, who, according to the history, had had laparoscopic sterilisation. As a new intrauterine system has to be inserted every 5 years, and has a failure rate of 20% after 1 year, a 39-year-old woman would need at least another two inserted to control dysfunctional bleeding. The optimum method of management would have been simple vaginal hysterectomy. This was not mentioned in the article, which contrasted the intrauterine system only with abdominal hysterectomy. The authors also claimed that “cost–benefit analysis showed that [the intrauterine system] Mirena was three times cheaper than hysterectomy”. This analysis should include the cost of three Mirenas ($260 each), insertion, doctors’ visits for Pap smears for 30 years, tampons and pads. Is this cheaper? After all, hysterectomy means no periods, pain, pregnancies, Pap smears or pads. What is wrong with vaginal hysterectomy? The fact that the woman had had three caesarean sections and laparoscopic sterilisation was not a contraindication.2 Patient 2, a 45-year-old woman with menorrhagia and small fibroids, could also have been managed with vaginal hysterectomy.3 There is no evidence that hysteroscopic resection of fibroids in a multiple-fibroid uterus, as recommended by the authors, will improve menorrhagia. They also state that an alternative technique, embolisation, has been “widely used”. This technique is experimental and, as they state, “has been associated with serious side effects, such as infection, bowel obstruction and loss of ovarian function”, as well as death.4 In our quest for management innovations for women with dysfunctional bleeding, we should decide whether the new technique is better than the gold standard, hysterectomy. As hysterectomy can be vaginal, laparoscopic with vaginal assistance, totally laparoscopic, or abdominal, one cannot just use the word “hysterectomy”, one must specify. Studies reveal that the vaginal approach is superior.2,5

David H Eizenberg

Martha Hickey,* Cynthia M Farquhar† * Associate Professor of Obstetrics and Gynaecology, University of Western Australia, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, WA 6008; † Associate Professor in Reproductive Medicine, National Women's Hospital, University of Auckland, Auckland, New Zealand. mhickeyATobsgyn.uwa.edu.au In reply: Eizenberg is correct in stating that the levonorgestrel-releasing intrauterine system Mirena is currently licensed as a contraceptive in Australia and not explicitly for treatment of menstrual disorders. He is also correct in stating that vaginal hysterectomy would be a management option for Cases 1 and 2 in our article.1 However, the purpose of our article was to explore newer options in management of menstrual disorders. This does not mean that “traditional” therapies such as hysterectomy are to be overlooked or superseded, and we did not attempt to compare the new therapies with hysterectomy. Dysfunctional uterine bleeding, although disruptive, is a benign condition, and treatment is symptomatic. We believe that women should be aware of all available therapeutic options, including hysterectomy, so that they can reach an informed decision.

Martha Hickey · Cynthia M Farquhar

Saul Wiener Allergist, Royal Melbourne Hospital, 46 Balaclava Road, East St Kilda, VIC 3183. To the Editor: In their study on the effectiveness of antivenom for redback spider bite, Isbister and Gray cast doubt on the current method of administering antivenom intramuscularly.1 Any study on the outcome of treating bites by venomous animals is limited by factors beyond the control of the investigator. These include the variability of the venom content in the animal’s venom apparatus, uncertainty regarding how much and where venom has been injected, and the delay before treatment. Between 1955 and 1957, I dissected the venom glands of 590 redback spiders for the production of antivenom.2 The yield of freeze dried venom per spider varied from 0.08 mg to 0.32 mg. Based on these findings, and to allow for dilution of antivenom by body fluids, “it was considered that 500 units of antivenene would constitute a suitable initial dose for the treatment of a bite by L. hasseltii”.3 This amount of antivenom will neutralise 5 mg of venom in vitro, and the antivenom is still issued in this strength by CSL Ltd. No fatalities have occurred from redback spider bite since antivenom became available in 1956,4 and reports from doctors have confirmed its efficacy and safety.5 If symptoms persist after the initial dose, or if diagnosis has been delayed, the initial dose of 500 units may have to be repeated. As Banham et al have wisely stated “treatment should be titrated against response”.6 Because of the risk of anaphylaxis, intramuscular injection, which has stood the test of time, is safer than the intravenous route.

Saul Wiener

Geoffrey K Isbister Clinical Envenoming Research Group, University of Newcastle, Newcastle Mater Misericordiae Hospital, Locked Bag 7, Hunter Region Mail Centre, NSW 2310 gsbiteATferntree.com In reply: We thank Wiener for his comments on our study. Although we challenge the use of intramuscular redback spider antivenom (RBS AV) in the article, we only suggested that the use of intramuscular antivenom needs review and that randomised controlled trials comparing intravenous and intramuscular RBS AV should be undertaken. Two such trials, in Western Australia and Newcastle, are currently in progress. There are no pharmacokinetic studies of RBS AV, but studies of other antivenoms suggest that the intramuscular route is less effective.1 In Tunisia, the intramuscular use of scorpion antivenom, which is also an F(ab')2 antivenom, similar to RBS AV, has been questioned for similar reasons.2,3 Studies in a rabbit model demonstrated that intramuscular antivenom induced only partial and delayed neutralisation of circulating toxins.3 More importantly, in a study of scorpion stings of children, the intramuscular administration of antivenom had far less effect on plasma venom concentrations and patient recovery times.2 We do not dispute that repeated doses of antivenom may be required, but the implication that only an initial dose was used in our study is incorrect. Half of the treated patients required repeat doses (6 ampoules in one patient). In a recent series of four patients with redback spider bites, intramuscular antivenom was ineffective, even though three patients received two or three ampoules. Subsequent intravenous antivenom was effective in all cases.4 There is no evidence that appropriately administered intravenous RBS AV (diluted in 200 mL of normal saline, over 20–30 minutes) is less safe than intramuscular antivenom. There is insufficient reason to prevent the use of intravenous antivenom if it is shown to be more effective than intramuscular antivenom. Although it is too early to change recommendations for the administration of RBS AV, it is essential that controlled trials be done.

Geoffrey K Isbister

Ian Gardiner, the second son of Scottish immigrants, was born in Sydney on 30 December 1915. He attended Canterbury Boys High School and studied medicine at the University of Sydney, graduating in 1939. During his undergraduate years he was a member of the Sydney University Regiment and represented the university at baseball. Ian did his residency at Royal South Sydney Hospital, where he met Betty, a charge nurse, whom he married in 1941. After a stint in general practice at Cessnock, Ian joined the Royal Australian Air Force as a medical officer. Having a keen interest in what is now called “electronics”, he was seconded to the Neurophysiology Department of Sydney University for research on “g” forces. In 1945, he spent 6 months in Dayton, Ohio, to further this work. Ian, in conjunction with Geoff Trahair and Vince Bennett, assembled the first electroencephalographic (EEG) machine in Australia. A plaque at the Royal Prince Alfred Hospital, Sydney, records this event. Between 1946 and 1967, Ian worked as a general practitioner in Sydney and other parts of New South Wales: Lidcombe, Helensburgh, Berridale and finally Ryde. He developed a large practice specialising in psychosomatic illnesses. Although this was very demanding work, Ian was renowned for his great patience and understanding. He was a GP of the “old school” — surgeon, anaesthetist, obstetrician, family counsellor, physician and friend to so many of his patients. From 1967 to 1978, he worked as a Medical Officer in psychiatry for the NSW Health Commission. Ian was meticulous in all things, from his copperplate writing to his spotless car and impeccable personal appearance. He had several passions in life. Firstly, red wine, for which he had developed a taste during his early GP days in Cessnock (near the Hunter Valley wineries). Secondly, lawn bowls, for which he won the state No. 2 Pennant with the Ryde Bowling Club. Thirdly, driving in the outback. He combined this interest with his professional life by providing a visiting psychiatric service to Broken Hill and the far west of New South Wales. Fourthly, electronics, a lifelong hobby and passion. Ian built his own radiogram, obtained his ham radio licence at 15 years of age, had his own transmitter and receiver, and was a constant purchaser at Dick Smith electronics stores. But Ian’s greatest passion was his family. For them he was a constant source of inspiration — unconventional, questioning and challenging. He died on 2 April 2003 of heart-related illness and is survived by his wife Betty and children Judy, Ian, Fiona and Susan. Judith R Gardiner, David Pullen

Judith R Gardiner · David Pullen

John Henry Winter Birrell, a general practitioner and former police surgeon, died on 25 March 2003 of myelodysplasia. He will be remembered especially for his tireless and ultimately successful campaigning to reduce road accident deaths by introducing Breathalyzer testing of drivers and compulsory wearing of seatbelts. John was born in Melbourne on 29 December 1924. As a student at Melbourne Grammar School, he excelled academically and on the football field. In 1942, he began studying medicine at the University of Melbourne and completed his first year with ease. Then, in defiance of his father’s wishes, John joined an army unit in Cowra. He was soon found and returned to university, but failing his second year enabled him to rejoin the army. He was posted to Papua New Guinea, where he joined the Medical Corps. He resumed his studies in 1944 and won the forensic medicine prize in his final year. Between 1952 and 1956, John was a lecturer in pathology at the University of Melbourne and a senior lecturer at Monash University. After working as Assistant Coroner’s Pathologist at the Melbourne City Morgue (1955–1957), he was selected to be Police Surgeon, a position he held for the next 20 years. One of his early duties was to do blood alcohol estimates of road crash victims. On call 24 hours a day at his home in Blackburn, his exposure to the carnage on Melbourne roads soon aroused his anger. He was horrified at the increasing number and severity of fatalities and injuries he witnessed. Joining the Traffic Injury Committee of the National Health and Medical Research Council in 1960, John’s influence was soon obvious when the committee recommended that seatbelts be fitted and worn in vehicles. He worked tirelessly with the media on seatbelt promotion, influenced politicians and parliamentary road safety committees, and educated schools and community groups about road safety issues. Several of his articles on seatbelts and the dangers of driving after drinking alcohol were published in the Journal in the 1960s.1,2 In the words of Basil Hetzel (Foundation Professor of Social and Preventive Medicine at Monash University), delivering the Boyer Lecture in 1971, “John Birrell became the public face on the issue of blood alcohol and road safety . . . the major force in arousing public awareness of the problem”. In 1966 it became an offence to drive with a blood alcohol level exceeding 0.05%. The mandatory wearing of fitted seatbelts by drivers and front-seat passengers became law in Victoria in January 1971 and was introduced in all states and territories by the end of the same year. It was in Victoria that “booze buses” (mobile breath-testing units) were first introduced (in 1990). In 1974, without the financial support of government or other alcohol and safety bodies, John made a successful bid to have the 7th International Conference on Alcohol, Drugs and Traffic Safety held in Melbourne in 1977. The event was an outstanding success, attracting extensive media coverage and raising community awareness about road safety issues. Another issue about which John felt very strongly was child abuse. He was the Patron of Australians Against Child Abuse. In 1977, John went into private practice in Foster (VIC), where he remained for 5 years. He then moved to Point Lonsdale, where, until a few years ago, he worked at the Community Health Centre in nearby Queenscliff. John is survived by his wife Jackie and sons John, Mike and Simon. Donald Gibb

Donald Gibb

Re: “Nocardia asteroides pneumonia with bacteraemia”, a letter by Figgis PA, Glanville AR, Harkness JL, in the 4 August 2003 issue of the Journal (Med J Aust 2003; 179: 171-172). The image in Box 3 should have shown the histological appearance of a liver biopsy, not the published lung biopsy. The correct image appears in the Box. The html and pdf versions of this article published on the eMJA website were corrected on 20 October 2003. 3: Liver biopsy in a patient with Nocardia asteroides pneumonia Core biopsy of liver, showing a granuloma within the central portal triad (arrow); the portal ducts are expanded and fibrosed with a patchy lymphocytic infiltrate (original magnification x 40; haematoxylin and eosin stain).

Patricia A Figgis · John L Harkness · Allan R Glanville

Practical peak A peak expiratory flow rate (PEFR) — alone (ie, without spirometry) — is good for detecting patients with chronic obstructive pulmonary disease (COPD) in the community, according to UK researchers. Data from a cross-sectional national survey of 3874 adults aged 50–90 years found that a PEFR of less than 80% detected more than 90% of the subjects with COPD, including all of those with moderate or severe disease. Although sensitive for COPD, it was not as specific; however, many of the false positive results were in smokers. BMJ 2003; 327: 653-654 Smokescreen Children and adolescents appear to have easy access to tobacco products via the Internet, say US authors. In their study, four adolescents (under adult supervision) were able to buy cigarettes from 90% of 55 vendors' websites located in 12 states. Although most of the sites had posted an age warning on their web-site and the adolescents lied about their age when making their orders, no age verification was sought for any of the deliveries. Although there is a variety of state legislation relating to cigarette sales to minors, there is no federal legislation in the USA that bans Internet and mail order tobacco sales to minors. More than half of the web-sites implicated in this study were located on Indian reservations, and tribal sellers have, in the past, claimed exemption from state laws because of sovereignty. JAMA 2003; 290: 1356-1359 Anaphylaxis again and again A Canberra allergy expert says that in any year, one in 12 patients who have suffered anaphylaxis will experience a recurrence and that one in 4 of these events will be severe. Professor Mullins had gained follow-up data for 304 patients who had been referred with anaphylaxis, finding that the best predictor of serious recurrence was the presence of serious symptoms on initial presentation. Although accidental ingestion of peanuts or tree nuts caused the largest number of relapses, the highest risk of any recurrence was associated with wheat and/or exercise sensitivity. Clin Exp Allergy 2003; 33: 1033-1040 Moving target In patients with nonvalvular atrial fibrillation who are at high risk for stroke, the target INR with warfarin should be set at a minimum of 2.0, aiming for an optimum of perhaps 2.5, say US researchers. Their advice is based on findings from their cohort study of 13 559 patients: anticoagulation with an INR set at 2.0 or more not only nearly halved the frequency of stroke but also reduced the severity and risk of death from stroke. The risk of serious haemorrhage was low until the INR was 4.0 or more. N Engl J Med 2003; 349: 1019-1026 Getting a life . . . or a mortgage? Traditional factors in the career choices young doctors make, such as remuneration and prestige, are being outgunned by lifestyle concerns in the USA.1 The specialties that senior medical students have sought to enter over the six years from 1996 to 2002 seem to reflect an increasing interest in having control over the hours worked per week and adequate time for leisure, family and other pursuits. In workforce terms, disciplines like anaesthetics and dermatology are winners, while positions in general practice, and even general surgery, remain unfilled. Meanwhile, in some parts of Canada medical students are graduating with debts of more than $100 000.2 Looking more like mortgages than student loans, these debts come courtesy of rising tuition fees, reduced government support, the replacement of grants with loans and an increasing reliance on lines of credit to cover living costs while studying. There is anecdotal evidence that career choices are being affected, with one graduate asking, "Is a career in public health going to be lucrative enough to pay off a 6-figure debt?" 1. JAMA 2003; 290: 1173-1178 2. CMAJ 2003; 169: 457-458 Women's health initiative Brisk walking for between 75 to 150 minutes a week will reduce the risk of breast cancer in postmenopausal women by about 18% when compared with inactive women, according to the US Women's Health Initiative (WHI) Cohort study. This study analysed data from 74 171 women aged between 50 and 79 years, of whom 1780 had breast cancer newly diagnosed over nearly 5 years of follow-up. The beneficial effect was even greater in those who exercised for longer durations; it was seen particularly in women who were of normal weight. The WHI study has previously found that in postmenopausal women the risks of hormone replacement therapy include breast cancer. JAMA 2003; 290: 1331-1336 — Dr Ann Gregory, MJA

Ann Gregory