Volume 182 Issue 12

The problem of surgical waiting lists requires multifactorial solutions The provision of public hospital services inevitably involves managing the demand for these services. This is usually achieved by rationing. Elective surgery is the easiest service for health administrators to manipulate to meet budget imperatives and to manage demand pressures, through controlling surgical waiting lists. In short, the pestle of demand grinds against the mortar of budget restriction in the management of elective surgical lists. Although health planners are able to accurately predict demand for surgical services, administrators often plan not to meet that demand because of budgetary restrictions. With effective management, the only day-of-surgery cancellations should be occasional patients with an acute change in their medical condition. In this issue of the Journal, Schofield and colleagues report on one aspect of demand management: the cancellation of operations on the day of surgery.1 This is almost unheard of in the private health-care sector, where the supply of surgical services is virtually uncapped. Schofield et al also shed some light on the reasons for these cancellations. In the tertiary-care hospital that was the focus of their investigations, the rate of on-the-day cancellations of surgery (11.9% overall, and 13.2% for weekday elective surgery) is a cause for concern. The Australian Council on Health Care Standards guideline is that the day-of-surgery cancellation rate should be low,2 which, in New South Wales, is interpreted to mean not exceeding 1.5%. In my own hospital, Nepean (also a tertiary-care hospital), it is about 3%. A higher rate of cancellations can be expected in hospitals where patients, such as those undergoing major general and cardiac surgery, depend postoperatively on a dedicated intensive-care bed. For these patients, Schofield et al found cancellation rates of 31.2% and 28.5%, respectively; these are higher than would usually be expected. As intensive-care beds are assigned in NSW as part of a statewide coordination service, the management of this problem requires involvement of agencies at a higher level than hospital administration. However, it is not clear why surgical services in the survey by Schofield et al, such as ear, nose and throat or plastic surgery (which should be largely independent of intensive-care and inpatient beds), had such high cancellation rates. The reasons for elective surgery cancellations revealed by Schofield and colleagues fell into five nearly even groups — lack of theatre time, lack of postoperative beds, cancellation by patient or carer, patient clinical change, and procedural reasons. As elective surgery is one of the most predictable aspects of hospital medicine, the great bulk of these cancellations could be avoided with better management systems. With effective management, the only day-of-surgery cancellations should be occasional patients with an acute change in their medical condition. Managing elective surgery more efficiently requires a well thought out management system with quarantining of resources to ensure patient flow. Such a system has recently been described by Ryan and colleagues — the 23-hour ward model.3 In this model, it is expected that the episode of care can be delivered within an envelope of 23 hours, during which time patients require only pain relief and monitoring in a supervised setting until fit for discharge. This model is quarantined from the rest of the hospital or area bed-base, either in a designated ward or a smaller hospital in the area. Patient care is protocol driven, and patients are not admitted unless they are on a clinical pathway. The protocol includes compulsory pre-admission and pre-anaesthetic assessment, careful construction of lists matching patients to available beds and operating-room slots, and a guarantee that elective procedures will not be cancelled. Patient flows are predetermined, with a staged recovery process. This model does not lead to significant increases in readmission rates, nor does it significantly affect community services.3 It is suitable for about 80% of patients requiring elective surgery. The NSW Surgical Service task force has recently recommended the adoption of this model, and the NSW Department of Health has advised all area health services to institute it. Adopting this model’s approach may also help patients who require stays of over 23 hours. A management process that links the predictable demand for elective surgery to operating sessions and beds can avoid cancellations and enable effective and predictable access for all patients. Waiting times are multifactorial and vary between areas, between hospitals in areas and between individual surgeons within hospitals.4 In addition to better management practices based on operational research,5 other solutions to the problem of waiting lists are needed. In elective orthopaedic surgery, there is a need for more resources for prostheses and a better system of prosthetic purchasing. In ear, nose and throat surgery, there is a need for more creative schemes to better utilise the few available specialists. Other solutions may involve contracting specific groups of patients to the private sector (the subject of a pilot study in NSW6) and developing whole new approaches, especially in the apparently insoluble area of intensive-care bed provision (eg, the surgical acute-care unit7). Currently, 1% of the NSW population is on a surgical waiting list, with similar figures in other states and territories. We have clear evidence of the harm that excessive waiting times cause patients.8 All available means must be used to solve this problem. Above all, there is a need to avoid the distress caused to patients by day-of-surgery cancellations.

Patrick C Cregan FRACS

A common-sense approach to reducing exposure to polluted air is required It is an unquestionable fact that regular physical activity is beneficial to health and longevity. Accordingly, it is common practice for physicians and other health care professionals to encourage exercise. However, people exercising in urban regions may be unwittingly at risk because of exposure to concentrated automotive pollution, a known risk factor for cardiovascular and respiratory disease. The physiological changes that occur during exercise probably act to compound the toxic effects of environmental air pollution, and certain patient populations may have increased sensitivity. People should not be deterred from regular exercise, as it is of known benefit, but when prescribing exercise, clinicians should extend appropriate advice to patients to avoid areas with high pollutant concentrations. What, then, is the evidence to support such advice? Automotive exhaust comprises a heterogeneous mixture of suspended particles and gases, the most common gases being sulphur dioxide, nitrogen dioxide, carbon monoxide and ozone. Unburnt fuel emits volatile organic compounds (eg, benzene, toluene) and the fuel combustion process liberates many thousands of chemicals in addition to particulate matter of varying size and composition. Ultrafine particulate matter, with an aerodynamic diameter < 0.1µm, is thought to be particularly harmful to health, as it is readily inhaled and absorbed into the circulation.1 Epidemiological data have identified individual components of air pollution, or pollution collectively, as promoters of cardiovascular and respiratory disease.2,3 Some compounds are also known or suspected carcinogens.4 Harmful effects on the body from pollutants are multifactorial, with acute or chronic exposures increasing the cellular processes associated with atherogenesis (the underlying cause of most cardiovascular disease), impairing pulmonary function, provoking local and systemic inflammation, disrupting cardiac autonomic control and inducing vascular dysfunction. Deleterious health effects may result from exposure to pollutants at concentrations that are lower than recommended air quality standards.5 Indeed, research to date has failed to determine a “threshold” limit for which there is no adverse health effect.6 In general, most large-scale time series analyses of the physiological effects of air pollution find an exposure-dependent relationship that crosses socioeconomic boundaries and poses a significant threat to everyone’s health. Importantly, certain populations may be particularly vulnerable to the effects of polluted air, such as children;7 people with asthma,8 diabetes9 or acute lower respiratory disease; and frail or elderly people with pre-existing heart and lung conditions.10 Why may exercise in polluted areas be particularly hazardous? During aerobic exercise, even at relatively low intensities, inspired air is taken in predominantly through the mouth, and there is a major increase in minute ventilation and diffusion capacity. These factors augment the respiratory uptake of airborne contaminants, with increased penetration to the lower gas-exchange regions of the lung. Indeed, the total amount of ultrafine particulate matter deposited in the respiratory tract of humans during moderate exercise has been shown to be about five times that at rest.11 As would be expected, when the concentration of pollutants increases, so too does the amount of inhaled matter. Thus, habitual exercise in highly polluted localities, such as alongside busy roadways, may increase the overall intensity, duration and frequency of exposure, all of which are relevant to the evaluation of an individual’s risk profile for disease.6 Pulmonary function may markedly decline after inhalation of pollutants during exercise. In one study, when adolescents with asthma were exposed to sulphur dioxide and sodium chloride aerosol during treadmill running, many displayed symptoms of wheezing and shortness of breath.12 Several other studies have shown that poor air quality and acute exposures during exercise may induce symptoms in people with asthma, impair athletic performance in healthy people,13 and contribute to exercise-induced myocardial ischaemia in patients with stable coronary artery disease.14 This information should not be interpreted as a reason for people living in cities to stop exercising. Rather, a common-sense approach to reducing or avoiding exposure to polluted air during exercise is advisable. In summary, there is sound evidence for an exposure-dependent relationship between air pollution, morbidity and mortality, particularly in relation to cardiovascular and respiratory illnesses. Although regular aerobic exercise is recommended for good health, there may be adverse health consequences for people who habitually exercise in areas of high ambient pollution. Despite this, it is not uncommon to see people running or cycling alongside congested roadways, and clinicians should advise patients to exercise on quiet roads or in parks and recreation areas. The best time of day to exercise is early in the morning, before the build-up of traffic and when it is cooler. This is relevant because the combination of sunlight and heat with certain compounds increases ozone production. Importantly, certain groups may be acutely susceptible to the effects of air pollution, and clinicians should advise them accordingly.

James E Sharman BHM(Hons), PhD

Assessment of real cost effectiveness, with data linked to individual health outcomes while protecting patient privacy, is an essential challenge we need to meet Pharmacogenetics and pharmacogenomics — the use of genetic and genomic information, respectively, to tailor drugs to the treatment of individual patients — make it possible to use information from the human genome in ways that will radically transform the prevention and treatment of human disease.1,2 Over the past several years, Australians have been given access to several drugs which can be prescribed under a taxpayer-funded scheme only if the patient has a specific molecular disease target that predicts a good treatment outcome. The first such drug was trastuzumab for the treatment of breast cancer in women whose tumours over-express the HER2 protein. This drug was supplied by the government from December 2001 through a special program outside the Pharmaceutical Benefits Scheme (PBS). Another drug, imatinib, was also listed on the PBS in December 2001 for use in the accelerated and blast phases of chronic myeloid leukaemia, and in October 2002 for use in the chronic phase of that disease. In December 2004, gefitinib was listed for the treatment of non-small cell carcinoma of the lung in patients with evidence of an activating mutation in the epidermal growth factor receptor gene. These drugs are likely to be harbingers of a stream of drugs in which genetic information about individuals or their tumours (whether they result from DNA or RNA sequence changes, or protein alterations) will be used to maximise the efficacy of treatment. Funding the provision of new biological agents under the PBS will present a major financial outlay. Though the number of eligible patients may be small, the costs per patient are high (eg, more than $45 000 per patient per year for imatinib and more than $50 000 per year for gefitinib and trastuzumab). The high cost of providing these drugs to relatively small numbers of patients will add to the cost of the PBS when annual growth in government expenditure on pharmaceuticals averaged 10.5% between 1992–93 and 2002–03 (increasing from $1.883 billion to $5.121 billion).3 The Australian Pharmaceutical Benefits Advisory Committee (PBAC) makes recommendations to government on which drugs to list on the PBS on the basis of their comparative clinical efficacy, safety and cost-effectiveness.4 Given the high price of many of these new and existing biological agents, it has been argued that alternative models of access are needed, because they may only be cost-effective in a subgroup of patients with a disease.5 The PBAC has used a number of strategies that allow access to new biological agents while respecting the principle of cost-effectiveness. These options depend critically on identifying the subgroup of patients in whom the drug is cost-effective compared with the main available alternative treatment. Patient groups are defined by the presence of particular molecular markers of disease severity, underlying disease mechanism, or treatment prognosis.4 The PBAC has recently developed a collaborative model to enable the listing of the tumour necrosis factor-alpha inhibitor class of biological agents (including etanercept, adalimumab and infliximab) and anakinra, an interleukin-1 receptor antagonist, all of which are used in managing rheumatoid arthritis. Although molecular markers were not part of the restrictions for these drugs, the collaborative model that was developed can be applied more broadly. This model involves working with key stakeholders in the relevant medical specialty, representatives from the pharmaceutical company producing the drug, and consumer organisations to develop restrictions that will ensure that the drugs are used in ways that are the most cost-effective.4,6 These restrictions include detailed rules for initiation and continuation of therapy. The initiation rules may include a specified diagnostic test and/or evidence that the patient has failed to respond to existing treatments for the condition. Continuation of treatment requires evidence of adequate benefit on some appropriate clinical or biological test. Patients who start taking the drug are required to sign an agreement indicating that they understand and accept that PBS-subsidised treatment will cease if the criteria defining a satisfactory response to the drug are not achieved in the follow-up clinical assessment.6 An underlying difficulty (and additional cost) in listings with molecular targets is that the mechanism for identifying the target population is not coordinated with the drug development process. We need to evaluate the effects of genetically or genomically targeted drugs that are listed on the PBS on patient outcomes to improve the existing regulatory arrangements for these new drugs. Ideally, such evaluations should use data that link information on drug use and individual health outcomes. Linked data are currently very difficult to obtain for reasons of patient privacy and confidentiality, but methods should be put in place at the time of drug listing, with appropriate privacy safeguards, that enable the impact of these drugs to be assessed. The policy and economic challenges posed by these drugs also warrant wider public discussion. Increased public appreciation of the challenges that these drugs pose to the PBS is essential if we are to develop a broadly supported policy that will make these very expensive drugs available to patients who have the potential to benefit from them at a price that reflects their therapeutic value and at a cost that the government and the taxpayer are prepared to bear.

Wayne D Hall AM, PhD · Robyn Ward MB BS, FRACP, PhD · Winston S Liauw MB BS, MMedSci, FRACP · Jo-anne E Brien BPharm, BS(Pharm), PharmD · Christine Y Lu BPharm, MSc

In September 2004, the members of the International Committee of Medical Journal Editors (ICMJE) published a joint editorial aimed at promoting registration of all clinical trials.1 We stated that we will consider a trial for publication only if it has been registered before the enrolment of the first patient. This policy applies to trials that start recruiting on or after 1 July 2005. Because many ongoing trials were not registered at inception, we will consider for publication ongoing trials that are registered before 13 September 2005. Our goal then and now is to foster a comprehensive, publicly available database of clinical trials. A complete registry of trials would be a fitting way to thank the thousands of participants who have placed themselves at risk by volunteering for clinical trials. They deserve to know that the information that accrues from their altruism is part of the public record, where it is available to guide decisions about patient care, and deserve to know that decisions about their care rest on all of the evidence, not just the trials that authors decided to report and that journal editors decided to publish. We are not alone in pursuing this goal. The World Health Organization (WHO), through meetings in New York, Mexico City, and Geneva, has brought us close to the goal of a single worldwide standard for the information that trial authors must disclose. Around the world, governments are beginning to legislate mandatory disclosure of all trials. For example, among the bodies considering new legislation is the US Congress, where the proposed Fair Access to Clinical Trials (FACT) Act would expand the current mandate for registration of clinical trials. Many other journals have adopted our policy of requiring trial registration. These initiatives show that trial registration has become a public issue. But, as our deadline for registration approaches, trial authors and sponsors want to be sure that they understand our requirements, so that reports of their research will be eligible for editorial review. The purpose of this joint and simultaneously published editorial is to answer questions about the ICMJE initiative and to bring our position into harmony with that of others who are working toward the same end. Our definition of a clinical trial remains essentially the same as in our September 2004 editorial: “Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome.” By “medical intervention” we mean any intervention used to modify a health outcome. This definition includes drugs, surgical procedures, devices, behavioural treatments, process-of-care changes, and the like. We update our 2004 editorial to state that a trial must have at least one prospectively assigned concurrent control or comparison group in order to trigger the requirement for registration. Among the trials that meet this definition, which need to be registered? The ICMJE wants to ensure public access to all “clinically directive” trials — trials that test a clinical hypothesis about health outcomes (eg, “Is drug X as effective as drug Y in treating heart failure?”). We have excluded trials from our registration requirement if their primary goal is to assess major unknown toxicity or determine pharmacokinetics (phase 1 trials). In contrast, we think the public deserves to know about trials that could shape the body of evidence about clinical effectiveness or adverse effects. Therefore, we require registration of all trials whose primary purpose is to affect clinical practice (phase 3 trials). Between these two extremes are some clinical trials whose prespecified goal is to investigate the biology of disease or to provide preliminary data that may lead to larger, clinically directive trials. We recognise that requiring public registration of trials whose prespecified goal is to investigate the biology of disease or to direct further research might slow the forces that drive innovation. Therefore, each journal editor will decide on a case-by-case basis about reviewing unregistered trials in this category. Authors whose trial is unregistered will have to convince the editor that they had a sound rationale when they decided not to register their trial. The ICMJE will maintain this policy for the next two years. We will then review our experience. Our September 2004 editorial specified the information that we would require for trial registration. Attendees at a recent meeting of the WHO registration advisory group identified a minimal registration dataset of 20 items (Box). The WHO-mandated items collectively address every key requirement that we established in our September 2004 editorial. The ICMJE supports the WHO minimal dataset and has adopted it as the ICMJE’s requirement: we will consider a trial for publication if the authors register it at inception by completing all 20 fields in the WHO minimal dataset. As individual editors, we will review the data in the registration fields when we decide whether to consider the trial for publication. We will consider a registration dataset inadequate if it has missing fields or fields that contain uninformative terminology. If an investigator has already registered a clinical trial in a publicly owned, publicly accessible registry using the data fields that we specified in our 2004 editorial, we will consider that registration to be complete as long as each field contains useful information. Acceptable completion of data fields is an important concern. It shouldn’t be, but it is. Many entries in the publicly accessible clinicaltrials.gov database do not provide meaningful information in some key data fields. A search conducted on May 4, 2005 (Deborah Zarin, MD, personal communication) indicates that certain pharmaceutical-company entries list a meaningless phrase (eg, “investigational drug”) in place of the actual name of the drug, even though a US law requires trial registrants to provide “intervention name” (http://www.fda.gov/cder/guidance/4856fnl.htm). Many companies and other entities are completing the data fields in a meaningful fashion. Data entries must include information that will be of value to patients and health professionals; the intervention name is needed if one is to search on that intervention. We recognise that clinical trial registries have many uses, but whatever the use, a worldwide uniform standard for a minimal database is necessary. We have participated in the WHO effort to establish a clinically meaningful trial registration process. The ICMJE supports this ongoing project. When it is complete we will evaluate the process, and if it meets our primary objectives, we will adopt it. We stated our requirements for an acceptable trial registry in the September 2004 editorial, and they remain the same. The registry must be electronically searchable and accessible to the public at no charge. It must be open to all registrants and not for profit. It must have a mechanism to ensure the validity of the registration data. The purpose of a clinical trials registry is to promote the public good by ensuring that everyone can find key information about every clinical trial whose principal aim is to shape medical decision-making. We will do what we can to help reach this goal. We urge all parties to register new and ongoing clinical trials. If in doubt about whether a trial is “clinically directive,” register it. Don’t use meaningless phrases to describe key information. Every trial participant and every investigator should be asking, “Is this clinical trial fully registered?” Minimal registration dataset* Item Comment 1. Unique trial number The unique trial number will be established by the primary registering entity (the registry). 2. Trial registration date The date of registration will be established by the primary registering entity. 3. Secondary IDs May be assigned by sponsors or other interested parties (there may be none). 4. Funding source(s) Name of the organisation(s) that provided funding for the study. 5. Primary sponsor The main entity responsible for performing the research. 6. Secondary sponsor(s) The secondary entities, if any, responsible for performing the research. 7. Responsible contact person Public contact person for the trial, for patients interested in participating. 8. Research contact person Person to contact for scientific inquiries about the trial. 9. Title of the study Brief title chosen by the research group (can be omitted if the researchers wish). 10. Official scientific title of the study This title must include the name of the intervention, the condition being studied, and the outcome (eg, The International Study of Digoxin and Death from Congestive Heart Failure). 11. Research ethics review Has the study at the time of registration received appropriate ethics committee approval (yes/no)? (It is assumed that all registered trials will be approved by an ethics board before commencing.) 12. Condition The medical condition being studied (eg, asthma, myocardial infarction, depression). 13. Intervention(s) A description of the study and comparison/control intervention(s) (For a drug or other product registered for public sale anywhere in the world, this is the generic name; for an unregistered drug the generic name or company serial number is acceptable). The duration of the intervention(s) must be specified. 14. Key inclusion and exclusion criteria Key patient characteristics that determine eligibility for participation in the study. 15. Study type Database should provide drop-down lists for selection. This would include choices for randomised vs. non-randomised, type of masking (eg, double-blind, single-blind), type of controls (eg, placebo, active), and group assignment, (eg, parallel, crossover, factorial). 16. Anticipated trial start date Estimated enrolment date of the first participant. 17. Target sample size The total number of subjects the investigators plan to enrol before closing the trial to new participants. 18. Recruitment status Is this information available (yes/no) (If yes, link to information). 19. Primary outcome The primary outcome that the study was designed to evaluate. Description should include the time at which the outcome is measured (eg, blood pressure at 12 months). 20. Key secondary outcomes The secondary outcomes specified in the protocol. Description should include time of measurement (eg, creatinine clearance at 6 months). * The data fields were specified at a meeting convened by the World Health Organization in April 2004; the explanatory comments are largely from the International Commitee of Medical Journal Editors.

Catherine D De Angelis · Jeffrey M Drazen · Frank A Frizelle · Charlotte Haug · John Hoey · Richard C Horton · Sheldon Kotzin · Christine Laine · Ana Marusic · A John P M Overbeke · Torben V Schroeder · Harold C Sox · Martin B Van Der Weyden

Objective: To establish the rate of and reasons for cancellations of surgery on the scheduled day in an Australian hospital.Design: Prospective survey.Setting: Major metropolitan tertiary hospital, 13 May to 15 November 2002.Main outcome measures: Proportion of operations cancelled on the day of surgery, obtained each day from the operating theatre list and a separate list of additions and cancellations compiled on the day; reasons for cancellations from the cancellation list, extended or confirmed, as necessary, by questioning of bookings and ward staff, or members of the surgical team; estimated and actual duration of each operation and patient information from hospital clinical records.Results: 7913 theatre sessions were scheduled by 133 surgeons in the study period; 941 of these (11.9%) were cancelled on the day, including 724 of 5472 (13.2%) elective procedures on working weekdays. Main reasons for cancellation were: no theatre time due to over-run of previous surgery (18.7%); no postoperative bed (18.1%); cancelled by patient (17.5%); and change in patient clinical status (17.1%). Procedural reasons (including patient not ready, no surgeon, list error, administrative cause, and communication failure) totalled 21.0%. Ear, nose and throat surgery experienced the most cancellations (19.6%), followed by cardiothoracic surgery (15.8%).Conclusions: There were five major reasons of similar magnitude for on-the-day surgery cancellations. We estimated that 60% of cancellations of elective procedures were potentially avoidable. Change of one factor leading to cancellation (eg, provision of more postoperative beds) is not likely to lead to improvement unless the other major factors are also tackled.

William N Schofield MA, DipEdPsych · George L Rubin FAFPHM, FACR · Michael Piza BA(Hons), MPH · Ying Yin Lai MScApplStat · Doungkamol Sindhusake BA, MPH, PhD · Michael R Fearnside MS, FRACS · Peter L Klineberg FANZCA

Objective: To evaluate the effectiveness of a community-based and GP-based intervention in reducing unnecessary antibiotic prescribing for upper respiratory tract infections (URTIs) including sore throats, sinusitis and otitis media.Design: Analysis of pharmacy dispensing data in June to October before (2000) and after (2001) the intervention, which commenced on 25 June 2001.Setting and participants: Local consumers, health professionals, the Adelaide Southern Division of General Practice, the South Australian Government, and the local media in a rural region of South Australia, covering about 2000 square kilometres, with a population of over 20 000.Intervention: Community dissemination of consumer information on antibiotic use for URTIs (including a local media campaign) and education of health professionals (including sessions with general practitioners at the four practices in the study area) on current Australian therapeutic guidelines for antibiotics, and a validated clinical scoring system for decision making in managing sore throat.Main outcome measures: Total dispensing data from local pharmacies for the months of June to October in 2000 and 2001, covering the six antibiotics considered most likely to be used for URTIs (amoxycillin, amoxycillin/clavulanic acid, cefaclor, doxycycline, erythromycin and roxithromycin).Results: The dispensing of the six antibiotics reduced by 32% overall, from 77.1 to 52.9 defined daily doses per 1000 population per day, with statistically significant reductions in the range of 31%–70% for individual antibiotics; there was no reduction for amoxycillin with or without clavulanic acid.Conclusion: The intervention was associated with reduced dispensing of unnecessary antibiotics for URTIs.

William B Dollman BPharm, MAppSc, FSHP · Vanessa T LeBlanc BA(Psych) · Lynette Stevens · Peter J O’Connor PhD · John D Turnidge MB BS, FRACP, FRCPA

Patients with chronic obstructive pulmonary disease and a stable daytime Pao2 of ≤ 55 mmHg (7.3kPa) live longer and have a better quality of life if provided with long-term continuous oxygen therapy. It is reasonable to offer continuous oxygen therapy also to patients with other lung diseases that cause chronic hypoxaemia. Indications for supplemental oxygen therapy during exercise (ambulatory oxygen therapy) and sleep (nocturnal oxygen therapy) are less clear.

Christine F McDonald PhD, FRACP · Alan J Crockett PSM, MPH · Iven H Young BSc, MB BS, PhD, FRACP

Objective: To conduct a systematic review of the evidence for the effectiveness of a range of possible treatments for depression in older people.Data sources: Literature search using the PubMed, PsycInfo and Cochrane Library databases.Data synthesis: Treatments that have been suggested to be effective for depression were grouped under three categories: medical treatments, psychological treatments, and lifestyle changes/alternative treatments. We describe each treatment, review the studies of its effectiveness in people aged ≥ 60 years, and give a rating of the level of evidence.Conclusions: The treatments with the best evidence of effectiveness are antidepressants, electroconvulsive therapy, cognitive behaviour therapy, psychodynamic psychotherapy, reminiscence therapy, problem-solving therapy, bibliotherapy (for mild to moderate depression) and exercise. There is limited evidence to support the effectiveness of transcranial magnetic stimulation, dialectical behaviour therapy, interpersonal therapy, light therapy (for people in nursing homes or hospitals), St John’s wort and folate in reducing depressive symptoms.

Cathy J Frazer PhD · Helen Christensen PhD · Kathleen M Griffiths PhD

The Solomon Islands is a nation of warm people, tropical islands, shipwrecks and malaria. It is also a nation in urgent need of specialised medical care. This is the story of my short time volunteering in the Solomon Islands for the ophthalmic division of the Royal Australasian College of Surgeons, Pacific Islands Project (PIP) in 2004. The PIP, in operation since 1996, is funded by the Australian Agency for International Development (AusAID) and encompasses specialists from 10 surgical specialties who volunteer their time to help address the shortage of local specialists in 11 Pacific Island countries. The ophthalmic team for the Solomon Islands is sponsored to make an annual trip. Eye disease is such a serious problem that they made a second trip in 2004 to the islands of Guadalcanal, Malaita and Gizo, their 11th since the project’s inception The Solomon Islands, formerly known as the British Solomon Islands, gained independence in 1978. They were the scene of some of the bloodiest land, sea and air battles of World War II, and are now emerging from 6 years of ethnic conflict. The predominantly Melanesian people of the Solomon Islands are among the poorest in the South Pacific.1 Honiara is a 3-hour flight from Brisbane, where I first met the PIP team — ophthalmologists Geoff Painter and Jeremy Smith, and ophthalmic nurses Bev Baily and Louise Fowler, all from Sydney — at the Solomon Island Airlines check-in counter. Honiara, GuadalcanalAfter arriving at Honiara-Henderson airstrip, we bounced and weaved along dilapidated roads to make our way to the National Referral Hospital in dusty Honiara. It is the only hospital in the archipelago that has an anaesthetist and the option of performing major surgery. However, it has no intensive care facilities and endures a chronic shortage of medical supplies. The team arrived to the sounds of an animated Christian preacher engaging the crowd of more than 500 patients on the hospital verandah. The patients had been queuing since dawn and many had walked for days on hearing of the impending arrival of an eye team. Essential to ophthalmic care in the Solomon Islands are the specialised eye nurses, headed by Wanta Aluta. Sister Wanta runs the eye clinic at the National Referral Hospital, provides training for the eye nurses at regional eye clinics, and is responsible for the essential triage before each overseas team visits. Dr Qalo, a Solomon Islander, is currently in an ophthalmology training program in Papua New Guinea, sponsored by Foresight Australia. At the clinic, the patients were lined up in rows and the two ophthalmologists moved along the rows using a portable slit lamp to diagnose the ophthalmic condition, most commonly, cataract. Patients had brought their own medical histories, which varied from a small exercise book to a scrap of card. Patients were put on the list for cataract surgery if their visual acuity was measured at less than 6/60. However, many could only discern hand movements and up to 30% were profoundly bilaterally blind. Only a select few with pressing reasons for securing surgery (such as driving a taxi or working as a teacher) were operated on at 6/60. Standard cataract surgery was extracapsular cataract extraction with the insertion of a posterior chamber intraocular lens. In most patients, the density of the cataract made phacoemulsification, and thus, modern small-incision cataract surgery, unsuitable. There were a significant number of young people with cataracts. One unforgettable patient was a 14-year-old boy with bilateral cataract who had lived most of his life being led around by his mother. His left cataract was removed during the team’s last PIP tour, and he now had uncorrected 6/4 vision in his left eye, a big smile, and was ready to have his right cataract removed. The severity of eye conditions is compounded by the delay in presentation. Most patients’ first port of call is a traditional healer for topical application of herbs termed “Kastom medicine”, which, at best, does nothing, and often introduces infection. Auki, MalaitaAfter 2 days in Honiara, Dr Painter and I joined Dr Qalo and Sister Wanta for a 3-hour speedboat trip to Malaita Province. No ophthalmic team had visited Malaita since 2001. We went straight from the port to the eye clinic at Kiluufi Hospital to begin consultations with the 112 patients. We greatly appreciated that Stephen, the Malaitan eye nurse, had measured the visual acuity and divided the group into cataracts and other disorders (mostly pterygium and infections). A disturbing number of children had lime burns on their corneas caused by touching lime hydroxide used by their parents in the preparation of their betel nut mixture. Many elderly patients had decreased visual acuity because of uncorrected refractive errors, for which there were no spectacles available. The general state of patients in Malaita was sobering. They were literally in rags. Worse still, many were hungry. Families generally subsist on vegetable plots with little cash income. Some had made the long journey to the eye clinic by canoe or on foot with scarce provisions over many days. One patient even had a hypoglycaemic attack on arrival at the clinic. Malaita is one of the poorest islands in the country because of its direct involvement in the ethnic conflict. After years of tension, the civil war came to a head on the main island of Guadalcanal in 1998. During the conflict, Malaitan settlers (many second-generation) fled Honiara and went back to Malaita. The impressive organisation at Kiluufi Hospital enabled us to commence surgery on the second day. The team was mostly self-sufficient, bringing two portable microscopes, ophthalmic instruments, an autoclave and disposables with them. Patients were given a peribulbar local anaesthetic by a Solomon Islander resident medical officer, and walked in and out of surgery. Insect repellant was a must to ward off malaria-laden mosquitoes from our exposed legs. The air-conditioned theatre made operating in the humid climate tolerable to us, but the patients needed blankets during the half-hour cataract procedure. After their surgery, the patients were led out to rest until review the next morning. Many slept on vacant benches, under desks or on straw mats on the floor. The pharmacy had no paracetamol for postoperative analgesia. Despite the environmental conditions, the rate of nosocomial infections and endophthalmitis was low. Each morning, I reviewed the postoperative patients and re-measured their visual acuity. Patients, many of whom were seeing for the first time in many years, were intensely grateful and said “Thank you for coming to Malaita”. Patients’ uncorrected visual acuity was tested preoperatively and then one day postoperatively (Box 1). Ideally, visual acuity would be tested again a few months later, but patients’ return to their far-flung homes after treatment makes long-term follow-up unrealistic. While we were working in Auki, Dr Smith and Dr John Szetu (who joined our Team from Vanuatu) worked diligently in Honiara performing a large number of procedures on the Guadalcanal patients we had triaged on arrival. They also introduced more modern technology in the form of phacoemulsification and posterior segment vitrectomy for treating retinal detachment, for the first time to the Solomon Islands. GizoThe third place on the PIP schedule was the beautiful island of Gizo, renowned worldwide as a diving Mecca. The team reunited, which increased surgical efficiency and enabled us to perform a record number of operations overall. ReflectionsWe completed 287 procedures in 2 weeks (Box 2), and provided valuable supplies and teaching. Despite this, time constraints meant that we were not able to extract all of the cataracts of the patients on the surgical list in Honiara or Auki. This left me feeling despondent, as the patients had waited so patiently for up to a week and were so gracefully resigned in their disappointment. Of course, they will be given priority in the future, but the sadness on their faces was obvious. I obtained invaluable experience on neglected ophthalmic disorders and the difficult conditions under which the Solomon Islander nurses and doctors work. It was a privilege to witness the work in the Solomon Islands by the PIP team, but especially the work done by Sister Wanta and her nurses. I now understand and appreciate how Australian development projects are assisting in the development of primary eye care in the Pacific Nations. Sadly, compared with their Pacific neighbours, the Solomon Islands are relatively well resourced. The PIP teams provided ophthalmic surgery, in addition to valuable supplies and teaching; VISION 2020 provided specialised training for eye nurses, who in turn provided a buffer of sustainable eye care during the ethnic conflict; and Foresight Australia provide the opportunity for specialised ophthalmic training. On a broader front, additional assistance is provided by the Regional Assistance Mission to the Solomon Islands (RAMSI), established by Australia and with other Pacific Island Nations at the request of the Solomon Islands government in 2003. RAMSI has authority for peacekeeping and the restoration of basic services, particularly in health. This has been broadly welcomed by most Solomon Islanders.2 The Solomon Islanders have been through difficult times, but their future is looking brighter. 1 Improvement in uncorrected visual acuity for 72 patients after extracapsular cataract surgery at Kiluufi Hospital, Malaita, Solomon Islands* * Vision tested preoperatively and one day postoperatively. Symbols and adjacent numbers indicate the number of patients with preoperative visual acuity as indicated by their position along the horizontal axis that improved postoperatively to the position shown on the vertical axis. The smallest symbols indicate one patient and are not labelled. 2 Presentations and surgery for eye disorders in the Solomon Islands during a 2-week visit by a Pacific Islands Project ophthalmic team in August 2004 Surgery Hospital Patients screened Cataract Pterygium (excision/ graft) Entropion (repair) Diabetic retinopathy (laser) National Referral Hospital 344 151 2 2 4 Kiluufi Hospital 112 72 1 1 na Gizo Hospital 124 38 10 6 na Total 580 261 13 9 4 na = not applicable.

Michelle L Baker MB BS

Two patients with anorexia nervosa and raised serum creatinine levels were found to have nephrocalcinosis on renal biopsy, an association not previously described. Clinical records Patient 1 A 26-year-old woman was referred with a serum creatinine level of 0.21 mmol/L (reference range [RR], 0.03–0.11 mmol/L). She had a 5-year history of anorexia nervosa, laxative misuse, and unexplained intermittent hypercalcaemia requiring hospital admissions (calcium, > 3.0 mmol/L). During one admission, she disclosed taking a vitamin preparation containing vitamin D3 200 IU and calcium phosphate 40 mg. Investigations for hypercalcaemia included assays of parathyroid hormone, parathyroid hormone-related peptide, vitamin D, 1,25-hydroxy vitamin D, osteocalcin, serum cortisol, serum angiotensin-converting enzyme, and 24-hour urinary calcium; thyroid function tests; and serum and urine protein electrophoresis. These were all in the normal range. A urine diuretic screen was negative on two occasions. Bone mineral density measurement was normal. On examination, the patient was thin, weighing 40 kg (height, 160 cm; body mass index, 15.6 kg/m2). Her blood pressure was 110/80 mmHg. Estimated glomerular filtration rate (GFR) was 29 mL/min per 1.73 m2 (normal mean value in young women is 125 mL/min per 1.73 m2). Urinalysis showed 18 000 erythrocytes/mL (RR, < 10 000/mL) and 0.17 g/day of proteinuria (RR, < 0.1 g/day). Autoimmune, hepatitis B and C serology were negative. C3 was 0.68 g/L (RR, 0.81–1.66 g/L) and C4 was 0.17 g/L (RR, 0.12–0.42 g/L). Her serum electrolytes at presentation are shown in Box 1. Ultrasound showed kidneys 9.5 cm and 9.3 cm in length, with possible calcification of the pyramids adjacent to the upper pole calyces. There was no calcification on plain abdominal x-ray. Her renal biopsy showed calcification in degenerate tubular basement membranes within the interstitium, and in three of 36 glomeruli. There was widespread interstitial fibrosis indicating chronic damage. One glomerulus showed basement membrane reduplication, but immunoperoxidase staining was negative. Eighteen months later, her renal function has remained unchanged. Patient 2 A 31-year-old woman was referred by her general practitioner because of a rise in serum creatinine level from 0.16 to 0.41 mmol/L. An eating disorder had been diagnosed 8 years earlier. Two years previously, diarrhoea and abdominal pain were investigated. A malabsorption screen, upper endoscopy, and small bowel biopsy were all normal. Colonoscopy showed melanosis coli, consistent with laxative misuse. One year before the current admission, she had been hospitalised with hypokalaemia and renal failure (Box 1). Her potassium was corrected with intravenous replacement. She discharged herself the following day. She reported having 30 bowel actions a day, and was taking spironolactone 25 mg daily, effervescent potassium chloride (14 mmol K+) 6 tablets/day, diazepam 2 mg as required, and diclofenac 50 mg as required. Her blood pressure was 100/60 mmHg, and she weighed 43.6 kg (height, 162.5 cm; body mass index, 16.5 kg/m2). Electrolytes on admission are shown in Box 1. Her serum calcium levels were high on two occasions, but normal on others. Mid-stream urine had no erythrocytes or pyuria, and 24-hour urine protein was 0.44 g/day. Ultrasound showed echogenic kidneys without calcification. Serum complement and autoimmune serology were negative. Twenty-four-hour urine biochemistry showed potassium 17 mmol/day (RR, 25–100 mmol/day); sodium 21.0 mmol/day (RR, 40–210 mmol/day), calcium 0.6 mmol/day (RR, 2.5–7.5 mmol/day); oxalate 0.23 mmol/day (RR, 0.04–0.34 mmol/day); and phosphate 18.0 mmol/day (RR, 10–40 mmol/day). Bone mineral density measurement was normal. Her creatinine level reduced to 0.23 mmol/L (estimated GFR, 26 mL/min per 1.73 m2) before she underwent a renal biopsy (Box 2). She subsequently had multiple episodes of hypokalaemia (potassium 2.0 mmol/L) despite large quantities of potassium supplements being supplied, with a positive urine laxative screen on two occasions. Serum calcium was intermittently high, the highest being 3.0 mmol/L (corrected for albumin). One year after her renal biopsy, nasogastric feeding increased her weight from 30 kg to 38 kg after 5 weeks. A year later, she developed pneumonia and septic shock, and died. A key clinical feature of anorexia nervosa is “the relentless pursuit of thinness”1 and a “desperate need to grow thinner”.2 People with this disorder often engage in behaviour that affects fluid and electrolyte balance, including vomiting, laxative or diuretic misuse, fluid restriction, and the injudicious use of health supplements. Anorexia nervosa can cause significant renal problems, some of which may have contributed to the development of nephrocalcinosis in our patients. Electrolyte disturbances include hypokalaemia, hyponatraemia, hypercalcaemia, hypomagnesaemia and hypophosphataemia.3,4 Hypokalaemia with metabolic alkalosis indicates either vomiting or diuretic misuse, whereas metabolic acidosis indicates laxative misuse.4 Hypokalaemia is rare in the absence of these behaviours.5 Body phosphate stores can be depleted, and refeeding can exacerbate hypophosphataemia, with serious consequences such as seizures and myocardial dysfunction.6 Renal function may also be affected by volume depletion. Nephrolithiasis has been reported in patients with anorexia nervosa,7-11 but, to our knowledge, nephrocalcinosis has not. Nephrocalcinosis results from excessive calcium deposition in the kidney, and renal failure may result from tubular cell injury, tubular obstruction by calcified debris, and atrophy of nephrons. Chronic inflammation and interstitial fibrosis accompany these changes.12 In a series of 350 patients with nephrocalcinosis, the commonest causes were primary hyperparathyroidism (34.1%), distal renal tubular acidosis (20.9%), and medullary sponge kidney (11.7%).13 Medullary calcification is typical in most of these conditions, but neither of our patients had computed tomography to demonstrate medullary calcification. Both patients had hyperphosphataemia secondary to reduced glomerular filtration rate (GFR), causing an elevated calcium-phosphate product, which predisposed them to tissue calcification. However, an alternative cause for impaired GFR was not found in either patient. Both the amount of calcification and its presence in glomerular and tubular basement membranes disclosed by renal biopsy argue against calcification secondary to other renal disease. Hypercalcaemia is the most likely cause of the nephrocalcinosis in Patient 1, probably due to use of a vitamin D preparation. However, vitamin D was not elevated on the occasion it was measured. In Patient 2, diclofenac use may have contributed to fluctuations in renal function, but does not explain the biopsy findings. Chronic severe hypokalaemia and laxative misuse characterised Patient 2, and in her case, diarrhoea and laxative misuse were the most prominent potential causes for hypokalaemia. However, her metabolic alkalosis is more consistent with diuretic misuse or vomiting (or both) than diarrhoea. Her low urinary potassium excretion does not disprove diuretic misuse, because she was taking a potassium-sparing diuretic (spironolactone), and her diuretic misuse may have been intermittent. Indeed, chronic use of frusemide for weight control has been associated with nephrocalcinosis in patients without anorexia nervosa.14,15 Chronic diarrhoea may contribute to nephrocalcinosis by causing volume depletion. Nephrocalcinosis associated with acute renal failure has been reported in relation to an oral sodium phosphate preparation used for bowel preparation for colonoscopy.16 Prolonged hypokalaemia can cause tubular atrophy, damage to tubular cells, interstitial lymphocyte infiltration, interstitial fibrosis and juxtaglomerular apparatus hyperplasia.17 Chronic tubulo-interstitial nephritis due to hypokalaemia has been described as a cause of end-stage renal disease in anorexia nervosa patients18 and may explain some of the chronic damage observed in Patient 2. ConclusionPatients with anorexia nervosa have potential risk factors that may predispose them to nephrocalcinosis, and this should be considered in the differential diagnosis of patients with eating disorders and abnormal renal function. 1 Electrolyte results for the two patients Patient 1 Patient 2 Reference range Admission 1 year prior Admission Sodium (mmol/L) 134 136 131 135–145 Potassium (mmol/L) 4.1 2.0 2.6 3.5–5.0 Chloride (mmol/L) 100 76 77 95–107 Bicarbonate (mmol/L) 25 41 36 23–31 Urea (mmol/L) 7.2 15.3 15.0 2.5–7.7 Creatinine (mmol/L) 0.214 0.285 0.410 0.03–0.11 Calcium* (mmol/L) 2.70 2.79 2.41 2.10–2.60 Albumin (g/L) 38 27 26 36–48 Phosphate (mmol/L) 2.02 2.07 3.35 0.60–1.40 Ca x P product (mg2/dL2) 5.5 Not measured 8.1 < 5.8† Magnesium (mmol/L) 0.87 Not measured 1.81 0.70–1.00 * Calcium value has been corrected for albumin. †Recommended by the Caring for Australians with Renal Impairment draft guidelines (http://www.kidney.org.au/cari/CARI_guidelines.php). 2 Renal biopsy from Patient 2 Six of 27 glomeruli were totally sclerosed and there was widespread interstitial fibrosis with tubular atrophy and interstitial lymphocytosis (a). Calcification was seen in glomerular basement membranes (b, arrow), within tubule lumens (c) and in tubular basement membranes (d, arrow). There was also intimal thickening of interlobular arteries, indicating arteriosclerosis and there were no significant abnormalities on immunofluorescence or electron microscopy. (Haematoxylin and eosin stain; original magnifications (a) × 40, (b) and (d) × 100, (c) × 200.)

Matthew A Roberts FRACP · Duncan P MacGregor FRCPA, PhD · Nick Paoletti FRANZCP · Francesco L Ierino PhD · Campbell R Thorpe FRANZCP, MPsych

Six patients being evaluated for phaeochromocytoma had misleading investigative findings: all initially had raised urinary catecholamine levels, and five had adrenal masses on imaging studies. Adrenalectomy in these five patients revealed only one pathologically confirmed phaeochromocytoma. Tricyclic antidepressant use produced misleading elevations in urinary catecholamine levels in three patients. 24-hour urine studies should be performed at least twice, after eliminating confounding factors (stressors, medications). Clinical recordThe details of six patients treated in the period April 1999 – October 2003 by members of the Section of Endocrine Surgery of the Royal Australasian College of Surgeons are outlined in Box 1. In all patients, clinical suspicion of phaeochromocytoma was raised by the presence of hypertension, paroxysmal symptoms, or both. Twenty-four-hour urinary catecholamine levels were found to be elevated, although in Patients 1–5 these abnormalities were confined to one or two analytes only. In all except Patient 2, adrenal lesions were discovered on imaging, with large haemorrhagic masses detected in patients with an acute presentation (Patients 5 and 6). Patients with abnormalities on computed tomography (CT) underwent surgery. In Patients 1, 3, and 4, the excised tissues were found to be pathologically normal or to show mild enlargement (benign). In Patients 5 and 6, blood clot and necrotic tissue comprised the bulk of the specimens (Box 2), with a phaeochromocytoma discovered in the latter patient. Of note, Patients 1–3 were receiving tricyclic antidepressants for non-standard uses that did not include the treatment of major depression. DiscussionFalse positive biochemical test results for phaeochromocytoma are common and present particular problems because of the low prevalence of the disease. The reported incidence of phaeochromocytoma is 2–8 per million people annually, accounting for less than 0.2% of all patients with hypertension.1 Despite the fact that phaeochromocytoma is a rare cause of hypertension, the diagnosis merits consideration in a potentially large group of patients for two reasons. Firstly, although the disease is frequently fatal if unrecognised, surgical removal is highly effective, achieving cure in greater than 90% of cases.2 Secondly, because no array of clinical indicators has proven to reliably include or exclude phaeochromocytoma,3 physicians must maintain a high level of suspicion and consider biochemical testing in patients at risk. The pretest probability for phaeochromocytoma is close to 0.5% (1 in 200 patients tested) in the presence of hypertension and suggestive symptoms.4 Assuming a specificity of 85% for biochemical testing, 30 false positive results are generated for every one patient with phaeochromocytoma identified.5 Fortunately, most false positive tests can be unmasked with careful additional investigation and/or the elimination of factors known to confound biochemical tests for levels of catecholamines and their metabolites. The misleading elevations in urinary noradrenaline levels in Patients 1–3 can be ascribed to their taking tricyclic antidepressants. Medications and conditions that may result in raised levels of plasma and/or urine catecholamines and their metabolites, and result in false positive test results for phaeochromocytoma, are listed in Box 3. Among these drugs, tricyclic antidepressants and phenoxybenzamine have been the most frequently implicated, together accounting for more than 40% of medication-associated false positive results in a recent large study.6 In Patients 3 and 4, false positive biochemical findings led to the identification of small (1.5 cm) adrenal masses on CT scanning, both of which were found, on histopathological examination, to be benign. Clinically unapparent adrenal masses (“incidentalomas”) are found in 2.1% of subjects at autopsy and in 1%–4% of abdominal imaging studies. Most of these masses are benign, hormonally inactive tumours that do not require surgical management.7 Phaeochromocytomas presenting with acute haemorrhage at presentation have been reported previously,8,9 with haemorrhagic tumours often losing characteristic imaging appearances and functional markers. Tumour necrosis may initially result in massive catecholamine release, followed by failure to demonstrate excess catecholamine levels, as was seen in Patient 6. Mildly elevated urinary catecholamine levels may also be seen as a consequence of hyperadrenergia from an acute stress response at the time of haemorrhage into a non-phaeochromocytoma lesion, as occurred in Patient 5. Role of biochemical testingAlthough measurement of plasma free metanephrine levels has been recently advocated by some groups, 24-hour urinary catecholamine levels and total metanephrine level have consistently proven to be the most specific tests available for the diagnosis of phaeochromocytoma.5,10 Elevations in the level of one or more of these analytes (above the 95% reference range designated as the upper limit of normal by laboratories) are common in patients with paroxysmal symptoms or poorly controlled hypertension not due to phaeochromocytoma. Thus, we recommend that higher cut-off values, roughly two times the upper limit of normal for most laboratories, be used to identify patients suitable for further workup. Repeat biochemical testing 6 weeks after stopping drugs likely to confound the results is ideal, and tests performed during major physical or psychological stress should be interpreted with extreme caution (if performed at all). It is important to note that alterations in plasma catecholamine levels may be caused not only by medications, but also by the underlying diseases being treated (eg, major depression in the case of tricyclic antidepressants or severe heart disease in the case of β-blockers).11-13 All patients should undergo at least two 24-hour urine collections for measuring levels of catecholamines and their metabolites. Clonidine suppression testing — the measurement of plasma free normetanephrine before and after the oral administration of 0.3 mg clonidine — is highly sensitive and specific, and may be a useful adjunct in patients with more than one prior set of equivocal tests.6 Role of imagingWhether imaging studies (both anatomical and functional) play a role in diagnosing phaeochromocytoma, as opposed to only localising tumours already diagnosed biochemically, remains controversial. In the patients described above, 131I‑metaiodobenzylguanidine scanning yielded true negative results in Patients 1–3, consistent with its known high specificity.4 However, current evidence suggests that, when appropriate biochemical tests are used, little discriminatory value is to be gained from imaging,14 and our experience illustrates how incidental radiographic findings may lead to unnecessary surgery. 1 Summary of the clinical records of six patients investigated for phaeochromocytoma Patient age/sex Presentation Blood pressure (mmHg) Medications 24-h Urinary catecholamine levels (nmol/d or μmol/d)* Radiological investigation† Surgical findings/ Clinical course Pathology Patient 1 49/M Weight loss (5 kg in 3 months), paroxysmal anxiety attacks, drenching sweats, chronic right flank pain 124/80 Clomipramine, 50 mg/day (anxiety) Adrenaline, 91/84 Noradrenaline, 860/1224 CT: 3 x 6-cm mass abutting upper pole of right kidney MIBG: negative Lobulated upper pole of kidney due to right renal artery branch running within posterior cleft Normal adrenal tissue Patient 2 41/M Migraines, chronic back pain, worsening hypertension, palpitations 145/85 Amitriptyline, 150 mg/day (migraine prophylaxis); amlodipine, 5 mg/day; ramipril, 5 mg/day; indapamide, 2.5 mg/day Adrenaline, 7/12 Noradrenaline, 485/1295 CT: No abnormalities MIBG: No abnormalities Normal findings on repeat urine studies after stopping amitriptyline — Patient 3 64/M Metastatic prostate cancer, poorly controlled hypertension 180/95 Imipramine, 100 mg/day (neuropathic pain); nifedipine, 180 mg/day; ramipril, 5 mg/day; chlorothiazide, 1000 mg/day Adrenaline, 115/99 Noradrenaline, 1070/1130 VMA, 33/38 CT: 1.5-cm left adrenal mass MIBG: negative Small left adrenal mass, macroscopically consistent with an adenoma Benign adrenal adenoma Patient 4 76/F Chronic hypertension, 15-month history of paroxysmal nausea and vomiting 144/80 Captopril, 25 mg/day Adrenaline, 65/129 Noradrenaline, 371/451 Dopamine, 1.55/2.02 CT: 1.5-cm left adrenal mass Smooth lesion palpable within left adrenal gland Enlarged adrenal gland (10.2 g; reference, 4 g) with thickened cortex but normal medulla Patient 5 75/M Sudden onset of intense back and left loin pain, chronic hypertension, weight loss (22 kg in 6 months), atrial fibrillation, diabetes, polymyalgia rheumatica 150/90 Warfarin, 5 mg/day; captopril, 25 mg/day; digoxin, 0.25 mg/day; isosorbide mononitrate, 60 mg/day; verapamil, 240 mg/day; prednisone, 5 mg/day; metformin, 2 g/day; rosiglitazone, 4 mg/day; thyroxine, 0.125 mg/day Adrenaline, 250 Noradrenaline, 720 Metanephrine, 1.68 Normetanephrine, 2.49 CT: 12-cm heterogeneous left adrenal mass (Box 2) Large blood clot with associated desmoplastic reaction occupying most of left adrenal gland Myelolipoma with haemorrhagic fat necrosis Patient 6 58/M Acute abdominal pain and hypertension, otherwise healthy 210/95 — Adrenaline, 2426/51 Noradrenaline, 18 370/464 Metanephrine, 13.3/0.8 Normetanephrine, 35.5/3.6 CT: 5-cm haemorrhagic left adrenal mass MRI (2 weeks after presentation): subacute haemorrhage into area without any distinct adrenal mass 12-cm dumbbell-shaped mass 3-cm phaeochromo-cytoma, large organising blood clot and necrotic tissue * Values separated by a forward slash represent separate collections, with abnormal values in bold. Reference ranges: adrenaline, < 100 nmol/d; noradrenaline, < 680 nmol/d; metanephrine, < 2.1 μmol/d; normetanephrine, < 5.6 μmol/d; VMA (vanillylmandelic acid), < 40 nmol/d; dopamine, < 3.0 μmol/d. †CT = computed tomography; MIBG = 131I-metaiodobenzylguanidine scanning; MRI = magnetic resonance imaging. 2 Computed tomography image of the haemorrhagic left adrenal mass in Patient 5 3 Medications and conditions that may cause false positive results of biochemical tests for phaeochromocytoma Medication or condition Test(s) confounded Tricyclic antidepressants Urinary catecholamines and metanephrines, plasma free metanephrines Clozapine Urinary catecholamines and metanephrines Phenoxybenzamine Plasma free metanephrines Calcium channel blockers Plasma noradrenaline, urinary noradrenaline, urinary adrenaline β-adrenergic blockers Urinary catecholamines and metanephrines, plasma free metanephrines (minor effect) α1-adrenergic blockers Urinary noradrenaline Sympathomimetics Urinary catecholamines and metanephrines, plasma free metanephrines Buspirone Urinary metanephrines Major physical or psychological stress* Urinary catecholamines and metanephrines, plasma free metanephrines * Hypoglycaemia, hypoxia, hypovolaemia, stroke, surgery, myocardial infarction, heart failure, severe pain, depression, panic disorder, sleep apnoea.

Jane L Harding MB BS · Michael W Yeh MD · Leigh W Delbridge MD, FRACS · Stan B Sidhu MB BS, FRACS · Bruce G Robinson MD, FRACP

Fractures in children are common, but the plasticity of children’s bones means that they may be incomplete. If a child has deformity, swelling or bony point tenderness in a limb after a fall, it is likely to be fractured. A fractured limb that appears deformed will most probably need to be reduced. Effective splinting, using whatever means is readily available, and early, adequate analgesia, can ameliorate the severe pain associated with a fracture. In young children with open growth plates, Salter–Harris type I injuries of the distal fibula are more common than ligament injuries of the ankle. After an ankle ligament injury, functional treatment — brace or tapes, with active physiotherapy — results in a better outcome than immobilisation. A child with a head injury, who does not lose consciousness, has only one or no episodes of vomiting, and is stable, alert and interactive, and neurologically normal, is extremely unlikely to have sustained an intracranial injury.

Simon J Young MB BS, DipCrim, FACEM · Peter L J Barnett MB BS, FRACP, FACEM · Ed A Oakley MB BS, FACEM

Jim Stockigt Senior Endocrinologist, Alfred Hospital, Melbourne; and Professor of Medicine, Monash University, VIC 3004. jrsATnetspace.net.au To the Editor: In May 2004, Sigma, the sole Australian supplier of l-thyroxine sodium, instructed pharmacists that thyroxine tablets should be stored refrigerated, both in pharmacies and after dispensing. Thyroxine bottles now carry explicit labels: “keep refrigerated” or “refrigerate at all times”. This instruction seems to have been accepted by health professionals, but patient-support groups immediately questioned the refrigeration directive. In response, Sigma conceded that thyroxine tablets can be stored at room temperature (< 25°C) for up to 4 weeks, with refrigeration still the preferred option. There are major unresolved issues about the potency, stability and bioavailability of various thyroxine preparations that are marketed competitively in the United States.1 With a single supplier in Australia, we can avoid between-preparation variations, provided that stability and consistency are maintained. The instruction to refrigerate thyroxine tablets seems to be uniquely Australian. None of my co-authors of the website <www.thyroidmanager.org>2 is aware of a refrigeration directive in any other country. The local instruction seems to have followed interaction between the Therapeutic Goods Administration and the manufacturer, so that unopened bottles could be marketed with a longer shelf life. Is the rest of the world missing out on something important? Is there something peculiar about the Australian formulation that makes it unstable at room temperature? Could this directive be without firm basis, or even dangerous? There is currently no evidence on whether thyroxine in already-opened, unsealed bottles is more or less stable at 4°C than at room temperature, but the need to keep the tablets dry has been widely emphasised.3 Consider the condensation that will occur during 200 daily openings of a refrigerated glass bottle, whatever it contains. If damp tablets lose potency, this would lead to apparent under-treatment. In the months since refrigerated storage was recommended in Australia, preliminary observations suggest that apparent under-dosage (ie, unexpected rises in serum TSH) may indeed occur in previously compliant patients (personal observation). If dosage were increased, the adjustment could result in over-treatment after a change to a fresh preparation. Thyroxine has a narrow therapeutic window, and excessive dosage can have serious effects, especially if there is associated cardiac ischaemia. While refrigeration of sealed bottles of thyroxine might extend the shelf life, the instruction to refrigerate unsealed bottles seems ill-advised. When an existing formulation is modified, it is generally the obligation of a manufacturer to demonstrate safety. The stability of tablets in sealed bottles and those in current use are quite separate issues. To establish how tablets in current use are influenced by refrigeration, it is necessary to measure the thyroxine content of remaining tablets from bottles of 200, opened and used daily for up to 6 months. Without such data, it is preferable to instruct patients not to store currently used bottles of thyroxine at refrigerator temperature.

Jim Stockigt

Ovais Siddiqui Regulatory and Medical Manager, Sigma Pharmaceuticals, Locked Bag 268, South Croydon, VIC 3136. ovais.siddiquiATsignet.com.au In reply: Sigma Australia acquired Oroxine (thyroxine sodium) from the original manufacturer in 1999, and launched Eutroxsig, an identical product, in 2002. During 2002–03, as a result of advances in analytical technology for some pharmaceutical products, product specifications, including shelf life and storage conditions, were updated, so that the product’s quality, safety and efficacy could be maximised or maintained throughout the claimed shelf life. For Oroxine and Eutroxsig, the new stability data showed a loss of up to 10% of thyroxine sodium in the first 6 months when stored below 25°C, with some plateauing thereafter. As an interim measure, Sigma, in agreement with the Therapeutic Goods Administration (TGA), decided to immediately reduce the shelf life from 24 to 12 months (“store below 25°C”) and set the lower release to 98.0% (up from 92.5%), while investigating reasons behind the loss in potency. The manufacturing process was confirmed to consistently yield tablets with very reproducible chemical and physical attributes in accordance with the release criteria. During manufacturing, however, about 2% of the thyroxine sodium is lost, with a corresponding similar increase in degradants. To limit the degradants responsible for the reduction in potency of thyroxine at room temperature, it was agreed with the TGA that thyroxine should be stored at 2°– 8°C (“Refrigerate. Do not freeze”), based on good stability data generated at this temperature. Consumer Medicine Information (CMI) and Product Information (PI) were updated in May/June 2004 to reflect this change. The new stability studies support the storage of Oroxine and Eutroxsig in the refrigerator; however, repeated in-use handling may result in an increase in condensation and microbial contamination. This may lead to changes in the physical characteristics of these products, including the growth of mould. There may be a further increase in condensation if the lid is not tightly closed. One possible solution is for patients to place up to 4 weeks’ supply of tablets in a spare, previously used, Oroxine or Eutroxsig amber-coloured bottle and store out of the fridge (below 25°C) for current use, while keeping the remaining stock in the fridge. Sigma is looking at options to improve the packaging so that the above problems are minimised or eliminated. Oroxine and Eutroxsig, manufactured by Sigma, are sold in Australia only. Sigma does not have access to formulation details, stability results and justification for the storage conditions used in other countries; therefore, we are unable to comment on such issues. As an Australian company, we are obliged to follow the regulatory guidelines of the Therapeutic Goods Act 1989 (Cwlth). Sigma recommends that the label instructions regarding storage conditions after opening be strictly followed to maximise the quality, safety and efficacy of the product.

Ovais Siddiqui

Christopher M MacIsaac,* Mark A Page,† Beverley-Ann Biggs,‡ Kumar Visvanathan§ * Associate Intensivist, † Registrar, ‡ Associate Professor, The Royal Melbourne Hospital, Grattan Street, Melbourne, VIC 3050; § Senior Research Fellow, Murdoch Children’s Research Institute, Melbourne, VIC. Christopher.macisaacATmh.org.au To the Editor: We report a recent case of toxic shock syndrome associated with menstruation which illustrates that this syndrome still occurs, even when tampons are used appropriately. A potential diagnostic test for the syndrome is also discussed. An 18-year-old woman presented with a 1-day history of fever, chills and severe back pain, with no other focal symptoms. On examination, she was febrile with a blood pressure of 75/40 mmHg, and had begun vomiting. She was treated empirically with intravenous ceftriaxone and flucloxacillin and resuscitated with intravenous fluids. Over several hours, the back pain resolved, and a widespread erythrodermic rash developed, centred mainly on the trunk. Further questioning revealed that the patient had removed a tampon shortly before presentation, as she had just ceased menstruating. Renal ultrasound examination, chest x-ray and blood cultures were non-diagnostic. She was treated with intravenous antibiotics for 4 days and discharged home with a further 10-day course of oral amoxycillin and clavulanic acid. At outpatient follow-up 3 weeks after admission, she reported desquamation of the skin of her palms and soles. Toxic shock syndrome was first described in 1978,1 and a strong association with Staphylococcus aureus, menstruation and tampon use was established in 1980.2 Toxic shock syndrome toxin-1 (TSST-1), a protein secreted by S. aureus, was the first of many toxins associated with the syndrome to be identified. The term “superantigen” was adopted to describe the ability of these toxins to cause a remarkable expansion of T lymphocytes displaying specific β chain variable regions of the T-cell antigen receptor. Superantigens bypass normal antigen presentation and can stimulate over 20% of all T cells, whereas a conventional antigen stimulates only in the order of 1 in 10 000 T cells. The signature feature of superantigen activity is the expansion of lymphocyte populations bearing the particular Vβ chains that bind the superantigen. In the case of TSST-1, this is Vβ2.3 Our patient consented to blood being sampled to investigate the Vβ profile of her T cells at follow-up. This investigation was part of a broader study on superantigens in sepsis that was approved by the Ethics Committee of the Royal Melbourne Hospital. The blood was stained with monoclonal antibodies against 24 Vβ families4 and analysed by flow cytometry. This showed a massive expansion of Vβ2 cells, which accounted for 28% of all CD4 lymphocytes (Box). Currently, there is no diagnostic test for toxic shock syndrome. Toxin production from cultured organisms can be established in vitro by some laboratories, but does not confirm toxin production in vivo. Detection of a “skewed” Vβ repertoire is a potential diagnostic test. Clearly, the sensitivity and specificity of the assay would need to be established before general application. To date, we have found skewed Vβ T-cell profiles in six independent cases of toxic shock syndrome. This patient had used tampons appropriately, including replacing tampons at least every 4 hours and not using them overnight, but nevertheless developed a life-threatening disease. The incidence of toxic shock syndrome peaked in the United States in 1980 and has since fallen substantially, as a result of factors including changed tampon absorbency. However, the incidence may be now increasing.5 Our case serves to remind us all to be vigilant for toxic shock syndrome in association with menstruation, and to consider the diagnosis in all patients with severe sepsis. Vβ profile of the T-cell antigen receptor of CD4 lymphocytes in a patient with toxic shock syndrome Vβ profile of CD4 cells from a patient 21 days after onset of toxic shock syndrome compared with the mean profile from 11 adult intensive-care patients with no evidence of infection. Note the massive expansion of cells carrying Vβ 2, for which toxic shock syndrome toxin-1 has known affinity.

Christopher M MacIsaac · Mark A Page · Beverley-Ann Biggs · Kumar Visvanathan

Patrick M Schlievert Professor, Microbiology, University of Minnesota, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA. patsATlenti.med.umn.edu Comment: As noted by MacIsaac et al above, my colleagues and I recently reported an increase in the incidence of staphylococcal toxic shock syndrome (TSS) in Minneapolis–St Paul in the United States, from 0.8 per 100 000 (in January 2000) to 3.4 per 100 000 (in December 2003).1 We noted that physicians across the United States were reporting TSS cases in increasing frequency. There are two major categories of staphylococcal TSS, menstrual and non-menstrual.2,3 Menstrual TSS is defined as occurring during menstruation or within the 2 days preceding its onset or the 2 days following its cessation; the illness is primarily, but not exclusively, associated with tampon use. Menstrual TSS is nearly always caused by the superantigen exotoxin, TSS toxin-1 (TSST-1).4 Superantigens significantly overactivate the human immune system to release cytokines that cause the clinical features of TSS (interleukin-1β [endogenous pyrogen]; tumor necrosis factor-α and β [capillary leak]; and interferon-γ and interleukin-2 [rash]).5 Non-menstrual TSS may occur in anyone, young or old, male or female, and today commonly follows superinfection of the upper respiratory tract after viral infection. Non-menstrual TSS is caused by TSST-1 (50%) or by staphylococcal enterotoxin B or C (together nearly 50%). The important question is what accounts for the fourfold rise in TSS that was reported in our 2004 study? We proposed several hypotheses. First, the increase in incidence partly results from the emergence of three strains of methicillin-resistant Staphylococcus aureus (MRSA), at least two of which are emerging worldwide. These strains are termed (by Centers for Disease Control [CDC] nomenclature) USA 1100 (TSST-1 positive), USA 400 (SEB/SEC, Panton–Valentine leukocidin [PVL] positive), and USA 300 (positive for an unknown superantigen as well as PVL). In our studies, USA 1100 strains currently comprise 20% of submitted isolates, compared with none before the year 2000. These isolates may produce 10 to 100 times more TSST-1 in vitro than their methicillin-sensitive S. aureus counterparts matched by pulsed-field gel electrophoresis profile. Thus, these organisms rapidly produce high levels of TSST-1, leading to TSS even when lower-absorbency tampons are used. In addition, the USA 400 and USA 300 strains are also emerging and are associated with increases in non-menstrual TSS. These latter isolates also produce more superantigens than their methicillin-susceptible counterparts. Secondly, in our 2004 study, physicians who submitted cultures to our laboratory defined cases of TSS based on patient presentation and the presence of an S. aureus strain producing one of the three causative exotoxins. Our TSS definition is likely to be broader than the strict CDC definition. Finally, we also noted that it is possible that women are beginning to menstruate and to use tampons at earlier ages. In addition, teenagers are bombarded with media advice that TSS is no longer a problem; failure to recognise the illness may lead to it becoming more severe before presentation. These lifestyle and awareness changes, combined with the emergence of high-toxin-producing strains and the expanded definition of TSS, may account for the observed increase in TSS. The increase does not appear to be caused by changes in tampon composition or absorbency.

Patrick M Schlievert

Andrew Firestone Psychiatrist; and Honorary Senior Lecturer, Monash University, Clayton, VIC 3168. afireATtpg.com.au To the Editor: Emerging evidence suggests that the so-called second-generation antipsychotics (SGAs), especially olanzapine and clozapine, can cause abnormal weight gain and increase the risk of diabetes mellitus.1-3 In Australia, there are calls for a prospective multicentre trial to compare the rates of weight gain and diabetes between SGAs.4,5 The Australian data presented here underline the pressing need for such a study. Data were examined for the 10-year period January 1994 to December 2003 for: Total prescriptions dispensed by the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme for 12 antipsychotic drugs; and Reactions reported in the same period to the Adverse Drug Reactions Advisory Committee (ADRAC) for each of these drugs, involving excessive weight gain or obesity, and diabetes mellitus or hyperglycaemic reactions. Reports were included in the survey only when it was considered that no other drug could be responsible. As clozapine is dispensed and recorded differently from other SGAs in Australia, complete data on numbers of prescriptions dispensed were not available. However, total Australian expenditure was available for each tablet strength of clozapine for the full 10-year study period, along with number of prescriptions dispensed and costs for the private hospital sector for the 4 years July 2000 to June 2004. Therefore, I calculated the average script cost for each tablet strength, and extrapolated the script numbers for the 10-year period, as shown in Box 1. Box 2 shows the “report rate” for each SGA for the side effects of weight gain or obesity, and diabetes or hyperglycaemia. The report rate for side effects was greater for clozapine than for any other SGA. Unfortunately, the true situation may be still worse. Clozapine is usually prescribed a month at a time, while the other drugs are prescribed for up to 6 months. Adjusting for this would widen the gap further. Moreover, as ADRAC promotes reporting for new drugs, the report rates for the five drugs introduced during the study period are probably inflated. Clozapine is not one of them. The limitations of ADRAC data are well known.4 Nevertheless, these are currently our best Australian data and strongly suggest that SGAs, of which risperidone has the most favourable profile, cause weight gain and diabetes much more often than the older antipsychotic agents. These data accord with previously published studies1 and support the US advice to avoid olanzapine and clozapine if possible. Recent PBS approval in Australia for use of olanzapine in bipolar disorder further underlines the urgent need for a prospective multicentre study to compare weight gain and glucose metabolism in patients taking antipsychotic drugs. Meanwhile, I suggest that: Patients who have abnormal weight gain with an SGA might be treated with chlorpromazine, trifluoperazine or haloperidol. PBS regulation of clozapine might be amended, to discourage its prescription until after failure of a “first-generation” as well as a second-generation antipsychotic drug. 1 Estimation of the total number of clozapine scripts in Australia Tablet strength (mg) Private hospitals data (Jul 2000–Jun 2004) Total clozapine used (Jul 1994–Jun 2004) Total prescriptions Cost ($) Average cost/ prescription ($) Cost ($) Estimated total prescriptions 25 3 650 230 929 63.27 9 636 814 152 313 50 25 1 443 57.72 85 980 1 490 100 21 057 6 632 499 314.98 153 276 771 486 624 200 69 24 392 353.51 463 131 1 310 Total 24 801 6 889 263 – 163 462 696 641 737 2 Report rates for side effects of antipsychotic drugs No. of years* No. of prescriptions dispensed No. of ADRAC reports Report rate (per million prescriptions dispensed) Weight gain† Diabetes‡ Weight gain† Diabetes‡ Chlorpromazine 10 950 221 0 0 0 0 Fluphenazine 10 327 126 0 0 0 0 Trifluoperazine 10 937 605 1 0 1.07 0 Pericyazine 10 657 514 0 0 0 0 Thioridazine 10 1 983 915 1 3 0.50 1.51 Haloperidol 10 1 499 254 2 0 1.33 0 Flupenthixol 9 121 132 0 0 0 0 Zuclopenthixol 8 93 839 0 1 0 10.66 Olanzapine 6 2 786 334 47 19 16.87 6.82 Quetiapine 4 271 957 1 4 3.68 14.70 Risperidone 9 1 298 156 6 2 4.62 1.53 Clozapine 10 641 737§ 41 61 63.89 95.05 ADRAC = Adverse Drug Reactions Advisory Committee. * Number of years with data available (as some drugs were introduced only after the start of the 10-year period). † Weight gain or obesity. ‡ Diabetes mellitus or hyperglycaemia. § Estimated number (see Box 1).

Andrew Firestone

To the Editor: The interesting case report by Currie and colleagues describes a variable cutaneous eruption of uncertain aetiology in a cluster of methadone-dependent patients.1 The rash was described as including pruritic, exanthematous, purpuric and eventually desquamative components, and typically as involving the trunk and extremities, particularly palms and soles. Secondary syphilis classically presents in a similar fashion, but no mention was made as to whether this had been excluded by serological testing. Indeed, the histology of the rash (perivascular inflammation, including plasma cell infiltrate, progressing to endarteritis) is similar to that seen in skin biopsies from methadone patients with secondary syphilis. However, an allergic or toxic cause appears to be implicated, in view of previous, well documented reports of hallucinogenic or other drug-related vasculitis published by ourselves2 and others.3-5

Vernon J Heazlewood

To the Editor: As a Victorian always on the lookout for something new, I read with interest the report by Currie and colleagues of a syndromic rash in patients attending methadone clinics in New South Wales.1 From the title I expected to read about a rash occurring as part of a syndrome, yet no group of concurrent symptoms was described. In fact, there was a long list with each patient of negative findings. I also had trouble deciding whether the four patients described indeed had the same rash. While the “lumpers” among us may consider it pedantic to split “rash” into more than one category, some doctors make an occupation of it quite successfully. For example, Patient 1 had petechiae and purpura, but no erythema and no involvement of the palms and soles. No photo, but nevertheless a nice description of vasculitis — common among intravenous drug users. Patient 2 had, from the look of the photo, a toxic erythema that resolved with desquamation of the palms and soles. No petechiae or purpura. Therefore, must be a different rash to Patient 1. Patient 3 is described as having “ a prominent purpuric rash involving both lower limbs”. However, the photo shows a macular erythema with some associated purpura that looks almost certainly to be an incidental manifestation of dependency. Difficult to say from a photo, as touch is so important in the diagnosis of true purpura. Of course, a 2 mm punch biopsy of the skin could resolve this almost instantly. Again, it is not clear whether this rash is similar to that seen in either Patient 1 or Patient 2. Patient 4 is described as having a red and itchy rash (erythematous and pruritic), but, from the photograph, we can clearly see that the rash is urticarial. This raises the possibility of urticaria, or urticarial vasculitis, or even erythema multiforme. Again, a skin biopsy would be very useful. The severe palmar peeling almost seems incongruous, but it does give me faith that buried in this report there might actually be a new desquamating rash associated with methadone use. In summary, I am still not clear whether the four patients described had the same rash, but I concur with the authors that several of these patients might warrant specialist assessment. Let’s hope they get it.

Rodney D Sinclair

In reply: The purpose of our report1 was to alert the wider medical community to the recent outbreak of a “syndrome” (“a group of symptoms and signs, which, when considered together, are known or presumed to characterise a disease or lesion”2) that included the development of various forms of rash in patients taking methadone syrup. Our report included four cases illustrating the different types of rash encountered to date. From October 2004, over 400 cases were reported from methadone clinics in New South Wales, although very few new cases have been reported since February 2005, presumably reflecting the success of preventive measures instituted by the NSW Health department. To date, the cause of this methadone-associated syndrome has not been elucidated. Skin biopsies of rash lesions have been performed in a number of our patients. All have shown chronic perivascular inflammation, with most demonstrating hyperkeratosis. A small number of patients have had a true leukocytoclastic vasculitis. As Heazlewood has commented, both secondary syphilis and illicit drugs such as amphetamines and cocaine have been reported to cause vasculitic rashes. However, none of the more than 50 patients in whom we have performed syphilis serological testing has had positive results, and few of our affected methadone patients have had urine drug-test results positive for amphetamine or cocaine use. We therefore believe that the syndrome we have described remains specific to the patients’ current use of methadone syrup. We are unaware of a rash that is “an incidental manifestation of dependency”, as suggested by Sinclair, but we would assure him that specialists from a wide variety of fields, including dermatology, immunology, immunopathology, infectious diseases, addiction medicine and epidemiology, have all been involved in the assessment and treatment of patients with this syndrome, and in the wider investigation of its pathogenesis.

Jon N Currie · Lisa Snell · Elizabeth M Benson

Huy A Tran Director and Associate Professor, Department of Clinical Chemistry, University of Newcastle, John Hunter Hospital, Locked Bag No. 1, Hunter Region Mail Centre, New Lambton Heights, NSW 2310. huy.tranAThnehealth.nsw.gov.au To the Editor: The interesting article by Gordon et al1 warrants further discussion with regard to the hypophosphataemia, “inappropriately” high level of serum 25‑hydroxyvitamin D, biochemical diagnosis of pancreatitis and management of hypercalcaemia. Fibroblast growth factor-23 (FGF-23) is a recently described 254‑amino-acid peptide that has been shown to have significant phosphaturic effect. It probably plays a major role in phosphate metabolism and homeostasis by rising after an oral phosphate load and falling after dietary phosphate restriction. In the patient discussed by Gordon et al, elevated FGF-23 level may, hypothetically, have been a major contributing factor to the low serum phosphate level. Although the understanding of this factor is still in its infancy, measuring the serum level of FGF-23 in the patient might have shed more light on the role of FGF-23 in phosphate homeostasis. However, FGF-23 levels do not correlate directly with serum phosphate levels, suggesting that FGF-23 exercises control via renal tubular cells, regulation of calcitriol levels or intestinal phosphate absorption. FGF-23 levels are also markedly elevated in chronic renal failure, partly in response to the chronic hyperphosphataemia and partly because of reduced renal clearance.2 Its action is independent of the traditional and better understood regulators of phosphate level, including parathyroid hormone and parathyroid hormone-related protein. The triad of high vitamin D level, hypercalcaemia and hypophosphataemia points strongly to a diagnosis of vitamin D intoxication, despite a patient history to the contrary. An alternative explanation is an inaccurate vitamin D assay from the supporting laboratory. This issue, which has been highlighted recently, has therapeutic relevance in monitoring vitamin D replacement therapy.3 In supporting the diagnosis of pancreatitis, serum lipase level remains the best biochemical test and is more specific than amylase level.4 The practice of dual amylase and lipase ordering in the investigation of such conditions is excessive, confusing and costly to the community and should be discouraged. The indication for bisphosphonate treatment in milk-alkali syndrome remains unclear and contradicts the underlying pathogenesis, which is believed to be that of excessive calcium ingestion. In the patient in question, excessive calcium ingestion overwhelmed the calcium homeostatic mechanism, resulting in severe hypercalcaemia. In such a milieu, osteoclasts would be heavily suppressed and inhibited, and thus the use of a bisphosphonate, whose major action is also by osteoclastic suppression, would be of little value other than in precipitating hypocalcaemia.5 Thus, expectant management as outlined by the authors would be sufficient to achieve normocalcaemia. As bisphosphonates are not without adverse effects,6 they should only be used after a clear diagnosis of hypercalcaemia has been made.

Huy A Tran

Adam P Morton Physician, Mater Hospital, Raymond Terrace, Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: I read with interest the Lessons from Practice article on milk-alkali syndrome during pregnancy.1 I would like to offer the following comments. The patient’s alkalosis was in fact more impressive than presented, as the authors used the reference range for serum bicarbonate in non-pregnant patients. During pregnancy, serum bicarbonate levels typically fall by about 4 mmol/L to compensate for the respiratory alkalosis caused by elevated progesterone levels stimulating respiratory drive. Given the patient’s life-threatening calcium level on presentation, I am interested to know whether calcitonin treatment or even dialysis was considered while waiting for the pamidronate to take effect. An important aspect that the authors did not discuss in relation to this case is the reassuring data on the safety of both proton-pump inhibitors and H2-receptor antagonists in pregnancy. While there is more experience with the latter, two recent studies found no evidence of teratogenicity in almost 900 cases of exposure to proton-pump inhibitors in the first trimester.2,3 Clinicians should feel comfortable about prescribing these medications in pregnancy. After reporting a similar case,4 I wrote to Walco, the manufacturers of Quick-Eze, who subsequently changed their product labelling to include a warning about the number of tablets that could be safely taken each day. Disappointingly, they did not include a warning about ingestion during pregnancy, as I suggested.

Adam P Morton

Michelle V Gordon,* P Shane Hamblin,† Lawrence P McMahon‡ * Registrar, † Head, Department of Endocrinology, Western Hospital, Private Bag, Gordon Street, Footscray, VIC 3011; ‡ Head, Department of Obstetric Medicine, Sunshine Hospital, St Albans, VIC. hamblin1ATbigpond.net.au In reply: Our case appears to be consistent with typical milk-alkali syndrome. While measuring fibroblast growth factor-23 (FGF-23) level might have been of hypothetical interest, it is unlikely that it would have influenced management. Vitamin D intoxication was considered once the 25-hydroxyvitamin D results became available, and we closely questioned our patient in relation to this possibility. She was insistent that she had not taken any vitamin D supplements. It is possible either that the patient did not wish to admit to taking vitamin D or that the assay was misleading, as suggested by Tran. We agree that bisphosphonate therapy should not be advocated when the diagnosis of milk-alkali syndrome is clear. In this case, however, the patient was drowsy and very ill; the full history relating to antacid ingestion was not obtained until after the bisphosphonate therapy had been given. With regard to Morton’s comments, the hypercalcaemia settled promptly, so fortunately calcitonin treatment and other measures did not need to be considered. Drug safety in pregnancy is a difficult issue, as the effects of fetal or neonatal damage may carry lifelong implications, and even relatively rare associations need to be considered with care. In addition, many pregnant women are uncomfortable about taking prescription medications during pregnancy, even though their doctors may have a more relaxed view. Currently, over-the-counter antacids are classed as category A drugs for pregnancy, whereas H2-receptor antagonists and proton-pump inhibitors are category B1 and B3, respectively. Cimetidine has been associated rarely with neonatal hepatic abnormalities,1 and it is still too early to state with confidence that proton-pump inhibitors are “safe”, despite promising initial analyses. Ironically, the potential dangers of over-the-counter calcium-containing antacids, as demonstrated in this case report and others, are not currently adequately acknowledged. We have written to the manufacturers of Rennie tablets requesting a package label warning advising consumers not to exceed six tablets a day.

Michelle V Gordon · P Shane Hamblin · Lawrence P McMahon

Ray Kernutt was born on 2 September 1926 in the small town of Wagin, south of Perth. At the age of 10, he won a scholarship to attend a prestigious school in Perth, but went instead to a public school at Albany, where his sister at boarding school was able to look after him. After matriculation, he studied science at Perth University before winning a scholarship to study medicine at the University of Melbourne. He graduated with honours in 1949. Over the next few years, Ray gained his Master of Surgery and Fellowship of the Royal Australasian College of Surgeons while working as a Hospital Medical Officer at the Royal Melbourne Hospital. He gained his Fellowship of the Royal College of Surgeons in London in 1955, but cut short his postgraduate position as Surgical Registrar to return to Australia. In 1956, he was appointed founding Senior Surgeon at the new surgical unit at Box Hill Hospital, Melbourne, a position he held until retirement. Ray was no stranger to rural surgery. Having attained a commercial pilots licence in 1963, he offered a surgical service to doctors in Apollo Bay and Tocumwal. He was also absorbed in breeding cattle on his 200 acre farming property at Whittlesea. On retirement from public hospital surgery and a busy private practice, Ray became bored with a life of relaxing and playing golf and was drawn to the prospect of rural general practice. He joined a practice in the small town of Cohuna, and, although by then in his 70s, diligently revived his medical skills to become knowledgeable about diabetes, hypertension and respiratory medicine. His undiminished skill, judgement and speed in surgery were also much valued by his colleagues. Ray also came out of retirement on several occasions to provide lengthy locums at other locations where there was an acute shortage of doctors (eg, Christmas Island, Nauru and Castlemaine). It was fitting that he served his last active service in Cohuna before reluctantly retiring due to ill health and failing eyesight. Ray was set apart from his colleagues, not only because of his superb technique and speed — a “surgeon’s surgeon” — but also as a dedicated rural GP. In 2002, he was presented with the first Honorary Fellowship of the Australian College of Rural and Remote Medicine. His last illness was short and unexpected, following complications of vascular investigations. He died on 27 September 2004, and is survived by his second wife, Jillian, and children Graeme, David, Gillian, Paul and Jonathon. Peter W Graham

Peter W Graham

Fast Facts: Smoking cessation. Robert West and Saul Shiffman. Oxford: Health Press, 2004 (78 pp). ISBN 1 903734 42 8. This is, quite simply, This is, quite simply, a terrific little book. Written by two highly respected figures in the field, it is a fount of evidence-based wisdom. It should be on the bookshelves of every health professional who counsels smoking cessation, or who wants to be well informed. The writing style is very approachable and the synthesis of the material is, for the most part, masterful. It provides a great summary of the main health effects and benefits of quitting. There are figures here that should motivate smokers to think about quitting: half of all long-term smokers who die lose 16 years of life on average; put another way, all smokers lose an average of 8 years of life. In addition, disability sets in 12 years earlier than for non-smokers. I compute this to be, on average, 4 more years of disability-affected life. West and Shiffman also clearly and concisely set out the best path to cessation — behavioural help augmented with pharmacotherapy — with useful hints for helping smokers quit. There is a good explanation of why it is worth health professionals persisting with encouraging cessation, even though, on any one piece of advice, very few clients will eventually quit. The authors also wisely counsel against too much pushing, suggesting annual review (unless a smoker opts to follow up). There were only three things in the book with which I had any serious disagreement. Firstly, I think the authors over estimate the benefits of bans on smoking as a means of encouraging smokers to quit. Secondly, they suggest that the greater incidence of smoking among low socioeconomic groups in many Western societies is due to a deficit of skills. I think it is due partly to less access to compelling information and, for some, the competing priorities of lives out of control or lacking in essential rewards. Finally, they assert that virtually all slip-ups end in relapse. While most do, relapse is far from inevitable, and the danger in assuming relapse will occur is that this may become a self-fulfilling prophecy. However, these quibbles, important as they are, do not distract overly from the utility of the book. Every health worker should have some capacity to help smokers quit, even if only in knowing useful referral sources. This book is a fantastic resource. Ron BorlandNigel Gray Distinguished Fellow in Cancer Prevention, The Cancer Council Victoria, VIC

Ron Borland

Rapid Refererence: Influenza. Jan Wilschut, Janet E McElhaney. London: Mosby, 2004 (viii + 216 pp). ISBN 0 7 234 3385 2. Culminating in the 2004 South-East Asian H5N1 outbreak, successive clusters, since 1997, of human infection with highly pathogenic avian influenza strains, have underscored the enormous potential public health threat posed by influenza, and the pressing need for effective control. The theme of this book is the growing threat from an influenza pandemic. It includes reference to events up to mid-2004 in Asia, which gives it a topical feel despite the familiarity of much of the subject matter. The book is constructed along traditional lines, with chapters on virus structure and replication, antigenic drift and shift, the immune response, pathogenesis, clinical features and diagnosis, social and economic impact, vaccination, treatment and prophylaxis, and novel developments in influenza control. There is much to like about this little book. It provides an extremely concise, yet thorough, and generally well balanced overview of influenza. The content is factually accurate, and it is very well referenced. The presentation is attractive and engaging with lots of well executed graphics and tables, and lists of key messages for each chapter presented in sidebars. The authors, an infectious diseases physician and a molecular virologist, have each published extensively on influenza-related topics. However, although the stated target audience is the general practitioner, the book covers rather more virology and immunology than would probably interest most readers, while combining pathogenesis, clinical presentation and laboratory diagnosis in a single chapter. At one and a half pages, the coverage of laboratory diagnosis in particular is a little sketchy. Vaccination and therapy are covered in greater depth in individual chapters. This book could be thoroughly recommended to anyone interested in an approachable and up-to-date concise overview of influenza. However, the relative brevity of the coverage of presentation and diagnosis might diminish its attraction to a general practitioner readership. Michael G CattonDirector Victorian Infectious Diseases Reference Laboratory Melbourne, VIC

Michael G Catton

An 81-year-old woman was fitted with a single-chamber pacemaker for atrial fibrillation and symptomatic bradycardia (Microny SR 2425T, Pacesetter, Sylmar, Calif, USA; silicone lead 1402 T, Siemens, Sylmar, Calif, USA). Seven years later, she presented with fatigue and presyncope of 1 week’s duration. She had also noticed contractions of the pectoral muscles on the left side of the chest. An electrocardiogram (Box 1) showed evidence of ventricular undersensing and non-capture, and a chest x-ray (Box 2) revealed complete fracture of the pacemaker lead. The pacemaker was replaced, and a new lead implanted using the cephalic vein cutdown approach. The patient’s medical record indicated that, 8 months previously, when she developed a cough, a chest x-ray had been performed by her physician. At around the same time, a routine check of the function of her pacemaker indicated that it was functioning normally. Re-examination of the x-ray revealed signs of lead erosion (Box 3) which had gone unnoticed. Thus, despite significant damage to the lead, pacemaker function may be unaffected. Friction of the lead, most often against the clavicle and the first rib (known as subclavian crush) can damage the lead. The incidence of fracture of pacemaker leads is about 1.0%–2.5% and increases with the age of the lead.1 A way of avoiding this complication is to introduce the lead into the axillary or cephalic vein rather than via subclavian vein puncture.2,3 Routine chest x-rays should be performed to monitor the condition of pacemaker leads, especially where they cross the clavicle. We recommend an annual chest x-ray for pacemaker-dependent patients. This may identify lead damage that may not be apparent during a standard pacemaker check, and thus, potentially, avoid syncope or sudden death. 1 Electrocardiogram on admission showing pacing spikes with evidence of ventricular undersensing and non-capture 2 Chest x-ray on admission showing complete section of the pacemaker lead at the level of the clavicle 3 Chest x-ray performed 8 months before admission, showing evidence of lead damage that went unnoticed

Stephane L Noble MD · Haran Burri MD · Henri Sunthorn MD

This year marks the 60th anniversary of the end of World War II. The following poem pays tribute to those who carry the legacy of that war. Thus we seeThe memories of war are embodied forever. I wrote this poem some months after a 65-year-old man consulted me in the mid-1980s complaining of a band of chest pain that two cardiologists had investigated without diagnosis. As a Polish prisoner-of-war in World War II, he had been enslaved in a German coalmine, starved and inadequately clothed. He described to me how, as winter progressed, he and his fellow prisoners would wire the decaying pieces of their clothes together. His shirt was reduced to a band of fabric around the middle of his chest. His current chest pain was in the same anatomical zone as that covered 45 years before by the remnants of his shirt. Thus we see and sew and save the triangular, square or without form, coloured bits of fabric that keep us warm. Thus we see the landscape under snow, “the infected winter of our condition”, and in seeing, know. Thus we sew, as freezing prisoners of war, the remnants of the clothes we wear, Dole. Too rough: thread of repair is not enough to make us whole. Thus we save, as lining for our trap, flotsam rescued from the wave, the storm, from life’s enthralling compromise — worn and wet rags to fill the gap — we have only man’s eyes.

Stephen Leeder AO

CorrectionRe: “Point-of-care testing of HbA1c and blood glucose in a remote Aboriginal Australian community” in the 16 May 2005 issue of the Journal (Med J Aust 2005; 182: 524-527). The authors of this article have requested that Max K Bulsara (School of Population Health, University of Western Australia; and Centre for Child Health Research, University of Western Australia, Telethon Institute of Child Health Research, Subiaco, WA) be included as an author. The corrected list of authors is David D Martin, Mark D S Shephard, Hayley Freeman, Max K Bulsara, Timothy W Jones, Elizabeth A Davis, Graeme P Maguire. The online version of this article (html and pdf) was corrected on 27 May 2005.

David D Martin MB BS, PhD · Timothy W Jones DCH, FRACP · Elizabeth A Davis FRACP · Mark D S Shephard MSc, MAACB · Hayley Freeman RN · Graeme P Maguire MPHTM, FRACP, PhD

Quid pro quo Australian researchers have suggested that any extra life gained by healthy, elderly people using low-dose aspirin is just as likely to be lost through related adverse events. Nelson and colleagues used epidemiological modelling to simulate the broad implications of routine low-dose (75–150 mg) aspirin use in a hypothetical Victorian population of 10 000 men and 10 000 women, aged 70 years or older, all without overt cardiovascular disease. Calculating health outcomes by applying available evidence, they found that the prevention of 721 myocardial infarctions and 54 ischaemic strokes would be offset by excess episodes of serious bleeding — 1071 gastrointestinal and 130 intracranial. However, they acknowledged that due to statistical uncertainty, this balance could, in reality, tip either way — towards harm or benefit. A randomised controlled trial in elderly people could help settle the matter. BMJ Online First 20 May 2005 (www.bmj.com) Dementia linked to obesity Mid-life overweight and obesity increase the risk for dementia in later life, according to US researchers. They followed a large multi-ethnic cohort of 5564 women and 4712 men aged 40-45 years who underwent detailed health evaluations at the start of the study. At the conclusion of follow up — an average of 27 years later — dementia had been diagnosed in 713 participants. Compared with people of normal weight in mid-life, people who were obese in mid-life were 75% more likely to have dementia; and overweight people were 35% more like to have dementia. This increase in risk was most marked in women, and could not be explained by the presence of common co-morbidities, such as diabetes and hypertension. BMJ Online First 16 May 2005 (www.bmj.com) Death by breastfeeding? Sudden infant death is a potential, albeit extremely rare, complication of breastfeeding, say US authors. They reported two cases of male infants, aged 5 and 6 weeks, who died while their mothers were breastfeeding them. Both mothers were distracted at the time of infant death — one was shopping, and the other was watching a movie in a cinema. Given that pre-mortem evaluation and post-mortem examination revealed no abnormality in the infants, the authors concluded their deaths were caused by oronasal obstruction associated with breastfeeding. J Paediatr Child Health 2005; 41: 215-217 No more Misters? With the rise of non-medically qualified surgical care practitioners in the UK, the president of the Royal College of Surgeons of England, Mr Hugh Phillips, has suggested that there may be a good case for surgeons to use the title of "doctor" — principally so that patients will know whether the person treating them is a doctor, or not.1 The tradition of addressing a surgeon as Mr (or Miss) is thought to have its origin in the days of the unqualified barber surgeons, becoming a symbol of status when the Royal College of Surgeons of London was set up in 1745.2 1. Ann R Coll Surg Engl (Suppl) 2005; 87: 153 2. BMJ 2005; 330: 1103 Asleep on the job? Australian editorialists, Grunstein and Rogers, say that there is evidence of a harsher legal climate for doctors who continue to work despite sleep loss — just as society and the law is tiring of dangerous drivers escaping punishment due to "fall asleep" defences. Falling asleep behind the wheel, in most cases, is now recognised as being foreseeable, avoidable and an act of recklessness. In fact, since 2003, a US state law known as "Maggie’s Law" has held that causing the death of another person in a motor vehicle accident after driving without any sleep in the previous 24 hours is a criminal offence. Grunstein and Rogers believe that unless senior medical staff review their own work hours and those of their on-call registrars, it will be only a matter of time before there will be a Maggie’s Law for doctoring. Intern Med J 2005; 35: 269-271 Predicting sudden death A man’s heart-rate profile during exercise and recovery could help predict his risk of sudden death, according to French researchers. They conducted exercise testing in a cohort of 5713 asymptomatic men, enrolled in the Paris Prospective Study I, aged 42-53 years. Over a 23-year follow-up period, 81 subjects died suddenly. The risk of sudden death was increased in subjects with a higher resting heart rate (> 75 beats per minute), a smaller increase in heart rate during the exercise, and a smaller drop in heart rate after stopping the exercise test. The researchers say their findings are consistent with the idea than an underlying autonomic nervous system imbalance predisposes such subjects to life-threatening cardiac arrhythmias. They suggest that regular exercise training may help to prevent sudden death in those at risk, by shifting autonomic balance through an increase in vagal activity. N Engl J Med 2005; 352: 1951-1958 Dr Ann Gregory, MJA

Ann Gregory