Improved understanding of the regulation of body weight and activity is leading to new treatment strategies

Joseph Proietto FRACP, PhD · Louise A Baur FRACP, PhD

Objectives: To document diagnosis rates of type 2 diabetes mellitus in children and adolescents in Western Australia over the past 12 years, the clinical characteristics of these patients and any comorbidities.Design: Review of a prospectively recorded diabetes database.Setting: Tertiary paediatric referral centre (the only such centre in WA).Patients: All children and adolescents aged < 17 years diagnosed with type 2 diabetes between 1990 and 2002 and managed by Princess Margaret Hospital Diabetes Unit.Main outcome measures: Anthropometric and demographic data; glycohaemoglobin (HbA1c) level; blood pressure; lipid levels; presence of acanthosis nigricans.Results: 43 patients (15 males and 28 females) were diagnosed with type 2 diabetes. Age (SD) at diagnosis was 13.6 (1.8) years. The rate of diagnosis has been progressively increasing (average annual increase in the unadjusted overall rates of type 2 diabetes was 27%). Twenty-three patients (53%) were of Indigenous origin and 18 (42%) resided in rural areas. The mean (SD) HbA1c level at diagnosis was 10.0% (3.2%). Seventy-two per cent of patients had acanthosis nigricans, 59% had hypertension, and 24% had hyperlipidaemia.Conclusions: There has been an increase in the diagnosis rate of type 2 diabetes in children and adolescents in WA. Comorbidities are frequent.

Sarah K McMahon MB BS(Hons) · Aveni Haynes MB BChir · Nirubasini Ratnam BSc(Hons), RN · Maree T Grant RN · Christine L Carne PGRN(Paed) · Timothy W Jones FRACP · Elizabeth A Davis FRACP

Mark Little,* Peter L Pereira,† Richard Mulcahy,‡ Teresa Carrette,§ Jamie Seymour¶ * Emergency Physician, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009. † Director, ‡ Emergency Physician, Cairns Base Hospital, Cairns, QLD. § Research Officer, ¶ Senior Lecturer, Department of Tropical Biology, James Cook University, Cairns, QLD. Mark.littleAThealth.wa.gov.au To the Editor: We are concerned that a recent report announced that the Queensland Ambulance Service now treats patients with hypertension caused by Irukandji syndrome with sublingual glyceryl trinitrate, based on an uncontrolled, unrandomised, unblinded “trial” of three patients.1 We believe the authors have made the justification for such treatment on questionable assumptions. The authors claim that venom from Carukia barnesi is a sodium channel agonist that causes massive noradrenaline release. This claim is based on a letter which reported whole C. barnesi being crudely blended and injected into piglets.2 There is no mention in this letter of any proven sodium channel agonist action.2 We are unconvinced that it was solely the venom of the jellyfish that resulted in a rise in noradrenaline levels in the piglets, especially since there has been a recent report of toxicity from homogenised jellyfish with the nematocysts (ie, venom) removed.3 While we believe that magnesium may be a promising treatment for patients with Irukandji syndrome, there has only been one case reported,4 and we are aware of several anecdotal failures, including the first patient in the letter by Fenner and Lewin.1 This does not constitute the justification for “proven effective treatment”. Fenner and Lewin claim that patients were envenomed by Carukia barnesi and yet provide no evidence. Carukia barnesi has yet to be discovered or reported south of Townsville. Two of us have reported that more than one jellyfish is responsible for Irukandji syndrome, and a second jellyfish has recently been identified.5 Accurate identification of the envenoming animal is essential in toxinology. Patients who present with Irukandji syndrome are in severe pain, and pain is a well known cause of hypertension. In a series of 116 patients with Irukandji syndrome, the mean dose of morphine administered was 31 mg.6 In the three patients reported by Fenner and Lewin, all were in severe pain, but only received 10 mg of morphine. In light of subtherapeutic analgesia, attributing the persistent hypertension solely to an unmanageable disease process is therefore premature and possibly incorrect. As a further confounder, might the reduction of blood pressure in two patients have resulted from the delayed onset of action of intramuscular morphine and promethazine? Without the addition of control patients to this trial, no conclusions can be drawn on the causative factors associated with this treatment. Too often in the past, unsupported treatments have been adopted, only to be abandoned several years later when shown to be ineffectual, or even dangerous to patients. There are too many assumptions, unsupported claims and confounders in Fenner and Lewin’s letter. Toxinology research needs good science and not poor anecdotes.

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

Richard J G Bonham Medical Director, Queensland Ambulance Service, PO Box 1425, Brisbane, QLD 4001. rbonhamATemergency.qld.gov.au Comment: I would like to clarify a few points. Firstly, all Queensland Ambulance Service (QAS) paramedics use glyceryl trinitrate (GTN) frequently to treat cardiac chest pain, and have done so for many years. They are very familiar with its effects and interactions. Secondly, a small number of intensive care paramedics (ICPs), the top tier of officer, with many years of training and experience and tertiary qualifications, have, for a number of years, been authorised to consult with the senior doctor at the receiving hospital for use of GTN to treat acute severe hypertension. In Queensland, GTN has been used for this indication in one or two patients per year, compared with its use in 25 000 patients with cardiac chest pain. Finally, QAS reviewed its protocol for managing marine envenomation after two people died from Irukandji syndrome two years ago. The current protocol for suspected Irukandji stings is now standard care, including oxygen, and vinegar if there is a visible sting, followed by aggressive pain management, including up to 30 mg of morphine intravenously. If the patient has significant hypertension (> 200/120 mmHg) after effective analgesia, ICP officers are able to consult with a senior doctor to administer GTN according to the above protocol. Obviously, the concern of the QAS Medical Advisory Council (comprising representatives of all medical specialty colleges and other medical groups) was to prevent avoidable cerebral haemorrhage or acute heart failure, as occurred in the two deaths from Irukandji syndrome, but, to date, such use of GTN has not been invoked.

Richard J G Bonham

Aspects of diabetes If Australia follows in the footsteps of other developed countries, we can expect that our children will fall victim to obesity and some of its complications. McMahon et al have looked back over the past 12 years at children presenting with type 2 diabetes in Western Australia. (→ Increase in type 2 diabetes in children and adolescents in Western Australia) National statistics are yet to be released, but the news is not good. As the use of metformin to treat type 2 diabetes has grown, the question of its use in pregnancy has also arisen. In “Metformin therapy and diabetes in pregnancy”, Simmons et al present an update from an Ad Hoc Working Party of the Australasian Diabetes in Pregnancy Society, which might help you decide when the benefits of this drug outweigh the risks. More fat This chapter of MJA Practice Essentials: Endocrinology by Proietto and Baur gives timely advice on the different management strategies for obesity (→ 10. Management of obesity). These involve the tried and true, as well as newer treatments on the horizon. Correspondents' corner Previous MJA articles (on travel insurance and overseas evacuation, and prehospital treatment of Irukandji syndrome) drew a flurry of responses (→ Sublingual glyceryl trinitrate as prehospital treatment for hypertension in Irukandji syndrome). We also have original reports of the relationship between the El Niño Southern Oscillation Index and hepatitis A transmission (→ El Niño Southern Oscillation and the transmission of hepatitis A virus in Australia), and of murine typhus infection in Victoria (→ Murine typhus: the first reported case from Victoria). Exercise your fatigue A randomised controlled trial of graded exercise (aerobic activity of the larger muscles) with “pacing” (varying duration of exercise with symptoms) shows the value of this treatment for people with chronic fatigue syndrome (CFS). Wallman and colleagues found that such activity improved physical work capacity, mood and cognition (→ Randomised controlled trial of graded exercise in chronic fatigue syndrome). This study adds to the evidence that such exercise should be the cornerstone for CFS treatment, says Lloyd in his editorial (→ To exercise or not to exercise in chronic fatigue syndrome? No longer a question). It’s not a cure, but it will at least improve quality of life while awaiting recovery. Out with guesstimates How well did Australian and English doctors do when asked to estimate the patient’s risk of disease in three clinical scenarios? Turn to the report of this survey by Attia et al to find out (→ Generating pre-test probabilities: a neglected area in clinical decision making). A fair bit does ride on our ability to estimate disease likelihood, says Scott (→ Estimating disease likelihood: a case of rubbery figures), as this determines our management approach. So, roll out the validated decision aids, avoid those vague rules of thumb, and let’s get closer to the mark! A grand IDEA When staff at a Melbourne hospital decided that spending the equivalent of 3 weeks a year on the phone for antibiotic approvals was way too much, they came up with IDEA3S (infectious diseases electronic antibiotic advice and approval system). Grayson and colleagues evaluate their computer-based system on (→ Impact of an electronic antibiotic advice and approval system on antibiotic prescribing in an Australian teaching hospital). Aching for a diagnosis The patient described by Rando et al has myalgia, hypercholesterolaemia (on atorvastatin), BMI of 32 kg/m2 (and rising), and CK level of nearly 5000 IU/L (→ Successful reintroduction of statin therapy after myositis: was there another cause?). What’s his diagnosis? You do the maths . . . Snowy Snapshot From the Indian subcontinent comes a case of a man with a cough, fever, respiratory signs and a striking x-ray. Bhalotra et al share the details of this patient’s rare condition (→ A pulmonary snowstorm). Change isn't progress This issue’s Postcard from the UK charts the most recent attempts to modernise Britain’s NHS. Believe it or not, say our UK correspondents, Australians may actually be better off than the Brits (→ Modernisation or reform? The NHS approach). Upping the anti How much anticoagulation should we aim for when treating recurrent thrombosis due to antiphospholipid antibody syndrome? Baker’s editorial applies the results of recent randomised trials to real life (→ Prevention of recurrent thrombosis in the antiphospholipid antibody syndrome: how long and how high with oral anticoagulant therapy?). Decision by subanalysis In this instalment of EBM: Trials on Trial, Simes and colleagues give a practical approach to interpreting and using subgroup analyses (→ Subgroup analysis: application to individual patient decisions). Peat and Naughton dissect a trial assessing how high-impact exercise affects the bone mineral content of prepubertal girls (→ Does high-impact exercise in the prepubertal period have an osteogenic effect in females?). Another time ... another place... Mind you, that you have a sound scientific theory to correlate your observations at the bedside. Mere experience by itself is nothing. If I take my dog to the bedside with me, he sees what I see. But he learns nothing from it. Why? Because he’s not a scientific dog. The Doctor’s Dilemma, act 1, 1913 George Bernard Shaw

Unravelling the uncertainties The antiphospholipid antibody syndrome is an autoimmune disease that commonly presents with either venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism), arterial thrombosis (ischaemic stroke, coronary thrombosis, peripheral arterial occlusion) or unexplained fetal loss. A high index of suspicion for the diagnosis is raised in patients with unusual thrombosis, those without obvious risk factors, or those who experience recurrent events. The diagnosis is based on presentation with one of the above clinical criteria and detection in the laboratory of persistent antiphospholipid antibodies. Clinically relevant antiphospholipid antibodies are identified by either functional coagulation assays (lupus anticoagulant) or immunoassays (anticardiolipin antibody, β2-glycoprotein-1 antibody).1,2 When considering the diagnosis of the antiphospholipid antibody syndrome, it is important to perform both clotting and serological tests, as they are concurrently positive in 50% of unequivocal cases.3 The detection of a lupus anticoagulant and/or medium- to high-titre IgG antiphospholipid antibodies is associated with an approximately 10-fold increase in risk of VTE.4,5 Unlike the treatment for other autoimmune disorders, anticoagulation rather than immunosuppression is the mainstay of treatment.1-3 About 40 000 tests for thrombophilia are performed in Australia each year . . . Why are we performing these tests? Significantly elevated levels of antiphospholipid antibodies are detected in up to 20% of patients with VTE, compared with only 2% of healthy adults.6 This means that clinicians will be frequently asked to make decisions based on positive antibody test results. With about 40 000 tests for thrombophilia performed in Australia each year,7 the question arises as to the impact of testing for antiphospholipid antibodies in clinical practice. Why are we performing these tests? Up to now the reason has been twofold. Firstly, there is a perception that there is a high risk of recurrent thrombotic episodes, and even death, when anticoagulation treatment is stopped in people with antiphospholipid antibodies. Several retrospective studies have suggested that treatment with warfarin should be continued for at least 12 months, if not longer or lifelong, as up to 70% of patients will have recurrent events without ongoing treatment.8,9 For patients with arterial occlusion, particularly those without other atherosclerotic risk factors (eg, smoking, diabetes, hyperlipidaemia, hypertension), recurrence of thrombosis from significant levels of antiphospholipid antibodies would be catastrophic. For such patients, anticoagulation is usually continued. For patients with VTE and no obvious risk factors, testing of antibody levels may help to resolve the current uncertainty about the optimal duration of anticoagulation treatment and may even help to determine whether anticoagulation should be stopped at all. In a multicentre study, 412 patients were prospectively followed after a first episode of VTE: within 4 years after ceasing warfarin, 29% of patients with IgG anticardiolipin antibodies had experienced further events, compared with 14% without antibodies.6 However, maintaining people on long-term warfarin therapy carries the inevitable risk of serious haemorrhage (1.1 events/100 patient-years) and anticoagulant-related death (0.25 deaths/100 patient years).10 If we had further data on the optimal duration of anticoagulation treatment, we would be in a better position to discuss with patients the risk versus benefit of ongoing treatment. The second reason for determining the presence of antiphospholipid antibodies is that it assists in deciding the optimal intensity of anticoagulation treatment. There is evidence from retrospective case series that recurrence of thrombotic episodes can occur even with moderate-intensity warfarin therapy (target international normalised ratio [INR], 2.0–3.0) when compared with higher-intensity therapy (target INR, 3.0–4.5).8,9 However, this information comes from specialised expert clinics for high-risk patients, and to generalise the findings to a large number of VTE patients without better evidence is problematic. The cost of having a higher INR (3.0–4.4 rather than 2.0–2.9) is the doubling of the risk of any bleeding event.10 A recent prospective randomised controlled trial on the efficacy and safety of high-intensity warfarin treatment (target INR, 3.0–4.0) versus standard-intensity treatment (target INR, 2.0–3.0) in 114 patients with arterial thrombosis and VTE with antiphospholipid antibodies attempted to address this uncertainty.11 The results of the trial showed that there was no difference in the rates of recurrent thrombosis and bleeding between the two groups. Although the confidence intervals were wide because the number of events was small, the study does give some guidance regarding treatment decisions for the majority of patients with thrombosis and antiphospholipid antibodies. However, there are several caveats: Patients were included after already receiving warfarin for variable periods of time, and only a third of patients were allocated to one of the trial groups within 6 months of thromboembolism. This means that patients who were at highest risk of recurrence or bleeding while on warfarin were excluded; Patients who already had recurrent thrombosis while receiving warfarin with a target INR > 2.0 were specifically excluded; Control of INR range was supervised by expert clinic staff, who kept INRs within range 70% of the time for the standard-intensity arm and 40% of the time for the high-intensity arm. Most of the patients out of the INR target range in the high-intensity group were below the therapeutic range. Whether this degree of control for a given target INR is achieved in everyday practice is uncertain and needs further validation. It highlights the difficulty of maintaining a narrow therapeutic target INR range with warfarin despite the best intentions. Given the limitations of the published studies, the clinician is still faced with uncertainty in dealing with patients with thrombosis and antiphospholipid antibodies. For most people with thrombosis and antiphospholipid antibodies, long-term standard-intensity warfarin with a target range INR 2.0–3.0 may be appropriate. However, there will still be patients with extensive or unusual thrombosis for whom higher-intensity anticoagulation treatment could be considered. This situation applies particularly to people in whom recurrence may be threatening to life, limb or organ, particularly when no other recognised risk factor for either VTE or atherothrombosis can be removed or modified. To reliably answer the question of how to manage patients with thrombosis and a significant level of antiphospholipid antibodies would require an inception cohort study, with patients randomised at diagnosis to different intensities of anticoagulation treatment.

Ross I Baker MB BS, FRACP, FRCPA

Objective: To assess the accuracy and variability of clinicians’ estimates of pre-test probability for three common clinical scenarios.Design: Postal questionnaire survey conducted between April and October 2001 eliciting pre-test probability estimates from scenarios for risk of ischaemic heart disease (IHD), deep vein thrombosis (DVT), and stroke.Participants and setting: Physicians and general practitioners randomly drawn from College membership lists for New South Wales and north-west England.Main outcome measures: Agreement with the “correct” estimate (being within 10, 20, 30, or > 30 percentage points of the “correct” estimate derived from validated clinical-decision rules); variability in estimates (median and interquartile ranges of estimates); and association of demographic, practice, or educational factors with accuracy (using linear regression analysis).Results: 819 doctors participated: 310 GPs and 288 physicians in Australia, and 106 GPs and 115 physicians in the UK. Accuracy varied from about 55% of respondents being within 20% of the “correct” risk estimate for the IHD and stroke scenarios to 6.7% for the DVT scenario. Although median estimates varied between the UK and Australian participants, both were similar in accuracy and showed a similarly wide spread of estimates. No demographic, practice, or educational variables substantially predicted accuracy.Conclusions: Experienced clinicians, in response to the same clinical scenarios, gave a wide range of estimates for pre-test probability. The development and dissemination of clinical decision rules is needed to support decision making by practising clinicians.

John R Attia MD, PhD, FRCPC · David W Sibbritt PhD · Ben D Ewald BMed, MMedSci · Balakrishnan R Nair FRCP, FRACP · Neil S Paget MA, DipEd · Rod F Wellard MEd, PhD · Lesley Patterson · Richard F Heller MD, FRCP

Geoffrey K Isbister Toxicologist, and Consultant Clinical Toxicologist, NSW Poisons Information Centre, Newcastle Mater Misericordiae Hospital, Locked Bag 7, Hunter Region Mail Centre, NSW 2310. gsbiteATferntree.com To the Editor: Fenner and Lewin describe three cases of Irukandji syndrome in which glyceryl trinitrate (GTN) was used to transiently lower blood pressure.1 However, they provide no evidence that this relieved the patients’ pain or improved their ultimate outcome (development of pulmonary oedema or myocardial injury); they therefore do not show sufficient evidence for instituting such therapy. It is worrying that, with little evidence, sublingual GTN is now recommended as a prehospital treatment in Irukandji syndrome. Although GTN has been used safely in other conditions, its use without adverse effects in three patients is not evidence that it can be used safely in treating jellyfish envenoming. It is of concern that the treatment of bites and stings remains based on anecdotal evidence, and that clinical toxinology has not moved with the rest of medicine to developing evidence-based approaches. Fenner and Lewin state, in their second paragraph, that intravenous magnesium has proven to be effective in treating symptoms of Irukandji syndrome. This is based on a single case report and no controlled trials. It simply provides a starting point so that properly designed studies can be done to determine if magnesium is effective and safe in Irukandji syndrome. It is not appropriate to suggest that magnesium is a proven therapy without further investigation. Are we not learning from previous problems in clinical toxinology and prehospital care? Both are areas of medicine where treatment protocols are rarely based on substantial evidence.2,3 The pressure immobilisation bandage was introduced for the first-aid treatment of Chironex fleckeri stings with no supporting evidence, and it has taken two well designed animal studies to show that this is dangerous.4,5 A recent well designed study in the United States showed that prehospital intubation by paramedics of patients with head injury resulted in transient desaturation in 57% of patients and significant bradycardia (< 50 bpm) in 19%.6 This occurred despite the paramedics describing the intubation as “easy” in 84% of the patients who desaturated. This shows that it is essential to properly evaluate the safety and efficacy of treatments before recommending them for prehospital use. Although the infrequency of many envenoming syndromes makes controlled studies difficult to do, it is essential that clinical investigators collaborate to institute such studies. This is now happening in Australia with the commencement of randomised controlled trials on redback spider antivenom, magnesium in Irukandji syndrome and hot-water first-aid in jellyfish stings. Hopefully we will move from anecdote to evidence in clinical toxinology with collaborative studies such as these.

Geoffrey K Isbister

Objective: To evaluate changes in quality of in-hospital care of patients with either acute coronary syndromes (ACS) or congestive heart failure (CHF) admitted to hospitals participating in a multisite quality improvement collaboration.Design: Before-and-after study of changes in quality indicators measured on representative patient samples between June 2001 and January 2003.Setting: Nine public hospitals in Queensland.Study populations: Consecutive or randomly selected patients admitted to study hospitals during the baseline period (June 2001 to January 2002; n = 807 for ACS, n = 357 for CHF) and post-intervention period (July 2002 to January 2003; n = 717 for ACS, n = 220 for CHF).Intervention: Provision of comparative baseline feedback at a facilitative workshop combined with hospital-specific quality-improvement interventions supported by on-site quality officers and a central program management group.Main outcome measure: Changes in process-of-care indicators between baseline and post-intervention periods.Results: Compared with baseline, more patients with ACS in the post-intervention period received therapeutic heparin regimens (84% v 72%; P < 0.001), angiotensin-converting enzyme inhibitors (64% v 56%; P = 0.02), lipid-lowering agents (72% v 62%; P < 0.001), early use of coronary angiography (52% v 39%; P < 0.001), in-hospital cardiac counselling (65% v 43%; P < 0.001), and referral to cardiac rehabilitation (15% v 5%; P < 0.001). The numbers of patients with CHF receiving β-blockers also increased (52% v 34%; P < 0.001), with fewer patients receiving deleterious agents (13% v 23%; P = 0.04). Same-cause 30-day readmission rate decreased from 7.2% to 2.4% (P = 0.02) in patients with CHF.Conclusion: Quality-improvement interventions conducted as multisite collaborations may improve in-hospital care of acute cardiac conditions within relatively short time frames.

for the CHI Cardiac Collaborative*

Pituitary adenomas are found in 10%–25% of unselected autopsy series and are evident in about 10% of asymptomatic individuals by magnetic resonance imaging. Diagnosis of pituitary disorders is often delayed by lack of awareness and the subtlety of symptoms and signs. Hypopituitarism is suspected when peripheral hormone concentrations are low without an elevation in the corresponding pituitary tropic hormone(s). Severe adult-onset growth-hormone deficiency results in reduced muscle mass, increased fat mass and diminished quality of life, which are reversed by growth hormone replacement therapy. While trans-sphenoidal surgery remains first-line treatment for acromegaly, drug treatment has an important role in controlling residual growth-hormone excess and, in some circumstances, as first-line treatment. Dopamine-agonist therapy (cabergoline or bromocriptine) is the treatment of choice for micro- and macroprolactinomas. In patients with suggestive clinical features, elevated 24-hour urine free cortisol level is usually sufficient to diagnose endogenous Cushing’s syndrome; careful additional investigation is needed to determine whether the cause is Cushing’s disease (pituitary adenoma secreting adrenocorticotropic hormone [ACTH]), ectopic ACTH secretion or adrenal disease.

David M Hurley PhD, FRACP · Ken K Y Ho MD, FRACP