Significant similarities between the challenges of lung transplantation in patients of all ages should lead to better access to this life-saving surgery for children and adolescents Lung transplantation (LTx) is firmly established as a therapy for end-stage lung and pulmonary vascular diseases in patients aged over 18 years and into the seventh decade of life.1,2 However, for those under the age of 18, be they child or adolescent, the role of LTx is less clear.3,4 In Australia, this has contributed to a perception that the risk of undertaking LTx in children and adolescents does not warrant the reward. Indeed, presently in this country, there is no major paediatric hospital offering a lung transplant program, likely recognising the complexity of treating such patients coupled with the potential risk of achieving poor results with a low case load — the reality is that the projected case numbers will only be of the order of four to eight per year across Australia and New Zealand. Thus, by focusing on successful LTx outcomes for an adolescent population, the article by Morton and colleagues in this issue of the Journal5 highlights a number of the key issues regarding the efficacy and utility of LTx for younger Australians (→ Successful lung transplantation for adolescents at a hospital for adults). Although adolescence refers to a transitional state from childhood to adulthood, patients 15 years and younger are generally excluded from adult hospitals and those 18 years and above excluded from paediatric hospitals. Two-thirds of the patients in the study by Morton et al could have been “routinely” treated in adult hospitals. Notwithstanding this limitation, the report gives important insight into the issues, experience and successful outcomes that can be achieved in younger lung transplant recipients. From this article, it is apparent that in Australia, a well developed, large adult LTx unit is able to use its highly specialised services to overcome some of the problems and deficiencies that can limit a stand-alone service for such a small population as children and adolescents requiring LTx. However, the age of any potential Australian lung transplant recipient is critically important — at this time, this technology is not being routinely offered to younger children. Indeed, at present, Australia’s youngest ever lung transplant recipient was aged 9 years at the time of LTx.6 The improved outcomes for LTx now described in adolescents5 should provide an impetus to provide access for younger potential LTx recipients. In looking to achieve this advance, we need to keep in mind that the transplant recipient’s age can matter in several different ways. Fortunately, severe lung disease warranting consideration of LTx in children and adolescents is relatively rare, although interestingly, it does have a bimodal distribution. The International Society for Heart and Lung Transplant (ISHLT) Registry 2005 paediatric report notes about 65 procedures performed worldwide each year.7 In older paediatric patients, typically over 12 years of age, about 70% will have cystic fibrosis as the primary indication for LTx, whereas in infants aged less than 3 years, the indication in about 60% is congenital heart disease or pulmonary hypertension. Despite the perception that transplant recipients fare worse if they are younger, the recent ISHLT Registry reports a half-life of around 5 years after LTx, and no significant survival difference between adults, adolescents and the very young.7 Rates of early graft dysfunction and late graft dysfunction (ie, bronchiolitis obliterans syndrome [BOS]) are also similar. However, causes of death are quite different, with adults and adolescents dying from respiratory failure related to BOS, and younger children dying from infection. The functional status of survivors is excellent, with over 80% reporting no activity limitations at 5 years,7 although morbidity related to the obligatory immunosuppressant drugs is very common across all age groups. Further, there are some specific issues (medical, psychosocial and legal) associated with LTx in adolescents and children compared with adults. Post-transplant lymphoproliferative disorders, growth retardation, respiratory tract infections and medical non-adherence appear much more commonly in children.8 As discussed by Morton and colleagues, facilitating compliance with therapies and medication are particularly challenging areas when working with adolescents.5 As an example, immunosuppressive protocols need to reflect potential concerns about physical appearance. Also, a particular “at risk” period arises when paediatric LTx recipients transition from paediatric to adult care.9 Performing major surgery with substantial short-term and long-term mortality risks in a patient unable to give consent presents ethical and legal dilemmas. For paediatric patients with severe lung disease, recent technological advances provide the potential to build on the excellent results of LTx in adolescents presented by Morton et al.5 Minimal waiting list mortality is a critical component of any assessment of the efficacy and utility of organ transplantation. Thus, the management of severe lung disease by experienced teams, with appropriate use of newer therapies such as bi-level positive airway pressure (BiPAP), dornase alfa and azithromycin in patients with cystic fibrosis, may lead to a successful “bridge to transplant”. Similarly, intravenous epoprostenol, oral bosentan and sildenafil may provide a bridge to transplant for patients of all ages with severe pulmonary hypertension. The study by Morton et al included several terminally ill individuals transplanted after support with mechanical ventilation or extra-corporeal membrane oxygenation.5 Morton and colleagues are to be commended for their successful endeavour, but we contend that further detailed discussion about excessive early mortality10 and resource use is needed before bridging in this fashion is routine in any age group. Such bridging has become increasingly used in the United States (11% of all LTx in 200611) and we believe that many, including ourselves, would argue that Australia does not have the intensive care facilities and staff to routinely bridge in this manner. There are also other developments that should increase transplant opportunities and access to LTx for children and adolescents, hopefully shortening waiting times, thereby further decreasing waiting list mortality, and potentially allowing at least the possibility of retransplantation in the event of late graft dysfunction. One possibility is that large-volume LTx transplant centres (typically not small-volume paediatric-only centres, as yet) might increase organ availability by using extended donor lungs (eg, where there are secretions or an abnormal chest x-ray, etc),12 or cadaveric or living-related lobar transplants (eg, so-called “cut-down lungs”).13 The use of cut-down lungs typically involves transplanting one lobe from each of two adults to make a bilobar transplant for a child or smaller adolescent. Although this resource-intensive and challenging operation is possible, some question the philosophy of undertaking the only known procedure to have a “potential 300% mortality”.13 Donation-after-cardiac-death (DCD) retrieval of lungs for transplantation (as distinct from the usual donation-after-brain-death retrieval) is also now a viable prospect being used to acquire adult lungs for LTx,14 and will soon be extended to paediatric DCD lung donation.15 Thus, evidently, expanding the complexity and extent of LTx offered to children and adolescents might consume significant resources, so LTx results must be carefully considered and evaluated to ensure continued successful outcomes. In this regard, we note with great interest the recent institution of a complex mathematical lung allocation score model by the American United Network for Organ Sharing (UNOS).16 This model uses disease-relevant clinical and physiological variables to predict who will get the most significant improvement in survival with LTx and, therefore, who should be preferentially transplanted. Although historically based, the model will evolve with ongoing clinical experience and should be able to provide new evidence to guide future practice. Interestingly, because of differences in diagnostic categories and post-LTx outcomes in younger lung transplant recipients, the UNOS lung allocation score is only to be applied to those aged over 12 years.16 So, although there are important differences to consider when evaluating the efficacy and utility of LTx across the wide age-spectrum of disease and physiology in the very young, adolescents and adults with terminal lung disease, there is also significant overlap. Medical and allied health experts in paediatric and adolescent medicine have much to offer adult LTx programs venturing into adolescent transplantation; their involvement should be routine. Similarly, units experienced in adult LTx bring knowledge and technology to paediatric and adolescent LTx that can only benefit the small number of critically ill young Australians previously without local access to LTx expertise.

Gregory I Snell MB BS, FRACP, MD · Glen P Westall MB BS, FRACP · Trevor J Williams MB BS, FRACP, MD

Postural syncope is a transient loss of consciousness secondary to a reduction in cerebral blood flow and is typically precipitated by standing. It is the commonest cause of recurrent transient loss of consciousness. Recurrent unexplained postural syncope is most often due to one of the five disorders of circulatory control: vasovagal syncope, postural tachycardia syndrome, chronic autonomic failure, initial orthostatic hypotension, or persistently low supine systolic blood pressure. Failure to identify the underlying cause of postural syncope can result in ongoing morbidity, impaired quality of life and high health care costs. With a detailed history, examination, blood pressure assessment and electrocardiography, most disorders of circulatory control can be diagnosed. In difficult cases, analysis of sympathetic nervous system and circulatory responses during head-up tilting can aid diagnosis. Treatment is challenging and compounded by a lack of evidence. Most patients can be managed in an outpatient setting, and hospital admission or emergency department assessment is rarely warranted.

Gautam Vaddadi MB BS, BMedSci, FRACP · Elisabeth Lambert BSc, PhD · Susan J Corcoran MB BS, FRACP · Murray D Esler MB BS, FRACP, PhD

Objective: To describe the results of lung transplantation (LTx) in adolescents at a hospital for adults.Design and setting: Prospective cohort study set in an LTx unit at an adult tertiary referral hospital from 1991 to 2006.Patients: 37 consecutive adolescent lung transplant recipients including 13 males and 24 females (mean age, 16.7 ± 2.0 [SD] years; range 12–19 years) who received heart–lung (six patients) or bilateral LTx (31 patients) for cystic fibrosis (29), congenital heart disease (four), acute respiratory failure (two), or another disorder (two). Two patients were transplanted after invasive ventilation, five after non-invasive ventilation and two after extracorporeal membrane oxygenation.Main outcome measures: Overall survival compared with an adult cohort; survival free of bronchiolitis obliterans syndrome (BOS); overall and BOS-free survival in those transplanted before and after January 2000.Results: Mean waiting time was 273 days (range, 5–964 days; median, 163 days), mean donor age was 28 years (range, 9–53 years). Median inpatient stay was 11 days (range, 7–94 days). Mean follow-up was 1540 ± 1357 days (range, 35–5163 days). The 5-year survival rate for the 16 patients transplanted before January 2000 was 38%, versus 74% for the 21 transplanted since January 2000 (P = 0.05; Mantel–Cox). Overall, 18 of 35 evaluable patients developed BOS. Only BOS was associated with an increased mortality risk (P < 0.01).Conclusion: LTx may be performed successfully in adolescents at a hospital for adults.

Judith M Morton MB BS, FRACP · Monique A Malouf MB BS, FRACP · Marshall L Plit MB, FRACP, PhD · Phillip M Spratt MB BS, FRACS · Allan R Glanville MB BS, FRACP, MD

Treating depression in teens Adding cognitive behaviour therapy (CBT) to a treatment regime of selective serotonin reuptake inhibitors (SSRIs) and routine clinical care does not appear to contribute to an improved outcome for depressed teenagers.1 A British randomised controlled trial assigned 208 adolescents suffering from moderate to severe major depression to one of two groups. Half received an SSRI and routine care alone, while the remaining participants also underwent weekly CBT for 12 weeks, then fortnightly for 12 weeks. Researchers used several rating scales of depression to assess the outcome at 6, 12 and 28 weeks. A similar proportion of teenagers across the groups showed significant improvement in their depressive symptoms over time, with almost 60% showing improvement by 28 weeks. There was no difference in the incidence of side effects between the treatment arms. An accompanying editorial comments that the evidence suggests monotherapy with an SSRI is reasonable as a treatment for teenagers with moderate to severe depression, but that therapy needs to be of adequate dosage, for a sufficient length of time, and under proper supervision.2 1 BMJ 2007; 335: 142 2 BMJ 2007; 335: 106-107 Eat less, live longer A gene acting in the central nervous system neurones of the nematode worm Caenorhabditis elegans may mediate the effect of dietary restriction on longevity. In a US study, worms were cultivated with different concentrations of a bacterial food source until a maximum life span was reached with a prescribed level of dietary restriction. The transcription factor gene skn-1 was found to be activated by a restricted diet. This gene signals peripheral tissues to increase metabolic activity and is critical in controlling the oxidative stress response. Organisms with a mutation of skn-1 were unable to maintain longevity with dietary restriction. The researchers propose that, as in the mammalian hypothalamus, levels of key intracellular metabolites act as signals of energy availability to control food intake and metabolism. They suggest a hormonal signal is released on dietary restriction which promotes metabolic activity, increases respiration, and prolongs life span. Nature 2007; 447: 545-549 Dual therapy for hypertension An antihypertensive medication, aliskiren, newly approved in the US, appears to have an additive effect in reducing blood pressure when used in combination with an angiotensin converting enzyme (ACE) inhibitor. Aliskiren is an angiotensin receptor blocker (ARB). Both ACE inhibitors and ARBs work by inhibiting the production or action of angiotensin II, resulting in increased plasma renin activity. In a randomised, double-blind placebo-controlled trial, 1797 patients with essential hypertension were assigned to four groups. The treatment groups received valsartan (an ACE inhibitor) alone, aliskiren alone, or a combination of both drugs for 8 weeks. Both drugs were administered at the maximum therapeutic dose. The placebo group received no active therapy. The combination of the ACE inhibitor and ARB resulted in a lowering of mean systolic blood pressure from baseline by 12.2 mmHg. This result was significantly greater than that achieved by either monotherapy or placebo. The combination of drugs showed a similar rate of adverse effects and biochemical abnormalities to the other treatment regimes —a result inconsistent with another large trial. The researchers comment that this may have been due to the inclusion of patients with impaired cardiovascular and renal function in the earlier study. Lancet 2007; 370: 221-229 Diet and breast cancer A diet very high in vegetables, fruit and fibre, and low in fat, does not appear to reduce recurrences or mortality in women who have survived early stage breast cancer, according to a US study. The randomised controlled trial followed over 3 000 women who had been previously treated for early breast cancer. The intervention group received regular telephone counselling and monthly newsletters promoting intake of fruit and vegetables and low fat meals. This group also attended cooking classes covering aspects of healthy eating. The control group were provided with printed materials outlining a diet high in fruit and vegetables and low in fat, and attended an average of one cooking class as opposed to four in the intervention group. The dietary pattern was shown to change significantly in the intervention group compared with the control group. The change in diet appeared to be maintained for the 6 years of the study. Researchers found there was no evidence for an intervention effect of dietary change on breast cancer recurrence or mortality in this group of women with breast cancer. The authors comment that the findings do not rule out a longer-term effect on survival of dietary alteration. JAMA 2007; 298: 289-298 Even CAD is in the genes Recent research analysing data from two large genome-wide association studies of coronary artery disease (CAD) and myocardial infarction has found several new genetic loci which individually and together have a significant effect on the risk of CAD. Of particular interest were loci on chromosome 9 (9p21.3), which were able to be identified by using recently developed high-density genotyping arrays. The authors comment on the usefulness of the genome-wide approach, whereby previously unsuspected loci which increase susceptibility to complex diseases can now be identified. N Engl J Med 2007; Jul 18 [Epub ahead of print]

Tanya Grassi

Objectives: To examine the relation between treatment intensity and level of risk in routine hospital care of patients with acute coronary syndromes (ACS), and to identify independent predictors of use or omission for each of eight evidence-based treatments.Design: Retrospective cohort study of patients fulfilling case definition for ACS in whom absolute risk of adverse outcomes was quantified (as low, moderate, or high risk) using formal prediction rules, and for whom treatment eligibility was determined using expert-agreed criteria.Participants and setting: 3912 consecutive or randomly selected patients admitted to 21 hospitals in Queensland, Australia between 1 August 2001 and 31 December 2005.Results: The proportions of eligible patients receiving treatment varied inversely with risk level in regard to reperfusion therapies of fibrinolytic therapy or primary angioplasty (low risk, 88.3%; moderate risk, 61.9%; high risk, 18.2%; P < 0.001), heparin (91.4%; 83.7%; 72.8%; P < 0.001) and early invasive intervention (33.6%; 24.0%; 18.5%; P < 0.001). Significantly more low- and moderate- than high-risk patients received β-blockers (87.0%; 88.5%; 79.1%; P < 0.001), lipid-lowering agents (87.3%; 84.8%; 65.8%; P < 0.001), and referral to cardiac rehabilitation (51.8%; 46.0%; 34.4%; P < 0.001) at discharge. The most frequent independent predictors of treatment omission in all patients included increasing age (5 of 8 treatments), previous ACS or atrial tachyarrhythmias (4 of 8), and past history of cerebrovascular accident or congestive heart failure (3 of 8). Conclusion: In routine care of ACS, eligible patients at high risk receive treatment less frequently than those at low and moderate risk. Reforms in professional education, routine use of risk stratification tools, guideline recommendations tailored to population-specific reductions in absolute risk, and better hospital networking with standardised triage and referral procedures for invasive procedures may help reduce selection bias in the delivery of indicated care.

for the CPIC Cardiac Collaborative

Objective: To measure the prevalence of overweight, obesity and the metabolic syndrome (MetS) in rural Australia.Design, setting and participants: Cross-sectional surveys were conducted in two rural areas in Victoria and South Australia in 2004–2005. A stratified random sample of men and women aged 25–74 years was selected from the electoral roll. Data were collected by a self-administered questionnaire, physical measurements and laboratory tests.Main outcome measures: Prevalence of overweight and obesity, as defined by body mass index (BMI) and waist circumference; prevalence of MetS and its components.Results: Data on 806 participants (383 men and 423 women) were analysed. Based on BMI, the prevalence of overweight and obesity combined was 74.1% (95% CI, 69.7%–78.5%) in men and 64.1% (95% CI, 59.5%–68.7%) in women. Based on waist circumference, the prevalence of overweight and obesity was higher in women (72.4%; 95% CI, 68.1%–76.7%) than men (61.9%; 95% CI, 57.0%–66.8%). The overall prevalence of obesity was 30.0% (95% CI, 26.8%–33.2%) based on BMI (≥ 30.0 kg/m2) and 44.7% (95% CI, 41.2%–48.1%) based on waist circumference (≥ 102 cm [men] and ≥ 88 cm [women]). The prevalence of MetS as defined by the US National Cholesterol Education Program Adult Treatment Panel III 2005 criteria was 27.1% (95% CI, 22.7%–31.6%) in men and 28.3% (95% CI, 24.0%–32.6%) in women; based on International Diabetes Federation criteria, prevalences for men and women were 33.7% (95% CI, 29.0%–38.5%) and 30.1% (95% CI, 25.7%–34.5%), respectively. Prevalences of MetS, central (abdominal) obesity, hyperglycaemia, hypertension and hypertriglyceridaemia increased with age.Conclusions: In rural Australia, prevalences of MetS, overweight and obesity are very high. Urgent population-wide action is required to tackle the problem.

Edward D Janus MD, PhD · Tiina Laatikainen MD, PhD · James A Dunbar MD · Annamari Kilkkinen MSc, PhD · Stephen J Bunker PhD · Benjamin Philpot BSc, GradDip (Actuarial Studies) · Philip A Tideman MB BS · Rosy Tirimacco BSc · Sami Heistaro MD, PhD

Until recently, liver transplantation was contraindicated in Jehovah’s Witness patients because of recipient-imposed restrictions on use of blood products. However, recent improvements in surgical and anaesthetic techniques and new procoagulant agents challenge this practice. We describe two Jehovah’s Witness patients who had successful liver transplantation without blood transfusion. To our knowledge, these are the first such cases in Australasia. The techniques used to minimise blood loss and transfusion requirements could potentially benefit all patients undergoing major surgery. Clinical recordsPatient 1A 48-year-old farmer with end-stage cirrhosis due to α-1 antitrypsin deficiency had evidence of moderate portal hypertension with splenomegaly and ascites (Child–Pugh score B), but no significant lung disease. He met minimum recipient suitability criteria for liver transplantation, according to the Transplantation Society of Australia and New Zealand (TSANZ) liver standing committee.1 As a Jehovah’s Witness, he would not accept transfusion of red blood cells, fresh frozen plasma or platelets. However, he indicated that he would accept blood fractions and recirculated autologous blood and cell-saved blood. A relative, also a Jehovah’s Witness with similar restrictions on use of blood products, offered to be a live liver donor, but this offer was rejected by the treating team on the basis of unacceptable donor risk. The patient was placed on the transplantation waiting list, and was treated with erythropoietin. Over 6 months, this increased the haemoglobin concentration from 112 g/L to 151 g/L (reference range [RR], 135–180 g/L). Results of other preoperative blood tests included: platelet count, 74 × 109/L (RR, 150–400 × 109/L); international normalised ratio (INR), 1.2 (RR, 0.9–1.3); serum concentration of bilirubin, 60 μmol/L (RR, < 20 μmol/L); albumin, 26 g/L (RR, 35–50 g/L); alanine aminotransferase (ALT), 102 U/L (RR, < 40 U/L); and creatinine, 143 μmol/L (60–110 μmol/L). Liver transplantation was performed using an organ from a 54-year-old deceased donor. The piggyback implantation technique, without venovenous bypass, was used. Coagulation was monitored intraoperatively using routine coagulation tests and thromboelastography (Haemoscope, Skopie, Ill, USA). The latter technique measures the kinetics and tensile strength of clot formation. Prophylactic aprotinin was administered as a bolus followed by a constant infusion. The patient also received cryoprecipitate, albumin, haemodilution, and autotransfusion of cell-saved and recirculated blood. On arrival in the intensive care unit, haemoglobin concentration was 118 g/L. The patient received recombinant factor VIIa to treat an INR of 3.4, and erythropoietin was continued. There was significant primary graft dysfunction, and ascites was slow to resolve. Three months after transplantation, the patient developed a pulmonary embolism and required anticoagulation. Currently, at 4 years after transplantation, the patient is well and works full time. Patient 2A 43-year-old woman with chronic hepatitis B infection was found to have an unresectable multifocal hepatocellular carcinoma at laparotomy. She had well compensated cirrhosis (Child–Pugh score A) with no evidence of portal hypertension, and met listing criteria for transplantation. A Jehovah’s Witness, she would not accept transfusion of red blood cells, fresh frozen plasma or platelets, but determined that she would accept blood fractions and recirculated autologous blood and cell-saved blood. Pretransplant laboratory results were: haemoglobin concentration, 129 g/L; platelets, 203 × 109/L; INR, 0.9; bilirubin, 7 μmol/L; albumin, 38 g/L; ALT, 58 U/L; and creatinine, 70 μmol/L. Liver transplantation was performed using an organ from a 42-year-old deceased donor. An inferior vena cava interposition technique was used without venovenous bypass because of the proximity of the tumour to this vessel. The central venous pressure was maintained below 5 cmH2O to minimise blood loss. The patient received cryoprecipitate, haemodilution, autotransfusion, and cell-saved and recirculated blood. Unfortunately, she had an allergic reaction to the colloidal plasma-volume substitute, gelofusine; coagulation studies and thromboelastography showed fibrinolysis, which was treated with aprotinin and recombinant factor VIIa. On arrival in the intensive care unit, haemoglobin concentration was 75 g/L, and INR was 1.3. Erythropoietin and iron supplements were started. Postoperative recovery was uncomplicated, and the patient remains well 3 years after the operation. DiscussionTo our knowledge, these are the first reported cases of liver transplantation in Jehovah’s Witness patients in Australasia. While the two patients filled accepted criteria for recipient suitability for liver transplantation,1 the likely need for blood transfusion would until recently have precluded this procedure. Liver transplantation is a well established and successful intervention for liver failure that results in long-term survival (70% at 10 years) in individuals who otherwise have minimal 1-year survival.2 The shortage of deceased donor livers remains the major factor limiting the number of liver transplantation operations in Australia and New Zealand. In 2000, the death rate while waiting for a donor liver in Australia and New Zealand was 40% for acute liver failure and 5%–8% for chronic liver disease.3 This donor shortfall creates an ethical dilemma in which the potential benefit to individual patients has to be balanced against the need to maximise the benefits of this scarce resource. Following a well publicised case in Edinburgh of a death due to acute liver failure, a recommendation was made for a colloquium to address the question of patient selection for liver transplantation and the need for a uniform code of practice in the United Kingdom. The colloquium, held in 1999, recommended that liver transplantation should be performed in patients when their expected survival is less than 12 months and the expected post-transplant survival is over 50% at 5 years.4 These recommendations have been incorporated into the minimum recipient listing criteria used by the TSANZ liver standing committee,1 and were met by both the reported patients. Over the past decade, improvements in surgical and anaesthetic techniques, combined with new procoagulant agents, have resulted in a dramatic reduction in the requirement for transfusion of blood and blood products during liver transplantation. In selected patients, the need for blood transfusions can be avoided completely.5,6 These advances have resulted in reassessment of the use of liver transplantation in Jehovah’s Witness patients. The first-ever reported liver transplantation in a Jehovah’s Witness patient was in 1994.7 Since then, transplantation has been successfully performed in selected individuals for acute and chronic liver failure without the need for blood products.8,9 Outcomes of liver transplantation in adult Jehovah’s Witness patients have been reported as 92% survival with a mean follow-up of 2.2 years (range, 0.3–5.6 years).10 Live-donor liver transplantation using Jehovah’s Witness donor/recipient pairs has more recently been reported.10 However, the risk to the potential live donor in the case of our first patient through refusing blood products, added to the known 0.5% mortality associated with donation of the right lobe of the liver, was thought to be excessive, and this option was rejected.11 As always, careful selection of the recipient is required. Two other Jehovah’s Witness patients referred to us for liver transplant assessment rejected, or were rejected for, transplantation: one, after lengthy consideration, refused to accept a donor liver; while the other had multiple hepatocellular cancer tumours which fell outside the minimal listing criteria. By way of comparison, in a previously reported series, only nine of 29 Jehovah’s Witness patients were found to be suitable for liver transplantation.9 The Jehovah’s Witness church teaches that blood transfusion (whole blood, red blood cells, white blood cells, platelets and plasma) should not be accepted, but individuals themselves are to decide whether to accept organ transplantation and blood fractions. Both our patients accepted the use of cryoprecipitate, albumin, recombinant factor VIIa, recirculated autologous blood and cell-saved blood, and signed a preoperative agreement to this effect. Consent to the use of these factors and techniques were minimum listing criteria required by the treating teams to proceed with liver transplantation. In selected Jehovah’s Witness patients with hypersplenism (not present in our patients), the use of partial splenic artery embolism increased platelet count, allowing transplantation to proceed.9,10 Transjugular intrahepatic portosystemic shunt formation has been less successful in reversing hypersplenism, and should not be used for this indication.12 Jehovah’s Witness patients with severe decompensated liver disease and coagulopathy (Child–Pugh score C), severe portal hypertension and renal failure are at high risk for perioperative mortality and should not receive liver transplantation. Preoperative use of erythropoietin to increase haemoglobin levels has a number of potential benefits. The most obvious is that the patient begins the procedure with a higher blood haemoglobin level. This also enables use of haemodilution to minimise red cell loss during the explant procedure, and autotransfusion to raise the haematocrit after haemostasis is secure. Maintaining a low central venous pressure also decreases blood transfusion requirements during liver transplantation.13 Although recombinant factor VIIa is expensive (average $6000 per patient), it reduces coagulopathy and transfusion requirements.14 Overall, use of these blood conservation techniques may result in a cost benefit, compared with use of large volumes of blood product.7,10 Successful liver transplantation is possible in selected Jehovah’s Witness patients, but early referral before the development of severe, decompensated liver disease is mandatory. Also, we believe that techniques that minimise blood loss and transfusion requirements for liver transplantation should be more widely practised to benefit all those undergoing major surgery.

Gary P Jeffrey FRACP, MD, MRCP · John McCall FRACS · Edward Gane MD, FRACP · Andrew W Mitchell FRACS · Neville M Gibbs MD, FANZCA · Vanessa Beavis FANZCA · Kerry Gunn FANZCA · Stephen Munn FRACS · Anthony K House MS, FRACS

To the Editor: Awareness about atypical and malignant modes of presentation of a clinical condition can avoid catastrophic outcomes, assist in correct diagnosis in the appropriate clinical setting and, as typified by the following case, offer complete cure. A 39-year-old woman presented with a 5-year history of intermittent, recurrent brief syncopal episodes. During an episode at presentation, telemetry showed torsade de pointes with ventricular fibrillation (Box), and external defibrillation was required to restore sinus rhythm. Amiodarone infusion was initiated at a local hospital before the patient was referred to our institution for further investigation and management. On presentation, her heart rate was 50 beats/min and her blood pressure was 170/95 mmHg. No other abnormalities were detected on examination. A resting electrocardiogram (ECG) showed prominent U waves, with a long QT interval (QTc of 540 ms). As the patient had mild hypokalaemia (serum potassium level, 3.1 mmol/L), mild hypocalcaemia (serum calcium level, 2.10 mmol/L) and a prolonged QT interval, the amiodarone infusion was discontinued, and supplementation with potassium and calcium was initiated. In view of the hypertension and hypokalaemia, primary aldosteronism was suspected. Serum cortisol, 24-hour urinary cortisol and 24-hour urinary catecholamine levels were normal. The plasma aldosterone/renin ratio was markedly elevated (1920/1.2 = 1595; normal, < 99). Failure of aldosterone suppression after acute saline loading was also noted. Computed tomography of the abdomen showed a right adrenal ovoid mass (1.9 × 1.2 cm). Adrenal vein sampling confirmed right lateralisation (right to left ratio, 40 : 1; aldosterone level in the right vein was 224 000 pmol/L while that in the left vein was 5570 pmol/L). Despite initial potassium supplementation, the hypokalaemia persisted and only improved after initiating diuretic therapy with amiloride. Two weeks later, laparoscopic right adrenalectomy was performed, and adrenocortical adenoma was confirmed histologically. After surgery, plasma aldosterone and renin levels normalised to 106 pmol/L and 8.9 mU/L, respectively. Nine months later, the patient was normotensive (without treatment) and had a normal ECG with no further recurrence of arrhythmias. This was a case of primary aldosteronism presenting as aborted sudden cardiac death and malignant syncope secondary to hypokalaemia-induced torsade de pointes. Most patients with primary aldosteronism are either asymptomatic or have symptoms related to hypertension or hypokalaemia (eg, polyuria, cramps, paraesthesia or muscle weakness); the diagnosis is often missed because of the non-specific clinical features. Primary aldosteronism presenting with cardiovascular collapse caused by hypokalaemic torsade de pointes and recurrent ventricular fibrillation is extremely rare, as is presentation as sudden cardiac death secondary to ventricular fibrillation.1 A prolonged QT interval has been reported in cases of primary aldosteronism,2 with values normalising after adrenalectomy.3 Torsade de pointes noted on telemetry in a 39-year-old woman

Aditya Kapoor · Timothy A Wells · Daniel Wong · John P O’Shea

Mifepristone (RU486), which is used for early medical abortion, can only be obtained in Australia under the Authorised Prescriber legislation (Section 19[5] of the Therapeutic Goods Act 1989 [Cwlth]); two of the authors have permission to obtain, prescribe and administer this drug in Cairns, Queensland. From July 2006 to April 2007, 10 women who fulfilled the Therapeutic Goods Administration (TGA) criteria of “life-threatening or otherwise serious” indications underwent medical abortion with mifepristone/misoprostol, and 12 women conforming with abortion requirements of Queensland law, but not TGA legislation for mifepristone administration, had medical abortions with the less preferable methotrexate/misoprostol combination. Although it is now more than a year since the cross-party vote in federal Parliament in February 2006 confirmed wide support for the right of Australian women to a medical abortion, we believe we are at present the only medical practitioners in Australia with permission to use mifepristone. Obtaining Authorised Prescriber status from the TGA is of necessity a complex and protracted process, involving ethics committee approval and auditing, and regular reporting to the TGA. Because of the current restrictions, we believe that women seeking medical abortion in Australia face barriers not experienced by women in other comparable countries, and that drug manufacturing and distributing companies may be discouraged from seeking to market mifepristone in Australia.

Caroline M de Costa FRANZCOG, FRCOG, MPH · Darren B Russell FRACGP, DipVen, FAChSHM · Naomi R de Costa LLB(Hons), GradDipLegalPrac · Michael Carrette MB BCh, FRANZCOG · Heather M McNamee MB ChB, FRACGP

To the Editor: Keks et al make a number of important points about the place of combination antidepressant strategies in the pharmacotherapy of depression.1 However, it is important for readers to note that the vigorous repudiation of combination treatments is a peculiarly Australian preoccupation. Our colleagues in Europe and North America are not nearly so troubled. Combination antidepressant treatments are widely used by specialists. A recent survey of Australian doctors working in psychiatry reported that 79% of respondents had used combination antidepressants and that 75% believed that general practitioners should be given information on their use.2 There is emerging evidence for the use of combination antidepressant strategies — from case series, open clinical trials, and randomised controlled trials (RCTs). The largest summation of the data is a meta-analysis which found that combination antidepressant treatment produced a 62% response rate when monotherapy had failed.3 Although this finding alone cannot be convincing because of the acknowledged lack of large sample RCTs, it is quite another matter to decry combination prescribing as clinically unsound based only on the history of augmentation treatments such as lithium and, to a lesser extent, thyroid hormone treatment when, anecdotally, they provide such clinically disappointing results. It is not unreasonable to assert the primacy of good clinical reasoning, including sensible prescribing of combination antidepressants, over rigid adherence to evidenced-based algorithms. This sort of thinking is allowable because the evidence base for the treatment of depression is poor. Meaningful guidelines cannot be produced while the evidence is predicated on the flawed proposition that depression is an “it” (a homogenous construct).4 GPs might well be puzzled by the zeal in academic psychiatry for monotherapy. They are advised to “optimise” monotherapy, but not told what this means. They are very familiar with models of staged polypharmacy for common chronic illnesses such as hypertension, epilepsy, diabetes, and asthma, but in psychiatric pharmacotherapy this is apparently unwise or too risky. The way such admonishments are usually framed is by reference to serious but rare adverse reactions (like the serotonin syndrome), without proper attention to the equally serious and probably more common problems with the current “simple” psychotropic drug options already used by GPs. Failure to contextualise these risks leads to a distortion of risk–benefit prescribing decisions and an unnecessary restriction of treatment choices. We must have a commonsense approach to the treatment of depression that recognises the proper context of our knowledge base. Combination antidepressant treatments may be “beyond the evidence”, but this alone is not a sufficient justification to stop using them.

Murray J Walters · Alston M Unwin · Sean B Gills