Position statement

End-organ damage associated with hypertension is more closely related to ambulatory blood pressure (ABP) than clinic or casual blood pressure measurements. ABP measurements give better prediction of clinical outcome than clinic or casual blood pressure measurements. The technique of ABP monitoring (ABPM) is specialised; validated monitors and appropriate quality control measures should be used. Interpretation of ABP profile should include mean daytime, night-time (sleep) and 24-hour measurements, and consideration of diary information and time of drug treatment. Reports may also include ABP "loads" (percentage area under the blood pressure curve above set limits) for daytime and night-time periods. Normal blood pressure values for adults are < 135/85 mmHg for daytime, < 120/75 mmHg for night-time, and < 130/80 mmHg for 24 hours. ABPM is indicated to exclude "white coat" hypertension and has a role in assessing apparent drug-resistant hypertension, symptomatic hypotension or hypertension, in the elderly, in hypertension in pregnancy, and to assess adequacy of control in patients at high risk of cardiovascular disease. White coat hypertension requires continued surveillance; patients who display this phenomenon may, in time, develop established hypertension. Appropriate use of ABPM may result in cost savings. Randomised controlled trials comparing management based on clinic or casual versus ABP measurements are needed.

and on behalf of the National Blood Pressure Advisory Committee of the National Heart Foundation of Australia

The majority of the "Australian COX-2-Specific Inhibitor (CSI) Prescribing Group" endorse the following points: CSIs are equivalent to non-steroidal anti-inflammatory drugs (NSAIDs) as anti-inflammatory agents. CSIs and NSAIDs modify symptoms but do not alter the course of musculoskeletal disease. CSIs do not eliminate the occurrence of ulcers or their serious complications, but are associated with considerably fewer peptic ulcers, slightly fewer upper GI symptoms and, according to published reports, fewer serious upper GI complications, notably bleeding, than NSAIDs. CSIs and NSAIDs have similar effects on renal function and blood pressure. Whether any CSI poses a risk to cardiovascular safety remains subject to debate. Comorbidities and coprescribed drugs must be considered before initiating CSI (or NSAID) therapy. Patients prescribed CSIs (or NSAIDs) should be reviewed within the first few weeks of therapy to assess effectiveness, identify adverse effects and determine the need for ongoing therapy

The Australian COX-2-Specific Inhibitor (CSI) Prescribing Group*

Preventive treatment Inhaled corticosteroids are indicated in children with asthma who have more than mild persistent asthma or are unresponsive to non-steroidal medications after 2–4 weeks. Initial administration of 400 µg/day of chlorofluorocarbon-beclomethasone dipropionate, or budesonide, or 200 µg/day of fluticasone propionate or hydrofluoroalkane-beclomethasone dipropionate, is suggested, with subsequent titration of the dose to achieve ongoing control with the lowest dose possible. In situations where asthma control cannot be achieved with the above doses of inhaled corticosteroids, the addition of a long-acting β2-agonist, theophylline or a leukotriene antagonist should be considered. Specialist referral is recommended in children requiring high doses of inhaled steroids, regular oral steroids or in whom there is concern about possible steroid side effects. Treatment of acute asthma Systemic corticosteroid therapy is recommended for children with moderate to severe acute asthma or if there is incomplete response to β2-agonists. Initial administration of 1 mg/kg prednisolone (maximum, 50 mg) orally is suggested, and this may be repeated every 12–24 hours, depending on response. While a course of up to three days is generally sufficient, in more severe cases a prolonged course (with tapering) may occasionally be indicated. The need for recurrent systemic corticosteroid therapy for acute episodes is an indication for reassessment of the child's interval therapy.

Peter P van Asperen MD, FRACP · Craig M Mellis MD, MPH, FRACP · Peter D Sly MD, FRACP

Position Statement Anticoagulation in pregnancy and the puerperium A Working Group on behalf of the Obstetric Medicine Group of Australasia MJA 2001; 175: 258-263 Abstract - Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium - Acute venous thromboembolism - Prophylaxis of venous thromboembolism - General - Previous thromboembolism - Previous single VTE and no recognised thrombophilia - Previous recurrent VTE or idiopathic VTE - Familial thrombophilia - Hyperhomocysteinaemia - Antiphospholipid syndrome and VTE - Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis - References - Authors' details - - More articles on Obstetrics & gynaecology and women's health Abstract For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium. Pregnant women who have had an acute thrombotic event should be delivered by a specialist team. In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised. Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard. Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia. Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists. Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain. Low molecular weight heparins (LMWH) are being used increasingly as standard treatment for venous thrombosis, replacing unfractionated heparin (UH) for both therapeutic and prophylactic anticoagulation. Compared with UH, LMWH have increased bioavailability and a longer half-life. They also have the benefits of ease of administration, often as a single daily dose, have reduced requirements for monitoring, and are associated with less heparin-induced thrombocytopenia, reduced bleeding complications and improved patient acceptability.1Heparins do not cross the placenta, whereas warfarin does.2,3 By contrast, warfarin is teratogenic between six and 12 weeks' gestation, and may cause fetal and neonatal bleeding if used during the second or third trimester. Except perhaps in women with mechanical heart valves, there is general agreement that UH or LMWH should be substituted for warfarin as soon as pregnancy is diagnosed. Long-term treatment with UH carries risks of maternal osteoporosis4-6 and heparin-induced thrombocytopenia. Consistent, long term therapeutic anticoagulation can be hard to achieve with subcutaneous UH, because of low bioavailability and the changing anticoagulant response to UH as pregnancy progresses, often requiring close laboratory monitoring. LMWH require much less monitoring and appear to carry a smaller risk of heparin-induced thrombocytopenia, bleeding, and probably osteoporosis.7-9 Data on the effectiveness and safety of LMWH in pregnancy are limited but systematic reviews are becoming available.10 Given the convenience of LMWH and doctors' increasing familiarity with their use, there is growing opinion that LMWH have a role in pregnancy in preference to UH. In this position paper we summarise current views and make consensus recommendations for anticoagulation in pregnancy and the puerperium. The consensus process followed for this article is summarised in Box 1. Management and prophylaxis of venous thromboembolism in pregnancy and the puerperium Acute venous thromboembolism Antenatal management: Clinical trials in non-pregnant patients show that LMWH are at least as effective and safe as UH in the initial management of acute proximal or calf deep venous thrombosis (DVT).1 Recurrence of thromboembolism is reduced by ongoing warfarin therapy and, in the case of proximal DVT, treatment should be continued for at least six months (C1). The standard initial treatment for pulmonary embolism, whether during pregnancy or not, remains intravenous UH (C2). For an antenatal DVT, treatment should start with a LMWH at the therapeutic dose recommended by the manufacturers9(Box 2) (C1). Intravenous UH may be preferred in situations where its short half-life and predictable reversibility by protamine sulfate are important (eg, when delivery or surgery may be imminent). Calf DVT should be treated in the same way as proximal DVT in pregnancy because of ongoing hypercoagulability during pregnancy (C2). If intravenous UH is used for the initial treatment of pulmonary embolism, therapeutic doses of LMWH may be commenced once the patient is haemodynamically stable (C1). Anticoagulation therapy should then be maintained until delivery (C1). It is generally recommended that therapeutic doses of UH or LMWH be continued throughout pregnancy.9,11,12 In practice, some clinicians change to a prophylactic dose of LMWH after 12 weeks of therapy if the woman is still pregnant, and continue with this dose until labour (Box 2) (C3). The rationale for this approach includes a declining risk of recurrence with time after acute venous thromboembolism (VTE),13 a desire to reduce osteoporosis associated with LMWH, and the suggestion from small trials in non-pregnant patients that lower prophylactic or intermediate doses of LMWH may be as effective as warfarin in preventing secondary recurrence of VTE.14-16 The safety of such a reduction of LMWH dose before 12 weeks after acute VTE in pregnancy needs to be established in clinical trials. Monitoring: There is no need to use an anti-factor Xa assay to monitor either therapeutic or prophylactic doses of LMWH (C2). Therapy with UH can be monitored and managed according to the activated partial thromboplastin time (APTT). Management of labour and delivery: Women requiring therapeutic anticoagulation should be counselled before delivery, which should be planned under the care of a specialist team (C1). Elective delivery allows for dose adjustment to minimise the opposing risks of bleeding at delivery and of further thrombosis.13 Vaginal delivery is preferable, as there is less risk of haemorrhage than with caesarean section. Delivery by caesarean section should be determined on the basis of obstetric indications (C1). The use of regional anaesthesia requires special consideration, and is outlined in Box 3. The intensity of anticoagulation therapy required during delivery depends on how recently the VTE occurred. If within the last month, each day without anticoagulation therapy is associated with a 1% absolute increase in the risk of recurrence.13 It is therefore important to minimise the time off anticoagulation. Intravenous UH should be substituted for LMWH 24-36 hours before obstetric intervention, aiming to maintain the APTT at 1.5-2 times baseline. After induction, UH therapy is ceased once labour is established, allowing the APTT to return to normal, usually within 4-6 hours. Women requiring elective caesarean section should cease UH therapy six hours before surgery to allow for the full range of obstetric and anaesthetic options (C1). If the VTE occurred between one and three months previously, therapeutic LMWH can be reduced to a prophylactic dose for 24-48 hours and labour can then be induced. The last dose of LMWH is given the night before induction. In women whose cervical assessment suggests that labour is likely to be established within a few hours of induction, the last dose of LMWH before induction may be withheld (C2). Women who have had a VTE more than three months previously and who are still receiving a therapeutic dose of LMWH can be switched to a prophylactic dose at 38 weeks' gestation, allowing spontaneous labour to occur. Again, LMWH are withheld at the onset of labour (C2). Alternatively, if a woman wishes to be assured of access to epidural anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (C2). Anti-embolism stockings, compression devices and electrical calf stimulators may be used and continued postpartum, especially if caesarean delivery is undertaken (C1). In all women in whom anticoagulants have been used, the third stage of labour should be managed actively with oxytocic therapy and controlled cord traction to minimise the risk of postpartum haemorrhage (C1). Postpartum management: Postpartum, anticoagulation therapy is usually recommenced at the same intensity as that used antenatally. Prophylactic doses can be recommenced within 2-6 hours of both vaginal and caesarean deliveries (C1). This may be prophylactic doses of LMWH or low-dose (12 000 U/24 h) UH infusion, if rapid reversal of anticoagulation may be required. Therapeutic doses of UH or LMWH may be reintroduced 24 hours after vaginal delivery (C2). Caution should be exercised in recommencing therapeutic doses of LMWH earlier than 24 hours after operative delivery because of the risk of surgical bleeding, but most women can be receiving therapeutic doses by 36-48 hours after caesarean section (C1). Warfarin therapy can then be initiated and, once therapeutic levels have been achieved, continued in place of LMWH to complete the six months of therapy and for at least six weeks postpartum. Neither medication contraindicates breastfeeding (C1). Prophylaxis of venous thromboembolism General VTE remains a major cause of maternal mortality in Australia, the United Kingdom and in the United States, occurring at a rate of approximately one death per 100 000 maternities.11,12,18 The rate is much higher in older women; in the UK, women aged over 39 years had a mortality rate of 1 per 3300 pregnancies.19 VTE can occur at any time during pregnancy; its prevalence is approximately equally distributed between the three trimesters.20 Although two-thirds of events occur antenatally, the day-by-day risk is greatest in the first weeks after delivery.20Major known risk factors for VTE in pregnancy and postpartum include caesarean section (particularly in labour), obesity, prolonged bed rest and immobility, pre-eclampsia, nephrotic syndrome, current infection and other recent surgery, in addition to previous VTE and thrombophilia. These risk factors often coexist and reinforce each other. A risk-assessment profile may be constructed, as suggested in the consensus report from the Royal College of Obstetricians and Gynaecologists,21 which recommends that: all "at risk" women should be monitored for symptoms and signs of VTE during the first week postpartum; hydration should be maintained and early mobilisation encouraged; graduated compression stockings with or without calf stimulation should be used during and after caesarean section in women at moderate risk (one or two risk factors); in women at high risk (three or more risk factors), LMWH or UH prophylaxis should be used and continued for at least five days. The efficacy or benefit of these interventions is unknown, as no high grade evidence is available. Previous thromboembolism In women who have had previous VTE, the risk of recurrence will be influenced by a number of factors, including whether the index event was spontaneous or provoked, the presence or absence of a family history of VTE, the presence of a known thrombophilia, or whether there has been more than one episode of VTE. The decision as to whether VTE prophylaxis is required throughout pregnancy or only postpartum may be based on this information (Box 4).22Women requiring prophylaxis during pregnancy can be managed with low-dose LMWH (Box 2). They can then be allowed to come into spontaneous labour (C2). LMWH are withheld at the onset of labour (C2). Alternatively, if such a woman wishes to be assured of access to regional anaesthesia, induction of labour can be offered, with the last dose of LMWH on the day before the day of induction (Box 3) (C2). Previous single VTE and no recognised thrombophilia Both earlier and more recent cohort data suggest that most pregnant women with a past history of a single precipitated thrombotic event in or out of pregnancy, or associated with the combined oral contraceptive pill, and who have no underlying thrombophilia, can be safely managed by careful observation before delivery and postpartum thromboprophylaxis for six weeks23 (C2). Previous recurrent VTE or idiopathic VTE Women who have either recurrent VTE, previous idiopathic VTE, or a previous VTE and a strong family history of VTE but with no demonstrated cause for thrombophilia, may be given thromboprophylaxis throughout pregnancy and for six weeks postpartum23,24 (C1). Familial thrombophilia Thromboembolism is a multifactorial disease, in many cases developing as a result of a thrombotic tendency (a thrombophilia) interacting with other factors, such as pregnancy.25,26 Situations in which such a thrombophilia may require consideration during pregnancy are: previous personal thromboembolic disease and known thrombophilia; no previous VTE, but a strong family history (ie, one or more first-degree relatives affected) and known thrombophilia; no previous VTE, strong family history, no previous investigations; no previous VTE, weak family history (ie, incidental finding of thrombophilia in a family member); and no personal or family history of VTE, but known thrombophilia detected after screening (eg, after obstetric complications or before starting to take the combined oral contraceptive pill). The known causes of familial thromboembolism differ in their risk of associated thrombosis.27 The prevalence of such thrombophilic disorders varies between populations.28 A combination of any two or more inherited factors substantially increases the risk of thromboembolism. Box 4 summarises the risk profiles of the various genetic thrombophilias and offers guidelines for therapy. Box 5 describes management during pregnancy of medical problems requiring anticoagulation outside pregnancy. Hyperhomocysteinaemia In women with a previous history of VTE and hyperhomocysteinaemia, it may be prudent to reduce plasma homocysteine concentrations by folate supplementation throughout pregnancy, in addition to other thromboprophylaxis (C2). Antiphospholipid syndrome and VTE The presence of a lupus anticoagulant or of moderately to strongly positive titres of anticardiolipin antibody (ACA) is a strong risk factor for recurrent VTE, especially in pregnancy. Suggestions for treatment are shown in Box 4. Unless there is an associated history of poor obstetric outcome (see below), low-dose aspirin therapy need not be added (C2). On the other hand, it is contentious whether women with a positive lupus anticoagulant with or without ACA with no previous history of VTE (eg, women with systemic lupus erythematosus) require any prophylactic treatment at all during pregnancy. Low-dose aspirin may be a reasonable option for such women (C1). Management and prophylaxis of obstetric problems associated with uteroplacental thrombosis A common pathophysiological link between various poor pregnancy outcomes, including recurrent miscarriage, stillbirth, placental abruption, fetal growth restriction and pre-eclampsia, is thrombosis in the uteroplacental circulation. Antiplatelet agents (especially low-dose aspirin) have been trialled, particularly for preventing pre-eclampsia. A recent systematic review has shown a 15% reduction in the incidence of recurrent pre-eclampsia when low-dose aspirin is used, less benefit for the prevention of preterm birth and no benefit for the prevention of fetal growth restriction.35 Whether LMWH or UH can be used safely and more effectively than just aspirin in placental vasculopathy, with or without thrombophilia, is currently under investigation. Only in the case of recurrent miscarriage associated with the antiphospholipid syndrome has the addition of UH to aspirin been shown to be beneficial.36 A number of small cohort studies in women with previous obstetric complications who were treated with LMWH showed a good outcome, but whether the outcome was related to the use of LMWH is uncertain.37,38While awaiting the results of further studies, and given the small numbers of affected women, no specific treatment recommendations can be made. We encourage clinicians to refer such patients to centres where randomised controlled trials are being carried out or where cohort studies are under way. Competing interests: The authors are grateful to Pharmacia Upjohn for an unrestricted financial grant towards the costs involved in the preparation of this article, although the company did not contribute in any way either to the analysis or to the recommendations. There are no other known conflicts of interest. Future research questions The working party identified further areas for research. These include: Comparison of LMWH versus intravenous UH in acute DVT and pulmonary embolism in pregnancy. High-dose versus low-dose LMWH therapy for secondary prophylaxis after acute DVT in pregnancy. The value of prospective blinded anti-Xa levels in the use of therapeutic LMWH in pregnancy. The timing, benefits and risks of any dose adjustment of LMWH/UH, particularly peripartum. Controlled longitudinal studies of bone density and fracture rates in women using long-term LMWH. Prevention of pregnancy-associated VTE: the risks and benefits of LMWH thromboprophylaxis during pregnancy and postpartum for specific groups. Prevention of adverse pregnancy complications related to placental insufficiency. Randomised studies to determine the efficacy of LMWH in improving subsequent pregnancy outcome in women with specific pregnancy complications and an underlying thrombophilia. A register of women being treated with anticoagulants during pregnancy. A register to determine the clinical significance of thrombophilias in particular patient groups. References Weitz J. Drug therapy: low molecular weight heparins. N Engl J Med 1997; 337: 688-698. Flessa H, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965; 934: 570-573. Forestier F, Sole Y, Aiach M, et al. Absence of transplacental passage of fragmin (Kabi) during the second and the third trimesters of pregnancy. Thromb Haemostas 1992; 67: 180-181. Dahlman TC, Sjoberg HE, Ringertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol 1994; 170: 1315-1320. Douketis JD, Ginsberg JS, Burrows RF, et al. The effects of long-term heparin therapy during pregnancy on bone density — a prospective matched cohort study. Thromb Haemost 1996; 75: 254-257. Barbour LA, Kick SD, Steiner JF, et al. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol 1994; 170: 862-869. Nelson-Piercy C. Heparin-induced osteoporosis in pregnancy. Lupus 1997; 6: 500-504. Farquharson RG. Heparin, osteoporosis and pregnancy. Br J Hosp Med 1997; 58: 205-207. Ginsberg J, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001; 199: 122S-131S. Sanson BJ, Lensing AW, Prins MH, et al. Safety of low molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258-1265. Toglia M, Weg J. Current concepts: venous thromboembolism during pregnancy. N Engl J Med 1996; 335: 108-114. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191-197. Gonzalez-Fajardo J, Arreba E, Castrodeza J, Perez J, et al. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30: 283-292. Das S, Cohen A, Edmonson R, et al. Low molecular weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: 521-527. Tryba M. European practice guidelines: thromboembolism prophylaxis and regional anesthesia. Regional Anesthes Pain Med 1998; 23 (6 Suppl 2): 178-182. Maternal mortality committee. Maternal deaths in Australia 1991-1993. Canberra: NHMRC, 1998. Department of Health. Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdom 1994-1996. London: The Stationery Office; 1998. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999; 54: 265-271. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on prophylaxis against thromboembolism in gynaecology and obstetrics. London: RCOG, 1995. McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999; 106: 756-766. Brill-Edwards P, Ginsberg J, Gent M, et al. Safety of withholding antepartum heparin in women with a previous episode of venous thromboembolism. N Engl J Med 2000; 343: 1439-1444. Letsky EA. Peripartum prophylaxis of thrombo-embolism. Baillieres Clin Obstet Gynaecol 1997; 11: 523-543. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-916. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342: 374-380. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves — a systematic review of the literature. Arch Intern Med 2000; 160: 191-196. Arnaout M, Kazma H, Khalil A, et al. Is there a safe anticoagulation protocol for pregnant women with prosthetic valves? Clin Exp Obstet Gynecol 1998; 25: 101-104. Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999; 33: 1642-1645. Lee LH, Liauw PCY, Ng ASH. Low molecular weight heparin for thromboprophylaxis during pregnancy in 2 patients with mechanical mitral valve replacement. Thromb Haemost 1996; 76: 628-630. Sadler L, McCowan L, White H, et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. Br J Obstet Gynaecol 2000; 107: 245-253. Rowan J, McCowan L, Raudkivi P, North R. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol. In press. Knight M, Duley L, Henderson Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia. Cochrane Database Syst Rev 2000; 2. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253-257. Brenner B, Hoffman R, Blumenfeld Z, et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-697. Riyazi N, Leeda M, de Vries J, et al . Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study. Eur J Obstet Gynecol Reprod Biol 1998; 80: 49-54. The authors of the Position Statement are listed below Authors' details Department of Obstetrics, University of Adelaide, Women's and Children's Hospital, North Adelaide, SA. William M Hague, FRCP, FRCOG, Senior Physician in Obstetric Medicine and Clinical Senior Lecturer. National Women's Hospital, Auckland, New Zealand Robyn A North, PhD, FRACP, Associate Professor in Obstetric Medicine. Flinders Medical Centre, Bedford Park, SA. Alexander S Gallus, FRCPA, FRACP, Haematologist and Professor. King Edward Memorial Hospital, Subiaco, WA. Barry N J Walters, MB BS, FRACP, Physician in Obstetric Medicine and Clinical Associate Professor, Department of Obstetrics and Gynaecology, University of Western Australia. Christopher Orlikowski, MB BS, FANZCA, Anaesthetist. Monash University, Monash Medical Centre, Melbourne, VIC. Robert F Burrows, FACOG, FRANZCOG, Professor of Maternal-Fetal Medicine. Mater Mothers' Hospital, South Brisbane, QLD Robert B Cincotta, FRANZCOG, CMFM, Specialist in Maternal-Fetal Medicine. North Western Adelaide Health Service, Adelaide, SA. Gustaaf A Dekker, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology. Mercy Hospital for Women, East Melbourne, VIC. John R Higgins, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology (currently, Professor of Obstetrics and Gynaecology, University College, Cork, Ireland). Royal Hospital for Women, Sydney, NSW. Sandra A Lowe, MD, FRACP, Physician in Obstetric Medicine. Royal North Shore Hospital, Sydney, NSW. Jonathan M Morris, MD, FRANZCOG, Senior Lecturer in Obstetrics and Gynaecology. Nepean Hospital, Sydney, NSW. Michael J Peek, PhD, FRANZCOG, Professor of Obstetrics and Gynaecology. Reprints will not be available from the authors. Correspondence: Dr W M Hague, Department of Obstetrics, Women's and Children's Hospital, North Adelaide, SA 5006. bill.hagueATadelaide.edu.au Make a comment 1: Consensus process The authors of this position statement are members of the Obstetric Medicine Group of Australasia (OMGA), with a particular clinical and research interest in managing pregnant women with thromboembolic problems. The authors were all members of the working party, and include six obstetricians, four obstetric physicians, an obstetric anaesthetist and a clinical haematologist. We met collectively in October 1999 to discuss the broad issues of the use of low molecular weight heparins in pregnancy before producing a draft document; this was subsequently modified by written comments and refined at teleconferences in May, June and September 2000. The position statement is a consensus statement inasmuch as there is little high-grade evidence from either randomised trials or other cohort studies on which to make recommendations, especially for management. Our recommendations have been annotated to reflect the degree of agreement among us as follows: C1 Complete consensus; C2 Near-complete consensus (nine or more of the 12 authors); and C3 No consensus. Back to text 2: Doses of low molecular weight heparins Low molecular weight heparin Therapeutic dose Prophylactic dose Dalteparin (Fragmin) 100U/kg twice daily 5000U daily Enoxaparin (Clexane) 1 mg/kg twice daily 40mg daily or 1.5mg/kg daily Back to text 3: Suggested guidelines for regional anaesthesia and levels of consensus (Box 1) Regional anaesthesia (epidural or spinal block) is contraindicated during anticoagulation therapy because of the increased (although unquantified) risks of spinal haematoma17 (C1). If a regional anaesthetic is desired in women who require anticoagulation therapy, an elective delivery will allow for a planned reduction in dose or a change to intravenous unfractionated heparin (UH) (C1). Therapeutic subcutaneous injections of low molecular weight heparins (LMWH) or UH should be ceased at least 24 hours, and preferably 36 hours, before regional anaesthesia (epidural or spinal block) (C1). Intravenous UH (used to permit a rapid return of the APTT to normal after cessation of the infusion) should be discontinued at least six hours, and preferably 12 hours, before regional anaesthesia (C1). In women receiving prophylactic LMWH, an interval of more than 20 hours from the last dose should allow the placement of a regional block with minimal risk of complications (C2). A normal activated partial thromboplastin time (APTT) does not ensure minimal anticoagulant effect of LMWH, and the platelet count should be determined to exclude heparin-induced thrombocytopenia (C2). If caesarean section is being undertaken, further doses of LMWH should be delayed for at least four hours after placement of an uncomplicated regional block, and longer if the regional block has been complicated (C1). Low-dose LMWH therapy can be continued after delivery if there have been no complications in the siting of the regional block.17 An epidural catheter can be removed 12-20 hours after a prophylactic dose of LMWH, and the next injection should be delayed by at least four hours after removal (C1). Women should be closely monitored postpartum for any symptoms or signs of spinal haematoma, in particular for numbness and weakness in the lower limbs, severe back pain, and bladder or bowel incontinence (C1). Back to text Box 4 consists of 4a, 4b, 4c, 4d. 4a: Suggested management guidelines and levels of consensus (see Box 1) Thromboprophylaxis against recurrent venous thromboembolism (VTE) in pregnant women with previous VTE and no identified thrombophilia, according to estimated pregnancy-related risk of thrombosis Single episode of VTE Thrombosis history Recurrent VTE Spontaneous Probable cause* Family history of VTE in one or more 1st degree relatives PrA (option ThA) (C2) PrA (C2) Negot (C2) No family history of VTE PrA (C1) Negot (C2) Nil (C2) *Risk factors present such as surgery, combined oral contraceptive pill. Back to text 4b: Anticoagulation to prevent venous thromboembolism (VTE) in pregnant women testing positive for lupus anticoagulant or anticardiolipin antibodies (ACA), according to estimated pregnancy-related risk of thrombosis Lupus anticoagulant and/or ACA IgG ACA IgG weak moderate-strong positive,* ACA Thrombosis history positive* IgM positive Recurrent VTE in pregnancy despite prophylaxis ThA (C1) ThA (C1) Recurrent VTE outside pregnancy ThA (C2) ThA (C2) Previous VTE PrA (C1) Negot (C1) No previous VTE Nil (C1) Nil (C1) *Based on the highest-ever titre measured in the individual patient. Back to text 4c: Preventing venous thromboembolism (VTE) in pregnant women with established thrombophilias, according to estimated pregnancy-related risk of thrombosis Thrombosis history Antithrombin deficiency (Very rare) Protein C deficiency (Rare) Protein S deficiency (Rare) FVL* or PGM† homozygous (Uncommon) FVL* or PGM† heterozygous (Common) Personal history of VTE independent of family history ThA (C2) PrA (C1) PrA (C1) PrA (C1) Negot (C1) Family history of VTE in one or more 1st degree relatives ThA/PrA (C3) PrA (C1) PrA (C1) PrA (C1) Negot (C1) Family history of VTE in a distant relative ThA/PrA (C3) PrA (C1) Negot (C1) Negot (C1) Nil (C1) No personal or family history of VTE ThA/PrA (C3) PrA (C1) Nil (C1) Nil (C1) Nil (C1) *G1691A mutation in the factor V gene [Factor V Leiden] causing activated protein C resistance; †G20210A mutation in the prothrombin (factor II) gene. Back to text 4d: Key to management recommendations ThA Therapeutic anticoagulation necessary throughout pregnancy and postpartum - very high risk (>20%). PrA Prophylaxis necessary throughout pregnancy and puerperium - high risk (10%-20%). Negot Need for prophylaxis negotiable on a case-by-case basis until further data become available - moderate risk (3%-10%). Nil Postpartum prophylaxis or no prophylaxis - low risk (3%). Back to text 5: Management during pregnancy of medical problems requiring anticoagulation therapy outside pregnancy (consensus levels are described in Box 1) Women with mechanical heart valves require therapeutic doses of anticoagulant medication throughout pregnancy to prevent valve thrombosis or maternal thromboembolic events9 (C1). Women with mechanical heart valves should be managed under joint subspecialty care (C1). The maternal benefits of warfarin (prevention of valve occlusion and systemic embolism) must be balanced against hazards to the fetus (congenital anomalies, intracranial haemorrhage and fetal loss).29 Unfractionated heparin (UH) and low molecular weight heparins (LMWH) are safe for the fetus, but there is still debate as to their therapeutic efficacy in the mother compared with that of warfarin.29-33 UH is associated with higher rates of maternal thromboembolic complications, including fatal events.29,33 There are limited data on the efficacy of LMWH in mechanical valves during pregnancy, but valve thrombosis may occur.34 High rates of maternal valve thrombosis occur if subtherapeutic doses of UH or LMWH are used.9,30 Women should participate in the choice of anticoagulation therapy (C2). In women with other diseases (eg, dilated cardiomyopathy) who require anticoagulation therapy to prevent thromboembolic complications, the use of therapeutic or prophylactic doses of LMWH will depend on the perceived risk of thromboembolism (C1). Back to text

MJA 2001; 175: 205-210 For editorial comment, see Breen Abstract - Background to the development of our position statement - Content of a core curriculum - Knowledge - Skills - Attitudes - Teaching methods - Assessment - The challenge of implementing the curriculum - Conclusion - References - Authors' details - - More articles on Ethics - More articles on Education Abstract Teaching ethics incorporates teaching of knowledge as well as skills and attitudes. Each of these requires different teaching and assessment methods. A core curriculum of ethics knowledge must address both the foundations of ethics and specific ethical topics. Ethical skills teaching focuses on the development of ethical awareness, moral reasoning, communication and collaborative action skills. Attitudes that are important for medical students to develop include honesty, integrity and trustworthiness, empathy and compassion, respect, and responsibility, as well as critical self-appraisal and commitment to lifelong education. In recent years, an international consensus has emerged that ethics and health law should be essential components of medical curricula.1-3 In line with this, teachers of medical ethics and law in UK medical schools have recently published a model for a core ethics curriculum.4 In Australia, concern for ethics teaching has developed, in part, as a result of the findings of the Doherty Report5 and through the Australian medical school accreditation process. The Australian Medical Council's statement, Goals and objectives of basic medical education,6 specifies that graduates completing basic medical education "should have knowledge and understanding of the principles of ethics related to health care and the legal responsibilities of the medical profession", and that graduates should have "an appreciation of the complexity of ethical issues related to human life and death, including the allocation of scarce medical resources". There is, however, less consensus as to what ethics should be taught, how it should be taught and who should teach it. In part, this is because ethics offers not so much a discrete or limited area of content, but a place for the consideration of values and for dialogue across boundaries and between different perspectives. In addition, there are many different ways to think about and analyse ethical issues in practising medicine, from a "principlist" approach through to virtue ethics, narrative ethics and ethics of care (Box 1). Despite this diversity, there is a core of skills and knowledge related to ethics that is as fundamental to the practice of medicine as basic sciences or clinical skills. This core is concerned primarily with equipping students to recognise and understand important ethical issues, to know how to make decisions about those issues, and to have a better basis for knowing what should be done (in any given situation) and why. Consideration of questions such as "What are ethical reasons and how do they differ from other reasons?", "What does 'informed consent' mean and how does it work in practice?", and "How do people wish to die?" is an essential component of medical education that falls within the domain of ethics. As members of the Association of Teachers of Ethics and Law in Australian and New Zealand Medical Schools (ATEAM), we offer here a position statement on an ethics core curriculum for Australasian medical schools. We believe that this curriculum meets the goals outlined by the Australian Medical Council.6 Background to the development of our position statement Our outline of an ethics core curriculum arose out of a meeting in June 1999 of teachers of ethics and law in medicine from 10 universities in Australia and New Zealand. The meeting covered a wide range of issues, with participants exchanging views on the teaching of ethics, based on personal experiences and informal consultations within their own institutions. Following this meeting, three separate working parties developed statements on the knowledge, attitudes and skills considered desirable for students to acquire from an ethics curriculum. The whole group met again in July 2000 and agreed to develop and refine the initial statements from the working parties by an email exchange of views. The core curriculum outlined here is the consensus statement that resulted from this process. During our meetings and subsequent consultations, it became apparent that most of the existing Australasian ethics courses are strongly congruent with one another and with other existing statements, such as the consensus statement by teachers of medical ethics and law in UK medical schools.4 We see our consensus statement very much as a living document, open to challenges and revisions as changes in medicine and society raise new and different ethical questions and as medical education continues to evolve. Content of a core curriculum Knowledge A core curriculum of ethics knowledge must address both the foundations of ethics and specific topics in ethics (Box 2). We have made a distinction between basic ethical concepts and ethics in clinical settings to highlight the importance of understanding basic principles and terminology that apply to ethical problems irrespective of any clinical situation. For example, informed consent can not be understood adequately without an understanding of autonomy, individual rights and paternalism. Skills The construction of a knowledge base in medicine involves skills of problem-solving, reasoning, critical thinking, collaboration and the active use of knowledge.11 Specific learning outcomes, in terms of these transferable skills, are sought as part of the process of independent life-long learning. Such skills are as relevant in ethics as they are in other domains of medicine. More specific skills (those of ethical awareness, moral reasoning and ethical practice) are also required to translate this knowledge into practice. Ethical awareness relates to the ability to recognise ethical issues present in a medical setting. This requires students, in practising medicine, to maintain and develop sensitivity to issues involving their patients. Skills in moral reasoning involve the ability to analyse ethical issues in a medical setting, to construct arguments and counterarguments that are valid and sound, and to examine and interpret the arguments of others. The specifically moral nature of these arguments requires that students have some familiarity with ethical theory and principles. After weighing competing claims and interests, justification for a particular moral position can be offered. Skills of ethical practice concern a range of skills necessary for ethically sensitive practice. They include the ability to communicate about ethical issues with patients, their relatives and other healthcare professionals; effective negotiation and collaboration with patients, their families and other members of the healthcare team; and skills necessary to implement ethical decisions in the face of institutional constraints. Students' relative powerlessness in the medical hierarchy can often inhibit them from presenting a dissenting ethical view, and so they need to be able to recognise and analyse an institutional culture, with specific attention given to how students might act ethically in the face of it.12-14 Attitudes The traditional model of medical ethics education suggests that its goal is not to improve the moral character of future physicians, but to give those with already formed sound moral character "the knowledge and skills required to practice good medical care".15However, increasing concern about the dehumanising and detrimental effects of institutional practice and the medical education process itself has led to recognition of the importance of promoting humanistic qualities and behaviour in medical ethics education.16 A broad community consensus on unacceptable professional behaviour also exists. Awareness and discussion of professional values, attitudes and behaviours should be fostered among students and their teaching staff, both to minimise direct patient harm and to recognise and reduce individual and cultural factors that may erode professional trust. Attitudes that are important for medical students to develop are those that promote patients' interests through the doctor-patient relationship, the interests of colleagues through professional relationships, and students' own well-being (Box 3). These attitudes are core components of professional identity; placing them within the ethics curriculum does not imply ethical ownership, but is a mechanism to ensure explicit teaching in this area. Teaching methods It is imperative that ethics teaching be precise, challenging and clinically relevant. The curriculum should target students' needs,17 reflect the ethical issues encountered in clinical and professional practice,18 and take account of empirical research in ethics where appropriate. Ethics teaching should also consider the informal, "hidden" curriculum displayed in the values and behaviours of clinical and preclinical teachers and in the ways in which hospitals and medical schools are organised. The subtle messages students acquire from their teachers and institutions are, arguably, the most important determinant of what values are learnt, how they are learnt and the impact they have on practice and the profession. There is no single "best" method by which ethics should be taught and, indeed, the evolution of ethics education has profited enormously from curricular experimentation and innovation. However, all forms of teaching must remain cognisant of the centrality of the individual's experience, or narrative, and must also be committed to the notion of dialogue between individuals and between professions, perspectives and ideologies. This creates the basis for the incorporation of multiple perspectives and multiple teachers into ethics programs. Although the conceptual and theoretical knowledge of ethics can easily be introduced through readings, lectures, seminars or computer-assisted instruction, ethics education is fundamentally discursive, and thus it is essential to facilitate at least some learning of ethics knowledge in small groups. Small-group learning using case studies and problem-solving exercises can be used both to amplify and extend more didactic teaching methods and also to reinforce the relevance of ethics to medicine (Box 4).19 Professional, clinical and social issues can also be taught by integration with clinical teaching in a number of other settings, including: formal "ethics" ward rounds;20 formal "ethics" grand rounds and unit meetings; discussion of ethical issues within clinical seminars; ethics journal clubs. The teaching of attitudes deserves particular mention. The capacity to clarify and critically evaluate one's own values and to integrate personal and professional values in the life of the student and doctor should be an essential part of the medical school curriculum. Teaching methods that have been employed successfully to accomplish these tasks include: values journals or portfolios; discussion of cases, with particular emphasis on critical appraisal of personal and professional values and attitudes; debriefing sessions that allow for reflection and discussion of attitudes and behaviours encountered in the day-to-day experience of medical students. Role modelling by teachers is a crucial influence on the attitudes and behaviour of future doctors.21,22 The unconscious assimilation of professional culture and the ethical capitulations that have been seen as necessary for advancement within that culture can be better recognised and dealt with in educational programs that explicitly aim to include these elements. Teachers of ethics can play an important role in modelling the very nature of ethics: the teaching process should be perceived as being emotionally supportive and academically encouraging, should be tolerant of multiple perspectives, should be interdisciplinary, and should actively involve clinicians as co-instructors and as role models for students. This also underscores the responsibility of teachers to develop as an ethical community and be alert to, and respond to, unethical behaviour among themselves and their students. Deeper and more focused learning of specific issues through elective courses in ethics should also be available, either as part of the medical curriculum or through interfaculty cooperative arrangements. Advanced elective modules in ethics that may be taken during the degree are an efficient way to offer courses for students with a particular interest in ethics. Finally, although it is essential to introduce ethics within the medical curriculum, ethics may be best learnt when individuals are faced with real-life ethical issues in clinical practice. For this reason, education in ethics should continue through postgraduate and vocational training and continuing education. Ethical, legal and institutional issues are now addressed in structured-release sessions within the Commonwealth-supported National Curriculum for Junior Doctors in the Prevocational Years.23 Assessment It is important that ethical knowledge, skills and attitudes be assessed. This signals to students that their medical school regards ethics as important and acknowledges the fact that students give more attention to the areas that are assessed. Assessment also provides an opportunity to demonstrate the relevance and integral nature of ethics in basic sciences as well as in clinical and professional interactions. There is no single method for assessing ethics knowledge and skills. A number of methods have been used, including written case reports, objective structured clinical examinations24 and group assessment of students' self-directed, problem-based learning skills. Skills of problem-solving, cooperation and self-motivation may be assessed by such means as self- or peer-ratings, assessments by tutors, literature searches, diaries or portfolios.25,26 The critical issue is not so much the method of assessment, but whether the assessment instrument is well designed and appropriate to the task. The challenge for ethics educators is to develop valid, relevant, rigorous and reliable measures for assessing ethics and for evaluating the incorporation of ethics into practice. The challenge of implementing the curriculum The breadth and depth of ethics teaching and the time devoted to it vary considerably between Australasian medical schools. Given the integrated nature of many programs, it is difficult to assess the total number of hours devoted to ethics teaching, but the nominal number of hours per year varies between three and 20 (Box 5). Some medical schools already have dedicated staff teaching ethics with recognised allocation of curriculum time, while others face a number of challenges in reaching the aims we have outlined. These challenges include the following: (a) Shortage of skilled staff. There are no uniform qualifications for teaching ethics in medical schools. Staff require not only a good understanding of moral philosophy, but also familiarity with (and confidence in dealing with) the medical environment. It is difficult to stipulate specific qualifications required, but, as with all university teaching, a higher degree with a major focus on ethics or an appropriate topic is highly desirable. (b) Competition for curriculum time. Many Australasian medical schools have revised their curricula in recent years. There continues to be pressure of curriculum time on all aspects of medical teaching. We have not stipulated the number of contact hours required to successfully implement the core curriculum, as this will vary with methods of teaching, available staff and other factors. An integrated curriculum will incorporate many ethical issues into existing topics — for example, a clinical term in surgery should include teaching on ethical aspects of informed consent to surgical treatment. The issue is not so much competition for extra time, but judicious collaboration with clinical colleagues. Perhaps the greatest challenge facing implementation of a core curriculum in ethics is that of gaining recognition of the skills and expertise required to teach ethics. Until ethics is accepted as an essential domain in medicine, no less important or specialised than anatomy or pharmacology, support for an ethics core curriculum may be lacking. However, given the relatively recent recognition of the need for teaching of communication skills, we trust that support for teaching of ethics is not far behind. Conclusion In this position statement we have argued for the importance of a core curriculum in medical ethics. We believe that the curriculum we have presented meets the Australian Medical Council's medical ethics education goals. Moreover, there continues to be an essential flexibility in the interpretation and implementation of such a curriculum within diverse medical schools. We have also considered the challenges involved in delivering a medical ethics curriculum within an integrated teaching program. These challenges are not insurmountable. Educating the doctors of tomorrow in the ethical practice of medicine is surely a task deserving of our continued best efforts. References Royal College of Physicians and Surgeons of Canada. Bioethics curricula. available at: <http://rcpsc.medical.org/english/ethics>. Accessed 10 July 2001. The teaching of medical ethics: fourth consultation with leading medical practitioners. Geneva: World Health Organization, 1995. Culver CM, Clouser KD, Gert B, et al. Basic curricular goals in medical ethics. N Engl J Med 1985; 312(4): 253-256. Teaching medical ethics and law within medical education: a model for the UK core curriculum. J Med Ethics 1998; 24(3): 188-192. Doherty RL (chairman). Committee of Inquiry into Medical Education and Medical Workforce. Australian medical education and workforce into the 21st century. Canberra: AGPS, 1988. Australian Medical Council. Goals and objectives of basic medical education. Guidelines for assessment and accreditation of medical schools. Canberra: AMC, 2000. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 4th ed. New York: Oxford University Press, 1994. Gillon R, Lloyd A, editors. Principles of health care ethics. Chichester: Wiley, 1994. Tovey P. Narrative and knowledge development in medical ethics. J Med Ethics 1998; 24: 176-181. Boyd KM, Higgs R, Pinching AJ, editors. The new dictionary of medical ethics. London: BMJ, 1997. Driscoll M. Psychology of learning for instruction. Boston: Allyn and Bacon, 1999. Christakis D, Feudtner C. Ethics in a short white coat: the ethical dilemmas that medical students confront. Acad Med 1993; 68(4): 249-254. Hicks LK, Lin Y, Robertson DW, et al. Understanding the clinical dilemmas that shape medical students' ethical development: questionnaire survey and focus group study. BMJ 2001; 322: 709-710. Doyal L. Closing the gap between professional teaching and practice. BMJ 2001; 322: 685-686. Miles SH, Lane LW, Bickel J, et al. Medical ethics education: coming of age. Acad Med 1989; 64: 705-713. Hafferty FW, Franks R. The hidden curriculum: ethics teaching and the structure of medical education. Acad Med 1994; 69: 861-871. Jacobson JA, Tolle BW, Stocking CB, Siegler M. Internal medicine residents' preferences regarding medical ethics education. Acad Med 1989; 64: 760-764. Pellegrino ED, Siegler M, Singer PA. Teaching clinical ethics. J Clin Ethics 1990; 1(3): 175-180. Parker M. Autonomy, problem-based learning and the teaching of medical ethics. J Med Ethics 1995; 21: 305-310. Siegler M. A legacy of Osler: teaching clinical ethics at the bedside. JAMA 1987; 239: 951-956. Wright S, Wong A, Newill C. The impact of role models on medical students. J Gen Intern Med 1997; 12: 53-56. Gordon JJ, Lyon PM. As others see us: students' role models in medicine. Med J Aust 1998; 169: 103-105. Postgraduate Medical Education Committee. Early postgraduate medical education. Available at: <http://meded.qmec.uq.edu.au/cpmec/index.asp>. Accessed 18 July 2001. Singer PA, Robb A, Cohen R, et al. Performance-based assessment of clinical ethics: the ethics objective clinical examination. Acad Med 1996; 71: 495-498. Savulescu J, Crisp R, Fulford KW, Hope T. Evaluating ethics competence in medical education. J Med Ethics 1999; 25: 367-374. Swanson D, Case S, Vleuten C. Strategies for student assessment. In: Boud D, Feletti G, editors. The challenge of problem-based learning. London: Kogan Page, 1991. Authors' details Department of Public Health, University of Adelaide, Adelaide, SA. Annette J Braunack-Mayer, BMedSci(Hons), PhD, Lecturer in Ethics. Centre for the Study of Health and Society, University of Melbourne, Melbourne, VIC. Lynn H Gillam, MA(Oxon), PhD, Lecturer in Health Ethics; and Research Fellow, Ethics Unit, Murdoch Children's Research Institute, Melbourne. Clinical School, St Vincent's Hospital, Melbourne, VIC. Edwina F Vance, MB BS, MBioethics, Fellow. Otago Bioethics Centre, University of Otago Medical School, New Zealand. Grant R Gillett, DPhil(Oxon), FRACS, Professor of Medical Ethics. Clinical Unit in Ethics and Health Law, University of Newcastle, Newcastle, NSW. Ian H Kerridge, MPhil, FRACP, Lecturer in Ethics; John McPhee, BCom (Hons)(Leg Stud), Consultant in Health Law; Peter Saul, FFICANZCA, MA, Clinical Lecturer in Ethics; David E Smith, MB BS, GradCertBioethics, General Medical Practitioner; Henry M Wellsmore, MAE, MSocSc, Lecturer in Ethics. School of Medicine, Flinders University, Adelaide, SA. Bogda Koczwara, FRACP, MBioethics, Coordinator, Personal and Professional Development; Wendy A Rogers, MRCGP, PhD, NHMRC, Sydney Sax Research Fellow, Department of General Practice; Brian F Stoffell, BA(Hons), PhD, Director of Medical Ethics. School of Community Medicine, University of New South Wales, Sydney, NSW. Paul M McNeill, LLB, PhD, Associate Professor of Ethics and Law in Medicine. School of Medicine, University of Tasmania, Hobart, TAS. Christopher J Newell, MA(Hons), PhD, Senior Lecturer. School of Medicine, University of Queensland, Brisbane, QLD. Malcolm H Parker, MB BS, MLitt(Hons), Senior Lecturer in Ethics and Professional Development. Department of Medical Education, University of Sydney, Sydney, NSW. Merrilyn Walton, BSW, MSW, Associate Professor of Ethical Practice. School of Medicine, James Cook University, Townsville, QLD. John S Whitehall, MB BS, FRACP, Associate Professor; and Domain Chair of Ethics and Personal Development, Director of Neonatology. Reprints will not be available from the authors. Correspondence: Dr A J Braunack-Mayer, Department of Public Health, University of Adelaide, SA 5005. annette.braunackmayerATadelaide.edu.au Make a comment 1: Approaches to ethics The "four principles" approach The "four principles" approach to ethics is based on principles of ethics articulated by Beauchamp and Childress.7 These principles are: Beneficence (the obligation to provide benefits); Non-maleficence (the obligation to avoid harm); Respect for autonomy (the obligation to respect the decision-making capacity of others); Justice (the obligation of fairness). It is claimed that these four principles encompass most, if not all, ethical issues in healthcare and provide a common set of moral commitments and a common language for discussing ethical issues.8 Narrative ethics Narrative ethics offers an alternative approach to principles, in which personal narrative, rather than a pre-identified framework, is central to any analysis and to decision-making. The emphasis is upon understanding the meaning of the situation for those involved. Narrative analysis draws upon skills of interpretation and reasoning by analogy to reach sound and defensible conclusions.8 This approach assumes that the most appropriate ethical solution can be reached through knowledge of the personal, cultural and social context of the individual.9 Ethics of care Ethics of care gives priority to caring as the most important moral principle in healthcare ethics, rejecting abstract and impersonal approaches to ethical analysis. In particular, care is contrasted with justice as a more appropriate moral principle. Like narrative ethics, ethics of care relies upon detailed information about the context of ethical decision-making in order to provide ethically sensitive and morally supportive care.10 Virtue ethics Virtue ethics starts with a consideration of particular qualities or virtues such as honesty, wisdom, or kindness rather than with concepts or rules. Becoming a good doctor involves learning through experience and from others and adopting an internal, value-based perspective, rather than following external rules or principles.10 This approach emphasises character and wisdom rather than focusing on the "right" result. Virtue ethicists believe that the intention to be a kind and compassionate person, rather than following a set of prescribed rules, results in a more integrated life with better-quality interactions. Back to text 2: Core knowledge for ethics in the medical curriculum FOUNDATIONS TOPICS Bioethical concepts Ethics in practice Disease, illness and suffering Models of the doctor-patient relationship Autonomy and agency Empathy, responsibility and accountability Personhood Determining capacity Competence and rationality Consent to and refusal of treatment Duty of care/beneficence Informed decision-making and disclosure Medical paternalism Legal aspects of the duty of care Vulnerability and trust Surrogate decision-making Medical veracity Involuntary treatment Harm Privacy and confidentiality issues Justice Compliance and adherence to treatment Life and death Futility/limiting, withdrawing treatment End-of-life decisions and causation of death Reproductive issues (including abortion) Professional ethical concepts Professionalism Professionalism, unprofessional conduct, self-regulation Professional issues for medical students and clinical governance Codes of ethics Student and physician impairments (eg, illness) Maintaining clinical competence Responding to clinical error Social ethical concepts Medical practice and research in society Individual and common good Cultural sensitivity in practice Individuals, families, societies and cultures Decision-making in conditions of uncertainty Human rights Resource allocation issues Models of healthcare delivery Public health ethics and legal obligations History and philosophy of medicine Evidence-based medicine and clinical judgement Status and uncertainties of science Ethical issues in complementary medicine Models of health, disease and care Commercialisation of medicine (including e-health) Medicalisation Human research ethics Goals and scope of medicine Issues in genetics and biotechnology Back to text 3: Core attitudes for ethics in the medical curriculum Honesty, integrity and trustworthiness Critical self-appraisal (including recognition of limitations and errors) Empathy and compassion Respect for (the dignity of) patients as people Respect for the roles of other healthcare professionals in the care of the patient Responsibilities of the medical professional towards the local and global community Responsibility and reliability Commitment to clinical competence and lifelong education Commitment to self-care Back to text 4: Examples of strategies for teaching ethics Scenarios incorporating ethical issues are used to prompt discussion, provide material for debate, or to set up role plays. Scenarios are used as triggers to explore issues. Students may be required to present their findings and understanding to others at a later time. This approach works in both "traditional" and "problem-based learning" courses. Students and their tutor discuss particular issues such as respect for colleagues and teachers, fidelity, promise-keeping and professional standards of behaviour, and how these concepts translate into a clinical setting. Issues of this sort may arise from the learning situation itself (eg, establishing and maintaining rules for attendance and commitment in shared tasks). Clinical situations are used as a prompt for students and staff to discuss ethical issues as they arise in the day-to-day practice of medicine. Students are required to keep a portfolio of current events as they are reported in the media, and to discuss this material in an essay and/or tutorial presentation. Students participate in a series of ethics tutorials, integrated with their clinical teaching, culminating in a group presentation to clinicians and students involving scripted role-plays on diverse ethical topics. Final-year students work on a statement of values that is incorporated into a declaration to be made during a prize-giving or graduation ceremony. Back to text 5: Ethics teaching in Australasian medical schools* University Year level taught Format Time allocated Adelaide All years† Lectures, seminars, PBL tutorials, self-directed learning, clinical modules Year 1: 10 hours Year 2: 10 hours Year 3: 25 hours Years 4-6: 3 hours/year Flinders All years Lectures, PBL tutorials, electives, web-based learning, portfolios, clinical teaching Year 1: 18 hours Year 2: 18 hours Year 3: 4 hours of formal lectures Melbourne All years Lectures, seminars, tutorials, PBL, self-directed learning, research projects, clinical teaching Year 1: 22 hours Year 2: 16 hours Year 3: 12 hours Years 4-6: 15 hours New South Wales All years Lectures, tutorials, workshops, clinical teaching Year 1: 6 hours Year 2: 35 hours Year 3: 28 hours Years 4-6: 5 hours/year Newcastle All years Seminars, tutorials, self-directed learning, clinical teaching Years 1-6: 40-50 hours Queensland All years† PBL tutorials, lectures, symposia, web-based learning, clinical teaching Years 1-2: 10% Years 3-4: 15% (% of curriculum) Sydney All years Lectures, theme sessions, PBL tutorials, portfolios, clinical teaching Years 1-3: weekly sessions Years 4-6: forum and integrated teaching Tasmania All years Lectures, tutorials, seminars, self-directed learning, electives, clinical teaching Years 1-6: 4 hours/year of formal lectures * As reported by ATEAM members. † Taught within EPPD stream. PBL = Problem-based learning. EPPD = Ethics, personal and professional development. Back to text

A Working Group, on behalf of the Association of Teachers of Ethics and Law in Australian and New Zealand Medical Schools (ATEAM)

CLASS="LinkBox"> Position Statement Metformin and intervention in polycystic ovary syndrome Robert J Norman, Warren J Kidson, Ross C Cuneo, Margaret R Zacharin on behalf of the Endocrine Society of Australia, the Australian Diabetes Society and the Australasian Paediatric Endocrine Group MJA 2001; 174: 580-583 For editorial comment, see Lobo Abstract - PCOS and insulin resistance - Metformin - Published studies on metformin in PCOS - What should doctors do? - References - Authors' details - - More articles ...

Robert J Norman · Warren J Kidson · Ross C Cuneo · Margaret R Zacharin

Note: This document has now been superseded by the 2006 edition. Click here to access the 2006 edition. Abstract Chronic heart failure (CHF) affects approximately 1% of people aged 50-59 years, and this high prevalence increases dramatically with age. CHF is a common reason for hospital admission and general practitioner consultation in the elderly. Common causes of CHF are ischaemic heart disease, hypertension and idiopathic dilated cardiomyopathy. Diagnosis of CHF is based on clinical features and objective measurement of ventricular function (eg, echocardiography). Management is directed at prevention, retarding disease progression, relief of symptoms and prolonging survival. Non-pharmacological approaches include exercise, home-based support and risk-factor modification. Angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of pharmacological therapy to prevent disease progression and prolong survival. ß-Blockers prolong survival when added to ACE inhibitors in symptomatic patients. Diuretics provide symptom relief and restoration or maintenance of euvolaemia. Spironolactone, angiotensin II receptor antagonists and digoxin may be useful in some patients. Surgical approaches in highly selected patients may include myocardial revascularisation, insertion of devices and cardiac transplantation. Most of the current information on the epidemiology of chronic heart failure (CHF) is derived from seven major overseas epidemiological studies published since 1985.1 There have been several consistent findings, including a sharp increase in prevalence with age and a marked male preponderance.2 The prevalence of CHF is approximately 1% in people aged 50 to 59 years, but over 50% in people 85 years and older. Information on the overall incidence and prevalence of CHF in Australia is derived mainly by extrapolation of overseas information. Based on data from the United States,3 it is likely that at least 300 000 Australians are affected with CHF and about 30 000 new cases are diagnosed annually. There are more reliable Australian data regarding hospitalisation for CHF -- in 1996 and 1997, 41 000 hospitalisations reported CHF as a principal diagnosis, and CHF accounted for 0.8% of all hospitalisations in Australia in these two years, with patients aged 70 years and over accounting for over three-quarters of all hospitalisations for CHF. During 1996 and 1997, CHF contributed 2% of all deaths.4 CHF also constitutes a common reason for consultations with general practitioners. A recent survey of 341 Australian general practitioners estimated that, for every 100 patients aged 60 years and over seen in general practice, 11 had known CHF and two would be newly diagnosed as having CHF based on clinical features and known aetiological factors.5 The cost burden associated with CHF is expected to increase markedly6 because of a number of factors, including: ageing of the population; the projected increase in the number of older people with coronary heart disease and hypertension; the decrease in case-fatality rates associated with acute coronary syndromes; and improved diagnosis of CHF because of increased use of sensitive techniques, such as echocardiography. There are no precise data for Australia relating to the economic burden associated with CHF. However, direct health costs for cardiovascular disease in 1993-94 were estimated at $3719 million (12% of total health care costs), and CHF has been estimated to account for $411 million of these costs, including $140 million per annum for costs of hospitalisation and $135 million per annum for nursing home costs. Causes and diagnosis Although systolic and diastolic CHF often coexist, the distinction between them is relevant to the therapeutic approach. Causes of chronic heart failure are shown in Box 1. Diagnosis is based on well-known clinical features and appropriate investigations, not only to confirm or exclude the diagnosis of CHF, but also to establish underlying causes for which particular treatment is necessary. Recommendations relating to the diagnosis of CHF are shown in Box 2. Management of chronic heart failure General non-pharmacological measures are important in the management of CHF and are summarised in Box 3, and recommendations for therapy in asymptomatic patients or to prevent CHF are summarised in Box 4. Details supporting the use of drugs in systolic CHF are summarised in Box 5 and the management of diastolic CHF is summarised in Box 6. Angiotensin-converting enzyme (ACE) inhibitors Because of the major importance of renin-angiotensin system activation in the progression of CHF, blockade of this system has become the cornerstone of successful therapy for systolic ventricular dysfunction. ACE inhibitors have been shown to: prolong survival (compared with placebo) in patients with New York Heart Association Class II, III and IV CHF;31,32 improve patient symptom status, exercise tolerance and reduce hospitalisation for worsening CHF45 (in some but not all studies); and increase ejection fraction compared with placebo in many studies. The optimal dose of ACE inhibitor has not been definitively determined. In one study that examined ACE inhibitor dosage, there was no difference in the combined endpoint of death, CHF hospitalisation or worsening CHF whether enalapril was used at 2.5 mg, 5 mg or 10 mg twice daily.46 In a study comparing lisinopril at doses of 2.5-5 mg and 32.5-35 mg daily, there was a marginal, non-significant reduction in mortality, with a significant but rather small (12%) reduction in the combined endpoint of death and all-cause hospitalisation with the higher dose.34 These data have been interpreted in many ways, but there is general agreement that all patients with CHF should be established on therapy with at least low doses of ACE inhibitors, and that an effort should be made to up-titrate to higher doses if possible. ß-Blockers As with ACE inhibitors, ß-blockers inhibit the adverse effects of chronic activation of a key neurohormonal system (in this case, the sympathetic nervous system) on the myocardium. These adverse actions may be mediated via ß1-receptors, ß2-receptors, and/or α1-receptors. Three ß-blockers — carvedilol (ß1-, ß2- and α1-antagonist),35 bisoprolol (ß1-selective antagonist, not currently available in Australia)36 and metoprolol extended release (ß1-selective antagonist, formulation not currently available in Australia)37 — have been shown to prolong survival in patients with mild to moderate CHF already receiving background ACE inhibitor therapy. More recently, carvedilol has been shown to prolong survival (35% relative reduction in risk of death)39 in a prospective study of patients with severe CHF symptoms who did not have overt volume overload or recent acute decompensation. Similar observations have been made from post-hoc analyses of subgroups with advanced heart failure symptoms in the above trials of metoprolol and bisoprolol. ß-Blocker therapy should not be initiated during a phase of decompensation, but only after the patient's condition has stabilised. ß-Blockers should be started at very low initial doses, then up-titrated slowly to target dose, with the expectation that it may take some months before clinical benefits occur. Adverse effects of initiation of ß-blockade in CHF are commonly observed and include symptomatic hypotension, worsening of underlying disease because of withdrawal of sympathetic drive, and bradycardia. However, side effects are usually transitory and rarely necessitate cessation of ß-blocker therapy. Patients with minimal symptoms (New York Heart Association Class II) derive little symptomatic benefit from ß-blocker therapy,47 while clinically significant improvements in symptom status are observed in those with more advanced disease. Symptomatic benefit is delayed with ß-blockade, and this may be an important issue in decision-making about starting the drug in severely symptomatic patients with limited life expectancy. Diuretics Diuretics are used to improve symptoms. They have been shown to increase urine sodium excretion and to decrease the physical signs of fluid retention in patients with CHF, thus rapidly improving symptom status. In patients with fluid overload, the aim is to achieve an increase in urine output and weight reduction of 0.5-1 kg daily, generally with loop diuretics, until euvolaemia (evaluated from clinical symptoms and signs as well as the patient's bodyweight) is achieved. Combined use of loop and thiazide diuretics is often used in clinical practice, although objective data supporting this combination are limited. The dose of diuretic should be regularly reassessed, as dosage may need to be adjusted based on whether the patient is considered to be volume overloaded or underloaded on clinical evaluation. Spironolactone Although traditionally considered a potassium-sparing loop diuretic, spironolactone has a number of other potential properties that make it an important agent in the treatment of CHF. Aldosterone receptors within the heart mediate fibrosis, hypertrophy and arrhythmogenesis. Thus, blockade of these receptors with spironolactone may theoretically provide benefit in CHF. This hypothesis has recently been supported by the observation of a 30% reduction in all-cause mortality and symptomatic improvement in advanced CHF patients receiving spironolactone (average, 25 mg per day) compared with placebo.40 The risk of the potentially lethal adverse effect of hyperkalaemia, particularly in the setting of concomitant renin-angiotensin system blockade and/or renal impairment, makes careful monitoring mandatory when using spironolactone. Digitalis The cardiac glycoside digoxin acts to inhibit sodium-potassium ATPase in patients with ventricular dysfunction; blockade of this enzyme has been associated with improved inotropic responsiveness. Digoxin may also sensitise cardiopulmonary baroreceptors, reduce central sympathetic outflow, increase vagal activity and has been shown to reduce renin secretion. There have been a number of studies in patients with CHF and sinus rhythm that support the favourable effect of digoxin on symptoms and ejection fraction. Withdrawal of digoxin in the presence of an ACE inhibitor leads to progressive clinical deterioration in symptom status as well as exercise tolerance.42 In contrast, the only placebo-controlled trial of mortality with digoxin yielded a neutral outcome.43 While deaths from worsening CHF were reduced with digoxin therapy, this was offset by an increase in sudden deaths. However, digoxin therapy was accompanied by a reduction in hospitalisation for worsened CHF and patients with more severe symptoms appeared to benefit symptomatically from the introduction of digoxin. Digoxin remains valuable therapy in CHF patients with concomitant atrial fibrillation (AF). Other drugs Hydralazine and isosorbide dinitrate — This combination of vasodilator drugs has shown marginal superiority compared with placebo in terms of overall mortality,48 and no benefit for hospitalisation. The ACE inhibitor enalapril was clearly shown to be superior to hydralazine and isosorbide dinitrate by reducing sudden deaths.44 Angiotensin II receptor antagonists — It is uncertain whether angiotensin II (AII) receptor antagonists offer additional benefits over ACE inhibitors. They are generally better tolerated than ACE inhibitors because they do not produce kinin-mediated side effects, such as dry cough. On the other hand, inhibition of kinin breakdown by ACE inhibitors may be an important component of their beneficial mechanism (ie, bradykinin-induced nitric oxide synthesis). Comparative studies of ACE inhibitors versus AII antagonists have tested these hypotheses,49,50 but have shown no evidence for superiority of AII receptor antagonists; indeed, there was a significant mortality benefit with the combination of ACE inhibitor and ß-blocker compared with the AII receptor antagonist and ß-blocker combination.50 It is possible (but not yet confirmed) that combination therapy with ACE inhibitors and AII antagonists may maximise the benefits of renin-angiotensin system blockade.41 There may also be an adverse interaction of this combination with ß-blockers.41 Based on the above findings, AII receptor antagonists may be considered as an alternative to ACE inhibitors for patients who are truly ACE-inhibitor intolerant as a result of kinin-mediated adverse effects such as cough.41 Drugs to avoid in chronic heart failure Anti-arrhythmic agents (apart from ß-blockers and amiodarone) should be avoided because of their pro-arrhythmic potential, negative inotropic effects, and a tendency to increase mortality. Calcium antagonists that are direct negative inotropic agents, such as verapamil and diltiazem, are absolutely contraindicated in patients with systolic CHF. Dihydropyridine calcium antagonists such as amlodipine and felodipine offer no survival benefit in systolic CHF.51-53 Tricyclic antidepressants should be avoided because of their pro-arrhythmic potential. Non-steroidal anti-inflammatory drugs (NSAIDs)54 should be avoided, as they can inhibit the effects of diuretics and ACE inhibitors and can worsen both cardiac and renal function. Cyclooxygenase (COX)-2 inhibitors appear to have similar adverse effects on salt and water retention as do standard NSAIDs.55 Pharmacological therapies reserved for advanced chronic heart failure Positive inotropic agents can improve cardiac performance during short-term and long-term therapy. -Adrenergic agonists (eg, dobutamine) and phosphodiesterase inhibitors (eg, milrinone) enhance cardiac contractility by increasing myocardial levels of cyclic adenosine monophosphate. However, despite favourable short-term haemodynamic and clinical effects, long term oral therapy with positive inotropic agents has not been shown to reliably improve symptoms or clinical status and has been associated with a significant increase in mortality.56-58 For similar reasons, long term intermittent infusions of positive inotropic therapy are not recommended. A small proportion of patients can not be weaned from inotropes despite repeated attempts, but are well enough with inotrope therapy to be managed at home with the aid of a portable pump and long-term IV access. This can be used as a bridging strategy to heart transplantation, or as palliation. Treatment of associated disorders CHF and cardiac arrhythmia Efforts should be made to restore and maintain sinus rhythm in patients with atrial fibrillation (AF). This may require episodic electrical cardioversion while patients are anticoagulated with warfarin. If sinus rhythm can not be maintained for prolonged periods, therapy should be directed at controlling the ventricular response rate (with digoxin, -blockers or amiodarone) and reducing thromboembolic risk by anticoagulation with warfarin.59 Use of amiodarone should be considered in patients who have frequent episodes of symptomatic ventricular tachycardia (VT), and as a component of therapy in patients at high risk of ventricular fibrillation (VF). Therapy with Class I anti-arrhythmic agents (eg, flecainide) is generally contraindicated in the presence of systolic CHF. CHF and ischaemic heart disease Specific treatment of ischaemia may represent the primary therapeutic option in selected patients presenting with symptoms of CHF. CHF patients with demonstrably reversible ischaemia should be considered for myocardial revascularisation procedures. Calcium antagonists should generally be avoided as anti-anginal therapy in patients with left ventricular ejection fractions below 40%. -Blockers represent a major component of anti-anginal therapy in CHF, and should be used whenever tolerated. Prophylactic nitrate therapy should usually be a component of anti-anginal therapy in CHF. Patients with severe angina and inoperable disease, together with systolic CHF, may be considered for prophylactic therapy with perhexiline, as long as plasma drug levels are monitored regularly to prevent toxicity. CHF and arthritis CHF patients with severe systolic dysfunction, hyponatraemia, or both, should not be treated with large doses of COX inhibitors (both non-selective and COX-2-selective) for arthritis, as these drugs will increase the risk of worsening CHF.54,55Low-dose aspirin (up to 150 mg/day) appears to be well tolerated in patients with CHF. Higher doses should probably be avoided.60 There is controversy at present about a possible interaction between aspirin and ACE inhibitors which might decrease the efficacy of the ACE inhibitors.61 Ancillary therapies Pacing Pacing may be needed to treat symptomatic bradyarrhythmias. Whenever possible, atrioventricular synchrony should be maintained in view of the significant contribution of atrial filling to cardiac output in CHF. Upgrading a ventricular pacemaker to a dual-chamber device should be considered in patients with CHF who have electrocardiographic evidence of organised atrial activity. Rate-responsiveness may also be a useful pacing characteristic in CHF patients. The use of biventricular pacing to resynchronise cardiac contraction in patients with systolic CHF and left bundle branch block is currently the subject of several international trials. Results so far are promising, with symptomatic benefit in patients programmed in biventricular mode.62 Longer-term and mortality data are awaited. Surgery (other than revascularisation) Surgical management of mitral regurgitation can produce significant improvement in both symptoms and left ventricular function. Left ventricular aneurysmectomy may benefit patients with CHF in whom a large aneurysm can be excised, particularly if the remaining myocardium is functionally normal and there is minimal residual coronary artery disease. Left ventricular free wall excision (frequently with concomitant mitral valve repair or replacement) aims to restore a normal myocardial mass-to-volume ratio in patients with severe left ventricular dilatation. This procedure has not yet been subjected to the clinical trials needed to define its place (if any) in managing CHF.63 Cardiomyoplasty via stimulated skeletal muscle wraps has been used to augment the function of the failing left ventricle in patients with New York Heart Association Class III symptoms and only modest left ventricular dilatation.64 Because of disappointing results with this approach, non-stimulated synthetic wraps, which passively restrict LV dilatation, have more recently been evaluated, with promising initial results.65 Left ventricular assist devices (LVADs) are most often used as a temporary bridge to cardiac transplantation or for recovery of the heart after cardiac surgery.66 While they have occasionally been used as a long-term alternative to cardiac transplantation, no device is approved for this indication. The prohibitive cost, large size, the fact that only part of the device is implantable and risk of complications (especially infection and thromboembolism) limit the widespread use of currently available LVADs in patients with end-stage CHF. Cardiac transplantation is an accepted therapy for certain patients with refractory CHF who meet eligibility criteria.67 The five-year survival is 65%-75%, but a shortage of donors means it is available only for a very small subset of patients. Diastolic heart failure Diastolic heart failure is common and may account for up to 40% of patients with heart failure. A proposed schema for management of diastolic heart failure is summarised in Box 6. It is important to note that these recommendations for therapy represent expert opinion only, as no randomised controlled trial has yet been completed with any agent specifically for diastolic CHF. Disclosure Many members of the Writing Panel have received paid honoraria for work performed on behalf of manufacturers of therapies described in these guidelines. However, no members of the Writing Panel stand to gain financially from their involvement in these guidelines and no conflicts of interest exist for Writing Panel members, the National Heart Foundation or the Cardiac Society of Australia & New Zealand. Reference Yamani M, Massie BM. Congestive heart failure: insights from epidemiology, implications for treatment. Mayo Clin Proc 1993; 68: 1214-1218. Kannel WB, Cupples A. Epidemiology and risk profile of cardiac failure. Cardiovasc Drugs Ther 1988; 2 Suppl 1: 387-395. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285: 1441-1446. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases, Australian facts. Canberra: AIHW and Heart Foundation of Australia, 1999. 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Keteyian SJ, Levine AB, Brawner CA, et al. Exercise training in patients with heart failure. A randomised, controlled trial. Ann Intern Med 1996; 124: 1051-1057. Rich MW, Beckham V, Wittenberg C, et al. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995; 333: 1190-1195. Stewart S, Vandenbroek A, Pearson S, et al. Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure. Arch Intern Med 1999; 159: 257-261. Naughton MT. Impact of treatment of sleep apnoea on left ventricular function in congestive heart failure. Thorax 1998; 53 Suppl 3: S37-S40. McDonald CD, Burch GE, Walsh JJ. Prolonged bed rest in the treatment of idiopathic cardiomyopathy. Am J Med 1972; 52: 41-50. 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Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the international nifedipine GITS study: intervention as a goal in hypertension treatment. Lancet 2000; 356: 366-372. Hansson L, Hedner T, Lund-Johansen P, et al Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359-365. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA 1997; 277: 739-745. Dargie HJ. Design and methodology of the CAPRICORN trial -- a randomised double blind placebo controlled study of the impact of carvedilol on morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail 2000; 2: 325-332. Freemantle N, Cleland JGF, Young P, et al. Beta-blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999; 318: 1730-1777. Kjekshus J, Pedersen TR, Olsson AG, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997; 3: 249-254. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991; 325: 293-302. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429-1435. Armstrong PW, Moe GW. Medical advances in the treatment of congestive heart failure. Circulation 1993; 88: 2941-2952. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100: 2312-2318. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349-1355. CIBIS II investigators and committees. The cardiac insufficiency bisoprolol study II (CIBIS II): a randomised trial. Lancet 1999; 353: 9-13. MERIT Investigators. Effect of metoprolol CR/XL in chronic heart failure. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001-2007. Carson PE. Beta-blocker treatment of heart failure. Prog Cardiovasc Dis 1999; 41: 301-321. Packer M, Coats AJS, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the survival of patients with severe chronic heart failure. New Engl J Med 2001. In press. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709-717. Thackray SD, Witte KK, Khand A, et al. Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure. Eur J Heart Fail 2001; 3: 117-124. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993; 329: 1-7. Digitalis Intervention Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525-533. Cohn JN, Johnson G, Ziesche S, et al A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-310. Pflugfelder PW, Baird MG, Tonkon MJ, et al. Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind placebo-controlled study of quinapril. J Am Coll Cardiol 1993; 22: 1557-1563. The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. Eur Heart J 1998; 19: 481-489. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997; 349: 375-380. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314: 1547-1552. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997; 349: 747-752. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial — the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582-1587. Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on survival. Evaluation Study Group. N Engl J Med 1996; 335: 1107-1114. Thackray S, Witte K, Clark AL, Cleland JG. Clinical trials update: OPTIME-CHF, PRAISE-2, ALL-HAT. Eur J Heart Fail 2000; 2: 209-212. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997; 96: 856-863. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000; 160: 777-784. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med 2000; 133: 1-9. Packer M, Carver JR, Rodeheffer RJ, et al, for the PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991; 325: 1468-1475. Hampton JR, van Veldhuisen DJ, Kleber FX, et al, for the Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Lancet 1997; 349: 971-977. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1-6. Mackstaller LL, Alpert JS. Atrial fibrillation: a review of mechanism, etiology, and therapy. Clin Cardiol 1997; 20: 640-650. Cleland JG, Bulpitt CJ, Falk RH, et al. Is aspirin safe for patients with heart failure? Br Heart J 1995; 74: 215-219. Hall D. The aspirin-angiotensin-converting enzyme inhibitor tradeoff: to halve and halve not. J Am Coll Cardiol 2000; 35: 1808-1812. Barold SS. Biventricular cardiac pacing : promising new therapy for congestive heart failure. Chest 2000; 118: 1819-1812. Dreyfus G, Mihealainu S. The Batista procedure. Heart 2001; 85: 1-2. Jessup M. Dynamic cardiomyoplasty: expectations and results. J Heart Lung Transplant 2000; 19 (8 Suppl): S68-S72. Raman JS, Power JM, Buxton BF, et al. Ventricular containment as an adjunctive procedure in ischemic cardiomyopathy: early results. Ann Thorac Surg 2000; 70: 1124-1126. Jaski BE, Lingle RJ, Reardon LC, Dembitsky WP. Left ventricular assist device as a bridge to patient and myocardial recovery. Prog Cardiovasc Dis 2000; 43: 5-18. Dabol R, Edwards NM. Cardiac transplantation and other therapeutic options in the treatment of end-stage heart disease. Compr Ther 2000; 26: 109-113. Authors' details National Heart Foundation of Australia, Melbourne, VIC. Henry Krum, MB BS, PhD, Associate Professor, Department of Epidemiology and Preventive Medicine, and Department of Medicine, Monash University, Alfred Hospital, Melbourne, VIC. Correspondence: Associate Professor H Krum, Clinical Pharmacology Unit, Department of Epidemiology and Preventive Medicine, and Department of Medicine, Monash University, Alfred Hospital, Prahran, 3181 VIC. henry.krumATmed.monash.edu.au * See background and evidence basis of recommendations box at the end of the article. Background and evidence basis of recommendations This article is a summary of evidence-based clinical practice guidelines on the best practice management of chronic heart failure (CHF) in the Australian setting recently developed by the National Heart Foundation of Australia (NHF) and the Cardiac Society of Australia & New Zealand (CSANZ). Financial and administrative support was drawn from both organisations. These guidelines were written by a multi-disciplinary panel comprising Associate Professor Henry Krum (Chair); Professor Andrew Tonkin (NHF); Associate Professor Michael Jelinek (CSANZ); Dr Mark Harris (Royal Australian College of General Practitioners); Professor John McNeil, Dr David Hunt, Dr David Kaye, Associate Professor Louise Burrell, Associate Professor Leonard Arnolda, Associate Professor Anne Keogh, Dr Peter Bergin, Dr Warren Walsh, Associate Professor Andrew Sindone, Dr David Hare, Ms Di Holst, Dr Gerry O'Driscoll, Professor John Horowitz, Dr Meroula Richardson, Dr Julian Smith, Dr Phil Spratt, Professor Leon Piterman, Dr Ian Cameron, Associate Professor Peter Macdonald, Dr Andrew Galbraith, Dr Alan Henderson, Ms Kylie Oliver, Dr Peter Martin; Mr Gerry Atkinson (Heart Support Australia); Ms Bev Motteram (Cardiomyopathy Association of Australia); Ms Helen Egan (NHF Program Manager); Dr Jacinta Halloran (medical writer). These guidelines were externally reviewed by the European Society of Cardiology Working Group on Heart Failure, American College of Cardiology/American Heart Association, Royal Australasian College of Physicians, Royal Australasian College of General Practitioners and New Zealand Guidelines Group. The aim was to develop recommendations towards achieving the best health outcomes for people with CHF. Current relevant literature was reviewed, with assessment of the quality of evidence for each recommendation adapted from the NHMRC 1999 Designation of Levels of Evidence.17 1: Causes of chronic heart failure Systolic (impaired ventricular contraction) Common causes: Ischaemic heart disease and prior myocardial infarction Hypertension Less common causes: Non-ischaemic idiopathic dilated cardiomyopathy Uncommon causes: Valvular heart disease Alcoholic cardiomyopathy Inflammatory cardiomyopathy, or myocarditis (traditionally associated with a history of viral infections such as enteroviruses, especially Coxsackie B virus) HIV-related cardiomyopathy Drug-induced cardiomyopathy, especially anthracyclines (eg, daunorubicin and doxorubicin, cyclophosphamide, paclitaxel and mitoxantrone) Peripartum cardiomyopathy Chronic arrhythmia Diastolic (impaired ventricular relaxation) Common causes: Hypertension Ischaemic heart disease Less common causes: Valvular disease, especially aortic stenosis Uncommon causes: Hypertrophic cardiomyopathy Restrictive cardiomyopathy 2: Recommendations for diagnosis of chronic heart failure (CHF) Level of evidence All patients with suspected CHF should have an objective measurement of ventricular function, preferably by transthoracic echocardiography EO Coronary angiography should be considered in patients with CHF who have a history of exertional angina or suspected ischaemic left ventricular dysfunction EO Haemodynamic measurements may be particularly helpful in patients with refractory CHF, recurrent diastolic CHF or in whom the diagnosis of CHF is in doubt EO Endomyocardial biopsy may be indicated in patients with cardiomyopathy with recent onset of symptoms, in whom coronary artery disease has been excluded by angiography, or in whom systolic ventricular dysfunction is suspected EO Nuclear cardiological testing, stress echocardiography and positron emission tomography can all be used to assess reversibility of ischaemia and viability of myocardium in CHF patients with myocardial dysfunction and coronary disease EO Thyroid function tests should be considered, especially in older patients who develop atrial fibrillation, and who have pre-existing heart disease EO EO=expert opinion. 3: Recommendations for non-pharmacological management of chronic heart failure (CHF) Level of evidence Regular physical activity is recommended.7 All patients with CHF should be referred to an exercise program specifically designed for patients with this condition, if available.7-10 II Patient support by doctor, pre-discharge nurse review with or without home visit is crucial for preventing deterioration in CHF status.11,12 II Sleep apnoea frequently coexists with CHF; patients with obstructive sleep apnoea may benefit from nasal continuous positive airway pressure.13 III CHF patients who have an acute exacerbation or are clinically unstable should have bed rest until their condition improves.14 IV Dietary sodium should be limited to below 200mg daily.15 IV Fluid intake should generally be limited (1.5 litres daily in mild to moderate CHF and 1 litre daily in severe CHF), especially if coexistent with hyponatraemia.16 IV Alcohol intake should generally be nil, but should not exceed 10-20g/day.16 IV Smoking should be strongly discouraged. EO Patients with CHF should be advised to weigh themselves daily and to consult their doctor if their weight increases by more than 1.5kg in a 24-hour period, or if they experience dyspnoea, oedema or abdominal bloating. EO Patients with CHF should be vaccinated against influenza and pneumococcal disease. EO Long flights may predispose to an exacerbation of CHF and should be undertaken with caution. High-altitude destinations should be avoided. Travel to very humid or hot climates should be undertaken with caution and fluid status should be carefully monitored. EO EO=expert opinion. Remaining evidence levels adapted from National Health and Medical Research Council Guideines.17 4: Recommendations for prevention of chronic heart failure (CHF) and treatment of asymptomatic left ventricular (LV) dysfunction Level of evidence All patients with asymptomatic systolic LV dysfunction should be treated with an angiotensin-converting enzyme (ACE) inhibitor and maintained on this therapy indefinitely, unless they are intolerant.18-20 I Antihypertensive therapy should be used to prevent subsequent CHF in patients with elevated blood pressure levels.21-27 I Commencement of therapy with an ACE inhibitor in patients at high risk of ventricular dysfunction (but without current evidence of ventricular impairment) may be considered in individual patients.20 II ß-Blockers should be used early after myocardial infarction (whether or not the patient has systolic ventricular dysfunction).28,29 II Statin therapy should be used as part of a risk factor management strategy to prevent ischaemic events and subsequent CHF in patients who fulfil criteria for commencement of lipid-lowering therapy.30 II Evidence levels adapted from National Health and Medical Research Council Guidelines.17 5: Recommendations for treatment of symptomatic chronic heart failure (CHF) Level of evidence First-line agents Angiotension-converting (ACE) enzyme inhibitors, if tolerated, are mandatory in all patients with systolic heart failure (left ventricular ejection fraction, <40%), whether symptoms are mild, moderate or severe.31-33 Every effort should be made to up-titrate to highest tolerance dose of ACE inhibitors.34 If this is not possible, a lower dose of ACE inhibitor to none at all. Diuretics should be used if necessary to achieve euvolaemia in fluid-overloaded patients. In patients with systolic left ventricular dysfunction, diuretics should never be used as monotherapy, but should always be combined with an ACE inhibitor to maintain euvolaemia. EO β-Blockers are recommended therapy, unless not tolerated or contraindicated, for patients with systolic CHF who remain mildly to moderately symptomatic despite appropriate doses of ACE inhibitors, as well as use of diuretics to optimise fluid status.35-38 I β-Blockers can also be recommended for patients with advanced symptoms of CHF.39 II Spironolactone is recommended for patients who have severe heart failure despite appropriate doses of ACE inhibitors and diuretics.40 II Angiotensin II receptor antagonists may be used as an alternative to ACE inhibitors for patients who are truly ACE-intolerant because of kinin-mediated adverse effects (eg, cough).41 II Second-line agents Digoxin can be considered in patients with advanced CHF for relief of symptoms and to reduce hopitalisation.42,43 It remains valuable therapy in CHF patients with atrial fibrillation. II Hydralazine and isosorbide dinitrate should be reserved for patients who are truly intolerant of ACE inhibitors, or for whom ACE inhibitors are contraindicated and no other therapeutic option exists.44 II EO=expert opinion. Remaining evidence levels adapted from National Health and Medical Research Guideines.17 Box 6 * With rare exceptions, patients with diastolic heart failure present with symptoms and signs of fluid overload, either pulmonary or systemic congestion, or both. † Choice of therapy will vary according to clinical circumstances (eg, thiazide diuretics in elderly patients or those with systolic hypertension; angiotension-converting enzyme [ACE] inhibitors in patients with left ventricular hypertrophy, diabetes or ischaemic heart disease; β-Blockers in patients with agina).

National Heart Foundation of Australia and Cardiac Society of Australia

MJA 2001; 174: 288-292 Abstract - Recommendations 1A - Recommendations 1B - Recommendations 2 - Recommendations 3 - Recommendations 4 - References - Authors' details - - More articles on Obstetrics & gynaecology and women's health Abstract Zoster immunoglobulin (ZIG) should be offered to pregnant, varicella-seronegative women with significant exposure to varicella-zoster virus (VZV) (chickenpox) infection. Oral aciclovir prophylaxis should be considered for susceptible pregnant women exposed to VZV who did not receive ZIG or have risk factors for severe disease. Intravenous aciclovir should be given to pregnant women who develop complicated varicella at any stage of pregnancy. Counselling on the risk of congenital varicella syndrome is recommended for pregnant women who develop chickenpox. ZIG should be given to a baby whose mother develops chickenpox up to 7 days before delivery or up to 28 days after delivery. Intravenous aciclovir should be given to babies presenting unwell with chickenpox, whether or not they received ZIG. Breastfeeding of babies infected with or exposed to VZV is encouraged. A mother with chickenpox or zoster does not need to be isolated from her own baby. If siblings at home have chickenpox, a newborn baby should be given ZIG if its mother is seronegative. The newborn baby does not need to be isolated from its siblings with chickenpox, whether or not the baby was given ZIG. After significant nursery exposure to VZV, ZIG should be given to seronegative babies and to all babies born before 28 weeks' gestation. Varicella-zoster virus (VZV) (chickenpox) infection can cause severe morbidity in the pregnant woman, the fetus, and the newborn baby. 1. Management of VZV infection in pregnancy The implications of primary VZV infection in pregnancy for the mother and for the fetus vary with the period of gestation. For the mother, the risk of adverse effects is greatest in the third trimester, whereas for the fetus the risk is greatest in the first and second trimesters. A. Maternal risk In normal adults, the mortality and morbidity of primary VZV infection is greater than in children. Only about 2% of all cases occur in adulthood, but they account for 25% of all VZV-related deaths.1 Pneumonitis is 25 times more common in adults.1,2A 1995 Australian study assessed VZV seronegativity in women presenting to antenatal clinics and found 22% of women aged 14-19 years, 14% of those aged 20-24 years, 5% of those aged 25-29 years and 2% of those aged 30 years and over had not had previous exposure and were therefore susceptible to VZV infection.3 Anecdotally, chickenpox infection in pregnancy is more severe than in non-pregnant adults, but there is scant supporting evidence.4 A survey of 164 000 pregnancies in the United Kingdom described 98 women with chickenpox, of whom seven developed severe illness and two died.5 The UK confidential inquiry into maternal deaths from 1985 to 1997 reported only seven deaths associated with VZV in pregnancy, all of which occurred in the second half of pregnancy. Other reports have also suggested increased severity of illness in the second half of pregnancy.6 Zoster immunoglobulin (ZIG), given prophylactically at the time of exposure, is known to prevent or reduce the severity of chickenpox.7-9 Aciclovir, an antiviral agent, shortens the duration of illness in young adults if administered during the incubation period or within 24 hours of the onset of the rash.10,11 When administered prophylactically (7 to 9 days after family exposure) it may be up to 84% protective against infection and able to modify the illness in the remaining family members.12 Although aciclovir is not licensed for use in pregnancy (because of concerns about adverse fetal effects), there have been no reports of adverse effects among hundreds of cases over several years of monitoring.13 Management algorithms (Boxes 1 and 2) have been devised for varicella exposure in pregnancy. Recommendations 1A Zoster immunoglobulin (ZIG) (Box 3) All pregnant women who have significant exposure to VZV infection (defined as "living in the same household as a person with active chickenpox or herpes zoster or face-to-face contact with a person with chickenpox or uncovered zoster for at least 5 minutes"), who have no history of chickenpox and who are seronegative (or serological testing is not readily available), should be offered ZIG.4-6 (E3) ZIG should be administered within 72 hours of exposure for maximal effect, although it may provide some benefit up to 96 hours after exposure for immunocompromised subjects.14 (E3) ZIG is ineffective, and should not be given, once clinical illness is established.15 (E4) Aciclovir (Box 3) There is no high level evidence on the use of aciclovir in pregnancy. Based on consensus view, we recommend: Consideration should be given to using oral aciclovir prophylaxis for susceptible pregnant women with significant exposure (defined above) who have not received ZIG, or who have any underlying risk factors, such as chronic lung disease, cigarette smoking,16 systemic corticosteroid treatment,17 impaired immunity,18 or are in the second half of pregnancy (Box 3). (E4) Intravenous aciclovir should be given for varicella pneumonitis or other complications at any stage of pregnancy.4,6,19 These complications include respiratory symptoms, neurological symptoms, haemorrhagic rash and/or continued fever or appearance of new lesions after 6 days.4 (E4) Extrapolation from data in children suggests that patients receiving systemic corticosteroid therapy or those with underlying immunodeficiency should be treated with intravenous aciclovir at the earliest sign of chickenpox.18,20,21 (E4) Management of delivery of the baby There is no evidence that ending the pregnancy speeds maternal recovery. Expedited delivery should only be considered for fetal compromise or if the gravid uterus is thought to be critically impairing maternal ventilation. B. Fetal risk Chickenpox in pregnancy may result in fetal varicella which is usually benign and self-limiting.1 Occasionally, it produces a characteristic pattern of abnormalities known as "congenital varicella syndrome" (CVS).22,23 CVS very occasionally follows maternal zoster infection.5 The risk of CVS after first-trimester maternal chickenpox was estimated from prospective studies as 2.2% (range, 0-9%; 95% CI, 0-4.6%).24-26 In a large prospective European study, the incidence of CVS was 0.4% after maternal chickenpox in the first 12 weeks of pregnancy, rising to 2% between weeks 13 and 20.24 After 20 weeks the risk is far lower, although isolated cases have been reported.3 The incidence of CVS in Australia is 1 in 107 000 pregnancies.27 The congenital defects are usually severe, causing cicatricial skin lesions, limb hypoplasia or paresis, microcephaly and ophthalmic lesions.22,24,28 It is hypothesised that these lesions result from virus reactivation in utero or disseminated zoster infection.2,29 Herpes zoster (shingles) occurs in early childhood in about 1% of otherwise asymptomatic infants exposed to maternal varicella during the second or third trimester.24At present, there is no reliable marker of in-utero virus reactivation or the predicted development of CVS. Serological tests are an insensitive marker of fetal VZV infection and subsequent fetal damage.24 The polymerase chain reaction (PCR) has been used to detect VZV in amniotic fluid: a negative PCR is associated with a favourable outcome, but a positive PCR correlates poorly with the development of CVS.26 As amniocentesis carries a risk of fetal loss, amniotic fluid PCR has a limited role. While ZIG may prevent or modify the course of chickenpox in pregnancy, it may not abolish the risk of fetal infection. Therefore, close ultrasound monitoring for the development of fetal abnormalities after maternal chickenpox or administration of ZIG in pregnancy is recommended. Recommendation 1B Counselling on the risk of congenital varicella syndrome is recommended for women who develop chickenpox during pregnancy. (E4) 2. Management of babies of mothers with perinatal chickenpox Maternal chickenpox in the peripartum period poses a risk of severe neonatal varicella, with a mortality rate up to 30%.30,31 The increased peripartum severity is attributed to a large transplacental inoculum of virus in the absence of protective maternal antibody. The timing of maternal infection in relation to delivery determines the risk to the infant.31 Infection with onset more than seven days before delivery ensures adequate transplacental passage of specific anti-VZV antibody to protect the infant.32 Infection with onset 7 days or less before delivery puts the infant at risk of severe neonatal varicella. Passive immunisation of the baby by giving ZIG immediately after delivery prevents or attenuates neonatal varicella and is essential.7,33 Maternal varicella starting 1-2 days after delivery is also associated with an increased risk of severe neonatal varicella from transplacental spread of the virus.30 However, babies of seronegative mothers exposed postnatally to varicella in the first 28 days after delivery apparently have increased risk of severe illness compared with older infants.33 If the mother develops chickenpox postnatally, her baby is evidently seronegative. Therefore, ZIG is recommended for seronegative babies up to 28 days old exposed to varicella.34,35 Recommendations 2 ZIG is indicated for the baby if maternal varicella develops up to 7 days before delivery or if the mother develops chickenpox up to 28 days after delivery.7,15,31-33 (E3) ZIG should be given to the baby as early as possible after delivery or exposure, but must be within 72 hours.31,32 (E4) Maternal herpes zoster is not an indication for ZIG administration to the baby. (E4) Clinical follow-up of infants receiving ZIG is essential and they should be admitted to hospital if any rash develops, because severe varicella can still occur despite passive immunisation.35,36 (E4) Intravenous aciclovir should be administered (a) to babies presenting with chickenpox who are unwell (eg, poor feeding, tachypnoea), whether or not they received ZIG; (b) to any high risk neonate who develops chickenpox and who inadvertently did not receive ZIG prophylaxis or for whom it was delayed beyond 24 hours; and (c) to immunocompromised neonates who develop chickenpox, including those who are premature or being treated with corticosteroids.18,21 (E4) Routine aciclovir prophylaxis in conjunction with ZIG is not currently recommended in the neonatal population, due to lack of evidence. (E4) Breastfeeding of infected or exposed babies is encouraged. (E4) A mother and/or her baby with active vesicles should be isolated from other mothers and babies, but an infected mother does not need to be isolated from her own baby. (E4) 3. Management of neonates exposed to VZV infection on the postnatal wards or at home The commonest neonatal exposure to VZV is when one or more siblings develops chickenpox in the weeks after delivery. The risk of the newborn developing severe disease from postnatal exposure is considerably less than from transplacentally acquired varicella, but some babies with postnatal exposure will develop severe disease.34 The risk to the newborn baby is determined primarily by the presence or absence of transplacentally acquired maternal IgG antibody. If the mother has had chickenpox, the risk from siblings is negligible. If not, the baby should be given ZIG, which will minimise the risk.34,35 Recommendations 3 ZIG should be administered to a baby up to 28 days old exposed to VZV if the mother is seronegative, her serostatus can not be determined, or if the infant was born at or before 28 weeks' gestation.15,37 (E3) A newborn baby does not need to be isolated from its siblings with chickenpox, whether or not the baby was given ZIG. (E4) Parents should be advised that medical attention should be sought if any signs of chickenpox develop. (E4) Admit to hospital for aciclovir treatment if baby becomes unwell (eg, poor feeding, tachypnoea). (E4) The role of prophylactic aciclovir is unproven. 4. Management of VZV exposure within the neonatal unit VZV poses a particular threat in this setting, because babies born prematurely are relatively deprived of the usual third-trimester transfer of transplacental antibodies.37-39 Spread of VZV is primarily by the respiratory route, so isolation in a separate room is desirable for babies with pneumonitis, and essential if they require artificial ventilation. Staff handwashing is important in reducing spread of the virus. VZV vaccines are now available in Australia, and immunisation of susceptible staff is strongly recommended.35 A significant exposure in the neonatal unit or on the postnatal ward is defined as:10,15 patient sharing the same open ward as a person with chickenpox or zoster; face-to-face contact with a person with chickenpox or zoster for at least 5 minutes; and contact for one hour or more with person (staff or patient) with chickenpox lesions or who developed lesions up to 48 hours later. All staff who have had significant exposure to an index case (see above) and who do not have a history of previous chickenpox infection or of VZV vaccination should have serological tests. If they are VZV antibody negative, they should be removed from clinical duties from days 7-21 after exposure (days 7-28 if they receive ZIG). Recommendations 4 Infants born after 28 weeks' gestation15 should only be given ZIG if they have had significant exposure (defined above) and serological tests show the mother to be seronegative. (E4) All infants born at or before 28 weeks' gestation or born weighing under 1000 g11,37,38 with significant exposure should be given ZIG regardless of the results of serological testing of the mother. (E4) Quarantine of cases should continue until all lesions have crusted.15 (E3) Quarantine of contacts should be from days 7-21 after exposure, and from days 7-28 after exposure if they received ZIG.15 (E3) Although quarantine of cases and those considered to have significant contact is recommended, this should not compromise medical and nursing care of a sick infant. (E4) Infants with pneumonitis requiring ventilation must be isolated. Where isolation facilities are unavailable, cases should be transferred to a unit with isolation facilities. (E4) Aim to discharge all patients requiring quarantine from hospital as soon as possible. (E4) Background and evidence basis of recommendations This position statement was circulated to all members of the Australasian Subgroup in Paediatric Infectious Diseases (ASPID) for comments. The comments were analysed by the authors, discussed with colleagues, and subsequent versions incorporating the comments were re-circulated to all ASPID members. The recommendations of ASPID on the management of VZV exposure and infection in pregnancy and the neonatal period are endorsed by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. The recommendations are based on the following levels of evidence (simplified from the NHMRC's "Quality of evidence ratings")40 E1 Level I Systematic review or meta-analysis of all relevant randomised controlled trials (RCTs) E2 Level II Well-designed RCTs E3 Level III Well-designed cohort or case-control studies E4 Level IV Consensus opinion of ASPID members References Joseph CA, Noah ND. Epidemiology of chickenpox in England and Wales, 1967-85. BMJ 1988; 296: 673-676. Centers for Disease Control. Varicella-zoster immune globulin for the prevention of chickenpox. MMWR Morb Mortal Wkly Rep 1984; 33: 84-90. Chant KG, Sullivan EA, Burgess MA, et al. Varicella-zoster virus infection in Australia. Aust N Z J Public Health 1998; 22: 413-418. Gilbert GL. Chickenpox during pregnancy. BMJ 1993; 306: 1079-1080. Nathwani D, Maclean A, Conway S, Carrington D. Varicella infections in pregnancy and the newborn. A review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection. J Infect 1998; 36 Suppl 1: 59-71. Smego RA Jr, Asperilla MO. Use of acyclovir for varicella pneumonia during pregnancy. Obstet Gynecol 1991; 78: 1112-1116. Brunell PA, Ross A, Miller LH, Kuo B. Prevention of varicella by zoster immune globulin. N Engl J Med 1996; 280: 1191-1194. Gershon AA. Prevention and treatment of varicella zoster virus infection. Pediatr Infect Dis J 1984; 3 (Suppl): 34-36. Bose B, Kerr M, Brookes E. Varicella zoster immunoglobulin to prevent neonatal chickenpox. Lancet 1986; 1: 449-450. Lin TY, Huang YC, Ning HC, Hsueh C. Oral acyclovir prophylaxis after intimate contact. Pediatr Infect Disease J 1997; 16: 1162-1165. Balfour HH Jr, Rotbart HA, Feldman S, et al. Aciclovir treatment of varicella in otherwise healthy adolescents. The Collaborative Aciclovir Varicella Study Group. J Pediatr 1992; 120: 627-633. Azano Y, Yoshikawa T, Suga S, et al. Postexposure prophylaxis of varicella in family contact by oral acyclovir. Pediatrics 1993; 92: 219-222. Andrews EB, Yankasksas BC, Cordero JF, et al. Aciclovir in pregnancy registry: 6 years' experience. The Acyclovir in Pregnancy Registry Advisory Committee. Obstet Gynecol 1992; 79: 7-13. US Department of Health and Human Services. Prevention of Varicella: Recommendations of the Advisory Committee on Immunisation Practices. MMWR Morb Mortal Wkly Rep 1996; 45 (RR-11): i-36. American Academy of Pediatrics. Varicella-zoster infection. In: Peter G, editor. 2000 Red Book: Report of the Committee of Infectious Diseases, 25th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2000: 624-638. Grayson ML, Newton-John H. Smoking and varicella pneumonia. J Infect 1988; 16: 312. Rice P, Simmons K, Carr R, Banatvala J. Near fatal chickenpox during prednisolone treatment. BMJ 1994; 309: 1069-1070. Balfour HH. Intravenous acyclovir therapy for varicella in immunocompromised children. J Pediatr 1984; 104: 134. Haake DA, Zakowski PC, Haake DL, Bryson YJ. Early treatment with acyclovir for varicella pneumonia in otherwise healthy adults. Rev Infect Dis 1990; 12: 788-797. Feldman S, Hughes WT, Daniels CB. Varicella in children with cancer: 77 cases. Pediatrics 1975; 56: 388-397. Reiches NA, Jones JF. Steroids and varicella. Pediatrics 1993; 92: 288-289. La Foret, Lynch LL. Multiple congenital defects following maternal varicella. N Engl J Med 1947; 236: 534-537. Scharf A, Scerr O, Enders G, Helftenbein E. Virus detection in the fetal tissue of a premature delivery with congenital varicella syndrome. A case report. J Perinat Med 1990; 18: 317-322. Enders G, Miller E, Cradock-Watson J, et al. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 1994; 343: 1548-1551. Pastuszak A, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 1994; 330: 901-905. Mouly F, Mirlesse V, Meritet J, et al. Prenatal diagnosis of fetal varicella zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases. Am J Obstet Gynecol 1997; 177: 894-898. Forrest JM, Mego S, Burgess MA. Congenital and neonatal varicella in Australia. J Paediatr Child Health 2000; 36: 108-113. Higa K, Dan K, Manabe H. Varicella-zoster virus infections during pregnancy: hypothesis concerning the mechanisms of congenital malformations. Obstet Gynecol 1987; 69: 214-222. Birthistle K, Carrington D. Fetal varicella syndrome -- a reappraisal of the literature. A review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection. J Infect 1998; 36 Suppl 1: 25-29. De Nicola LK, Hanshaw JB. Congenital and neonatal varicella. J Pediatr 1979; 94: 175-176. Erlich RM, Turner JAP, Clarke M. Neonatal varicella. J Pediatr 1958; 53: 139-147. Miller E, Cradock-Watson JE, Ridehalgh MKS. Outcome of newborn babies given anti-varicella zoster immunoglobulin after perinatal maternal infection with varicella zoster virus. Lancet 1989; 2: 371-373. Hanngren K, Grandien M, Granstrom G. Effect of zoster immunoglobulin for varicella prophylaxis in the newborn. Scand J Infect Dis 1985; 17: 343-347. Rubin L. Disseminated varicella in the neonate and implications for immunoprophylaxis in neonates exposed to varicella. Pediatr Infect Dis J 1986; 56: 100-102. Australian Technical Advisory Group on Immunisation, Commonwealth Department of Health and Aged Care. The Australian immunisation handbook. 7th edition. Canberra: NHMRC/AGPS, 2000: 231-238. Reynolds L, Struik S, Nadel S. Neonatal varicella: varicella zoster immunoglobulin (VZIG) does not prevent disease. Arch Dis Child Fetal Neonatal Ed 1999; 81: F69-F70. Linder N, Waintraub I, Smetana Z, et al. Placental transfer and decay of varicella-zoster virus antibodies in preterm infants. J Pediatr 2000; 137: 85-89. Conway SP, Dear PRF, Smith I. Immunoglobulin profile of the preterm baby. Arch Dis Child 1985; 60: 208-212. Wang E, Prober C, Arvin A. Varicella zoster virus antibody titres before and after administration of zoster immune globulin to neonates in an intensive care nursery. J Pediatr 1985; 103: 113-114. National Health and Medical Research Council. How to use the evidence: assessment and application of scientific evidence. Table 1.3. <http://www.health.gov.au/nhmrc/publicat/pdf/cp69.pdf> (accessed February 2001). Authors' details King George V Hospital, Sydney, NSW. Anne-Marie Heuchan, MB, MRCP, Fellow in Neonatal Medicine. The Children's Hospital at Westmead, Sydney, NSW. David Isaacs, MD, FRACP, FRCPCH, Paediatric Infectious Diseases Physician; and Clinical Professor, University of Sydney. Reprints will not be available from the authors. Correspondence: Professor D Isaacs, Department of Immunology and Infectious Diseases, The Children's Hospital at Westmead, PO Box 4001, Westmead, NSW 2145. davidiATchw.edu.au Make a comment 1: Management of significant exposure* to varicella zoster virus (VZV) during pregnacy (Algorithm 1) *Significant exposure is defined as living in the same household as a person with active chickenpox or herpes zoster or face-to-face contact with a person with chickenpox or zoster for at least 5 minutes. †Risk factors for severe maternal VZV infection are second half of pregnancy, underlying lung disease, immunocompromised, and smoker. See Box 3 for dosage of zoster immunoglobulin (ZIG) and aciclovir. Recommendations based on consensus view. Back to text 2: Management of chickenpox in pregnancy (Algorithm 2) *Complications: respiratory symptoms, haemorrhagic rash, persistent fever >6 days, and new lesions developing >6 days. †At high risk are those women in the second half of pregnancy with underlying lung disease, who are immunocompromised, and who smoke. See Box 3 for doses of aciclovir. Recommendations based on consensus view. Back to text 3: Administration and dosage of zoster immunoglobulin (ZIG) and aciclovir Zoster immunoglobulin High-titre ZIG is available from the Red Cross Blood Transfusion Service in Australia on a restricted basis for the prevention of VZV infection in high-risk subjects. Each vial contains 2mL (16% solution of gammaglobulin fraction of human plasma from donors with high titre of varicella antibodies + thiomersal 0.01% w/v). The recommended dose is 2mL for children 0-5 years, 4mL for children 6-12 years and 6mL for adults.32 Administration is by intramuscular injection, with few adverse effects other than local discomfort reported. This can be lessened if the ZIG is at room temperature when administered. ZIG should never be given intravenously.36 Aciclovir Aciclovir appears to be a safe and relatively well tolerated drug, although it may impair renal function if given to patients who are not adequately hydrated.17 It is not licensed for use in pregnancy but appears to be safe12 and its use is indicated in the high-risk situations outlined. The recommended intravenous dose for treating VZV infection in adults and infants is 10-20mg/kg every 8 hours. The oral dose for adults is 800mg five times daily. The use of oral aciclovir in neonates is not recommended. Back to text

on behalf of the Australasian Subgroup in Paediatric Infectious Diseases of the Australasian Society for Infectious

Position Statement Non-valvular atrial fibrillation and stroke prevention Graeme J Hankey, on behalf of the National Blood Pressure Advisory Committee of the National Heart Foundation* MJA 2001; 174: 234-239 Abstract - Warfarin versus control - Aspirin versus control - Warfarin versus aspirin - Warfarin combined with aspirin - Warfarin versus other antiplatelet agents - Who to treat and with what? - Who is at high risk of stroke and thromboembolism without treatment? - Who is at high risk of haemorrhage with anticoagulant treatment? - Recommendations for antithrombotic therapy for AF - References - Authors' details - - More articles on Cardiology and cardiac surgery Abstract Atrial fibrillation (AF) affects 5% of people older than 65 years. Among patients with AF, the risk of stroke averages about 5% per year. The risk of stroke increases cumulatively with increasing age, previous transient ischaemic attack or stroke, hypertension, diabetes, impaired left ventricular function and a large left atrium. Management aims to identify and treat the underlying cause, control the ventricular rate, restore and maintain sinus rhythm, and minimise the risk of stroke. Warfarin reduces the risk of stroke by about two-thirds, and aspirin by about one-fifth. The risk of anticoagulant-associated haemorrhage increases with serious concomitant disease, and with poorly controlled hypertension and poorly controlled anticoagulation. All patients with chronic AF should be considered for oral anticoagulant therapy, and the decision based on the balance between the risks of thromboembolism and bleeding. The recommended INR (international normalised ratio) is 2.0-3.0. Treating 1000 "average" AF patients (ie, those with a 5% per year risk of stroke) with warfarin prevents about 30 strokes and causes at least two episodes of major haemorrhage each year. Treating 1000 AF patients with aspirin prevents about 15 strokes each year. Atrial fibrillation (AF) is a common arrhythmia. Its prevalence increases with age, from about 2% in the general population, to 5% in people older than 65 years, and 10% in people older than 75 years1,2 (E4; level-of-evidence codes are described in Box 13). It may occur as a single episode, a series of recurrent episodes ("paroxysmal" AF), or continuously ("permanent" or "chronic" AF). Atrial fibrillation is an important arrhythmia because it may signify underlying heart disease, it may cause symptoms of decreased cardiac output (eg, malaise, effort intolerance) or palpitations, and it is associated with an increased risk of systemic thromboembolism and stroke. This risk of stroke averages about 5% per year among all individuals in AF, which is about 5-6 times greater than for people of the same age who are in sinus rhythm (E32).1,2 The management of AF has four principal objectives: To confirm and document the arrhythmia; To identify and treat the underlying cause; To relieve symptoms of decreased cardiac output by controlling the ventricular rate and restoring and maintaining sinus rhythm; and To reduce the risk of systemic thromboembolism, particularly stroke. All patients, except perhaps the very elderly and infirm, should undergo investigation for underlying causes of AF, including thyroid function tests and echocardiography (E4).4 In haemodynamically stable patients, β-blockade, verapamil or diltiazem can be used to control the heart rate (E4). Recent-onset AF reverts spontaneously within 24 hours in at least half of patients (irrespective of whether or not they are taking digoxin) (E33).5 Patients who have been in AF for more than 48 hours should be considered for anticoagulation therapy and strategies to restore and maintain sinus rhythm. Warfarin should be administered for three weeks before cardioversion is attempted.6 If cardioversion can not be postponed for three weeks, the patient should undergo anticoagulation therapy with intravenous heparin and warfarin,7 and be considered for transoesophageal echocardiography (TOE) (E32). Cardioversion can probably be undertaken safely (with limited risk of stroke) if TOE excludes left atrial and appendage thrombus (and the patient is treated with heparin and warfarin) (E2).8,9 However, if transoesophageal echocardiography identifies left atrial and appendage thrombus, then cardioversion is contraindicated until the patient has been anticoagulated for at least three weeks (E4). The relative merits of cardioversion by electrical shock and medical therapy have been discussed recently.4,10 Direct current cardioversion has never been subjected to a randomised trial, but appears to be the most effective method of restoring sinus rhythm. Its main disadvantage is the need for general anaesthesia. Digoxin and verapamil are ineffective for converting AF to sinus rhythm. Flecainide or sotalol are the preferred medical therapies in younger patients without structural heart disease, and amiodarone in older patients (E2).11 The chances of successful cardioversion are greater if the AF is of recent onset and the left atrial size is normal (E33).12 After successful cardioversion, warfarin therapy should be continued for at least four weeks to prevent clot formation in the "stunned" left atrium (E33).13,14 Antiarrhythmic drug therapy should also be continued to prevent recurrent AF, but this still occurs in 40%-50% of patients after 12 months' follow-up despite drug therapy. If the patient has a low risk of recurrence of AF (eg, "lone" AF) and remains in sinus rhythm for one month after cardioversion, anticoagulation therapy with warfarin can be ceased (E4). In patients at higher risk of recurrence (Box 2), it may be more appropriate to continue warfarin therapy for longer or indefinitely (E4). For patients who are elderly (in whom AF is usually chronic and antiarrhythmic drug therapy may be risky) or have asymptomatic chronic AF, it is often reasonable to avoid attempted cardioversion, accept the AF and aim for adequate ventricular rate control (digoxin combined with β-blockade, verapamil or diltiazem) and long term anticoagulation therapy (E4). The results of clinical trials in patients with asymptomatic AF (of rate control and antithrombotic therapy versus attempted cardioversion and maintenance of sinus rhythm to avoid warfarin) are awaited. Strategies for reducing the risk of stroke and systemic thromboembolism in patients with AF have been studied in several randomised controlled trials over the past decade.15-25 Warfarin versus control Primary prevention Five large randomised controlled primary prevention trials have shown that, in people with chronic non-valvular AF, warfarin reduced the risk of stroke by about two-thirds (68%; 95% CI, 50%-79%; P < 0.001), from about 4.5% to 1.4% per year overall, with little increase in frequency of major bleeding (warfarin, 1.2%; control, 1.0%), or intracranial haemorrhage (warfarin, 0.3% per year; control, 0.1% per year) (E1).15-19,26 This means that warfarin will prevent about 30 strokes per 1000 patient-years of treatment at a cost of at least two serious bleeding episodes per 1000 patients treated for one year. It must be stressed, however, that this acceptable rate of bleeding was achieved in patients who were carefully selected, screened and closely followed; 53%-93% of eligible patients with AF were not included in the trials because of an increased risk of bleeding. Exclusion criteria included old age (> 75 years), serious illness (liver, kidney, brain or malignant disease), alcoholism, fall risk (eg, syncope), forgetfulness, non-steroidal anti-inflammatory drug therapy, and uncontrolled hypertension. Secondary prevention One secondary prevention trial (the European Atrial Fibrillation Trial [EAFT]) showed that, in people with chronic non-valvular AF and symptoms of previous transient ischaemic attack (TIA) or stroke, who have a risk of stroke of 12% per year, warfarin therapy (target INR, 2.5-4.0) reduced the risk of stroke by about two-thirds (66%; 95% CI, 53%-80%), to 4% per year (E2).20 The annual incidence of major bleeding complications was 2.8% in the anticoagulant group and 0.7% in the placebo group. No intracranial bleeds were identified in patients assigned to warfarin. Thus, warfarin prevents about 80 strokes per 1000 patient-years in patients who have had a TIA or stroke and who are in AF, at a cost of at least 20 serious bleeding episodes per 1000 patients treated for one year. The timing of anticoagulation therapy after recent ischaemic stroke depends on the risk of recurrent thromboembolism (Box 2) and the risk of haemorrhagic transformation of the brain infarct (which is higher within the first two weeks and in patients with large brain infarcts and uncontrolled hypertension [E32]27). Common empirical practice is to treat patients with fibrillating acute ischaemic stroke immediately with aspirin (300 mg daily) and then, depending on the above factors, begin warfarin (5 mg daily) between days three and 14 after stroke onset, aiming to achieve an INR of 2.0.28 However, randomised trials comparing aspirin with heparin during the first two weeks of acute ischaemic stroke among patients in AF show no benefit from early anticoagulation, because any net gains from reduction in recurrent ischaemic stroke are offset by the excess hazards of haemorrhagic stroke (E1).29,30 Aspirin versus control Three primary prevention and three secondary prevention trials have shown that, in people with AF, aspirin reduced the incidence of stroke by 22% (95% CI, 2%-38%), from 5.2% (placebo) to 3.7% (aspirin) per year for primary prevention (absolute risk reduction: 1.5% per year), and from 12.9% (placebo) to 10.4% (aspirin) per year for secondary prevention (absolute risk reduction, 2.5% per year) (E1).31Aspirin was not associated with any significant excess of intracranial haemorrhage (aspirin, 0.16%; control, 0.13%) or major extracranial bleeding (aspirin, 0.5%; control, 0.6%) (E1).31 This means that aspirin might prevent about 10 to 20 strokes per 1000 patient-years of treatment, depending on the type of patient treated and their baseline risk of stroke, with little risk of major bleeding. A speculative interpretation of these data is that, in patients with AF, aspirin prevents strokes due to atherothromboembolism, but not cardiogenic embolism. This interpretation is based on the magnitude of the effect (a 20% relative risk reduction), which is very similar to the effect of aspirin in patients with symptomatic atherothromboembolism of the brain, heart and limbs.32 Whether aspirin combined with adjusted-dose warfarin would be safe and more effective (in preventing both atherothrombotic and cardiogenic strokes) than warfarin alone in patients with AF remains unknown.33 Warfarin versus aspirin The relative benefits and risks of warfarin and aspirin have been studied in three trials,15,20,21 all of which showed that warfarin was associated with half the risk of stroke compared with aspirin (47% relative risk reduction; 95% CI, 28%-61%; P < 0.01) (E1).26 Warfarin combined with aspirin For patients with AF who are at high risk of stroke, adding aspirin (325 mg daily) to low-intensity, fixed-dose warfarin, adjusted to an INR of 1.2-1.5, was not as effective in preventing stroke or systemic thromboembolism as standard adjusted-dose warfarin therapy, maintaining an INR of 2.0-3.0 (event rates, 7.9% per year v. 1.9% per year, respectively; P < 0.0001), and there is no difference in the rates of major bleeding (E2).22 Three subsequent trials also suggested that adjusted-dose warfarin (INR, 2.0-3.0) was superior to low-intensity anticoagulant therapy or an aspirin- anticoagulation regimen (E1).23-25 Warfarin versus other antiplatelet agents An Italian study reported that a new antiplatelet agent, indobufen (100-200 mg twice daily), was as effective as adjusted-dose warfarin (INR, 2.0-3.5) in preventing stroke, systemic embolism, myocardial infarction or vascular death in 916 patients with non-valvular AF and recent (within 15 days) TIA or non-disabling ischaemic stroke (E2).34 The 12-month event rates were 10% in the warfarin group and 12% in the indobufen group (P = 0.47). However, the number of patients and outcome events were quite small, follow-up was short, and it is possible that a true difference was not detected. Future studies are planned to evaluate the safety and effectiveness of other, newer antiplatelet agents (such as clopidogrel, oral glycoprotein IIb/IIIa receptor inhibitors, and oral thrombin inhibitors) and combination antiplatelet therapies (such as aspirin-ticlopidine, aspirin-clopidogrel, and aspirin-dipyridamole) as strategies of thromboprophylaxis in AF. Who to treat and with what? Not all patients with AF benefit from thromboprophylactic treatment. The decision to treat depends on the balance between the risk of thromboemboli without treatment and the risks of thromboemboli and haemorrhage with treatment in each patient, as well as the patient's willingness to accept the potential risks, costs, and inconvenience of treatment in order to possibly benefit. The current profile of individual risk of thromboembolism and bleeding complications (see below) remains imprecise and continues to be refined as new data emerge.7 Who is at high risk of stroke and thromboembolism without treatment? The important independent prognostic factors for an increased risk of stroke among individuals with AF are increasing age, a history of previous TIA or stroke, hypertension, diabetes mellitus, and transthoracic echocardiographic evidence of moderate to severe left ventricular systolic dysfunction (E1).7,26,35-37 Echocardiographic evidence of left atrial enlargement (E2) and left atrial spontaneous echo densities ("smoke"), possibly indicative of stasis of blood, are also significant risk factors for stroke36-39 (E33). These risk factors are cumulative: for people younger than 65 years with no risk factors the untreated annual risk of stroke is about 1%, whereas with one or more risk factors it is about 5%; for people aged 65-75 years with no risk factors the annual risk of stroke is about 4%, and with one or more risk factors it is about 6% per year; and for people older than 75 years with no risk factors the risk of stroke is about 3%-4%, whereas with one or more risk factors it is about 8% (see Box 2) (E1).7,26 Who is at high risk of haemorrhage with anticoagulant treatment? The major risk factors for anticoagulant-associated intracranial haemorrhage include fragile intracranial blood vessels (previous symptomatic cerebrovascular disease, computed tomography brain scan evidence of small vessel disease ["leukoaraioisis"]), high blood pressure (poorly controlled hypertension), and excessive anticoagulation (INR, > 3.5) or factors predisposing to it, such as confusion, dementia, inadequate anticoagulant monitoring, alcoholic liver disease, and a tendency to falls (E2).40,41 Increasing age is a risk factor for all of these risk factors, and is thus a potent risk factor for anticoagulant-associated haemorrhage. Among a subgroup of patients in the Stroke Prevention in Atrial Fibrillation (SPAF) II trial (mean age, 80 years), the rate of intracranial haemorrhage was as high as 1.8% per year in those allocated to warfarin therapy (target INR, 2.0-4.5) and 0.8% among those who were assigned to aspirin (E2).21 Although the target INR in this study was higher than currently recommended (INR, 2.0-3.0), these data suggest that the low rate of intracranial haemorrhage documented in the five primary prevention AF trials15-19 may not apply to very elderly individuals (who were not well represented in many of these trials -- the mean age of the patients studied in the AF trials was 69 years, and only about a quarter were older than 75 years). Recommendations for antithrombotic therapy for AF Current practice necessitates individualisation of therapy after an integrated clinical assessment that evaluates thromboembolic risk due to AF, other potential indications for anticoagulant therapy, risk of haemorrhage, and non-medical factors relating to compliance, capacity to have the INR monitored at least monthly, gait instability, risk of other trauma, and patient values and preferences.42,43 Decision analysis can also be useful.44The role of transthoracic echocardiography (TTE), in addition to excluding structural heart disease in all patients who first present with AF, is to further refine stroke risk in the small group of patients with a low risk of stroke according to clinical factors. Although TOE is more sensitive in detecting left atrial thrombus and spontaneous echo contrast, which are markers for increased risk of thromboembolism,36-39 it is more invasive and is usually only required to improve risk stratification among individuals with a relative contraindication to warfarin or in whom TTE is inadequate. The choices of thromboprophylactic agents for atrial fibrillation include warfarin, which is the most effective but also the most risky treatment, and aspirin, which is less effective than warfarin but safer (E1). The combination of aspirin and low dose warfarin is no more effective than aspirin alone (E1).22,23 The most appropriate treatment regimen is one in which patients at high risk of stroke and low risk of haemorrhage are treated with warfarin, and patients at low risk of stroke or high risk of haemorrhage are treated with aspirin. Who not to treat Individuals with AF who are aged less than 60 years and have no evidence of any concurrent heart disease have a very low risk of a thromboembolic event (about 0.6% per year).45 The potential benefits of aspirin in these patients (which may reduce the risk of stroke by 0.12% per year [20% of 0.6%]) may be offset by an equal potential risk of aspirin-associated haemorrhagic stroke of 0.12%.46 Who to treat with aspirin Aspirin is indicated for individuals in AF who are at fairly low absolute risk of stroke, such as those without any of the independent thromboembolic risk factors listed above, or those at risk of an anticoagulant-related haemorrhage which exceeds the risk of stroke (more than 1% per year) (E1). For some people, such as the elderly and those with hypertension, whose risks of stroke and haemorrhage are both high, the treatment decision can be difficult, and may be determined ultimately by the patient's preferences.42,43Patients taking aspirin should be monitored over time and their treatment changed to warfarin if risk factors emerge; this occurs in 10%-15% of patients being treated with aspirin per year.21 Who to treat with warfarin Warfarin is indicated for individuals with chronic AF who are at high absolute risk of stroke (> 4% per year), such as those with any of the independent thromboembolic risk factors listed above, and a lower risk of haemorrhage (E1) (see Box 2). Similarly, anticoagulant therapy should also be considered in patients with paroxysmal AF, again depending on the thromboembolic risk factors (Box 2) as well as the frequency and duration of the paroxysms. Although clinical trial evidence suggests the stroke rate of patients with paroxysmal AF is similar to that of patients with chronic AF,26 the trials did not specifically examine the benefits of antithrombotic therapy in patients with paroxysmal AF. Furthermore, the range of thromboembolic risk in such patients is likely to be extremely wide, from very low for patients who have one short paroxysm once a year to considerably higher for patients who have daily lengthy paroxysms. What is the optimal target INR? The intensity of oral anticoagulant therapy that provides the best balance between the prevention of thromboembolism and the occurrence of bleeding complications appears to be an INR of between 2.0 and 3.0, but may be lower (INR, 1.8 to 2.0) in patients at greater risk of bleeding (eg, the elderly), and may be higher in patients at greater risk of thromboembolism, such as those with prosthetic heart valves [INR, 3.0-4.0]) (E32).47,48It is important to emphasise that, in people in whom anticoagulant therapy is indicated, the risk of stroke increases substantially when the INR falls below 2.0. Patients with an INR of 1.7 have twice the odds of stroke (95% CI, 1.6-2.4 times), and those with an INR of 1.5 have 3.3 times the odds of stroke (95% CI, 2.4-4.6 times) as those with an INR of 2.047 (E32). What if warfarin therapy needs to be ceased? When cessation of warfarin therapy is required because of other (usually surgical) procedures, it is necessary to stratify the invasiveness of the procedure (minimal versus major) and the short-term risk of thromboembolism. Warfarin can be discontinued for five days before a major procedure and continued at a decreased dose for a minor procedure. Therapy should be reinstituted as soon as possible after invasive procedures. Patients at high risk of thromboembolism (eg, severe mitral stenosis, mechanical mitral prosthesis, left ventricular dysfunction) should be admitted to hospital early for intravenous administration of heparin during warfarin cessation. References Lake FR, Cullen KJ, de Klerk NH, et al. Atrial fibrillation and mortality in an elderly population. Aust N Z J Med 1989; 19: 321-326. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-988. National Health and Medical Research Council. A guide to the development, implementation, and evaluation of clinical practice guidelines. Canberra: NHMRC, 1999. Kilborn MJ. Atrial fibrillation. Med J Aust 1999; 170: 498-504. Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. Ann Intern Med 1987; 106: 503-506. Stoddard MF. Risk of thromboembolism in new onset or transient atrial fibrillation. Prog Cardiovasc Dis 1996; 39: 69-80. Laupacis A, Albers G, Dalen J, et al. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 (5 Suppl): 579S-589S. Klein AL, Grimm RA, Black IW, et al. Cardioversion guided by transesophageal echocardiography: The ACUTE Pilot Study. A randomised, controlled trial. Ann Intern Med 1997; 126: 200-209. Bashir M, Grimm RA, Jaber WA, et al. Elderly patients do not have an excessive risk for complications or recurrence following transoesophageal echocardiography-guided cardioversion of atrial arrhythmias: results from the ACUTE registry. J Am Coll Cardiol 2000; 35 (Suppl A): 119A (abstract no. 1097-73). Catherwood E, Fitzpatrick WD, Greenberg ML, et al. Cost-effectiveness of cardioversion and anti-arrhythmic therapy in nonvalvular atrial fibrillation. Ann Intern Med 1999; 130: 625-636. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000; 342: 913-920. Resnekov L. Present status of electroversion in the management of cardiac dysrhythmias. Circulation 1973; 47: 1356-1363. Lown B, Perlroth MG, Kaidbey S, et al. "Cardioversion" of atrial fibrillation: a report on the treatment of 65 episodes in 50 patients. N Engl J Med 1963; 269: 325-331. Manning WJ, Silverman DI, Gordon SPF, et al. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328: 750-755. Petersen P, Boysen G, Godfredsen J, et al. Placebo-controlled randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. Lancet 1988; i: 175-179. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990; 323: 1505-1511. Stroke prevention in atrial fibrillation study: final results. Circulation 1991; 84: 527-539. Connolly SJ, Laupacis A, Gent M, et al, for the CAFA Study Coinvestigators. Canadian atrial fibrillation anticoagulation (CAFA) study. J Am Coll Cardiol 1991; 18: 349-355. Ezekowitz MD, Bridgers SL, James KE, et al, for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) Investigators. Warfarin in the prevention of stroke associated with atrial fibrillation. N Engl J Med 1992; 327: 1406-1412. Secondary prevention in nonrheumatic atrial fibrillation and transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993; 342: 1255-1262. Warfarin versus aspirin for the prevention of thrombo-embolism in atrial fibrillation. Stroke prevention in atrial fibrillation II study. Lancet 1994; 343: 687-691. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high risk patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638. Gullov AL, Koefoed BG, Petersen P, et al. Mini-dose warfarin and aspirin in atrial fibrillation. Second Copenhagen Atrial Fibrillation Aspirin and Anticoagulation Study (AFASAK 2). Arch Intern Med 1998; 158: 1513-1521. Vermeer F, Langenberg M, Hellemons BS, et al. Primary prevention of arterial thrombo-embolism in non-rheumatic atrial fibrillation: results of the PATAF study. Eur Heart J 1998; 19 (Abstract Suppl): 154. Pengo V, Zasso A, Barberi F, et al. Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998; 82: 433-437. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomised controlled trials. Arch Intern Med 1994; 154: 1449-1457. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial haemorrhage. Facts and hypotheses. Stroke 1995; 26: 1471-1477. Gallus AS, Baker RI, Chong BH, et al, on behalf of the Australasian Society of Thrombosis and Haemostasis. Consensus guidelines for warfarin therapy. Recommendations from the Australasian Society of Thrombosis and Haemostasis. Med J Aust 2000; 172: 600-605. Berge E, Abdelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355: 1205-1210. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349: 1569-1581. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999; 131: 492-501. Collaborative overview of randomised trials of anti platelet therapy. I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994; 308: 81-106. Peverill RE. Warfarin or aspirin: both or others? Med J Aust 1999; 171: 321-326. Morocutti C, Amabile G, Fattapposta F, et al, for the SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. Stroke 1997; 28: 1015-1021. Predictors of thromboembolism in atrial fibrillation: clinical features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992; 116: 1-5. Predictors of thromboembolism in atrial fibrillation: echocardiographic features of patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern Med 1992; 116: 6-12. Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation. A prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998; 158: 1316-1320. Fatkin D, Feneley M. Stratification of thromboembolic risk of atrial fibrillation by transthoracic echocardiography: the relative role of left atrial appendage function, mitral valve disease, and spontaneous echo contrast. Prog Cardiovasc Dis 1996; 39: 57-68. Jones EF, Calafiore P, McNeil J, et al. Atrial fibrillation with left atrial spontaneous contrast detected by transoesophageal echocardiography is a potent risk factor for stroke. Am J Cardiol 1996; 78: 425-429. Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med 1996; 156: 409-416. A randomised trial of anticoagulants versus aspirin after cerebral ischaemia of presumed arterial origin. The Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) Study Group. Ann Neurol 1997, 42: 857-865. Man-Son-Hing M, Laupacis A, O'Connor A, Wells G. Warfarin for atrial fibrillation: the patient perspective. Arch Intern Med 1996; 156: 1841-1848. Gage BF, Cardinalli AB, Owens DK. Cost-effectiveness of preference-based antithrombotic therapy for patients with nonvalvular atrial fibrillation. Stroke 1998; 29: 1083-1091. Thomson R, Parkin D, Eccles M, et al. Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation. Lancet 2000; 355: 956-962. Kopecky SL, Gersh BJ, McGoon MD. The natural history of lone atrial fibrillation: a population-based study over three decades. N Engl J Med 1987; 317: 669-674. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke. A meta-analysis of randomised controlled trials. JAMA 1998; 280: 1930-1935. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with non-rheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-546. Cannegieter SC, Rosendal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17. Background and evidence basis of recommendations The National Heart Foundation (NHF) Consensus Guidelines for Non-valvular Atrial Fibrillation and Stroke Prevention were written by Clinical Associate Professor Graeme J Hankey on behalf of the National Blood Pressure Advisory Committee of the NHF, which comprises Professor L Wing (chair), Dr A Boyden, Dr A Dart, Dr K Duggan, Clinical Associate Professor G Hankey, Dr M Nelson, Professor I Puddey, Dr M Stowasser, and Dr J Vial. The draft guidelines were circulated for comment to the above members of the committee, who have clinical and research expertise or interests in hypertension, atrial fibrillation, and stroke prevention. Comment was also sought from the Medical Director of the Heart Foundation, Professor Andrew Tonkin. All comments were incorporated into the final document, which was ratified by the Heart Foundation's Cardiovascular Health Advisory Committee. All available evidence from controlled experimental and observational studies was combined with clinical experience to provide recommendations according to the National Health and Medical Research Council Quality of Evidence ratings.3 Authors' details National Heart Foundation of Australia, Melbourne, VIC. Graeme J Hankey, MD, FRACP, Consultant Neurologist and Head of Stroke Unit, Royal Perth Hospital, Perth, WA, and Clinical Associate Professor, Department of Medicine, University of Western Australia. Reprints will not be available from the author. Correspondence: Clinical Associate Professor G J Hankey, Stroke Unit, Royal Perth Hospital, Wellington Street, Perth, WA 6001. gjhankeyATcyllene.uwa.edu.au * L Wing (chair), A Boyden, A Dart, K Duggan, M Nelson, I Puddey, M Stowasser, J Vial 1: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system3 for assessing the level of evidence: E1 Level I Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1 Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2 Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group. E33 Level III-3 Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV Evidence obtained from case-series, either post-test, or pretest and post-test. Back to text 2: Risk stratification and prophylaxis in atrial fibrillation High risk (6%-12% per year risk of stroke) Age >65 years and hypertension or diabetes Previous transient ischaemic attack (TIA) or stroke Valvular heart disease o Heart failure Recent myocardial infarction Impaired left ventricular function on echocardiography Thyroid disease o Left atrial thrombus or left atrial spontaneous echo contrast (TOE done on basis of clinical suspicion) Treatment: Warfarin (target INR 2.0-3.0) if possible and not contraindicated. Moderate risk (2%-5% per year risk of stroke) Age 65 years and hypertension or diabetes Age >65 years and not in high risk group Treatment: Warfarin (target INR 2.0-3.0) or aspirin 75-300mg daily, depending on individual case and echocardiography findings. Low risk (≤1% per year risk of stroke) Age 65 and no hypertension, diabetes, TIA, stroke, or other clinical risk factors Treatment: None, or aspirin 75-300mg daily. Back to text

Graeme J Hankey

Recommendations from the Australasian Society of Thrombosis and Haemostasis Abstract The anticoagulant effect of warfarin should be kept at an international normalised ratio (INR) of about 2.5 (desirable range, 2.0-3.0), although a higher level may be better in a few clinical conditions. The risk of bleeding increases exponentially with INR and becomes clinically unacceptable once the INR exceeds 5.0. Warfarin therapy should be continued for around six weeks for symptomatic calf vein thrombosis, and for 3-6 months after proximal deep vein thrombosis (DVT) that occurs after surgery or limited medical illness. Therapy for six months or longer could be considered for DVT occurring without an obvious precipitating factor, proven recurrent venous thromboembolism (VTE), or if there are continuing risk factors. Oral anticoagulants prevent ischaemic stroke in atrial fibrillation (AF). Maximum efficacy requires an INR > 2.0, but some benefit remains at an INR of 1.5-1.9. Patients aged over 75 years are at greatest risk of intracranial bleeding during warfarin therapy for AF, and the target INR may be reduced to 2.0-2.5, or perhaps as low as 1.5-2.0, in such patients. Warfarin should be withheld if it is more likely to cause major bleeding than to protect from stroke (eg, in young people with isolated AF where the annual baseline risk of stroke is < 1%). In patients with AF, aspirin is less effective than warfarin (much less effective after such patients have had a stroke or transient cerebral ischaemia). In people with prosthetic heart valves, an INR of 2.5-3.5 is probably sufficient for bileaflet or tilting disc valves, but a higher target INR is necessary for caged ball or caged disc valves. The addition of aspirin (100 mg/day) further decreases the risk of embolism but increases the risk of gastrointestinal bleeding. Warfarin is used for preventing and treating venous or arterial thrombosis and embolism. It is a potentially hazardous drug, causing major bleeding in 1%-2% of people treated, and intracranial bleeding in about 0.1%-0.5% during each year of therapy. These risks are well recognised, but strong recent evidence that many otherwise healthy people with atrial fibrillation (AF) or venous thromboembolism (VTE) can benefit from long term warfarin therapy has led to a major increase in its use. These consensus guidelines offer advice on the selection of patients for warfarin therapy and management of such patients. The recommendations draw on proceedings of the Fifth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy,1 and are consistent with the most recent Guidelines on oral anticoagulation developed for the British Society for Haematology.2 Warfarin therapy and management of complications The INR The INR (international normalised ratio) is a good indicator of effectiveness and risk of bleeding during warfarin therapy and is best kept at about 2.5, with a target range of 2.0-3.0, for most clinical indications, although higher levels may be better for certain patients (Box 1). The lower limit of this target range recognises a threshold level for effectiveness, while the upper limit is set to minimise bleeding. Starting and maintaining warfarin therapy The daily maintenance dose of warfarin differs greatly between individuals, commonly between 0.5 mg/day and 15 mg/day, and often fluctuates over time. The average maintenance dose is about 4.5 mg/day, although this is lower in the elderly. The drug is rapidly and completely absorbed and immediately blocks further hepatic synthesis of the functional vitamin K-dependent haemostasis factors (II, VII, IX, X, protein C, protein S). However, its impact on the INR is delayed until preformed coagulation factors are removed, so dose adjustment must allow for these delayed effects. The plasma half-life of warfarin is about 36 hours.3 In the past, it was customary to use a loading dose of 10 mg. However, for most situations, a reduced starting dose of 5 mg per day will achieve an INR of 2.0 in four to five days.4 INR is measured daily or every second day during the first week of treatment, with the dose of warfarin (taken in the evening) titrated against the morning's INR. It is then measured at increasing intervals depending on response. Many patients, once the dose is stable, can be well controlled with 4-6-weekly testing and dose adjustment, but others need more frequent assessment. An empirical approach to warfarin dosing can be smooth and effective but published dose-adjustment tables can help.2 Old age, reduced body weight, and impaired cardiac or liver function all predict a smaller than average dose requirement. Multiple comorbidities and a need for many drugs increase the risk of an unstable anticoagulant response. The effect of warfarin is subject to multiple interactions. These include the dietary content or extent of absorption of vitamin K, the absorption of warfarin and its effect on the liver (which are increased or decreased by many other drugs), and the clearance of blood-clotting factors.1,3 Intercurrent illness, starting or stopping therapy with other drugs (especially antibiotics and amiodarone) and changes in diet or bowel function can all influence the INR. Rechecking the INR within a few days of any change in medication or clinical condition is prudent. Bleeding is minimised by regular monitoring to avoid an excessive INR and by educating patients about how warfarin works, why their dose requirement may change, and the likely settings and symptoms of bleeding complications. Successful warfarin therapy requires a partnership with patients, who should be encouraged to have their INR checked soon after any change in their normal routine. Clinics should periodically audit their results with warfarin therapy and review exceptional cases. Between 50% and 75% of INRs are likely to fall into their designated therapeutic range.5 Two recent Australian case reports are reminders that bioequivalence has not been formally demonstrated for Coumadin and Marevan (both from Boots Healthcare Australia, Sydney, NSW), the two locally available formulations of warfarin.6 Warfarin and bleeding Major bleeding has been reported in 1.1%-8.1% of patients during each year of long-term warfarin therapy (1.1%-2.7% by anticoagulant clinics managing patients with prosthetic heart valves,7-9 1.3% in atrial fibrillation trials, and 2.8%-8.1% after a stroke or transient ischaemic attack10-12). Risk factors include old age, serious illness (cerebral, cardiac, kidney or liver disease), cerebrovascular or peripheral vascular disease, and an unstable anticoagulant effect. Forgetfulness, non-steroidal anti-inflammatory drugs and alcohol abuse may also contribute.7,9,13-15 Warfarin appears to be especially hazardous after a transient ischaemic attack or minor stroke; in one trial, 14 months of warfarin therapy with a relatively high target INR of 3.0-4.5 increased major bleeding from 0.9% to 8.1%, intracranial bleeding from 0.5% to 4.1%, and fatal intracranial bleeding from 0.2% to 2.6% (relative to low dose aspirin therapy).12 Bleeding is most likely during the first three months of treatment, and often follows trauma or unmasks a previously unsuspected comorbidity.8,13-15Age alone is not a contraindication to warfarin therapy. Although one report showed that each decade above the age of 40 raised the risk of major bleeding by almost 50%, with a maximum effect above 70 years,7 others have found that age below 70 years has no influence.8,15 The INR is the dominant determinant, whether bleeding is expressed as the absolute risk per annum (Box 2) or as relative risk. In a 1996 study, the bleeding rate was doubled as the INR increased from 2.0-2.9 to 3.0-4.4, quadrupled between 4.5-6.0, and was multiplied by five when the INR was above 7.0.15 There is a consistent increase in major bleeding (including intracranial bleeding16) when the INR exceeds 4.0-5.5.7,11,14 A 1997 trial found that each increase in INR by 0.5 multiplied the risk of major bleeding (mostly intracranial) by 1.43.12 Managing an excessively prolonged INR or bleeding caused by warfarin therapy An INR above 5.0 requires close monitoring and often needs intervention, as determined by the level of the INR and the presence or absence of bleeding (Box 3). The INR often remains elevated for some days, even if warfarin is withheld, but small amounts of vitamin K1 quickly correct the INR to safer levels. In most patients, 1-2.5 mg of oral vitamin K1 reduces the INR from 5.0-9.0 to 2.0-5.0 within 24-48 hours; this intervention is usually sufficient in the absence of bleeding.17,18 These small doses are obtained by withdrawing the desired amount from a 10 mg vial of injectable vitamin K1 and giving this orally or parenterally. When the INR is > 9.0, then 5 mg vitamin K1 may be more appropriate and can be given orally, subcutaneously or intravenously (very rarely, the last may cause a serious anaphylactoid reaction). In people with a massive accidental or self-inflicted warfarin overdose, the long half-life of warfarin means that the INR may rebound over several days as the effects of vitamin K1 wear off. In any case, the response to vitamin K1 needs to be monitored. Bleeding caused by a warfarin overdose is controlled with clotting factor replacement (Box 3), and this may also be indicated in the absence of bleeding when the risk is very high.19 Bleeding or an unstable dose-response should trigger a review of the need for warfarin. Continued treatment will require closer monitoring of the INR, both to detect the transient warfarin resistance caused by too much vitamin K1, and to avoid further overanticoagulation. Heparin treatment may be required to cover a prolonged period of warfarin resistance. Interrupting warfarin therapy for surgery When there is a need for surgery, the risk of perioperative bleeding under continued warfarin therapy must be balanced against the risk of thromboembolism if warfarin therapy is stopped.20Most surgery, including hip or knee replacement and many thoracic or abdominal operations, can proceed under continued warfarin cover without undue bleeding (provided the INR during and soon after surgery is about 1.5-2.0). Warfarin therapy is a contraindication for regional anaesthesia (eg, spinal, epidural, brachial blocks) and is unacceptable where even minor bleeding might cause critical damage (as in neurosurgery and some plastic surgery). It is also unpopular with most surgeons. However, the absolute daily risk of a serious thromboembolic event is small in most people with AF, previous systemic embolism or a prosthetic heart valve (the hazard is greatest from mitral and older-model prosthetic valves, and in patients with more than one prosthetic valve). Thus, it is safe to stop warfarin therapy for several days before and after surgery in such patients. High-dose heparin cover for these indications is rarely indicated as the risk of bleeding is usually prohibitive.20 The risk of recurrence is greatest during the first four weeks after VTE, so warfarin therapy should not be interrupted during this time if at all possible. If anticoagulants must be stopped for surgery soon after VTE, a vena cava filter can be placed to minimise the risk of life-threatening pulmonary embolism. Specific indications for warfarin therapy Deep vein thrombosis and pulmonary embolism Prevention: Heparins are now usually the preferred drugs for the prevention of perioperative VTE, but warfarin retains a limited role when the risk of thrombosis is very high. Its main role is in long-term therapy. Warfarin is no less effective than low molecular weight heparins after hip or knee replacement, and the risk of bleeding is similar or lower when therapy is started at about the time of surgery and continued at least until patients are fully mobile.21 Treatment: Anticoagulants prevent early thrombus extension and embolism and minimise late recurrence. Heparin treatment can be stopped after a minimum of five days when warfarin therapy is also being given, provided that the two drugs are overlapped for at least four days and the INR has exceeded 2.0 for two or more days.22 Increasingly, deep vein thrombosis (DVT) is now managed at home -- an approach preferred by many patients and made possible by trials which found that initial treatment with low molecular weight heparins given in a fixed dose by subcutaneous injection is no less effective or safe after DVT than standard heparin therapy. Home heparin therapy requires close monitoring to ensure compliance and a safe and effective start for warfarin therapy.23,24 Although warfarin is now usually given for 3-6 months after VTE, there is growing evidence that the optimal duration of treatment is determined by the patient's clinical presentation. Six to 12 weeks of warfarin therapy is probably enough when DVT follows surgery or transient immobilisation ("secondary" DVT), as recurrence is minimised by six weeks of treatment after symptomatic calf vein DVT,7 and by three months of treatment after proximal DVT.25,26 However, warfarin therapy for longer than six months may be required after "idiopathic" DVT, recurrent VTE, or when there is a continuing cause like cancer or an inherited or acquired "hypercoagulable" state.27-30 Whether, in these circumstances, warfarin should be given for 12 months, two years, or longer, remains under active investigation. For individuals, the choice will also be influenced greatly by risk of bleeding. Controversies in the management of DVT and VTE Calf vein thrombosis: Although calf vein DVT poses little immediate threat and is commonly believed to be clinically unimportant, it has the potential to extend and embolise. In a randomised comparison where 51 patients with symptomatic calf DVT were treated for five days with heparin only or with heparin followed by ongoing warfarin therapy, there was a recurrence during the next three months in eight of 28 patients from the first group (23%: seven clinically suspected and confirmed; five with proximal extension and one with embolism), but none in the second.31 Therefore, patients with calf vein thrombosis should be treated with warfarin unless there are contraindications. Accuracy of diagnostic tests for DVT: Venous ultrasonography has now replaced venography as the first-line diagnostic test for clinically suspected DVT. Despite its limited sensitivity to small calf vein DVTs, a negative ultrasound result almost excludes thrombosis when there is a low pretest clinical probability for DVT (a DVT score of zero on a checklist of clinical features obtained before ultrasonography, such as active cancer, immobilisation, major surgery, entire leg swelling, localised tenderness, calf swelling, pitting oedema and collateral superficial veins).32 However, for patients in whom the pretest clinical probability is moderate (DVT score of 1-2) or high (score, > 3), a negative ultrasound result does not exclude a small DVT, and they should have either early venography or further ultrasonography once or twice within the next seven days in case there is proximal extension of an undetected calf thrombus. This approach is validated by extensive clinical follow-up.33 Recurrent or idiopathic DVT or VTE: In a randomised trial of patients presenting with recurrent DVT, oral anticoagulant therapy for six months was followed by a recurrence in 21% during four years of follow-up, compared with 3% when treatment was continued. However, ongoing warfarin therapy increased the rate of major bleeding during the four years from 2.7% to 8.6%, while mortality remained unchanged.27 Similarly, in a separate trial of management after a first "idiopathic" VTE, warfarin therapy for three months was followed by recurrence in 16 of 77 patients during 10 months of follow-up, compared with only one of 76 patients in whom warfarin therapy was continued.30 However, the use of warfarin increased the annual risk of major bleeding from zero to 4%.30 These high rates of bleeding reinforce the need for careful risk assessment when considering patients for long term anticoagulant therapy after VTE. The results of these trials suggest that warfarin therapy should be continued for one year after an "idiopathic" or recurrent VTE if the risk of bleeding is acceptable, and that treatment should be extended to two years if warfarin control is straightforward and the bleeding risk remains low. Atrial fibrillation Warfarin is now widely used to prevent systemic embolism in otherwise healthy patients with atrial fibrillation (AF). In clinical trials, warfarin consistently reduced the annual risk of a first ischaemic stroke (including stroke with a residual functional deficit) by almost 70% (from 7% to 3% per annum) and mortality by 33%, at the cost of a small increase in serious bleeding (from 1.0% to 1.3% per annum).10,34,35 The prevalence of AF rises from about 3% at 65 years to more than 10% by 85 years, and AF accounts for about 1.5% of all strokes in people aged 50-59 years, and almost 25% of strokes in people aged 80-89 years. Age is therefore an important determinant of ischaemic stroke in AF (the relative risk [RR] of stroke in AF rises by 1.4 with each decade).35 Previous stroke or transient ischaemic attack (RR, 2.5), diabetes (RR, 1.7), and treated hypertension (RR, 1.6) also contribute, as do heart failure, ischaemic heart disease, a large left atrium, and left ventricular dysfunction.10 Stroke is unlikely in isolated AF but becomes more likely as additional risk factors accumulate (Box 4). This makes warfarin therapy inappropriate for young people with AF alone and no other cardiac risk factor (isolated AF), as their annual risk of stroke (< 1%) is low enough to ensure that risk of bleeding always equals or exceeds any likelihood of gain. Because of the risk of bleeding, these reports raise important questions about the best target level of INR, and about which patients with AF should be offered long-term warfarin therapy. The incidence of stroke is minimised by an INR > 2.0 and increases exponentially below this level, but some benefit remains while the INR is 1.5-1.9. When considering warfarin therapy for AF, each candidate requires a formal estimate of the relative risks of stroke (Box 4) and bleeding (Box 2). Controversies about the use of warfarin or aspirin to prevent stroke in atrial fibrillation Stroke and the INR: The risk of stroke during warfarin therapy for AF is dictated by the INR. Below 2.0, the relative risk doubles at 1.7, triples at 1.5, sextuples at 1.3, and reaches 18 times once the INR is normal, but nothing is gained by increasing the INR beyond its therapeutic threshold of 2.0.36 Results were similar when warfarin was given for secondary stroke prevention in patients with AF who had already developed a stroke or transient cerebral ischaemia.11 Again, in a randomised trial in which patients with AF plus at least one other risk factor for stroke were given either warfarin in a dose to prolong their INR (INR, 2.0-3.0; median, 2.4) or aspirin combined with a low dose of warfarin (0.5-3.0 mg/day; INR, 1.2-1.5; median, 1.3), the dose aiming for the higher INR was clearly superior.37 Aspirin or warfarin for AF? The 30% risk reduction in stroke from aspirin treatment is well below the 70% achieved with warfarin therapy.10 In a blinded analysis of clinical outcomes when the two drugs were compared, warfarin was better at preventing cardioembolic strokes and strokes of uncertain cause.38 This is consistent with the small effect observed with aspirin for secondary stroke prevention in patients with AF and who have had a stroke or TIA -- warfarin reduced the risk of recurrence by 62%, compared with only 16% for aspirin.39 It may be a useful compromise to reserve aspirin for patients with uncomplicated AF whose baseline risk of embolism is low. Warfarin, INR and aspirin in elderly patients with AF: Age above 75 years and a high INR both increase the hazard from intracranial and other major bleeding during warfarin therapy. Because there is some residual benefit at an INR of 1.5-1.9, this reduced target range may offer an acceptable exchange of safety for benefit in some elderly patients. Where the risk of bleeding is high, aspirin is less effective, but safer than warfarin. Cardioembolic stroke prevention in conditions other than AF There is evidence that cardioversion to correct a recent cardiac arrhythmia should be delayed until after three weeks of anticoagulant cover to prevent systemic embolism.35 Warfarin prevents embolic stroke and other arterial embolism, as well as VTE, after myocardial infarction (MI), and is often given for 3-6 months when MI is followed by intraventricular thrombus formation (risk factors include transmural anterior infarction and ventricular dysfunction).40 A good case also exists for long term warfarin therapy in some patients with ongoing left ventricular dysfunction.41,42Prosthetic heart valves Improved design has greatly reduced the thrombogenicity of mechanical prosthetic heart valves, but the need for effective, lifelong warfarin therapy remains because systemic embolism is still the main source of late mortality and morbidity. The risk is determined by the type of valve and its position (higher for mitral than aortic valves, greatest when both are replaced). Tissue valves, by contrast, are almost free of thromboembolic complications, except during the first three months.43The American College of Chest Physicians recommends an INR of 2.0-3.0 for recent-model bileaflet or tilting disc valves, and 2.5-3.5 for older and more thrombogenic valves that have a caged ball or disc; patients with a newly placed bioprosthetic (tissue) valve require three months of warfarin and an INR of 2.0-3.0.43 However, in our view, because the evidence is incomplete, it remains prudent to retain a target range of 2.5-3.5 for most ("low-risk") prosthetic valves while aiming higher (3.0-4.5) for older and more thrombogenic models, provided there is no contraindication (Box 1). This view is consistent with recent recommendations from the British Society for Haematology.2 Antiplatelet drugs alone are ineffective, but combining dipyridamole or aspirin (100 mg/day) with warfarin reduces the risk of systemic embolism. Meta-analysis suggests that the penalty for adding aspirin is a 2.5-times increase in major gastrointestinal bleeding,44 so the combination is perhaps best avoided, except in patients considered to be at unusually high risk of systemic thromboembolism (more than one mechanical valve, previous embolism, associated AF).43 Special circumstances for anticoagulation Antiphospholipid antibody syndrome and factor V Leiden: Two retrospective surveys of clinical outcomes in patients with antiphospholipid antibody syndrome and venous and/or arterial thrombosis suggest that warfarin therapy fails to prevent recurrent thromboses unless the INR is prolonged above 3.0.45,46 This contrasts with a more recent report of few recurrences while the INR was 2.0-3.5.47 Without better information, and until randomised trials are complete, it is not possible to make a firm recommendation about the optimal target range for this condition. The effect of aspirin alone in preventing thrombosis in the antiphospholipid antibody syndrome is unclear.45-47 There is no current evidence to suggest that patients with factor V Leiden-heterozygous abnormality should require more intense anticoagulation. It is still uncertain whether the duration of therapy should be increased in these patients, as evidence from reports about the risk of recurrent VTE is conflicting.28,29,48 Oral anticoagulants in pregnancy: Oral anticoagulants cross the placenta and should be avoided throughout pregnancy, especially during the first and third trimesters.49 Treatment at 6-12 weeks' gestation causes calcified epiphyses (chondrodysplasia punctata) and a characteristic nasal hypoplasia in offspring,50 while later exposure is associated with central nervous system abnormalities, including microcephaly.51 In one report, almost 30% of children (10 of 35) born to mothers with a prosthetic heart valve were malformed if acenocoumarol was taken through 6-12 weeks' gestation, but none of 19 developed a malformation when this drug was replaced with heparin before the sixth week.52 Continuing warfarin therapy until term also exposes infants to the risk of intracranial and other major bleeding during birth. Heparins do not cross the placenta and do not cause these problems.53-55 It is safe to breastfeed during warfarin therapy as there is minimal excretion into breast milk.56 References Hirsh J, Dalen JE, Anderson D, et al. Oral Anticoagulants. Mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 1998; 114 Suppl: 445S-469S. Walker ID, Machin S, Baglin TP, et al. Guidelines on oral anticoagulation. 3rd ed. Br J Haematol 1998; 101: 374-387. Holbrook AM, Wells PS, Crowther NR. Pharmacokinetics and drug interactions with warfarin. In: Poller L, Hirsh J, editors. Oral anticoagulants. Sydney: Arnold, 1996: 30-48. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5 mg and 10 mg warfarin loading doses. Arch Intern Med 1999; 159: 46-48. Rose P. Audit of anticoagulant therapy. J Clin Pathol 1996; 49: 5-9. Coumadin and Marevan are not interchangeable. Aust Adverse Drug React (ADRAC) Bull 1999; 18: 6. van der Meer FJM, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562. Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17. Levine M, Raskob GE, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114 Suppl: 511S-523S. Laupacis A, Boysen G, Connolly S, et al. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457. The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333: 5-10. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42: 857-865. Landefeld S, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 1993; 95: 315-328. Fihn SD, McDonnell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993; 118: 511-520. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423-428. Hylek EM, Singer D. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902. Weibert RT, Le DT, Kayser SR, Rapaport SI. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997; 125: 959-962. Crowther M, Donovan D, Harrison L, et al. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost 1998; 79: 1116-1118. Makris M, Greaves M, Philips W, et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1996; 77: 477-480. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511. Clagett GP, Anderson FA, Geerts WH, et al. Prevention of venous thromboembolism. Chest 1998; 114 Suppl: 531S-560S. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998; 114 Suppl: 561S-578S. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682-687. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-681. Schulman S, Rhedin A-S, Lindmarker P, et al. Comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 1661-1665. Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal DVT. Thromb Haemost 1995; 74: 606-611. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336: 393-398. van den Belt AGM, Sanson B-J, Simioni P, et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med 1997; 157: 2227-2232. Simioni P, Prandoni P, Lensing AWA, et al. The risk of recurrent venous thromboembolism in patients with an Arg506 to Gln mutation in the gene for factor V (Factor V Leiden). N Engl J Med 1997; 336: 399-403. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-907. Lagerstedt CI, Olsson C-G, Fagher BO, et al. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985; 2: 515-518. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795-1798. Heijboer H, Buller HR, Lensing AW, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993; 329: 1365-1369. Singer DE. Overview of the randomized trials to prevent stroke in atrial fibrillation. Ann Epidemiol 1993; 3: 563-567. Laupacis A, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 Suppl: 579S-589S. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-546. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638. Miller VT, Pearce LA, Feinberg WM, et al. Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation. Neurology 1996; 46: 238-240. European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342: 1255-1262. Cairns JA, Theroux P, Lewis HD Jr, et al. Antithrombotic agents in coronary artery disease. Chest 1998; 114 Suppl: 611S-633S. Fuster V, Gersh BJ, Giuliani ER, et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981; 47: 525-531. Al-Khadra AS, Salem DN, Rabd WR, et al. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol 1998; 31: 749-753. Stein PD, Alpert JS, Dalen JE, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1998; 114 Suppl: 602S-610S. Cappelleri JC, Fiore LD, Brophy MT, et al. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a metaanalysis. Am Heart J 1995; 130: 547-552. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117: 303-308. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-997. Krnic-Barrie S, O'Connor CR, Looney SW, et al. A retrospective review of 61 patients with antiphospholipid syndrome: analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997; 157: 2101-2108. Eichinger S, Pabinger I, Stumpflen, et al. The risk of recurrent venous thromboembolism in patients with and without Factor V Leiden. Thromb Haemost 1997; 77: 624-628. Ginsberg J, Barron W. Pregnancy and prosthetic heart valves. Lancet 1994; 344: 1170-1172. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338: 1128-1137. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140. Iturbe-Alessio I, del Carmen Fonseca M, Mutchinik O, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315: 1390-1393. Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin therapy during pregnancy. Risks to the fetus and mother. Arch Intern Med 1989; 149: 2233-2236. Fejgin MD, Lourwood DL. Low molecular weight heparins and their use in obstetrics and gynecology. Obstet Gynecol Surv 1994; 49: 424-431. Sanson B-J, Lensing AWA, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672. Orme ML, Lewis PJ, de Swiet M, et al. May mothers given warfarin breast-feed their infants? BMJ 1977; 1: 1564-1565. Background and evidence basis of recommendations The Australasian Society of Thrombosis and Haemostasis Consensus Guidelines for Warfarin Therapy were written on behalf of the Australasian Society of Thrombosis and Haemostasis (ASTH). The writing committee was commissioned by council and consisted of Associate Professor A S Gallus (Chairman), Dr R I Baker, Professor B H Chong, Dr P A Ockelford and Associate Professor A M Street. The guidelines were developed after extensive consultation with the membership of the ASTH, including several workshops and teleconferences. The draft recommendations were open for comment and discussion at the 1998 annual scientific meeting of the ASTH in Sydney. They draw upon review of all available evidence from published studies and from clinical experience. The aim is to provide an Australian perspective on the evidence to guide all practitioners in the safe and effective use of oral anticoagulants in hospital and the community. We are grateful for the help of Dr K McGrath, Dr M Herzberg (Quality Assurance Program in Haematology, Royal College of Pathologists of Australasia), Dr P Montanaro (Royal Australian College of General Practitioners), Dr P Steele (Australia and New Zealand Cardiac Society) and Professor J Fletcher (International Union of Angiology). Authors' details Australasian Society of Thrombosis and Haemostasis, Perth, WA. Alex S Gallus, FRACP, FRCPA, Chairman; Ross I Baker, FRACP, FRCPA; Beng H Chong, FRACP, FRCPA; Paul A Ockelford, FRACP, FRCPA; Alison M Street, FRACP, FRCPA. Reprints will not be available from the authors. Correspondence: Professor A S Gallus, Director, SouthPath, C/- Flinders Medical Centre, Bedford Park, SA 5042. 1: Range of international normalised ratio (INR) recommended for specific applications of warfarin therapy* Condition INR range Preventing DVT (high risk patients, like those who have had hip replacement) 2.0-3.0 Therapy after DVT or pulmonary embolism 2.0-3.0 Preventing systemic embolism Atrial fibrillation Valvular heart disease After myocardial infarction Tissue heart valves (first 3 months) 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0 Bileaflet mechanical heart valve (aortic) 2.5-3.5 Mechanical prosthetic heart valve (high risk) 3.0-4.5 Preventing recurrence of myocardial infarction 3.0-4.5 Thrombosis in antiphospholipid antibody syndrome 3.0-4.5 DVT=deep vein thrombosis . *Based largely on the 5th American College of Chest Physicians Consensus Conference1 and consistent with current recommendations of the British Society for Haematology.2 2: Risk of major bleeding (% per annum) and international normalised ratio (INR) - findings of two studies23,30 INR Study 130 Study 223 < 2.0 2.0-2.9 3.0-3.9 4.0-4.9 5.0-5.9 ≥ 6 3% 2%-3% 2%-3% 4% 5% 5%-13% 0 1% 3% 4% 50% 3: Managing overdose and bleeding during warfarin therapy* Clinical setting Action INR >5.0 but < 9.0 (no bleeding) Stop warfarin, give 1-2.5mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5 INR ≥9.0 (no bleeding) Stop warfarin, give 5mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5, clotting factor replacement? if high risk of bleeding Major bleeding (any level of INR) Stop warfarin, give 5mg vitamin K1, clotting factor replacement, measure INR as required, assess need to restart warfarin INR=international normalised ratio. *Based on Makris et al, 1996.19 ?Blood products available in Australia for clotting factor replacement after warfarin overdose include fresh frozen plasma and Prothrombinex-HT (CSL Limited), a factor II, IX and X concentrate. 4: Risk of ischaemic stroke in patients with atrial fibrillation (AF), grouped by age and other risk factors* (derived from Laupacis et al10) Risk categories Patients affected per annum Lone atrial fibrillation† Age < 60 years Age 60-69 years Age 70-79 years Age ≥80 years 0 1.6% 2.1% 3.0% Age < 65 years No risk factors One or more risk factors 1.0% 4.9% Age 65-75 years No risk factors One or more risk factors 4.3% 5.7% Age >75 years No risk factors One or more risk factors 3.5% 8.1% *Hypertension, diabetes, previous stroke or transient ischaemic attack. †Atrial fibrillation without transient ischaemic attack or stroke, myocardial infarction, hypertension or heart failure.

Alex S Gallus · Ross I Baker · Beng H Chong · Paul A Ockelford

Position Statement Use, misuse and abuse of androgens The Endocrine Society of Australia consensus guidelines for androgen prescribing Ann J Conway, David J Handelsman, Douglas W Lording, Bronwyn Stuckey, Jeffrey D Zajac on behalf of the Endocrine Society of Australia MJA 2000; 172: 220-224 Abstract - Use of androgens - Misuse of androgens - Abuse of androgens - Key references - Authors' details - - More articles on Endocrinology Abstract Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17α-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended. Androgens are hormones that are based on the structure of testosterone, the major male sex hormone, and are capable of developing and maintaining masculine sexual characteristics (including the genital tract, secondary sexual characteristics, and fertility) and the anabolic status of somatic tissues. All androgens have similar biological effects because they all act through the single androgen receptor. Their effects in different tissues are diversified by metabolism of testosterone to its active metabolites by the enzymes 5α reductase (which converts testosterone to 5α-dihydrotestosterone, an androgen with enhanced potency acting on the androgen receptor) and aromatase (which converts testosterone to oestradiol, which acts on the oestrogen receptor). Use of androgens The main medical use of androgens (Box 1) is as androgen replacement therapy (ART) for established androgen deficiency.1-3 Classical androgen deficiency occurs in about 1 in 200 men, due to testicular disorders that directly reduce testosterone output, or hypothalamic-pituitary disorders that reduce pituitary luteinising hormone (LH) secretion, which is the main drive to testosterone production by the interstitial (Leydig) cells of the testes. Although classical androgen deficiency is relatively easy to recognise, diagnosis of less severe androgen deficiency can be more difficult. Owing to its subtle and variable clinical features, the diagnosis may easily be missed, denying patients simple and effective medical treatment with often striking subjective benefits. Potential extensions of classical indications to partial androgen deficiency remain to be fully evaluated for clinical safety and efficacy. These indications include age, androgen deficiency secondary to a chronic medical condition or its treatment, hormonal male contraception, and postmenopausal symptoms.4-6 Until more definitive objective evidence is available regarding the safety and efficacy of prescribing androgens for these indications, they remain suitable for carefully monitored, controlled clinical research trials, but not for routine medical treatment. Pharmacological applications of androgens (Box 1) usually represent second-line therapy where more specific treatments are not yet available or have failed. Androgen treatment can evoke a strong placebo response. In men without genuine androgen deficiency, this placebo effect invariably wanes with time, leading to confusion and dissatisfaction with treatment. In addition, once androgen therapy has commenced, the biochemical changes can cloud further interpretation of results for months. Therefore, androgen replacement therapy should be commenced only after androgen deficiency is clearly established.2,3 Diagnosis of androgen deficiency1-3 Diagnosis of androgen deficiency involves the recognition of appropriate clinical features, with confirmation by biochemical testing. Important clinical features required to evaluate testicular function include reproductive history (including pubertal development), fertility status, changes in sexual function and body hair growth, known testicular pathology, drug use, and occupation. Physical examination should record androgenisation (secondary sexual characteristics, especially body hair distribution, musculature and gynaecomastia) and testis volumes (by orchidometry). Serum LH, follicle-stimulating hormone and testosterone levels should be measured, on at least two separate days and preferably in the morning, to minimise the effects of random and laboratory fluctuations and diurnal rhythms. Direct measurements of free testosterone, if available, may help establish the diagnosis of androgen deficiency, but require extensive validation. Indirect measurements of free testosterone, such as the free androgen index (testosterone/sex hormone binding globulin [SHBG] ratio), correspond poorly with direct measurements and lack empirical validation as a diagnostic test. Additional tests that may be required to identify underlying disorders include karyotyping, pituitary radiology and measurement of prolactin levels, serum ferritin levels, iron saturation and, increasingly, genetic diagnosis. Androgen deficiency is unlikely in men with mean testis volume > 20 mL without atrophy, with a plasma testosterone level consistently above 20 nmol/L, or presenting with erectile dysfunction and a plasma testosterone level consistently above 8 nmol/L (Box 2). Where the diagnosis is not clear, referral to a clinical endocrinologist with experience in this area is recommended.1 Androgen replacement therapy1-3 ART is indicated to rectify androgen deficiency of any cause sufficient to cause clinical consequences. After puberty, there is no age limit to ART. Androgen-deficiency effects may manifest as changes in one or more androgen-sensitive functions; for example, psychosexual function, or loss of anabolic effects on bone, muscle, blood-forming marrow and other androgen-responsive tissues. Apart from decreased spermatogenesis, ART can rectify all clinical features of androgen deficiency, which usually respond within 1-2 months of starting therapy, although the full effect may take longer. Dosage: Standard ART is either testosterone enanthate (Primoteston in castor oil; Schering) or mixed testosterone esters (Sustanon in arachis oil; Organon) as 250 mg in 1 mL oil at 14-day intervals. Deep intramuscular injections are usually given into the upper and outer quadrant of the buttock, although some patients prefer the deltoid or lateral thigh muscle sites. Few men can manage self-injection with the viscous oil vehicle. For all ART, testosterone and its esters should be used in preference to synthetic androgens, because of their established safety and efficacy, as well as ease of dose-titration and assay monitoring. Lower starting doses may occasionally be needed, especially in previously untreated elderly men and during first induction of puberty. Less frequent dosing intervals (eg, every three weeks) are occasionally necessary for those unable or unwilling to have standard dosage, but are accompanied by more extreme peaks and troughs in blood testosterone levels, which may exaggerate symptom fluctuations. An inadequate clinical response raises doubt about androgen deficiency as the cause of recalcitrant symptoms. Rarely, an inadequate clinical response may require increased dosage. If suboptimal symptomatic benefit is supported by biochemical evidence of inadequate maintenance of androgen levels (low trough testosterone levels with or without persistently supranormal LH levels in primary hypogonadism), the same dose may be injected at 10-day intervals. Persistently inadequate responses indicate that unresponsive symptoms are not due to androgen deficiency; further escalation in dose or frequency is not warranted. Men with mild or partial androgen resistance due to androgen-receptor mutations may benefit from high-dose androgen therapy. As the underlying disorders are almost always permanent, life-long ART after the age of puberty is usually necessary. Long term therapeutic compliance depends on an acceptable regimen. Crossover studies indicate that patients strongly prefer the stable testosterone levels and smoother clinical effects provided by implants or transdermal formulations, compared with the wide fluctuations in testosterone levels and symptoms during intramuscular testosterone ester injections. Thus, although ART should commence with injections, alternative modalities (Box 3) may improve compliance. Factors to consider include cost, convenience, availability, familiarity with alternatives, and tolerance for frequent injections. Monitoring: Monitoring of ART is mainly to ensure effective androgen replacement by a regimen tailored to the patient's needs, aiming to maintain adequate therapeutic compliance by continuation of treatment. Serial clinical observation of clinical well-being and major symptoms of androgen deficiency, together with limited numbers of hormonal assays, is usually adequate. Restoration of sexual function has a low threshold for androgen action, so adequate libido and potency is a necessary, but not sufficient, indication of clinically adequate androgen replacement. Blood hormone assays have limited utility in optimising an ART regimen at the start of treatment and in evaluating androgen replacement. Trough blood testosterone levels (ie, before the next scheduled dose) within the eugonadal reference range can be a valuable guide to the adequacy of parenteral androgen replacement, but random blood testosterone levels are not useful for monitoring with either oral or injectable testosterone. In men with hypergonadotropic hypogonadism, suppression of blood LH levels into the eugonadal reference range indicates adequate ART, whereas persistent non-suppression of LH after 3-6 months of regular treatment indicates inadequate dosage or compliance. In hypogonadotropic hypogonadism, blood gonadotropin levels are uninterpretable. Serial evaluation of bone density (especially vertebral trabecular bone) by dual-photon absorptiometry at 1-2-year intervals may be useful in evaluating the adequacy of long-term androgen effects on bone. Other biochemical indices of androgen action, such as haemoglobin, SHBG, and high density lipoprotein cholesterol levels, reflect only supraphysiological effects and are too insensitive for routine monitoring of ART. Androgen deficiency is protective against prostate disease, and ART may restore the risks to those equivalent to, but no more than, eugonadal men of similar age. Screening of men receiving ART for cardiovascular and prostate disease need be no more intensive than for men of similar age not on ART. Precautions and side effects14-17 Adverse effects of androgen treatment are uncommon. Virilisation may occur with androgen therapy in women or children; androgen therapy in these settings requires expert management. Truncal acne and hair growth, weight gain, gynaecomastia and male-pattern hair loss may be observed, and should be managed symptomatically. Certain side effects are characteristic of specific therapeutic modalities (eg, discomfort from intramuscular injections, extrusion of subdermal implants, gastrointestinal disturbance from oral testosterone undecanoate). Polycythaemia may occur disproportionately often in older men treated with testosterone ester injections. In addition, certain testosterone formulations have distinctive effects due to their pharmacokinetic features (eg, reduced levels of SHBG, high density lipoprotein cholesterol and other hepatic proteins due to supraphysiological hepatic testosterone exposure). This may be due to injectable testosterone esters (via high peak blood testosterone concentrations) or oral testosterone undecanoate (via high first-pass portal testosterone concentrations), whereas more steady formulations (transdermal, implants) exhibit fewer or no such effects. Oral synthetic androgens that have a 17α-alkyl substituent (oxandrolone, fluoxymesterone, danazol) are inherently hepatotoxic, causing cholestatic hepatitis, peliosis hepatis and hepatic tumours. Other classes of synthetic androgen, such as 19-nortestosterone derivatives (nandrolone, MENT) and the 1-methyl androgens (mesterolone, methenolone), are not hepatotoxic. Absolute contraindications to androgen therapy are prostate or breast cancer in men. Androgen therapy should be started in men over the age of 40 only after exclusion of undiagnosed prostate disease. Precautions are required for: older men starting androgen treatment, where it may precipitate urinary obstruction or unfamiliar increases in libido; pubertal boys, in whom excessive dosage may accelerate epiphyseal closure, leading to shortened final stature; parenteral androgen therapy in men with bleeding disorders; competitive athletes, who may be disqualified; androgen-sensitive epilepsy, migraine, sleep apnoea or polycythaemia; and cardiac or renal failure or severe hypertension susceptible to fluid overload from sodium and fluid retention. Misuse of androgens Medical misuse of androgens involves prescription with no acceptable medical indication. Some common examples of misguided prescribing of androgens in the absence of established androgen deficiency include: Male infertility: There is no indication for androgen therapy in male infertility. The only likely consequence is an adverse effect of suppressing spermatogenesis. Male sexual dysfunction or impotence: Androgen deficiency (with or without hyperprolactinaemia) is an uncommon (< 5%) cause of men presenting with erectile dysfunction. In such men, excluding androgen deficiency as a readily treatable underlying cause is essential. In the unusual event of severe androgen deficiency presenting with erectile dysfunction, the underlying cause needs to be identified, and plans for life-long ART need to be established. "Male menopause" or "andropause": There is still no evidence that the modest decreases in circulating blood testosterone levels which commence during mid-life have any clinical importance. The risks and benefits of androgen supplementation for partially androgen-deficient older men require further evaluation by placebo-controlled studies. Androgen treatment may be inappropriate, wasteful, and involve placebo effects. Terms such as "male menopause" and "andropause" are misleading; they have little place in meaningful medical or scientific discourse. Elderly men (> 65 years):18 There is no basis for androgen therapy based on age per se. Further controlled clinical trials are needed to evaluate the potential role of androgen supplementation in ageing. While some preliminary placebo-controlled studies suggest short-term benefits for muscle, bone and quality of life, findings are not yet consistent and the identification of appropriate treatment objectives and target subgroups, as well as overall analyses of risks, benefits and costs, are lacking. Specifically, it remains to be determined whether androgen supplementation has significant and sustained clinical benefits in older men with low-normal plasma total testosterone and normal LH levels. At present, there is no basis for androgen treatment outside properly designed clinical trials. Treatment of non-specific symptoms: There is no basis for androgen therapy based on symptoms in the absence of established androgen deficiency. In addition to the unproven safety and efficacy, the placebo effect of androgen injections may be confusing to both doctor and patient. When placebo effects wane, further confusion and dissatisfaction with treatment may be expected. Abuse of androgens Illicit use of androgens19-24 ("anabolic steroids") depends largely on obtaining androgens without legal prescription to be used in the absence of any medical indication. Illicit androgen use became epidemic over the past four decades, since androgens were reportedly first used in elite competitive power sports. A recent placebo-controlled study has shown that high-dose androgen administration does improve muscle size and strength in healthy eugonadal men. Whether these changes enhance athletic performance, whether they are sustained, and whether they apply to older men remains to be clarified. Medical prescription appears to support only a small proportion of illicit androgen use, but such activity has been formally ruled as a breach of professional standards by medical boards in most States and by the Royal Australasian College of Physicians. Highly motivated young men can be very sophisticated in manipulating and pressuring general practitioners while attempting to obtain prescriptions for androgens. The doctor is often led to believe that other practitioners are prescribing androgens for young men, and that he or she is being uncaring or negligent by not acceding to the patient's wishes. We recommend that general practitioners resist these pressures. Fortunately, most people appear ultimately to lose interest in this form of drug abuse. Background and evidence basis of recommendations The Endocrine Society of Australia (ESA) Consensus Guidelines for Androgen Prescribing were written on behalf of the Endocrine Society of Australia. The ad hoc Writing Committee commissioned by the ESA's Council was Dr A J Conway, Professor D J Handelsman (Chair), Associate Professor D W Lording, Dr B Stuckey, and Associate Professor J D Zajac. The draft guidelines were extensively circulated for comment to active members of the ESA with clinical expertise or interests in male reproductive endocrinology. Comments were incorporated into the final document, which was ratified by the ESA's Council. Androgen therapy, in regular clinical use for over 60 years, is one of the oldest hormonal regimens in modern therapeutics. As a long established standard and effective form of hormone replacement for many decades, placebo-controlled studies are unavailable and now unacceptable. Consequently, the NHMRC Quality of Evidence Ratings for these recommendations are those appropriate to an expert committee reviewing all available evidence from controlled experimental and observational studies as well as clinical experience. Key references Diagnosis and management of androgen deficiency Behre HM, Yeung CH, Nieschlag E. Diagnosis of male infertility and hypogonadism. In: Nieschlag E, Behre HM (eds): Andrology: Male Reproductive Health and Dysfunction. Berlin:Springer, 1997: 87-111. Plymate SR. Male Hypogonadism. In: Becker KL (ed): Principles and Practice of Endocrinology and Metabolism. 2nd ed. Philadelphia: J B Lippincott Company, 1995: 1056-1082. Nieschlag E, Wang C, Handelsman DJ, et al (eds) (1992). Guidelines for the use of androgens in men. Geneva, Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organisation. Male contraception Cummings DE, Bremner WJ. Prospects for new hormonal male contraceptives. In: Bremner WJ (ed): Clinical Andrology. Philadelphia: W B Saunders Company, 1994: 893-922. Handelsman DJ. Contraception in the male. In: DeGroot LJ (ed): Endocrinology. 3rd ed. Philadelphia: W B Saunders, 1994: 2449-2458. Androgen therapy in systemic disease Liu PY, Handelsman DJ. Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM (eds):Testosterone: Action, Deficiency and Substitution. 2nd ed. E Nieschlag, Behre HM (eds), Berlin, Springer-Verlag, 1998. Comparative pharmacology of androgen formulations Bals-Pratsch M, Langer K, Place VA, Nieschlag E. Substitution therapy of hypogonadal men with transdermal testosterone over one year. Acta Endocrinologica 1988; 118: 7-13. Behre HM, Oberpenning F, Nieschlag E. Comparative pharmacokinetics of androgen preparations: application of computer analysis and simulation. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 115-135. Cantrill JA, Dewis P, Large DM et al. Which testosterone replacement therapy? Clin Endocrinol (Oxf) 1984; 24: 97-107. Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. A randomised clinical trial of testosterone replacement therapy in hypogonadal men. Int J Androl 1988; 11: 247-264. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab 1990; 71: 216-222. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992; 74: 623-628. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab 1980; 51: 1335-1339. Safety of androgens Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 1996; 125: 1-13. Barrett-Connor E. Testosterone, HDL-cholesterol and cardiovascular disease. In: Bhasin S, Gabelnick HL, Spieler JM et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 215-223. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994; 40: 341-349. Gooren LJ, Polderman KH. Safety aspects of androgen therapy. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 182-203. Androgen and the ageing male Tenover JL. Androgen therapy in aging men. In: Bhasin S, Gabelnick HL, Spieler JM, et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 309-318. Androgen abuse Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. Handelsman DJ, Gupta L. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian secondary school students. Int J Androl 1997; 20: 159-164. Lin GC, Erinoff L (eds). (1990). Anabolic Steroid Abuse. National Institute on Drug Abuse Research Monograph Series. Rockville, US Department of Health and Human Services. Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-199. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS. Anabolic-androgenic steroid use in the United States. JAMA 1993; 270: 1217-1221. Young NR, Baker HWG, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab 1993; 77: 1028-1032. Authors' details Endocrine Society of Australia, Sydney, NSW. Ann J Conway, MB BS, FRACP; David J Handelsman, MB BS, PhD, FRACP; Douglas W Lording, MB BS, FRACP; Bronwyn Stuckey, MB BS, FRACP; Jeffrey D Zajac, PhD, FRACP. Reprints will not be available from the authors. Correspondence: Associate Professor J D Zajac, Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050. j.zajacATmedicine.unimelb.edu.au Make a comment 1: Use, misuse and abuse of androgens Use Physiological (androgen deficiency) 1-3 Classical androgen deficiency ("hypogonadism") Age-related partial androgen deficiency Micropenis (neonatal) Delayed puberty Aged men* Androgen deficiency secondary to chronic disease* Induced androgen deficiency Hormonal male contraception* Pharmacological (non-androgen deficiency)4-6 Osteoporosis Anaemia due to marrow or renal failure Advanced breast cancer Excessively tall stature in boys Misuse Inappropriate indications In absence of proven androgen deficiency: Male infertility Sexual dysfunction/impotence "Male menopause", "andropause" Older men (>65 years) Non-specific symptoms Abuse19-24 Absence of medical indication Sporting Competitive power sports (athletics, weightlifting, football, swimming, rowing, boxing) RecreationalBodybuilding Cosmetic"Body beautiful" subculture OccupationalSecurity, police, armed forces, professional sports * These indications remain to be fully evaluated for safety and efficacy in controlled clinical trials. Back to text 2: Biochemical evaluation of the diagnosis of androgen deficiency in men with clinical features consistent with hypogonadism* Testosterone level†Luteinising hormone level†Diagnosis<8 nMHigh‡Androgen deficiency (hypergonadotropic hypogonadism§)<8 nMNot highAndrogen deficiency (hypogonadotropic hypogonadism§)8-15 nMHigh‡Androgen deficiency (Leydig cell failure)8-15 nMNot highAndrogen deficiency not confirmed: unproven therapeutic benefit of androgen replacement therapy>20 nMAnyExcludes androgen deficiency>30 nM**High‡Androgen resistance*There is necessarily an arbitrary component to this type of table. It is based on current experience and should be subject to changes according to further clinical evidence. †Blood sample classification based on at least two separate morning blood samples. ‡"High" luteinising hormone level is defined as > 1.5 times the upper limit of the eugonadal reference range for young men. §Hypergonadotropic and hypogonadotropic hypogonadism are also referred to as primary and secondary hypogonadism, respectively. Compensated Leydig cell failure is a form of partial androgen deficiency in which androgen replacement is often beneficial. **Elevated testosterone is defined as above the upper limit of the eugonadal reference range for young men. Back to text 3: Androgen treatment modalities7-13 Testosterone implants Fused cylindrical pellets of pure crystalline testosterone that form a subdermal depot Provide stable, physiological levels of testosterone for 4-6 months following a single implantation of four 200 mg (800 mg) implants Implantation uses a trochar and cannula technique under office sterile conditions, and requires local anaesthesia Main adverse effect is extrusion of implants via the insertion site 1-2 months after implantation Extrusion rate (about 10%) depends on operator experience and patient's physical activity Minor adverse effects related to the minor office surgery (bleeding, infection) are infrequent (<5%) Should only be used for patients who have demonstrated satisfactory tolerance of androgen effects with shorter-acting preparations Transdermal testosterone Administered daily via androgen-impregnated adhesive skin patches or hydroalcoholic gels (not yet available in Australia) Other depot testosterone formulations Newer injectable esters (testosterone undecanoate, testosterone buciclate) Testosterone-laden biodegradable microspheres Both these formulations deliver stable, physiological testosterone levels for 2-3 months following injection Oral testosterone undecanoate Useful where parenteral testosterone is undesirable (eg, bleeding disorders or anticoagulation) or poorly tolerated Administered as 160-240 mg (four to six 40 mg capsules), divided into 2-4 doses per day Second-line formulation for routine ART, because of frequency of administration, high hepatic load, gastrointestinal intolerance, and higher cost Back to text

Ann J Conway · David J Handelsman · Douglas W Lording · Bronwyn Stuckey · Jeffrey D Zajac

Position Statement New classification and criteria for diagnosis of diabetes mellitus Position Statement from the Australian Diabetes Society,* New Zealand Society for the Study of Diabetes, Royal College of Pathologists of Australasia and Australasian Association of Clinical Biochemists Peter G Colman,* David W Thomas, Paul Z Zimmet,* Timothy A Welborn, * Peter Garcia-Webb and M Peter Moore MJA 1999; 170: 375-378 Introduction - What are the new diagnostic criteria? - What about the oral glucose tolerance test? - Diabetes in pregnancy - How has the classification of diabetes changed? - Impaired glucose tolerance and impaired fasting glycaemia - References - Authors' details - - More articles on Endocrinology Introduction Recently, there has been major growth in knowledge about the aetiology and pathogenesis of different types of diabetes and about the predictive value of different blood glucose levels for development of complications. In response, both the American Diabetes Association (ADA) and the World Health Organization (WHO) have re-examined, redefined and updated the classification of and criteria for diabetes, which have been unchanged since 1985. While the two working parties had cross-representation, they met separately, and differences have emerged between their recommendations. The ADA published its final recommendations in 1997,1 while the WHO group published its provisional conclusions for consultation and comment in June 1998.2 The WHO process called for comments on the proposal by the end of September 1998, with the intention of finalising definitive classification and criteria by the end of December 1998 and of publishing these soon thereafter. However, WHO publications need to go through an internal approval process and it may be up to 12 months before the final WHO document appears. A combined working party of the Australian Diabetes Society, New Zealand Society for the Study of Diabetes, Royal College of Pathologists of Australasia and Australasian Association of Clinical Biochemists was formed to formulate an Australasian position on the two sets of recommendations and, in particular, on the differences between them. This is an interim statement pending the final WHO report, which will include recommendations on diabetes classification as well as criteria for diagnosis. We see it as very important to inform Australasian health professionals treating patients with diabetes about these changes. Position Statement key messages What are the new diagnostic criteria? The new WHO criteria for diagnosis of diabetes mellitus and hyperglycaemia are shown in Box 1. The major change from the previous WHO recommendation3 is the lowering of the diagnostic level of fasting plasma glucose to 7.0 mmol/L, from the former level of 7.8 mmol/L. For whole blood, the proposed new level is 6.1 mmol/L, from the former 6.7 mmol/L. This change is based primarily on cross-sectional studies demonstrating the presence of microvascular4 and macrovascular complications5 at these lower glucose concentrations. In addition, the 1985 WHO diagnostic criterion for diabetes based on fasting plasma glucose level ( 7.8 mmol/L) represents a greater degree of hyperglycaemia than the criterion based on plasma glucose level two hours after a 75 g glucose load ( 11.1 mmol/L).6 A fasting plasma glucose level of 7 mmol/L accords more closely with this 2 h post-glucose level. Recommendation: The ADA and the WHO committee are unanimous in adopting the changed diagnostic level, and the Australasian Working Party on Diagnostic Criteria recommends that healthcare providers in Australia and New Zealand should adopt it immediately. Clinicians should note that the diagnostic criteria differ between clinical and epidemiological settings. In clinical practice, when symptoms are typical of diabetes, a single fasting plasma glucose level of 7.0 mmol/L or 2 h post-glucose or casual postprandial plasma glucose level of 11.1 mmol/L suffices for diagnosis. If there are no symptoms, or symptoms are equivocal, at least one additional glucose measurement (preferably fasting) on a different day with a value in the diabetic range is necessary to confirm the diagnosis. Furthermore, severe hyperglycaemia detected under conditions of acute infective, traumatic, circulatory or other stress may be transitory and should not be regarded as diagnostic of diabetes. The situation should be reviewed when the primary condition has stabilised. In epidemiological settings, for study of high-prevalence populations or selective screening of high-risk individuals, a single measure -- the glucose-level 2 h post-glucose load -- will suffice to describe prevalence of impaired glucose tolerance (IGT). What about the oral glucose tolerance test? Previously, the oral glucose tolerance test (OGTT) was recommended in people with a fasting plasma glucose level of 5.5-7.7 mmol/L or random plasma glucose level of 7.8-11.0 mmol/L. After a 75 g glucose load, those with a 2 h plasma glucose level of < 7.8 mmol/L were classified as normoglycaemic, of 7.8-11.0 mmol/L as having IGT and of 11.1 mmol/L as having diabetes. The new diagnostic criteria proposed by the ADA and WHO differ in their recommendations on use of the OGTT. The ADA makes a strong recommendation that fasting plasma glucose level can be used on its own and that, in general, the OGTT need not be used.1 The WHO group2 argues strongly for the retention of the OGTT and suggests using fasting plasma glucose level alone only when circumstances prevent the performance of the OGTT. There are concerns that many people with a fasting plasma glucose level < 7.0 mmol/L will have manifestly abnormal results on the OGTT and are at risk of microvascular and macrovascular complications. This has major ramifications for the approach to diabetes screening, particularly when the Australian National Diabetes Strategy proposal,7 launched in June 1998 by Dr Michael Wooldridge, Federal Minister for Health and Aged Care, has early detection of type 2 diabetes as a key priority. Recommendation: The Australasian Working Party on Diagnostic Criteria has major concerns about discontinuing use of the OGTT and recommends that a formal recommendation on its use in diabetes screening be withheld until the final WHO recommendation is made. However, in the interim, the OGTT should continue to be used. Diabetes in pregnancy The ADA has retained its old criteria for diagnosis of gestational diabetes.1 These differ from those recommended by both WHO2 and the Australian Working Party on Diabetes in Pregnancy8 and are generally not recognised outside the United States. The new WHO statement retains the 1985 WHO recommendation that both IGT and diabetes should be classified as gestational diabetes. This is consistent with the recommendations of the Australasian Diabetes in Pregnancy Society, which recommended a diagnostic 2 h venous plasma glucose level on the OGTT of 8.0 mmol/L. In New Zealand, a cut-off level of 9.0 mmol/L has been applied.8 How has the classification of diabetes changed? The proposed new classification encompasses both clinical stages and aetiological types of hyperglycaemia and is supported by numerous epidemiological studies. The classification by aetiological type (Box 2) results from new knowledge of the causes of hyperglycaemia, including diabetes. The terms insulin-dependent and non-insulin-dependent diabetes (IDDM and NIDDM) are eliminated and the terms type 1 and type 2 diabetes retained. Other aetiological types, such as diabetes arising from genetic defects of -cell function or insulin action, are grouped as "other specific types", with gestational diabetes as a fourth category. The proposed staging (Box 3) reflects the fact that any aetiological type of diabetes can pass or progress through several clinical phases (both asymptomatic and symptomatic) during its natural history. Moreover, individuals may move in either direction between stages. Impaired glucose tolerance and impaired fasting glycaemia Impaired glucose tolerance (IGT), a discrete class in the previous classification, is now categorised as a stage in the natural history of disordered carbohydrate metabolism. Individuals with IGT are at increased risk of cardiovascular disease, and not all will be identified by fasting glucose level. In reducing the use of the OGTT, the ADA recommended a new category -- impaired fasting glycaemia (IFG) -- when fasting plasma glucose level is lower than that required to diagnose diabetes but higher than the reference range (< 7.0 mmol/L but 6.1 mmol/L). Limited data on this category show that it increases both risk of progressing to diabetes9 and cardiovascular risk.5 However, data are as yet insufficient to determine whether IFG has the same status as IGT as a risk factor for developing diabetes and cardiovascular disease and as strong an association with the metabolic syndrome (insulin resistance syndrome). IFG can be diagnosed by fasting glucose level alone, but if 2 h glucose level is also measured some individuals with IFG will have IGT and some may have diabetes. In addition, the number of people with OGTT results indicating diabetes but fasting plasma glucose level < 7.0 mmol/L is unknown, but early data suggest there may be major variation across different populations.10 A number of studies, including the DECODE initiative of the European Diabetes Epidemiology Group, have reported that individuals classified with IFG are not the same as the IGT group.11-15 The European Group believes that, on available European evidence, the ADA decision to rely solely on fasting glucose level would be unwise. Recommendation: The Australasian Working Party on Diagnostic Criteria recommends immediate adoption of the new classification. However, clinicians should be aware that some cases of diabetes will be missed unless an OGTT is performed. Thus, if there is any suspicion or other risk factor suggesting glucose intolerance, the working party continues to recommend use of an OGTT pending the final WHO recommendation. References Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183-1197. Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. World Health Organization. Diabetes mellitus. Report of a WHO study group. Technical report series 727. Geneva: WHO, 1985. McCance DR, Hanson RL, Charles MA, et al. Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes. BMJ 1994; 308: 1323-1328. Charles MA, Balkau B, Vauzelle-Kervoeden F, et al. Revision of diagnostic criteria for diabetes [letter]. Lancet 1996; 348: 1657-1658. Finch CF, Zimmet PZ, Alberti KGMM. Determining diabetes prevalence: a rational basis for the use of fasting plasma glucose concentrations? Diabet Med 1990; 7: 603-610. Colagiuri S, Colagiuri R, Ward J. National diabetes strategy and implementation plan. Canberra: Diabetes Australia, 1998. Hoffman L, Nolan C, Wilson D, et al. Gestational diabetes mellitus -- management guidelines. The Australasian Diabetes in Pregnancy Society. Med J Aust 1998; 169: 93-97. Charles MA, Fontbonne A, Thibult N, et al. Risk factors for NIDDM in white population. Diabetes 1991; 40: 796-799. Keen H. Impact of new criteria for diabetes on pattern of disease. Lancet 1998; 352: 1000-1001. DECODE Study Group on behalf of the European Diabetes Epidemiology Study Group. Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data. BMJ 1998; 317: 371-375. De Vegt F, Dekker JM, Stehouwer CDA, et al. The 1997 American Diabetes Association criteria versus the 1985 World Health Organization criteria for the diagnosis of abnormal glucose tolerance. Diabetes Care 1998; 21: 1686-1690. Harris MI, Eastman RC, Cowie CC, et al. Comparison of diabetes diagnostic categories in the US population according to 1997 American Diabetes Association and 1980-1985 World Health Organization diagnostic criteria. Diabetes Care 1997; 20: 1859-1862. Unwin N, Alberti KGMM, Bhopal R, et al. Comparison of the current WHO and new ADA criteria for the diagnosis of diabetes mellitus in three ethnic groups in the UK. Diabet Med 1998; 15: 554-557. Chang C-J, Wu J-S, Lu F-H, Lee H-L, et al. Fasting plasma glucose in screening for diabetes in the Taiwanese population. Diabetes Care 1998; 21: 1856-1860. Authors' details Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, VIC. Peter G Colman, FRACP, MD, Director. Chemical Pathology Services, Women's and Children's Hospital, Adelaide, SA. David W Thomas, FRACP, FRCPA, Head. International Diabetes Institute, Melbourne, VIC. Paul Z Zimmet, FRACP, MD, Director. Diabetes Centre, Sir Charles Gairdner Hospital, Perth, WA. Timothy A Welborn, FRACP, PhD, Head. St John of God Pathology, Perth, WA. Peter Garcia-Webb, MD, FRCPA, Chemical Pathologist. Diabetes Centre, Christchurch Hospital, Christchurch, NZ. M Peter Moore, FRACP, Clinical Director. Reprints will not be available from the authors. Correspondence: Dr P G Colman, Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, VIC 3050. Email: peter.colmanATnwhcn.org.au Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Key messages Diagnosis of diabetes is not in doubt when there are classical symptoms of thirst and polyuria and a random venous plasma glucose level 11.1 mmol/L. The Australasian Working Party on Diagnostic Criteria for Diabetes Mellitus recommends: Immediate adoption of the new criterion for diagnosis of diabetes as proposed by the American Diabetes Association (ADA) and the World Health Organization (WHO) - fasting venous plasma glucose level 7.0 mmol/L; Immediate adoption of the new classification for diabetes mellitus proposed by the ADA and WHO, which comprises four aetiological types - type 1, type 2, other specific types, and gestational diabetes - with impaired glucose tolerance and impaired fasting glycaemia as stages in the natural history of disordered carbohydrate metabolism. Awareness that some cases of diabetes will be missed unless an oral glucose tolerance test (OGTT) is performed. If there is any suspicion or other risk factor suggesting glucose intolerance, the OGTT should continue to be used pending the final WHO recommendation. Back to text 1: Values for diagnosis of diabetes mellitus and other categories of hyperglycaemia2Glucose concentration (mmol/L [mg/dL]) Whole blood Venous Capillary Diabetes mellitusFasting 6.1 ( 110) 6.1 ( 110) or 2 h post-glucose load 10.0 ( 180) 11.1 ( 200) or bothImpaired glucose tolerance (IGT)Fasting (if measured)< 6.1 (< 110) < 6.1 (< 110) and 2 h post-glucose load 6.7 ( 120) 7.8 ( 140) and < 10.0 (< 180) and < 11.1 (< 200) Impaired fasting glycaemia (IFG)Fasting 5.6 ( 100) and 5.6 ( 100) and < 6.1 (< 110) < 6.1 (< 110) 2 h post-glucose load (if measured)< 6.7 (< 120) < 7.8 (< 140) Glucose concentration (mmol/L [mg/dL]) Plasma* Venous Capillary Diabetes mellitusFasting< 7.0 ( 126) 7.0 ( 126) or 2 h post-glucose load 11.1 ( 200) 12.2 ( 220) or bothImpaired glucose tolerance (IGT)Fasting (if measured)<7.0 (<126) < 7.0 (< 126) and 2 h post-glucose load 7.8 ( 140) 8.9 ( 160) and < 11.1 (< 200) and < 12.2 (< 220) Impaired fasting glycaemia (IFG)Fasting 6.1 ( 110) and 6.1 ( 110) and < 7.0 (< 126) < 7.0 (< 126) 2 h post-glucose load (if measured)< 7.8 (< 140) < 8.9 (< 160) For epidemiological or population screening purposes, the fasting or 2 h value after 75 g oral glucose may be used alone. For clinical purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day, unless there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms. Glucose concentrations should not be determined on serum unless red cells are immediately removed, otherwise glycolysis will result in an unpredictable underestimation of the true concentrations. It should be stressed that glucose preservatives do not totally prevent glycolysis. If whole blood is used, the sample should be kept at 0-4oC or centrifuged immediately, or assayed immediately. Table reproduced with permission from Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. Copyright John Wiley & Sons Limited. Back to text2: Aetiological classification of disorders of glycaemia* Type 1 (-cell destruction, usually leading to absolute insulin deficiency) Autoimmune Idiopathic Type 2 (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance) Other specific types Genetic defects of -cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug or chemical induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes Gestational diabetes * As additional subtypes are discovered, it is anticipated they will be reclassified within their own specific category. Includes the former categories of gestational impaired glucose tolerance and gestational diabetes. Table reproduced with permission from Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation. Diabet Med 1998; 15: 539-553. Copyright John Wiley & Sons Limited. Back to textBack to text

Peter G Colman · David W Thomas · Paul Z Zimmet · Timothy A Welborn · Peter Garcia-Webb

Adult domiciliary oxygen therapy Position statement of the Thoracic Society of Australia and New Zealand Iven H Young, Alan J Crockett and Christine F McDonald Evidence shows that patients with chronic obstructive pulmonary disease and a stable daytime PaO2 of 55 mm Hg or less will have longer life expectancy if given supplemental oxygen to keep the PaO2 above 60 mm Hg, preferably for longer than 15 hours a day, including sleep. There is some evidence for improved quality of life. It is reasonable to offer this therapy for other lung diseases which cause chronic hypoxaemia, and there are also less well defined indications for supplemental oxygen during exercise, sleep and air travel. (MJA 1998; 168: 21-25) → This position statement has been superseded by a new statement published in 2005. Click here for the new statement. Introduction - Indications - Contraindications - Investigations - Reassessment - Dangers - Quality of life - Methods of domiciliary oxygen delivery - Authorisation of oxygen therapy - References - Authors' details - - ©MJA1997 Introduction Domiciliary oxygen therapy is an effective but potentially expensive therapy that should be prescribed to those in whom there is evidence for benefit. This position paper is a consensus statement based on evidence from English-language publications up to 1996 obtained by search of MEDLINE with keywords domiciliary oxygen, home oxygen and LTOT (long term oxygen therapy). The paper is an update of the position statement published in the Journal in 1991.1 Supplementary oxygen may benefit patients whose disability is related to decreased oxygen concentration in arterial blood. The most common cause of chronic hypoxaemia in Australia is chronic obstructive pulmonary disease (COPD), and there is more substantial information about use of domiciliary oxygen in this condition than in any other. In COPD, domiciliary oxygen is the only therapy (apart from smoking cessation) shown to reduce mortality.2,3 There is also evidence that it alleviates right heart failure caused by cor pulmonale, enhances neuropsychological function, and improves exercise performance and capacity to undertake the activities of daily living.4 Although long term oxygen therapy has been best studied in COPD, other possible indications include hypoxaemia associated with cyanotic congenital heart disease, severe congestive cardiac failure, diffuse interstitial lung disease, advanced lung cancer or cystic fibrosis,5 and, in general, any illness with chronic hypoxaemia as an important feature. In the absence of hypoxaemia, oxygen therapy is unlikely to contribute usefully to relief of dyspnoea, heart failure or angina. Indications Continuous (at least 15 hours/day) oxygen therapy: Long term continuous oxygen therapy should be considered for patients with stable chronic lung disease, particularly COPD, who have an arterial PO2 (PaO2) consistently less than or equal to 55 mm Hg when breathing air, at rest and awake. At assessment (see Investigations), the patient's condition must be stable and all reversible factors (such as anaemia) should be remediated.6 Because gas exchange may improve substantially on ceasing cigarette smoking, assessment should be made at least a month after the patient has stopped smoking. Polycythaemia (Hb > 170 gm/L), clinical or electrocardiographic (ECG) evidence of pulmonary hypertension, as well as episodes of right heart failure, are consistent with the systemic effects of chronic hypoxaemia and strengthen the case for therapeutic use of oxygen. Patients with these complications should be prescribed continuous oxygen if their stable PaO2 is 55-59 mm Hg. In COPD, continuous oxygen therapy is of most benefit for patients with increased arterial PCO2 ( >45 mm Hg).3 As the benefit has been shown to increase with increasing daily use of oxygen for up to 19 hours per day,3 patients should be advised to use oxygen whenever the physical restriction imposed by the oxygen therapy is not onerous. Intermittent oxygen therapy: The use of intermittent oxygen may be considered for: Patients with fibrotic or obstructive lung diseases during exercise, as supplementary oxygen may improve exercise capacity. Benefit cannot be predicted by a resting test and may occur irrespective of resting or exercise hypoxaemia. Benefit should be established by comparing exercise endurance when breathing oxygen and when breathing air (using a treadmill, stationary bicycle or six-minute walk test). Room air is probably adequate for this comparison, as there appears no difference in exercise endurance between breathing room and cylinder air.7 The Society's position on the controversal use of oxygen during exercise is summarised in Box 1. Patients with acute asthma living in isolated areas or prone to sudden life-threatening episodes while they are awaiting medical attention or evacuation by ambulance. During air travel, particularly long distance flights out of Australia. Commercial passenger aircraft operate at cabin pressures between about 1500 and 3000 metres above sea level, with the lowest pressure likely to be experienced for a significant time being equivalent to 2500 metres above sea level. This is analogous to breathing 15% oxygen at sea level. Sufficient supplementary oxygen should be given during flight to keep the PaO2 above 50 mm Hg, which is commonly achieved by increasing the usual flow by 1-2 L/min. Patients who qualify for continuous oxygen at home will require this supplementation. Others can be tested for the effects of 15% oxygen in the laboratory before the flight. Further, those travelling to high-altitude destinations may need an increase in their oxygen prescription during their sojourn.4 Patients with late stage interstitial or neoplastic lung disease with significant hypoxaemia. Supplementary oxygen may provide symptomatic relief. Patients in the latter category will generally have a life expectancy of three months or less. Duration of use may be extended as long as necessary to relieve symptoms. The prescription of home oxygen for patients with chronic heart failure and/or angina is not well supported by evidence of efficacy, and a decrease in mortality with this therapy has not been verified. A high inspired oxygen concentration of 50% may modestly improve exercise duration in heart failure,8 but concentrations this high are difficult to attain with current home delivery systems. Nocturnal oxygen therapy: This may be indicated in patients with hypoxaemia during sleep. This diagnosis should be considered in patients whose arterial gas tensions are acceptable when awake, but who have daytime somnolence, polycythaemia or right heart failure. The clinical importance of isolated nocturnal hypoxaemia (i.e., without daytime hypoxaemia or obstructive sleep apnoea) was recently established.9 In patients with this condition, nocturnal oxygen at 3 L/min over three years was found to reduce pulmonary hypertension, but not to alter mortality, in comparison with a control group over this relatively short period. Although data are insufficient to make rigorous recommendations for this group, and further studies are needed, the current consensus is that those whose nocturnal arterial oxygen saturation falls to 88% or less should be treated with nocturnal oxygen. Hypoxaemia during sleep should be distinguished from sleep apnoea caused by upper airway obstruction, which requires other forms of therapy (such as continuous positive airway pressure and nocturnal ventilation). The diagnosis is by formal sleep studies. These are essential if obstructive sleep apnoea is suspected in a patient with chronic airflow limitation; this combination is suggested by daytime hypercapnia. Contraindications Supplementary oxygen is not indicated for: Patients with severe airflow limitation whose main complaint is dyspnoea, but who maintain a PaO2 greater than 60 mm Hg and who show no secondary effects of chronic hypoxia; Patients who continue to smoke cigarettes, because of the increased fire risk and the probability that the poorer prognosis conferred by smoking will offset treatment benefit; Patients who have not received adequate therapy of other kinds (e.g., inhaled and oral bronchodilators, treatment of right ventricular failure and of any respiratory infection); and Patients who are not sufficiently motivated to undertake the discipline required in oxygen therapy. Investigations Establish the nature and severity of the pulmonary disorder responsible for hypoxaemia (usually obstructive or fibrotic lung disease) by appropriate tests, including objective tests of pulmonary function. Undertake clinical, ECG, echocardiographic and radiological assessment of right heart failure and pulmonary hypertension. Measure haemoglobin level. Polycythaemia, the usual response to chronic hypoxaemia in otherwise healthy people, is not always seen in those with hypoxaemia of chronic lung disease. The degree to which it is adaptive or adds to the burden of disordered function through increased blood viscosity is controversial. Anaemia is always a burden and should be investigated and corrected. Undertake other appropriate tests, according to clinical findings, for other major diseases which might be expected to seriously limit survival. As noted above, it is appropriate to prescribe oxygen for symptomatic relief in patients with a very limited prognosis. Before introducing oxygen therapy, undertake optimal treatment of the pulmonary disorder while monitoring improvement with objective tests (usually simple tests of ventilatory capacity such as FEV1 and vital capacity).6 Treatment may include maximum therapy of airway obstruction, attention to nutrition and body weight, an exercise rehabilitation program, control of infection and treatment of cor pulmonale. When the patient's condition has been stabilised and drug therapy optimised over about four weeks, the degree of hypoxaemia should be determined by measurement of arterial blood gases while the patient is breathing air at rest. This should include measurements of PaO2 at rest on at least two occasions and, when indicated, measurements of PaO2 or arterial oxygen saturation during sleep. In patients selected for oxygen therapy, assess the adequacy of relief of hypoxaemia (PaO2 > 60 mm Hg, SaO2 > 90%) and/or improvement in exercise capacity or nocturnal arterial oxygen saturation while using a practical oxygen delivery system. Reassessment Patients should be reassessed a month after starting continuous or nocturnal oxygen therapy, both clinically and by measurement of PaO2 and PaCO2 with and without supplementary oxygen. It should then be decided whether the treatment has been properly applied and whether it is worthwhile or should be abandoned. This one-month review is particularly important to confirm that the low entry PaO2 was not spurious because the patient was unstable at the time of sampling. Subsequent review should be undertaken at least annually, or more often according to the clinical situation. Some patients will show a sustained rise in PaO2 to > 60 mm Hg when breathing air, but current thinking is that this represents the reparative effects of supplementary oxygen and should not be a rationale for stopping therapy.4 This recommendation may change with further evidence. A patient having intermittent oxygen therapy should also undergo periodic reassessment, but this may be unnecessary and undesirably disruptive for those with a limited prognosis. Dangers Pulmonary oxygen toxicity has not been seen at the low rates of flow used for long-term oxygen therapy. However, supplementary oxygen in patients with increased arterial PCO2 may depress ventilation, increase physiological deadspace, and further increase arterial PCO2. This is suggested by an obvious decrease in respiratory rate and depth, as well as the development of somnolence and disorientation. In long-term oxygen therapy, the increase in arterial PCO2 is usually small and well tolerated. It was not a practical problem in two large trials, probably because patients were in a stable condition.2,3 However, serious hypercapnia may occasionally develop, making continued oxygen therapy impractical. Risk appears greater during acute exacerbations of disease. Sedatives (particularly benzodiazepines), narcotics, alcohol and other drugs which impair the central regulation of breathing should not be used in patients with hypercapnia receiving oxygen therapy. Quality of life With the potential restriction of movement imposed by long-term continuous oxygen therapy, it is possible that the treatment may only prolong suffering rather than improve quality of life. However, for patients who qualify according to the above criteria, the improvement in quality of life will mostly outweigh the restriction imposed. There is some evidence that women experience more improvement than men in several quality-of-life dimensions.10 Whether oxygen therapy is worthwhile for a particular individual must be determined by a comprehensive clinical assessment rather than solely, or mainly, by the increase achieved in PaO2. Methods of domiciliary oxygen delivery There are three methods of oxygen supply for the home: Cylinders: These contain compressed pure oxygen gas and deliver 100% oxygen at the outlet. Sizes and contents vary (see Box 2), and a regulator, flow meter, spanner and key wheel are needed to connect the tubing to the cylinder. These components are mostly interchangeable for the different cylinder sizes, although cylinder C requires a specific regulator. Several portable light-weight cylinders are available which allow the patient to leave home for several hours. Cylinders are available from Medical Gases Australia, BOC Gases and Sunrise Medical. Oxygen concentrators: These are floor-standing electrically driven devices that entrain room air, extract the nitrogen in molecular sieves and deliver oxygen at the outlet. They run off the domestic electricity supply, and, as they do not store significant amounts of gas, they must run all the time that oxygen is needed. Most of these units deliver 90%-95% oxygen at the outlet when operating at a flow rate of 2 L/min; the percentage falls with increasing flow rate (to about 78% oxygen at 5 L/min), depending on the model. All units currently available in Australia are imported, and there are several distributing agents (including Medical Gases Australia, BOC Gases, Anaesthetic Supplies, and Sunrise Medical). Rental fees are about $100 per month. A back-up standard D-size oxygen cylinder is recommended in case of concentrator breakdown or power failure. Liquid oxygen systems: These systems, now available in Australia, conserve space by storing oxygen in liquid form at 2 1831/4C (30 L of liquid oxygen is equivalent to 25 800 L of gaseous oxygen). The oxygen is delivered through coils, where it vaporises. Two tanks are needed: a large storage tank, which is filled by the supplier as required (e.g., one unit has a 25 800 L gaseous capacity, equivalent to seven E-size cylinders), and a portable unit filled from the larger tank for ambulatory use. Comparisons between supply methods There is no significant difference in the quality of oxygen delivery among the above methods. Advantages and disadvantages of each are compared in Box 3. For patients receiving intermittent oxygen, D-size cylinders or concentrators are the most appropriate mode of supply, while for most patients receiving continuous or nocturnal oxygen concentrators are favoured. Further aspects of concentrators to be considered are: Concentrators are cheaper than cylinders if use is equivalent to three E-size cylinders per month, but electricity costs must be considered (council rebates may apply). Concentrators can be wheeled around the home but are heavy (about 21-26 kg) and difficult to move upstairs and in and out of cars. Concentrators cannot be used for nebulisation, as the pressure delivered is too low (35-63 kPa, compared with 140 kPa for nebuliser pumps). If the anticipated need is for longer than two years, then it is cheaper to buy than to rent a unit. On the other hand, rental is not affected by the hours per day the machine is used and includes maintenance costs (about $180 annually). Regular maintenance of concentrators, including changing and cleaning of filters and checking of alarm systems, is essential. Conservation devices These are small devices introduced between the oxygen source and the patient to ensure that oxygen is delivered only during inspiration and not wasted during expiration. They are useful cost- and time-conserving devices for cylinders and liquid oxygen systems, especially portable units, and can prolong the use of a C-size cylinder from two to 10 hours. As many conservation devices switch on the flow by sensing negative pressure at the nares via the nasal cannula, they may not trigger if the patient mouth-breathes (unless the cannula is transferred to the mouth); many breathless patients become mouth breathers when they are more distressed. These devices are of no value with concentrators and should not be used with transtracheal delivery systems. Delivery to the patient All patients should receive careful and detailed instruction on how to operate and obtain optimal benefit from their oxygen equipment. Flow rate should be set in the range 1-5 L/min, at the lowest rate needed to maintain a resting PaO2 of 60 mm Hg (in practice, most often 2 L/min). It should be increased by 1 L/min during exercise and sleep. Humidifiers are not needed as flow rates are low, and ambient air entrainment supplies sufficient humidification for the total inspired gas. Extrasoft nasal prongs are recommended for continuous oxygen use, but may become uncomfortable at flow rates over 2-3 L/min and in the long term. Facemasks may be preferred for at least some of the time. Simple masks are adequate; complex Venturi masks are not necessary; the appropriate mask should be selected using measurements of arterial oxygen tension. Both nasal prongs and masks are also acceptable for intermittent oxygen use. In selected patients needing 24-hour oxygen therapy, transtracheal delivery systems may have advantages.12 These allow substantially lower flow rates, as the tracheal cannula fills the tracheal and upper airway deadspace with oxygen during each expiration. This may be a crucial advantage in patients needing high flow rates. In addition, portable systems become more useful with this conserving effect, and the delivery tubing can be hidden under clothing. However, care of this relatively invasive appliance is demanding -- the patient must learn to clean and replace the cannula often, as it may become obstructed by formation of "mucous balls" at the tip -- and it will be attractive to only a few. Authorisation of oxygen therapy Current guidelines for prescription through the Program of Aids for Disabled People specify that respiratory physicians and cardiologists are authorised prescribers. It could be argued that other groups should be authorised as long as the guidelines are adhered to. At present, any medical practitioner may order home oxygen if the patient meets the costs. References Breslin AB, Colebatch HJ, Engel LA, Young IH. Adult domiciliary oxygen therapy. Med J Aust 1991; 154: 474-477. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980; 93: 391-398. Report of the Medical Research Council Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1: 681-686. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. ATS Official Statement. Am J Respir Crit Care Med 1995; 152 Suppl: 77-120. Recommendations for long term oxygen therapy (LTOT). Report of a European Society of Pneumology Task Group. Eur Respir J 1989; 2: 160-165. Cooper CB, Waterhouse J, Howard P. Twelve year clinical study of patients with hypoxic cor pulmonale given long term domiciliary oxygen therapy. Thorax 1987; 52: 105-110. McKeon JL, Tomlinson JC, Tarrant PE, Mitchell CA. Portable oxygen in patients with severe chronic obstructive pulmonary disease. Aust N Z J Med 1988; 18: 125-129. Restrick LJ, Davies SW, Noone L, Wedzicha JA. Ambulatory oxygen in chronic heart failure. Lancet 1992; 340: 1192-1193. Fletcher EC, Luckett RA, Goodnight-White S, et al. A double-blind trial of nocturnal supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg. Am Rev Respir Dis 1992; 145: 1070-1076. Crockett AJ, Cranston JM, Moss JR, Alpers JH. Initial trends in quality of life and survival in CAL patients on domiciliary oxygen therapy. Monaldi Arch Chest Dis 1996; 51: 64-71. Kampelmacher MJ, van Kesteren RG, Deenstra M, et al. Long-term oxygen therapy. Neth J Med 1994; 44: 141-152. Christopher KL, Spofford BT, Petrun MD, et al. A program for transtracheal oxygen delivery. Assessment of safety and efficacy. Ann Intern Med 1987; 107: 802-808. (Received 8 Apr, accepted 18 Sep, 1997) Authors' details Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW. Iven H Young, PhD, FRACP, Head. Department of Respiratory Medicine, Flinders Medical Centre, Adelaide, SA. Alan J Crockett, MPH, Senior Hospital Scientist. Austin and Repatriation Medical Centre, Melbourne, VIC. Christine F McDonald, PhD, FRACP, Respiratory Physician. Reprints: The Thoracic Society of Australia and New Zealand, 145 Macquarie Street, Sydney, NSW 2000. E-mail: iveny AT mail.med.usyd.edu.au Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Iven H Young · Alan J Crockett · Christine F McDonald

Specific allergen immunotherapy for asthma A Position Paper of the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Immunology and Allergy MJA 1997; 167: 540-544 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/MJA/>". Introduction - Atopy, allergens and asthma - Rationale for using immunotherapy for asthma - Clinical trials - Allergen extracts and route of administration - Adverse effects - Practical aspects of administering immunotherapy - References - Authors' details Make a comment - - ©MJA1997 Introduction Specific allergen immunotherapy (desensitisation, hyposensitisation) is the technique of treating IgE-mediated disease with increasing doses of an allergen in order to decrease sensitivity to that allergen. First used early this century, 60 million patients annually are now treated with immunotherapy throughout the world. The only absolute indication for immunotherapy is a life-threatening reaction after a Hymenoptera (bee or wasp) sting; all other indications are relative (see indications and contraindications for immunotherapy). Many randomised controlled trials have shown that hayfever caused by airborne pollens and house dust mite responds to this therapy.1 The use of specific allergen immunotherapy in asthma remains controversial. Despite this, the Thoracic Society of Australia and New Zealand and the Australasian Society of Clinical Immunology and Allergy believe that all strategies which may impact on the morbidity and mortality of asthma should be assessed. The cost-effectiveness of this therapy also needs to be addressed in the context of the total cost of asthma in Australia, the mid-estimate of which in 1991 was $652 million (National Asthma Campaign, 1992). We present an overview and do not cover all aspects of this subject. Interested readers are referred to recent reviews.1-9 Atopy, allergens and asthma Allergy is best defined as an exaggerated response on exposure to an allergen following prior exposure, and mediated by an immune reaction involving IgE. The same clinical picture may result from non-immune mechanisms. Atopy is an increased tendency to IgE-based sensitivity resulting in production of specific IgE antibody to common environmental allergens, such as house dust mite, pollens, moulds or animal danders. This sensitisation occurs in genetically predisposed people after exposure to low concentrations of allergen; cigarette smoke and viral infections may assist in the sensitisation process. About 40% of the population is atopic, and about half of this group develop clinical disease ranging from trivial rhinitis to life-threatening asthma. After sensitisation, continuing exposure to allergens leads to a significant increase in the prevalence of asthma.10 Ninety per cent of children and 80% of adults with asthma are atopic.10 Once sensitisation has occurred, re-exposure to allergen is a risk factor for exacerbations of asthma.11 Effective management of allergic asthma includes pharmacological therapy and allergen avoidance. For example, avoiding dust mite allergen can reduce symptoms and the need for medication. Rationale for using immunotherapy for asthma Asthma is an inflammatory disease characterised by the presence of cells such as eosinophils, mast cells, basophils, and CD25+ T lymphocytes in the airway walls. There is close interaction between these cells, because of the activity of cytokines which have a variety of communication and biological effector properties. Chemokines attract cells to the site of inflammation and cytokines activate them, resulting in inflammation and damage to the mucosa.12 With chronicity of the process, secondary changes occur, such as thickening of basement membrane and fibrosis.13 An immunological reaction to allergen is the initiating event of airway inflammation in many cases of asthma.14 Continued exposure to allergen results in chronic inflammation. Current therapy aims to suppress this inflammation with inhaled corticosteroids, sodium cromoglycate, or nedocromil sodium, all of which interfere with the cellular and cytokine interactions by diverse mechanisms, but do not address the initiating event in allergic asthma. By withdrawing the allergen or altering the immune response to allergen, it is theoretically possible to control the allergic trigger of asthma. Immunological changes have been described after immunotherapy. These include an initial rise in specific serum IgE, followed by a fall, and a rise in specific IgG ("blocking antibody"). Specific IgG titres correlate poorly with the degree of protection. Immunotherapy leads to a reduction in mediator release from mast cells in vitro, alterations in lymphocyte subsets, and a downregulation of IL-4 production from T cells.15 Several studies have shown a reduction in inflammation and a decrease in bronchial hyperresponsiveness after immunotherapy.1,16,17 There are strong theoretical arguments why immunotherapy should be used early in the course of the disease, before irreversible secondary changes such as fibrosis have occurred. Further, data are emerging to suggest that immunotherapy may also influence the progression of clinical disease.3,7 Immunotherapy should not be regarded as an alternative to established forms of preventive therapy, as recommended by the National Asthma Campaign.18 A systematic cost-benefit analysis of immunotherapy has not yet been undertaken. Clinical trials There have been numerous randomised placebo- controlled double-blind trials of immunotherapy for asthma. Comparison of these trials is difficult, not only because of the inherent problems of trials involving asthma (such as standardisation of inclusion and outcome criteria), but also because of differences in allergen extracts and dosage regimens. A meta-analysis can address some of these difficulties, and has recently been applied to 20 randomised controlled trials of immunotherapy for asthma in both adults and children.19 This meta-analysis found a clinically useful improvement from immunotherapy with house dust mite and with other allergens (see Box below). It concluded that immunotherapy is a treatment option in highly selected patients (discussed more fully below) with allergic asthma. The reviews cited in this position paper,1-9 the meta-analysis19 and further controlled studies published in the last five years20-24 provide references to the most important trials of immunotherapy. Allergen extracts and route of administration Although several routes of allergen delivery have been used in immunotherapy, only subcutaneous injection has been studied in detail and shown to be effective. Giving allergen extract sublingually is not recommended as studies have failed to show long-term efficacy.25 Trials with giving birch pollen orally appeared promising, but large doses were required and there was a high incidence of side effects. Further studies of oral immunotherapy using modified preparations are under way. Intranasal administration of pollen extracts resulted in an unacceptable level of side effects. Local bronchial immunotherapy with mite extract in patients with asthma has been studied in a controlled trial but failed to produce significant clinical improvement.26 Most allergen extracts used in Australia for immuno therapy of inhalant allergy are alum-precipitated. Such preparation slows the absorption of allergen, reducing the risk of serious anaphylaxis and providing sustained immune stimulation. There is no reliable standardisation of biological activity for many allergen extracts used in Australia. Mass and concentration of active material are not useful guides to biological activity. The concentrations of the slow-release (alum-precipitated) preparations are expressed in "protein nitrogen units" and not biological activity. Aqueous preparations of some allergens, including Dermatophagoides pteronyssinus, are standardised against a WHO standard and are extremely potent. Their use in asthma should be restricted to specialist centres. Adverse effects Local reactions Mild swelling and erythema at the site of the injection is to be expected. It may persist for 24 hours or more and is not a cause for concern. A more severe reaction over 50 mm in diameter is an indication for reduction in the subsequent dose. Systemic reactions These include sneezing, bronchospasm, urticaria and, in more severe cases, anaphylaxis with hypotension and collapse. They must always be regarded seriously. Although they usually occur within 30 minutes of the injection, they may be delayed for several hours with the use of alum-precipitated preparations. Recent data from the UK estimate that the incidence of severe systemic reactions was 1 in 500 injections,1 but most occurred with aqueous extracts, and alum-precipitated extracts appeared to be much safer. The incidence of anaphylaxis with Allpyral (Bayer, Pymble, NSW), the alum-precipitated material available in Australia, was reported to be 1 in 27 854 courses of treatment, and of anaphylaxis and/or bronchospasm, 1 in 14 998 courses of treatment.27 The Committee on the Safety of Medicines, in the United Kingdom, reported in 1986 that in the 29 years from 1957 to 1986 during which 1 459 273 courses of treatment were given, there were 29 deaths from immunotherapy -- 16 in patients where the indication for therapy was asthma.27 Highly purified and potent aqueous extracts were involved in most of these deaths, and no deaths were reported with the Allpyral extract. Subsequent reports indicated a much lower incidence of anaphylaxis and deaths in France and the US,28,29 where one major difference in practice is that treatment is administered by specialists with expertise in the area. In Australia, five deaths from immunotherapy were reported to the Adverse Drug Reactions Advisory Committee in the 21 years from 1972 to 1993. Four were in patients with asthma, and in each case there was a divergence from recommended procedure. Long term adverse effects There is no increase in the prevalence of vasculitis, autoimmune disease or monoclonal gammopathies during or after immunotherapy.30 Further, there is no evidence that long term worsening of asthma occurs with immunotherapy. Practical aspects of administering immunotherapy These guidelines relate to specific allergen immunotherapy for the treatment of asthma in patients with clinical manifestations and/or need for treatment of ongoing bronchial hyperreactivity. The decision to prescribe immunotherapy is based on appropriate patient selection, appropriate antigen selection, and whether potential benefits outweigh associated risks. Only a practitioner or team with training and experience in the management of both asthma and immunotherapy should make the decision. Suitably qualified practitioners include thoracic physicians with training and expertise in allergy, or clinical immunologist/allergists with training and expertise in asthma. It is the responsibility of the supervising consultant to (a) decide whether a patient needs to be treated in a hospital, and (b) ensure that the medical practitioner giving immunotherapy receives written instructions on patient assessment and immunotherapy protocol. Informed consent according to currently accepted guidelines must be obtained from patients before starting immunotherapy. Immunotherapy should be given only by a medical practitioner familiar with immunotherapy, conversant with resuscitative procedures, and in a setting where the following resuscitation equipment is immediately available: adrenaline 1:1000 for intramuscular use (adrenaline is the drug of choice for the immediate management of systemic reactions to immunotherapy), oxygen, an inflatable bag and mask ventilator, a nebuliser and bronchodilator nebuliser solution, needles and tubing for intravenous access, intravenous fluids suitable for volume replacement, parenteral antihistamine, and parenteral corticosteroid. The practitioner and a second appropriately trained health care professional should be present during immunotherapy to assist if resuscitation is required. Each patient requires an individual dosage schedule according to the degree of sensitivity and clinical reaction to the injections. The principle of therapy is to start with a small dose and gradually increase it as tolerated. Supervising consultants will have the training and experience necessary to determine the starting dose and appropriate schedule. Flexibility in dosage is essential and rigid adherence to predetermined dosage schedules is inappropriate. Extracts should be stored in a refrigerator at 4°C , clearly marked with the patient's identifier(s) and replaced in the refrigerator immediately after use. Before injection, the extract should be examined visually and discarded if its appearance has changed. The contents of the bottle should be mixed well to avoid variation in dosage. When changing to a new batch of unstandardised extract (such as Allpyral), the first dose should be reduced by 25% to take account of possible variation in biological activity of the preparations. Each patient should have his or her own individual vial of extract -- laws in some States forbid multiple use of vials for different patients. Every patient should be assessed clinically on each occasion before an injection is given , with particular attention to stability of asthma as indicated by peak flow charts, intercurrent illness, reaction to the last injection and any change in medication. Spirometry or peak flow meter readings must be taken before injection and, if more than 20% below the best recent recorded reading for that patient, the injection should not be given. The readings should be repeated 30 minutes after the injection and immediately any lower respiratory symptoms arise during the period of observation -- a fall of 10% or more is an indication for reducing the dose of the next injection. The medical practitioner must be responsible for selecting the dose and having it checked by a second health professional. Injections are given subcutaneously, a suitable site being the tissue overlying the triceps muscle group. After introducing the needle, and before starting the injection, the plunger should be withdrawn gently to ensure that the needle is not placed intravenously. There is no consensus about the optimal time that a patient must remain under observation . However, we recommend 45 minutes, as serious reactions after that time are rare. Reactions may be delayed with alum-precipitated preparations but they are usually minor. Before discharge patients should be examined to record the size of the local reaction, ensure that there are no signs of a systemic reaction, and to repeat spirometry or peak flow readings. Patients must not engage in strenuous physical exercise or take hot baths or saunas for six hours after the injection. Patients should monitor their peak flow at home ; excessive variability would indicate a need for re-evaluation of asthma and immunotherapy. A local swelling larger than 50 mm requires a reduction in dosage. Patients should be instructed to measure the diameter of any local reaction should it increase in size after leaving medical supervision, and report this before the next injection. Some practitioners "cover" therapy by giving prophylactic antihistamines to reduce the local reactions. This practice may make it difficult to judge the effects of therapy, both locally and systemically, and to modify dosage accordingly. It may also block the initial manifestations of an anaphylactic reaction. Use of this practice is a matter of judgement, but if prophylactic drugs are used use must be consistent. Injection schedules vary with individual patients, but the Allpyral preparations are administered every 1-2 weeks until a maintenance dose is reached. Maintenance injections are administered every 2-4 weeks. It should be re-emphasised that immunotherapy schedules are individualised and fixed schedules are not recommended, particularly when aqueous extracts, which are becoming more readily available in Australia, are used. The duration of therapy for optimal management is unknown at present. With bee and wasp venom immunotherapy, there is evidence that five years of maintenance injections will provide long term protection in almost all patients. There is no corresponding evidence in inhalant allergy and practice varies. Dust mite injections are often continued for 2-3 years if there is a response, and preseasonal immunotherapy with grass pollen is repeated for 2-3 years. References Position paper on allergen immunotherapy. Report of a BSACI Working Party. Clin Exp Allergy 1993; 23 Suppl 3: 1-44. WHO/IUIS Working Group Report. Current status of allergen immunotherapy. Lancet 1989; 1: 259-261. Position paper: immunotherapy. The European Academy of Allergology and Clinical Immunology (EAACI). Allergy 1993; 48 (14 Suppl): 9-35. Platts-Mills TAE. Allergen-specific treatment for asthma. Am Rev Respir Dis 1993; 148: 553-555. Lockey RF, Bukantz SC, editors. Allergen immunotherapy. New York: Marcel Dekker, 1991. Walls RS. Desensitisation injections: do they have a role? Aust Prescriber 1989; 12: 90-92. Bousquet J, Michel F-B. Specific immunotherapy in asthma: is it effective? J Allergy Clin Immunol 1994; 94: 1-11. Malling H-J. Immunotherapy in Europe. Clin Exp Allergy 1994; 24: 515-521. Greenberger PA, editor. Immunotherapy of IgE-mediated disorders. Immunol Allergy Clin North Am 1992; 12: 1-203. Sporik RB, Chapman MD, Platts-Mills TAE. House dust mite exposure as a cause of asthma. Clin Exp Allergy 1992; 22: 897-906. Gelber LE, Seltzer LH, Bouzoukis JK, et al. Sensitization and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital. Am Rev Respir Dis 1993; 147: 573-578. Corrigan CJ, Kay AB. T cells and eosinophils in the pathogenesis of asthma. Immunol Today 1992; 13: 501-506. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989; 1: 520-524. Lenfant C. Global initiative for asthma: global strategy for asthma management and prevention. NHLBI/WHO Workshop Report. Bethesda, Md.: National Institutes of Health, January 1995. (Publication No. 95-3659.) O'Brien RM, Byron KA, Varigos GA, Thomas WR. House dust mite immunotherapy results in a decrease in Der p2-specific IFN- g and IL-4 expression by circulating T lymphocytes. Clin Exp Allergy 1997; 27: 46-51. Rak S, Bjornson A, Hakanson L, et al. The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure. J Allergy Clin Immunol 1991; 88: 878-888. Nagata M, Shibasaki M, Sakamoto Y, et al. Specific immunotherapy reduces the antigen-dependent production of eosinophil chemotactic activity from mononuclear cells in patients with atopic asthma. J Allergy Clin Immunol 1994; 94: 160-166. Asthma management handbook. 2nd ed. Melbourne: National Asthma Campaign, 1996. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of randomised controlled trials. Am J Resp Crit Care Med 1995; 151: 969-974. Bousquet J, Hejjaoui A, Soussana M, Michel F. Double-blind placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid. J Allergy Clin Immunol 1990; 85: 490-497. Haugard L, Dahl R. Immunotherapy in patients allergic to cat and dog dander. I. Clinical results. Allergy 1992; 47: 249-254. Alvarez-Cuesta EJ, Cuesta-Herranz J, Puyana-Ruiz J, et al. Monoclonal antibody-standardised cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. J Allergy Clin Immunol 1994; 93: 556-566. Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med 1996; 334: 501-506. Adkinson NF, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med 1997; 336: 324-331. Bjšrksten B. Local immunotherapy is not documented for clinical use. Allergy 1994; 49: 299-301. Crimi E, Voltolini S, Troise C, et al. Local immunotherapy with Dermatophagoides extract in asthma. J Allergy Clin Immunol 1991; 87: 721. Committee on Safety of Medicines. CSM update. Desensitising vaccines. BMJ 1986; 293: 948. Warner JO, Kerr JW. Hyposensitisation. BMJ 1987; 294: 1179-1180. Stewart GE, Lockey RF. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol 1992; 90: 567-578. Katelaris CH, Walls RS. A study of possible ill effects from prolonged immunotherapy in treatment of allergic diseases. Ann Allergy 1984; 53: 257-261. Authors' details The Thoracic Society of Australia and New Zealand, Melbourne, VIC. Reprints: Dr P I Field, Honorary Secretary, 145 Macquarie Street, Sydney, NSW 2000. Australasian Society of Clinical Immunology and Allergy, Melbourne, VIC. No reprints will be available. Correspondence: Dr D Gillis, Honorary Secretary, PO Box 204, Mt Albert, VIC 3127. <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Position Statement Asthma in pregnancy and lactation A position paper for the Thoracic Society of Australia and New Zealand Christine F McDonald and Jonathan G W Burdon MJA 1996; 165: 485-488 Introduction - Literature search - Effects of pregnancy on asthma - Effects of asthma on pregnancy - Management of asthma in pregnancy - Pharmacological therapy - Labour - Breastfeeding - Patient education - Monitoring - References - Author's Details - - More articles on Respiratory medicine This position statement was developed as a consensus view between the two authors and was subsequently reviewed by the Education and Research Sub-Committee of the Thoracic Society of Australia and New Zealand, whose membership comprises six respiratory physicians with a broad range of interests in research and clinical respiratory medicine. This Committee also sought the opinion of an external reviewer with expertise in the subject. The following conclusions were reached: Physiological changes which occur during pregnancy may affect asthma control. Regular monitoring (monthly or every six weeks) of asthmatic women should occur throughout pregnancy. Regular therapy, including the use of inhaled steroids, is recommended. Well-controlled asthma should have no adverse effects on pregnancy, labour or breastfeeding. Medicines used to control asthma carry less risk to the mother and baby than a severe attack of asthma. Good asthma management will result in a birth outcome similar to that experienced by women without asthma. Introduction Pregnant women with asthma should be reassured that their asthma medication carries less risk to the fetus than a severe asthma attack. Inadequately treated asthma can cause maternal and fetal hypoxaemia, which leads to complications during pregnancy and poorer birth outcomes. Here, we outline the effects of asthma on pregnancy (and vice versa) and the management of asthma during pregnancy and the postpartum period. Literature search We searched the literature, using the MEDLINE database, for the period 1985-1995 and the keywords "asthma" and "pregnancy". Standard textbooks on asthma were also reviewed. A total of 146 papers were identified and other papers contained within their references were also reviewed. Thirty-three papers were found suitable. Effects of pregnancy on asthma Although bronchial hyperresponsiveness lessens during mid-pregnancy,1 studies reporting changes in asthma severity during pregnancy show widely differing results.2-5 Overall, the data indicate that the clinical severity of asthma during pregnancy improves in about 30% of women, remains stable in about 50% and worsens in about 20%.6Factors responsible for the variation in asthma severity during pregnancy include an increase in circulating free cortisol,7,8 a decrease in bronchomotor tone and an increase in serum concentrations of cyclic adenosine monophosphate.8 These changes would normally improve the asthma, but in pregnancy other competing factors, including exposure to fetal antigens and alterations in cell-mediated immunity, may worsen asthma symptoms.8 Asthma may be further complicated by sinusitis and rhinitis, which occur in about 35% of pregnant women, but vascular dilatation and congestion of the mucosa of the upper respiratory tract (vasomotor rhinitis of pregnancy) does not involve the lower airways.9 The physiological respiratory changes which occur during pregnancy may affect asthma control (Box). Changes in blood gases secondary to acute asthma will be superimposed on the physiological respiratory alkalosis of pregnancy. Therefore, a normal or elevated PCO2 associated with acute asthma will indicate respiratory compromise of greater severity in pregnancy than in the non-pregnant state. The dyspnoea of pregnancy must be differentiated from dyspnoea caused by asthma. Indeed, patients who develop asthma during pregnancy may wrongly attribute dyspnoea to the pregnancy, which can lead to undermedication and severe maternal and fetal hypoxaemia. It is difficult to predict which women will experience worsening of their asthma during pregnancy, but the severity of the condition before pregnancy,2,8 and an absence of the expected decrease in IgE concentration during pregnancy,8,13 should alert the clinician to this possibility. If asthma is going to worsen, it will usually do so between 24 and 36 weeks' gestation. Symptoms are likely to be less troublesome in the peripartum period. In most women, asthma severity returns to the prepregnant state within three months of delivery,1,5 but in rare cases it may be worse than before the pregnancy. Effects of asthma on pregnancy The fetus exists in a precarious state of oxygenation and is dependent for its oxygen supply on maternal arterial oxygen content, venous return and cardiac output, and uterine artery and placental bloodflow. Compensating mechanisms of the fetus to combat potentially adverse conditions of oxygenation include a haemoglobin level of at least 16 g/dL and a P50 of 22 mmHg (indicating a left shift in the oxyhaemoglobin dissociation curve). Poorly controlled asthma or severe asthma attacks further threaten the fetus because of increased maternal hypoxaemia and diminution of uterine artery bloodflow secondary to hypocapnic vasoconstriction. These women have an increased incidence of low birthweight and premature babies, neonatal hypoxia, complications during labour, and perinatal and maternal mortality.14-17 Hyperemesis gravidarum, maternal haemorrhage and pre-eclampsia are more common in this group.14 For these reasons, it has been argued that a pregnancy complicated by asthma should be regarded as a high risk pregnancy.16 However, the babies of most asthmatic women (i.e., those with well controlled asthma) show no difference in birthweight, Apgar scores or rates of congenital malformation when compared with those of non-asthmatic mothers.5,15,16 Management of asthma in pregnancy The management of asthma during pregnancy is similar to that at any other time: treatment should be aggressive, with the aim of eliminating symptoms and restoring and maintaining normal lung function. Guidelines for asthma management have been published by the National Asthma Campaign and are highly recommended.18 Cooperation between the respiratory physician and obstetrician is important throughout pregnancy for women with severe asthma. Pharmacological therapy Care should be taken with pharmacological therapy during pregnancy, particularly in the first trimester, when the risk of congenital defects is greatest. Fortunately, the medicines currently used in the treatment of asthma have been found in practice to have a good safety profile during pregnancy. The drug categories listed here are those of the Australian Drug Evaluation Committee's categorisation of risk of drug use in pregnancy.19 Bronchospasm relaxants β2-Agonists (category A): There is no evidence of a teratogenic risk with the commonly used inhaled β2-agonists salbutamol, terbutaline and fenoterol. Intravenous salbutamol may be used to delay the onset of labour in some circumstances and there is a theoretical risk that oral β2-agonists could also have this effect. Delayed labour does not occur with bronchodilators administered by metered-dose inhaler or wet nebulisation. Ipratropium bromide (category B1): Although there is less experience with this drug, it appears to be safe for use during pregnancy, as it is poorly absorbed when administered by the inhaled route and has not been identified as imparting an increased risk of fetal malformations. Salmeterol (category B3): These newer long-acting agents have not been tested extensively in pregnant women. Theopyllines (category A): The use of theophyllines remains controversial. They may aggravate the nausea and reflux suffered by some pregnant women and can cause transient neonatal tachycardia and irritability.20,21 Teratogenicity has been shown in animals,22,23 and there are occasional case reports of cardiovascular abnormalities in humans.24 However, larger human studies have not shown any significant increase in fetal abnormalities.25,26 It has been suggested that theophyllines be withheld during the first trimester.26 If they are used, serum theophylline levels should be measured as drug metabolism may alter during pregnancy. Preventive inhalations and aerosols Sodium cromoglycate (category A): This drug appears to have no adverse fetal effects. Nedocromil sodium (category B1): Animal studies have not shown any teratogenic effects, but, as with all new drugs, care should be exercised, especially in the first trimester. Inhaled corticosteroids Beclomethasone and budesonide (category B3): These are the mainstay of treatment in moderate to severe asthma and both appear to have a good safety profile in pregnancy. Although beclomethasone is a known animal teratogen, its use in pregnant women has not been associated with teratogenicity. The largest human experience of inhaled corticosteroids is with beclomethasone and it is therefore the inhaled steroid of choice in pregnancy.9 Less information is available on the use of budesonide in pregnancy as it is a newer drug. If moderate to severe asthma is well controlled with budesonide, the risks of destabilising the condition by changing from budesonide to beclomethasone must be weighed against the potential benefits of using a medicine which has been more extensively studied. Fluticasone (category B3): Experience with this drug in pregnancy is more limited. Oral corticosteroids (Category A) These are sometimes necessary for severe asthma in pregnancy but usually only for short periods. An increased risk of cleft palate and placental abnormalities has been reported in animals given huge doses of oral steroids.27,28 These abnormalities have not been reported in humans, and the results of animal studies should not deter the practising clinician from using oral corticosteroids if required. Methotrexate and other steroid-sparing agents have an occasional role in the treatment of some individuals with severe resistant asthma. However, these drugs are contraindicated in women of childbearing age who are trying to conceive or who are pregnant. Labour There is no increase in the induction of labour, use of forceps or emergency caesarean sections in women with asthma, but elective caesarean sections are more common. Women with very severe asthma may be advised to have an elective caesarean section at a time when their asthma control is good. Close cooperation between the respiratory physician, obstetrician and anaesthetist is particularly important at this time. Symptoms of asthma during labour are generally easily controlled with standard asthma therapy. Acute asthma attacks in labour are rare, but prostaglandin F2alpha (Dinoprost, UpJohn) and ergometrine cause bronchoconstriction. Their use in the induction of labour, the initiation of the third stage of labour and for placental separation should be avoided.29 There is no evidence that oxytocin causes bronchoconstriction. Breastfeeding Breastfeeding should be continued in women with asthma as breast milk confers some immunity to infection to the baby, especially to respiratory and gastrointestinal infections. Breast milk may contain very small amounts of the drugs used to treat asthma, but, in general, these are not known to be harmful to the infant. Corticosteroids are about 90% protein bound in the blood and are not secreted into breast milk in any significant quantity. However, the manufacturers of budesonide have recommended discontinuation of this drug during lactation because of an absence of information regarding its transmission into breast milk. The decision to alter a successful medication regimen that is controlling the mother's asthma must be weighed against any potential detrimental effects to the infant from continuation of the drug. Although less than 1% of maternal theophylline is transferred to the infant,30 it has been suggested that women breastfeed their baby before taking this drug to minimise its side effects.31 It is recommended that tetracycline antibiotics and iodine-containing mixtures be avoided in pregnant and lactating women as they may cause dental discoloration and goitre in the baby. Patient education Environmental trigger factors which cause deterioration in asthma control or may lead to acute asthma attacks must be avoided and pregnant women should be urged to stop smoking. Mothers should be advised about the importance of avoiding exposure to allergens and environmental tobacco smoke in the first years of their child's life to reduce the potential for later asthma development.32 Monitoring Women with asthma should be reviewed at least every four to six weeks (and more frequently if needed) so that early changes in respiratory function can be detected and treated expeditiously. Although formal spirometry may be indicated from time to time, lung function can be easily monitored at home with a peak flow meter.33 The doctor should formulate an asthma action plan with the patient, to be put into effect if her condition deteriorates.33If a woman with asthma is closely monitored, pregnancy outcomes approaching those of the general population can be expected.34 Well-controlled asthma should have no adverse effect on pregnancy, labour or breastfeeding. References Juniper EF, Daniel EE, Roberts RS, et al. Improvement in airway responsiveness and asthma severity during pregnancy. A prospective study. Am Rev Respir Dis 1989; 140: 924-931. Williams DA. Asthma and pregnancy. Acta Allergol 1967; 22: 311-323. Turner ES, Greenberger PA, Patterson R. Management of the pregnant asthmatic patient. Ann Intern Med 1980; 93: 905-919. Greenberger PA, Patterson R. Management of asthma during pregnancy. N Engl J Med 1985; 312: 897-902. Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, post-partum and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988; 81: 509-517. Burdon JGW, Goss G. Asthma and pregnancy. Aust N Z J Med 1994; 24: 3-4. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 1981; 139: 492-498. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976; 37: 164-168. National Heart, Lung and Blood Institute. Report of the Working Group on Asthma and Pregnancy. Executive Summary: Management of asthma during pregnancy. J Allergy Clin Immunol 1994; 93: 139-162. Prowse CM, Gaensler EA. Respiratory and acid-base changes during pregnancy. Anesthesiology 1965; 26: 381-392. Rees GB, Pipkin KB, Symonds EM, et al. A longitudinal study of respiratory changes in normal human pregnancy with cross sectional data on subjects with pregnancy-induced hypertension. Am J Obstet Gynecol 1990; 162: 826-830. Gee JBL, Packer BS, Millen JE, et al. Pulmonary mechanics in pregnancy. J Clin Invest 1967; 46: 945-952. Gazioglu K, Kaltreider NL, Rosen M, et al. Pulmonary function during pregnancy in normal women and patients with cardiopulmonary disease. Thorax 1970; 25: 445-450. Hernandez E, Angell CS, Johnson JW. Asthma in pregnancy: current concepts. Obstet Gynecol 1980; 55: 739-743. Gordon M, Niswander KR, Berendes H, et al. Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynecol 1970; 106: 421-429. Bahna SL, Bjerkedal T. The course and outcome of pregnancy in women with bronchial asthma. Acta Allergol 1972; 27: 397-406. Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986; 78: 349-353. National Asthma Campaign. Asthma Management Handbook. Melbourne: National Asthma Campaign Ltd, 1993. Australian Drug Evaluation Committee. Medicines in Pregnancy. 3rd ed. Commonwealth Department of Health and Family Services, 1996. 20. Yeh TF, Pildes RS. Transplacental aminophylline toxicity in a neonate [letter]. Lancet 1977; 1: 910. Labovitz E, Spector S. Placental theophylline transfer in pregnant asthmatics. JAMA 1982; 247: 786-788. Gilbert EF, Bruyere HJ, Ishikawa S, et al. The effect of methylxanthines on catecholamine-stimulated and normal chick embryos. Teratology 1977; 16: 47-52. Ishikawa S, Gilbert EF, Bruyere HJ, et al. Aortic aneurysms associated with cardiac defects in theophylline-stimulated chick embryos. Teratology 1978; 18: 23-30. Park JM, Schmer V, Myers TM. Cardiovascular anomalies associated with prenatal exposure to theophylline. South Med J 1990; 83: 1487-1488. Schatz M. Asthma during pregnancy: interrelationships and management. Ann Allergy 1992; 68: 123-133. Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest 1995; 107: 642-647. Fainstat T. Cortisone-induced congenital cleft palate in rabbits. Endocrinology 1954; 55: 502-508. Blackburn WR, Kaplan HS, McKay DG. Morphologic changes in the developing rat placenta following prednisolone administration. Am J Obstet Gynecol 1963; 92: 234-246. Math AA, Hedqvist P. Effect of prostaglandins F2 and E2 on airway conductance in healthy subjects and asthmatic patients. Am Rev Respir Dis 1975; 111: 313-320. Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics 1979; 57: 518-525. Berkowitz R, Coustan DR, Mochizuki TK. Handbook for prescribing medications during pregnancy. 2nd ed. Boston: Little, Brown and Co, 1986. Peak JK. Prevention of asthma. Eur Respir J 1996; 9: 1545-1555. The Thoracic Society of Australia and New Zealand. Peak flow meter use in asthma management. Med J Aust 1996; 164: 727-730. Stenius-Aarniala B, Piilrila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988; 43: 12-18. Authors' details Department of Respiratory Medicine, Austin and Repatriation Medical Centre, Heidelberg, VIC. Christine F McDonald, PhD, FRACP, Consultant Respiratory Physician. Department of Respiratory Medicine, St Vincent's Hospital, Melbourne, VIC. Jonathan G W Burdon, MD, FRACP, Consultant Respiratory Physician. Reprints: Dr J G W Burdon, Director, Department of Respiratory Medicine, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, VIC 3065. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Physiological respiratory changes in pregnancy Dyspnoea Dyspnoea is experienced by 60%-70% of women at some time during pregnancy,10 most commonly in the first or second trimester. Mechanical factors do not seem to play a major role in its pathogenesis because it frequently occurs before any increase in abdominal girth. Early pregnancy: Dyspnoea may be caused by rising circulating maternal progesterone levels, which result in a progressive increase in minute ventilation of up to 40% by the end of the first trimester, largely as a result of increases in tidal volume.11 Late pregnancy: Dyspnoea later in pregnancy is (likely to be) caused by a combination of the hyperventilation of pregnancy and restriction due to uterine enlargement. The latter leads to a small reduction in both residual volume and functional residual capacity, while total lung capacity is maintained by an increase in inspiratory capacity.12,13 Changes in peak flow rates and forced expiratory volume in one second (FEV1) are small and of no clinical significance.1,13 Respiratory alkalosis Maternal gas exchange is mildly disordered as a result of the increase in minute ventilation.11 A slight rise in arterial oxygen tension, a change in carbon dioxide tension and pH changes are common and indicate a mild respiratory alkalosis. The changes in arterial blood gas tensions occur despite increases in oxygen consumption and carbon dioxide production in the last few months of pregnancy.11 Back to text

Christine F McDonald

Position Statement Paediatric advanced life support The Australian Resuscitation Council Guidelines The Advanced Life Support Committee of the Australian Resuscitation Council MJA 1996; 165: 199-206 Basic cardiorespiratory resuscitation - Advanced life support - Techniques in paediatric advanced life support - Medications and fluids used in paediatric advanced life support - Management after resuscitation - Cessation of cardiopulmonary resuscitation - Contributors - References - Register to be notified of new articles by email - These guidelines by the Australian Resuscitation Council (ARC) provide brief step-by-step outlines of the management of common life-threatening emergencies in infants and children. The guidelines are similar, but not identical, to guidelines published by the American Heart Association 1 and the European Resuscitation Council. 2 An international liaison committee (including representation from the ARC) is attempting to resolve differences and will in due course publish common advisory statements. The current guidelines are specifically for advanced life support, but some essential techniques of basic life support are presented. Further details of basic life support for infants and children 3 and specific guidelines for resuscitation of asphyxiated newborn infants have been published. 4,5 Basic cardiorespiratory resuscitation Cardiorespiratory arrest should be suspected when the infant or child loses consciousness, appears pale or cyanosed, or is apnoeic or pulseless (see definitions in Box 1). Assess airway and breathing by observing movement of the chest and feeling for expired breath. Position the head and neck to maintain an open airway. Movement of the chest without expiration implies an obstructed airway. If the obstruction is not relieved by backward head tilt and chin lift or by forward jaw thrust, the pharynx should be inspected with a laryngoscope and cleared of any secretions, vomitus or blood with a sucker (Yankauer). Forceps (Magill) may be needed to extract a foreign body. If spontaneous ventilation is not immediately resumed, artificial ventilation is commenced with mouth-to-mask expired air, a self-inflating resuscitation bag or an oxygen-inflated bag and mask circuit. Supplemental 100% oxygen should be added. Insertion of an oropharyngeal airway (Guedel) may facilitate ventilation. Assess the circulation by palpating the carotid, brachial or femoral pulse. Commence external cardiac compression (ECC) if a pulse is not palpable or it is: < 80 beats per minute (bpm) in a newborn or infant; < 60 bpm in a small child; < 40 bpm in a large child. Precede ECC with 2-5 slow breaths to reinflate the lungs. The patient should be placed on a firm surface, and compression directed to the lower sternum to a depth approximating a third of the anteroposterior diameter of the chest, or at a depth of 2-3 cm and rate of 100/min for a newborn or infant; depth of 3-4 cm and rate of 100/min for a small child; depth of 4-5 cm and rate of 80-100/min for a large child. ECC for a newborn or infant can be performed with two fingers, although a better technique is to encircle the chest with both hands, compressing the sternum anteriorly with the thumbs while stabilising the vertebral column posteriorly with the fingers. The rescuer's hands must encircle the chest freely and not restrict chest expansion. ECC for a small child can be performed with the heel of one hand and, for a large child or teenager, with two hands. A cycle should be 50% chest compression and 50% relaxation. Combine ECC and assisted ventilation in an infant or small child in a ratio of 5 : 1. For a large child or teenager in whom a two-handed technique of ECC is required, a single rescuer may achieve better circulation and ventilation with a ratio of compression to ventilation of 15 : 2. If a mask is used, breaths should be delivered between successive compressions to allow adequate expansion of the lungs, but if an endotracheal tube is used coordination is less crucial as effective ventilation can be given against the resistance imposed by ECC. For the asphyxiated newborn, ECC should be at a rate of 120/minute and ventilation at 40-60/min (i.e., in a ratio of 3 : 1). 5,6 Advanced life support Advanced life support implies a patent airway by endotracheal intubation, mechanical ventilation with oxygen, the treatment of cardiac arrhythmias, the treatment of the cause of cardiorespiratory arrest and of complications arising from its management. When several rescuers are in attendance, tracheal intubation and ventilation, display of the electrocardiograph (ECG) and access to the circulation should be attempted simultaneously. Thereafter treatment should be guided by the cardiac rhythm (see Flowchart in Box 2). Tracheal intubation is the first priority. This establishes and maintains a patent airway, facilitates mechanical ventilation with 100% oxygen, minimises pulmonary aspiration, enables suctioning of the trachea and provides a route for the administration of selected drugs. If intubation cannot be accomplished easily, ventilate and oxygenate the patient using a mask before reattempting intubation. Assess the cardiac rhythm by displaying the ECG via chest leads or the defibrillator paddles. Proceed with drug therapy or immediate direct current (DC) shock (Box 2), while maintaining ECC and mechanical ventilation with supplemental 100% oxygen. Secure access to the circulation with a peripheral intravenous (IV) cannula. If cannulation is difficult, do not waste time (more than 90 seconds) with repeated unsuccessful attempts -- instead use the intraosseous (IO) route or the (less effective) respiratory tract via the endotracheal tube (ETT). 7 All drugs and resuscitative fluids may be given via the IO route but only adrenaline, atropine and lignocaine may be given via the ETT. Central venous cannulation of the subclavian or internal jugular veins should not be attempted initially as it wastes time and is potentially hazardous. However, cannulation of an external jugular or femoral vein may be easily accomplished. Surgical cutdown onto a vein may be required. Intracardiac injection should not be attempted unless all alternative methods of access to the circulation are impossible. The doses of drugs, DC shock and fluid therapy are based on body weight, which may be estimated according to age if the weight is unknown: Newborn: 3.5 kg 1 year: 10 kg 1-9 years: (age in years x 2) + 8 kg 10 years and over: age in years x 3.3 kg. Doses may also be prescribed on the basis of height. 8,9 Drug doses according to the 50th percentiles of weight and height for age are given in Box 3. Asystole or severe bradycardia If the cardiac rate is unresponsive to ventilation with 100% oxygen, asystole or pulseless severe bradycardia ( < 80 bpm in an infant, < 60 bpm in a small child, < 40 bpm in a large child or teenager) should be treated with adrenaline (10 µg/kg IV or IO, or 100 µg/kg via the ETT). The subsequent dose of adrenaline by any route is up to 100 µg/kg. If sinus rhythm cannot be restored, sodium bicarbonate (1 mmol/kg IV or IO) and/or atropine (20 µg/kg IV, IO or ETT), with additional doses of adrenaline, may be successful. If facilities are available, cardiac pacing (via the oesophageal, transcutaneous, transvenous or epicardial routes) may be effective. Ventricular fibrillation and pulseless ventricular tachycardia The only effective treatment of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) is DC shock. If the onset of VF is recent or is observed, a precordial thump may be given (although its efficacy has not been proven) and defibrillation should be attempted before any other treatment. The initial DC shock treatment of VF or pulseless VT is 2 J/kg, increasing to a maximum of 4 J/kg 10,11 in a series of three shocks. If sinus rhythm does not occur, give adrenaline (10 µg/kg IV or IO, or 100 µg/kg ETT) and a further three shocks of 4 J/kg. Persistent or refractory VF or VT may be treated with lignocaine (1 mg/kg IV, IO or ETT) followed by another series of up to three shocks of 4 J/kg. If the VF or VT remains refractory, alternative agents (bretylium tosylate 5 mg/kg, sodium bicarbonate 1 mmol/kg, magnesium sulfate 0.05-0.1 mmol/kg) may be tried, in combination with adrenaline (100 µg/kg IV, IO or ETT) and a series of three shocks of 4 J/kg. However, no drug has been conclusively proven to improve the efficacy of DC shock. Electromechanical dissociation (pulseless electrical activity) Electromechanical dissociation exists if pulses are absent despite relatively normal coordinated electrical activity on the ECG. It may be due to poor intrinsic myocardial contractility or secondary to a number of remediable causes, including hypoxaemia, hypovolaemia, severe acidosis, tension pneumothorax, pericardial tamponade, hyperkalaemia, hypocalcaemia, poisoning with a calcium channel blocker or hypothermia. It may also be due to massive pulmonary embolism. Treatment is with adrenaline, 10 µg/kg IV or IO or 100 µg/kg ETT initially, with subsequent doses up to 100 µg/kg by any route. If the electromechanical dissociation is persistent, consider hypovolaemia or severe acidosis and give a bolus of crystalloid or colloid fluid (20 mL/kg IV or IO) and/or sodium bicarbonate (1 mmol/kg). An underlying cause should be sought by clinical examination and investigations, including a chest x-ray, 12-lead ECG and echocardiograph if possible. Supraventricular tachycardia Supraventricular tachycardia (SVT) may cause severe hypotension or pulselessness. Synchronised DC shock (0.5-1 J/kg) should be given immediately to a pulseless patient. If blood pressure is adequate, vagal stimulation or drug therapy may be used. Adenosine is the drug of first choice. Alternatives are digoxin, a beta-blocker or a calcium channel blocker. Calcium channel blockers should not be used to treat SVT in infants because their negative inotropic effect may be fatal. Techniques in Paediatric advanced life support are given in Box 4. Medications and fluids used in paediatric advanced life support are summarised in Box 5. Management after resuscitation The cause of cardiorespiratory arrest should be sought and specifically treated. Complications of the resuscitation procedure should also be sought, especially if secondary deterioration occurs. This includes a chest x-ray to check the position of the endotracheal tube, to exclude pneumothorax, lung collapse or aspiration and to check the cardiac silhouette, and a blood sample for estimation of the haemoglobin level, pH, gas tensions and electrolyte and glucose concentrations. Supportive therapy should be provided until there is recovery of function of vital organs. This may include oxygen therapy, mechanical ventilation, inotropic infusion and renal support for several days or longer. Recovery in infants and children is usually slow because cardiorespiratory arrest is often secondary to prolonged global hypoxaemia and ischaemia with prior damage of other organs. Particular care should be taken to ensure adequate cerebral perfusion with well oxygenated blood and adequate blood pressure. Cessation of cardiopulmonary resuscitation The decision to cease cardiopulmonary resuscitation should be based on a number of factors, including the patient's pre-arrest condition, response to resuscitation, remediable factors, likely outcome and the opinions of experienced medical personnel. References Emergency Cardiac Care Committee and Subcommittees of the American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. JAMA 1992; 268: 2171-2302. Paediatric Life Support Working Party of the European Resuscitation Council. Guidelines for paediatric life support. BMJ 1994; 308: 1349-1355. Manual Australian Resuscitation Council. Policy Statements. Policies 12.1-12.9, November 1995. (Located at the Royal Australasian College of Surgeons, Spring Street, Melbourne.) Emergency Cardiac Care Committee and Subcommittee of the American Heart Association. Guidelines for cardio resuscitation and emergency cardiac care. JAMA 1992; 268: 2276-2281. Roy RN, Betheras FR. The Melbourne chart -- a logical guide to neonatal resuscitation. Anaesth Intens Care 1990; 18: 348-357. The Advanced Life Support Committee of the Australian Resuscitation Council. Adult advanced life support. The Australian Resuscitation Council Guidelines. Med J Aust 1993; 159: 616-621. Tibballs J. Endotracheal and intraosseous drug administration for paediatric CPR. Aust Fam Physician 1992; 21: 1477-1480. Lubitz SL, Seidel JS, Chameides L, et al. A rapid method for estimating weight and resuscitation drug dosages from length in the pediatric age group. Ann Emerg Med 1988; 17: 576-581. Oakley P, Phillips B, Molyneux E, Mackway-Jones K. Updated standard reference chart. BMJ 1993; 306: 1613. Chameides L, Brown GE, Raye JR, et al. Guidelines for defibrillation in infants and children. Report of the American Heart Association Target Activity Group: cardiopulmonary resuscitation in the young. Circulation 1977; 56 (suppl): 502A-503A. Gutgesell HP, Tacker HA, Geddes LA, et al. Energy dose for ventricular defibrillation of children. Pediatrics 1976; 58: 898-901. Rogers FB. Technical note: a quick and simple method of obtaining venous access in traumatic exsanguination. J Trauma 1993; 34: 142-143. Hornchen U, Schuttler J, Stoeckel H, et al. Endobronchial instillation of epinephrine during cardiopulmonary resuscitation. Crit Care Med 1987; 15: 1037-1039. Jasani MS, Nadkarni VM, Finkelstein MS, et al. Effects of different techniques of endotracheal epinephrine administration in pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest. Crit Care Med 1994; 22: 1174-1180. Patterson M, Boenning D, Klein B. High dose epinephrine in pediatric cardiopulmonary arrest (CPA). Pediatric Emerg Care 1994; 10: 310. Goetting MG, Paradis NA. High-dose epinephrine improves outcome from pediatric cardiac arrest. Ann Emerg Med 1991; 20: 22-26. Contributors This document was drafted and revised by Dr James Tibballs at the request of the Australian Resuscitation Council. Submissions were received from members of the Advanced Life Support Committee of the ARC and from Dr R Henning, Dr F Shann, Ms S Kinney (Melbourne); Dr A Duncan (Perth); Dr J McEniery, Dr G Delbridge, Dr B Lister (Brisbane); Dr B Wilkins, Dr R Choong, Dr B Duffy, Dr T Gratten-Smith, Dr I Alexander, Dr M Schindler, Dr J Gillis, Dr A O'Connell, Dr D Schell, Dr O Miller (Sydney); Dr S R Keeley, Dr A J Slater, Dr G M Shaw, Dr J Raftos (Adelaide); Dr E R Segedin (Auckland); Dr L Quan (Seattle); and Dr D Zideman (London). Members of the Advanced Life Support Committee: Dr M Allen (ARC South Australian Branch). Dr R A Capps (Australian Defence Force). A/Prof V Callanan (ARC Chairman; and Australian and New Zealand College of Anaesthetists). Ms J Dennett (Confederation of Australian Critical Care Nurses). Mr M Draheim (ARC Tasmanian Branch). Ms J Finn (Royal College of Nursing, Australia). Dr L Grigg (Cardiac Society of Australia and New Zealand; and National Heart Foundation). Mr A Hadj (Royal Australasian College of Surgeons). Mr J Hall (Institute of Ambulance Officers, Australia). Mr K Hambrecht (Co-opted member). Prof G A Harrison (Chairman, ARC Advanced life Support Committee; and Australian and New Zealand College of Anaesthetists). Dr I Jacobs (ARC Western Australian Branch). Mr O Juul (ARC New South Wales Branch). Mr S Leahy (Surf Lifesaving Association of Australia). Ms J Maclean (Royal Lifesaving Society, Australia). Dr P Morley (ARC Victorian Branch). Dr J O'Callaghan (Co-opted member). Dr A Phillips (Royal Australian College of General Practitioners). Mr C Smith (ARC Queensland Branch). Dr J Taylor (Co-opted member). Dr J Tibballs (Australian and New Zealand Intensive Care Society). Mrs E P Tyler (Australian Red Cross Society). Dr J Wassertheil (Australasian College for Emergency Medicine). Dr J Williamson (St John Ambulance Australia). No reprints will be available. Correspondence: Dr J Tibballs, Intensive Care Unit, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052. ©MJA 1996 Home |