Volume 173 Issue 9

Research Recent trends in the use of antidepressant drugs in Australia, 1990-1998 Peter McManus, Andrea Mant, Philip B Mitchell William S Montgomery, John Marley and Merran E Auland MJA 2000; 173: 458-461 For editorial comment, see Parker Abstract - Introduction - Methods - Results - Discussion - Acknowlegdements - References - Authors' details - - - More articles on General practice and primary care Abstract Objective: To determine the pattern of use of antidepressant drugs in the Australian community, 1990-1998, and to compare this with those of other developed countries. Design: Retrospective analyses of prescription and sales data, together with information about patient encounters for depression (from an ongoing survey of service provision by general practitioners) and population-based prevalence estimates for affective disorders (from community health surveys). Main outcome measures: National and international consumption of antidepressants, expressed in defined daily doses (DDDs) per 1000 population per day. Changes in both the frequency of general practice patient encounters for depression and population-based prevalence estimates for affective disorders. Results: Dispensing of antidepressant prescriptions through community pharmacies in Australia increased from an estimated 12.4 DDDs/1000 population per day in 1990 (5.1 million prescriptions) to 35.7 DDDs/1000 population/day in 1998 (8.2 million prescriptions). There has been a rapid market uptake of the selective serotonin reuptake inhibitors (SSRIs), accompanied by a decrease of only 25% in the use of tricyclic antidepressants (TCAs). In 1998, the level of antidepressant use in Australia was similar to that of the United States, while the rate of increase in use between 1993 and 1998 was second only to that of Sweden. In Australia, depression has risen from the tenth most common problem managed in general practice in 1990-91 to the fourth in 1998-99, and the number of people reporting depression in the National Health Surveys (1995 v 1989-90) has almost doubled. Of the prescriptions dispensed in 1998 for antidepressant drugs subsidised by the Pharmaceutical Benefits Scheme, 85% were written by general practitioners, and 11.2% by psychiatrists. Conclusions: As in most developed countries, antidepressant use increased between 1990 and 1998. The rapid market uptake of the new antidepressants, particularly SSRIs, is likely to have been driven by increased awareness of depression, together with availability and promotion of new therapies. Introduction The World Health Organization report on the global burden of disease placed major depression fourth among the leading causes of disease burden in the developing world in 1990, and predicted that it would rise to second by the year 2020.1 In parallel with the increasing awareness of depression as an important health issue, the past decade has seen an increase in the pharmacotherapy options for managing depression with the arrival of several new classes of antidepressants. To review trends in antidepressant use in Australia, the Drug Utilisation Sub-Committee (DUSC) of the Pharmaceutical Benefits Advisory Committee, Department of Health and Aged Care, convened a working group in 1998. The working group, which comprised representatives from the DUSC and from the Australian Pharmaceutical Manufacturers Association (APMA), reviewed Australian and international data on antidepressant sales and dispensing. The aim was to determine patterns of antidepressant use in Australia between 1990 and 1998 and to compare Australian patterns with those in similar developed countries. To assist in interpretation of Australian drug use trends, the group reviewed changes in both the frequency of general practice patient encounters for depression and in population-based prevalence estimates for affective disorders. Methods Prescription and sales data Prescription dispensing data were obtained from the database maintained by the DUSC that monitors the dispensing of prescription medicines through community pharmacies in Australia.2 No data on public hospital use are included in this database. The measurement units used are either prescription volumes or the number of defined daily doses (DDDs) per 1000 population per day. The DDD is based on the assumed average daily dose of the drug when used for its main indication by adults. It is the unit approved by the World Health Organization (WHO) for drug use studies, and allows for comparisons independent of differences in price, preparation and quantity per prescription.3 Within the data on dispensing of antidepressant drugs subsidised by the Pharmaceutical Benefits Scheme (PBS), it is also possible to determine the major specialty of the prescribing doctor. Data on total sales of antidepressants from wholesalers to retail and hospital pharmacies for all countries, except Sweden, were obtained from IMS Health Incorporated. IMS Health is the leading international provider of information on drug usage to the pharmaceutical and healthcare industries.4 Data were retrieved as kilograms of active ingredient and then converted to DDDs per 1000 population per day. Excluded were the use of lithium, Hypericum (St John's wort) or tryptophan, and combinations involving these drugs or their active constituents. Utilisation data for Sweden, where separate local arrangements apply, were supplied by the Swedish Association of the Pharmaceutical Industry (LIF). The 1999 WHO defined daily doses (DDDs) were used in calculations. Drugs unique to particular markets that did not have DDDs available were provisionally assigned values using standard references and information provided by drug information centres in the countries involved.5 Prescriber surveys Information related to general practice patient encounters for depression was obtained from the General Practice Statistics and Classification Unit of the Family Medicine Research Centre (FMRC), University of Sydney, which is conducting an ongoing survey of service provision by general practitioners (GPs).6 This involves 1000 randomly selected, active, recognised GPs per year, each recording details of 100 consecutive consultations on structured encounter forms. Rolling recruitment ensures that the recording weeks are distributed evenly over the year and that there is constant change in participants. These data can be compared with the findings of an earlier FMRC study of morbidity and treatment in general practice that used simpler but compatible methods.7 Information on prescribing by specialists is not included in these GP surveys. Community health surveys The 1995 National Health Survey was a household survey conducted by the Australian Bureau of Statistics to obtain national benchmark information on a range of health-related issues and to enable the monitoring of trends in health over time.8 A previous health survey, collecting broadly comparable data, was conducted in 1989-90.9The 1997 National Survey of Mental Health and Wellbeing of Adults was also conducted by the Australian Bureau of Statistics and used a representative sample of people aged 18 years or over living in private dwellings.10 The survey was interview-based with a diagnostic component administered through a modified version of the WHO Composite International Diagnostic Interview (CIDI). The CIDI translates the criteria of the Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV),11 and the International classification of diseases, 10th edition (ICD-10),12 into sets of questions that can be readily answered by the general adult population. Specific combinations of symptoms may indicate a specific mental disorder. Results Antidepressant use in Australia The dispensing of prescriptions for antidepressants through community pharmacies in Australia increased from an estimated 12.4 DDDs/1000 population per day in 1990 (5.1 million prescriptions) to 35.7 DDDs/1000 population per day in 1998 (8.2 million prescriptions). Trends in the use of the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), moclobemide, venlafaxine and nefazodone between 1990 and 1998 are shown in Box 1. The market uptake of the SSRIs has been rapid and accompanied by a decrease of only 25% in the use of the TCAs. Other new agents included moclobemide (a reversible monoamine oxidase type A inhibitor), nefazodone (a 5-HT2 antagonist) and venlafaxine (a serotonin-noradrenaline reuptake inhibitor). The 10 most commonly dispensed antidepressants in Australia in 1998 were, in descending order, sertraline, dothiepin, paroxetine, amitriptyline, fluoxetine, doxepin, moclobemide, imipramine, venlafaxine and citalopram. Of these, only the four tricyclic antidepressants were on the market in 1990, with dothiepin alone maintaining or improving its position over this period. Of the PBS-subsidised prescriptions dispensed for antidepressants in 1998, 85% were written by GPs, while 11.2% were written by psychiatrists. International comparisons We compared retail and hospital sales of antidepressants in Australia and seven major developed countries for the years 1993 and 1998 (Box 2). In 1998, sales of antidepressants in Australia (34.2 DDDs/1000 population per day) were similar to those of the United States (34.2 DDDs/1000 population per day), less than in Sweden (37.1 DDDs/1000 population per day) and France (36 DDDs/1000 population per day) and higher than in Canada (30.8 DDDs/1000 population per day) and the United Kingdom (30.4 DDDs/1000 population per day). Germany and Italy had considerably lower usage levels (12 and 9.9 DDDs/1000 population per day, respectively). The rate of increase in Australia between 1993 and 1998 was second only to that of Sweden. For these same countries in 1998, Box 3 shows the percentage split (based on DDDs/1000 population per day) of the antidepressant market by drug class. There was considerable variability in the percentage that TCAs represented of overall antidepressant use, from a low level of 11% in Sweden through to a high of 67% in Germany. Australia, Canada and France had a similar profile, with TCAs representing about 20% of antidepressant use. Venlafaxine was marketed in all eight of the countries surveyed and ranged between 1.5% and 5.2% of the total use. Mianserin had a low level of use in most countries, except for France and Italy, where it represented about 4% of antidepressant use. It was not available in North America. Similarly, moclobemide had a low level of use in most countries, except in Australia, where it represented 12% of the antidepressant market. Prescriber surveys Surveys conducted in 1990-91 and 1998-99 by the Family Medicine Research Centre have shown the increasing prominence of depression as a problem managed in general practice.6,7 In 1998-99, depression ranked as the fourth most common general practice problem, compared with the tenth in 1990-91. The rate of patient encounters involving depression per 100 encounters has increased from 2.1 in 1990-91 to 3.5 in 1998-99. In 1998-99, compared with 1990-91, antidepressants were more likely to be prescribed per every 100 encounters for depression (58.4 prescriptions [95% CI, 56.1-60.8] v 52.3 prescriptions [95% CI, 49.2-55.5]). Comparisons with age and sex demographics for total general practice encounters (women, 58.7%) suggest that female patients were over-represented at encounters for depression. The most frequent patient age group in encounters at which a tricyclic antidepressant was prescribed was 45-64 years (38%), whereas for encounters at which SSRIs were prescribed it was 25-44 years (43%). Sex distribution was similar for both drug groups, with about a third of the patients being men. Depression was the most common problem for which TCAs and SSRIs were prescribed in 1998-99, although the proportion of TCAs prescribed for depression (48.8% [95% CI, 44.3%-53.3%]) was lower than that of SSRIs (81.9% [95% CI, 79.7%- 84.1%]). Other specific problems managed with TCAs were sleep disturbance (7%), anxiety (5%) and back complaints (4.5%). For the SSRIs, these were anxiety (5.8%) and phobia/compulsive disorder (1.7%). When used for depressive disorders, TCAs had a prescribed daily dose consistently lower than the WHO DDD. The prescribed daily doses and DDDs for the most commonly dispensed TCAs were amitriptyline (mean, 59 mg; median, 50 mg; DDD, 75 mg), doxepin (mean, 61 mg; median, 50 mg; DDD, 100 mg) and dothiepin (mean, 85 mg; median, 75 mg; DDD, 150 mg). The prescribed daily doses for the most commonly dispensed SSRIs were much closer to the DDD: fluoxetine (mean, 24 mg; median, 20 mg; DDD, 20 mg), paroxetine (mean, 23 mg; median, 20 mg; DDD, 20 mg) and sertraline (mean, 72 mg; median, 50 mg; DDD, 50 mg). Community health surveys The 1997 National Mental Health and Wellbeing Profile of Adults identified a 5.8% prevalence of affective disorders (depression, 5.1%; dysthymia, 1.1%) during the 12 months before the survey among people aged 18 years or over.10 Women were more likely than men to have experienced affective disorders (7.4% compared with 4.2%). Although based on self-reports, household surveys conducted by the Australian Bureau of Statistics in 1989-90 and 1995 identified marked changes in the number of people reporting current or previous depression. In the 1995 National Health Survey, 8.1 persons per 1000 population reported depression as a long term condition, compared with 2.8 persons per 1000 in the 1989-90 survey. For depression as a recent illness, 11.4 per 1000 population reported this in 1995, compared with 5.8 per 1000 in 1989-90.8,9 Discussion The past decade has seen a remarkable change in the number of people recognised with and managed for depression, in the range of drug therapy options available, and in the volume of antidepressants prescribed. Previously, depression had been reported as under-recognised and undertreated.13-15Prominent among the likely reasons for this change are increased community awareness of depression as an important health issue, and attempts, most notably through government and community campaigns, to reduce the stigma of mental illness and the gaps in professional expertise inhibiting adequate recognition and treatment of depression.16,17 Coincident with these campaigns, important treatment recommendations were released in the United Kingdom in 1992 (the Royal College of General Practitioners and the Royal College of Psychiatrists) and, in the United States, in 1993 (Agency for Health Care Policy and Research).13,18 In Australia, the Psychotropic drug guidelines19 are the endorsed national standard, and the National Health and Medical Research Council has published clinical practice guidelines for managing depression in young people.20,21 The 1995 Australian National Health Survey showed that the number of people reporting depression as a recent and/or long term condition had nearly doubled compared with the earlier survey conducted in 1989-90. Such a change in the true underlying prevalence of disease is unlikely over a relatively short period of time, and the increase is far more likely to reflect a greater awareness of depression, with patients being more comfortable about coming forward for help and doctors, particularly in general practice, being more willing to provide it. This increased awareness of depression by doctors and patients, together with the availability and promotion of new drug therapy options (between 1990 and 1998, five SSRIs have been approved for PBS subsidy together with moclobemide, venlafaxine and nefazodone), accounts for the rise from the tenth to the fourth most common problem managed in general practice between 1990-91 and 1998-99. In 1998-99, encounters for depression were also more likely to generate a prescription for an antidepressant. This change is reflected in drug utilisation statistics. The market uptake of the SSRIs has been rapid and, remarkably, accompanied by only a relatively small decrease in the use of the TCAs. As a result, the overall antidepressant market has expanded greatly, with utilisation (as defined by DDDs/1000 population per day) being nearly three times greater in 1998 than in 1990. Prescription rates, however, have risen only 60% over that time, as the newer antidepressants are more likely to be dosed closer to the DDD than the older tricyclic antidepressants. TCAs are prescribed for sleep disturbance in a small proportion (7%) of patients, which is not the case for SSRIs. Most developed countries have seen similar trends, with sales in Australia consistent with US sales and slightly higher than those in the UK. The percentage that the SSRIs represented of total antidepressant use in Australia in 1998 was similar to that in the United Kingdom. The considerably lower levels of antidepressant use in Germany are probably related to Germany's strong tradition of use of complementary medicines (substantial use of Hypericum preparations [St John's wort] were not included in the comparisons); and the lower levels in Italy may be because, in 1994-98, SSRIs were not reimbursed by the national health system in Italy, but were fully paid for by the patient (Dr Alberto Vaccheri, Associate Professor, Department of Pharmacology, University of Bologna, personal communication, June 1999). Although there are interesting differences between countries, the rapid uptake of the new antidepressants is likely to have been driven by increased awareness, together with the availability and promotion of new therapies. The drug utilisation patterns, supported by evidence from population and general practice surveys, showed that there has been growth in the actual market rather than just redistribution within the market. Public health benefits of this major change in drug use (eg, reductions in suicide rates) are anticipated in the long term, but measuring population-level outcomes from changes will not be easy. Acknowledgements Other members of the Antidepressants Working Group who helped prepare these data were the Australian Pharmaceutical Manufacturers Association and the pharmaceutical industry (Susan Alexander, Mark Bradley, Michelle Burke, Liz Campbell, Victoria Croker, Marnie Firipis, Deborah Monk, Michael Ortiz, Ruth Stokes, Nick Williams). Drug Utilisation Sub-Committee secretariat (John Dudley). General Practice Statistics and Classification Unit, Family Medicine Research Centre, University of Sydney (Helena Britt and Geoff Sayer, who conducted the analyses of the depression data from BEACH). Disclosure: Philip B Mitchell has been a member of scientific advisory boards for Eli Lilly, SmithKline Beecham and Wyeth. References Murray CJ, Lopez AD. The global burden of disease: summary. Cambridge, Mass: Harvard School of Public Health, Harvard University Press (on behalf of the World Health Organization and the World Bank), 1996. Edmonds DJ, Dumbrell DM, Primrose JG, et al. Development of an Australian drug utilisation database: a report from the Drug Utilization Sub-Committee of the Pharmaceutical Benefits Advisory Committee. PharmacoEconom 1993; 3: 427-432. World Health Organization Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment. 2nd edition. Oslo, Norway: WHO, 1998. Hurley SF, McNeil JJ, Berbatis CG. Sources of Australian pharmacoepidemiology data. Commun Health Stud 1988; 12(1): 82-96. World Health Organization Collaborating Centre for Drug Statistics Methodology. ATC Index with DDDs, 1999. Oslo, Norway: WHO, 1998. Britt H, Sayer GP, Miller GC, et al. BEACH (Bettering the Evaluation And Care of Health): a study of general practice activity, six-month interim report. AIHW Catalogue No. GEP 1. Canberra: Australian Institute of Health and Welfare (General Practice series no.1). Bridges-Webb C, Britt H, Miles D, et al. Morbidity and treatment in general practice in Australia 1990-1991 [Errata in Med J Aust 1993; 158: 72, 652]. Med J Aust 1992; 157 (Suppl Oct 19): S1-S56. Australian Bureau of Statistics. 1995 National Health Survey: use of medications, Australia. Canberra: ABS, 1995. (Catalogue No. 4377.0.) Australian Bureau of Statistics. 1989-90 National Health Survey: summary of results, Australia. Canberra: ABS, 1991. (Catalogue No. 4364.0.) Australian Bureau of Statistics. 1997 Mental Health and Wellbeing: profile of adults. Canberra: ABS, 1997. (Catalogue No. 4326.0.) American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV). Washington, DC: APA, 1994. World Health Organization. International classification of diseases, 10th edition (ICD-10). Geneva: World Health Organization, 1993. Paykel ES, Priest RG. Recognition and management of depression in general practice: a consensus statement. BMJ 1992; 305: 1198-1202. Hirschfeld RMA, Keller MB, Pamico S, et al. The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA 1997; 277: 333-340. Kendrick T. Prescribing antidepressants in general practice: watchful waiting for minor depression, full dose treatment for major depression. BMJ 1996; 313: 829-830. Paykel ES, Tylee A, Wright A, et al. The Defeat Depression Campaign: psychiatry in the public arena. Am J Psychiatry 1997; 154 (6 Suppl): 59-65. The National Mental Health Strategy. Community Awareness Program: a review. Canberra: Commonwealth Department of Health and Aged Care, November 1998. US Department of Health and Human Services. Agency for Health Care Policy and Research (AHCPR). Depression in primary care: Vol 11. Treatment of major depression. Rockville, Md: AHCPR, 1993. Psychotropic drug guidelines. 4th edition. Melbourne: Therapeutic Guidelines, 2000. National Health and Medical Research Council. Depression in young people. A guide for general practitioners. Canberra: NHMRC, 1997. National Health and Medical Research Council. Depression in young people. A guide for mental health professionals. Canberra: NHMRC, 1997. (Received 5 May, accepted 31 Aug, 2000) Authors' details Drug Utilisation Sub-Committee, Department of Health and Aged Care, Canberra, ACT. Peter McManus, MMedSc, BPharm, Secretary. South Eastern Sydney Area Health Service, Sydney, NSW. Andrea Mant, MD, FRACGP, MA, Area Adviser, Quality Use of Medicines; and Associate Professor, School of Community Medicine, University of New South Wales, Sydney, NSW. School of Psychiatry, University of New South Wales, NSW. Philip B Mitchell, MD, FRANZCP, FRCPsych, Professor; and Administrative Director, Mood Disorders Unit, Prince of Wales Hospital, Sydney, NSW. Health Economics and Outcomes Research, Eli Lilly Australia Pty Ltd, Sydney, NSW. William S Montgomery, BPharm, DipHospPharm, GradCertHealthEcon, Health Outcomes Research Manager. Department of General Practice, University of Adelaide, Adelaide, SA. John Marley, MD, MB ChB, Professor. Health Economics and Pricing Department, SmithKline Beecham (Australia) Pty Ltd, Melbourne, VIC. Merran E Auland, PhD, Health Economist. No reprints will be avaliable from the authors. Correspondence: Mr P McManus, Secretary, Drug Utilisation Sub-Committee, Mail Drop Point 83, Department of Health and Aged Care, GPO Box 9848, Canberra, ACT 2601. peter.mcmanusAThealth.gov.au Make a comment Back to text Back to text Percentage split of antideprssant sales (based on defined daily doses per 1000 population per day) by drug class in 1998 (data for all countries, except Sweden, from IMS Health; Swedish data from the Swedish Association of the Pharmaceutical Industry). SSRI = selective serotonin reuptake inhibitor. TCA = tricyclic antidepressant. Back to text

Peter McManus · Andrea Mant · Philip B Mitchell · William S Montgomery · John Marley · Merran E Auland

Notable Cases Non-alcoholic steatohepatitis in children and adolescents Nicholas D Manton, Jill Lipsett, David J Moore, Geoffrey P Davidson Anthony J Bourne and Richard T L Couper MJA 2000; 173: 476-479 We describe 17 children with non-alcoholic steatohepatitis. All had elevated levels of serum liver enzymes and 16 were morbidly obese. Liver biopsy showed variable steatosis and fibrosis in nine patients. At follow-up, 12 of 14 patients had persistent morbid obesity and 11 had elevated liver enzyme levels. Methods - Clinical findings - Discussion - References - Authors' details - - More articles on Gastroenterology Non-alcoholic steatohepatitis (NASH) is well recognised in adults. It occurs with obesity, insulin resistance or insufficiency and associated metabolic abnormalities such as hyperlipidaemia and hyperglycaemia. NASH also occurs in childhood, but, in this group, it is not as well characterised. Obese, prepubertal children are at risk of liver disease, with liver biopsies showing fatty change, inflammation and fibrosis with progression to necrosis and cirrhosis.1-4We report here selected features of NASH in children presenting to a tertiary care child and adolescent hospital. We aimed to determine: the demographic details of these children; the presenting clinical signs and symptoms, and any associated conditions; the biochemical and radiological findings; the range of histopathological findings with liver biopsy; and the clinical and biochemical outcomes. Methods Patient identification Patients were retrospectively identified by searching a computerised database of histopathological specimens at the Women's and Children's Hospital (formerly the Adelaide Children's Hospital) for the years 1972-1999. All liver biopsies in this period were reviewed, and cases selected if the liver biopsy showed steatosis. Clinical details, investigations and disease course were determined (retrospectively) from the hospital records. The patients' weight/ideal body weight ratios were calculated using charts from the National Centre for Health Statistics Growth Curves for Children.5 Exclusion criteria Patients were excluded when a known cause of steatosis was present. These included inborn errors of metabolism, viral hepatitis, autoimmune hepatitis, total parenteral nutrition, cystic fibrosis or Wilson's disease. Liver biopsies Fatty change was described as macrovesicular or microvesicular, and the extent of steatosis was graded as mild, moderate or severe. The presence of inflammation was graded as mild, moderate or severe. Fibrosis was described (eg, portal tract fibrosis, perisinusoidal fibrosis, septal fibrosis, bridging fibrosis, cirrhosis). In all cases, tissue was submitted for electron microscopy. Clinical findings Seventeen patients were identified: 11 males and six females. Most (14 of 17) were identified in the past five years. Mean age ± SD was 11.7 ± 1.7 years (range, 9-15 years). Persisting intermittent abdominal pain (10 patients) was the commonest presenting symptom. Two patients were identified after hepatomegaly on review for known insulin dependent diabetes mellitus (IDDM) and, in two patients, abnormal liver function tests (LFTs) were detected incidentally during investigation for apparently unrelated problems (seizure and diarrhoeal illness). One patient (Patient 17) was asymptomatic and was investigated because his twin brother (Patient 13) was found to have NASH. Five patients had relevant family history: one had parents and brother with morbid obesity; one had a family history of Gilbert disease, a disorder of bilirubin conjugation; one had a father with cirrhosis; and two were twins with obesity and abnormal liver function test results. Box 1 summarises the clinical, biochemical and radiological findings for our patients. Sixteen of the 17 patients were morbidly obese (> 24% over ideal body weight [IBW]; mean, 53%; range, 25% to 118% over IBW). Eight patients had hepatomegaly either on clinical or ultrasound examination. Alanine aminotransferase (ALT) was elevated in all patients, gamma glutamyl transferase (GGT) was elevated in eight, and alkaline phosphatase (ALP) was normal in all patients. Five patients had elevated triglyceride levels and two had elevated total serum cholesterol levels. Ultrasound examination in 11 patients showed increased echogenicity (suggestive of increased liver fat) in 10. The liver biopsy changes included both macro- and microvesicular steatosis. Inflammation was present in eight patients and fibrosis was present in nine patients. The degree of fibrosis ranged from mild portal tract fibrosis to bridging fibrosis to probable cirrhosis (as identified in a repeat biopsy in one of the patients). Increased glycogen (intracellular and intranuclear) was seen in the two patients with known IDDM and a third patient in whom a subsequent diagnosis of IDDM was made. Mallory's hyalin was not seen in any of the cases on immunohistochemical staining, a noteworthy finding given that Mallory bodies are said to be seen more commonly in alcoholic steatohepatitis than in NASH.5 Box 2 shows the follow-up data. Eleven patients had continued elevation of liver enzyme levels, and persistent obesity despite counselling. Two of the obese patients had normalisation of LFTs with weight loss. None of the other obese patients lost weight, and in these patients liver enzyme levels remained elevated. One of the patients with diabetes (the only patient who was not morbidly obese) had normalisation of LFTs with improved diabetes control. Seven of the more recently identified patients were treated with ursodeoxycholic acid; one had normalisation of LFTs with weight loss. Discussion The association of abnormalities in liver function and morphological changes on liver biopsy (steatosis, inflammation and/or fibrosis) with obesity and insulin resistance/insufficiency is well established in adults and becoming increasingly recognised in children. Most cases of NASH in the paediatric age group have been described in older children and adolescents.1,2 Our series of 17 patients shows that children may be asymptomatic or present with vague, non-specific complaints, which conform to those described previously.6 One of our patients had marked acanthosis nigricans, a finding indicative of insulin resistance and reported recently in another study.2 Most of our patients were identified over the past 5-7 years, and we believe this is largely due to the increased awareness of this condition and the increasing prevalence of obesity in children in Australian society.7 Clinical findings In our series, all but one of the patients who had ultrasound of the liver showed variable enlargement and increased echogenicity, consistent with fatty change. In a study of 72 obese children,4 increased echogenicity was found in 53% of cases, and the authors proposed ultrasound as a useful tool to determine liver involvement in obese children. Certainly, our experience agrees with this. However, liver ultrasound will not detect the more subtle histopathological features of more severe liver damage, such as fibrosis. Only liver biopsy can demonstrate such abnormalities. Elevated ALT and GGT levels were the most common findings with LFTs. This is consistent with another study,4 in which ALT was the most elevated enzyme and the ALT/AST ratio was the reverse of that seen in alcoholic steatohepatitis. We found no correlation between presenting signs and symptoms, LFT abnormalities, and the morphological changes at liver biopsy, unlike those reported in adult patients with NASH.8 Liver histology We found a wide variation in biopsy findings, from steatosis alone to steatohepatitis and mild fibrosis to probable cirrhosis (with documented progression on repeat biopsy). In the patients with known glucose intolerance, increased glycogen within hepatocyte cytoplasm and nuclei was noted. In addition, in Patient 1 (where increased glycogen was noted), IDDM was subsequently diagnosed. In adults, NASH follows a relatively benign clinical course compared with alcoholic steatohepatitis.8,9 Although follow-up data in the paediatric age group are limited, the finding of evolving cirrhosis in one of our patients highlights the view that NASH may be a progressive disease.10-12 Rashid and Roberts have speculated that at least some patients with cryptogenic cirrhosis occurring in adulthood may have had NASH since childhood.2 A recent study13 found that NASH is under-recognised in many adults with so-called cryptogenic cirrhosis (with as many as 74% of such patients having a history of obesity or diabetes mellitus). Septal fibrosis occurs frequently in overweight adult patients with abnormal LFTs.14 Pathogenesis The pathogenesis of NASH is still being determined. A recent study15 based on data from the National Health and Nutrition Examination Survey concluded that reduced serum levels of fat-soluble antioxidants are present in obese children. Oxidant stress injury may be pivotal in the pathogenesis of NASH,16 resulting in adipose tissue synthesis of tumour necrosis factor (TNF). TNF antagonises insulin receptors, leading to glucose intolerance, hyperlipidaemia and steatosis. Another study17 suggests that fatty livers are vulnerable to liver ATP depletion and necrosis, indicating that altered hepatic energy homoeostasis may be involved. Increased lipid peroxidation may increase hepatic stellate cell activation.18 Activated stellate cells are matrix-producing myofibroblast-like cells which are thought to be responsible for the laying down of fibrous tissue in hepatic fibrosis.18 Intervention At this stage, therapy is limited to weight control and treatment of insulin lack or resistance. Although weight loss in adult patients has been effective in leading to regression of fatty change,19 in all but two of our obese patients weight control was not achieved and abnormalities of liver function persisted. Seven of our patients were treated with ursodeoxycholic acid, and one showed normalisation of LFTs (with weight loss). Ursodeoxycholic acid improves LFTs in patients with NASH.20 It is thought that this agent is cytoprotective and, by preventing membrane injury, may reduce liver injury in NASH.20 In our institution, treatment of NASH with ursodeoxycholic acid is largely a matter of individual preference for treating physicians, and guidelines have not been established. Recommendations Children presenting to paediatric outpatient units who are morbidly obese should have their LFTs measured, and should be counselled regarding weight loss. If the baseline LFTs are elevated, the measurements should be repeated in 3-4 months. If the LFTs are still abnormal, then other investigations (including hepatitis B and C virus serology, autoimmune antibody screen, caeruloplasmin levels, and serum triglyceride, cholesterol and blood sugar levels) should be performed and liver biopsy considered. Liver biopsy and other investigations might be performed earlier if the liver enzyme levels are grossly elevated. References Baldridge AD, Perez-Atayde AR, Graeme-Cook F, et al. Idiopathic steatohepatitis in childhood: a multicentre retrospective study. J Pediatr 1995; 127: 700-704. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000; 30: 48-53. Ludwig J, McGill DB, Lindor KD. Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol 1997; 12: 398-403. Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci 1997; 42: 1428-1432. National Centre for Health Statistics Growth Curves for Children. Adapted from Hamill PVV: NHCS Growth Curves for Children. DHEW Publication (PHS) 78-1650. Neuschwander-Tetri B, Bacon B. Nonalcoholic steatohepatitis. Med Clin N Am 1996; 80: 1147-1165. Lazarus R, Wake M, Hesketh K, Waters E. Change in body mass index in Australian primary school children, 1985-1997. Int J Obes Relat Metab Disord 2000; 24: 679-684. Lee R. Nonalcoholic steatohepatitis, a study of 49 patients. Hum Pathol 1989; 20: 594-598. Mohd R, James O, Burt A, et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714-1719. Bacon B, Farakvash M, Janney C, Neuschwander-Tetri B. Nonalcoholic steatohepatitis: tightening the morphological screws on a hepatic rambler. Hepatology 1995; 21: 1742-1743. Propst A, Propst T, Judmaier G, Vogel W. Prognosis in nonalcoholic steatohepatitis [letter]. Gastroenterology 1995; 108: 1607. Kim W, Poterucha J, Porayko M, et al. Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation 1996; 62: 1802-1805. Caldwell S, Oelsner D, Iezzoni J, et al. Cryptogenic cirrhosis: clinical characterisation and risk factors for underlying disease. Hepatology 1999; 29: 664-669. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000; 118: 1117-1123. Strauss R. Comparison of serum concentrations of α-tocopherol and β-carotene in a cross-sectional sample of obese and nonobese children (NHANES III). J Pediatr 1999; 134: 160-165. Lavine J. Relative antioxidant deficiency in obese children: a weighty contributor to morbidity? [editorial]. J Pediatr 1999; 134: 132-133. Cortez-Pinto H, Chatham J, Chacko VP, et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282: 1659-1664. Reeves H, Burt A, Wood S, Day C. Hepatic stellate cell activation occurs in the absence of hepatitis in alcoholic liver disease and correlates with the severity of steatosis. J Hepatol 1996; 25: 677-683. Lieverse R, Jansen J, Masclee A, Lamers C. Gastrointestinal disturbances with obesity. Scand J Gastroenterol 1993; 200: S53-S58. Laurin J, Lindnor K, Crippin J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 1464-1467. (Received 3 Apr, accepted 3 Aug, 2000) Authors' details Women's and Children's Hospital, Adelaide, SA. Nicholas D Manton, MB BS, Registrar, Department of Histopathology; Jill Lipsett, PhD, FRCPA, Histopathologist, Department of Histopathology; David J Moore, MB BS, FRACP, Paediatric Gastroenterologist, Department of Gastroenterology; Geoffrey P Davidson, MD, FRACP, Director, Department of Gastroenterology; Anthony J Bourne, MB BS, FRACPA, Director, Department of Histopathology; Richard T L Couper, MB ChB, FRACP, Paediatric Gastroenterologist, Department of Gastroenterology, and University of Adelaide Department of Paediatrics. Reprints will not be available from the authors. Correspondence: Dr R T L Couper, University of Adelaide Department of Paediatrics and Department of Paediatric Gastroenterology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006. rcouperATmedicine.adelaide.edu.au Make a comment 1: Clinical and investigation findings Patient Examination Biochemistry* Ultrasound Liver biopsy 1 (M, 13)† 27% over IBW acanthosis nigricans ALT ratio 3.2 GGT ratio 4.4 AST ratio 1.9 Enlarged EL Severe macrovesicular steatosis with increased glycogen 2 (F, 13) 27% over IBW short stature, hepatomegaly ALT 3.2 GGT 1.1 AST 3.0 Enlarged EL Moderate macro- and microvesicular steatosis with increased glycogen and moderate inflammation 3 (F, 11) 118% over IBW ALT 1.3 GGT 5.5 Normal Severe macro- and microvesicular steatosis 4 (F, 9) 45% over IBW ALT 2.2 nd Severe macrovesicular steatosis, mild portal tract inflammation, mild portal tract fibrosis 5 (M, 12) 10% over IBW tender hepatomegaly ALT 11.3 GGT 5.1 Enlarged EL Moderate macro- and microvesicular steatosis, scattered glycogenated nuclei 6 (M, 11) 115% over IBW ALT 3.2 GGT 1.6 AST 1.6 Fatty change Severe mixed macro- and microvesicular steatosis with bridging fibrosis and evolving cirrhosis 7 (M, 13) 81% over IBW hepatomegaly ALT 1.2 nd Moderate macrovesicular steatosis, mild portal tract inflammation 8 (M, 14) 74% over IBW ALT 16.0 GGT 4.9 EL Severe macrovesicular steatosis, mild septal fibrosis 9 (M, 15) 88% over IBW ALT 2.5 AST 1.5 TG 1.8 EL Severe macrovesicular steatosis, minimal perisinusoidal fibrosis 10 (F, 10) 32% over IBW ALT 20.7 GGT 1.4 Cholesterol 1.2 nd Moderate macro- and microvesicular steatosis, mild portal tract inflammation 11 (M, 13) 60% over IBW mild abdominal tenderness ALT 1.3 GGT 1.1 TG 1.5 nd Mild macrovesicular steatosis 12 (M, 11) 55% over IBW enlarged liver ALT 1.6 TG 1.7 EL Moderate macro- and microvesicular steatosis, moderate portal tract inflammation, portal tract fibrosis with bridging 13‡ (M, 12) 37% over IBW ALT 2.2 EL Moderate macro- and microvesicular steatosis, mild perisinusoidal fibrosis 14 (F, 9) 44% over IBW palpable liver edge ALT 3.6 nd Moderate macrovesicular steatosis, focal hepatocyte necrosis, mild portal tract inflammation, mild perisinusoidal fibrosis 15 (F, 10) 26% over IBW palpable liver edge ALT 2.8 Cholesterol 1.2 EL Mild macrovesicular steatosis, mild portal tract inflammation 16 (M, 11) 25% over IBW palpable liver edge ALT 4.7 TG 1.1 EL Severe macro- and microvesicular steatosis, mild portal tract inflammation, portal tract fibrosis with early bridging 17‡ (M, 12) 37% over IBW ALT 4.8 TG 1.3 nd Severe macrovesicular steatosis, mild portal tract fibrosis with early bridging *Biochemistry results are given as a ratio of the measured value of serum liver enzyme, serum triglyeride, or serum cholesterol levels over the normal maximum for the particular method used. †Sex and age at presentation. ‡Twins. IBW=ideal body weight. ALT=alanine aminotransferase. GGT=gamma glutamyl transferase. AST=aspartate aminotransferase. TG=Serum triglycerides. EL=echogenic liver. nd=not done. Back to text 2: Outcome data at latest follow-up Patient Follow-up period Percentage over IBW Biochemistry* Remarks 1 6 years 45% ALT 1.9 GGT 5.8 Subsequently diagnosed with IDDM and Alstrom syndrome 2 Lost to follow-up 3 6 years 25% Rapid weight loss with puberty, normalisation of LFTs 4 15 months 36% ALT 3.4 5 2.5 years 8% Normalisation of LFTs with improved diabetes control 6 2.5 years 60% ALT 1.7 Persisting obesity with some improvement in LFTs. Treated with ursodeoxycholic acid. Follow-up liver biopsy showed probable cirrhosis 7 Lost to follow-up 8 2 years 78% ALT 4.1 GGT 1.9 Treated with ursodeoxycholic acid 9 1 year 51% ALT 4.0 10 4 months 30% ALT 8.0 GGT 2.0 11 1 year 56% ALT 2.3 GGT 1.4 12 1 year 57% ALT 7.9 GGT 2.2 13† 15 months 36% ALT 3.0 Treated with ursodeoxycholic acid 14 14 months 36% ALT 3.8 Treated with ursodeoxycholic acid 15 Not yet reviewed 16 1 year 15% Normalisation of LFTs with weight loss. Treated with ursodeoxycholic acid 17† 1 year 45% ALT 2.9 Treated with ursodeoxycholic acid *Biochemistry results are given as ratio of the measured value of serum liver enzyme levels and the normal maximum for the method used. †Twins. LFT=liver function test. ALT=alanine aminotransferase. GGT=gamma glutamyl transferase. Back to text

Nicholas D Manton · Jill Lipsett · David J Moore · Geoffrey P Davidson · Anthony J Bourne

Medicine and the Community Improving services to bereaved relatives in the emergency department: making healthcare more human Aled G Williams, Debra L O'Brien, Kylie J Laughton and George A Jelinek MJA 2000; 173: 480-483 For editorial comment, see Kissane Abstract - What do relatives want? - The best way to break bad news - The Sir Charles Gairdner Hospital ED bereavement protocol - Conclusions - References - Authors' details - - More articles on Emergency medicine Abstract Death and bereavement are often poorly dealt with in emergency departments. Guidelines exist for optimal care of bereaved relatives. Establishing a limited bereavement program in a busy emergency department is quite feasible. Bereaved relatives appreciate a more "human" approach from hospital staff. Ultimately hospital staff also benefit from confronting issues surrounding death in the emergency department. Sudden death in the hospital emergency department (ED) is highly emotionally charged for relatives and staff. It is difficult to deal sensitively with death in a busy ED. Doctors find dealing with relatives difficult because of poor training in communication, fear of being blamed, a perceived "failure" in their skills, fear of expressing emotion, and their own fears about death.1-3 Death may be glossed over as we move to the next patient in the ever-increasing queue. Talking to the family may be seen as a chore and a waste of precious time on a busy shift. In not confronting these issues, however, we risk increasing job dissatisfaction and burnout.4 We also diminish the "human" side of our role as doctors. For relatives, the death of a loved one is difficult enough to cope with when it is expected. Deaths in an ED are often sudden and unexpected; the environment is confusing and unfamiliar; there may be difficulty getting information; and medical and nursing staff are usually strangers. This occurs in an atmosphere of high stress in which access to the patient may be restricted. All of these factors increase the likelihood that relatives will experience an abnormal grief reaction, with associated threats to physical and emotional wellbeing.5-7 Here we review the current literature on care of unexpectedly bereaved relatives and outline the changes we made in improving this service in our hospital's ED. What do relatives want? Relatives feel helpless and uninformed, and their experience is often negative. What they want during this very stressful time has been documented: to receive prompt attention from staff on arrival and frequent updates on their loved one's condition;6,7 to be with the patient before death, including during resuscitation;8 to know that the patient received prompt and appropriate treatment from prehospital and hospital staff;8 to be informed of the death in a compassionate and unhurried manner;7,8 to be assured that the patient's belongings will be properly handled;6,7 to be told what to do next (eg, how to contact an undertaker; when to go home);7 and to have the opportunity for follow-up with the hospital to answer unresolved questions.6,7 The best way to break bad news Most medical staff find breaking bad news to relatives stressful and draining, but we must not underestimate the importance of our interactions. The family will review the events of the day, including attitudes and responses of staff, again and again for months. Relatives' perceptions can profoundly affect their grief response, positively or negatively.5,7,9 Every family is different and each bereavement experience is unique, so some degree of flexibility is essential. There are, however, well established guidelines (for a summary, see Box). Initial contact with the family. Initial contact with relatives is often made over the phone. A senior doctor or nurse should first identify himself or herself and then the relative answering the phone. In general, the relative should not be told over the phone that the patient has died (if this is the case) -- the caller should simply outline events, say that the patient is very ill and ask the relative to come as soon as possible.5,7,9 The caller should try to ensure that there is somebody with the relative or able to drive them to the hospital. If informing relatives by phone is unavoidable10-12 (eg, if they live a long distance away), the caller should make greater efforts to ensure that the relative receiving the call is not left alone (eg, by asking if there is anyone who can be with the person, or offering to call a friend or relative).5 A member of staff should meet the relatives on arrival, confirm their identity and show them to a private area.7,12,13This should be a comfortably furnished room with access to a telephone. If the patient is undergoing resuscitation, a senior member of staff should explain this early and prepare the relatives for the possibility of death.6 A member of staff should offer to contact a priest or other spiritual counsellor. The family should, if possible, be given the opportunity to witness the resuscitation -- many relatives feel strongly that they should be at the patient's side, or may simply want to confirm that everything possible is being done.6,10 Relatives witnessing the resuscitation should be accompanied by a staff member to explain what is happening and answer questions. Keeping the family informed. A member of staff should stay with the family, giving them frequent updates on the progress of resuscitation.5,7,8 Informing the family of the death. This should be done by the doctor responsible for the patient.5,7 The doctor's presence implies that everything possible was done to save the patient's life. Introducing oneself and sitting down indicates a willingness to spend as much time as the family needs. Next it is important to identify who is in the room and what their relationship is to the deceased. (Friends should generally be asked to wait outside.5,10) The patient should be referred to by name as the doctor establishes what the family already knows, then fills in the details, beginning with what happened to the patient before arrival at the hospital.5,7,10 It is quite appropriate to inform relatives of details, such as the fact that the patient was "unconscious and didn't feel any pain".10,14 When informing relatives of the death, use plain English ("is dead" or "died") rather than euphemisms like "passed away", which some people misinterpret.7,12,13 The doctor's next responsibility is to facilitate grieving.5,7 The initial reaction will probably be shock. The doctor should allow some time for this to ease, but then the family should be encouraged to express feelings and ask questions. It may be best to just sit quietly for a while to share their grief.7 Sometimes it is appropriate to use touch, such as placing a hand on the arm to comfort a relative.10,14 After the initial shock, one of three emotions usually predominates:5 Denial -- this initial defence mechanism should be recognised and tolerated. It can allow time to adjust to the reality of death; Anger -- this may be directed at hospital staff. Usually, once expressed, the anger will diminish; Guilt -- this represents an inward expression of anger. Relatives may blame themselves. A simple statement from the doctor, exonerating the family, can provide much relief in the days and weeks to follow. Viewing the deceased. Most families wish to view or hold the deceased and this can facilitate the grieving process.5,7,10,13 If they do not wish to, this should be accepted.7,13 Medical or nursing staff should spend time preparing the family, especially if the body has been mutilated or if medical apparatus has been left in place for postmortem examination. Staff should remain discreetly to answer questions before withdrawing.7,10,13 Identifying "at risk" family members. Some family members are at greater risk of severe grief reaction, or even suicide, than others. Identifying these relatives can be difficult, but severe grief reactions are more likely to occur in cases where:7,10 the death was sudden or violent (eg, due to suicide or homicide); the person who died was a child; the person who died was a spouse or partner (especially if the relationship involved a high level of conflict or over-dependence); the relative feels he or she may have contributed to the death; the relative is particularly vulnerable because of past psychiatric illness or lack of a support network. Relatives at high risk of experiencing a severe grief reaction should be encouraged to have a friend or relative stay for 1-2 days. Relatives openly expressing suicidal intent, or even psychotic reactions, may require urgent psychiatric intervention. Concluding process. The family should be informed if a postmortem examination is needed. In Australia, coroner's department counselling services can be of assistance. The services of a funeral director need to be engaged and the deceased's personal property handed over to relatives. As relatives may forget much of what is said, it is useful to provide a brochure containing information about the grieving process, notes on practical matters and a list of useful phone numbers.11 Hospital staff should answer final questions and inform the family doctor. Many families need to be given "permission" to go home.7,11 Follow-up. Many relatives appreciate contact with the hospital after they leave.7,10,11 They may need further information to help resolve important issues, and they like to feel that the hospital actually cares. The Sir Charles Gairdner Hospital ED bereavement protocol The protocol Our hospital's bereavement protocol developed from a discussion of "death and dying" at one of our registrar teaching sessions, which made us aware that we could be doing much more to help bereaved relatives. We decided to set up a bereavement program using best practice guidelines.7,15,16We aimed to provide a service that was relatively simple and easily absorbed into existing staff workload, of benefit to relatives and not intimidating to staff. It was also important to make the program as unobtrusive as possible for relatives and to provide some continuity with staff who were present at the time of the person's death (there is some evidence of an adverse effect on grieving if these factors are not taken into account17). The main features of our program were: an education package for medical and nursing staff; intervention of a social worker at the time of death or by written referral out of hours; an information brochure for relatives, containing notes on the grieving process and practical issues, and contact details for useful agencies, including the name and number of the ED social worker; timely notification of the family's general practitioner by phone or fax, immediately or by the next working day; a sympathy card sent to the closest relative, handwritten and signed by the doctor and nurse most closely involved; a follow-up phone call by the social worker at one week to assess needs, and an offer for interview with the doctor involved; a further follow-up phone call at six weeks (relatives had been told that they would be contacted at this stage and were free to decline). The program was administered through the Social Work Department, which was responsible for keeping records of when calls were due and for coordination with medical staff. Practical issues to be dealt with included staff education (and overcoming staff resistance to the program), administration, and managing the extra workload for the social worker and medical and nursing staff. Because of the round-the-clock nature of the service, staff education and notification of the social worker sometimes created difficulties, especially at times of staff changeover. Initially, some staff saw the program as overly intrusive and "none of our business", and some vigorously opposed the idea of sending a sympathy card. These problems were largely overcome when positive reactions from families were fed back to staff, or when staff received direct thanks or cards. The initial problem of locating the appropriate medical and nursing staff to sign cards was solved by getting the head of department or the program's consultant to sign. There was minimal additional workload for medical and nursing staff, most of the extra time being that spent with grieving relatives, once or twice a month. Outcomes Of 37 deaths in the ED in the first seven months of the program, three were not referred to the social worker and were not followed up. All 34 remaining families wished to be enrolled in the program and received a call and a card during the first week after bereavement. Two relatives declined a follow-up phone call at six weeks, feeling they had enough support. Others were very happy with the call at six weeks -- one relative commented that she had looked forward to it for days, while another telephoned to rearrange the timing, as she would be away during the sixth week. Three families requested further interviews. We received much spontaneous positive feedback from relatives. Nearly all expressed gratitude verbally, and 10 relatives sent a written thank you as well. There was even an appreciative letter to the editor published in The West Australian newspaper, and one relative volunteered to join the hospital's Women's Auxiliary. Some comments from relatives were: "I thought that my mother had died alone, as I wasn't at her side. When I got the card and phone calls I realised that she had died among caring strangers, and that was a source of great comfort to me." "It was wonderful to get the card from Dr X. I'm glad my mother died at your hospital where everybody cares." "I've told all my friends that, when they die, your hospital is the place to do it."(!!) Tangible benefits of our program are hard to measure. As well as helping in the grieving process, for many people our program gave a positive image of the hospital as an institution which treated them as people with feelings and not just a "number". We hope this helps to make the face of emergency medical care in our community more "human". We believe it was also a beneficial process for staff. Apart from the formal education, which was positively received, many staff members were surprised by the appreciation shown by relatives. Some had assumed that relatives and patients wanted a formal and "professional" approach to bereavement and had sought to maintain "emotional distance". To their surprise, they found that spending time and commiserating with the family and showing a more "human" side were very well received. Conclusions Setting up a bereavement program is not difficult if staff are motivated. Provided the number of deaths per year in the ED is not excessive, the increased workload is small and easily absorbed. Although difficult to quantify, there are benefits to relatives, staff and the hospital. For us, the most important lesson is that relatives want to be treated with compassion by a caring professional. Being more "human" in our delivery of healthcare may just be beneficial for us as well. References Buckman R. Breaking bad news: why is it still so difficult? BMJ 1984; 288: 1597-1599. Schmidt TA, Tolle SW. Emergency physicians' responses to families following patient death. Ann Emerg Med 1990; 19: 125-128. Seravalli EP. The dying patient, the physician and the fear of death. N Engl J Med 1988; 319: 1728-1730. Honigman B, Armstrong J. Life and death. In: Rosen P, editor. Emergency medicine: concepts and clinical practice. 4th edition. St Louis, Missouri: Mosby, 1998: 197-212. Dubin WR, Sarnoff JR. Sudden unexpected death: intervention with the survivors. Ann Emerg Med 1986; 15: 54-57. Parrish GA, Holdren KS, Skiendzielewski JJ, et al. Emergency department experience with sudden death: a survey of survivors. Ann Emerg Med 1987; 16: 792-796. Walters DT, Tupin JP. Family grief in the emergency department. Emerg Med Clin North Am 1991; 9: 189-206. Fanslow J. Needs of grieving spouses in sudden death situations: a pilot study. J Emerg Nurs 1983; 9: 213-216. Soreff SM. Sudden death in the emergency department: a comprehensive approach for families, emergency medical technicians, and emergency department staff. Crit Care Med 1979; 7: 321-323. Edlich RF, Kubler-Ross E. On death and dying in the emergency department. J Emerg Med 1992; 10: 225-229. Von Bloch L. Breaking the bad news when sudden death occurs. Soc Work Health Care 1996; 23: 91-97. Adamowski K, Dickinson G, Weitzman B, et al. Sudden unexpected death in the emergency department: caring for the survivors. CMAJ 1993; 149: 1445-1451. Olsen JC, Buenefe ML, Falco WD. Death in the emergency department. Ann Emerg Med 1998; 31: 758-764. Hamilton GC. Sudden death in the ED: telling the living. Ann Emerg Med 1988; 17: 382. Yates DW, Ellison G, McGuiness S. Care of the suddenly bereaved. BMJ 1990; 301: 29-31. Coolican MB, Pearce T. After care bereavement program. Crit Care Nurs Clin North Am 1995; 7: 519-527. Williams WV, Polak PR. Follow up research in primary prevention: a model of adjustment in acute grief. J Clin Psychol 1979; 35: 35-45. Authors' details Emergency Department, Sir Charles Gairdner Hospital, Perth, WA. Aled G Williams, MB ChB, FACEM, Emergency Physician. Debra L O'Brien, MB BS, FACEM, Emergency Physician. Kylie J Laughton, BA, BSocWk, Emergency Department Social Worker. George A Jelinek, MD, FACEM, Professor and Chairman, Emergency Medicine, University of Western Australia. Reprints will not be available from the authors. Correspondence: Dr A G Williams, Emergency Department, Sir Charles Gairdner Hospital, Verdun Street, Nedlands, WA 6009. aled.williamsAThealth.wa.gov.au Make a comment Recommended actions for medical and nursing staff in dealing with grieving relatives Contacting family Request family's urgent attendance Do not inform of death over phone Arrival of family Show to private room with phone Give prompt update on patient's condition Offer spiritual or other counsellor During resuscitation Stay with family Give regular updates Allow relatives to be with patient After death Inform family in an unhurried manner Facilitate grieving Identify "at risk" relatives Allow deceased to be viewed Concluding process Attend to "formalities" (eg, coroner) Give brochure containing useful information and contact numbers Address final questions Follow-up Contact general practitioner Send sympathy card Make phone call at one and six weeks, as appropriate Allow opportunity for interview with treating doctor to address unanswered questions Back to text

Aled G Williams · Debra L O'Brien · Kylie J Laughton · George A Jelinek

Medicine and the Community The perpetrators of domestic violence Sarah E Romans, Marion R Poore and Judy L Martin MJA 2000; 173: 484-488 See Articles 1, 2 and 4 of this series Abstract - Our understanding - Why? - Who? - Problems with research - What can be done? - Issues - Treatment - How effective? - Conclusions - References - Authors' details - - More articles on General practice and primary care

Sarah E Romans · Marion R Poore · Judy L Martin

Abstract - Mechanism - Injection therapy - Transurethral alprostadil - Selective inhibitors - Guidelines - Conclusion - References - Authors' details Abstract Erectile dysfunction (ED) is a common condition and can usually be managed pharmacologically, with drugs delivered by intracavernosal injection (ICI), transurethrally or orally. The cardiovascular status of the patient and his overall fitness for renewed sexual activity must be assessed before treatment for ED is initiated. The efficacy of sildenafil is related to the extent and severity of ED, and is significantly reduced in patients with severe vasculogenic ED, ED associated with diabetes and after radical prostatectomy. Alprostadil (prostaglandin E1) is the drug of first choice in patients treated with ICI; it is effective in 72.6% of men with ED and is associated with a low risk of priapism and cavernosal fibrosis. Transurethral alprostadil is significantly less effective than alprostadil ICI, producing improved erections in 30%-40%, but rigid erections in only 10%, of men with ED. There is Level II evidence that: alprostadil ICI is an effective treatment for ED papaverine ICI is associated with a high risk of cavernosal fibrosis and priapism papaverine ICI should be restricted to informed patients refractory to treatment with alprostadil ICI transurethral alprostadil is less effective than alprostadil ICI sildenafil is an effective treatment for ED. Erectile dysfunction (ED) is the inability to achieve and maintain an erection of sufficient rigidity for satisfactory sexual intercourse.1 Community-based epidemiological studies suggest that sexual dysfunction, particularly ED, is a common disorder in men, and is associated with reduced quality of life.2,3 While it was previously thought that most impotence in men was psychogenic, we now know that there is a physical basis for most men's impotence. One of the most significant advances in our understanding has been the recognition that blood flow into the corpora cavernosa is regulated by smooth muscle tone, and that this mechanism can be pharmacologically altered. Mechanism of erection An erection is initiated when psychoneuroendocrine stimuli activate efferent autonomic nerves to relax penile vascular and corpus cavernosal trabecular smooth muscle. The mechanism of erection is described in Box 1. The penis loses its rigidity when the activation of sympathetic constrictor nerves after ejaculation increases the tone of the smooth muscles and the helicine arteries and trabeculae, resulting in decreased arterial inflow and increased venous outlow. The mechanisms that maintain flaccidity are unknown. Priapism is an uncommon, but potentially serious, adverse effect associated with some of the therapies described below -- its management is outlined in Box 2. Intracavernosal injection therapy Self-administered intracavernosal injection (ICI) therapy, using vasodilator drugs which relax the arterial and trabecular smooth muscle, is an effective treatment for ED4 (E2). (See Box 3 for an explanation of level-of-evidence codes.5) Papaverine Papaverine is a potent, non-specific smooth muscle relaxant which increases smooth muscle intracellular adenosine 3',5'-monophosphate (cAMP) by its action as a non-selective cAMP phosphodiesterase inhibitor, causing vasodilatation of penile vascular and sinusoidal smooth muscle.6 Papaverine has a relatively short plasma half-life (1-2 hours) and is extensively metabolised in the liver. After intracavernosal injection, the peak serum concentration is several times lower than after extracavernosal injection, suggesting that the corpus cavernosum is a separate pharmacokinetic compartment from which elimination of papaverine is much slower than from the systemic circulation.7A meta-analysis of the largest published studies on the use of papaverine reports that it is effective in 53% of men with ED, as measured by the ability to produce an erection of sufficient rigidity for sexual intercourse8 (E1). However, the efficacy of ICI papaverine is limited by local adverse effects, principally priapism (in 7%)8 and intracavernosal fibrosis, presenting as penile deformity or curvature (reported in one study in 50% and 95%, respectively, of long term users).9 Fibrosis is related to poor injection technique, frequent injections and long term use. Because of these adverse effects, papaverine should be restricted to informed patients in whom other medications are ineffective. Papaverine hepatotoxicity is rarely a clinical problem and may manifest either as an increase in liver transaminase concentrations, which is relatively common (> 1%), or as a drug-induced hepatitis, which is rare (< 0.1%).10 Adrenergic blockers It is well recognised that drugs which block α-adrenoceptors (such as prazosin) can produce erection, and even priapism. Thus, intracavernosal injection of α-adrenergic-blocking drugs seems a logical way of producing penile erection. Phentolamine, a competitive α-adrenoceptor antagonist with affinity for α1- and α2-adrenoceptors, produces tumescence, but rarely an erection, when injected intracavernosally. However, when phentolamine is combined with papaverine, 68% of users respond with a rigid erection8 (E1). Alprostadil Alprostadil (prostaglandin E1, or PGE1) is an eicosanoid derived from arachidonic acid (see Box 4 for a profile of alprostadil). The mechanism of its vasodilating action is not completely understood. Alprostadil increases levels of intracellular cAMP by modulation of adenyl cyclase, leading to a decrease in the free calcium concentration and subsequently to smooth muscle relaxation.11 It may also modulate the presynaptic release of noradrenaline. Alprostadil has a short duration of action and a plasma half-life of less than one minute because of rapid pulmonary clearance of up to 80% after the first pass through the lung. When injected intracavernosally, approximately 30% of the drug is metabolised within the corpora cavernosa, which may explain why significantly fewer episodes of priapism occur with alprostadil than with papaverine. Multiple studies have shown that alprostadil has superior efficacy and reduced risk of priapism and intracavernosal fibrosis compared with papaverine (alone or combined with phentolamine). A meta-analysis found that alprostadil resulted in an erection of sufficient rigidity for sexual intercourse in 72.6% of men with ED8 (E1). The principal side effect of intracavernosal injection of alprostadil is pain at the site of injection, which occurs in up to 30% of patients. Priapism is a rare complication. Although early experience suggested that fibrosis was uncommon with alprostadil ICI, recent long term studies show an incidence of fibrosis and scar formation of 9%-23.3% in mid-term and long-term users, so patients should be warned of the possibility of penile fibrosis before starting treatment12,13 (E4). Studies in human fibroblasts have shown that alprostadil suppresses collagen synthesis induced by transforming growth factor (TGF-β1). An imbalance between PGE1 and TGF-β1 in the corpora cavernosa, as a result of anoxia or endothelial damage due to ischaemia, hypercholesterolaemia or hyperglycaemia, may cause increased extracellular matrix deposition, inhibition of smooth muscle growth, and eventually fibrosis.14 Inhibition of collagen synthesis by alprostadil may, in part, explain the low incidence of cavernosal fibrosis with this drug. Polyagent intracavernosal injection therapy Intracavernosal injection therapy with alprostadil in combination with other agents such as papaverine, phentolamine and atropine may be effective in patients in whom maximum-dose alprostadil monotherapy is ineffective.15,16 A comparative study reported a 91.6% response rate to a combination of alprostadil, papaverine and phentolamine15 (E32). Polyagent ICI appears effective as "salvage therapy" in patients with severe arteriogenic ED and mild to moderately severe cavernosal venous leakage in whom alprostadil alone is ineffective.16 However, a significant number of patients remain refractory to ICI therapy. Treatment guidelines proposed by the 1998 New South Wales Health Complaints Commission Inquiry into Impotence Treatment emphasise the importance of adhering to good manufacturing practices to ensure sterility of polyagent medication.17 Transurethral alprostadil Alprostadil can also be administered as a microsuppository into the distal urethra. A translucent hollow-stem applicator is used to insert the microsuppository after urination, the residual urine acting as both a lubricant and a diluent for the microsuppository. The drug is absorbed directly into the urethral endothelium and is transferred into the corpora cavernosa primarily by venous channels that communicate between the corpus spongiosum and the corpora cavernosa. These channels appear to increase in number, but particularly in size, with age. Alprostadil is rapidly absorbed from the urethra (only 20% remains after 10 minutes) and produces vasodilatation in the penile vasculature; plasma levels are either low or undetectable. Transurethral alprostadil has a brief serum half-life of between 30 seconds and 10 minutes because of rapid pulmonary clearance after the first pass through the lung. No effect on spermatozoa motility, viability or membrane integrity has been shown, and the mean increase in the PGE1 content of the ejaculate (123 mg) is less than the normal day-to-day variability for prostaglandins. In extensive double-blind placebo-controlled clinical trials sponsored by manufacturers, 65.9% of men achieved an erection adequate for intercourse after administration of transurethral alprostadil in a doctor's office,8 and 64.9% of these men reported intercourse at least once with home treatment, with significant improvements in quality of life, particularly in the domains of self-esteem and sexual and non-sexual aspects of their relationships with their partners17 (E2). The efficacy of alprostadil was found to be similar regardless of age or the cause of ED, including vascular disease, diabetes, surgery, and trauma. The use of an adjustable penile constriction band with transurethral alprostadil may augment the drug effect. However, several postmarketing studies failed to produce similar results to those of the trials sponsored by manufacturers. One reported that only 27% of patients achieved erections sufficient for intercourse during in-office testing, and that, because of this limited efficacy, adverse effects and cost, more than 80% of patients did not continue to use transurethral alprostadil at home18 (E4). Another study comparing transurethral and intracavernosal alprostadil reported total erectile response rates of 43% and 70%, respectively, complete rigid erections in only 10% versus 48%, and rates of penile pain or burning in 31.4% versus 10.6%19 (E4). The most frequently reported adverse effects associated with transurethral alprostadil are penile pain (32%), urethral bleeding or spotting (5%) and dizziness (3%).17 As syncope was reported in 0.4% of patients,17 the initial dose titration should be performed in the doctor's office. Discomfort after administration was commonly reported as mild and transient, but 7% of patients discontinued treatment because of adverse effects. Priapism and cavernosal fibrosis were found in less than 0.1% of patients using the transurethral preparation and less than 1% of those using the intracavernosal injection. Vaginal burning or itching was reported by 5.8% of partners. Unless a condom is used, transurethral alprostadil should not be used if the female partner is pregnant. Selective phosphodiesterase inhibitors Sildenafil Sildenafil citrate, a potent, competitive phosphodiesterase type 5 (PDE-5) isoenzyme inhibitor (see Box 4 for a profile of this drug), is the first oral medication to show significant and reliable efficacy in most patients with ED20 (E2). After the nitric oxide/cGMP pathway is activated by sexual arousal, inhibition of PDE-5 isoenzyme (see Box 1) by sildenafil results in increased cavernosal concentrations of cGMP and an augmented penile erection in men with ED. In early studies, sildenafil was effective in restoring erectile function and improving intercourse success rates in a wide range of patients, including those with hypertension, diabetes, spinal cord injury, other concomitant medical conditions, and in patients taking a wide variety of concomitant medications. Its efficacy was related to the cause, extent and severity of ED, and was significantly reduced in patients with severe vasculogenic ED, ED associated with diabetes, and after radical prostatectomy ED20,21 (E2, E32). More recent studies report a response rate to sildenafil of 65%, significant improvement in quality of life and a 35% incidence of adverse effects22 (E33). Failure to respond to sildenafil suggests severe vasculogenic ED resulting from advanced penile artery atherosclerosis or severe cavernosal venous leakage, or a combination of both. The action of sildenafil on the nitric oxide/cGMP pathway seems complementary to the action of other vasoactive agents, and combined therapy may be effective in patients who do not respond to a single therapy. A recent study reported that 34% of patients in whom maximum-dose ICI is ineffective responded to sildenafil, and a further 31% responded to a combination of the two, giving an overall "salvage" rate of 65%23 (E33). Sildenafil produces an erection within 25-60 minutes and remains active even at four to five hours after being taken. Sildenafil should be administered with caution in patients with retinitis pigmentosa, as some patients with this inherited condition have genetic disorders of retinal phosphodiesterase and there is no published safety information. Sildenafil is extensively metabolised, predominantly by CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes, and is converted to an active metabolite (M1), with an in-vitro potency for PDE-5 of approximately 50% of the parent drug, which accounts for about 20% of sildenafil's pharmacologic effects. Both sildenafil and the metabolite have terminal half-lives of about four hours. The adverse effects of sildenafil, reported in clinical trials, were transient, mild to moderate in nature, and dose-dependent. The most common adverse effects were headache (15.8%), flushing (10.5%), dyspepsia (6.5%) and nasal congestion (4.2%). Discontinuation of treatment was comparable for patients receiving sildenafil (2.6%) and placebo (2.3%). Priapism was not reported in these studies or in any of the clinical trials of sildenafil. As there is a degree of cardiac risk associated with sexual activity, doctors must assess the cardiovascular status of their patients before initiating any treatment for ED, including sildenafil. Sildenafil has been shown to potentiate the hypotensive effects of nitrates and may be associated with large and sudden drops in systemic blood pressure. It is therefore contraindicated in patients who use prescribed nitric oxide-donating drugs or nitrates in any form for ischaemic heart disease, or recreational nitrites (eg, amyl nitrite), regardless of frequency. Caution should also be exercised in patients with asymptomatic coronary artery disease stabilised with medical treatment, coronary revascularisation, congestive heart failure combined with borderline low blood pressure, or a multidrug regimen for high blood pressure.24 These patients remain at a slightly increased risk of developing angina pectoris or acute myocardial infarction, which may necessitate treatment with short-acting nitrates, including intravenous sodium nitroprusside, by ambulance or hospital emergency staff. Guidelines for the evaluation and treatment of erectile dysfunction Treatment for ED depends on both its cause and severity, but other factors, such as efficacy, adverse effects, acceptability to patient and partner, psychological effects, reversibility and cost, are also important. A guide to managing ED is shown in Box 5. Although the primary cause of most ED is organic, there are invariably compounding psychological factors, such as "performance anxiety"; psychosexual counselling may be an important option for both the patient and his partner. Patients and their partners should be informed of all available treatment options. Doctors remain responsible for conducting a thorough medical history, physical examination and appropriate investigations to establish the extent, severity and causes of ED. In patients regarded as fit for renewed sexual activity, first-line treatment with an oral phosphodiesterase inhibitor such as sildenafil is appropriate if there are no contraindications. Patients in whom sildenafil is ineffective, who can not tolerate its adverse effects or who have contraindications are best treated with alprostadil, either as ICI or the transurethral preparation. Men who fail to respond to maximum-dose alprostadil can be managed with ICI containing alprostadil combined with other agents such as papaverine and phentolamine. Men in whom drug treatment is ineffective may elect to undergo implantation of an intrapenile prosthesis, but many choose to limit their sexual activity to non-penetrative sex. Conclusion As the population ages, quality-of-life expectations will increase. Many men now recognise that ED need not be a consequence of advancing age, nor a result of chronic illness or radical prostate cancer surgery. Most patients with ED can be successfully treated with medications. Several new oral treatments for ED are currently undergoing clinical evaluation and may increase the therapeutic options considerably. Information for patients is given in Box 6. Disclosure: Chris G McMahon is a member of the speaker panels for Pharmacia Upjohn, Pfizer and Abbott/Vivus, the manufacturers of Caverject, Viagra and MUSE. He was also a member of the Caverject and MUSE medical advisory boards, a medical consultant to Pfizer, and a clinical investigator for Pharmacia Upjohn, Pfizer, Bayer, Eli Lilly, Icos Corporation, Abbott, Senetek PLC, Pentech and American Medical Systems. References NIH Consensus Conference. Impotence, NIH Consensus Development Panel on Impotence. JAMA 1993; 270: 83-90. Pinnock CB, Stapleton AM, Marshall VR. Erectile dysfunction in the community: a prevalence study. Med J Aust 1999; 171: 353-357. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281: 537-544. Linet OI, Ogrinc FG. Efficacy and safety of intra-cavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med. 1996; 334: 873-877. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, AusInfo, 1999. Poch G, Kukovetz WR. Papaverine-induced inhibition of phosphodiesterase activity in various mammalian tissues. Life Sci 1971; 10: 133-144. Hakenberg O, Wetterauer U, Koppermann U, Liffimann R. Systemic pharmacokinetics of papaverine and phentolamine: Comparison of intravenous and intracorporal application. Int J Impotence Res 1990; 2 (Suppl 2): 247-248. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of world-wide experience. J Urol 1996; 155: 802-815. De Rose AF, Oppezzi GF, Scotto S. [Local complications of papaverine-induced erection: follow-up at 7 years] [Article in Italian]. Arch Ital Urol Androl 1993; 65: 289-293. Brown LS, Christopher AH, Koehler M, et al. Hepatotoxicity related to intracorporal pharmacotherapy with papaverine. Urology 1998; 52: 844-847. Paoletti R. Biochemistry and pharmacology of prostaglandin E1: introductory remarks. In: Sinzinger H, Rogatti W, editors. Prostaglandin E1 in atherosclerosis. New York: Springer-Verlag, 1986: 3-7. Chen RN, Lakin MM, Montague DK, Ausmundson S. Penile scarring with intracorporal injection therapy using prostaglandin E1: a risk factor analysis. J Urol 1996; 155: 138-140. Chew KK, Stuckey BG, Earle CM, et al. Penile fibrosis in intracavernosal prostaglandin E1 injection therapy for erectile dysfunction. Int J Impotence Res 1997; 9: 225-229; discussion, 229-230. Moreland RB, Traish A, McMillin MA, et al. PGE1 suppresses the induction of collagen synthesis by transforming growth factor-beta 1 in human corpus cavernosum smooth muscle. J Urol 1995; 153: 826-834. Padma-Nathan H. The efficacy and synergy of polypharmacotherapy in primary and salvage therapy of vasculogenic erectile failure. Int J Impotence Res 1990; 2: 257-258. McMahon CG. Comparison of the response to the intracavernosal injection of a combination of papaverine and phentolamine, prostaglandin E1 alone and a combination of all three in the management of impotence. Int J Impotence Res 1991; 3: 133-142. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997; 336: 1-7. Fulgham PF, Cochran JS, Denman JL, et al. Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting. J Urol 1998; 160: 2041-2046. Porst H. Transurethral alprostadil with MUSE (medicated urethral system for erection) vs intracorporal alprostadil -- a comparative study in 103 patients with erectile dysfunction. Int J Impotence Res 1997; 9: 187-192. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338: 1397-1404. Dinsmore WW, Hodges M, Hargreaves C, et al. Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects. Urology 1999; 53: 800-805. Jarow JP, Burnett AL, Geringer AM. Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment. J Urol 1999; 162: 722-725. McMahon CG, Samali R, Johnston HM. Treatment of Intracorporal Injection Non-Responders with Sildenafil Alone or in Combination with Polyagent Intracorporal Injections. J Urol 1999; 162: 1992-1997. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999; 33: 273-282. Authors' details North Shore Private Hospital, Sydney, NSW. Chris G McMahon, MB BS, FACSHP, Sexual Health Physician. Reprints will not be available from the author. Correspondence: Dr C G McMahon, Suite 11, Level 3, North Shore Private Hospital, 1 Westbourne Street, St Leonards, NSW 2065. cmcmahonATmail.usyd.edu.au 1: Mechanism of erection Non-adrenergic, non-cholinergic nerves and vascular endothelium release nitric oxide in response to sexual arousal, which activates cytoplasmic guanylate cyclase, converting GTP into cGMP. The increased levels of cGMP alter transmembrane calcium ion flux, resulting in cavernosal smooth muscle relaxation, dilatation of cavernosal and helicine arteries and engorgement of lacunar spaces. The expanding lacunar spaces compress the subtunical venous plexus against the tunica albuginea, decreasing cavernosal venous outflow, increasing intracavernosal pressure, with resulting penile rigidity. Cyclic nucleotides, such as cGMP, are hydrolysed by cyclic nucleotide phosphodiesterases. GTP=guanosine triphosphate; GMP=guanosine monophosphate; cGMP=cyclic guanosine monophosphate. Back to text 2: Management of prolonged erection (priapism) Always use alprostadil monotherapy as first-line ICI treatment. Use lowest possible effective dose. Inform patient of the risk of prolonged erection and the procedure to be followed if the penis is still rigid, as follows: 2 hours after administration - 120mg pseudoephedrine 4 hours after administration - repeat 120mg pseudoephedrine and walk briskly for 10-15 minutes 6 hours after administration - regard as medical emergency and contact the treating doctor or a hospital emergency department immediately. Patients may require aspiration of corpora and irrigation with dilute vasoconstrictors or, in refractory priapism, surgical drainage. Back to text 3: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system5 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 with a 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 pre-test and post-test. Back to text 4: Drugs: profiles of alprostadil and sildenafil Alprostadil Action and onset Alprostadil (prostaglandin E1) induces an erection by relaxation of trabecular smooth muscle and dilatation of cavernosal arteries. Alprostadil may be administered by intra-cavernosal injection (Caverject, Pharmacia Upjohn) or by a transurethral suppository (MUSE, Abbott/Vivus Corp.). An erectile response occurs within 5-15 minutes of intracavernosal injection (ICI) and within 7-25 minutes of transurethral administration. Arousal is usually required to produce a maximal response. Detumescence usually commences within 10-20 minutes of ejaculation or cessation of sexual arousal, but complete flaccidity may not occur for a further 1-2 hours. Dosage Both Caverject and MUSE are administered 10-20 minutes before planned sexual activity. Dosage is individualised by initial supervised dosage titration, with the aim of establising the lowest possible effective dose (see below). Caverject injection is available in three different concentrations in 1mL ampoules (5µg, 10µg and 20µg), with a kit containing a syringe, needle, alcohol swab and written instructions. Patients should be instructed in sterile injection technique, used needle disposal and the management of prolonged erections (&lt 2h; Box 2) by trained medical personnel. The maximum frequency of use is no more than three times a week, with at least 24 hours between doses. For ED of vasculogenic, psychogenic or mixed aetiology, start with 5µg and titrate in 5µg increments to a maximum of 40µg until an erectile response sufficient for sexual intercourse occurs or there are intolerable adverse effects. For ED of wholly neurogenic aetiology (spinal cord injury), start with 1.25µg and titrate in 1.25µg increments until an erectile response sufficient for sexual intercourse occurs or there are intolerable adverse effects. Transurethral alprostadil (MUSE) is available in dosages of 125µg, 250µg, 500µg, and 1000µg. It is administered after urination, the patient remaining standing for approximately 10 minutes. The two lower dosages are recommended for initial dosing, with stepwise dose titration to a maximum of 1000µg, until either an erectile response sufficient for sexual intercourse or intolerable adverse effects occur. Because of the potential for symptomatic hypotension and syncope, the initial dose titration should be conducted under medical supervision. The maximum frequency of use is no more than two doses per 24-hour period. Adverse effects Alprostadil ICI: Mild penile pain (15%-20%), priapism (0.25%) and cavernosal fibrosis with long term use (5%-10%). Cavernosal fibrosis may result in the formation of nodules, penile curvature or deformity, or impaired erectile function. Adverse effects of intraurethral alprostadil include penile pain (25%-35%), urethral bleeding or spotting (5%), priapism (0.1%) and symptomatic hypotension (3%) and syncope (0.4%). Drug interactions Unlikely because only low or undetectable amounts of alprostadil (< 2pg/mL) are found in the peripheral venous circulation. Slidenafil Action and onset Sildenafil citrate is a potent, competitive phosphodiesterase type 5 (PDE-5) isoenzyme inhibitor. When sexual arousal activates the nitric oxide/cGMP pathway via non-adrenergic, non-cholinergic nerves, inhibition of PDE-5 results in increased cavernosal levels of cGMP, relaxation of penile vascular and trabecular smooth muscle, increased cavernosal blood flow and augmented penile tumescence or erection. An erectile response to sexual arousal may occur 0.5-5 hours after dosing. Ingestion on an empty stomach may result in a response after 30 minutes, whereas ingestion after a high-fat meal may delay onset for up to 3 hours. Detumescence occurs immediately after ejaculation or cessation of sexual arousal. The erectile refractory period is often reduced, allowing subsequent arousal to produce a second erection in some men. Dosage Sildenafil is available in 25mg, 50mg and 100mg tablets. The recommended starting dose is 50mg, taken one hour before planned sexual activity, with subsequent dose titration (to a maximum of 100mg) until the desired erectile response is achieved. Use is limited to once-daily administration. Patients aged over 65 years, those with significant renal impairment (creatinine clearance rate, < 30mL/min) or hepatic impairment, or those taking potent cytochrome P450 3A4 inhibitors, should start with a dose of 25mg. Adverse effects Adverse effects are dose-related and are usually of mild to moderate severity. The most common are headache, facial and upper-trunk flushing, dyspepsia and nasal congestion. Transient alteration in colour vision may occur at a dose of 100mg. No cases of priapism were reported in initial studies. Drug interactions The concomitant use of potent cytochrome P450 3A4 inhibitors (eg, erythromycin, ketoconazole, itraconazole, protease inhibitors), as well as the nonspecific CYP inhibitor cimetidine, is associated with increased plasma levels of sildenafil. Concomitant administration of CYP3A4 inducers, such as rifampicin, will decrease plasma levels of sildenafil. Sildenafil potentiates the hypotensive effects of nitrates and should not be taken by patients who use nitric oxide donors or nitrates in any form. Patients' fitness for renewed sexual activity should be assessed before initiating treatment Back to text 5: Evaluation and treatment of erectile dysfuntion Back to text 6: Important messages for patients Erectile dysfunction is common and is usually due to physical disease. The speed and extent of the male and female sexual response reduces as men and women age - patient treatment expectations should be appropriate for age. Erectile dysfunction is associated with cigarette smoking, hypertension, peripheral vascular disease, diabetes mellitus and depression, and can be an indicator of other underlying, unrecognised physical disease. There is always a contributing psychological component, and psychosexual therapy may result in restoration of potency, even when there is a contributing physical cause - not all men require treatment with medication. Some men can be successfully treated with a combination of sexual education, changes in lifestyle and medication. Many couples have fulfilling sexual relationships without penetrative sexual intercourse - not all men need to have potency restored. Men with long term erectile dysfunction and chronic medical illness (eg, coronary artery disease, chronic obstructive pulmonary disease), must have their fitness for renewed sexual activity assessed before initiation of treatment. Men with angina who take prescribed nitrates should not take sildenafil. Back to text

Chris G McMahon