Letters

In reply: Our article aimed to show how history is often rewritten in narrative forms that are more appealing to the human need for heroes and for clear, memorable moral lessons.1 The challenge is to sort out whether the matters at stake are those of narrative style or substantial differences of fact. Hugh felt our approach was patronising to Fleming — but we were at pains to emphasise his "genius" for making important causal connections. He also had a genius for seeking adulation — which in no way disqualifies him from deserving to share the Nobel Prize for Medicine with Chain and Florey. Hugh also criticised our assertion that "Fleming had little idea what to do with his mould apart from dabbing it on infected wounds" — yet his counterexample, that in 1929 Fleming used "penicillin to treat pneumococcal conjunctivitis in one of his assistants", illustrates the point. Let us also not forget that a Belgian group had discovered the penicillin mould in 1920, and recognised its antimicrobial properties well before Fleming did. The challenge is to foresee and drive the application of knowledge rather than to leave facts in a dormant but pregnant state. Vellar's fascinating letter proposes that a dental abscess and two extractions, rather than Florey's drinking of hydrochloric acid, caused his "pinched smile". A mutually compatible hypothesis is that Florey was prone to this infection because of tooth damage caused by the acid. Vellar also provides further support for the quixotic spread of knowledge and the personal motivations and obsessions that influence researchers. Florey's transport of sulfanilamide to Melbourne was apparently not to popularise the new and revolutionary drug, but to treat his daughter. It also raises a fascinating, if ironic, possibility: was Florey's life saved by sulfanilamide, allowing him to continue on his yet-to-be-forged endeavour of the purification of penicillin?

Ivo D Vellar

To the Editor: Perhaps for reasons of space, Tobin et al, in their article on community versus individual benefit,1 have omitted an important public health justification for confidentiality. If patients are fearful that the doctor's obligation to notify the authorities could lead to a loss of privileges (in the case cited, a driver's licence), they may fail to attend for diagnosis and treatment. This understandable anxiety warrants a mention in this debate.

Peter C Arnold · Bernadette M Tobin · Steven R Leeder · Ernest R Somerville

In reply: Arnold makes a good point. We agree with him, and would resist today's increasing tendency, on public health grounds, to make it mandatory for doctors to report a variety of conditions suffered by their patients. In general the community is well served if doctors have the discretion to decide, in any particular case, whether the public interest in maintaining a patient's confidentiality is outweighed by the public interest in breaching that confidentiality in order to protect innocent third parties.

Peter C Arnold · Bernadette M Tobin MA PhD · Steven R Leeder PhD FRACP FFPHM · Ernest R Somerville MB BS FRACP FRCP

To the Editor: End-of-life issues: Case 11 illustrates an increasingly common scenario confronting physicians caring for older patients. The case example of a nursing home resident with stroke, dementia and the onset of pneumonia highlights the importance of encouraging patients to prepare for future medical decision-making. This can be done through the use of enduring guardianship, medical powers-of-attorney or advance care directives ("living wills"). Documenting these matters allows people to appoint others to make healthcare decisions on their behalf, and to indicate what treatment they would want in various clinical circumstances, should they no longer be competent to do so. If "Mrs W" had appointed an enduring guardian to deal with issues of healthcare and medical consent, or had indicated in an advance care directive what her wishes would be if she were to become seriously ill, the decision-making process may well have been clearer. The other issue this scenario raises is the need to check whether Mrs W's daughter could have made medical decisions for her mother. In New South Wales, if the daughter had been in a caring role for her mother before nursing-home placement, she could be considered the "person responsible" (similar to the old concept of "next of kin"). Under the Guardianship Act 1987 (NSW), the "person responsible" is able to act as a substitute decision-maker for healthcare and medical treatment. While it would clearly still be good, sensible medical practice to involve other family members in discussion about Mrs W's future, it would ultimately be the daughter, as the "person responsible", who would be able to make those decisions.

Susan E Kurrle

In reply: We agree with Kurrle about the importance of encouraging patients to prepare for future medical decision-making. The strategies she suggests are practical and useful. However, we believe that the difficulties confronting physicians in caring for older patients require us to go further and to rethink what represents excellent care at the end of life. Today, death from acute illness has largely been superseded by death from chronic illness, and the latter generally follows one of three main trajectories: cancer, organ system failure or dementia/frailty.1 Our systems of care for people who are near the end of life need to reflect the ways in which elderly people actually decline and die. If we wish to promise elderly people what a decent society should be able to promise them (accurate diagnoses, excellent control of symptoms, the absence of any gaps in care and of any "surprises" in their condition and its treatment, clarity about the role of their family in caring for them, a way of dying that accords with their hopes, and, most importantly, help to live the remaining part of their lives "to the full"), we need to rethink the care provided during hospitalisation of older people at the end of their lives.1

Susan E Kurrle · Bernadette M Tobin MA PhD · Ian D Cameron FACRM FAFRM PhD

To the Editor: Community-acquired methicillin resistance in Staphylococcus aureus was only reported in eastern Australia as recently as 1998.1 We report a case of community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) causing cellulitis and bacteraemia. A 30-year-old man presented to the emergency department with a short history of heel pain. There was no history of trauma, diabetes, drug misuse, contact with hospitals or previous antibiotic treatments before the current illness. Examination showed that he had a temperature of 37.7°C and sinus tachycardia of 120 beats per minute. There was extensive cellulitis surrounding a superficial collection of pus over the left heel; this was incised and drained. Initial investigations showed only neutrophilia. Blood cultures, but no swabs, were taken. Therapy with daily intravenous injections of 1 g ceftriaxone, given at home by an ambulatory care service, was initiated. The following day, blood cultures showed the presence of gram-positive cocci identified as a Staphylococcus sp., and the treatment was changed to 2 g of cephazolin 12-hourly, intravenously. On the second day Staphylococcus aureus resistant to oxacillin was isolated. There was susceptibility to erythromycin, clindamycin, tetracycline, ciprofloxacin, vancomycin, rifampicin and fusidic acid. Treatment with vancomycin (1 g 12-hourly, by means of a peripherally inserted central catheter) resulted in clinical improvement within 48 hours and was continued for a total of two weeks, followed by oral rifampicin and fusidic acid. A bone scan and echocardiogram showed no significant abnormality. Resolution was complete at six weeks and the patient returned to work. Methicillin-resistant Staphylococcus aureus (MRSA) is now a common cause of skin and soft tissue infections.2-4 MRSA was not acquired outside hospital until the 1980s, when intravenous drug users from Detroit were reported with MRSA bacteraemia. Such community-acquired strains have now been reported worldwide, including in Australia.5 These strains are usually non-multiresistant MRSA,3 which are highly pyogenic, readily communicable and predominantly cause skin and soft tissue infections. However, CAMRSA endocarditis and a bacteraemic osteomyelitis have been described. We believe this to be the first case of CAMRSA bacteraemia to be reported in Australia. Community-acquired MRSA strains have become a common cause of community-acquired staphylococcal infection in Australia.2,3 It is now recommended that swabs be routinely taken to cover the possibility of drug-resistant organisms such as MRSA.1-3 The appropriate initial management of suspected or high-risk cases is unclear, but might include treatment with vancomycin or gentamicin before the availability of antibiotic sensitivity test results.

Nicholas Collins · lain B Gosbell · Stephen F Wilson

To the Editor: The recent article by the Obstetric Medicine Group of Australasia alluded to the increasing relevance and importance of thrombophilia screening following adverse pregnancy outcomes, namely recurrent miscarriage, stillbirth, retarded intrauterine growth and pre-eclampsia.1 Formerly, these outcomes were generally attributed to "placental insufficiency", where a cause was not readily identified. Screening for disorders in the uteroplacental circulation after such adverse pregnancy outcomes was formerly confined to investigations for an autoimmune basis, such as antinuclear antibodies, anticentromere antibodies, anti-DNA antibodies and the lupus inhibitor. However, in recent years, it has become more apparent that inherited or acquired thrombophilias may play a significant role in certain adverse pregnancy outcomes.2-5 Reports from Israel2,3 and elsewhere have suggested that thrombophilias can be found in up to 65% of women with recurrent pregnancy loss of unknown cause, as well as in cases of intrauterine growth retardation, stillbirth, placental abruption and pre-eclampsia. It is also known that certain thrombophilic factors are more likely to produce thrombogenic changes and hence are possible deficiencies in the uteroplacental circulation. Preliminary work has shown that treating women who have had recurrent pregnancy loss complicated by thrombophilia with antithrombotic agents (low molecular weight heparins) is beneficial, with improved pregnancy outcomes in a significant number of these cases.3 With the growing understanding of the role of thrombophilias in pregnancy, it seems that thrombophilia screening will assume a more prominent role in investigating patients after recurrent miscarriage, stillbirth, intrauterine growth retardation and pre-eclampsia.

David Morgans

To the Editor: I agree with the assessment by Del Mar and colleagues of available data according to evidence-based guidelines on hormone replacement therapy (HRT) after mastectomy.1 As they note, these data are not definitive. Standard practice has been to avoid oestrogen use in women with a history of breast cancer. Ours is an increasingly litigious society and courts make decisions according to different criteria than do scientists. In particular, precedent is very important to the law of tort, even if the scientific basis for the precedent is unproven. For some years now, I have seen 100 or more new patients per year with recently diagnosed early breast carcinoma. By the time I see them, every single one already knows that: anti-oestrogens are used in treatment of breast cancer; and women are at least 30% more likely to develop breast cancer after five years of HRT. Further, these women fear recurrence of breast cancer more than any other health problem. Hence, I am concerned that the sound evidence-based conclusions reached by Del Mar and colleagues could be successfully challenged in court by a woman who developed recurrence of breast cancer while receiving HRT. In addition to the costs and stress for the individual practitioner involved and other members of his medical indemnity organisation, such action would set back scientific enquiry into this important subject, possibly forever. There is a wealth of well conducted research into non-oestrogenic management for menopausal symptoms. Lifestyle measures (clothing and activity) and dietary modifications (avoiding spicy foods, alcohol) have a role in well-being. Oral progestogens, clonidine, venlafaxine, black cohosh, and probably tibilone, all produce better outcomes than placebo.2 Evening primrose oil, pyridoxine, dong quai, Chinese herbs, progestogen and yam creams, and phytoestrogens do not work better than placebo.3 The last may actually be harmful. Advisory statements for general practitioners about oestrogen replacement therapy for managing menopausal symptoms after breast cancer should be prefaced with this information, as should any discussion with patients. I do prescribe oestrogens for distressing menopausal symptoms after breast cancer treatment, but only after several consultations to allow time for women to appreciate the uncertainties involved.

Robert N Hitchins

To the Editor: I was pleased to see the issue of hormone replacement therapy (HRT) after breast cancer raised by Del Mar and colleagues in a recent issue of the Journal.1 However, I was a little disappointed to see that Australian research in this area had been "missed" by their search.2,3 There are a number of other studies that I am aware of which would suggest to me that perhaps their search technique was not particularly thorough.4-7 Nonetheless, I should add that I do agree with their conclusions. In fact, I am not aware of any clinical trials that have shown an adverse effect of HRT after a diagnosis of breast cancer. However, the studies examined by Del Mar and colleagues are all population studies and not randomised controlled trials. I also think it's important that the readers of the Journal understand that there are other strategies for controlling menopause symptoms after breast cancer, such as the use of progestins, antidepressants and stress-reduction techniques. Even though the evidence we have suggests that HRT after breast cancer is "safe", we do not have even one published randomised trial on this question, so caution should be the rule. HRT after breast cancer should always be viewed as a last resort.

Robert N Hitchins MB BS, FRACP, FAChPM · Christopher M Pyke MB BS, FRACS, FACS

To the Editor: While I have little concern with the conclusion of the article by Del Mar and colleagues,1 I have some concerns about its use to portray a mode of healthcare delivery where any given health practitioner, armed only with what can be gleaned from the Internet, can issue advice. For example, in such a circumstance, should not the general practitioner also refer to the National Health and Medical Research Council clinical practice guidelines on the management of early breast cancer,2 which suggests that the "safety of oestrogen replacement therapy in women with breast cancer has not yet been established", and, further, that "HRT [hormone replacement therapy] and women with breast cancer" is an area where research is needed? Should the doctor also point out to the patient that she is eligible to enter a prospective randomised trial looking at the use of HRT following breast cancer treatment versus the best non-hormonal treatment of menopausal symptoms, currently being administered by the Australian and New Zealand Breast Cancer Trials Group (as part of International Breast Cancer Study Group trial 17-98)? How should practitioners protect themselves when they find the management they are recommending is outside that recommended in the evidence-based guidelines published by specialty groups? A few other minor points: the content of the article refers to women with breast cancer, whereas the title refers only to women who have had mastectomy, and the imaginary patient asked about loss of libido, which was not addressed at any subsequent point in the article.

Christopher B Del Mar MD FRACGP FAFPHM · Paul P Glasziou PhD FRACGP FAFPHM

In reply: Eden, Pyke and Hitchins are happy with the findings of the rapid literature search that we performed for the general practitioner who wanted to know about the safety of HRT in a woman treated for breast cancer. However, they have concerns with the process. Eden is worried that we missed two Australian publications on the issue. In fact, they misunderstand our intentions. Firstly, we did not raise the issue, nor deliver an "advisory statement". It was the general practitioner who asked the question. We were trying to provide a rapid (few days) and responsive service to provide credible information to help a doctor manage a patient. Secondly, we were not able to undertake a full systematic review (which would take a full-time researcher as long as six months and would cost accordingly).1 Instead, our best strategy was to use a cascade process of searching, looking first for the most rigorous study types that would answer the clinical question. If not available we go to the next most rigorous, and so on, stopping when we find the relevant evidence.2 For this question, the ideal study type would be a meta-analysis of randomised controlled trials (RCTs). However, no RCTs were available (as Eden, and the guidelines to which Pyke refers, note), and we had to content ourselves with observational studies. We should remember that no evidence for safety is not the same as evidence for danger. What is important is that we did not miss any trials. Legal issues worry many doctors, even when decisions are supported by best research evidence,3 but, rather than pose a medicolegal threat, we believe that this evidence-based approach is more likely to protect doctors. Why? Failures in communication are the most common preventable cause for doctors being sued by patients.4 Yet, taking the trouble to find empirical information such as this and then discussing it with the patient is surely the most effective way of communicating the pros and cons of different treatment strategies (including, we agree, alternatives such as those mentioned by Hitchins). In the end the patient has to decide on the basis of the risks and benefits, and the choice can often be extremely difficult. It is likely to be more dangerous to assume the patient has abdicated this responsibility to the doctor without checking first. Can doctors be sued for a "safe" decision that leaves a patient exposed to unnecessary symptoms? It may be dangerous to assume that doctors can play "safe" in any one direction. Why do experts take exception when non-experts delve in their areas for the best evidence to manage patients? After all, a cat may look at a king.5 Experts seem to welcome the attention, but seem to think they should be dispensing the information. However, until the information can be delivered more effectively, this sort of stopgap system will have to do.

Robert N Hitchins

To the Editor: Fitzgerald and Isaacs' recent article on genotype–phenotype correlations in healthcare professionals describes some truly original research in an area of exceptional relevance.1 However, some of their conclusions fail the analytical technique described by others as "the common sense test".2 Most obviously, the finding of complete deletion of all personality genes in orthopaedic surgeons sits uncomfortably with clinical experience, which suggests a plethora of witty and indeed charismatic members of that specialty. The authors have erred in making an admission of reading The Medical Journal of Australia on at least a semi-regular basis as an inclusion criterion for the study. As this would include only a minuscule proportion of the orthopaedic population, their sampling was surely unrepresentative. By the same criterion, it is likely that there are few theatre sisters who would admit to being semi-regular readers of the Journal. Those who do are probably married to members of the medical profession, which would explain the (bel) indifference phenotype.

Dominic A Fitzgerald · David Isaacs

In reply: We welcome Brown's observations. However, with regard to orthopaedic surgeons, we are unaware of any correlation between affability and ability.

Lachlan Brown MB BS, FRACGP

To the Editor: The recent article by Chapman et al1 and a case report published some years previously in the Journal2 indicated that hyponatraemia may occur during indapamide therapy. However, it should be noted that the data came from spontaneous adverse drug reaction reporting, and therefore can give no indication of the incidence or relative risk of hyponatraemia compared with other diuretics. Nor can it give the incidence of hyponatraemia as a proportion of side effects occurring during indapamide therapy. The presentation of these data appears to cause some confusion, including an interpretation that hyponatraemia was more common with indapamide therapy than other diuretics.3 However, adverse events may be more likely to be reported for drugs which are usually well tolerated. Hyponatraemia led to discontinuation of therapy in only eight out of 3000 patients in the PROGRESS study.3,4 Previous controlled studies of indapamide (2.5 mg or sustained-release 1.5 mg daily) have found no significant overall changes in serum sodium levels.3 Hyponatraemia associated with indapamide therapy may occur with a recommended dose of 2.5 mg, which does not have a significant diuretic effect. Indapamide appears to be useful for treating central diabetes insipidus, raising the possibility that hyponatraemia occurs because of an inappropriate antidiuretic hormone secretion syndrome.6 Indapamide-related hyponatraemia may be more common in elderly women,1 as is the case for hyponatraemia associated with selective serotonin reuptake inhibitors. Hyponatraemia associated with indapamide therapy appears to be sporadic and uncommon and may be avoided by appropriate monitoring of serum electrolyte levels.

Laurence G Howes · John McEwen · John E Marley

To the Editor: I was impressed by the article on the seven deadly genes in a recent issue of the Journal.1 Your readers may also be interested to learn that we have recently discovered an entire family of antisocial recessive genes in colleagues and patients. 2 These include the stalk-r gene (not only in patients who stalk doctors, but also in doctors who molest their patients3) and the hum-r gene for socially inappropriate comicality, which clearly invites correlation with the dub (formerly cyn) gene for cynicism and medical humour.1 I cordially wish Fitzgerald and Isaacs the Best of British (and Irish) luck with the lofty ambitions expressed in the penultimate paragraph of their discussion; and, together with Arthur Koestler, we speculate that "in lieu of abolishing language the only way to curb human destructiveness would be to retool the brain", and that "advances in genetic engineering might encourage evolution along its path".4

Lachlan Brown

In reply: Howes writes that previous studies have not shown significant hyponatraemia with indapamide. Our article highlighted that hyponatraemia was reported in a much larger proportion of all types of adverse drug reactions to indapamide than to chlorothiazide in Australia. As we clearly acknowledged, "Voluntary reporting systems do not provide a basis for calculating incidence or robust risk estimates". In the PROGRESS study, 1770, and not 3000, participants were exposed to 2–2.5 mg of indapamide.1 The mean age of participants given active therapy in that study was 64 years and 30% were women. Details of the eight patients withdrawn because of hyponatraemia were not published. Importantly for indapamide, chlorothiazide and the other comparator (hydrochlorothiazide with amiloride), more than 80% of the patients with hyponatraemia in our study of Australian adverse reaction reports were aged 65 years or older (mean age for indapamide, 69.3 years, unpublished data), and at least 78% were female. Given that indapamide formulations have been promoted as a replacement for chlorothiazide notwithstanding the acknowledged limitations of the data, our article was appropriate in alerting practitioners to the possibility of hyponatraemia, particularly in elderly women.

Laurence G Howes MB BS, PhD, FRACP · John McEwen MB BS, MSc, MPS · John E Marley MD, MB ChB

To the Editor: Your editorial comment1 about the fact that the "Death and Dying" issue of the Journal [19 November 2001] contained no obituaries because "the obituary tray was empty" prompts me to make a suggestion. Having, over the years, written obituaries for colleagues, including one for my own father, I have always believed we would do colleagues a great favour if each of us wrote our own obituary and left it in the keeping of a colleague, to be dealt with at the appropriate time. Not only would it ensure that the obituary included services for which the departed would like to be remembered, but it would also save the writer of the obituary a great deal of time in research. PS. Now in my own 91st year, I've not yet written my own obituary.

H Stuart Patterson

To the Editor: Although treatment with vitamin D has been shown to reduce hip fracture risk in elderly institutionalised people,1 there has been a perception that vitamin D deficiency is generally uncommon in countries with high sunlight exposure such as Australia. We studied the prevalence of vitamin D deficiency in older people in residential aged-care facilities (hostels and nursing homes) in the northern Sydney area as part of the FREE study (Fracture Risk Epidemiology in the Elderly), a prospective study of fracture incidence in more than 2000 participants. Here, we report baseline serum 25(OH) vitamin D concentrations in the first 386 participants, determined in partially purified lipid extracts using a competitive protein binding assay.2 The sample comprised 252 women and 134 men (mean ± SE age, 86.7 ± 0.6 v 81.2 ± 0.7 years, respectively; P < 0.001). The mean serum 25(OH)D level was 17 nmol/L (SD, 12) and median serum 25(OH)D level was 15 nmol/L (interquartile range, 9 to 22). Vitamin D deficiency (defined as a serum 25(OH)D concentration < 28 nmol/L) was present in 86% of women and 68% of men. There was no significant difference in serum vitamin D levels between women in nursing homes versus women in hostels, nor between men in nursing homes versus those in hostels. Although serum vitamin D levels were low throughout the year, a small rise was observed in summer (P < 0.01). Length of stay in the residential facility was not a predictor of serum vitamin D level. Mean parathyroid hormone levels were 93 pg/mL (normal range, 12–72 pg/mL) and rose when vitamin D levels dropped below 21 nmol/L, indicating secondary hyperparathyroidism. A number of previous studies have suggested a high prevalence of vitamin D deficiency in older institutionalised Australians in southern States,2-4 but we are unaware of any published studies in Sydney (latitude 33°S). However, as the prevalence of vitamin D deficiency in older people living in the community in Geelong is low,5 our study suggests that factors like confinement indoors is more important than latitude. Given the relationship between vitamin D status and fracture, with more than 72 500 nursing home residents and 60 200 hostel residents in Australia in 1997, our findings indicate that vitamin D deficiency represents a significant public health problem in elderly institutionalised Australians regardless of geographical location. Importantly, this problem could be solved relatively simply by measures such as a short period of daily sunlight exposure or giving moderate doses of vitamin D annually to nursing home and hostel residents.

Philip N Sambrook · Ian D Cameron · Robert G Cumming · Stephen R Lord · Jennifer M Schwarz · Angelika Trube · Lynnette M March

To the Editor: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients with cardiovascular disease, including those taking perhexiline for severe ischaemic heart disease. Elevated serum perhexiline concentrations have been observed during therapy with the SSRIs fluoxetine and paroxetine, which are known to be strong inhibitors of cytochrome P450 2D6, the enzyme system responsible for the hepatic metabolism of perhexiline.1 The Adverse Drug Reactions Advisory Committee has received five reports of a possible interaction between perhexiline and SSRIs, but none of these involved the SSRIs citalopram or fluvoxamine, which are generally considered to be weak inhibitors of cytochrome P450 2D6. I describe here a case of perhexiline toxicity that occurred within 10 days of starting citalopram therapy. An 82-year-old man was admitted to hospital for drainage of a femoral abscess. His medical history included bilateral hip replacements, ischaemic heart disease, hypertension, renal artery stenosis, renal calculi, gout, gastroesophageal reflux disease and prostate cancer. His medications included (daily) aspirin 100 mg, isosorbide mononitrate 120 mg, pravastatin 40 mg, allopurinol 300 mg, celecoxib 200 mg, lorazepam 2 mg, nitrazepam 10 mg; (twice daily) perhexiline 100 mg; and paracetamol and tramadol as needed. On Day 51 after admission the patient underwent first-stage revision of an infected hip implant under general anaesthesia, and on Day 60 citalopram was commenced (10 mg daily for four days, then 20 mg daily). On Day 70, the patient complained of diarrhoea, nausea and dizziness. Citalopram was discontinued but the nausea was slow to settle. After a perhexiline assay on Day 75 revealed a high serum concentration (see Box), the perhexiline dose was reduced to 100 mg daily and the patient's nausea settled. Previous perhexiline concentrations on a dose of 100 mg twice daily had ranged from 0.29 to 0.34 mg/L over a two-year period. Tests of renal and hepatic function were normal throughout the patient's hospital stay. While in hospital, the patient was given celecoxib (a cytochrome P450 2D6 inhibitor) at a constant dose between Days 1 and 95, and meropenem (not a documented cytochrome P450 2D6 inhibitor) between Days 51 and 95. These patterns of administration suggest that neither of these drugs had a significant effect on perhexiline concentration. On the other hand, the laboratory evidence of a marked inhibition of perhexiline metabolism during treatment with citalopram suggests that caution is required when prescribing citalopram (or any other SSRI) for a patient taking perhexiline.2 Serum concentrations (mg/L) of perhexiline and perhexiline metabolite Day 48 Day 75 Day 95 Perhexiline (therapeutic range, 0.15–0.60 mg/L) 0.37 0.82 0.27 Perhexiline metabolite 3.53 0.37 2.22 Ratio of perhexiline to perhexiline metabolite 0.10 2.22 0.12

Karin Nyfort-Hansen

To the Editor: Hydroxymethylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (or statins) are widely prescribed, and any class-specific side effect has the potential to affect many thousands of patients. The statin drugs are well recognised as a cause of mild and usually transient hepatitis.1-3 Cholestatic liver injury has been reported with simvastatin4 and atorvastatin,5 but pravastatin has only been implicated as a cause in one report.6 We report a 64-year-old woman who was twice treated with pravastatin sodium and who, on both occasions, demonstrated cholestasis, which, at its peak, was associated with minimal hepatocellular injury. Our patient presented to the liver clinic of the John Hunter Hospital in 2001 for investigation of abnormal liver function test results. She was taking diltiazem, aspirin, irbesartan plus hydrochlorothiazide, and pravastatin as therapy for hypertension and hyperlipidaemia. She consumed less than 10 g alcohol per week. Liver function tests showed a predominant elevation of alkaline phosphatase and γ-glutamyltransferase, with a minimal rise in alanine and aspartate aminotransferases, a picture consistent with cholestasis rather than hepatocellular disease (see Box). She had started taking pravastatin in the three months preceding her referral, and commented that when she was taking the drug in the previous year she had also had abnormal liver test results. Her liver function test results in 1998 were normal. Two ultrasound examinations of the liver, performed after five months of taking pravastatin in the first period and two months after beginning her second period of therapy, showed normal liver size and echogenicity, and no sign of obstructive liver disease. Tissue antibodies, viral studies for hepatitis viruses, α1-antitrypsin and iron studies were all either normal or negative. Renal function was normal throughout. She had no biochemical evidence of impaired hepatocellular function, and for this reason liver biopsy and endoscopic retrograde cholangiopancreatography were not undertaken. In view of the association the patient made between previously ceasing therapy with the drug (because she felt unwell) and improving liver function, therapy (which was recommenced by the cardiologist for hyperlipidaemia) was again suspended and within two months liver test results improved markedly. We believe that in the absence of other markers of liver disease and with improvement of liver function on both occasions that therapy with pravastatin was suspended, it is likely that this patient has twice developed a cholestatic response to pravastatin. Patient's liver function test results during and after two periods of pravastatin therapy Initial period Second period* Normal range Pravastatin No pravastatin Pravastatin No pravastatin Test Month 0 Month 4 Month 5 Month 6 Month 10 Month 0 Month 1 Month 2 Month 3 Bilirubin (µmol/L) < 20 7 13 5 7 10 11 11 7 9 Alkaline phosphatase (U/L) < 115 230 362 220 213 242 291 347 186 171 γ-Glutamyltransferase (U/L) < 25 259 625 353 231 195 297 463 167 126 Alanine aminotransferase (U/L) < 40 26 85 31 25 28 25 49 16 18 * Commenced seven months after initial episode. Patient's results were normal two years before the initial period.

Robert G Batey · Michelle Harvey

To the Editor: A potentially important, if somewhat crude, means of suicide prevention involves restricting the availability of commonly used methods. In 1967, for example, restrictions on barbiturate prescribing in Australia led to declines in its use for suicide and in overall suicides.1 A crucial concern with this approach is that distressed individuals might use alternative, more lethal, methods. In Britain, there is just such a concern in relation to recent legislation restricting the availability of paracetamol.2 Analysis of the natural experiment investigated by Balit and colleagues3 does not, however, provide useful insights into the impact of paracetamol sales restrictions. Their most consistent finding was that, despite restricted availability for the period studied, paracetamol accounted for about 10% of all contacts with the two poisons information centres in both time periods. In Britain, in 1998, paracetamol purchases from chemists and supermarkets were restricted rather than banned.4 Up to 16 g (32 tablets) may be purchased from pharmacies and 8 g from supermarkets. The aim was not to prevent overdose but to reduce its severity. Presumably, over the periods studied by Balit et al, paracetamol was simply unavailable. As their analysis is based on calls to poisons information centres rather than on the clinical records of people presenting to hospital, they could not assess whether changes in paracetamol availability influenced indicators of severe poisoning — death and liver damage. A decline in the number of severe paracetamol poisonings, without a change in total episodes of paracetamol overdose, might be considered the most important end-point. Attention is drawn to statistically significant rises in calls concerning ibuprofen in one centre and aspirin in the other. The clinical significance of these observations is questionable. Overdoses of ibuprofen are less harmful than paracetamol,5 and the significant rise in aspirin overdose represents an increase from two calls per year to five per year — an increase of only three calls. Of note is the fact that the largest absolute decline in calls related to paracetamol (from 423 per year in 1997–1999 to 370 per year in 2000). Furthermore, as only two time points are compared, it is impossible to determine whether the increases reflect year-on-year changes in use of particular drugs for overdose, as might occur with increased ibuprofen sales. Legislation seeking to influence patterns of harm through changing the availability of drugs which are beneficial when used safely should be monitored carefully.4 Balit et al do not provide convincing evidence concerning the effects of paracetamol sales restrictions on population health.

Corrine R Balit BPharm · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson FRCP(Ed), FRACP · Ian M Whyte MB BS, FRACP

To the Editor: In their recent article,1 Balit et al concluded "restriction of paracetamol-containing products may inadvertently increase poisoning with potentially more toxic agents". As manufacturers of one brand of ibuprofen tablets and the only brand of ibuprofen suspension in Australia, we would like to comment on the article and its conclusion. We understand that the objective of the audit was to determine whether the occurrence of paracetamol and non-paracetamol analgesic deliberate self-poisoning and accidental paediatric poisoning was affected by two periods of recall of paracetamol products. However, our concern is that the article's conclusion — "may inadvertently increase poisoning with potentially more toxic agents" — is not linked to any long term outcomes nor any follow-up regarding ongoing sequelae. This conclusion might give the impression that ibuprofen is more toxic than paracetamol when taken in an overdose situation, whether deliberate or accidental. It might also give the impression that overdoses of ibuprofen leave the patient with ongoing morbidity. In addition, we note that the percentage change in deliberate self-poisonings at both the NSW Poisons Information Centre (PIC) and the Hunter Area Toxicology Service for the periods when paracetamol was restricted, although seemingly large and statistically significant for the PIC, both came from a very low base (0.9% and 0.8% of all calls, respectively).

David Gunnell · Anthea Steans

In reply: There appears to be some misunderstanding about both the conclusions and the methodology of our study.1 We showed that when the availability of one analgesic (paracetamol) decreased, the use of the next most available analgesic increased in deliberate and accidental self-poisonings. We did not look at the relative toxicity of the analgesics, but referred to the published literature on acute paracetamol and ibuprofen overdoses in children, noting that serious complications of acute overdose in children have only been reported with ibuprofen.2-4 Data reported in the study not only included a poisons information centre, but also included data from hospital presentations. The Hunter Area Toxicology Service (HATS) manages all patients with poisoning in the Newcastle region and is based at the Newcastle Mater Misericordiae Hospital. The limitation of the small sample size in the HATS data was discussed in the article, highlighting the fact that, as this was an opportunistic study, it was not possible to increase the sample size. However, the conclusions drawn were based on two different data sets, with a much larger sample size for the NSW Poisons Information Centre data. Overdose is a significant public health problem that requires appropriate post-marketing vigilance. For drugs that are commonly taken in overdose, it is important to take advantage of opportunities to assess the potential effect of any change in availability.

David Gunnell

To the Editor: We read with interest the case report of Ward and colleagues, describing methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin in a patient being treated for lower-limb ischaemia.1 We conclude that this antibiotic resistance may not have developed if the patient had been treated with conventional vascular therapy. The patient had diabetes, was haemodialysis-dependent and continued to smoke. Bilateral lower-limb ischaemia in such a patient is an indication for early vascular assessment, including angiography, debridement of non-viable tissue and, if possible, revascularisation. The option of early below-knee amputation should always be considered for such a patient. Broad-spectrum antibiotics administered over a long period to patients with ischaemic tissue can provide the ideal medium for development of multiresistant organisms. In this patient, 41 days of chronic infection, combined with the decreasing nutritional status typical of haemodialysis patients, contributed to the breakdown of both below-knee amputation sites and the ongoing sepsis. The difficult decision to preserve or amputate an ischaemic limb is best made by a vascular surgeon in consultation with the patient. Amputation should not be seen as treatment failure but as another stage of vascular disease. Early amputation preserves the physical condition and nutrition of patients and allows earlier transfer to rehabilitation units, with an improved result.2

Anthony J Grabs · Reginald SA Lord

To the Editor: The Lipid management guidelines — 2001 supplement1 is no doubt full of cardiovascular wisdom. Unfortunately, the authors appear oblivious to the fact that people are more than just cardiovascular systems. I found no mention of the risks of violent deaths associated with low cholesterol levels, which in some studies have been found to offset the decreased cardiovascular mortality benefits.2 In 1995, Engstrom et al neatly reviewed the relevant issues for those interested in populations of whole people. They cite studies which found low cholesterol levels to be associated with homicidal offenders with habitual violent tendencies when under the influence of alcohol, boys with aggressive conduct disorder, and criminals with antisocial personality, as well as with increased depressive symptoms in men aged 50–89 years. Further, an evaluation of six primary prevention trials found a significant increase in violent deaths in groups receiving interventions to reduce serum cholesterol levels.2 Engstrom et al also reviewed studies which found increased aggression in cynomolgus monkeys fed a low-fat diet. This appeared related to reduced serotonin activity, as serotonin is widely known to reduce aggression. In fairness, Engstrom and colleagues also cited studies which have not found an association between low cholesterol levels and aggression. If the increase in violent deaths associated with changing the dietary habits of whole populations turns out to be more than a red herring, the ethical and financial implications will be staggering. This evidence is not so conclusive as to have made me change my own relatively low-fat diet, but they do make me wonder if my irritation about the oversight in the Lipid management guidelines — 20011 might have something to do with my low fat intake!

Christopher H Cantor