1536

effects of nifedipine tablets would be expected to be reduced by this time after dose. The effects of the treatment combination of nifedipine and atenolol on the ECG exercise response may have been underestimated. Second, since the drug was given only twice daily, the failure of the study to detect a difference in angina frequency, GTN intake, or Holter results with the combination of nifedipine and beta-blocker compared with beta-blocker alone may have been the result of inadequate dosing frequency of nifedipine. Akhras and Jackson could test this by looking at the timing of episodes of angina, GTN intake, and ECG abnormalities on Holter monitoring in relation to the time of the last treatment. In our view, therefore, Akhras and Jackson should have given more thought to the pharmacokinetics of nifedipine tablets. They are wrong to conclude that nifedipine tablets are not additive to beta-blockade in the treatment of angina without having studied this formulation of nifedipine at its peak effect. Blood Pressure Unit, Department of Medicine, St George’s Hospital Medical School, London SW17 0RE, UK 1

DONALD R. J. SINGER FRANCESCO P. CAPPUCCIO GRAHAM A. MACGREGOR

Cappuccio FP, Markandu ND, Tucker FA, MacGregor GA. Dose response and length of action of nifedipine capsules and tablets in patients with essential hypertension: a randomised crossover study. Eur J Clin Pharmacol 1986; 30:

Dr Orlander reports very small usage of triple therapy for angina pectoris, which is both interesting and surprising. We believe there is a far greater use of triple therapy in the UK. His patients on triple therapy are clearly different from ours who were experiencing stable angina pectoris, and our findings should not be extrapolated inappropriately to those who have initially been managed for unstable angina. All our patients were taking daily aspirin. In any trial where subjective variables play a major part in the assessment it is important to obtain as much objective information as possible. Patients can experience less angina because they are doing less and are less well rather than experiencing pharmacological benefit. Exercise ability therefore assumes an important role in evaluation of therapeutic efficacy. A clear-cut benefit from triple over double or monotherapy should have shown itself in 12 stable patients. With no clear benefit demonstrated in our 18 patients any further difference is likely to be only marginal. Cardiac

Department, Guy’s Hospital,

Prevention and management of ovarian

hyperstimulation syndrome

723-25. 2

Singer DRJ, Markandu ND, Shore AC, MacGregor GA. Captopnl and nifedipine in combination for moderate to severe essential hypertension,. Hypertension 1987; 9: 629-33.

SIR,-I share the interests of Dr Akhras and Dr Jackson in the potential clinical problem of polypharmacy for angina. In an attempt to design a similar study, in which we had hoped to reduce the number of medications in patients on triple therapy (betablocker, calcium channel blocker, nitrate) for angina, the medication profiles of all outpatients at the Boston VA Medical Center were assessed. Three geographically separate outpatient clinics use a computerised central pharmacy. Only 79 (01%) of 75 868 patients were on triple therapy. The charts of 10 of these patients (all men) were reviewed. The median age of this group was 69. In 9 cases the time of initiation and/or indication for triple therapy was clearly recorded. 4 had started on triple therapy within the previous 6 months, and the indication in 4 patients was hospital admission for unstable angina or acute myocardial infarction. It seemed that patients could not realistically and ethically be asked to participate in a study to reduce their cardiac medications and the potential for decreased triple therapy in this institution is remote.

How were Akhras and Jackson’s patients recruited and were they using aspirin? I think that these workers put too much emphasis on the exercise test as an endpoint. The difference in mean number of weekly angina attacks, which favoured all the multidrug regimens, may be more important clinically. The difference between atenolol alone and atenolol plus nifedipine is a one-third reduction in angina episodes, and this difference might have been significant had it been sustained in a larger number of patients. VA Medical Centre, Boston, Massachusetts 02130, USA

*** These letters have been shown whose reply follows.-ED L.

JAY D. ORLANDER to

Dr

Jackson and Dr Akhras,

SiR,—Before initiating our study we confirmed the clinical efficacy of nifedipine retard in patients with stable angina pectoris, using both subjective and objective variables (ref 4 in our paper). We demonstrated objective benefits on exercise testing 10-12 h after dosage (ie, at the trough point). Exercise testing earlier might have been expected to yield a greater benefit from the atenolol/ nifedipine combination rather than less. Dr Singer and colleagues make the mistake of extending pharmacokinetic studies in hypertension to angina without taking into account clinical data. We provided objective evidence for the rationale of our regimens and are confident of the accuracy of our fmdings which have the additional value of being relevant to clinical practice.

GRAHAM JACKSON FAWAZ AKHRAS

London SE1 9RT, UK

SIR,-We welcome

Nov

2 editorial on ovarian but would like to present an hyperstimulation syndrome (OHSS), alternative approach to this complication of treatment with fertility your

drugs. We use an in-vitro fertilisation (IVF) treatment protocol that includes pituitary suppression with buserelin, a fixed daily dose (1-5-6 ampoules) of human menopausal gonadotropins (hMG), human chorionic gonadotropin administration (hCG, 10 000 units) at a leading follicle diameter of 17-22 mm and transvaginal, ultrasound-directed, follicle aspiration (TV UDFA). We use vaginal ultrasonography alone to monitor the number and size of follicles that

develop;

most

patients

have

only

two scans

before

oocyte collection. Since January, 1990, we have not measured oestrogen concentrations in patients receiving hMG, nor have we cancelled any IVF treatment cycle because of possible OHSS. We believe that patients with a large number of follicles ( > 25) are at risk of OHSS but will not come to serious harm if they are identified, receive hCG at a small leading follicle size, and have every follicle aspirated at egg collection; they should also be told to return for review if they have abdominal swelling and be managed actively if their condition worsens. Between Jan 1, 1990, and Oct l, 1991, we initiated 1330 routine IVF treatment cycles; 14 patients (1-1%) required hospital admission because of severe OHSS, but none had thromboembolic complications. The median number of follicles in these cycles was 15 (range 0-78); in 20% of cycles there were 26 or more follicles, and 93% of the patients who were admitted were in this group. The pregnancy rate per oocyte retrieval in patients with 26 or more follicles was 28% whereas the overall rate was 22%. In another 157 patients who received a fixed protocol of buserelin and hMG before diagnostic laparoscopy and laparoscopic egg collection in the same period, the frequency of severe OHSS requiring hospital admission was significantly higher (4-5% vs 1-1 %, X2 test p < 0’001) than in the group who had TV UDFA. This higher frequency might be due to the greater tendency for follicles deep in the ovary to escape aspiration with laparoscopic collection than with TV UDFA. Alternatively, hCG might have been given at a larger leading follicle size in some patients than would have been the case with an

individually-tailored protocol. Aspiration seems to protect against OHSS by removing some follicular component, probably granulosa cells. If follicles are flushed as well as aspirated, removal of granulosa cells should be more complete and protection should be greater than with aspiration alone. We gave up routine flushing during TV UDFA in December, 1990, because we found it did not substantially improve oocyte recovery rates. The frequency of OHSS requiring hospital admission was 0-6% (4/720) in 1990 but increased to 1-6% (10/610) in 1991. We are prospectively investigating follicle flushing to protect against OHSS.

1537

You did

not

emphasise

the

importance

of

paracentesis in

management of established severe OHSS. We admit patients with OHSS for intravenous fluid therapy (crystalloid solutions only) if they complain of nausea and vomiting, have tense ascites, or their packed cell volume is greater than 45%. Rehydration improves urine output and reverses haemoconcentration (thereby reducing the risk of thrombosis) but increases ascites. We now do paracentesis early, by the transvaginal route, with TV UDFA equipment. Our experience with more aggressive transvaginal paracentesis has been the same as that reported by Aboulghar et al:l it not only relieves symptoms of tense ascites immediately, but it also seems to be followed by diuresis and to accelerate disease resolution. Those at risk of an exaggerated response to hMG should be treated with the lowest possible dose, but they are not always identified in advance. Even with the most careful adjustment of hMG dosage some of these patients tend to respond in all or nothing fashion. It is essential to distinguish between ovulation induction cycles, in which follicles are allowed to rupture, and superovulation cycles, in which follicles are aspirated and oocytes collected. When many follicles grow, ovulation induction cycles should be cancelled, but superovulation cycles can be allowed to proceed provided that all follicles are aspirated and the other measures that we have outlined are taken.

JOHN WATERSTONE Assisted

Conception Unit, King’s College School of Medicine and Dentistry, London SE5 8RX, UK

STEPHEN BENNETT RODRIGO RIBEIRO RUTH CURSON JOHN PARSONS

MA, Mansour RT, Serour GI, Amin Y. Ultrasonically guided vaginal aspiration of ascites in the treatment of severe ovarian hyperstimulation syndrome. Fertil Steril 1990; 53: 933.

1. Aboulghar

Innsbruck coma scale SIR,-There is much confusion among intensive care physicians and nurses about the correlation between dilated pupils and brain death. In their article on predicting non-survival after trauma with the Innsbruck coma scale Dr Benzer and colleagues (Oct 19, p 977) attribute a score of 0 to completely dilated pupils and of 1 to dilated pupils. This should be reversed because completely dilated pupils (mydriasis) are evidence of preserved sympathetic outflow and/or third cranial nerve dysfunction, and are incompatible with a diagnosis of brain death. The pupils in brain death are in the mid-position (4-6 mm diameter) and unreactive to light. This concept2 is apparently not appreciated by many physicians and nurses,3 and this may lead to premature interruption of resuscitation attempts. Intensive Care Unit,

Ospedale Civico, CH 6900 Lugano, Switzerland

Attempts at resuscitation often include the administration of high doses of catecholamines. Because these drugs cause the pupils to dilate, this dilatation must be excluded as a diagnostic criterion. The abandonment of resuscitation attempts should therefore not be determined by pupil dilatation, but, when possible, by other, more reliable indices such as irreversible circulatory failure and

electroencephalographical findings. A. BENZER G. MITTERSCHIFFTHALER

University Clinic for Anaesthesia and Intensive Medicine, A-6020 Innsbruck, Austria

M. MAROSI G. LUEF F. PÜHRINGER K. DE LA RENOTIERE H. LEHNER E. SCHMUTZHARD

SIR,-Dr Benzer and colleagues emphasise the value of the Innsbruck coma scale, which accurately predicted non-survival in the first 21 days in the limited patient group with scores of 0 or 1 out of a total of 21. Of major importance, however, are patients with longer life expectancy. Moreover, patients in the state of general anaesthesia are not accessible for coma scale rating. The management of these patients requires early decisions about intensive care treatment and prognostic indices about the usefulness of long term neurorehabilitation. Modem imaging methods are mandatory, permitting direct morphological assessment of the extent, location, and nature of brain damage. Since the superiority of magnetic resonance imaging (MRI) in neurological applications is well established,’ we used it in the work-up of 150 patients with severe closed head injury. We found an excellent correlation between lesion pattern and neurological deficit. MRI proved to be more sensitive than computed tomography in the detection of parenchymal lesions in all stages of traumatic brain diseased The Innsbruck coma scale is of great value in mass accidents, when a preselection of trauma victims has to be made. In daily practice, however, individual therapeutic decisions cannot be based solely on clinical ratings. To improve the clinical (and economical) management of severe brain trauma, evaluation of sustained brain damage by MRI and improved clinical assessment by coma scales are

complementary.

Department of Magnetic Resonance Imaging and Spectroscopy, University Hospital, A-6020 Innsbruck, Austria

GÜNTHER BIRBAMER WERNER JUDMAIER STEPHAN FELBER WOLFGANG BUCHBERGER FRANZ AICHNER

1. Molyneux AJ. Computed tomography and radiation doses. Lancet 1991; 337: 1164. 2. Birbamer G, Aichner F, Kampfl A, Felber S, Luz G, Gerstenbrand F. MR-Imaging of inner cerebral trauma. Abstract: 8th Annual congress of the European Society for Magnetic Resonance in Medicine and Biology, Zurich, Apr 18-21; 1991.

F. DE’ CLARI

Indoor radon and childhood 1. Smith MC, Bleck TP. Techniques for determining brain death. J Crit Illness 1989; 4: 67-73. 2. Plum F, Posner JB. The diagnosis of stupor and coma. 3rd edition. Philadelphia: FA Davis, 1980: 317. 3. Bleck TP. Dilated pupils and brain death. Ann Intern Med 1990; 112: 632.

*** This letter has been shown to Dr Benzer and colleagues, whose

reply follows.-ED. L. SIR,-Dr de’Clari’s comments are representative of a wide body of opinion among clinicians. A coma scale, by definition, can never by used to determine death; it measures the degree of coma and can be used only on the living. de’Clari’s arugment includes a basic misinterpretation if he equates completely dilated pupils (0 points) in the Innsbruck coma scale with the diagnosis of brain death. The purpose of our study was not the determination of brain death with a clinical scale but an evaluation of the scale as it related to the survival of trauma victims within 21 days of injury. We agree that dilated pupils alone are no reason to abandon resuscitation.

cancer

SIR,-Henshaw and colleagues have reported a significant correlation between mean indoor radon concentrations and the international incidence of all childhood cancers.1 However, the National Radiological Protection Board (NRPB) has demonstrated wide variation in indoor radon concentrations in different parts of the UK and even from house to neighbouring housed so average national levels are meaningless when considering radon in the aetiology of cancer. We have done a case-control study measuring indoor radon concentrations over the same 3-month period in the bedroom and living room of children in the Wessex health region. The cases comprised children with cancer diagnosed within the preceding 3 years, 45 % of whom had acute lymphoblastic leukaemia. Controls were matched for age and area of residence. Cases who had moved house since one year prior to diagnosis and controls who had moved house within the last year were not recruited. Radon detectors were supplied and processed by NRPB and readings were seasonally adjusted. The measurements for the two

Prevention and management of ovarian hyperstimulation syndrome.

1536 effects of nifedipine tablets would be expected to be reduced by this time after dose. The effects of the treatment combination of nifedipine an...
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