Monitoring TURP

947

because in several patients increasing from 3 x4 mg to 3 x 8 mg daily seemed to improve the antiemetic effect. PCP is well described in patients receiving intensive

chemotherapy including prolonged high-dose steroids,2 usually

as

part of the management of high-grade lymphomas, and cotrimoxazole prophylaxis is a routine part of treatment in these

patients. However, PCP as a complication of antiemetic therapy is less well recognised. EMA/CO results in consistent but manageable

myelosuppression and since the appearance of 2 cases of PCP-like infections coincided with an increase in the dose of dexamethasone used we think it likely that these two episodes were due to the high steroid exposure resulting from the regular weekly chemotherapy. In the two studies recently reported chemotherapy was administered with 14 or 21 day intervals, providing an average dose of 24 and 18 mg dexamethasone, respectively, per week compared with 48 mg per week for patients receiving EMA/CO. When intensive weekly chemotherapy regimens of this type are being used there is thus a strong case for using non-steroid antiemetic prophylaxis (eg, domperidone, prochloperazine,

PDGF.6 This might enhance the effect of PDGF released from platelet plugs both in the clubbed finger and the arterial wall. Since platelet changes are determined in the megakaryocyte a study of the biology of this cell might help to explain many vascular changes, including those in clubbing.

J. F. M. is Bntish Heart Foundation professor of Cardiovascular Science. Department of Medicine, King’s College School of Medicine and Dentistry, London SE5 9PJ, UK University Department of

2. 3.

5.

London W6 8RF, UK

1. Newlands ES, Bagshawe

KD, Begent RHJ, Rustin GJS, Holden L. Results with the EMA/CO regimen in high nsk gestational trophoblastic rumours, 1979-1989. Br J Obstet Gynaecol 1991; 98: 550-57. 2. Browne M, Hubbard SM, Longo DL, et al. Excess prevalence of Pneumocystis carinii pneumonia in lymphoma patients receiving chemotherapy Ann Intern Med 1986; 104: 338-44.

Finger clubbing SIR,-For finger clubbing has been a sign without a pathophysiological meaning. Fox and colleagues’ finding (Aug 3, p 313) that the capillaries in clubbed fmgers contain material that is antigenically positive for platelets supports Dickinson and Martin’s1 hypothesis that platelet-derived growth factor (PDGF) liberated from megakaryocytes and platelet clumps was responsible for the cellular hyperplasia. This has several implications. Firstly, clubbing has become a sign of a change in the megakaryocyte-platelet axis. Our data show that megakaryocytes are larger in patients with carcinoma of the lung than in controls.2 Platelets have no nuclei and only residual amounts of mRNA. Platelet PDGF is determined by megakaryocyte mRNA for PDGFTherefore, clubbing might be a sign of altered synthetic capacity by megakaryocytes in carcinoma of the lung (and other diseases where it occurs). Secondly, Fox and colleagues’ finding is indirect evidence that platelet production results from fragmentation of megakaryocyte cytoplasm in the pulmonary circulation.’ In clubbing one could postulate that activated megakaryocytes and megakaryocyte cytoplasmic particles pass from the pulmonary arterial circulation into the systemic circulation via abnormal circulation around lung tumours or chronic pulmonary inflammation. In cyanotic congenital heart disease, this may occur via right to left shunts. Thirdly, their finding might throw some light on the role of platelets in atherogenesis. Atherosclerosis is a proliferative disease of the vessel wall in which PDGF has been implicated. Evidence has been presented that the initial arterial wall proliferation is secondary to the occlusion by platelets of vasa vasorum in the vessel wall. These vessels are the same size as those Fox and colleagues found to contain platelets in clubbing. If release of PDGF from platelets in such vessels can cause cellular hyperplasia in finger clubbing, then analogous changes might occur in the arterial wall secondary to release of PDGF from platelets occluding the microcirculation of the vessel wall. Hypoxia of tissue distal to occlusion of the microcirculation with platelets will probably arise. Exposure of cultured cells to hypoxia can cause an increase in their production of mRNA for several centuries

CJ, Martin JF. Megakaryocytes and platelet clumps as the course of finger clubbing. Lancet 1987; ii: 1434-35. Knstensen SD, Bath PMW, Gladwin AM, Thorpe JAC, Martin JF. Increased megakaryocyte size in bronchial carcinoma Eur J Clin Invest 1989; 19: A5. Gladwin AM, Carrier MJ, Beesley JE, Lelchuk R, Hancock, Martin JF. Identification of mRNA for PDGF B-chain in human megakarycoytes isolated using a novel immunomagnetic separation method. Br JHaematol 1990; 76: 333-39. Martin JF, Levine RF. Evidence in favour of the lungs and against the bone marrow as the site of platelet production. In: Page CP, ed. The platelet in health and disease. Oxford: Blackwell Scientific Publications, 1991: 1-9. Martin JF, Booth RG, Moncada S. Arterial wall hypoxia following thrombosis of the vasa vasorum is an initial lesion in atherosclerosis Eur J Clin Invest 1991; 21:

1. Dickinson

4.

Department of Medical Oncology, Charing Cross Hospital,

STEEN D. KRISTENSEN

Aarhus, Denmark

ondansetron)

KIERAN MCCORMACK GORDON J. S. RUSTIN DAVID B. SMITH E. S. NEWLANDS

Cardiology,

Skejby Hospital,

and adding dexamethasone only if the emesis is very difficult to control. Prophylactic co-trimoxazole in conjunction with dexamethasone may also be considered but is not used with EMA/CO because of the potential interaction with methotrexate.

or

JOHN F. MARTIN

355-59. 6. Sakanassen KS, Powell JS, Raines EW, Ross R. Selective expression of platelet denved growth factor B-chain mRNA by human endothelial cells and by human peripheral blood monocytes but not by smooth muscle cells. Thromb Haemost 1987; 58: 261.

Alfuzosin for

benign prostatic hypertrophy

SIR,-Mr C:happle (July 20, p 182), commenting on our report (June 15, p 1457) of alfuzosin, a novel a1-blocker, in benign prostatic hypertrophy (BPH), records his own experience with prazosin. There is now little doubt that al-blockade with several agents such as alfuzosin, doxazosin, indoramin, prazosin, terazosin, and YM 617, can afford measurable relief to many patients with BPH: however, xl-blockers do not seem to reverse permanently the pathophysiology of BPH. It has been suggested that about 40 per 100 patients who do not need surgery can be maintained indefinitely on medical treatment; because their condition is not progressive, such patients may reach a certain stage, thereafter remaining stable.l,2. Our study only partly answered the questions of long-term treatment with an oc,-blocker, since an improvement in voiding symptoms was seen after 6 months of alfuzosin. In fact, this improvement was maintained in patients who continued alfuzosin in an open study, up to 12 months (n =121 ), 18 months (n=56), 24 months (n = 45), and 30 months (n= 19) (unpublished data), without the development of tolerance or side-effects due to long-term administration. Since candidates for

in BPH may need treatment for many years, the response to and compliance with such drugs remain critical issues; furthermore, the notion of long-term treatment in BPH has to be defmed.

crl-blockade

long-term

Service of Urology, Hôpital de Bicêtre, 94270 Kremlin-Bicêtre, France

H. BENSADOUN

Synthelabo Recherche, Paris

M. C. DELAUCHE-CAVALLIER P. ATTALI

A. JARDIN

1. Caine M. Alpha-adrenergic blocker for the treatment of benign prostatic hyperplasia.

Urol Clin North Am 1990; 17: 641-49. 2. Ball AJ, Feneley RCL, Abrams PH. The Br J Urol 1981; 53: 613-16.

natural history of untreated "prostatism".

Monitoring TURP SIR,-In your Sept 7 editorial you note that none of the methods used to detect irrigation fluid absorption-from use of radioisotopes to monitoring changes in serum sodium-have found general favour in urological practice. The breath alcohol method correlates well with changes in serum sodium, but neither detects acute perivesical absorption. Continuous sodium monitoring with an intravenously placed electrode is technically insufficiently reliable.’ New portable blood gas and electrolyte analysers giving results in 90 s with 250 III whole blood samples can be used in operating theatres and allow the convenient measurement of whole blood sodium

948

changes. Installation of such machines in theatres would encourage frequent intraoperative sodium sampling to become routine and, together with volumetric irrigation fluid balance, would keep patient risk to a minimum. Department of Chemical Pathology, Beaumont Hospital,

W. P. TORMEY

Dublin 9, Ireland 1. Watkins-Pitchford

JM, Payne SR, Rennie CD, Riddle PR. Hyponatraemia during practical prevention. Br J Urol 1984; 56: 676-78.

transurethral resection: its

Compatibility of clozapine and chloroquine SiR,—Dr Gerson and colleagues (July 27, p 262) draw attention to possible clozapine incompatibilities. Some fatal interactions between the dibenzepine neuroleptic clozapine and antiypretics/analgesics have led to much caution and safeguards in the use of this drug. Because of restrictions on use, data on the compatibility of clozapine with other drugs are not readily available. With respect to possible interactions of clozapine and antimalarial agents, no information could be gained from the producer or from toxicological centres or institutions monitoring drug interactions on a large scale. A male caucasian patient, now aged 30 years, was first admitted in 1977 for psychiatric hospital care and was diagnosed as having schizoaffective psychosis. Since 1977 he has been on clozapine, after severe extrapyramidal symptoms developed with conventional neuroleptics. Since then he has had three more admissions to hospital despite clozapine maintenance and additional antidepressive therapy. Otherwise the patient has been active, completing various qualifications and doing well in his job. However, a slight residual syndrome remains. Clozapine had always been tolerated well, with doses ranging between 12.5 and 275 mg daily, with normal white blood cell (WBC) and platelet counts and hepatic function. On recovery from the last phase of his illness in 1988 the patient resumed work and planned to visit Brazil. Because antimalarial prophylaxis was indicated, he was told about the possibility of a drug interation. He decided to undertake this trip (from Dec 8, 1988, to Jan 7, 1989) but on his own volition reduced polyvalent antimalarial therapy to diphosphate of chloroquine only. He was advised to have weekly blood counts while taking chloroquine in Brazil, but he did so only once. The combination of the two drugs was well tolerated. Even after close questioning the patient reported no adverse reactions. Baseline and controls showed

an

average WBC count of 7-23

x

10/1

and

platelets 201-6 x 109/1 between Feb 2, 1988, and May 24, 1989 (7 blood counts). Between Dec 1, 1988, and Jan 2, 1989, chloroquine intake was 23g, the daily clozapine dose being 25 mg. In this one patient, control testing and follow-up showed that the two compounds potentially noxious to bone-marrow function were well tolerated. Although the clozapine dose was fairly low, the continuous administration of the drug since 1977 is an additional factor to be taken into account--doses in that period ranged from 12-5 to 275 mg daily. Psychiatry Department I, Landes-Nervenkrankenhaus Valduna, A-6830 Rankweil, Austria

PETER KONIG A. KÜNZ

Pesticide intoxication and chronic CNS effects SIR,-Dr Rosenstock and colleagues’ (July 27, p 223) statement, "We conclude that even single episodes of clinically significant organophosphate intoxication are associated with a persistent decline in neuropsychological functioning", should be accepted with caution. Their study included only 36 patients, with a question about single or multiple poisons (eg, solvent exposure). The case/control ratio was 1/1 instead of 1/2 or 1/3. Furthermore, both cases and controls had episodes of pesticide intoxication without medical attention or admission to hospital. The statistical significance of the results is uncertain. In the statistical analysis, the role of the point estimate, the confidence interval (CI), and the p-value should all be taken into account. Is there really an importance of a lower CI limit of 06 with a point estimate of only 1 5, as in the visual memory test, or a lower

CI limit of - 2with a point estimate of 32, as in the motor reaction time? Such lower limits indicate no significance and inconclusive results. The difficulty of interpreting these types of results has been pointed out by others,l as have the drawbacks of neurobehavioural testing procedures in this type of study. If one recognises these difficulties, Rosenstock and colleagues’ conclusion is risky. Their results may point out a tendency to have neuropsychological problems after organophosphate intoxication, but the data certainly are not compelling. One might as easily conclude that the difference between the cases and controls is the fact of admission to hospital and possible adverse consequences of treatment (atropine without pralidoxime), since the controls were defmed as occupationally exposed to pesticides with episodes of pesticide intoxication but no hospital admission. Department of Family Medicine, Agromedicine Program, Medical University of South Carolina, Charleston, South Carolina 29407, USA

STANLEY H. SCHUMAN

Department of Agricultural Chemistry, Oregon State University, Corvallis, Oregon

SHELDON L. WAGNER

1. Braitman LE. Confidence intervals assess both clinical significance and statistical significance. Ann Intern Med 1991, 114: 515-17 2. Matarazzo JD Psychological assessment versus psychological testing. Am Psychol

1990, 45: 999-1017.

*** This letter has been shown to Dr Rosenstock and her colleagues, whose reply follows.-ED. L. Sj[R,—Dr Schuman and Dr Wagner raise concerns about our study design and conclusions. We are confused by their comments about statistical significance, including sample size and matching ratios. While a priori attention to components of calculating study power is very important, these considerations are irrelevant when, as in our study, results indicate consistent, statistically significant differences. Had we claimed clinical significance on the basis of non-statistically significant trends, or had we claimed no effect, with our admittedly small sample size, then study power would be an

important question. We agree with Schuman and Wagner that the point estimate, the confidence interval (CI), and the p-value are important in consideration of statistical significance. To this list we add consistency of fmdings. As we indicate, although worse performance was observed among the previously poisoned cohort for all neuropsychological outcomes, it was significantly worse (p < 001; 95 % CI of point estimate excluding zero) for only 9 of 14 subtests. For example, we do not claim that differences in motor reaction time differ (95% CI = - 2-0, 66) but in the same table we denote significant differences in visual memory (the point estimate is 1-7 and not 1-5, as Schuman and Wagner state, CI=0’6, 2-5). Whether the roughly 25% worse performance on this latter test is clinically significant, however, is an important issue and was not addressed by our study design. We did observe a more than 10% difference between cohort mean values in 12 of 14 subtests studied, and a more than 20% difference in 7 of these subtests. We encourage further study to answer remaining important questions about the effects of specific pesticides, the contribution of chronic versus acute overexposures, and the clinical significance in individuals of altered neuropsychological functioning. With respect to effects of therapy, there is no evidence that atropine, when given appropriately to reverse cholinesterase inhibition of acute organophosphate poisoning, is associated with acute or chronic central-nervous-system disturbance. Even if it were, atropine remains the mainstay of treatment and is potentially life-saving. Pralidoxime is also an indicated concomitant treatment, but it is expensive and not readily available in most developing countries. The effects of atropine are not only unlikely to have contributed to our fmdings, but any attempts to untangle this treatment from the poisoning would probably prove not only impossible but also unsound. We too believe that the results of any one epidemiological study should be interpreted with caution. We find increasing evidence-experimental, clinical, and epidemiological-of the risk for chronic

neurological sequelae after substantial organophosphate pesticide