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Unfriendly takeover SiR,—The commentary by Dr Andrew Herxheimer (March 21, 732) on the evolution of the Pharmaceuticals Unit (PHA) in the European regional office of WHO (WHO/EURO) underlines a p

concern that is shared by many of those who have worked closely with PHA as either national representatives or individuals. We were recently (November, 1991) advisers two"Meeting to discuss reorientation of the Pharmaceuticals Programme" at WHO/EURO. The discussions focused on the future of the PHA and its relation with the Quality of Care and Technologies assessment unit. Our perception was that WHO/EURO is facing major economic and strategic difficulties. The document developed during the meeting and formally approved by the director of WHO/EURO included a clear plea to maintain high competence at PHA, both clinical pharmacological and pharmaceutical. A welldefined agenda for action was established, which welcomed a broader interplay between the two units whenever possible. As external advisers, we felt that organisational changes should not interfere with the professional integrity of PHA activities. The intention to broaden the perspectives of its activities, interventions, and evaluations beyond drug-based ones was agreed, and shortterm as well as long-term strategies were indicated. No doubt the heavy pressures on WHO/EURO to assist emergencies in Eastern and Central Europe have diverted and confounded longer term priorities, such as education and research. In our opinion, one of the crucial roles of WHO/EURO is to stimulate development of Europe-wide collaboration. Hence the urgent need to fill the post of regional adviser to pharmaceuticals and to provide auxiliary staff and resources. We believe it unlikely that WHO/EURO can solve the present drug emergency unless its emphasis shifts to a scientifically based clinical pharmacological and epidemiological approach. This change is probably the only way to ensure that appropriate advice is given and to facilitate communication to develop reliable reference groups for promoting sound national drug policies.

Institute of Pharmacological Research "Mario Negri", 20157 Milan, Italy

GIANNI TOGNONI P. K. M. LUNDE

Statistical correction for measurement

imprecision SIR,-Your recent editorial (March 7, p 587) emphasised that imprecise measurement of a risk factor tends to dilute the observed relation between that risk factor and the risk of a disease; this notion has also been discussed by MacMahon and coworkers.1 They proposed that a statistical correction for the "regression dilution bias" should be included in the presentation of data from prospective epidemiological studies. Phillips and Davey Smith2 have noted that statistical control for a confounding factor is not perfect when there is measurement imprecision in the confounder. They have presented a method of statistical correction in a multivariate modeJ.2 Neither MacMahon et al nor Phillips and Davey Smith make a distinction between the measurement imprecision and the true (biological or behavioural) intrasubject variability over time. Both of these sources of intrasubject variation reduce the correlation between a single measurement of a risk factor and the frequency of that risk factor in a cohort. Measurement imprecision can be assessed by short-term repeat measurements. Remeasurements of a risk factor after several years are influenced by both measurement imprecision and true intrasubject variability, which is dependent on the tracking of that risk factor. While statistical correction for measurement imprecision may be warranted, statistical adjustment of the relation between a risk factor and the risk of a disease (eg, in relative risk) may be questionable. If a risk factor truly varies in an individual over time, the probability of disease associated with that risk factor (pathophysiological impact) may also vary over time, or be less than if the risk factor remained constant. Theoretically, this could be the case for blood pressure and serum triglycerides in coronary heart disease. Both blood pressure and blood triglycerides vary in a circadian pattern, as well as seasonally and over the life-span of an

individual. Blood pressure varies according to physical strain and reactivity to emotional stimuli. Blood triglyceride concentrations, and to some extent blood pressure, also varies according to the fasting state of an individual. Data from the seven countries study suggest that changes in blood pressure might increase the risk of coronary heart disease, even when allowing for a given blood pressureIf this were true, then a correction based on the intrasubject variability of blood pressure could erroneously exaggerate the strength of association between blood pressure and risk. Studies with repetitive measurements of blood lipids over time should investigate the impact of the variability of lipids on the risk of coronary heart disease. I suggest that both the assessment of true intrasubject variability and the measurement imprecision by means of short and long term repeat measurements should be a part of all epidemiological studies, and that a statistical correction in both bivariate and multivariate analysis should be applied for measurement imprecision, but only with great caution for the true intraindividual variability. Research Institute of Public Health,

University of Kuopio, Box 1627, 70211 Kuopio, Finland

JUKKA T. SALONEN

1. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765-74. 2. Phillips AN, Davey Smith G. How independent are "independent" effects? Relative risk estimation when correlated exposures are measured imprecisely. J Clin Epidemol 1991; 44: 1223-31. 3. Farchi G, Capocaccia R, Verdecchia A, Menotti A, Keys A. Risk factor changes and coronary heart disease in an observational study. Int J Epidemiol 1981; 10: 31-40.

Retractor

design and the lingual

nerve

SiR,—Mrs Brahams (March 28, p 801) draws attention to an important complication of one of the most frequent operations in oral surgery-removal of wisdom teeth. Although there may be room for improvement in retractor design to prevent lingual nerve damage, the number of patients affected might be reduced by adhering more closely to agreed criteria for surgical intervention. Indications for removal of wisdom teeth have been the subject of a National Institutes of Health (NIH) consensus conference:’ these are, recurrent pericoronitis, follicular cyst, caries not amenable to restorative procedures, internal or external resorption, and periodontal disease. However, no prospective studies have identified the proportion of lower wisdom teeth actually removed where surgery, according to these criteria, was not indicated. We therefore evaluated treatment decisions made by six oral surgeons in National Health Service hospitals for 28 consecutive male and 44 female patients, aged 15-44 years (mean 25), referred for lower wisdom tooth assessment. Patients were interviewed and examined by an independent assessor immediately after treatment decisions had been made. The assessor recorded the presence or absence of local disease on standard proformas, and treatment decisions were then evaluated by a panel of two further independent assessors, according to NIH consensus criteria. Of the 139 wisdom teeth examined, 56 were erupted, 78 partly erupted, and 5 fully erupted. 29 patients had been scheduled for surgery under general anaesthesia and 37 under local anaesthesia; 6 patients were not scheduled for surgery. 53 teeth did not meet criteria for surgery, of which 39 (74%) had nevertheless been scheduled for removal; if a single episode of pericoronitis is regarded as an indication for removal, then a further 12 wisdom teeth scheduled for surgery met consensus criteria and the remaining 27 did not. These findings suggest that of the 125 teeth that were scheduled for removal, 22% could have been left in situ. 14 patients who were scheduled to have both lower wisdom teeth removed under local anaesthesia (surgery usually done at two separate outpatient visits) could, if criteria had been adhered to more strictly, have avoided the removal of disease-free contralateral teeth. Although preventive measures have been responsible for striking decreases in dental disease, it would be a pity if such strategies included prophylactic removal of wisdom teeth-a procedure that gives rise to complications like any other surgical operation. There seems to be scope for reducing the numbers of wisdom teeth that are removed,

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can be no better protection against lingual nerve than avoiding surgery, such a reduction could only decrease damage the numbers of potential litigants.

and since there

Department of Oral Surgery, Medicine, and Pathology, University of Wales College of Medicine, Cardiff CF4 4XY, UK

J. P. SHEPHERD M. R. BRICKLEY

development conference for removal of third molars. J Oral Surg 1980; 38: 235-36.

1. NIH consensus

SIR,-Mrs Brahams reports medical negligence involving design and lingual nerve damage in procedures for

retractor

extraction of wisdom teeth. Without going into a debate on the technical aspects of this particular problem, it is regrettable that such judgment, at least in the first case, seems to have been based on the fact that there was an unfortunate outcome. The fact that a judgment of negligence can be based on outcome is untenable, whether from a medical, a statistical, or, I would hope, a

judicial viewpoint. Patients might logically think that if something goes wrong in a procedure there must have been negligence. Research has also shown that even among doctors, knowledge of the outcome

(permanent damage or transitory symptoms) substantially

influences their judgment on whether treatment was adequate or not.’ There is still considerable doubt about what effect practice guidelines might have on malpractice claimsHowever, in view of the biased nature of judgments based on outcome, new objective criteria, as incorporated in practice guidelines, might help to avoid acceptance of unjust claims (judicial negligence) of medical

negligence. Institut Universitaire de Médecine Sociale et Préventive, CH 1005 Lausanne, Switzerland

J. P. VADER

Caplan RA, Posner KL, Cheney FW. Effect of outcome on physician judgements of appropriateness of care. JAMA 1991; 65: 1957-60. 2. Garnick DW, Hendncks AM, Bernnan TA. Can practice guidelines reduce the number and costs of malpractice claims? JAMA 1991; 266: 2856-60. 1.

QALYfied arterial reconstruction SiR,—Your editorial about the choice between amputation or arterial reconstruction (April 11, p 900) missed a chance to apply the quality-adjusted life years (QALY) argument. Our unit, by means of our own costings and an average of our own and international vascular patency/rehabilitation rates, confirmed the cost-benefit of reconstructions.’ In the league table, a successful reconstruction compared well with, for example, hip replacement at a QALY rating of about ;E1000-2000; amputation compared more closely with renal dialysis, costing about [30 000 per QALY. On grounds of humanity, the case for reconstruction is sound; on economic grounds, it is certainly very persuasive. St Richard’s

D. ALLEN Hants

Hospital,

Southampton SO9 4PE,

(±0-96) mg/1 (n=6), respectively. Prospective, randomised, multicentre trials are now in progress worldwide to explore the full potential of meropenem given at 40 mg/kg thrice daily for the treatment of meningitis.

J. PETER DONNELLY Department of Haematology, Academisch Ziekenhuis Nijmegen, 6500 HB Nijmegen, Netherlands 1.

ALFONSE M. HORREVORTS ROBERT W. SAUERWEIN BEN E. DE PAUW

Norrby SR. Role of cephalosporins in the treatment of bacterial meningitis in adults: overview with special emphasis on ceftazidime. Am J Med 1985; 79 (suppl 2a):

56-61. 2. Winston DJ, Ho WG, Bruckner DA, Champlin RE. Beta-lactam antibiotic therapy in febrile granulocytopenic patients: a randomized trial comparing cefoperazone plus piperaciliin, ceftazidime plus piperacillin, and imipenem alone. Ann Intern Med

1991, 115: 849-59. 3. Patel JB, Giles RE. Meropenem: evidence of lack of proconvulsive tendency in mice. J Antimicrob Chemother 1989; 24 (suppl A): 307-09.

Pericardial effusions after bone-marrow

transplantation

Hospital,

Chichester

Royal South

an alternative, but the high doses necessary are associated with seizures.2 Meropenem has comparable activity to imipenem but does not appear toxic to the central nervous system (CNS).3 This encouraged us to consider using it to manage a difficult case of iatrogenic meningitis caused by two distinct strains of Ps aeniginosa. A 24-year-old man had been treated elsewhere for lymphoblastic lymphoma, but severe meningitis had developed after his Ommaya reservoir had become infected after a contaminated injection of methotrexate. Therapy was started with ceftazidime and gentamicin, and he was transferred to our hospital where the reservoir was removed. However, cerebrospinal fluid (CSF) cultures remained positive with a strain that was now resistant to ceftazidime. Despite a change of treatment to amikacin 1-5 g daily and ciprofloxacin 800 mg daily, the organism persisted, although it was still susceptible to both agents and to tobramycin, imipenem, and meropenem (MIC 0-25 mg/1). Therefore treatment was changed to intravenous and intrathecal tobramycin and meropenem given at a dose of 2 g thrice daily intravenously (38-5 mg/kg per dose) on a compassionate basis. After improvement, chemotherapy was resumed and tobramycin was discontinued. After 4 weeks of neutropenia meropenem was discontinued, but meningitis recurred 1 week later. A rapid response was again achieved with the same therapy, allowing the next cycle of chemotherapy to be given. 4 weeks later the patient went home for 2 weeks without antibiotics before being readmitted for a bone marrow autograft. Meropenem was given as prophylaxis for 8 weeks, after which the patient was discharged. 4 months later he is alive and well. Meropenem was given for 18 weeks, over twice the duration than in any other patient to date, yet it was well tolerated with no evidence of CNS or other toxicity. The high dose of 2 g also resulted in CSF concentrations similar to those encountered so far: mean trough and peak values (±95% CI) of 0-5 (±0-14) mg/1 (n = 10) and 1-6

might provide

UK

A. D. B. CHANT

1 Allen

DR, Chant ADB. Cost-effectiveness of treating critical ischaemia using quality-adjusted life years. Br J Surg 1990; 77: 348.

High-dose meropenem in meningitis due to Pseudomonas aeruginosa SIR,-Meropenem (ICI-194660; ICI Pharmaceuticals) is a new dehydropeptidase-stable carbapenem currently under late-phase III evaluation for treatment of infection. We have treated 55 febrile, neutropenic patients all of whom have tolerated the drug well. Experience in bacterial meningitis is limited to 7 children who responded to between 0-8 and 2 g daily after an average of 18 days without any adverse events. Meningitis due to Pseudomonas aeniginosa is rare and requires a combination of ceftazidime with an aminoglycoside.1 Should resistance develop, imipenem-cilastatin

SIR,-Despite the use of cardiotoxic chemoradiotherapy, pericardial effusion is a very rare complication of bone-marrow transplantation (BMT). Dr Angelucci and colleagues (Feb 1, p 287) report 8 cases of cardiac tamponade among 400 thalassaemia patients transplanted under the busulphan-cyclophosphamide regimen.! This group had previously not encountered cardiac tamponade among 300 leukaemia transplant cases, and the Seattle group has reported only 3 cases of pericardial effusion in patients with malignant diseased An additional case was described by Veys et al in a 22-year-old woman with acute lymphocytic leukaemia given BMT with cyclophosphamide and total body irradiation.2 We are treating a 27-year-old woman with acute nonlymphocytic leukaemia (FAB M2) who had a pericardial effusion 15 days after autologous, 4-hydroperoxycyclophosphamide-purged BMT. Before BMT, she had received induction and consolidation chemotherapy with idarubicin (60 mg/m2 cumulative dose) and cytarabine. The pretransplant echocardiogram revealed normal cardiac function with an ejection fraction of 60%. Conditioning consisted of cyclophosphamide (200 mg/kg) and busulphan without

Retractor design and the lingual nerve.

1116 Unfriendly takeover SiR,—The commentary by Dr Andrew Herxheimer (March 21, 732) on the evolution of the Pharmaceuticals Unit (PHA) in the...
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