1117

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

1118

immediate evidence of electrocardiographic voltage depression. Progressive cardiac enlargement was noted on weekly chest X-rays, and by day 53 a large right pleural effusion had accumulated. An echocardiogram revealed a moderate pericardial effusion with evidence of right atrial and right ventricular free-wall early diastolic collapse, but no doppler findings of left heart tamponade. The patient remained symptom-free with no cardiac complaints. Evaluation of the transudative pleural effusion (including viral culture) revealed no infective cause. Serial echocardiograms over the next month showed slow, incomplete resolution of the effusion. Pericardial effusions in association with overt cardiac dysfunction and/or pericarditis have been identified in 4 of 63 consecutive transplants done in Paris.3 However, effusions without concurrent cardiac disease, as seen in our patient, are uncommon in patients with leukaemia and after transplantation. In a series of 500 patients at our centre requiring echocardiographic directed pericardiocentesis, 142 had malignant disease, but only 5 of the effusions occurred in patients with leukaemia. This case represents the first pericardial effusion occurring in over 200 transplants done at our centre and empahsises the rarity of this disorder.

Departments of Hematology and Cardiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA

STUART L. GOLDBERG MARK A. WILKOWSKE JOHN R. DALEY JAMES B. SEWARD DENNIS A. GASTINEAU MARK R. LITZOW

1. Bearman SI, Petersen FB, Schor RA, et al. Radionuclide ejection fractions in the evaluation of patients being considered for bone marrow transplantation: risk for cardiac toxicity Bone Marrow Transplant 1990; 5: 173-77. 2. Veys PA, McAvinchey R, Rothman MT, et al. Pericardial effusion following conditioning for bone marrow transplantation in acute leukaemia. Bone Marrow Transplant 1987; 2: 213-16. 3. Cazin B, Gorin NC, Laporte JP, et al. Cardiac complications after bone marrow transplantation. Cancer 1986; 57: 2061-69.

Atopy at 3 years in high-risk infants fed whey hydrolysate or conventional formula serious illness in infants and children, and the prevalence of atopy has increased over the past 10-15 years.1 Food hypersensitivity has a role in the pathogenesis of some allergic disorders in young children.2 It has been suggested that if feeding a particular formula from birth in a high-risk group is associated with a decreased incidence of atopic disease at 18 months, the occurrence of allergic disease may be said to have been delayed.3 Interim data from trials with hypoallergenic formulae do suggest a decreased incidence of allergy up to 18 months.4,5 For the first time, follow-up beyond 18 months is reported here. Only infants (n = 75) with a family history in at least two first-degree relatives were included. 15 infants dropped out for the evaluation at 3 years because their families had moved away (10), because permission for blood sampling at age 6 months was refused (despite parental consent before the trial) (4), or because soy formula was used before 6 months (1). Details of patients and method are published elsewhere,s and clinical details, in summary, are:

SllR,-Atopic

disease

causes

Family history* IgE at day 5 (U/m), range)

IgE>07/>13Uperml Household cat/dog (others) Smoking (mother/father) Day care Sibling at school *As both parents/one

Group 1 (n=2B) 14/13/1

Group 2 (n=30) 19/9/2

02-56

0.2-4.3

8/5

12/4

4(4)

5(1)

0/5

0/4

12 11

18 8

parent + sib/both parents+sib. The infants were randomised to two groups between birth and 6 months (group 1 was’fed exclusively a hypoallergenic formula during 6 months, except for crushed apple from 4 months onwards; group 2 was fed conventional cows’ milk formula, also with crushed apple from 4 months). After 6 months, all babies were given a normal varied diet. Only the "classic" features of probable allergic origin were considered (vomiting, diarrhoea, colic, atopic dermatitis, urticaria, wheezing, chronic rhinitis, allergic

conjunctivitisS). Statistical analysis was by Fisher’s exact probability test (one-sided). A significant difference in atopic features between the two groups persisted to age 3 years: Period

(mo)

0-6 6-12 0-12 12-36 0-36

Feature* Eczema

(minor/severe)

Wheezing Rhinitis, minor Conjunctivitis

Group 1

Group 2

p

2 6 6 5 7

13 5 16 8 17

0-002 NS 0029 NS 0.018

3/3

1/5

2 0

2 1 0

-

*Total patients with feature 5

in

group 1, 8 m group 2

The difference is due entirely to the "postponement effect" or decreased incidence of atopy during the first 6 months of life (diet period). Once the diet has become "normal" without restriction both groups progress in a similar fashion-there is no difference if the groups are compared from 6 months on rather than from birth on.

Academic Children’s Hospital, Free University of Brussels, 1090 Brussels, Belgium

YVAN VANDENPLAS

1. Burr ML, Butland BK, King S, Vaughan-Williams E. Changes in asthma prevalence two surveys 15 years apart. Arch Dis Child 1989; 64: 1452-56. 2. Atherton DJ. Diet and atopic eczema. Clin Allergy 1988; 18: 3215-28. 3. Subcommittee on Nutrition and Allergic Disease. Elk Grove Village, Illinois: American Academy of Pediatrics, 1990 4. Chandra RK, Hamed A. Cumulative incidence of atopic disorders in high risk infants fed whey hydrolysate, soy, and conventional cow milk formulas. Ann Allergy 1991; 67: 129-32. 5. Vandenplas Y, Hauser B, Van den Borre C, Sacre L, Dab I. Preliminary results on the effect of feeding a whey hydrosylate formula on the long term prophylaxis of atopic disease in high nsk infants. Ann Allergy (in press)

Fever in

neutropenic patients treated with representing enhanced host

GM-CSF

defence SIR,--Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to promote neutrophil recovery after cytotoxic chemotherapy.1,2 The objective is to reduce infectious complications and the need for systemic antibiotic treatment. In many centres, all febrile neutropenic patients are treated empirically with broad-spectrum parenteral antibiotics, irrespective of the cause of fever. If GM-CSF induces fever this could lead to overuse of rather than a reduction in antibiotic prescribing in patients treated with GM-CSF. Indeed, this has happened in some studies.2,3 In one double-blind placebo-controlled trial recipients of allogeneic bone-marrow transplants (BMT) were treated for 2 weeks with GM-CSF or placebo.’ No differences were noted in fever days and episodes but the number of days on systemic antibiotics was lower in the GM-CSF group. Several patients were not treated with broad-spectrum antibiotics, while antibiotic prophylaxis was continued, because the fever was thought to be due to GM-CSF. Infectious complications and mortality related to infection were lower in the GM-CSF group. We think that the administration of broad-spectrum antibiotics can be restricted in patients on GM-CSF if the following criteria are met: (1) negative cultures, no specific or localising signs of infection (clinical, radiological, or laboratory), and no major complaints; (2) the patient is clinically completely stable; and (3) a relation between time of GM-CSF administration and temperature rise has been established by temporarily withdrawing GM-CSF and then

rechallenging. Apart from the controversy about whether or not GM-CSF causes fever it must be stressed that fever is not necessarily due to infection and may represent activation of the immune system.5 Professor Kluger (Feb 22, p 491) argues that "careful consideration must be given to the possibility that fever-due to biological response modifiers such as interleukin-2-might be helping the patient to rid him or herself of the tumour". This argument, in our opinion, holds for GM-CSF also. Interleukin-6 (IL-6) is thought to modulate the