Correspondence
Ibuprofen in Patients with Cystic Fibrosis
N Engl J Med 1995; 333:731-732September 14, 1995
- Article
To the Editor:
We have some concern about the study of high-dose ibuprofen in patients with cystic fibrosis by Konstan et al. (March 30 issue).1 Only the group of children under 13 years old benefited from ibuprofen, and just 36 patients in this group completed the study. For a disease that is as variable as cystic fibrosis, 36 patients is a small sample on which to base important conclusions. In addition, ibuprofen has documented nephrotoxic effects,2,3 yet we could find no discussion of this important problem in the article.
3 ReferencesEdward R. Carter, Lt.Col., M.C.
Donald R. Moffitt, Col., M.C.
Madigan Army Medical Center, Tacoma, WA 98431-50001
Konstan MW ,Byard PJ ,Hoppel CL ,Davis PB . Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995;332:848-854
Full Text | Web of Science | Medline2
Clive DM ,Stoff JS . Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984;310:563-572
Full Text | Web of Science | Medline3
Marasco WA ,Gikas PW ,Azziz-Baumgartner R ,Hyzy R ,Eldredge CJ ,Stross J . Ibuprofen-associated renal dysfunction: pathophysiologic mechanisms of acute renal failure, hyperkalemia, tubular necrosis, and proteinuria. Arch Intern Med 1987;147:2107-2116
CrossRef | Web of Science | Medline
To the Editor:
In the study by Konstan et al., long-term, high-dose ibuprofen was used in young children with cystic fibrosis. The authors report that at the termination of the treatment, the decline in forced expiratory volume in one second (FEV1) and other variables, expressed as percentages of the predicted values, was smaller in the ibuprofen group than in the control group.
Prediction equations for these measurements are based on height. Neither the patients' heights before or after treatment nor the absolute values of the pulmonary-function tests are given. We wonder whether the small observed differences in the final results may have been due, at least in part, to differences in growth between the ibuprofen and placebo groups. If such differences were mainly in leg length, the relation between height and lung variables, which depend on lung size, could have been altered. A possible effect of nonsteroidal antiinflammatory drugs on bone growth has been suggested by the results of experimental studies.1,2
2 ReferencesCharlotte Colp, M.D
Beth Israel Medical Center, New York, NY 10003Jack Lieberman, M.D
17813 Lemarsh St., Northridge, CA 913251
Li XJ ,Jee WS ,Li YL . Flurbiprofen enhances growth and cancellous and cortical bone accumulation in rapidly growing long bones. Bone 1989;10:35-44
CrossRef | Web of Science | Medline2
Mizuno H ,Liang RF ,Kawabata A . Effects of oral administration of various non-steroidal anti-inflammatory drugs on bone growth and bone wound healing in mice. Meikai Daigaku Shigaku Zasshi 1990;19:234-250
Medline
Author/Editor Response
The authors reply:
To the Editor: Carter and Moffitt are concerned about the small size of the subgroup with the strongest response to ibuprofen in our study. It is important to emphasize that the intention-to-treat analysis of data in all 84 study patients showed significant differences in FEV1, as well as the percentage of ideal body weight, between the ibuprofen and placebo groups. These results are from the most conservative analysis. The sample size was determined a priori and was adequate to detect a clinically significant effect of treatment on FEV1. The long duration of the trial (four years) allowed us to study substantially fewer subjects than would have been necessary in a shorter study: the variability in the rate of change in FEV1 decreases dramatically as the study period increases. For example, to detect a benefit of ibuprofen in a two-year study, more than 400 patients would have to be enrolled.
Carter and Moffitt remind us of the possible adverse renal effects of ibuprofen, which are rare and may not be detected in a study of this size. In patients with cystic fibrosis and long-term use of ibuprofen, renal disease may develop at a rate similar to that in the general population, or at a higher rate, since patients with cystic fibrosis are frequently treated with other nephrotoxic drugs, such as tobramycin. We monitored renal function carefully in our patients for precisely this reason, and we believe such monitoring is important in patients with cystic fibrosis treated with ibuprofen. Blood levels of potentially toxic antibiotic agents cleared by the kidneys should also be monitored carefully in patients treated with ibuprofen, since it reduces renal blood flow and may impair renal clearance of these drugs.
Colp and Lieberman wonder about the effect of ibuprofen on long-bone growth. The patients in the ibuprofen group did not differ significantly from the controls in the percentile for height at the start of the study or in the change in height during the study. We reported pulmonary-function data as percentages of predicted values to permit comparisons among subjects who differed in age, sex, and height. Colp and Lieberman postulate that our results may derive from the stimulatory effect of ibuprofen on long-bone growth, not from an effect on the lungs. If this were the case, however, one would expect the taller patients in the ibuprofen group to have lower apparent percentages of predicted FEV1 and, thus, a greater apparent decline in the variable with time and growth. Such an effect would be in the opposite direction from our results. In addition, the beneficial effect of ibuprofen on chest-radiograph scores cannot be explained by differences in growth.
Michael W. Konstan, M.D.
Pamela J. Byard, Ph.D.
Pamela B. Davis, M.D., Ph.D.
Rainbow Babies and Children's Hospital, Cleveland, OH 44106-5000
