- Email: [email protected]
Drug interactions affecting theophylline clearance
838
Editorial correspondence
gen concentration that may be as much as 39 ppm greater than or 23 ppm less than that of the control group. Contrary to their conclusion, their data m a y well "support the concept that colicky infants produce more hydrogen from malabsorbed carbohydrate than noncolicky infants." 1 have the impression that our premier pediatric journals allow articles that are flawed in this way to appear with distressing lrequency. The issue of type II errors is certainly not a new one. 25 Does THE JOURNAL have an editorial process designed to exclude these errors systematically?
Robert D. Mauro, MD Children's Hospital University of Colorado School of Medicine Denver, CO 80218
The Journal of Pediatrics May 1990
ical investigators from continuing to shed some objective light on the pathogenesis of colic.
Jeffrey S. Hyams, MD M. Alex Geertsma, MD William R. Treem, MD Departments of Pediatrics Hartford Hospital St. Francis Hospital Hartford, CT 06115 REFERENCE
1. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, N.J.: Lawrence Erlman Associates, 1988.
REFERENCES
1. Feinstein A R . Clinical biostatistics. St Louis: CV Mosby, 1977:331-2. 2. Freiman JA, Chalmers TC, Smith H, Kuebler RR. The importance of beta, the type II error, and sample size in the design and interpretation of the randomized controlled trial: survey of 71 "negative trials." In: Bailar JC, Mosteller F, eds. Medical uses of statistics. Waltham, Mass.: N E J M Books, 1986:289-304. 3. Angell M. Negative studies. N Engl J Med 1989;32l:4646. 4. Brown G. Errors, types I and II. A m J Dis Child 1983;137:58691. 5. Berwick DM. Experimental power: the other side of the coin. Pediatrics 1980;65:1043-5.
Replies To the Editor: Dr. Mauro is correct in stating that our data indicate only that "we may not conclude with confidence that the two groups [control vs colic] are different." If we were to try to exclude a type I1 error on the basis of the modest size of our study population, we would have had to expand each subgroup to between 33 and 400 patients to allow us to accept the null hypothesis. 1 Given the fact that it took us 2 years to recruit and study 24 patients, it is clear that even the most tenacious or well-funded investigator would have had difficulty. Our study was intended to examine the clinical observation that colicky infants are more "gassy" than noncolicky ones. This question could be practically and noninvasively addressed by breath hydrogen monitoring, and this was the approach we took. Inspection of our data does indeed suggest that there is a broad range of hydrogen excretion in both groups and certainly no clinically relevant difference, That the infants with the highest hydrogen excretion exhibited no discomfort was also indicative of a lack of relationship between gas production and symptoms. We commend Dr. Mauro for bringing to our attention the issue of type II errors, but hope that his comments will not dissuade clin-
To the readers: W e are always grateful for criticisms of our editorial processes, but we can assure Dr. Mauro that the Editor and his staff are well aware of the type I! error. Indeed, many manuscripts are rejected on this basis, some without peer review. It seemed to us, however, that even casual inspection of the data presented by H y a m s et al. would lead one to conclude that no clinically important differences in colonic gas production were present in these two groups of infants. With the kind of overlap shown in the figure, one might have reached that conclusion even if the differences were shown to be statistically different (type I error). We believed that the lack of correlation between the extremes of colonic gas excretion and infant behavior also supported the authors' conclusion. To provide an answer to the broader implications of Dr. M a u ro's final question, we can add that it is not practical to obtain a biostatistical review of every article published in THE JOURNAL, but that we seek such opinions when the reviewers or we believe them to be necessary. We welcome comments such as Dr. Mauro's, so as to improve our batting average.
Joseph M. Garfunkel, MD Editor
Drug interactions affecting theophylline clearance To the Editor: Rooklin's article in the "Priority on Pediatric A s t h m a " supplement (J PEDIATR 1989;115:841-5) states that propranolol increases theophylline clearance. Propranolol inhibits antipyrine and theophylline elimination, therefore decreasing theophylline clearance. Adults receiving concurrent theophylline and propranolol therapy have demonstrated a mean decrease in theophylline clearance of 37%. 1 Because patients with asthma would not ordinarily be treated with a nonspecific fl-adrenergic blocking agent such as propranolol, this drug interaction may be of limited clinical relevance. One sig-
Volume 116 Number 5
nificant drug interaction not mentioned by Dr. Rooklin is that between theophylline and the fluoroquinolone antibiotics, which may find increasing use in the adolescent patient with asthma or cystic fibrosis and a multiply resistant respiratory infection. The concomitant administration of these agents may result in significantly elevated theophylline serum concentrations. Wijnands et al. 2 reported a 63.6% decrease in mean theophylline clearance with concomitant enoxacin therapy, and a 30.4% decrease in clearance with concomitant ciprofloxacin therapy. The authors proposed that this interaction is due to the 4-oxo-piperidine metabolite, a structure similar to the imidazole group of cimetidine, which may inhibit theophylline clearance through competition for hepatic enzymes. Wijnands et al. recommended a 50% reduction ixi theophylline dose before initiating concomitant therapy with enoxacin, or frequent plasma theophylline concentration measurements without preadjustment of the dose if ciproftoxacin is prescribed. 2 A review by Raoof et al. 3 describes a mean 10.5/~g/ml (58 ~,mol/L) increase in serum theophylline concentration in 61% of patients after initiation of ciprofloxacin therapy. One third exhibited theophylline concentrations >_20 t~g/ml (>_110 t~mol/L), with 50% demonstrating clinical symptoms of significant theophylline toxicity. 3 Careful monitoring of serum theophyUine concentrations should be conducted to avoid toxic effects in patients receiving concomitant theophylline and fluoroquinolone p harmacotherapy. Jennifer Meyer Harris, PharmD Assistant Professor of Clinical Pharmacy Purdue University School of Pharmacy and Pharmacal Sciences West Lafayette, IN 47907 REFERENCES
1. Conrad KA, Nyman DW. Effects of metoprolol and propranolol on theophylline elmination. Clin Pharmacol Ther 1980;28:463-7. 2. Wijnands WJA, Vree TB, Van Herwaarden CLA. The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol 1986;22:677-87. 3. Raoof S, Wollschlager C, Khan FA. Ciprofloxaein increases serum levels of theophylline. Am J Med 1987;82(suppl 4A):115-8.
Indomethacin and ischemic brain injury in neonates To the Editor. We read with great interest the article by Bada etal. (J PEDIATR 1989;115:631-7). Indomethacin is known to reduce cerebral blood flow. 1 If the cerebral vasoconstriction induced by indomethacin may be useful in preventing intraventricular hemorrhage (IVH) in the tiny baby, one must consider that ischemic brain injury could Occur,
We reported the outcome of exposure in utero to indomethacin in twins born at 30 weeks of gestational age. 2 They had experienced
Editorial correspondence
839
severe renal failure and cerebral ischemic hemorragic lesions. One of them died when 3 days old. Ultrasonography showed periventricular flares and subependymal hemorrhage. The other twin survived with severe neurologic impairment associated with multicystic encephalomalacia. It was difficult to assess the role of indomethacin in brain damage because both twins were severely ill. We report here another pair of twins exposed in utero to indomethacin. The pregnancy was monochorial biamniotic and marked by the occurrence of premature labour at week 25. The mother was given indomethacin orally, 200 mg/day, during the 10 days preceding birth. The twin boys were delivered vaginally at week 27. Birth weight was, respectively, 960 and 905 gm. They were treated with mechanical ventilation and oxygen for a mild respiratory distress syndrome. No arterial hypotension or abnormal body temperature was noted. They had mild renal failure at 2 days of age but no cardiac dysfunction or abnormal di~aresis. Low urinary prostaglandin E2 values were found: 4 mg/24 hr; 7 mg/24 hr (Institut Pasteur, Paris). The renal function became normal a few days later. The kidneys were normal by ultrasonography. Both infants had bilateral periventricular flares on cerebral ultrasonography at 2 and 7 days age. Large cysts appeared bilaterally in the parietal occipital areas by 18 days of age. Magnetic resonance imaging showed a similar pattern of periventricular leukomalacia without a hemorrhagic signal. Both infants had spasticity. These cases suggest the possible ischemic effect of indomethacin in the occurrence of periventricular leukomalacia, because we could find no other predisposing cause in our patients. Low urinary prostaglanl~in Ez levels argue for transplacental passage of indomethacin. Periventricular densities and large cysts appeared early in the neonatal period, suggesting an antenatal occurrence of the insult. Further investigation is needed to show the safety of this drug when administered antenatally. In neonates, the effect of indomethacin on cerebral hemodynamics and oxygenation is not well documented. Most studies on newborn infants have used Doppler velocimetry to assess the effect of this drug on cerebral vessels. Cerebral arterial velocity reflects cerebral blood flow only if the caliber of the insonated vessel remains constant. Furthermore, cerebral hemodynamics involves not only the assessment of cerebral blood flow but also other measures of cerebrovascular function (e.g., cerebral oxygen delivery, cerebral blood volume, and cerebrovascular reactivity). The incidence of periventricuiar leukomalacia when indomethacin is used to prevent IVH has not been determined. Until more data are available to demonstrate the safety of this drug, the generalized use of indomethacin for the reduction of IVH cannot be recommended. J. Haddad, MD J. Messer, MD R. Casanova, MD U. Simeoni, MD D. Willard, MD Neonatal service University Hospital of Hautepierre 67098 Strasbourg Cedex, France
Editorial correspondence
gen concentration that may be as much as 39 ppm greater than or 23 ppm less than that of the control group. Contrary to their conclusion, their data m a y well "support the concept that colicky infants produce more hydrogen from malabsorbed carbohydrate than noncolicky infants." 1 have the impression that our premier pediatric journals allow articles that are flawed in this way to appear with distressing lrequency. The issue of type II errors is certainly not a new one. 25 Does THE JOURNAL have an editorial process designed to exclude these errors systematically?
Robert D. Mauro, MD Children's Hospital University of Colorado School of Medicine Denver, CO 80218
The Journal of Pediatrics May 1990
ical investigators from continuing to shed some objective light on the pathogenesis of colic.
Jeffrey S. Hyams, MD M. Alex Geertsma, MD William R. Treem, MD Departments of Pediatrics Hartford Hospital St. Francis Hospital Hartford, CT 06115 REFERENCE
1. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, N.J.: Lawrence Erlman Associates, 1988.
REFERENCES
1. Feinstein A R . Clinical biostatistics. St Louis: CV Mosby, 1977:331-2. 2. Freiman JA, Chalmers TC, Smith H, Kuebler RR. The importance of beta, the type II error, and sample size in the design and interpretation of the randomized controlled trial: survey of 71 "negative trials." In: Bailar JC, Mosteller F, eds. Medical uses of statistics. Waltham, Mass.: N E J M Books, 1986:289-304. 3. Angell M. Negative studies. N Engl J Med 1989;32l:4646. 4. Brown G. Errors, types I and II. A m J Dis Child 1983;137:58691. 5. Berwick DM. Experimental power: the other side of the coin. Pediatrics 1980;65:1043-5.
Replies To the Editor: Dr. Mauro is correct in stating that our data indicate only that "we may not conclude with confidence that the two groups [control vs colic] are different." If we were to try to exclude a type I1 error on the basis of the modest size of our study population, we would have had to expand each subgroup to between 33 and 400 patients to allow us to accept the null hypothesis. 1 Given the fact that it took us 2 years to recruit and study 24 patients, it is clear that even the most tenacious or well-funded investigator would have had difficulty. Our study was intended to examine the clinical observation that colicky infants are more "gassy" than noncolicky ones. This question could be practically and noninvasively addressed by breath hydrogen monitoring, and this was the approach we took. Inspection of our data does indeed suggest that there is a broad range of hydrogen excretion in both groups and certainly no clinically relevant difference, That the infants with the highest hydrogen excretion exhibited no discomfort was also indicative of a lack of relationship between gas production and symptoms. We commend Dr. Mauro for bringing to our attention the issue of type II errors, but hope that his comments will not dissuade clin-
To the readers: W e are always grateful for criticisms of our editorial processes, but we can assure Dr. Mauro that the Editor and his staff are well aware of the type I! error. Indeed, many manuscripts are rejected on this basis, some without peer review. It seemed to us, however, that even casual inspection of the data presented by H y a m s et al. would lead one to conclude that no clinically important differences in colonic gas production were present in these two groups of infants. With the kind of overlap shown in the figure, one might have reached that conclusion even if the differences were shown to be statistically different (type I error). We believed that the lack of correlation between the extremes of colonic gas excretion and infant behavior also supported the authors' conclusion. To provide an answer to the broader implications of Dr. M a u ro's final question, we can add that it is not practical to obtain a biostatistical review of every article published in THE JOURNAL, but that we seek such opinions when the reviewers or we believe them to be necessary. We welcome comments such as Dr. Mauro's, so as to improve our batting average.
Joseph M. Garfunkel, MD Editor
Drug interactions affecting theophylline clearance To the Editor: Rooklin's article in the "Priority on Pediatric A s t h m a " supplement (J PEDIATR 1989;115:841-5) states that propranolol increases theophylline clearance. Propranolol inhibits antipyrine and theophylline elimination, therefore decreasing theophylline clearance. Adults receiving concurrent theophylline and propranolol therapy have demonstrated a mean decrease in theophylline clearance of 37%. 1 Because patients with asthma would not ordinarily be treated with a nonspecific fl-adrenergic blocking agent such as propranolol, this drug interaction may be of limited clinical relevance. One sig-
Volume 116 Number 5
nificant drug interaction not mentioned by Dr. Rooklin is that between theophylline and the fluoroquinolone antibiotics, which may find increasing use in the adolescent patient with asthma or cystic fibrosis and a multiply resistant respiratory infection. The concomitant administration of these agents may result in significantly elevated theophylline serum concentrations. Wijnands et al. 2 reported a 63.6% decrease in mean theophylline clearance with concomitant enoxacin therapy, and a 30.4% decrease in clearance with concomitant ciprofloxacin therapy. The authors proposed that this interaction is due to the 4-oxo-piperidine metabolite, a structure similar to the imidazole group of cimetidine, which may inhibit theophylline clearance through competition for hepatic enzymes. Wijnands et al. recommended a 50% reduction ixi theophylline dose before initiating concomitant therapy with enoxacin, or frequent plasma theophylline concentration measurements without preadjustment of the dose if ciproftoxacin is prescribed. 2 A review by Raoof et al. 3 describes a mean 10.5/~g/ml (58 ~,mol/L) increase in serum theophylline concentration in 61% of patients after initiation of ciprofloxacin therapy. One third exhibited theophylline concentrations >_20 t~g/ml (>_110 t~mol/L), with 50% demonstrating clinical symptoms of significant theophylline toxicity. 3 Careful monitoring of serum theophyUine concentrations should be conducted to avoid toxic effects in patients receiving concomitant theophylline and fluoroquinolone p harmacotherapy. Jennifer Meyer Harris, PharmD Assistant Professor of Clinical Pharmacy Purdue University School of Pharmacy and Pharmacal Sciences West Lafayette, IN 47907 REFERENCES
1. Conrad KA, Nyman DW. Effects of metoprolol and propranolol on theophylline elmination. Clin Pharmacol Ther 1980;28:463-7. 2. Wijnands WJA, Vree TB, Van Herwaarden CLA. The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol 1986;22:677-87. 3. Raoof S, Wollschlager C, Khan FA. Ciprofloxaein increases serum levels of theophylline. Am J Med 1987;82(suppl 4A):115-8.
Indomethacin and ischemic brain injury in neonates To the Editor. We read with great interest the article by Bada etal. (J PEDIATR 1989;115:631-7). Indomethacin is known to reduce cerebral blood flow. 1 If the cerebral vasoconstriction induced by indomethacin may be useful in preventing intraventricular hemorrhage (IVH) in the tiny baby, one must consider that ischemic brain injury could Occur,
We reported the outcome of exposure in utero to indomethacin in twins born at 30 weeks of gestational age. 2 They had experienced
Editorial correspondence
839
severe renal failure and cerebral ischemic hemorragic lesions. One of them died when 3 days old. Ultrasonography showed periventricular flares and subependymal hemorrhage. The other twin survived with severe neurologic impairment associated with multicystic encephalomalacia. It was difficult to assess the role of indomethacin in brain damage because both twins were severely ill. We report here another pair of twins exposed in utero to indomethacin. The pregnancy was monochorial biamniotic and marked by the occurrence of premature labour at week 25. The mother was given indomethacin orally, 200 mg/day, during the 10 days preceding birth. The twin boys were delivered vaginally at week 27. Birth weight was, respectively, 960 and 905 gm. They were treated with mechanical ventilation and oxygen for a mild respiratory distress syndrome. No arterial hypotension or abnormal body temperature was noted. They had mild renal failure at 2 days of age but no cardiac dysfunction or abnormal di~aresis. Low urinary prostaglandin E2 values were found: 4 mg/24 hr; 7 mg/24 hr (Institut Pasteur, Paris). The renal function became normal a few days later. The kidneys were normal by ultrasonography. Both infants had bilateral periventricular flares on cerebral ultrasonography at 2 and 7 days age. Large cysts appeared bilaterally in the parietal occipital areas by 18 days of age. Magnetic resonance imaging showed a similar pattern of periventricular leukomalacia without a hemorrhagic signal. Both infants had spasticity. These cases suggest the possible ischemic effect of indomethacin in the occurrence of periventricular leukomalacia, because we could find no other predisposing cause in our patients. Low urinary prostaglanl~in Ez levels argue for transplacental passage of indomethacin. Periventricular densities and large cysts appeared early in the neonatal period, suggesting an antenatal occurrence of the insult. Further investigation is needed to show the safety of this drug when administered antenatally. In neonates, the effect of indomethacin on cerebral hemodynamics and oxygenation is not well documented. Most studies on newborn infants have used Doppler velocimetry to assess the effect of this drug on cerebral vessels. Cerebral arterial velocity reflects cerebral blood flow only if the caliber of the insonated vessel remains constant. Furthermore, cerebral hemodynamics involves not only the assessment of cerebral blood flow but also other measures of cerebrovascular function (e.g., cerebral oxygen delivery, cerebral blood volume, and cerebrovascular reactivity). The incidence of periventricuiar leukomalacia when indomethacin is used to prevent IVH has not been determined. Until more data are available to demonstrate the safety of this drug, the generalized use of indomethacin for the reduction of IVH cannot be recommended. J. Haddad, MD J. Messer, MD R. Casanova, MD U. Simeoni, MD D. Willard, MD Neonatal service University Hospital of Hautepierre 67098 Strasbourg Cedex, France