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Use of fentanyl in neonates
EDITORIAL CORRESPONDENCE Autoimmune enteropathy, anti-tubular basement membrane antibodies, and glomerulonephritis To the Editor." We read with interest the article by Colletti et al. (J PED~ATR 1991;118:858-64) reporting the case of a child with autoimmune enteropathy and membranous glomerulonephritis (MGN) at presentation. Such cases are perhaps more frequent than was previously thought. Several years ago, we analyzed the clinical history and pathologic features of 16 children with anti-tubular basement membrane (anti-TBM) nephritis. 1 Of particular interest was the association of the disease with severe diarrhea or small intestine anti-epithelial cell antibodies (AECA), or both, in five boys. Harner et al. 2 described "anti-TBM antibody and nephrotic syndrome associated with milk hypersensitivity" in a 6-month-old boy with atopic dermatitis and intractable diarrhea. Jejunal villous atrophy and MGN with anti-TBM nephritis were present. One investigator (Wilson C: personal communication, December 1982) demonstrated the presence of anti-TBM, anti-brush border, and anti-jejunal mueosa antibodies. After intravenous administration of methylprednisolone and parenteral alimentation, proteinuria gradually decreased, but diarrhea persisted. The child died from bilateral interstitial pneumonia and marasmus (Harner MH: personal communication, June 1983). The case of a 2-year-old boy with MGN and anti-TBM nephritis was reported by Martini et al. 3 With steroids and parenteral nutrition, proteinuria and anti-TBM antibodies disappeared, but intestinal malabsorption and AECA persisted. Atrioventricular block and hemolytic anemia developed, and the child died suddenly (Martini A: personal communication, March 1986). Two brothers were followed by M. Broyer of H6pital NeckerEnfants Malades, Paris. The older boy had diarrhea at the age of 5 months of age, followed by bronchitis, asthma, dermatitis, and polyarthritis. Jejunal villous atrophy was present. With a glutenfree diet, the diarrhea slowly abated. At the ageof 5 years, the boy had proteinuria, glycosuria, and aminoaciduria. Renal biopsy showed MGN with anti-TBM nephritis. With steroid therapy, the anti-TBM antibodies disappeared and renal function remained normal. The boy's brother had diarrhea at the age of 9 months, treated by a gluten-free diet, and allergic manifestations. At the age of 8 years, he had thrombocytopenic purpura requiring splenectorny, and then had renal insufficiency, proteinuria, and glycosuria. Renal biopsy showed anti-TBM nephritis in the absence of MGN. In spite of steroids and cyclophosphamide, end-stage renal failure developed. The presence of ACEA was not investigated in any of the brothers. The last boy, followed by M. Dillon of the Institute of Child Health, London, had sterold-resistant nephrotic syndrome at the age of 1 year, and microeytic"anemia. Renal biopsy showed MGN. Renal function began to deteriorate with the development of acidosis, glycosuria, and generalized aminoaciduria. Anti-TBM, anti-gastric parietal, and gut epithelial cell antibodies were present. Gut biopsy specimens showed only inflammatory cells in the jeju-
nal and large bowel lamina propria. A second renal biopsy revealed MGN with anti-TBM nephritis. In spite of steroids, cyclophosphamide, and plasma exchanges, end-stage renal failure developed (Dillon M: personal communication, August 1983). If we add to these observations those of the two first cousins with MGN and tubulointerstitial nephritis reported by Ellis et al., 4 we can emphasize several points: First, all these patients were boys. Second, a genetic susceptibility may be suggested. Third, there is a wide spectrum of digestive abnormalities. Fourth, patients frequently have other clinical disorders at presentation, aliergies often being noted. We add a further comment on treatment. The patient described by Colletti et al. remains dependent on total parenteral nutrition. Intractable diarrhea was also noted by Harner et al. 2 and by Marfini et al. 3 I learned from Dillon (personal Communication, October 1989) that he knew of four other children with anti-TBM antibodies and prominent gut disease associated with anti-small bowel antibodies. They were treated with cyclosporine, marked improvement in the gastrointestinal disease occurred, and after they had been intravenously fed for a number of years, they were tolerating a fairly normal diet. Micheline Levy, MD Unite de Rbcherches d'Epidemiologie Genetique I N S E R M U. 155 Ch~teau de Longchamp Bois de Boulogne 75016 Paris, France REFERENCES 1. Levy M, Gagnadoux MF, Broyer M, Habib R. Human antitubular basement membrane antibody disease. In: Brodehl J, Ehrich JHH, eds. Pediatric nephrology. New York: SpringerVerlag, 1984:201-8. 2. Harner MH, Nolte M, Wilson CB, et al. Anti-TBM antibody and nephrotic syndrome associated with milk hypersensitivity [Abstract]. Third InternatiOnal Congress of Pediatric Nephrology, Washington, D.C., 1974. 3. Martini A, Scotta MS, Notarangelo LD, Maggiore G, Guarnaccia S, de Giacomo C. Membranous glomerulopathy and chronic intestinal enteropathy associated with autoantibodies directed against renal tubular basement membrane and the cytoplasm of intestinal epithelial cells. Acta Paediatr Scand 1983;72:931-4. 4. Ellis D, Fisher SE, Smith WI, Jaffe R. Familial occurrence of renal and intestinal disease associated with tissue autoantibodies. Am J Dis Child 1982;136:323-6.
Use of fentanyl in neonates To the Editor: An article I in THE JOURNAL describes a complication of prolonged fentanyl administration to neonates. An editorial 2 in the same issue makes cogent suggestions concerning the need for careful evaluation of new drugs before we employ them in pediatric patients. An additional caveat is necessary. Drugs for the neonate,
659
660
Editorial correspondence
particularly the premature baby, require additional evaluations beyond those necessary before use of new agents in older children. Specifically, if we are to avoid a repetition of the sulfisoxazole-kernicterus debacle, we must ensure that any drug employed in the treatment of neonates does not adversely affect the binding of bilirubin to albumin. The sulfa story is the paradigm. Sulfisoxazole was used empirically to treat neonatal sepsis on the basis of its documented efficacy in older children and adults. The epidemic of bilirubin encephalopathy that ensued was finally traced back to use of this drug. 3 Subsequent in vitro studies documented the high-affinity binding of sulfizoxazole to the primary bilirubin binding site on albumin, 4 thus increasing the serum concentration of free, unconjugated bilirubin and increasing the risk of toxic effects in the central nervous system. 5 Other sulfa drugs, however, do not bind as avidly to this site on albumin 6 and, presumably, have less toxicity. Thus the mere fact that some drugs in a given chemical family are safe for use in neonates does not ensure that all are similarly innocuous. Fentanyl is now being employed during the neonatal period with virtually the same rationale: it is effective and safe in the treatment of older patients and has advantages over other opiates in that population, and, in addition, other opiates have not been demonstrated to affect bilirubin binding. However, to the best of my knowledge, there is no evidence to reassure us that fentanyl does not displace bilirubin from albumin. The same can be said for midazolam, another drug that is beginning to "trickle down" from the pediatric to the neonatal intensive care unit. Thus far, there are no warning signs of a sudden upsurge in the incidence of bilirubin encephalopathy. This may be a manifestation of that medical maxim "It is better to he lucky than to be good." A better maxim to keep in mind is that those who do not learn from history are condemned to repeat it. Neither fentanyl nor midazolam is essential to the care of the neonate; there are other effective analgesics and sedatives with extensive track records of safety. They may lack the theoretical benefits of the newer agents, but until adequate studies are performed, those putative advantages remain just that, theoretical. I believe it is far better to be careful than to be lucky. The malpractice industry would no doubt disagree.
David M. Coulter, MD Division of Neonatology University of Utah School of Medicine and LDS Hospital Salt Lake City, UT 84143 REFERENCES
l. Arnold JH, Truog RD, Scavone JM, Fenton T, Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J PEDIATR 1991;119:639-43. 2. Kauffman RE. Fentanyl, fads, and folly: who will adopt the therapeutic orphans? J PEDIATR 1991;119:588-89. 3. Silverman W, Anderson D, Blanc W, et al. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956;18:614-25. 4. Odell GB. Studies in kernicterus. I. The protein binding of bilirubin. J Clin Invest 1959;38:823-33.
The Journal of Pediatrics April 1992
5. Wennberg RD. The importance of free bilirubin acid salt in bilirubin uptake by erythrocytes and mitochondria. Pediatr Res 1988;23:443-7. 6. Broderson R. Competitive binding of bilirubin and drugs to human serum albumin studies by enzymatic oxidation. J Clin Invest 1974;54:1353-64.
Estimates of metabolic rate in obese and nonobese adolescents To the Editor: Previous studies 1-3 suggested that the currently available regression equations overestimate the resting metabolic rate ( R M R ) in adults. Dietz et al. (J PEDIATR 1991 ;118:146-9), in their interesting article, could not confirm these doubts in a mixed group of obese and nonobese adolescents. However, in a cohort of obese female adolescents, they found that the Mayo Clinic nomogram and the Food and Agriculture Organization, World Health Organization, and United Nations University No. 1 equations overestimate the RMR. As a part of an ongoing project, we have also studied the R M R in obese (26 boys, 20 girls) and nonobese (21 boys, 19 girls) adolescents. The mean (_+ SE) age, body weight, height, and body fat of the obese and nonobese cohort were 13.3 • 0.3 versus 12.8 • 0.3 years, 87.7 _+ 3.2 versus 41.5 _+ 1~5 kg, 162 + 1.5 versus 153 _+ 1.9 cm, and 38.1% + 0.5% versus 19.3% _+ 0.9%, respectively. The R M R was measured after an overnight fast for 30 minutes by means of an open-circuit calorimeter (Deltatrac MBM-100; Instrumentarium Corp., DATEX Division, Helsinki, Finland), with the ventilated-hood method. Children were allowed to accommodate to the hood for 30 or 45 minutes before the commencement of the measurement. During the investigation the children were lying quietly. All but the Cunningham equation significantly overestimated the R M R in both obese and nonobese children in comparison with the measured values (Table). Our results
T a b l e . C o m p a r i s o n o f m e a s u r e d resting m e t a b o l i c rate values with R M R e s t i m a t e d f r o m s t a n d a r d predictive e q u a t i o n s in obese and n o n o b e s e a d o l e s c e n t s Measured or predicted values (kcal/day) Method* Measured R M R Harris-Benedict Mayo Clinic nomogram Cunningham F A O / W H O / U N U No. 1 F A O / W H O / U N U No. 2
Obese adolescents 1682 1882 2047 1685 2022 1920
_+ 45 • 49t _+ 42? _+ 40 • 57? + 60t
Nonobese adolescents 1186 1302 1446 1226 1320 1326
_+ 32 • 24? _+ 31? • 24 • 26? +- 26t
Values are expressed as mean +_ SE. FAO, Food and Agriculture Organization; WHO, World Health Organization; UNU, United Nations Univet:sity. *Dietz et al. (J Pediatr 1991;118:146-9) tP <0.01.
nal and large bowel lamina propria. A second renal biopsy revealed MGN with anti-TBM nephritis. In spite of steroids, cyclophosphamide, and plasma exchanges, end-stage renal failure developed (Dillon M: personal communication, August 1983). If we add to these observations those of the two first cousins with MGN and tubulointerstitial nephritis reported by Ellis et al., 4 we can emphasize several points: First, all these patients were boys. Second, a genetic susceptibility may be suggested. Third, there is a wide spectrum of digestive abnormalities. Fourth, patients frequently have other clinical disorders at presentation, aliergies often being noted. We add a further comment on treatment. The patient described by Colletti et al. remains dependent on total parenteral nutrition. Intractable diarrhea was also noted by Harner et al. 2 and by Marfini et al. 3 I learned from Dillon (personal Communication, October 1989) that he knew of four other children with anti-TBM antibodies and prominent gut disease associated with anti-small bowel antibodies. They were treated with cyclosporine, marked improvement in the gastrointestinal disease occurred, and after they had been intravenously fed for a number of years, they were tolerating a fairly normal diet. Micheline Levy, MD Unite de Rbcherches d'Epidemiologie Genetique I N S E R M U. 155 Ch~teau de Longchamp Bois de Boulogne 75016 Paris, France REFERENCES 1. Levy M, Gagnadoux MF, Broyer M, Habib R. Human antitubular basement membrane antibody disease. In: Brodehl J, Ehrich JHH, eds. Pediatric nephrology. New York: SpringerVerlag, 1984:201-8. 2. Harner MH, Nolte M, Wilson CB, et al. Anti-TBM antibody and nephrotic syndrome associated with milk hypersensitivity [Abstract]. Third InternatiOnal Congress of Pediatric Nephrology, Washington, D.C., 1974. 3. Martini A, Scotta MS, Notarangelo LD, Maggiore G, Guarnaccia S, de Giacomo C. Membranous glomerulopathy and chronic intestinal enteropathy associated with autoantibodies directed against renal tubular basement membrane and the cytoplasm of intestinal epithelial cells. Acta Paediatr Scand 1983;72:931-4. 4. Ellis D, Fisher SE, Smith WI, Jaffe R. Familial occurrence of renal and intestinal disease associated with tissue autoantibodies. Am J Dis Child 1982;136:323-6.
Use of fentanyl in neonates To the Editor: An article I in THE JOURNAL describes a complication of prolonged fentanyl administration to neonates. An editorial 2 in the same issue makes cogent suggestions concerning the need for careful evaluation of new drugs before we employ them in pediatric patients. An additional caveat is necessary. Drugs for the neonate,
659
660
Editorial correspondence
particularly the premature baby, require additional evaluations beyond those necessary before use of new agents in older children. Specifically, if we are to avoid a repetition of the sulfisoxazole-kernicterus debacle, we must ensure that any drug employed in the treatment of neonates does not adversely affect the binding of bilirubin to albumin. The sulfa story is the paradigm. Sulfisoxazole was used empirically to treat neonatal sepsis on the basis of its documented efficacy in older children and adults. The epidemic of bilirubin encephalopathy that ensued was finally traced back to use of this drug. 3 Subsequent in vitro studies documented the high-affinity binding of sulfizoxazole to the primary bilirubin binding site on albumin, 4 thus increasing the serum concentration of free, unconjugated bilirubin and increasing the risk of toxic effects in the central nervous system. 5 Other sulfa drugs, however, do not bind as avidly to this site on albumin 6 and, presumably, have less toxicity. Thus the mere fact that some drugs in a given chemical family are safe for use in neonates does not ensure that all are similarly innocuous. Fentanyl is now being employed during the neonatal period with virtually the same rationale: it is effective and safe in the treatment of older patients and has advantages over other opiates in that population, and, in addition, other opiates have not been demonstrated to affect bilirubin binding. However, to the best of my knowledge, there is no evidence to reassure us that fentanyl does not displace bilirubin from albumin. The same can be said for midazolam, another drug that is beginning to "trickle down" from the pediatric to the neonatal intensive care unit. Thus far, there are no warning signs of a sudden upsurge in the incidence of bilirubin encephalopathy. This may be a manifestation of that medical maxim "It is better to he lucky than to be good." A better maxim to keep in mind is that those who do not learn from history are condemned to repeat it. Neither fentanyl nor midazolam is essential to the care of the neonate; there are other effective analgesics and sedatives with extensive track records of safety. They may lack the theoretical benefits of the newer agents, but until adequate studies are performed, those putative advantages remain just that, theoretical. I believe it is far better to be careful than to be lucky. The malpractice industry would no doubt disagree.
David M. Coulter, MD Division of Neonatology University of Utah School of Medicine and LDS Hospital Salt Lake City, UT 84143 REFERENCES
l. Arnold JH, Truog RD, Scavone JM, Fenton T, Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J PEDIATR 1991;119:639-43. 2. Kauffman RE. Fentanyl, fads, and folly: who will adopt the therapeutic orphans? J PEDIATR 1991;119:588-89. 3. Silverman W, Anderson D, Blanc W, et al. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956;18:614-25. 4. Odell GB. Studies in kernicterus. I. The protein binding of bilirubin. J Clin Invest 1959;38:823-33.
The Journal of Pediatrics April 1992
5. Wennberg RD. The importance of free bilirubin acid salt in bilirubin uptake by erythrocytes and mitochondria. Pediatr Res 1988;23:443-7. 6. Broderson R. Competitive binding of bilirubin and drugs to human serum albumin studies by enzymatic oxidation. J Clin Invest 1974;54:1353-64.
Estimates of metabolic rate in obese and nonobese adolescents To the Editor: Previous studies 1-3 suggested that the currently available regression equations overestimate the resting metabolic rate ( R M R ) in adults. Dietz et al. (J PEDIATR 1991 ;118:146-9), in their interesting article, could not confirm these doubts in a mixed group of obese and nonobese adolescents. However, in a cohort of obese female adolescents, they found that the Mayo Clinic nomogram and the Food and Agriculture Organization, World Health Organization, and United Nations University No. 1 equations overestimate the RMR. As a part of an ongoing project, we have also studied the R M R in obese (26 boys, 20 girls) and nonobese (21 boys, 19 girls) adolescents. The mean (_+ SE) age, body weight, height, and body fat of the obese and nonobese cohort were 13.3 • 0.3 versus 12.8 • 0.3 years, 87.7 _+ 3.2 versus 41.5 _+ 1~5 kg, 162 + 1.5 versus 153 _+ 1.9 cm, and 38.1% + 0.5% versus 19.3% _+ 0.9%, respectively. The R M R was measured after an overnight fast for 30 minutes by means of an open-circuit calorimeter (Deltatrac MBM-100; Instrumentarium Corp., DATEX Division, Helsinki, Finland), with the ventilated-hood method. Children were allowed to accommodate to the hood for 30 or 45 minutes before the commencement of the measurement. During the investigation the children were lying quietly. All but the Cunningham equation significantly overestimated the R M R in both obese and nonobese children in comparison with the measured values (Table). Our results
T a b l e . C o m p a r i s o n o f m e a s u r e d resting m e t a b o l i c rate values with R M R e s t i m a t e d f r o m s t a n d a r d predictive e q u a t i o n s in obese and n o n o b e s e a d o l e s c e n t s Measured or predicted values (kcal/day) Method* Measured R M R Harris-Benedict Mayo Clinic nomogram Cunningham F A O / W H O / U N U No. 1 F A O / W H O / U N U No. 2
Obese adolescents 1682 1882 2047 1685 2022 1920
_+ 45 • 49t _+ 42? _+ 40 • 57? + 60t
Nonobese adolescents 1186 1302 1446 1226 1320 1326
_+ 32 • 24? _+ 31? • 24 • 26? +- 26t
Values are expressed as mean +_ SE. FAO, Food and Agriculture Organization; WHO, World Health Organization; UNU, United Nations Univet:sity. *Dietz et al. (J Pediatr 1991;118:146-9) tP <0.01.