TY - JOUR
T1 - Failure of cholecystokinin-octapeptide to prevent TPN-associated gallstone disease
AU - Tsai, Susan
AU - Strouse, Peter J.
AU - Drongowski, Robert A.
AU - Islam, Saleem
AU - Teitelbaum, Daniel H.
N1 - Funding Information:
This study was part of a larger, double-blind, randomized, prospective multicenter, controlled trial to assess whether CCK can prevent or reduce the severity of TPN-associated cholestasis. The primary outcome measure was conjugated bilirubin levels, as a measure of the development and severity of TPN-associated cholestasis (results not yet published). A secondary outcome measure was whether CCK could reduce the incidence of biliary sludge and cholelithiasis. The study was assigned Investigation of New Drug 42,898 and was funded by the FDA Orphan Products Grant Program. Full Institutional Review Board approval was given for this study. Between May 1996 and August 2003, 116 infants were enrolled in a prospective, randomized, controlled trial at the CS Mott Children's Hospital. Each patient was anticipated to require a prolonged course of TPN, and each was enrolled in the study. Indications for TPN were as follows: severe prematurity (<1000 g at birth and with an estimated Dubowitz gestational age of ≤28 weeks); necrotizing enterocolitis (NEC), as defined by a Bell grade of II or higher [10] ; gastroschisis; and severe jejunoileal atresia, whereby the condition resulted in a loss equal to or exceeding 50% of the anticipated small bowel length for a given gestation age [11] . In a prospective, blinded, and randomized fashion, these patients received either CCK or placebo until they were tolerating more than 50% of their energy requirement enterally, or for a total of 8 weeks of treatment. The dose of CCK administered intravenously was 0.4 μg/kg every 12 hours. Infants were not enrolled if their conjugated bilirubin was more than 1.0 mg/dL. Finally, infants were excluded if they received ursodeoxycholic acid before the study, and no patients received this drug during their time on the study. Infants were randomized to receive the study drug (CCK) or placebo, based on an established randomization chart. Block randomization with a randomly chosen block size of 2 or 4 within center was used. Randomization tables and envelopes were generated by the Department of Biostatistics at the University of Michigan. Control of drug randomization and distribution was done by the Investigational Drug Service.
PY - 2005/1
Y1 - 2005/1
N2 - Gallstone formation is a common problem in neonates on prolonged courses of total parenteral nutrition (TPN). The authors hypothesized that the use of cholecystokinin-octapeptide (CCK), given at the time of TPN administration, would prevent gallstone formation in a high-risk group of patients with TPN. A prospective, randomized, blinded, controlled trial of neonates who were on a prolonged course of TPN for prematurity (25 infants), necrotizing enterocolitis (NEC, 8 infants), or abdominal surgery (5 infants) were selected randomly to receive CCK vs placebo. Patients remained on the study until taking more than 50% of energy enterally. Children were recalled between 2 and 4 years after completing TPN for ultrasonographic examination of their hepatobiliary tree. Neonates (38 studied) required a mean (±SD) of 33 ± 16 days of TPN. Cholelithiasis was detected in 4 (10%) infants. Cholecystokinin-octapeptide was not effective in preventing the formation of gallstones (3 stones in infants receiving CCK, P =. 51). Diagnosis (P =. 56), birth weight (P =. 54), gestational age (P =. 18), and duration of TPN (P =. 53) did not correlate with gallstone formation. To address the management of these stones, all 4 were placed on a prolonged course of ursodeoxycholic acid (mean duration, 11.6 ± 5.4 months). Two additional infants (not in the original study) with TPN-associated gallstone disease were also given a trial of ursodeoxycholic acid. Serial ultrasounds were performed every 6 months. No patient achieved any degree of stone dissolution. One patient underwent cholecystectomy for symptomatology. Total parenteral nutrition-associated gallstones were detected in 10% of children, and most are nonsymptomatic. Cholecystokinin-octapeptide prophylaxis was not effective in preventing TPN-associated gallstones. In addition, the use of ursodeoxycholic acid did not dissolve gallstones, once identified. Future methods will be needed to address the prevention and treatment of these stones.
AB - Gallstone formation is a common problem in neonates on prolonged courses of total parenteral nutrition (TPN). The authors hypothesized that the use of cholecystokinin-octapeptide (CCK), given at the time of TPN administration, would prevent gallstone formation in a high-risk group of patients with TPN. A prospective, randomized, blinded, controlled trial of neonates who were on a prolonged course of TPN for prematurity (25 infants), necrotizing enterocolitis (NEC, 8 infants), or abdominal surgery (5 infants) were selected randomly to receive CCK vs placebo. Patients remained on the study until taking more than 50% of energy enterally. Children were recalled between 2 and 4 years after completing TPN for ultrasonographic examination of their hepatobiliary tree. Neonates (38 studied) required a mean (±SD) of 33 ± 16 days of TPN. Cholelithiasis was detected in 4 (10%) infants. Cholecystokinin-octapeptide was not effective in preventing the formation of gallstones (3 stones in infants receiving CCK, P =. 51). Diagnosis (P =. 56), birth weight (P =. 54), gestational age (P =. 18), and duration of TPN (P =. 53) did not correlate with gallstone formation. To address the management of these stones, all 4 were placed on a prolonged course of ursodeoxycholic acid (mean duration, 11.6 ± 5.4 months). Two additional infants (not in the original study) with TPN-associated gallstone disease were also given a trial of ursodeoxycholic acid. Serial ultrasounds were performed every 6 months. No patient achieved any degree of stone dissolution. One patient underwent cholecystectomy for symptomatology. Total parenteral nutrition-associated gallstones were detected in 10% of children, and most are nonsymptomatic. Cholecystokinin-octapeptide prophylaxis was not effective in preventing TPN-associated gallstones. In addition, the use of ursodeoxycholic acid did not dissolve gallstones, once identified. Future methods will be needed to address the prevention and treatment of these stones.
KW - Cholecystokinin
KW - Cholelithiasis
KW - Total parenteral nutrition
UR - http://www.scopus.com/inward/record.url?scp=12444323678&partnerID=8YFLogxK
U2 - 10.1016/j.jpedsurg.2004.09.036
DO - 10.1016/j.jpedsurg.2004.09.036
M3 - Article
C2 - 15868595
AN - SCOPUS:12444323678
SN - 0022-3468
VL - 40
SP - 263
EP - 267
JO - Journal of Pediatric Surgery
JF - Journal of Pediatric Surgery
IS - 1
ER -