Objective. To determine whether cholecystokinin-octapeptide (CCK-OP) would prevent or ameliorate parenteral nutrition-associated cholestasis (PNAC) among high-risk neonates treated with total parenteral nutrition.
Study Design. This was a multicenter, double-blind, randomized, controlled trial conducted between 1996 and 2001.
Patients. Neonates at risk for the development of PNAC included very low birth weight neonates and those with major surgical conditions involving the gastrointestinal tract.
Setting. Tertiary care hospitals.
Intervention. Patients were randomized to receive CCK-OP (0.04 μg/kg per dose, twice daily) or placebo. Eligible infants were all <30 days of age. Patients were enrolled within 2 weeks after birth or within 7 days after surgery.
Outcome Measures. The primary outcome measure was conjugated bilirubin (CB) levels, which were measured weekly. Secondary outcome measures included incidence of sepsis, times to achieve 50% and 100% of energy intake through the enteral route, number of ICU and hospital days, mortality rate, and incidences of biliary sludge and cholelithiasis.
Results. A total of 243 neonates were enrolled in the study. CCK-OP administration did not significantly affect CB levels (1.76 ± 3.14 and 1.93 ± 3.31 mg/dL for CCK-OP and placebo groups, respectively; mean ± SD). Secondary outcome measures also were not significantly affected by the study drug.
Conclusions. Use of CCK-OP failed to reduce significantly the incidence of PNAC or levels of CB. CCK-OP had no effect on other secondary measures and should not be recommended for the prevention of PNAC.
7/6/2005
To the Editor-
We read with interest the randomised-controlled trial of cholecystokinin-Octaeptide for the prevention of parenteral nutrition associated cholestasis (PNAC) in the recent issue of Pediatrics.1 We wish to raise the following issues in relation to the negative results of this trial. [1] Details of guidelines for enteral feeding during the entire study period would have been helpful as treatment with cholecystokinin- Octaeptide was to be stopped once the neonate received > 50% of energy needs through the enteral route. Practices such as the use of minimal enteral feeds are expected to improve the tolerance to enteral feeds, minimise the need for parenteral nutrition and affect the outcomes of interest. [2] The inclusion criteria at the start of the trial [Birth weight <1000gms and gestation <28 weeks) were not the most appropriate from the clinical point of view. Barring the exception of a few with refractory feed intolerance most extremely low birth weight (ELBW) neonates usually reach enteral feeds ~140-150ml/kg/day by third week of life and PNAC is a rarity in such cases. [3] The sample size estimation based on the preliminary prospective data (n=21) and historical controls is (matched for gestation and duration of parenteral nutrition) an issue. The neonates in the preliminary study (18 surgical and 3 low birth weight neonates) were not representative of the enrolment criteria (ELBW and <28 weeks) for the trial. Thus the incidence of PNAC (intervention: 9%, Control: 38%) used for estimating the sample size and the desired effect size (60% reduction in the incidence of PNAC) for the trial were not appropriate at least till the change of enrolment criteria halfway through the trial. Institutional data either on ELBW and <28 weeks gestation neonates or those with surgical conditions like short bowel syndrome and gastroschisis would have been more appropriate for designing the trial that needed significant amount of time, effort, and money. [4] The numbers in the patient flow chart do not tally. Total 421 neonates were assessed for eligibility, 115 were excluded and 243 were randomised, leaving 63 neonates unaccounted for. [5] Discussion about the cost factor would have been helpful.
Sincerely
Girish Deshpande, DNB. Department of Neonatal Paediatrics KEM Hospital for Women, Perth Western Australia 6008 E-mail: Girish.Deshpande@health.wa.gov.au
References: Teitelbaum DH, Tracy Jr TF, Aouthmany MM et al. Use of Cholecystokinin- Octapeptide for the Prevention of Parenteral Nutrition-Associated Cholestasis Pediatrics 2005; 115: 1332-1340.
Conflict of Interest:
None declared