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Establishing Enteral Feeding in Preterm Infants with Feeding Intolerance: A Randomized Controlled Study of Low-dose Erythromycin

Ng, Steven Chin-Yuen*; Gomez, Joseph Manuel†; Rajadurai, Victor Samuel†; Saw, Seang-Mei‡; Quak, Seng-Hock§

Journal of Pediatric Gastroenterology & Nutrition: November 2003 - Volume 37 - Issue 5 - pp 554-558
Original Articles-Liver and Nutrition

Objective: A prospective, double-blind, randomized, controlled trial was conducted to evaluate the effect of low-dose erythromycin on the time taken to attain full enteral feedings in preterm infants with very low birth weight and feeding intolerance.

Methods: Two groups of preterm infants (birth weight ≤ 1500 g) with feeding intolerance were randomized to either low-dose erythromycin (5 mg/kg every 8 hours) or 5% dextrose placebo, both of which were discontinued 1 week after full enteral feedings were tolerated. The primary outcome variable was the time taken to attain full enteral feedings of at least 130 mL/kg/d.

Results: The gestational age at birth was similar in the two groups (erythromycin, 27.1 ± 1.9 weeks; placebo, 27.5 ± 2.9 weeks). The mean birth weight of the erythromycin group was lower (806.3 ± 215.6 g) than the placebo group (981.4 ± 285.4 g; P = 0.18), and included more infants who were small for gestational age (4/13 = 31% versus 1/11 = 9%; P = 0.224). There was no difference between the two groups with regard to the volume of feedings they were receiving at the time of enrollment. Reduction in symptoms of gastroesophageal reflux was similar in the two groups. 3 of 13 in the erythromycin group and 4 of 11 in the placebo group improved during the study (P = 0.565). The mean time to attain full enteral feedings after enrollment was 24.9 + 2.9 days in the erythromycin group and 30.8 ± 4.1 days in the placebo group, a difference that did not reach statistical significance (P = 0.17).

Conclusions: Low-dose erythromycin did not reduce the time taken to attain full enteral feedings in preterm infants with very low birth weight and feeding intolerance. Gastroesophageal reflux decreased as a consequence of maturation of the gastrointestinal tract and not because of erythromycin. These preliminary results justify verification in larger multicenter trials.

One of the major challenges facing the neonatologist is to help the preterm infant attain full enteral feeds without the complications of necrotizing enterocolitis and parenteral nutrition-related septicemia or cholestasis. Erythromycin is a potent analog of the gastrointestinal hormone motilin, which promotes gastric emptying and induces phase III migratory motor complexes (MMCs). Erythromycin induces intense bursts of phase III MMC contractile activity, which propagates from stomach to ileum in both animals (1–3) and humans (4).

Erythromycin at standard antimicrobial doses has been used successfully to treat gastrointestinal dysmotility in three case series of preterm infants (4–6). However, two randomized trials (7,8) comparing the effects of prophylactic erythromycin on the establishment of enteral feeding in preterm infants did not demonstrate a reduction in the time needed to establish full enteral feedings. A recent randomized study (9) in which 56 preterm infants with feeding intolerance were treated with either oral erythromycin 12.5 mg/kg every 6 hours for 14 days or saline placebo reported attainment of half, three quarters, and full enteral feeds significantly faster in the erythromycin group. In another double-blind randomized, placebo-controlled crossover study of 20 preterm infants with feeding intolerance (10), oral erythromycin (10 mg/kg every 8 hours) given for 7 days resulted in increased antral contractility and reduced whole gut transit time.

Published studies have suggested that doses of erythromycin lower than those normally given for antimicrobial activity may result in better prokinetic activity (2,11,12). Apart from two abstracts showing no improvement in premature infant feeding tolerance with intravenous low-dose erythromycin (13,14), this is the first randomized, controlled trial in preterm infants with feeding intolerance treated with low-dose oral erythromycin. It was our objective to ascertain whether low dose, oral erythromycin would hasten establishment of full enteral feedings in preterm infants less than 1500 g with feeding tolerance and to assess the side effects of this therapy (15–18).

*Department of Neonatology, Children's Medical Institute, National University Hospital; †Department of Neonatology, Kandang Kerbau Women's & Children's Hospital; ‡Department of Community, Occupational & Family Medicine, National University of Singapore and §Department of Paediatrics, Children's Medical Institute, National University Hospital

Received January 15, 2003; accepted June 1, 2003.

Address correspondence and reprint requests to: Dr. Steven Ng, Consultant and Clinical Lecturer in Paediatrics, Department of Neonatology, Children's Medical Institute, National University Hospital, Singapore 119074 (e-mail: ngcy@nuh.com.sg).

Presented in part at the 7th Congress of the Asia Pan-Pacific Society of Pediatric Gastroenterology & Nutrition, Cairns, Queensland, Australia, April 21–24, 2001.

© 2003 Lippincott Williams & Wilkins, Inc.