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Late infection in a randomised controlled trial of pre-emptive morphine analgesia in preterm infants

Presented at the Neonatal Society 2004 Autumn Meeting (programme).

Menon G1, Boyle EM1, McIntosh N2, Anand KJS3

1 Neonatal Unit, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Little France, Edinburgh, UK
2 Department of Child Life and Health, University of Edinburgh, UK
3 University of Arkansas for Medical Sciences, Akansas, USA

Hypothesis: Morphine increases the incidence of late sepsis in preterm infants.

Objectives: 1. To study the effect of morphine on the rate of positive blood culture between 72 hours of age and the attainment of full enteral feeds (PBC), and 2. to look at independent influences on this rate.

Background: Morphine is commonly used to provide analgesia and sedation for neonates receiving intensive care. The NEOPAIN study (1) showed that pre-emptive use of morphine in ventilated preterm infants does not reduce the likelihood of death or major neuromorbidity. This might be because important adverse effects of morphine were nullifying its beneficial effects on preterm physiology. Morphine causes neuromuscular slowing of the mature gut. Such an effect in preterm infants could result in increased nosocomial infection because of slower feed advancement leading to (a) the greater use of intravenous lines and feeding and (b) bacterial translocation across a poorly primed gut.

Methods: The NEOPAIN study was a multicentre, double blind, randomised controlled trial of preemptive morphine (M) or placebo (P) infusion in ventilated preterm infants. A loading dose of study drug (100μg/kg of morphine) was followed by an infusion for up to 14 days at a dose dependent on gestation (23-26 weeks: 10μg/kg/hr, 27-29 weeks: 20μg/kg/hr, 30-32 weeks: 30μg/kg/hr). Additional “open-label” morphine (A) could be given if clinically indicated. Detailed information was kept about morphine administration. For the purpose of the current study, additional information about blood cultures was gathered retrospectively by 6 centres. Ethical approval for the study was obtained from the hospital and university Research Ethics Committees for each site.

Results: Intention to treat analysis did not show a difference between groups in the proportion of babies with PBC (M 62/267, P 54/263, Chi square P=0.45). There was no difference in PBC between the 4 groups comprising babies who got morphine or placebo with or without A (Chi square, P=0.86). Similarly babies who got any morphine did not show a different rate of PBC compared to those who got none (Chi square, P=0.93). No relationship was found between the total weight related dose, in those babies who received any morphine, and the risk of PBC (Mann Whitney U test, P=0.225). On univariate analysis (Chi square), there was marked variation in the rate of PBC by centre (P=0.026). Logistic regression analysis using factors showing a univariate association, showed that centre and age at full enteral feeds were independent predictors of PBC.

Conclusions: In this study, babies who received morphine were not more likely to have blood culture evidence of late sepsis prior to establishment of full enteral feeds. There were significant inter-unit differences in positive blood cultures. Although not obviously related to the use of morphine, late positive blood culture was independently influenced by age of establishment of full enteral feeds.

1. Anand KJ, Hall RW, Desai N, et al. Lancet 2004;363:1673-82.

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