Arginine supplementation in prevention of necrotizing enterocolitis in the premature infant: an updated systematic review

Abstract

BackgroundHypoxic-ischemic injury is thought to play a significant role in necrotizing enterocolitis (NEC). Nitric Oxide (NO) is the principal inhibitory neurotransmitter in the gut and is involved in regulation of mucosal blood flow and maintenance of mucosal integrity. NO is synthesized from L-arginine by NO synthases. Our primary objective was to determine the effectiveness of supplemental L-arginine versus placebo in prevention of NEC in preterm infants ≤ 34 weeks gestational age by systematic review of published randomized controlled trials (RCTs).MethodsThis review included RCTs in which L-arginine was administered as a supplement to neonates to prevent NEC. Searches were conducted in OVID MEDLINE, EMBASE, PubMed, and CINAHL from their dates of inception to July, 2014. Inclusion criteria were informed parental consent, neonates born at ≤ 34 weeks gestation, and birth weight ≤ 1500 g. Exclusion criteria included neonates with severe congenital anomalies and inborn errors of metabolism. Incidence of NEC was the primary outcome measure. Whole data were analyzed by RevMan 5.1 (Update Software, Oxford, UK). Outcome data were analyzed to determine risk ratios, number needed to treat, confidence intervals, and test for overall effect.ResultsTwo trials including 425 neonates were eligible for this review. Of these, 235 neonates were included in the study. L-arginine had a 59% reduction in the incidence of stage II and III NEC (RR 0.41, 95% CI 0.20 to 0.85, NNT = 9) compared with placebo (P = 0.02). A similar finding was identified for all stages of NEC (60% reduction, RR 0.40, 95% CI 0.23 to 0.69, NNT = 5) (P = 0.001). At age 3 yrs, there was no significant difference between the 2 groups in terms of any neurodevelopmental disability (RR 0.65; 95% CI 0.23-1.83, P = 0.41).ConclusionsL-arginine supplementation appears to be protective in prevention of NEC in preterm infants and without any significant impact on neurodevelopmental outcomes at 36 months of corrected age. With the addition of the results of one more study to the literature, an intriguing role for L-arginine supplementation continues to gain support. However, large multi-centre RCTs are needed before this can become common practice.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2431-14-226) contains supplementary material, which is available to authorized users.

Correlation between plasma levels of arginine and citrulline in preterm and full‐term neonates: Therapeutical implications

“…The present report confirms previous findings showing lower levels of arginine and citrulline in preterm neonates than in full‐term neonates . The low levels of arginine and citrulline in the premature neonates suggest that they are not capable of synthesizing the required amount of arginine.…”

“…The consequences include serious conditions contributing to high morbidity and mortality of preterm neonates. Such conditions include impairment of the synthesis of proteins in which arginine is an essential building blocks (such as histones) hyperammonemia necrotizing enterocolitis, respiratory distress syndrome, and intraventricular hemorrhage . In some cases, such as hyperammonemia, these conditions might be corrected with arginine and citrulline administration but in other conditions may not be corrected.…”

“…The present report confirms previous findings showing lower levels of arginine and citrulline in preterm neonates than in full-term neonates. [8][9][10][24][25][26] The low levels of arginine and citrulline in the premature neonates suggest that they are not capable of synthesizing the required amount of arginine. In fact, there is a low expression of the genes coding carbamoyl phosphate synthase (CPS-1) ornithine carbamoyl phosphate transferase (OCT), pyrroline-5-carboxylate reductase (P5CR), 27,28 argininosuccinate synthase (ASS) 29 , and argininosuccinate lyase (ASL) 21 in preterm neonates.…”

Therapeutic Benefits of l-Arginine: An Umbrella Review of Meta-analyses

“…Of these, 84 were excluded, and after further review, 2 more meta-analyses were excluded because they were both based on the statistical analysis of only 2 clinical trials (one investigated the use of L-arginine supplementation on clinical outcome for patients with acute myocardial infarctions, and the other investigated the use of L-arginine supplementation in prevention of necrotizing enterocolitis in premature infants). 7,8 The remaining 7 meta-analyses were retrieved for inclusion in this umbrella review. [9][10][11][12][13][14][15] A flow chart of the selection process of the meta-analyses is shown in Figure 1, and Table 1 provides the detailed analysis from the 7 meta-analyses reviewed.…”

Pathogenesis of neonatal necrotizing enterocolitis

“…NO is a free radical that modulates many physiologic processes including vascular tone, tissue homeostasis, neurotransmission, platelet aggregation, mucosal integrity, reperfusion injury, and inflammation [73][74][75][76]. It acts locally via paracrine effects due to its short half-life, solubility in water and lipids, permeability, and ability to diffuse rapidly [77].…”