The Journal of Pediatrics
Volume 140, Issue 4 , Pages 389-391, April 2002

Arginine supplementation and the prevention of necrotizing enterocolitis in very low birth weight infants☆☆☆

University of Florida Department of Pediatrics Gainesville, FL 32610-0296

Article Outline

Abbreviations:  NEC , Necrotizing enterocolitis, NO , Nitric oxice, VLBW , Very low birth weight

 

See related article, p 425

With increased survival of very low birth weight (VLBW) infants, necrotizing enterocolitis (NEC) has emerged at the forefront of diseases that concern neonatologists. The high mortality, morbidity, suffering, and monetary costs associated with NEC underscore the necessity for improved treatment and prevention. Unfortunately, the cellular basis of this disease is poorly understood. We have relied primarily on descriptions of risk factors1 to guide our treatment and preventative regimens. Current treatment modalities are often inadequate because of the rapid progression of NEC from its initial diagnosis. Prevention, rather than treatment, is of the utmost priority. Several preventive modalities have been studied, including the use of prophylactic oral antibiotics,2 immunoglobulin G-immunoglobulin A,3 probiotics,4 egg phospholipids,5 and acidification of formula.6 Most of these trials have a small sample size; some have never been repeated. Others, such as prevention with oral aminoglycosides, have shown efficacy, but the emergence of resistant microorganisms has prevented their continued use. Probably the most widely studied preventive measure that has demonstrated success until now is the use of human milk.7

Several studies in animal models suggest that inhibitors of the inflammatory cascade, such as anti-inflammatory cytokines,8 platelet activating factor inhibition,9 and recombinant growth factors, may be beneficial in the prevention of experimental NEC.10 These studies are of value in helping us understand the pathophysiologic features of NEC, but they may not be using practical agents for the prevention of NEC in the patient care setting. They do not attack the proximal component of the pathophysiologic cascade leading to NEC. Once initiated, the progress of the disease is difficult to stop. Routine administration of these agents is also likely to be relatively expensive when used prophylactically.

The article by Amin et al11 in this issue supports the exciting possibility that supplementation of a nutrient, arginine, may be beneficial in the prevention of NEC. This study follows work by Zamora,12 Becker,13 Wu,14 and others that suggest that arginine nutrition in the premature neonate is suboptimal and that low plasma arginine concentration is a risk factor for the development of NEC. Amin et al conducted a prospective, double-blind, placebo-controlled study of 152 premature infants who were randomized to receive supplemental L -arginine or placebo with oral feeds/parenteral nutrition during the first 28 days of life. The major outcome measure was the development of NEC, but nutrient intakes, plasma ammonia, arginine, and amino acid concentrations were also measured during the course of the study. NEC developed in significantly fewer infants in the arginine-supplemented group than in the placebo controls (6.7% vs 27.3%). Furthermore, plasma arginine concentrations were lower in both groups at the time of the diagnosis of NEC, again emphasizing the relationship of low plasma concentrations of this amino acid and the development of NEC. The authors conclude that arginine supplementation in premature infants reduced the incidence of all stages of NEC.

Several aspects of this study are of note. The prevalence of NEC in the placebo group was an extraordinarily high 27.3%; this included infants with Stage I NEC, a somewhat subjective diagnosis. The prevalence of infants with Stage II NEC was 16.9%, which still appears very high compared with the 6% to 7% seen in the National Institute of Child Health and Human Development Neonatal Network and Pediatrix Network15 (personal communication, Clark R). Therefore, whether this decrease in NEC is applicable to other neonatal ICUs with a lower incidence of NEC is questionable.

The staging of NEC, originally developed by Bell et al,15, 16 is a commonly used instrument that has been helpful in the diagnosis and management of NEC. However, Stage I NEC encompasses a broad spectrum of loosely defined criteria that are not directly diagnostic of intestinal pathologic features. These may represent a myriad of problems including simple feeding intolerance, sepsis, gastroenteritis, ileus, or metabolic problems. Stage II usually denotes that the infant has radiographic signs, such as pneumatosis intestinalis, that are typical of the disease and denote true intestinal pathologic features. Stage I may be useful in alerting the staff to the possibility that NEC may be developing, but is so highly nonspecific that its use as an outcome measure is of questionable benefit. The improved outcome in Stage I patients suggests a positive effect but may not relate directly to intestinal disease. Nevertheless, the trends seen in the study with Stage II disease, which is a more concrete outcome, do raise the possibility of a real effect on the intestine.

Another aspect of the study is the focus on arginine as the substrate for the nitric oxide (NO) reaction. As such, it is hypothesized that the mechanism of the preventive effect against NEC is because of the vasodilator effect of NO generated in this reaction. The role of arginine and its potential effects extend well beyond the generation of NO. Of all the amino acids, arginine is the richest in nitrogen and plays a myriad of roles.14 It is a precursor for the synthesis of other amino acids, notably, glutamine and glutamate, both of which play critical roles in intestinal metabolism. The higher concentration of plasma glutamine in the arginine-supplemented infants may be more than just an incidental finding and may be involved in the mechanism of action of arginine-mediated protection. Other metabolic intermediates closely aligned to arginine are nucleotides, polyamines, and ornithine, all of which have beneficial effects on the gastrointestinal tract.14

In summary, the study of Amin et al11 provides important new information to the increasing body of knowledge about nutrients that are conditionally essential in VLBW infants. As this study suggests, arginine supplementation may play a significant role in the prevention of NEC and/or other neonatal morbidity. If future trials that are focused on NEC as a primary outcome are to be planned, consideration should be given to only comparing patients who have Stage II and Stage III NEC. This does, however, lead to another dilemma: the number of patients required for such a study. It is reasonable to assume that a decrease in NEC from 6% (a number expected in the control group) to 2% (a number comparable to previous studies of human milk)16 would be clinically significant. The number of patients required in the control and supplemented groups for such a study would be approximately 450 patients, excluding death and patient exit from the study. This would achieve an α = .05 and a power (1-β) = 0.80 in a 2-tailed test. Consideration should also be given to stratification and whether the infants are also receiving human milk versus formula in such a study. Reality dictates that the study of NEC as a primary outcome in VLBW infants would be a major challenge no matter what intervention is chosen. Arginine supplementation has excellent theoretic potential in playing a role in nutrition of the VLBW infant. However, its specific beneficial roles still need to be determined; they may extend well beyond the prevention of NEC.

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References 

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  10. Dvorak B, Halpern MD, Holubec H, Williams CS, McWilliams DL, Dominguez JA, et al.  Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol. 2002;282:156–164
  11. Amin JH, Zamora SA, McMillan DD, Fick GH, Butzner JD, Parsons HG, et al.  Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr. 2002;140:425–431
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  14. Wu G, Meininger CJ, Knabe DA, Bazer FW, Rhoads JM. Arginine nutrition in development, health and disease. Curr Opin Clin Nutr Metab Care. 2000;3:59–66
  15. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al.  Very low birth weight outcomes of the national institute of child health and human development neonatal research network, January 1995 through December 1996. Pediatrics. 2001;107(E1):
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☆ Reprint requests: Josef Neu, MD, University of Florida, Department of Pediatrics, PO Box 100296, Gainesville, FL 32610-0296.

☆☆ J Pediatr 2002;140:389-91.

PII: S0022-3476(02)25065-9

doi:10.1067/mpd.2002.124306

Refers to article:

  • Arginine supplementation prevents necrotizing enterocolitis in the premature infant

    Harish J. Amin, Samuel A. Zamora, Douglas D. McMillan, Gordon H. Fick, J.Decker Butzner, Howard G. Parsons, R.Brent Scott
    The Journal of Pediatrics April 2002 (Vol. 140, Issue 4, Pages 425-431)

The Journal of Pediatrics
Volume 140, Issue 4 , Pages 389-391, April 2002

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