Arginine supplementation for prevention of necrotising enterocolitis in preterm infants

Shah P, Shah V

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs


Dates

Date edited: 08/06/2007
Date of last substantive update: 01/05/2007
Date of last minor update: / /
Date next stage expected 16/05/2009
Protocol first published: Issue 3, 2003
Review first published: Issue 4, 2004

Contact reviewer

Dr Prakeshkumar S Shah
Staff Neonatologist, Mount Sinai Hospital
Department of Paediatrics and Department of Health Policy, Management and Evaluation
University of Toronto
Rm 775A
600 University Avenue
Toronto
Ontario CANADA
M5G 1XB
Telephone 1: +1 416 586 4761
Telephone 2: +1 416 334 6661
Facsimile: +1 416 586 8745
E-mail: pshah@mtsinai.on.ca

Contribution of reviewers

Dr. P S Shah
Literature search and identification of trials
Evaluation of methodological quality of trials
Data collection
Verification of data and entry in Revman
Writing the text of review

Dr. V Shah
Literature search and identification of trials
Evaluation of methodological quality of trials
Data collection
Verification of data
Revision of the review

Internal sources of support

Mount Sinai Hospital, University of Toronto, Toronto, CANADA

External sources of support

None

What's new

This updates the review "Arginine supplementation for prevention of necrotising enterocolitis in preterm infants" published in The Cochrane Library, Issue 4, 2004 (Shah 2004).

Follow up data from one included study (Amin 2002) were available in an abstract form. The data were included in this version as post-hoc analysis.

Dates

Date review re-formatted: / /
Date new studies sought but none found: 20/04/2007
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 20/04/2007
Date reviewers' conclusions section amended: 20/04/2007
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis


Arginine supplements for preventing severe, damaging inflammation of the gastrointestinal (GI) tract (necrotising enterocolitis) in infants born before 37 weeks gestation (preterm)

Necrotising enterocolitis (NEC) may be caused by an infant's immaturity, a lack of blood flow to the GI tract (ischemia), and surface (mucosa) breakdown resulting from infection or feeding with strong/concentrated (hyperosmolar) solutions. It can result in feeding intolerance, problems with intestinal motility or a very sick infant. To protect the GI tract the body makes a natural substance, nitric oxide, from the amino acid arginine. Plasma arginine concentrations are reported to be low in very low birth weight infants and preterm infants who develop NEC. Adding extra arginine to the feeding solution may, therefore, prevent NEC. The review authors searched the literature for controlled studies evaluating the efficacy and safety of arginine supplementation. Adding extra arginine to a preterm infant's feed, starting between 2 to 5 days of age and continued until 28 days of age, reduced the risk of developing NEC in one good quality study (in 152 infants born at less than 32 weeks gestation). Five infants had to be treated for one to benefit. This was the only study identified and it had a high incidence of NEC possibly because it included even the lowest grade of NEC. No significant side effects directly attributable to too much arginine were observed. Possible effects of supplementing arginine are a lowering of blood pressure and change in control of blood glucose.

Abstract



Background


Immaturity, ischemia, and disturbances in gut mucosal integrity due to infections or hyperosmolar feeds are some of the suspected mechanisms in the development of necrotising enterocolitis (NEC) in preterm infants. Decreased concentration of nitric oxide is proposed as one of the possible cellular mechanisms for NEC. Plasma arginine concentrations were found to be lower in infants who developed NEC. Arginine can act as a substrate for the production of nitric oxide in the tissues and arginine supplementation may help in preventing NEC.

Objectives


To examine the effect of arginine supplementation on the incidence of NEC in preterm neonates.


Search strategy


A literature search was performed using the following databases: MEDLINE (1966 - April 2007), EMBASE (1980 - April 2007), CINAHL (1982 - April 2007), Cochrane Controlled Trials Register (Issue 2, 2007 of Cochrane Library) and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991-2007). No language restrictions were applied.

Selection criteria


Study design: randomized or quasi-randomized controlled trials
Population: preterm neonates.
Intervention: enteral or parenteral arginine supplementation (in addition to what an infant may be receiving from enteral or parenteral source), compared to placebo or no treatment; arginine administered orally or parenterally for at least seven days in order to achieve adequate plasma arginine levels (145 umol/l).
Outcomes: any of the following outcomes - NEC, death prior to discharge, death due to NEC, surgery for NEC, duration of total parenteral nutrition, plasma concentrations of arginine and glutamine at baseline and seven days after intervention, side effects of arginine.

Data collection & analysis


The methodological quality of the trials was assessed using the information provided in the studies and by personal communication with the author. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and mean difference (MD) as appropriate.

Main results


Only one eligible study was identified. The methodological quality of the included study was good. There was a statistically significant reduction in the risk of developing NEC (any stage) in the arginine group compared with the placebo group [RR 0.24 (95% CI 0.10, 0.61), RD -0.21 (95% CI -0.32, -0.09)]. No significant side effects directly attributable to arginine were observed. In this updated version, follow up data from this trial were available that revealed no statistically significant difference in the adverse outcomes.

Reviewers' conclusions


The data are insufficient at present to support a practice recommendation. A multicentre randomized controlled study of arginine supplementation in preterm neonates is needed, focusing on the incidence of NEC, particularly the more severe stages (2 or 3).


Background


Necrotising enterocolitis (NEC) has been was categorized in three different stages by Bell 1978 and later modified by Walsh 1986. The clinical features vary from constitutional symptoms such as feeding intolerance to severe systemic symptoms including cardiorespiratory decompensation, coagulopathy, peritonitis and ascites with or without pneumoperitoneum. Due to marked variability in the clinical manifestations, the reported incidence of NEC varies from 4 - 22% among very low birth weight infants in various centres (Stoll 1994).

The exact etiology of NEC is unknown. Suspected pathophysiologic mechanisms include immaturity, ischemia, disruption of mucosal integrity, formula feeding, hyperosmolar load to intestine, infection and bacterial translocation (Caplan 2001). Animal experiments have shown that subsequent to ischemia the intestinal permeability increased (Langer 1993) and that may lead to passage of bacteria and endotoxins into the intestinal wall affecting mucosal integrity. Intestinal dysmotility and disruption in mucosal integrity play important roles in the pathogenesis of NEC (Di Lorenzo 1995).

Nitric oxide is important in normal gastrointestinal function from several perspectives. First, nitric oxide is an important regulator of vasomotor function (Stark 1992). Inadequate concentration of nitric oxide leads to vasoconstriction of the intestinal vessels, which might lead to ischemia and a predisposition to NEC. Second, nitric oxide acts as a neurotransmitter for enteric non-adrenergic non-cholinergic neurons that regulate peristalsis (Boeckxstaens 1991). Lack or inadequacy of nitric oxide can alter intestinal motility. Third, nitric oxide inhibits leucocyte adherence and modulates the inflammatory responses in the intestine (Akisu 2002) to various insults. Therefore, it is important to achieve normal concentration of nitric oxide in the gastrointestinal (GI) tract. Due to its volatile nature, nitric oxide can not be delivered to the GI tract in its present form. An indirect method of achieving adequate concentration is by supplementing substrates such as arginine for its production.

Arginine is an amino acid that is a precursor for proteins (Wu 1998) and nitric oxide synthase. The availability of plasma arginine is important for the formation of nitric oxide (Castillo 1995; Zamora 1998). Plasma arginine concentration was found to be 95+/- 25 umol/l in term breast fed (n = 16) infants (Wu 1986). In extremely low birth weight infants (< 1,000 g birth weight) who were fed on formula feeds (n = 2) the mean arginine concentration was found to be 37 umol/l (range 13 - 60 umol/l) while the mean arginine concentration was 53 umol/l (range 3 - 116 umol/l) in breast fed (n=9) infants (Ventura 1987). In a case control study, Becker 2000 found that arginine and glutamine levels were similar at day three, but significantly lower at day seven and 14 in infants who developed NEC. Zamora 1997 found statistically significantly reduced plasma arginine concentration in preterm infants who developed NEC compared to control infants even after adjusting for the intake of arginine and day of life. The recommended minimum and maximum concentrations of arginine in preterm infant formula are 72 mg/100 kcal and 104 mg/100 kcal respectively (Klein 2002). These requirements are higher in infants who are stressed due to higher utilization in conditions like NEC or pulmonary hypertension. The concentration of arginine found in the current formula is 47 - 51 mg/100 kcal (according to manufacturer's specifications). Therefore, preterm infants have low arginine levels and intakes. Supplementation of arginine may help in the prevention of NEC by promoting nitric oxide synthesis.

In an experimental model of hypoxemia/reoxygenation-induced NEC in mice, dietary supplementation of arginine had a protective effect as evidenced by lower injury score on histopathological examination (Akisu 2002). In a piglet model of NEC, continuous infusion of arginine reduced the severity of intestinal injury (Di Lorenzo 1995). However, in a rat model of ischemia reperfusion injury, nitric oxide was not found to play a protective role in immature and newborn intestine (Chan 2002). Therefore, conflicting reports exist from animal experiments regarding the role of nitric oxide in the pathogenesis of NEC.

Arginine supplementation can cause alteration in glucose homeostasis (both hypo and hyperglycemia) and histaminergic side effects (Vosatka 1994). It was found that inhibition of nitric oxide synthesis reduced hypotension in endotoxin mediated septic shock in rats and thus promotion of nitric oxide synthesis in infants with sepsis may lead to irreversible septic shock (Thiemermann 1990). This makes it imperative that any human studies of arginine supplementation to prevent NEC should be rigorously evaluated for both benefit and risk.

The objective of this review was to evaluate the efficacy and safety of arginine supplementation in decreasing the incidence of NEC among preterm neonates. As the rise in the plasma levels of arginine depends on the dose of arginine used, a subgroup analysis was planned based on the dose of arginine administered. In addition, the baseline incidence of NEC is low in infants > 32 weeks gestation, so a subgroup analysis based on this cut off was planned to examine the efficacy of arginine in lower gestational age group infants.

Objectives


To examine the effect of arginine supplementation on the incidence of NEC in preterm neonates. Subgroup analyses based on the dose of arginine and the gestational age of participants (< or = 32 weeks, > 32 weeks) were planned for this review.

Criteria for considering studies for this review



Types of studies


Randomized or quasi-randomized controlled trials

Types of participants


Preterm infants less than 37 weeks gestation at birth

Types of interventions


Arginine supplementation (in addition to what an infant may be receiving from enteral or parenteral source) versus placebo or no treatment administered orally or parenterally for at least seven days in order to achieve plasma arginine levels at or above the upper end of normal range (145 umol/l in term breast fed infants).

Types of outcome measures


Primary outcome:

Incidence of NEC (any stage) using Bell's criteria (Bell 1978; Walsh 1986) diagnosed prior to discharge

Secondary outcomes:


Post-hoc secondary outcomes:
Neurodevelopmental outcome among survivors (including incidences of cerebral palsy, cognitive delay, blindness and deafness).

Search strategy for identification of studies


MEDLINE was searched (1966 - April 2007) using MeSH terms: enterocolitis necrotizing; enterocolitis; enteritis; colitis; enterocolitis, pseudomembranous; enterocolitis, acute; infant, premature; infant, newborn; infant, premature, disease; clinical trials; randomized controlled trials; random allocation; prospective studies; and arginine.

Other databases that were searched include: EMBASE (1980 - April 2007); CINAHL (1982 - April 2007); the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007) and the reference lists of identified trials and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991 - 2007). No language restrictions were applied.

The following types of articles were excluded: letters, editorials/commentaries, reviews, lectures.

Methods of the review


All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review.

Quality of included trials was evaluated independently by both reviewers, using the following criteria:

1. Masking of randomization
2. Masking of intervention
3. Completeness of follow-up
4. Masking of outcome assessment
There were three potential answers to these questions: yes, no, can't tell.

Data from the primary author were obtained when published data provided inadequate information for the review or where relevant data could not be abstracted. Retrieved articles were assessed and data were abstracted.

Statistical methods included calculation of relative risk (RR), risk difference (RD), number needed to treat (NNT) and mean difference (MD) when appropriate. Ninety five percent confidence intervals (CI) were used for these estimates of treatment effects. A fixed effect model was to be used for meta-analyses. Heterogeneity was evaluated using the I2 statistic.

We performed unplanned subgroup analyses based on stage of NEC (stage 1, 2 or 3) because of the subjective nature of the diagnosis of stage 1 NEC.

Description of studies


Only one eligible study, Amin 2002, was identified. Clinical details concerning the participants, interventions and outcomes are given in the table, Characteristics of Included Studies.

Amin 2002 randomized preterm neonates < 32 weeks and < 1250 g to receive L-arginine (1.5 mmol/kg/day) or placebo (normal saline) in equivalent volume. L-arginine was added to parenteral nutrition solution until infants were able to tolerate >40% of feeds, after which L-arginine or placebo supplementation was provided via enteral route. The administration of study medication started between 2-5 days of age and continued until 28 days of age. The goal was to increase plasma arginine concentrations from a baseline level of 99 umol/l to 164 umol/l (upper limit of normal in healthy full term breast fed infants was 148 umol/l). Other clinical management decisions were left to the clinical care team responsible for the patients. A total of 152 patients were enrolled (75 patients in the L-arginine group and 77 patients in the placebo group).

The primary outcome assessed in the Amin 2002 study was the incidence of NEC (stage 1, 2 and 3 according to Bell 1978). Secondary outcomes assessed were the incidences of various stages of NEC, death due to NEC, death due to any cause, and concentrations of arginine, glutamine and ammonia at baseline, 14 and 28 days of age. The incidences of intraventricular hemorrhage, sepsis, hypotension and patent ductus arteriosus were recorded for both groups. All the survivors were followed up until the completion of the study (28 days of age). Long-term outcome data were reported in an abstract format (Amin 2002); manuscript for full publication is being prepared (personal communication from the author).

Methodological quality of included studies


For the study included in the review, assessments of methodological quality are given in the table, Characteristics of Included Studies. The methodological details for the study were extracted from the published information and by contacting the primary author.

In Amin 2002, randomization was performed centrally by the pharmacist (information obtained from author - Dr. Amin). Allocation was concealed. Masking of the intervention was done so that investigators, parents and caretakers were unaware of treatment allocation. Crossover was not allowed (information provided by author - Dr. Amin) and contamination was not possible because the study drug was not available outside the trial. Outcome assessment (various stages of NEC prior to the completion of study) were blinded as the assessors were not aware of treatment allocation. All randomized patients were accounted for in the analysis of outcomes.

Amin 2002 reported outcome at 36 months postmenstrual age in survivors. It is not mentioned in the abstract that the assessors of follow-up were blinded or not as to the intervention. Of the 145 eligible infants for the follow up, 135 (93%) infants were followed.

Results


ARGININE SUPPLEMENTATION VS PLACEBO (Comparison 01):

Primary outcome:

Incidence of NEC (any stage according to Bell 1978) among all randomized patients (Outcome Table 01.01):

There was a statistically significant reduction in the risk of developing NEC (any stage) in the arginine group as compared with placebo group (RR 0.24 [95% CI 0.10, 0.61], RD -0.21 [95% CI -0.32, -0.09]). The number of patients needed to treat with arginine to prevent the development of NEC among preterm infants < 32 weeks according to this study was 5 (95% CI 3, 11).

Unplanned subgroup analyses according to various stages of NEC are reported below.

a. NEC stage 1 (according to Bell 1978 staging criteria) (Outcome Table 01.02):

There was borderline statistically significant reduction in the risk of developing NEC stage 1 [RR 0.06 (95% CI 0.00, 1.03), RD -0.10 (95% CI -0.18, -0.03)].

b. NEC stage 2 (according to Bell 1978 staging criteria) (Outcome Table 01.03):

There was borderline statistically significant reduction in the risk of developing NEC stage 2 [RR 0.39 (95% CI 0.15, 1.05), RD -0.10 (95% CI -0.20, 0.00)].

c. NEC stage 3
(according to Bell 1978 staging criteria)

None of the patients in either group developed stage 3 NEC.

Secondary outcomes:

a. Mortality (Outcome Table 01.04)

Death due to any cause:

There were three deaths in the arginine group and none in the placebo group. This did not reach statistical significance (RR 7.18 [95% CI 0.38, 136.75], RD 0.04 [95% CI -0.01, 0.09]).

Death due to NEC:

None of the patients in either group died due to NEC.

b. Surgery for NEC


None of the patients in either group required surgical intervention for NEC.

c. Duration of total parenteral nutrition administration


The data on this outcome are not available.

d. Plasma concentration of arginine and glutamine at baseline and after the start of supplementation (Tables 01.05, 01.06):

Plasma arginine concentrations at baseline prior to supplementation were not significantly different between the two groups (MD -10 umol/l [95% CI -23.85, 3.85]). However, plasma arginine concentrations were statistically significantly higher in the group supplemented with arginine at 14 days (MD 70.00 umol/l [95% CI 50.40, 89.60]) and at 28 days of age (MD 79.00 umol/l [95% CI 57.09, 100.91]). Plasma glutamine concentrations at baseline prior to supplementation (MD -42 umol/l [95% CI -91.88, 7.88]) and at 14 days after supplementation (MD 27.00 umol/l [95% CI -22.88, 76.88]) were not statistically significantly different between the two groups; however, there was a statistically significant difference (higher in the arginine supplemented group) in the plasma glutamine concentrations at 28 days of age (MD 82.00 umol/l [95% CI 17.72, 146.28]).

e. Side effects of arginine supplementation (Outcome Table 01.07):

f. Hypotension

There was no statistically significant difference in risk of developing hypotension after 24 hours of age between treatment and placebo (RR 1.03 [95% CI 0.41, 2.59], RD 0.00 [95% CI -0.09, 0.10]).

ii. Alteration in glucose homeostasis

None of the patients in either group developed hypoglycemia during the study period.

Planned subgroup analyses based on gestational age and dose of arginine were not undertaken in the review due to lack of available data.

Post-hoc outcomes: Neurodevelopmental disability among survivors

a. Cerebral palsy: There was no statistically significant difference in the risk of cerebral palsy between two groups (RR 0.88, 95% CI 0.19, 4.08).

b. Cognitive delay (cognitive index < 70): There was no statistically significant difference in the risk of cerebral palsy between two groups (RR 0.78, 95% CI 0.13, 4.81).

c. Visual impairment: None of the infant in either group developed visual impairment.

d. Deafness: There was no statistically significant difference in the risk of cerebral palsy between two groups (RR 3.52 95% CI 0.15, 84.98).

Discussion


An extensive literature search was conducted to identify trials that might qualify for this review. However, only one trial was identified. The number of neonates enrolled in this trial was 152. This version includes update with follow up data from the Amin 2002 study.

The quality of the included study was good, suggesting that extracted data were valid. However, there were some concerning issues regarding this study. The incidence of NEC in the control group was 27.3%, a rate well above that (5 - 10%) reported in recent studies in similar populations. The authors included stage 1 NEC as an outcome, the diagnosis of which is highly subjective and non-specific. The use of stage 1 NEC as an outcome in a prophylactic study is questionable due to the inherent possibility of over-diagnosis, i.e. labelling cases as NEC when they do not have NEC. Because of masking in this study, it is unlikely that any such over-diagnosis was biased. The factors responsible for the high incidence of NEC in this center are unknown. When only patients with stage 2 NEC were analyzed, a trend towards reduction that was not statistically significant was noted. The lack of significance of these post-hoc analyses may be due to reduced sample size in each different stage. Follow-up report reveals that there is no increased risk of neurodevelopmental impairment in survivors.

Arginine supplementation for prevention of NEC could be an important avenue for further research. However, the sample size required for prevention of stage 2 or 3 NEC will be significantly higher than the sample previously studied (for an absolute risk reduction of 50% from a base line incidence of 6% with an alpha of 0.05 and power of 0.8, 750 patients would be required to be studied in each arm). Such a study will require a multicenter undertaking. The fact that Amin 2002 were able to demonstrate reduced concentration of arginine in the patients who developed NEC compared to those who did not develop NEC points towards the possibility of increased utilization or reduced absorption of the substrate, and therefore supports the rationale for undertaking such a study. No significant side effects were observed with supplementation of arginine in the dose of 1.5 mmol/kg, despite reaching arginine levels marginally higher than in normal breast fed term newborn infants. This further supports the rationale for a future study.

Reviewers' conclusions



Implications for practice


Based on one small randomized controlled study of prophylactic administration of arginine for the prevention of NEC in preterm neonates, arginine supplementation may be effective. However, present data are insufficient to support a practice recommendation.

Implications for research


A multicenter randomized controlled study of arginine supplementation in preterm neonates is needed, focusing on the incidence of NEC, stage 2 or 3.


Acknowledgements


Authors would like to acknowledge Prof. Stanley Zlotkin for reviewing the protocol and expert advice. We would also like to thank Dr Harish Amin for providing details from their study.

Potential conflict of interest


None.

Characteristics of included studies

StudyMethodsParticipantsInterventionsOutcomesNotesAllocation concealment
Amin 2002Double blind placebo controlled randomized study
1. Masking of randomization: Yes
2. Masking of intervention: Yes
3. Completeness of follow-up: Yes
4. Masking of outcome assessment: Yes
152 infants < or = 32 weeks gestation at birth and birth weight < or = 1250 g were enrolled after parental consent.
Arginine group (75 neonates): Mean (SD) birth weight was 952 (216) g and gestational age was 27.4 (2.6) weeks
Placebo group (77 neonates): Mean (SD) birth weight was 955 (175) g and gestational age was 27.6 (1.8) weeks
Exclusion criteria: Severe congenital anomalies, congenital non-bacterial infections, evidence of intraventricular hemorrhage grade > or = 2, conjugated hyperbilirubinemia, inborn error of metabolism, exchange transfusion during the study period, preexisting renal failure defined as urine output < 0.5 ml/kg/hr for > 8 hours)
Arginine group n=75: 1.5 mmol/kg/day of L-arginine supplemented either with parenteral nutrient solution or enterally when infant was able to tolerate >40% of total feeds from randomization (day 2-5) till 28 days of age
Placebo group n=77: Equal volume of placebo solution (normal saline) given similar to arginine supplementation in identical vials from randomization (day 2-5) till 28 days of age
NEC (any stage)
NEC stage 1
NEC stage 2
Mortality due to NEC
Mortality due to any cause
Plasma arginine, glutamine concentrations at baseline, at 14 and 28 days of age
A

References to studies

References to included studies

Amin 2002 {published data only}

Amin H, Soraisham AS, Sauve R. Does L-arginine supplementation used in the prevention of NEC in < or =1250gm birth weight infnats adversely impact neurodevelopment? E-PAS 2006;59:2862.228.

Amin HJ, Zamora SA, McMillan DD, Fick GH, Butzner JD, Parsons HG, Scott RB. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. Journal of Pediatrics 2002;140:425-31.

* indicates the primary reference for the study

Other references

Additional references

Akisu 2002

Akisu M, Ozmen D, Baka M, Habif S, Yalaz M, Arslanoglu S et al. Protective effect of dietary supplementation with L-arginine and L-carnitine on hypoxia/reoxygenation-induced necrotizing enterocolitis in young mice. Biology of the Neonate 2002;81:260-5.

Becker 2000

Becker RM, Wu G, Galanko JA, Chen W, Maynor AR, Bose CL, Rhoads JM. Reduced serum amino acid concentrations in infants with necrotizing enterocolitis. Journal of Pediatrics 2000;137:785-93.

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187:1-7.

Boeckxstaens 1991

Boeckxstaens GE, Pelckmans PA, Bult H, De Man JG, Herman AG, van Maercke YM. Evidence for nitric oxide as mediator of non-adrenergic non-cholinergic relaxations induced by ATP and GABA in the canine gut. British Journal of Pharmacology 1991;102:434-8.

Caplan 2001

Caplan MS, Jilling T. New concepts in necrotizing enterocolitis. Current Opinions in Pediatrics 2001;13:111-5.

Castillo 1995

Castillo L, DeRojas-Walker T, Yu YM, Sanchez M, Chapman TE, Shannon D et al. Whole body arginine metabolism and nitric oxide synthesis in newborns with persistent pulmonary hypertension. Pediatric Research 1995;38:17-24.

Chan 2002

Chan KL, Hui CW, Chan KW, Fung PC, Wo JY, Tipoe G, Tam PK. Revisiting ischemia and reperfusion injury as a possible cause of necrotizing enterocolitis: Role of nitric oxide and superoxide dismutase. Journal of Pediatric Surgery 2002;37:828-34.

Di Lorenzo 1995

Di Lorenzo M, Bass J, Krantis A. Use of L-arginine in the treatment of experimental necrotizing enterocolitis. Journal of Pediatric Surgery 1995;30:235-41.

Klein 2002

Klein CJ. Nutrient requirements for preterm infant formulas. Journal of Nutrition 2002;132:1395S-577S.

Langer 1993

Langer JC, Sohal SS, Riddell RH. Mucosal permeability to 51Cr EDTA following subclinical intestinal ischemia-reperfusion injury in the weanling rat. Journal of Pediatric Surgery 1993;28:601-5.

Stark 1992

Stark ME, Szurszewski JH. Role of nitric oxide in gastrointestinal and hepatic function and disease. Gastroenterology 1992;103:1928-49.

Stoll 1994

Stoll BJ. Epidemiology of necrotizing enterocolitis. Clinics in Perinatology 1994;21:205-18.

Thiemermann 1990

Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. European Journal of Pharmacology 1990;182:591-5.

Ventura 1987

Ventura V, Brooke OG. Plasma amino acids in small preterm infants fed on human milk or formula. Archives of Disease in Childhood 1987;62:1257-64.

Vosatka 1994

Vosatka RJ, Kashyap S, Trifiletti RR. Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biology of the Neonate 1994;66:65-70.

Walsh 1986

Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatric Clinics of North America 1986;33:179-201.

Wu 1986

Wu PYK, Edwards N, Storm MC. Plasma amino acid pattern in normal term breast-fed infants. Journal of Pediatrics 1986;109:347-9.

Wu 1998

Wu G, Morris SM, Jr. Arginine metabolism: nitric oxide and beyond. The Biochemical Journal 1998;336:1-17.

Zamora 1997

Zamora SA, Amin HJ, McMillan DD, Kubes P, Fick GH, Butzner JD, Parsons HG, Scott RB. Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis. Journal of Pediatrics 1997;131:226-32.

Zamora 1998

Zamora SA, Amin HJ, McMillan DD, Fick GH, Butzner JD, Parsons HG, Scott RB. Plasma L-arginine concentration, oxygenation index, and systemic blood pressure in premature infants. Critical Care Medicine 1998;26:1271-6.

Other published versions of this review

Shah 2004

Shah P, Shah V. Arginine supplementation for prevention of necrotising enterocolitis in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2004.

Comparisons and data

Comparison or outcome
Studies
Participants
Statistical method
Effect size
01 Arginine vs placebo
01 NEC any stage
1
152
RR (fixed), 95% CI
0.24 [0.10, 0.61]
02 Stage 1 NEC
1
152
RR (fixed), 95% CI
0.06 [0.00, 1.03]
03 Stage 2 NEC
1
152
RR (fixed), 95% CI
0.39 [0.15, 1.05]
04 Mortality
RR (fixed), 95% CI
Subtotals only
05 Plasma arginine concentrations (umol/l)
WMD (fixed), 95% CI
Subtotals only
06 Plasma glutamine concentrations (umol/l)
WMD (fixed), 95% CI
Subtotals only
07 Side effects
RR (fixed), 95% CI
Subtotals only
08 Cerebral palsy
1
135
RR (fixed), 95% CI
0.88 [0.21, 3.80]
09 Cognitive delay (Cognitive index <70)
1
135
RR (fixed), 95% CI
0.78 [0.14, 4.55]
10 Visual impairment
1
135
RR (fixed), 95% CI
Not estimable
11 Deafness
1
135
RR (fixed), 95% CI
3.52 [0.15, 84.98]

 

01 Arginine vs placebo

01.01 NEC any stage

01.02 Stage 1 NEC

01.03 Stage 2 NEC

01.04 Mortality

01.04.01 Mortality due to any cause

01.04.02 Mortality due to NEC

01.05 Plasma arginine concentrations (umol/l)

01.05.01 Baseline

01.05.02 On day 14

01.05.03 On day 28

01.06 Plasma glutamine concentrations (umol/l)

01.06.01 Baseline

01.06.02 On day 14

01.06.03 On day 28

01.07 Side effects

01.07.01 Hypotension

01.07.02 Hypoglycemia

01.08 Cerebral palsy

01.09 Cognitive delay (Cognitive index <70)

01.10 Visual impairment

01.11 Deafness


Contact details for co-reviewers

Dr Vibhuti S Shah
Staff Neonatologist
Department of Paediatrics
Mount Sinai Hospital
Room 775A
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: 416 586 4816
Telephone 2: 416 664 6708
Facsimile: 416 586 8745
E-mail: vshah@mtsinai.on.ca

 

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.