Glutamine supplementation to prevent morbidity and mortality in preterm infants

Tubman TRJ, Thompson SW, McGuire W

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

Dates

Date edited: 13/11/2007
Date of last substantive update: 13/11/2007
Date of last minor update: / /
Date next stage expected 13/11/2009
Protocol first published: Issue 2, 1999
Review first published: Issue 2, 1999

Contact reviewer

Dr Richard TRJ Tubman, BSc MD FRCP(Ed) FRCPCH
Consultant Neonatologist
Neonatal Intensive Care Unit
Royal Maternity Hospital
Grosvenor Road
Belfast
Northern Ireland UK
Telephone 1: + 44 2890 632491
Telephone 2: + 44 2890 633808
Facsimile: + 44 2890 635485
E-mail: richard.tubman@royalhospitals.n-i.nhs.uk

Contribution of reviewers

TRJT and SWT developed the original protocol and undertook the first review. For this update, TRJT and WM screened the title and abstract of all studies identified in the primary search and screened the full text of the report of each study identified as of potential relevance. TRJT and WM assessed the methodological quality of the included trials and extracted the relevant information and data from each included study independently. TRJT and WM completed the final review.

Internal sources of support

ANU Medical School, Canberra, AUSTRALIA
Royal Maternity Hospital, Belfast, UK

External sources of support

None

What's new

This updates the existing review of "Glutamine supplementation to prevent morbidity and mortality in preterm infants" published in The Cochrane Library, Issue 1, 2005 (Tubman 2005).

One new trial was identified for this update (Bober-Olesinska 2005). Inclusion of data from this trial did not change the main findings or conclusions of this review.

Dates

Date review re-formatted: 03/09/1999
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 30/08/2007
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Glutamine is an important nutrient for growth and development. Glutamine may be especially important in aiding recovery from critical illness. This review found several well-conducted randomised controlled trials that assessed the impact of providing extra glutamine to preterm infants. These trials did not find any evidence that glutamine supplementation affected the risk of death, serious infection, serious gastrointestinal complications, or adverse long-term development.

Abstract

Background

Glutamine endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress. Trials in adults have suggested that glutamine supplementation improves clinical outcomes in critically ill adults. It has been suggested that glutamine supplementation may benefit preterm infants, particularly very low birth weight infants.

Objectives

To determine the effects of glutamine supplementation on mortality and morbidity in preterm infants.

Search strategy

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - July 2007), EMBASE (1980 - July 2007), conference proceedings, and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that compared glutamine supplementation versus no glutamine supplementation in preterm infants at any time from birth to discharge from hospital.

Data collection & analysis

The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two authors. Data were synthesised using a fixed effects model and reported using typical relative risk, typical risk difference and weighted mean difference.

Main results

2365 preterm infants have participated in seven randomised controlled trials. All of the participating infants were of very low birth weight. Three trials assessed enteral glutamine supplementation and four trials assessed parenteral glutamine supplementation. The trials were generally of good methodological quality with adequate allocation concealment, blinding of caregivers and assessors to the intervention, and complete or near-complete follow-up of recruited infants. Glutamine supplementation does not have a statistically significant effect on mortality: typical relative risk 0.98 (95% confidence interval 0.80 to 1.20); typical risk difference 0.00 (95% confidence interval -0.03 to 0.02). The only trial that assessed long-term outcomes did not find any statistically significant differences in various assessments of neurodevelopment at 18 months corrected age. Glutamine supplementation does not have a statistically significant effect on other neonatal morbidities including invasive infection, necrotising enterocolitis, time to achieve full enteral nutrition, or duration of hospital stay.

Reviewers' conclusions

The available data from good quality randomised controlled trials indicate that glutamine supplementation does not confer benefits for preterm infants. The narrow confidence intervals for the effect size estimates suggest that a further trial of this intervention is not a research priority.

Background

Glutamine is the most abundant amino acid in plasma and muscle in humans (Bergstrom 1974). Under normal conditions glutamine is the preferred respiratory fuel for rapidly proliferating cells such as enterocytes (Windmueller 1982) and lymphocytes (Newsholme 1985). It is a regulator of acid-base balance via ammonium, as well as an important precursor of nucleic acids, nucleotides, amino sugars and protein (Krebs 1980).

Research in experimental animals and in adults has suggested a number of roles for glutamine during critical illness. In these situations the amino acid appears to be "conditionally essential" (Lacey 1990). In animal models of experimental enterocolitis glutamine supplementation has been associated with a reduction in mucosal damage, improved nitrogen balance, lower rates of sepsis and improved survival (Klimberg 1990; Rombeau 1990). In these situations glutamine supplementation probably provides extra energy for the increased cell division and proliferation seen in response to gastrointestinal injury. Lower sepsis rates may result from reduced microbial translocation across the gut wall.

In studies in adult humans, glutamine has been shown to attenuate gut atrophy in the fasting state (O'Dwyer 1989), maintain ATP levels in oxidant injured cells (Hinshaw 1990), and preserve immune cellularity of the gastrointestinal in prolonged parenteral feeding (Alverdy 1992). Parenteral glutamine in adults is well tolerated metabolically and appears to have no toxic effects (Ziegler 1990). In a small clinical trial, adults receiving glutamine-supplemented parenteral nutrition after surgery had less deterioration in gastrointestinal permeability and mucosal integrity compared to those receiving parenteral nutrition without glutamine (van der Hulst 1993). A systematic review of randomised controlled trials in adult surgical or critically ill patients suggests that glutamine supplementation may reduce infectious complications, duration of hospital stay, and (possibly) mortality (Novak 2002). A Cochrane review of randomised controlled trials found that patients undergoing bone marrow transplantation who receive parenteral nutrition with glutamine versus standard parenteral nutrition have fewer episodes of sepsis and a shorter duration of hospital admission (Murray 2004). In a randomised trial of enteral glutamine supplementation in patients with multiple trauma, there was a reduction in infectious episodes in the treatment group (Houdijk 1998).

Glutamine is abundant in human milk, but present only in much lower levels in formula milk and not present in standard parenteral nutrition solutions. Given the above findings in adults, it is reasonable to hypothesize that glutamine supplementation in preterm infants (particularly very low birth weight infants) might enhance gastrointestinal mucosal integrity, thus improving enteral feed tolerance, growth and development, and ultimately shorten hospital stay. Enhanced gastrointestinal barrier function and lymphocyte production might reduce the rate of late-onset sepsis or necrotising enterocolitis, and so reduce mortality and adverse neurodevelopmental outcomes.

Objectives

To determine the effects of glutamine supplementation compared to no supplementation on mortality and morbidity in preterm infants. Subgroup analyses of enteral and parenteral glutamine supplementation were prespecified because evidence from systematic reviews of these interventions in adult patients suggests different effect sizes for various outcomes (Novak 2002).

Criteria for considering studies for this review

Types of studies

Controlled trials using either random or quasi-random patient allocation.

Types of participants

Preterm infants (gestational age less than 37 completed weeks).

Types of interventions

Glutamine supplementation versus no supplementation, by the parenteral or enteral route, in addition to a standard nutrition regime. Glutamine supplementation must have been given at some time between birth and discharge from hospital.

Types of outcome measures

Primary outcomes:
1. Death prior to hospital discharge.
2. Neurodevelopmental outcomes at greater than, or equal to, 12 months of age (corrected for preterm birth) measured using validated assessment tools, and classifications of disability, including auditory and visual disability. Severe neurodevelopmental disability will be defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment.

Secondary outcomes:
1. Invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine, or from a normally sterile body space.
2. Necrotising enterocolitis: At least two of the following features: Pneumatosis coli on abdominal X ray; abdominal distension or abdominal X ray with gaseous distension or frothy appearance of bowel lumen (or both); blood in stool; lethargy, hypotonia, or apnea (or combination of these).
3. Growth during the trial period: Weight gain (grams per day, or grams per kilogram per day), linear growth (millimetres per week), head growth (millimetres per week), skinfold thickness growth (millimetres per week).
4. Days, from birth, to establish full enteral tube feeds (at least 150 ml/kg/day), independently of parenteral fluids or nutrition.
5. Days, from birth, to discharge to home from hospital.

Search strategy for identification of studies

The standard search strategy of the Cochrane Neonatal Review Group was used. This consisted of searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - July 2007), and EMBASE (1980 - July 2007). The electronic search used the following text words and MeSH terms: Infant, Newborn OR infan* OR neonat* OR Enterocolitis, Necrotizing OR NEC OR enterocolitis AND glutam* OR L-glutamine. The search outputs were limited with the relevant search filters for clinical trials. No language restriction was applied. References in previous reviews and studies were examined. Abstracts presented at the Society for Pediatric Research and European Society for Pediatric Research, published in the journal Pediatric Research between 1990 and 2006, were searched. Trials reported only as abstracts were eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria. The Journal of Pediatric Gastroenterology and Nutrition (1990 - 2006) was searched. The UK National Research Register (http://www.nrr.nhs.uk), and Current Controlled Trials (http://www.controlled-trials.com) websites were searched for completed or ongoing trials. (MeSH terms: glutamine, infants, newborn, nutrition).

Methods of the review

1. The title and abstract of all studies identified by the above search strategy were screened and the full articles for all potentially relevant trials obtained. The full text of any potentially eligible reports was re-assessed and those studies that did not meet all of the inclusion criteria were excluded. Any disagreements were discussed until consensus was achieved.

2. The criteria and standard methods of the Cochrane Neonatal Review Group were used to independently assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or carers and assessors to intervention, and completeness of assessment in all randomised individuals. Additional information from the trial authors was requested to clarify methodology and results as necessary.

3. A data collection form was used to aid extraction of relevant information from each included study. Each review author extracted the data separately. Any disagreements were discussed until consensus was achieved. If data from the trial reports were insufficient, the trialists were contacted for further information.

4. Outcomes for categorical data are presented as relative risk, risk difference, and number needed to treat, with respective 95% confidence intervals. For continuous data, the weighted mean difference with 95% confidence interval was used.

5. The treatment effects of individual trials and heterogeneity between trial results was examined by inspecting the forest plots. The impact of heterogeneity in any meta-analysis was assessed using a measure of the degree of inconsistency in the studies' results (I- squared statistic). If statistical heterogeneity was noted, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) were explored using post hoc sub group analyses. A fixed effects model for meta-analyses was used.

Description of studies

Seven trials that fulfilled the eligibility criteria were identified; five small single-centre studies (Bober-Olesinska 2005; Lacey 1996; Neu 1997; Thompson 2003; van den Berg 2005), and two large multicentre trials (Poindexter 2004; Vaughn 2003).

Participants: A total of 2365 preterm infants participated in the included trials. 90% of these infants participated in the two largest trials (Poindexter 2004; Vaughn 2003). All participating infants were of very or extremely low birth weight and were recruited to a trial within the first few days of postnatal life.

Intervention: Four trials assessed the effect of parenteral glutamine supplementation (Bober-Olesinska 2005; Lacey 1996; Poindexter 2004; Thompson 2003). Three trials examined the effect of enteral glutamine supplementation (Neu 1997; van den Berg 2005; Vaughn 2003).

Outcomes: Reported outcomes included mortality, the incidence of invasive infection, necrotising enterocolitis, the duration of parenteral nutrition administration, time taken to establish full enteral nutrition, rate of weight gain, and length of hospital admission. Only Poindexter 2004 assessed long-term neurodevelopmental outcomes. Six trials reported the incidence of as an outcome.

Two studies that may be eligible for inclusion if further information on methodology can be obtained from the trialists were identified. In one study it is unclear if the participants were preterm or term infants (Barbosa 1999). In a second study, it is unclear if the infants were randomly allocated to the intervention groups (Li 2007). The respective principal investigators have been contacted to seek this information.

Methodological quality of included studies

The trials were generally of good methodological quality with adequate allocation concealment (randomisation in central pharmacy, computer generated sequence in sealed opaque envelopes) and blinding of caregivers and assessors. Six trials (Bober-Olesinska 2005; Neu 1997; Poindexter 2004; Thompson 2003; van den Berg 2005; Vaughn 2003) achieved complete or near-complete follow-up and reported intention to treat analyses. Lacey 1996 reported post-recruitment withdrawal of about 50% of participants, mainly due to non-compliance with protocol issues, and did not include these infants in analyses of outcomes. There are insufficient data in the published report to allow intention-to treat re-analyses. Therefore, the published data from this trial was not included in any of the meta-analyses. The study investigators have been contacted to seek data on these outcomes for all of the infants recruited to the trial. If these data become available, they will be included in a future update of this review.

Results

GLUTAMINE SUPPLEMENTATION VERSUS NO SUPPLEMENTATION (PARENTERAL OR ENTERAL ROUTE) (COMPARISON 01):

Primary outcomes
Death prior to hospital discharge (Outcome 01.01): Six trials reported this outcome (Bober-Olesinska 2005; Neu 1997; Poindexter 2004; Thompson 2003; van den Berg 2005; Vaughn 2003). None of the studies found a statistically significant difference. Meta-analysis of the data did not reveal a statistically significant difference: Typical relative risk 0.98 (95% confidence interval 0.80 to 1.20); typical risk difference 0.00 (95% confidence interval -0.03 to 0.02). There was no evidence of statistical heterogeneity.

Neurodevelopment: Poindexter 2004 conducted comprehensive neurodevelopmental follow-up of the trial cohort. About 85% of the infants have been reviewed at 18 months corrected age for neurological assessment. The investigators report that they have not found any statistically significant differences between the groups for any of the neurodevelopmental outcomes assessed. 30 month follow-up on all of these infants is planned. These data will be included in an update of this review when they become available.

Secondary outcomes
Invasive infection (Outcome 01.02):
Data were available from four trials (Bober-Olesinska 2005; Neu 1997; Poindexter 2004; Thompson 2003; Vaughn 2003). None of the studies found a statistically significant difference. Meta-analysis did not reveal a statistically significant difference: Typical relative risk 1.01 (95% confidence interval 0.91 to 1.13); typical risk difference 0.00 (95% confidence interval -0.04 to 0.04).

Necrotising enterocolitis (Outcome 01.03): None of the five individual studies that reported this outcome found a statistically significant difference (Neu 1997; Thompson 2003; Poindexter 2004; van den Berg 2005; Vaughn 2003). Meta-analysis did not reveal any statistically significant difference: Typical relative risk 0.98 (95% confidence interval 0.76 to 1.27); typical risk difference 0.00 (95% confidence interval -0.02 to 0.02). There was no evidence of statistical heterogeneity.

Growth during the trial period (Outcome 01.04): Only one trial reported the rate of weight gain during the study period (Thompson 2003). The investigators did not find a statistically significant difference: Mean difference 1.3 grams/ kilogram/ day (95% confidence interval -1.66 to 4.26). Poindexter 2004 did not find a statistically significant difference in the weight of surviving infants in each group when they reached 36 weeks' postmenstrual age. van den Berg 2005 reported no statistically significant difference in weight at the end of the study period (day 30). Vaughn 2003 reported no statistically significant difference in the weight at hospital discharge. Other growth parameters (linear growth, head growth, skinfold thickness) were not reported in any of the trials.

Days from birth to establish full enteral feeds (Outcome 01.05): Data were available from three studies (Poindexter 2004; Thompson 2003; van den Berg 2005). Meta-analysis did not find a statistically significant difference: Weighted mean difference -1.8 days (95% confidence interval -3.6 to 0.1). There was significant statistical heterogeneity (Chi-squared 6.48 (p= 0.04), I-squared 69.1%). There do not appear to be major differences between these studies in terms of quality, participants, intervention regimens, or outcome assessments.

Days, from birth, to discharge to home from hospital (Outcome 01.06): Data were available from four studies (Poindexter 2004; Thompson 2003; van den Berg 2005; Vaughn 2003). Meta-analysis did not find a statistically significant difference: Weighted mean difference 0.13 days, 95% confidence interval -3.3 to 3.6).

Subgroup analyses
ENTERAL GLUTAMINE SUPPLEMENTATION (COMPARISON 02) (including the following studies - Neu 1997; van den Berg 2005; Vaughn 2003):
Clinical Outcomes (Outcomes 02.01- 02.05):
Meta-analysis of the available data from these trials did not detect any statistically significant effects in mortality (typical relative risk 0.95 (95% confidence interval 0.55 to 1.64); typical risk difference 0.00 (95% confidence interval -0.04 to 0.03), invasive infection (typical relative risk 0.95 (95% confidence interval 0.77 to 1.18); typical risk difference -0.01 (95% confidence interval -0.08 to 0.05), necrotising enterocolitis (typical relative risk 1.07 (95% confidence interval 0.67 to 1.71); typical risk difference 0.01 (95% confidence interval -0.03 to 0.04), time to full enteral feeds (weighted mean difference -2.9 days (95% confidence interval -5.92 to 0.12) days, or duration of hospital stay (weighted mean difference -1.3 days (95% confidence interval -5.9 to 3.3).

PARENTERAL GLUTAMINE SUPPLEMENTATION (COMPARISON 03) (including the following studies - Bober-Olesinska 2005; Lacey 1996; Poindexter 2004; Thompson 2003): Clinical Outcomes (Outcomes 03.01- 03.06):
Meta-analysis of the data available from these trials did not detect any statistically significant effect on mortality (typical relative risk 0.98 (95% confidence interval 0.79 to 1.23); typical risk difference 0.00 (95% confidence interval -0.04 to 0.04), invasive infection (typical relative risk 1.07 (95% confidence interval 0.94 to 1.21); typical risk difference 0.03 (95% confidence interval -0.02 to 0.08), or necrotising enterocolitis (typical relative risk 0.94 (95% confidence interval 0.69 to 1.29); typical risk difference -0.01 (95% confidence interval -0.04 to 0.02), time to full enteral nutrition (weighted mean difference -1.1 days (95% confidence interval -3.4 to 1.2), or duration of hospital stay (weighted mean difference -1.9 days (95% confidence interval -3.2 to 7.1).

Discussion

The major finding of this review is that glutamine supplementation does not have a statistically significant effect on mortality in preterm infants. The narrow 95% confidence interval around the estimate of effect suggests that a modest but clinically important effect has not been missed. Data from the largest trial also indicate that glutamine supplementation does not affect long-term neurodevelopmental outcomes (Poindexter 2004). With regard to secondary outcomes, no evidence of an effect on the rate of invasive infection, the incidence of necrotising enterocolitis, or on any of the feeding or growth parameters measured was found.

The biologically plausible effects of glutamine supplementation relate to its role in the repair and growth of rapidly dividing tissues. This action is consistent with the evidence of benefit of glutamine supplementation in critically ill adult patients (Houdijk 1998; Murray 2004; Novak 2002). Although the population of preterm infants who participated in the trials identified in this review were all of very low birth weight (and of extremely low birth weight in the largest trial), it may be that any benefits of glutamine supplementation are confined to those infants who are critically ill, for example with severe gastrointestinal disease such as necrotising enterocolitis. Glutamine supplementation may be beneficial in the recovery phase of these illnesses when infants are severely metabolically compromised and glutamine availability is rate-limiting for tissue repair (Grover 2007; SIGN). Additionally, many of the participating infants in the included trials may not have been truly glutamine-deficient as they received glutamine from breast milk, or received glutamate (a precursor for glutamine) from milk or parenteral nutrition.

Reviewers' conclusions

Implications for practice

Evidence from good quality randomised trials suggests that the routine use of parenteral or enteral glutamine supplementation does not affect mortality or other important clinical outcomes for preterm infants.

Implications for research

Further evaluation of routine glutamine supplementation in preterm infants is not a research priority. Instead, it may be appropriate to focus research effort on assessing the effect of glutamine supplementation in preterm infants with severe gastrointestinal disease (Grover 2007).

Acknowledgements

We are very grateful to Drs Brenda Poindexter, Reece Clark, Ruurd van Elburg, and Bober-Olesiñska for supporting this Cochrane review by discussing aspects of their published findings and for sharing unpublished data (Poindexter 2004; van den Berg 2005; Vaughn 2003; Bober-Olesinska 2005).

Potential conflict of interest

TRJT was principal investigator in one of the included trials (Thompson 2003).

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Bober-Olesinska 2005	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.	55 very low birth weight infants	Treatment: glutamine dipeptide added to standard parenteral nutrition solution to make 20% of total amino acid content (N=25). Control: no added glutamine (N=30).	Nosocomial infection episodes, rate of necrotising enterocolitis.	Abstract in English. Article in Polish (not yet translated). Further information received courtesy of Dr Bober-Olesiñska	A
Lacey 1996	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: no. Blinding of outcome measurement: yes.	78 babies enrolled. Age less than 4 days, parenteral nutrition for less than 3 days Must have met at least 6 of the following criteria: birthweight <1500g, gestational age <32 weeks, 5-minute Apgar score < 6, need for >21% oxygen, need for ventilatory assistance, low blood pressure for age, suspected intraventricular haemorrhage, presence of patent ductus arteriosus, presence of umbilical, arterial and venous catheters and birthweight <1000g.	Treatment: glutamine added to parenteral nutrition solution (N= 39). Control: Parenteral nutrition without added glutamine (N= 39).	Primary: time to full enteral feeds, duration of administration of parenteral nutrition, duration of mechanical ventilation, average weight gain per day.	Glutamine was added to parenteral nutrition at concentrations of between 15% to 25% weight per volume of the aminoacid mix. The protocol specified that participating infants should continue to receive parenteral nutrition for at least seven days. The first group of four babies received glutamine in an open-label study. It is not clear whether these babies were included in the final analysis. Of the 78 babies enrolled, 34 were subsequently excluded for the following reasons: insufficient time on TPN (8 treated and 8 control), surgery or transfer (1 treated and 3 control), development of necrotising enterocolitis (2 treatment and 2 control) or death (5 treatment and 4 control). One was excluded as a "statistical outlier" (allocation not stated). One of the 22 remaining controls did not have blood cultures taken. We have not been able to re-analyse the outcomes for all of the enrolled infants (intention-to-treat).	A
Neu 1997	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.	68 babies enrolled. Age < 3 days Birthweight 500-1250 g Gestational age 24-32 weeks. Enteral feeding regimen beginning on day 3 and continuing to day 30 of life.	Treatment: glutamine added to commercial preterm formula feed (N=35). Control: no added glutamine (N=33).	Average weight, length and head circumference in three time phases (1-14, 15-21 and 22-30 days) Adherence to feeding protocol. Frequency of positive blood cultures. Frequency of necrotising enterocolitis. Duration of hospital stay.	The intervention group received 0.08 grams per kilogram per day of glutamine at the start of the study (day 3), increasing to 0.31 grams per kilogram per day by day 13. Glutamine supplementation was stopped on day 30. All infants received the same level of parenteral nutrition (without added glutamine) while enteral feeds were being advanced. Of the 68 babies enrolled, 27 were withdrawn from the study for the following reasons: transfer (1 treated and 1 control), illness or intolerance of enteral feeding (9 treated and 16 control). All but the two infants who were transferred from the study centre were included in the analysis whether they were able to adhere completely to the feeding protocol or not.	A
Poindexter 2004	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.	1433 babies (birthweight 401-1000 grams) enrolled within 72 hours of birth.	Treatment: 20% glutamine added to standard parenteral nutrition solution (N=721). Control: no added glutamine (N=712).	Primary: Composite outcome of death or late-onset sepsis. Secondary: Number of episodes of late-onset sepsis, rate of necrotising enterocolitis, duration of mechanical ventilation, length of hospital stay, measures of feeding tolerance and intolerance, duration of parenteral nutrition, measures of growth.	The caregivers were not aware whether participating infants received glutamine-supplemented or non-supplemented parenteral nutrition.	A
Thompson 2003	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.	35 babies enrolled on day one of post-natal life: Birthweight < 1000 g, or < 1500 g with a need for mechanical ventilation or more than 40% oxygen.	Treatment: 2.5% glutamine solution given along with standard parenteral nutrition (N=17). Control: no added glutamine (N=18).	Time to full enteral feeds, number of episodes of sepsis, rate of weight gain, measures of feeding tolerance and intolerance, rate of necrotising enterocolitis.	Infants in the intervention group received a solution of 2.5% L-glutamine given as a separate but simultaneous infusion with the remainder of the parenteral nutrition. The glutamine comprised approximately 16% of total amino acids. Control infants received an infusion of water indistinguishable in appearance to the glutamine solution. Parenteral nutrition and glutamine supplementation was discontinued when enteral feeding exceeded 80% of total energy requirements.	A
van den Berg 2005	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.	102 very low birth weight infants.	Treatment: enteral glutamine supplementation (up to 0.3 grams/ kilogram/ day) (N=52). Control: placebo (alanine) (N=50). Trial continued from day 3 to day 30 of post-natal life.	Death, necrotising enterocolitis, time to establish full enteral feeds, duration of hospital stay.	Infants were randomly allocated to receive either enteral glutamine (up to 0.3 grams/ kilogram/ day) or alanine (placebo) supplementation to breast milk or formula from day 3 to day 30 of post-natal life. Caregivers and assessors were not aware which solution infants received.	A
Vaughn 2003	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.	649 babies enrolled: Age < 7 day, birthweight 500-1250 g.	Treatment: 5 ml/kg of 3% glutamine solution given enterally 12-hourly for the first 28 days (N= 314). Control: no added glutamine (N= 335).	Primary: Number of babies with positive blood cultures from 7 days to 36 weeks postmenstrual age. Secondary: Number of episodes of sepsis, measures of growth, rates of other neonatal morbidities including necrotising enterocolitis, and length of hospital stay.	Infants received either 5 ml per kilogram of 3% glutamine every 12 hours (0.3 grams/ kilogram/ day) or the same volume of sterile water via an enteral feeding tube for the first 28 days of post-natal life. Caregivers and assessors were not aware which solution infants received. Although 105 (56 treated and 49 control) babies left the study before completing a full course of treatment due to death (39), transfer to another hospital (24), necrotising enterocolitis (24), meeting exclusion criteria after enrollment (12), discharge home (2) and parental request (4), outcome analyses in the published report and in this review are intention-to treat.	A

Characteristics of ongoing studies

Study	Trial name or title	Participants	Interventions	Outcomes	Starting date	Contact information	Notes
SIGN	Surgical Infants Glutamine Nutrition Trial, Glutamine Supplementation in parenteral nutrition of surgical newborn infants	Surgical infants below the age of 3 months requiring parenteral nutrition N=250	Treated: glutamine supplemented TPN. Control: isonitrogenous TPN	Duration of TPN, number of episodes of sepsis, time to first episode of sepsis.	1st Sept 2002	Prof Agostino Pierro, Paediatric Surgery Unit, Institute of Child Health, 30 Guildford Street, London WC1N 1EH SIGN.trial@ich.ucl.ac.uk	Multicentre Trial in UK

References to studies

References to included studies

Bober-Olesinska 2005 {published data only}

Bober-Olesinska K, Kornacka MK. Effects of glutamine supplemented parenteral nutrition on the incidence of necrotizing enterocolitis, nosocomial sepsis and length of hospital stay in very low birth weight infants. Medycyna Wieku Rozwojowego 2005;9:325-33.

Lacey 1996 {published data only}

Lacey JM, Crouch JB, Benfell K, Ringer SA, Wilmore CK, Maguire D, Wilmore DW. The effects of glutamine-supplemented parenteral nutrition in premature infants. Journal of Parenteral and Enteral Nutrition 1996;20:74-80.

Neu 1997 {published data only}

Dallas MJ, Bowling D, Roig JC, Auestad N, Neu J. Enteral glutamine supplementation for very-low-birth-weight infants decreases hospital costs. Journal of Parenteral and Enteral Nutrition 1998;22:352-6.

* Neu J, Roig JC, Meetze WH, Veerman M, Carter C, Millsaps M, et al. Enteral glutamine supplementation for very low birth weight infants decreases morbidity. Journal of Pediatrics 1997;131:691-9.

Roig JC, Meetze WH, Auestad N, Jasionowski T, Veerman M, McMurray CA, Neu J. Enteral glutamine supplementation for the very low birthweight infant: plasma amino acid concentrations. Journal of Nutrition 1996;126:1115S-1120S.

Poindexter 2004 {published data only}

Poindexter B, Langer J, Dusick A, Ehrenkranz R, for the NICHD Neonatal Research Network. Early provision of parenteral amino acids in ELBW infants- relationship with growth and neurodevelopmental outcome at 18 months corrected age. In: Pediatric Research. Vol. 55. 2004:382A.

* Poindexter BB, Ehrenkrantz RA, Stoll BJ, Wright LL, Poole WK, Oh W, et al. Parenteral glutamine supplementation does not reduce the risk of morbidity or late-onset sepsis in extremely-low-birthweight infants. Pediatrics 2004;113:1209-15.

Poindexter BB, Ehrenkranz RA, Stoll BJ, Koch MA, Wright LL, Oh W, et al. Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants. American Journal of Clinical Nutrition 2003;77:737-43.

Thompson 2003 {published data only}

Thompson SW, McClure BG, Tubman TRJ. A randomised controlled trial of parenteral glutamine in ill very low birth weight neonates. Journal of Parenter and Enteral Nutrition 2003;37:550-3.

van den Berg 2005 {published data only}

van den Berg A, Fetter WP, Westerbeek EA, van der Vegt IM, van der Molen HR, van Elburg RM. The effect of glutamine-enriched enteral nutrition on intestinal permeability in very-low-birth-weight infants: a randomized controlled trial. Journal of Parenteral and Enteral Nutrition 2006;30:408-14.

van den Berg A, van Elburg RM, Twisk JW, Fetter WP. Glutamine-enriched enteral nutrition in very low birth weight infants. Design of a double-blind randomised controlled trial. BMC Pediatrics 2004;4:17.

* van den Berg A, van Elburg RM, Westerbeek EA, Twisk JW, Fetter WP. Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial. American Journal of Clinical Nutrition 2005;81:1397-404.

Vaughn 2003 {published data only}

Vaughn P, Thomas P, Clark R, Neu J. Enteral glutamine supplementation and morbidity in low birth weight infants. Journal of Pediatrics 2003;142:662-8.

References to studies awaiting assessment

Barbosa 1999 {published data only}

Barbosa E, Moreira AM, Goes JE, Faintuch J. Pilot study with a glutamine-supplemented enteral formula in critically ill infants. Rev Hosp Clin Fac Med S Paulo 1999;54:21-4.

Li 2007 {published data only}

Li ZH, Wang DH, Dong M. Effect of parenteral glutamine supplementation in premature infants. Chinese Medical Journal 2007;120:140-4.

References to ongoing studies

SIGN {unpublished data sought but not used}

Prof. Agostino Pierro. Surgical Infants Glutamine Nutrition Trial.

* indicates the primary reference for the study

Other references

Additional references

Alverdy 1992

Alverdy JA, Aoys E, Weiss-Carrington P, Burke DA. The effect of glutamine-enriched TPN on gut immune cellularity. Journal of Surgical Research 1992;52:34-8.

Bergstrom 1974

Bergstrom J, Furst P, Noree L, Vinnars E. Intracellular free amino acid concentrations in human muscle tissue. Journal of Applied Physiology 1974;36:693-7.

Grover 2007

Grover Z, Tubman R, McGuire W. Glutamine supplementation for young infants with severe gastrointestinal disease. In: Cochrane Database of Systematic Reviews, Issue 1, 2007. Chichester UK: John Wiley & Sons, Ltd.

Hinshaw 1990

Hinshaw DB, Burger JM. Protective effect of glutamine on endothelial cell ATP in oxidant injury. Journal of Surgical Research 1990;49:222-7.

Houdijk 1998

Houdijk AP, Rijnsburger SG, Jansen J, Wesdorp RI, Weiss JK, McCamish MA, Teerlink T, Meuwissen SG, Haarman HJ, Thijs LG, van Leeuwen PA. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772-6.

Klimberg 1990

Klimberg VS, Salloum RM, Kasper M, Plumley DA, Dolson DJ, Hautamaki RD, Mendenhall WR, Bova FC, Bland KI, Copeland EM, Souba WW. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Archives of Surgery 1990;125:1040-5.

Krebs 1980

Krebs H. Glutamine metabolism in the animal body. In: Mora J, Palacios R, editor(s). Glutamine: metabolism, enzymology and regulation. New York: Academic Press, 1980:319-29.

Lacey 1990

Lacey J, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutrition Reviews 1990;48:297-309.

Murray 2004

Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. In: Cochrane Database of Systematic Reviews, Issue 3, 2004. Chichester, UK: John Wiley & Sons, Ltd.

Newsholme 1985

Newsholme EA, Crabtree B, Ardawi MS. Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance. Quarterly Journal of Experimental Physiology 1985;70:473-89.

Novak 2002

Novak F, Heyland D K, Avenell A, Drover J W, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Critical Care Medicine 2002;30:2022-9.

O'Dwyer 1989

O'Dwyer ST, Smith RJ, Hwang TL, Wilmore DW. Maintenance of small bowel mucosa with glutamine enriched parenteral nutrition. Journal of Parenteral and Enteral Nutrition 1989;13:579-85.

Rombeau 1990

Rombeau JL. A review of the effects of glutamine-enriched diets on experimentally induced enterocolitis. Journal of Parenteral and Enteral Nutrition 1990;14:100S-105S.

van der Hulst 1993

Van der Hulst RRW, van Kreel BK, von Meyenfeldt MF, Brummer RJM, Arends JW, Deutz NEP, Soeters PB. Glutamine and the preservation of gut integrity. Lancet 1993;334:1363-5.

Windmueller 1982

Windmueller HG. Glutamine utilization by the small intestine. Advances in Enzymology and Related Areas of Molecular Biology 1982;53:201-37.

Ziegler 1990

Ziegler TR, Benfell K, Smith RJ, Young LS, Brown E, Ferrari-Baliviera E, Lowe DK, Wilmore DW. Safety and metabolic effects of L-glutamine administration in humans. Journal of Parenteral and Enteral Nutrition 1990;14:137S-146S.

Other published versions of this review

Tubman 1999

Tubman TRJ, Thompson SW. Glutamine supplementation to prevent morbidity in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 2, 1999. Oxford: Update Software.

Tubman 2001

Tubman TRJ, Thompson SW. Glutamine supplementation to prevent morbidity and mortality in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2001. Oxford: Update Software.

Tubman 2005

Tubman TR, Thompson SW, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 1, 2005. Chichester, UK: John Wiley & Sons, Ltd.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Enteral or parenteral glutamine supplementation versus no supplementation
01 Death prior to hospital discharge	6	2342	RR (fixed), 95% CI	0.98 [0.80, 1.20]
02 Invasive infection	5	2240	RR (fixed), 95% CI	1.01 [0.91, 1.13]
03 Necrotising enterocolitis	6	2342	RR (fixed), 95% CI	0.98 [0.76, 1.27]
04 Rate of weight gain (grams/ kilogram/ day)	1	28	WMD (fixed), 95% CI	1.30 [-1.66, 4.26]
05 Time to full enteral nutrition (days)	3	1299	WMD (fixed), 95% CI	-1.76 [-3.59, 0.06]
06 Duration of hospital stay (days)	4	1894	WMD (fixed), 95% CI	0.13 [-3.32, 3.58]
02 Enteral glutamine supplementation versus no supplementation
01 Death prior to hospital discharge	3	819	RR (fixed), 95% CI	0.95 [0.55, 1.64]
02 Invasive infection	2	717	RR (fixed), 95% CI	0.95 [0.77, 1.18]
03 Necrotising enterocolitis	3	819	RR (fixed), 95% CI	1.07 [0.67, 1.71]
04 Time to full enteral nutrition (days)	1	102	WMD (fixed), 95% CI	-2.90 [-5.92, 0.12]
05 Duration of hospital stay (days)	2	684	WMD (fixed), 95% CI	-1.30 [-5.92, 3.32]
03 Parenteral glutamine supplementation versus no supplementation
01 Death prior to hospital discharge	3	1523	RR (fixed), 95% CI	0.98 [0.79, 1.23]
02 Invasive infection	3	1523	RR (fixed), 95% CI	1.07 [0.94, 1.21]
03 Necrotising enterocolitis	3	1523	RR (fixed), 95% CI	0.94 [0.69, 1.29]
04 Rate of weight gain (grams/ kilogram/ day)	1	28	WMD (fixed), 95% CI	1.30 [-1.66, 4.26]
05 Time to full enteral feeds (days)	2	1197	WMD (fixed), 95% CI	-1.11 [-3.40, 1.18]
06 Duration of hospital stay (days)	2	1210	WMD (fixed), 95% CI	1.95 [-3.25, 7.15]

01 Enteral or parenteral glutamine supplementation versus no supplementation

01.01 Death prior to hospital discharge

01.02 Invasive infection

01.03 Necrotising enterocolitis

01.04 Rate of weight gain (grams/ kilogram/ day)

01.05 Time to full enteral nutrition (days)

01.06 Duration of hospital stay (days)

02 Enteral glutamine supplementation versus no supplementation

02.01 Death prior to hospital discharge

02.02 Invasive infection

02.03 Necrotising enterocolitis

02.04 Time to full enteral nutrition (days)

02.05 Duration of hospital stay (days)

03 Parenteral glutamine supplementation versus no supplementation

03.01 Death prior to hospital discharge

03.02 Invasive infection

03.03 Necrotising enterocolitis

03.04 Rate of weight gain (grams/ kilogram/ day)

03.05 Time to full enteral feeds (days)

03.06 Duration of hospital stay (days)

Contact details for co-reviewers

Dr William McGuire
Associate Professor of Neonatology
Department of Paediatrics and Child Health
Australian National University Medical School
Canberra Hospital Campus
Canberra
ACT 2606 AUSTRALIA
Telephone 1: +61 2 62442222
Facsimile: +61 2 62443112
E-mail: william.mcguire@act.gov.au

Dr Sam Thompson
Consultant Paediatrician
Craigavon Area Hospital
68 Lurgan Road
Portadown
Craigavon IRELAND
BT27 5AU
Telephone 1: +44 2838 334444
Facsimile: +44 2838 350068
E-mail: STHOMPSON@cahgt.n-i.nhs.uk

This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2008 (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.