Glutamine supplementation for young infants with severe gastrointestinal disease

Grover Z, Tubman R, McGuire W

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

Dates

Date edited: 15/11/2006
Date of last substantive update: 12/10/2006
Date of last minor update: / /
Date next stage expected 30/11/2008
Protocol first published: Issue 2, 2006
Review first published: Issue 1, 2007

Contact reviewer

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

Contribution of reviewers

All authors contributed to the development of the protocol. Zubin Grover and William McGuire undertook the electronic and hand searches, screened the title and abstract of all studies identified, and the full text of potentially relevant reports. Each author independently assessed the methodological quality of the included trials, extracted the relevant information and data, and 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

Dates

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

Text of review

Synopsis

Currently, there is insufficient evidence to determine whether giving young infants with severe gastrointestinal problems supplemental glutamine is beneficial.

Glutamine is an amino acid that helps tissues, particularly in the gastrointestinal tract, recover from damage. We looked for evidence that giving extra glutamine to young infants with severe bowel problems helps them to recover faster and more fully. At present, data are only available from two small trials and these are insufficient to determine whether glutamine supplements are beneficial or harmful. Further trials are needed. One such large trial is on-going and when data from that study are reported we will update this Cochrane review.

Abstract

Background

Endogenous glutamine biosynthesis may be insufficient to meet the needs of infants with severe gastrointestinal disease. Studies using animal models of gastrointestinal disease and controlled trials in adult patients have suggested that glutamine supplementation improves clinical outcomes.

Objectives

To assess the evidence from randomised controlled trials that providing supplemental glutamine reduces mortality and morbidity in infants with severe gastrointestinal disease.

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, 2006), MEDLINE (1966 - August 2006), EMBASE (1980 - August 2006), conference proceedings, and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that compared glutamine supplementation versus no glutamine supplementation in infants (up to three months old, corrected for preterm birth) with severe gastrointestinal disease (defined as a congenital or acquired gastrointestinal condition that is likely to necessitate providing parenteral nutrition for at least 24 hours).

Data collection & analysis

Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two reviewer authors, and synthesis of data using relative risk, risk difference and weighted mean difference.

Main results

Two trials in which a total of 100 infants participated were identified. In one trial, a minority of participants were infants older than three months. These studies were generally of good methodological quality but were underpowered to detect clinically important effects of glutamine supplementation. Meta-analysis did not reveal a statistically significant difference in the risk of death before hospital discharge [typical relative risk 1.57 (95% confidence interval 0.25 to 9.66); typical risk difference 0.02 (95% confidence interval -0.06 to 0.10)], nor in the rate of invasive infection [typical relative risk 1.22 (95% confidence interval 0.55 to 2.70); typical risk difference: 0.04 (95% confidence interval -0.12 to 0.20)].

Reviewers' conclusions

The available data from randomised controlled trials are not sufficient to determine whether glutamine supplementation confers clinically significant benefits for infants with severe gastrointestinal disease. Further trials are needed.

Background

Glutamine is a key source of energy for rapidly dividing cells such as enterocytes, lymphocytes, macrophages, and neutrophils (Windmueller 1980; Newsholme 1999). Although glutamine can be synthesised in vivo, it is considered a "conditionally essential" amino acid in catabolic states, where demand outstrips supply (Lacey 1990). Plasma glutamine levels fall during critical illness or following major surgery (Parry-Billings 1990; Parry-Billings 1992), and glutamine deficiency may limit tissue recovery in these situations (Newsholme 2001). In animal models of enterocolitis, providing supplemental glutamine aids gut recovery, probably by providing additional energy for enterocyte division and proliferation (Klimberg 1990; Rombeau 1990). In some (though not other) animal models, peri- or post-operative glutamine supplementation has been demonstrated to accelerate bowel anastomosis healing (da Costa 2003; McCauley 1991). In adult surgical or critically ill patients, evidence exists that glutamine supplementation (above 0.2 grams per kilogram per day) preserves gut mucosal integrity and reduces infectious complications, duration of hospital stay, and (possibly) mortality (Van der Hulst 1993; Novak 2002; Murray 2004).

The Cochrane review of randomised controlled trials of glutamine supplementation for preterm infants (including 2300 participants in six trials) concluded that there is no evidence that glutamine supplementation benefits or harms preterm infants (Tubman 2005). Although the infants who participated in these trials were all of very low birth weight, most were clinically stable. Any putative benefits of glutamine supplementation might be confined to critically ill infants for whom glutamine availability is rate-limiting for tissue repair, for example, infants with severe gastrointestinal disease such as necrotising enterocolitis or infants who have undergone major gastrointestinal surgery (Pierro 2002). Glutamine is present in human breast milk, but it is present only in much lower quantities in formula milks (Agostini 2000), and it is absent from standard parenteral nutrition solutions because it is not stable in an aqueous environment (Khan 1991). Infants who have severe gastrointestinal disease or who are recovering from major gastrointestinal surgery are, therefore, unlikely to receive sufficient glutamine to meet demands.

Synthetic glutamine-containing dipeptides that are more stable in aqueous solutions are now available (Furst 1997). It is now more feasible to provide supplemental glutamine to infants with severe gastrointestinal disease. This may confer several benefits. Accelerating anastomosis and wound healing and enhancing gut mucosal integrity might help infants to tolerate enteral feeding earlier and thereby shorten their duration of hospitalisation. Enhancing gut barrier function and lymphocyte production might reduce the rate of acquired sepsis, lower mortality, and, in the longer term, lower rates of adverse neurodevelopmental outcomes.

There is a theoretical concern that supplemental glutamine, via its metabolic products glutamate and ammonia, may have adverse neurological effects in high concentrations (Garlick 2001). However, metabolic studies in preterm infants have found that parenteral glutamine supplementation (up to 0.6 grams per kilogram per day) limits whole body proteolysis without increasing plasma amino acid or ammonia levels (Kalhan 2005). Enterally administered glutamine is metabolised entirely in the splanchnic compartment and does not affect whole body ammonia or urea nitrogen levels (Parimi 2004). Systematic reviews have found no evidence of adverse effects of glutamine supplementation in adults or in (clinically stable) preterm infants (Novak 2002; Tubman 2005).

Objectives

To assess the evidence from randomised controlled trials that providing supplemental glutamine for infants with severe gastrointestinal disease reduces mortality, decreases the time taken to establish enteral feeding, reduces nosocomial infection, shortens the duration of hospitalisation, increases growth rates, and prevents adverse neurodevelopmental outcomes.

If sufficient data were available, the following subgroup analyses were planned:
1. Trials where participants were predominantly (more than 80%) term infants versus trials where participants were predominantly preterm infants.
2. Trials where participants were infants with necrotising enterocolitis versus trials where participants were infants who had undergone gastrointestinal surgery for other indications.
3. Trials where infants received enteral glutamine supplementation versus trials where supplemental glutamine was given parenterally.
4. Trials where the aim was to give at least 0.2 grams per kilogram per day of glutamine versus trials where less glutamine supplementation was given.

Criteria for considering studies for this review

Types of studies

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

Types of participants

Neonates and young infants (up to three months old, corrected for preterm birth) with severe gastrointestinal disease defined as a congenital or acquired gastrointestinal condition that is likely to necessitate providing parenteral nutrition for at least 24 hours; for example, acute necrotising enterocolitis, anterior abdominal wall defect, intestinal obstruction. Infants should have been enrolled to participate in the trial within one week after gastrointestinal surgery or after the onset of necrotising enterocolitis (if treated non-surgically).

Necrotising enterocolitis should have been diagnosed using Bell's criteria (or modifications), that is, the presence of at least two of the following features: pneumatosis coli on abdominal radiograph; abdominal distension or abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both); blood in stool; lethargy, hypotonia, or apnoea, or combination of these (Bell 1978; Walsh 1986).

Types of interventions

Glutamine supplementation versus no supplementation or placebo by the parenteral or enteral route. No minimum duration of intervention was specified.

Types of outcome measures

Primary outcomes:
1. Mortality in the neonatal period (up to 28 days) and/or prior to hospital discharge.
2. Time to establish full enteral feeds independent of parenteral fluids or nutrition.

Secondary outcomes:
1. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebro-spinal fluid, urine, or from a normally sterile body space.
2. Time to discharge from hospital.
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 Neurodevelopmental outcomes at greater than, or equal to, 12 months of age (corrected for preterm birth) measured using validated assessment tools such as Bayley Scales of Infant Development.
5. Severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. Each of these sub-categories of severe disability will also be analysed separately.

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, 2006), MEDLINE (1966 - August 2006), and EMBASE (1980 - August 2006). 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 2005, 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 - 2005) 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

Two trials, in which a total of 100 infants participated, fulfilled eligibility criteria (Albers 2005; Duggan 2004). These were single-centre studies undertaken between 2000 and 2004 in surgical neonatal and paediatric intensive care centres in Europe (Albers 2005) and North America (Duggan 2004). The smaller of the trials was a pilot study that aimed to assess feasibility and safety (Duggan 2004). Another small (N = 13) trial has been published in abstract form (Nolin 2001). Further details on methodology of this trial are being sought in order to determine if it fulfills the review inclusion criteria. One on-going trial, the "Surgical Infants Glutamine Nutrition" trial was identified (SIGN). This United Kingdom multi-centre study aims to complete recruitment during 2007 (see: http://www.controlled-trials.com/isrctn/trial/GLUTAMINE/0/83168963.html).

One trial that appeared potentially eligible was excluded after further evaluation of the full report (Barbosa 1999). Most participants in this small trial (N = 9) were infants with non-gastrointestinal disease.

Participants:
Albers 2005 enrolled 80 children of gestational age greater than 30 weeks and chronological age less than two years. This trial therefore did not strictly fulfil our a priori population criterion (infants less than three months old). However, we decided to include the trial because the report stated that most (69 of the 80) participants were less than six months old at enrolment. The report did not provide subgroup data for infants less than three months old. The trial authors have been contacted to seek these data. The most common gastrointestinal conditions affecting participants were necrotising enterocolitis, congenital bowel atresia or obstruction, anterior abdominal wall defects, and Hirschsprung disease. Infants were not expected to be able to tolerate enteral nutrition for at least four days following gastrointestinal tract surgery. The median postnatal age at enrolment was 11 days.

Duggan 2004 enrolled 20 young infants with severe gastrointestinal diseases; necrotising enterocolitis, intestinal atresia, or anterior abdominal wall defects. Most participants were preterm (average gestational age at birth 33 weeks). Their median postnatal age at enrolment was 15 days.

Interventions:
Albers 2005: On the second post-operative day, infants in the intervention group received a standard parenteral nutrition solution supplemented with L-glutamine sufficient to provide 0.4 grams per kilogram per day. Control infants received parenteral nutrition with an isonitrogenous amino acid solution. The caregivers were not aware whether participating infants received glutamine-supplemented or non-supplemented parenteral nutrition. The protocol specified that participating infants should continue to receive full parenteral nutrition until at least the sixth post-operative day when enteral feeding was gradually re-introduced.

Duggan 2004: When judged by the attending clinicians to be ready to tolerate the introduction of enteral feeds, participating infants were randomly allocated to either glutamine-supplemented expressed human milk or hydrolysed formula milk versus human milk or formula without added glutamine (but with an iso-osmolar mix of non-essential amino acids). The glutamine-supplemented and non-supplemented milks were indistinguishable to the parents, care-givers, and assessors. The intervention group received 0.08 grams per kilogram per day of glutamine at the start of the study. This increased to 0.31 grams per kilogram per day by two weeks post enrolment. 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.

Outcomes:
Albers 2005 assessed the effect of parenteral glutamine supplementation on intestinal permeability (urinary excretion ratios of lactulose and rhamnose) and nitrogen balance. Mortality, duration of intensive care admission, and rates of nosocomial infection were reported as secondary outcomes.

Duggan 2004 assessed the effect of enteral glutamine supplementation on the time taken to establish full enteral feeding, rates of nosocomial infection, and growth during the study period.

Methodological quality of included studies

Although the trials were small, their methodological quality was generally good. Both studies achieved adequate allocation concealment by randomisation in a central pharmacy (Albers 2005), or use of a random numbers table generated sequence in sealed opaque envelopes (Duggan 2004). Both trials blinded caregivers and assessors to the intervention and all achieved complete or near-complete follow up.

Results

Comparison 01: Glutamine supplementation (parenteral or enteral) versus no supplementation

Primary outcomes

Mortality prior to hospital discharge. Outcome 01.01 (two trials reported data):
Albers 2005 reported that two of 41 infants allocated to glutamine supplementation died during the total hospital stay versus none (of 38) in the control group [relative risk 4.64 (95% confidence interval 0.23 to 93.7); risk difference 0.05 (95% confidence interval -0.03 to 0.13)]. Duggan 2004 reported (via personal communication) that none (of 9) infants in the intervention group and one (of 11) infants in the control group died before hospital discharge [relative risk 0.4 (95% confidence interval 0.02 to 8.78); risk difference -0.09 (95% confidence interval -0.32 to 0.14)]. Meta-analysis did not reveal a statistically significant difference: [typical relative risk 1.57 (95% confidence interval 0.25 to 9.66); typical risk difference 0.02 (95% confidence interval -0.06 to 0.10)]

Time to establish full enteral feeds (one trial reported data).
Duggan 2004 reported that there was not a statistically significant difference in the time taken to establish full enteral feeding in the intervention group [median 39 days (inter-quartile range 12 to 99 days)] versus the control group [21 days (inter-quartile range six to 59 days)]. Albers 2005 did not report time taken to establish full enteral feeding. The trial authors have been contacted to seek this information.

Secondary outcomes

Incidence of invasive infection. Outcome 01.02 (two trials reported data):
Albers 2005: Nine of 41 infants in the intervention group versus six of 38 infants in the control group had an episode of bloodstream infection [relative risk 1.39 (95% confidence interval 0.55 to 3.54); risk difference: 0.06 (95% confidence interval -0.11 to 0.23)]. Duggan 2004: two of nine infants in the intervention group versus three of 11 infants in the control group had an episode of bloodstream or urinary tract infection [relative risk 0.81 (95% confidence interval 0.17 to 3.87); risk difference: -0.05 (95% confidence interval -0.43 to 0.33)].

Meta-analysis of data from the two trials did not reveal any statistically significant difference in the incidence of invasive infection [typical relative risk 1.22 (95% confidence interval 0.55 to 2.70); typical risk difference: 0.04 (95% confidence interval -0.12 to 0.20)].

Time to discharge from hospital (one trial reported data).
Albers 2005 did not find a statistically significant difference in the time to hospital discharge: intervention group (median 32 days, inter-quartile range 16.8 to 44.8 days) compared to control infants (median 31.5 days, inter-quartile range 14 to 64 days). Duggan 2004 did not report time to hospital discharge. These data are not readily available at present (personal communication from trial authors).

Growth during the trial period. Outcome 01.03 (one trial reported data):
Duggan 2004 did not find a statistically significant difference in the rate of weight gain during the study period: 17.6 (standard deviation 6.4) grams per day in the study group versus 13.8 (standard deviation 16.2) grams per day in the control group: Mean difference 3.80 (95% confidence interval -6.65 to 14.25) grams per day. The report also stated that there was not a statistically significant difference in the rate of change in length or "arm anthropometrics" but data were not presented. Albers 2005 did not report on growth parameters. The trial authors have been contacted to seek this information.

Neurological assessments were not undertaken in either of the trials.

Rates of neurodevelopmental disability were not measured in either of the trials.

Subgroup analyses

Trials where participants were predominantly (more than 80%) term infants versus trials where participants were predominantly preterm infants:
Duggan 2004 recruited preterm infants predominantly - see above for study findings. For Albers 2005, the precise distribution of gestational age at birth is not clear.

Trials where participants were infants with necrotising enterocolitis versus trials where participants were infants who had undergone gastrointestinal surgery for other indications:
In Albers 2005, 19 of 80 participating infants had necrotising enterocolitis. In Duggan 2004, eight of 20 participating infants had necrotising enterocolitis. Subgroup data for infants with necrotising enterocolitis versus other surgical gastrointestinal conditions were not presented in either report.

Trials where infants received enteral glutamine supplementation versus no supplementation and trials where supplemental glutamine was given parenterally versus no supplementation:
Comparisons 02 and 03. Outcomes 02.01- 02.03, 03.01):
Albers 2005 studied the effect of parenteral glutamine supplementation - see above for study findings.
Duggan 2004 studied the effect of enteral glutamine supplementation - see above for study findings.

Trials where the aim was to give at least 0.2 grams per kilogram per day of glutamine versus trials where less glutamine supplementation was given:
Both trials aimed to provide at least 0.2 grams per kilogram per day on average of glutamine - see above for study findings.

Discussion

Although glutamine supplementation has not been shown to improve outcomes for clinically stable preterm infants (Tubman 2005), it may be that there are benefits for infants under severe metabolic stress, particularly infants with severe gastrointestinal disease where glutamine deficiency may be rate limiting for tissue healing and repair and for maintaining intestinal immunological integrity (Newsholme 2001; Van der Hulst 1993; Alverdy 1992). Systematic review of trials in which critically ill adults have participated suggests that glutamine supplementation might be associated with a lower rate of infection, shorter hospital stays, and (possibly) lower mortality. (Novak 2002).

Currently there are only two published trials that have examined the effect of glutamine supplementation for infants with severe gastrointestinal disease (Albers 2005; Duggan 2004). A total of 100 infants were enrolled in these trials. Although methodologically sound, these trials were underpowered to assess clinically important effects on the specified outcomes of this review. Meta-analysis was possible for two outcomes (in hospital mortality and incidence of invasive infection). No statistically significant differences for these outcomes were detected. Furthermore, the included trials and the on-going trials recruited a heterogeneous group of participants with a range of severe gastrointestinal diseases. This population heterogeneity may limit meaningful evaluation of the effect of glutamine supplementation. For example, the effect of glutamine supplementation may be different for sick, very preterm infants recovering from acute severe necrotising enterocolitis compared with term infants who have had reduction of an anterior abdominal wall defect, but are otherwise metabolically and physiologically stable. When further data are available from on-going trials, subgroup analyses by gestational age at birth (term versus preterm) or by type of gastrointestinal disease may be needed to define which, if any, groups of infants benefit from glutamine supplementation.

Variation in the route of administration of supplemental glutamine (enteral versus parenteral) is also a potentially important source of trial heterogeneity that may affect outcomes. Systematic review of trials in adults suggests that parenteral supplementation confers more clinical benefits than enteral supplementation (Novak 2002). However, laboratory studies have suggested that using the enteral route results in a much higher concentration of free glutamine being delivered to the intestinal mucosa and that this reduces bacterial translocation and invasive infection (Panigrahi 1997). The theoretical disadvantage to enteral administration is that glutamine is metabolised entirely in the splanchnic compartment with no net increase in free glutamine delivery to other organs (Parimi 2004). The most appropriate route of delivery may also be affected by the underlying gastrointestinal condition. For example, it may not be possible to deliver enteral glutamine to very preterm infants with severe necrotising enterocolitis, but this may be the most appropriate route for clinically stable infants recovering from a less physiologically destabilising gastrointestinal condition.

Reviewers' conclusions

Implications for practice

The currently available data from two small trials are insufficient to determine whether glutamine supplementation improves important clinical outcomes for young infants with severe gastrointestinal disease. Another small study has been undertaken but is not published in full yet (Nolin 2001). A large multi-centre trial is on-going (SIGN). When data from these trials are available they will be included in an update of this review. Glutamine should only be used in the setting of a randomised controlled trial until the results of ongoing trials are assessed.

Implications for research

A large randomised controlled trial is required to address this question. One such trial, examining the effect of parenteral supplementation in young infants recovering from gastrointestinal surgery, is currently in progress (SIGN). It may also be appropriate to undertake a large randomised controlled trial to assess whether enteral supplementation is beneficial for young infants with severe gastrointestinal disease. Future trials may need to be of sufficient size to allow subgroup analyses by type of gastro-intestinal disease and by gestational age categories.

Acknowledgements

Professor Christopher Duggan for supporting this review by providing further details about his trial (Duggan 2004 ). Professor Satish Kalhan for sharing data and for advising on glutamine metabolic studies in young infants.

Potential conflict of interest

None.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Albers 2005	Blinding of randomisation: yes Blinding of intervention: yes Complete follow-up: yes Blinding of outcome measurement: yes	80 children of gestational age greater than 30 weeks and chronological age less than 2 years. Exclusion criteria: renal or hepatic dysfunction, an inborn error of metabolism, immunodeficiency, use of corticosteroids, preexistent life expectancy less than 6 months and simultaneous participation in another trial. Setting: Sophia Children's Hospital/ Erasmus Medical Centre, Rotterdam, The Netherlands. One infant was withdrawn from the study within 3 days post-randomisation when it became clear that enteral feeding would be well tolerated. This infant was not included in any intention-to-treat analyses.	Intervention (N= 41): On the second post-operative day infants in the intervention group received a standard parenteral nutrition solution supplemented with L-glutamine sufficient to provide 0.4 grams per kilogram per day. Control (N=39): Infants received parenteral nutrition with an isonitrogenous aminoacid solution. The protocol specified that participating infants should continue to receive full parenteral nutrition until at least the sixth post-operative day when enteral feeding was gradually re-introduced.	1. Intestinal permeability (sugar absorption test). 2. Nitrogen balance. 3. Death prior to hospital discharge. 4. Length of intensive care unit and of hospital stay. 5. Episodes of invasive infection. 6. Use of antibiotics.	This trial did not strictly fulfil our a priori population criterion of including only infants less than 3 months old. However, we made a consensus decision to include the trial because the report stated that most (69 of the 80) participants were less than 6 months old at enrolment. We have contacted the trial investigator to determine whether outcome data are available for infants less than 3 months old.	A
Duggan 2004	Blinding of randomisation: yes Blinding of intervention: yes Complete follow-up: yes Blinding of outcome measurement: yes	20 infants with significant gastrointestinal illness including necrotising enterocolitis requiring laparotomy and resection, intestinal atresia, omphalocele, gastroschisis, intestinal volvulus, or malrotation. Exclusion criteria: significant hepatic, renal or metabolic disease necessitating protein restriction less than 1.0 gram per kilogram per day, significant extra-intestinal disease (cystic fibrosis, severe hypoxic ischemic encephalopathy), or extreme short bowel syndrome (defined as less than 25 cm of residual bowel length). Setting: Children's Hospital, Boston, USA.	Intervention (N= 9): Glutamine-supplemented (up to 0.31 grams per kilogram per day) expressed human milk or hydrolysed formula milk. Control (N=11): Human milk or formula without added glutamine. The study milk was introduced when infants were assessed as ready to tolerate enteral feeding and continued until day 30.	1. Time taken to establish full enteral feeding. 2. Rates of nosocomial infection. 3. Growth during the study period. 4. In hospital mortality (personal communication from trialists).		A

Characteristics of excluded studies

Study	Reason for exclusion
Barbosa 1999	Most participants in this small trial (N = 9) were infants with non-gastrointestinal disease.

Characteristics of ongoing studies

Study	Trial name or title	Participants	Interventions	Outcomes	Starting date	Contact information	Notes
SIGN	SIGN trial- Surgical infants glutamine nutrition trial.	250 infants less than 3 months old cared for in 12 surgical paediatric centres in the United Kingdom who require parenteral nutrition for congenital for acquired gastrointestinal disease or anomalies.	Intervention: Parenteral glutamine (stable dipeptide solution): 0.4 grams per kilogram per day. Control: Isonitrogenous amino acid solution.	1. Incidence of invasive infection. 2. Time to achieve full enteral feeding. 3. Growth. 4. Nutrient intake. 5. Biochemical measures of hepatic function.	2002 (aiming to complete recruitment in 2007).	Prof Agostino Pierro, Paediatric Surgery Unit, Institute of Child Health, 30 Guildford Street, London WC1N 1EH SIGN.trial@ich.ucl.ac.uk

References to studies

References to included studies

Albers 2005 {published data only}

Albers MJ, Steyerberg EW, Hazebroek FW, Mourik M, Borsboom GJ, Rietveld T, Huijmans JG, Tibboel D. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial. Annals of Surgery 2005;241:599-606.

Duggan 2004 {published data only}

Duggan C, Stark AR, Auestad N, Collier S, Fulhan J, Gura K, Utter S, Teixeira-Pinto A, Donovan K, Lund D. Glutamine supplementation in infants with gastrointestinal disease: a randomized, placebo-controlled pilot trial. Nutrition 2004;20:752-6.

References to excluded studies

Barbosa 1999 {published data only}

Barbosa E, Moreira EA, Goes JE, Faintuch J. Pilot study with a glutamine-supplemented enteral formula in critically ill infants. Revista do Hospital das Clínicas 1999;54:21-4.

References to studies awaiting assessment

Nolin 2001 {published data only}

Nolin F, Beaumier L. Parenteral glutamine supplementation decreases whole body protein breakdown and improves net protein balance in surgical neonates. In: Pediatric Research. Vol. 49. 2001:349A.

References to ongoing studies

SIGN {published data only}

Prof. Agostino Pierro.

* indicates the primary reference for the study

Other references

Additional references

Agostini 2000

Agostoni C, Carratu B, Boniglia C, Riva E, Sanzini E. Free amino acid content in standard infant formulas: comparison with human milk. Journal of the American College of Nutrition 2000;19:434-8.

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.

Bell 1978

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

da Costa 2003

da Costa MA, Campos AC, Coelho JC, de Barros AM, Matsumoto HM. Oral glutamine and the healing of colonic anastomoses in rats. Journal of Parenteral and Enteral Nutrition 2003;27:182-5.

Furst 1997

Furst P, Pogan K, Stehle P. Glutamine dipeptides in clinical nutrition. Nutrition 1997;13:731-7.

Garlick 2001

Garlick PJ. Assessment of the safety of glutamine and other amino acids. Journal of Nutrition 2001;131:2556S-61S.

Kalhan 2005

Kalhan SC, Parimi PS, Gruca LL, Hanson RW. Glutamine supplement with parenteral nutrition decreases whole body proteolysis in low birth weight infants. Jourhal of Pediatrics 2005;146:642-7.

Khan 1991

Khan K, Hardy G, McElroy B, Elia M. The stability of L-glutamine in total parenteral nutrition solutions. Clinical Nutrition 1991;10:193-8.

Klimberg 1990

Klimberg VS, Salloum RM, Kasper M, Plumley DA, Dolson DJ, Hautamaki RD, et al. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Archives of Surgery 1990;125:1040-5.

Lacey 1990

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

McCauley 1991

McCauley R, Platell C, Hall J, McCulloch R. Effects of glutamine infusion on colonic anastomotic strength in the rat. Journal of Parenteral and Enteral Nutrition 1991;15:437-9.

Murray 2004

Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. In: Cochrane Database of Systematic Reviews, Issue 2, 2002.

Newsholme 1999

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Newsholme 2001

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Comparisons and data

01 Glutamine supplementation (parenteral or enteral) versus no supplementation

01.01 Death prior to hospital discharge

01.02 Incidence of invasive infection

01.03 Weight gain during trial period (grams per day)

02 Enteral glutamine supplementation versus no supplementation

02.01 Death prior to hospital discharge

02.02 Incidence of invasive infection

02.03 Weight gain during trial period (grams per day)

03 Parenteral glutamine supplementation versus no supplementation

03.01 Death prior to hospital discharge

Comparison or outcome
Studies
Participants
Statistical method
Effect size

01 Glutamine supplementation (parenteral or enteral) versus no supplementation

01 Death prior to hospital discharge
2
99
RR (fixed), 95% CI
1.57 [0.25, 9.66]

02 Incidence of invasive infection
2
99
RR (fixed), 95% CI
1.22 [0.55, 2.70]

03 Weight gain during trial period (grams per day)
1
20
WMD (fixed), 95% CI
3.80 [-6.65, 14.25]

02 Enteral glutamine supplementation versus no supplementation

01 Death prior to hospital discharge
1
20
RR (fixed), 95% CI
0.40 [0.02, 8.78]

02 Incidence of invasive infection
1
20
RR (fixed), 95% CI
0.81 [0.17, 3.87]

03 Weight gain during trial period (grams per day)
1
20
WMD (fixed), 95% CI
3.80 [-6.65, 14.25]

03 Parenteral glutamine supplementation versus no supplementation

01 Death prior to hospital discharge
1
79
RR (fixed), 95% CI
4.64 [0.23, 93.71]

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Glutamine supplementation (parenteral or enteral) versus no supplementation
01 Death prior to hospital discharge	2	99	RR (fixed), 95% CI	1.57 [0.25, 9.66]
02 Incidence of invasive infection	2	99	RR (fixed), 95% CI	1.22 [0.55, 2.70]
03 Weight gain during trial period (grams per day)	1	20	WMD (fixed), 95% CI	3.80 [-6.65, 14.25]
02 Enteral glutamine supplementation versus no supplementation
01 Death prior to hospital discharge	1	20	RR (fixed), 95% CI	0.40 [0.02, 8.78]
02 Incidence of invasive infection	1	20	RR (fixed), 95% CI	0.81 [0.17, 3.87]
03 Weight gain during trial period (grams per day)	1	20	WMD (fixed), 95% CI	3.80 [-6.65, 14.25]
03 Parenteral glutamine supplementation versus no supplementation
01 Death prior to hospital discharge	1	79	RR (fixed), 95% CI	4.64 [0.23, 93.71]

Contact details for co-reviewers

Dr Zubin Grover
Registrar
Paediatrics and Child Health
The Canberra Hospital
Canberra
ACT AUSTRALIA
2606
E-mail: zubin.grover@act.gov.au

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

This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the Review.