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Glutamine supplementation for young infants with severe gastrointestinal disease

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Authors

Jennifer VE Brown1, Thirimon Moe-Byrne1, William McGuire2

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


1Centre for Reviews and Dissemination, University of York, York, UK [top]
3Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK [top]

Citation example: Brown JVE, Moe-Byrne T, McGuire W. Glutamine supplementation for young infants with severe gastrointestinal disease. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD005947. DOI: 10.1002/14651858.CD005947.pub4.

Contact person

William McGuire

Hull York Medical School & Centre for Reviews and Dissemination, University of York
York
Y010 5DD
UK

E-mail: William.McGuire@hyms.ac.uk

Dates

Assessed as Up-to-date: 09 October 2014
Date of Search: 23 September 2014
Next Stage Expected: 10 October 2016
Protocol First Published: Issue 2, 2006
Review First Published: Issue 1, 2007
Last Citation Issue: Issue 12, 2014

What's new

Date / Event Description
09 October 2014
New citation: conclusions not changed

Updated search in September 2014 identified one new study (Ong 2012) (publication of the SIGN trial previously identified as ongoing) for inclusion in this review.

The status of trial NCT00647036 is not known.

25 September 2014
Updated

This updates the review "Glutamine supplementation for young infants with severe gastrointestinal disease" published in The Cochrane Database of Systematic Reviews (Brown 2012).

History

Date / Event Description
29 March 2012
New citation: conclusions not changed

Updated search in November 2011 did not identify any new studies for inclusion in this review.

One new potentially relevant ongoing trial was identified (NCT00647036). The status of another possibly ongoing trial is not known (SIGN).

29 March 2012
Updated

This updates the review "Glutamine supplementation for young infants with severe gastrointestinal disease" published in The Cochrane Database of Systematic Reviews (Grover 2007).

18 September 2008
Amended

Converted to new review format.

12 October 2006
New citation: conclusions changed

Substantive amendment

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Abstract

Background

Endogenous glutamine biosynthesis may be insufficient to meet the needs of people with severe gastrointestinal disease. Results from studies using experimental animal models of gastrointestinal disease have suggested that glutamine supplementation improves clinical outcomes. This review examines evidence on the effect of glutamine supplementation in young infants with severe gastrointestinal disease.

Objectives

To assess the effect of supplemental glutamine on mortality and morbidity in young infants with severe gastrointestinal disease.

Search methods

We searcheed the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 8), MEDLINE, EMBASE, and CINAHL (from inception to September 2014), conference proceedings, and reference lists from 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 if necessary) 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 and analysis

Two review authors assessed trial eligibility and risk of bias and undertook data extraction independently. We analysed the treatment effects in the individual trials and reported the risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference for continuous data, with 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses.

Main results

We found three trials in which a total of 274 infants participated. The trials were of good methodological quality but were too small to detect clinically important effects of glutamine supplementation. Meta-analyses did not reveal a statistically significant difference in the risk of death before hospital discharge (typical RR 0.79, 95% CI 0.19 to 3.20; typical RD -0.01, 95% CI -0.05 to 0.03) or in the rate of invasive infection (typical RR 1.37, 95% CI 0.89 to 2.11; typical RD 0.08, 95% CI -0.03 to 0.18]).

Authors' conclusions

The available data from randomised controlled trials do not suggest that glutamine supplementation has any important benefits for young infants with severe gastrointestinal disease.

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Plain language summary

Glutamine supplementation for young infants with severe gastrointestinal disease

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, only three trials are available; results suggest that supplemental glutamine has no benefit for these infants.

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Background

Description of the condition

Severe gastrointestinal disease - including acute necrotising enterocolitis (NEC), spontaneous localised intestinal perforation, congenital gut anomalies and atresias, anterior abdominal wall defects, Hirschsprung's disease, and acute malrotation or volvulus - is an important cause of morbidity, mortality and neuro-disability in newborn and young infants (Kays 1996; Hajivassiliou 2003). Infants with severe gastrointestinal disease experience more episodes of invasive infection, have lower levels of nutrient intake, grow more slowly, and have longer duration of intensive care and hospital stay than gestation-comparable infants without gastrointestinal disease (Dalla Vecchia 1998; Donnell 2002; Abdullah 2007). Severe NEC, especially if treated surgically, is associated with a higher rate of long-term neurological disability, which may be a consequence of infection and under-nutrition during a critical period of brain development (Stoll 2004; Rees 2007).

Description of the intervention

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 and glutamine deficiency may limit tissue recovery in these situations (Parry-Billings 1990; Parry-Billings 1992; Newsholme 2001). While glutamine is present in human breast milk, infant formula is low in glutamine, and standard parenteral nutrition solutions contain no glutamine because it is not stable in an aqueous environment (Khan 1991; Agostini 2000). Thus, infants who have severe gastrointestinal disease or who are recovering from major gastrointestinal surgery are unlikely to receive sufficient glutamine. Synthetic glutamine-containing dipeptides that are stable in aqueous solution are available, however (Furst 1997). It is therefore feasible to provide supplemental glutamine to infants with these conditions.

In theory, glutamine supplementation may confer several benefits to young infants with severe gastrointestinal disease. 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. In fact, improving gut barrier function and lymphocyte production may reduce the rate of acquired infection, lower mortality, and in the longer term, lower rates of adverse neurodevelopmental outcomes.

How the intervention might work

In experimental animal models of enterocolitis, providing supplemental glutamine aided gut recovery, probably by providing additional energy for enterocyte division and proliferation (Klimberg 1990; Rombeau 1990). Peri- or postoperative glutamine supplementation may also accelerate bowel anastomosis healing (McCauley 1991; da Costa 2003). In adult surgical or critically ill patients, some evidence exists that glutamine supplementation preserves gut mucosal integrity and reduces infectious complications and (possibly) mortality (Van der Hulst 1993; Novak 2002; Estivariz 2008). However, concerns about trial quality and publication bias have limited the reliability and applicability of these findings (Avenell 2009; Murray 2009). More recent, larger and better quality trials have failed to demonstrate clinically important benefits of glutamine supplementation in this population (Andrews 2011).

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 g/kg/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 not found evidence of adverse effects of glutamine supplementation in adults or in clinically stable preterm infants (Novak 2002; Avenell 2009; Murray 2009; Moe-Byrne 2012).

Why it is important to do this review

A previous Cochrane review on routine glutamine supplementation for preterm infants concluded that there is no evidence of any benefits or harms (Moe-Byrne 2012). 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 NEC or infants who have undergone major gastrointestinal surgery (Pierro 2002).

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Objectives

To determine whether supplemental glutamine for infants with severe gastrointestinal disease reduces mortality, decreases the time taken to establish enteral feeding, reduces the incidence of late-onset invasive infection, shortens the duration of hospitalisation, increases growth rates, and prevents adverse neurodevelopmental outcomes.

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Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

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

NEC 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; and 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. We did not pre-specify a minimum duration of intervention.

Types of outcome measures

Primary outcomes
  1. Death prior to hospital discharge.
  2. Neurodevelopmental outcomes assessed beyond infancy (neurological evaluations, developmental scores, and classifications of disability including auditory and visual disability, non-ambulant cerebral palsy, and developmental delay) and cognitive and educational outcomes (intelligence quotient and/or indices of educational achievement measured using a validated tool, including school examination results).
Secondary outcomes
  1. Time from trial entry to establish full enteral feeds independent of parenteral fluids or nutrition.
  2. Incidence of invasive infection during hospital admission as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine, or from a normally sterile body space (number of participants per group with one or more episodes).
  3. Time from trial entry to discharge from hospital.
  4. Growth during the trial period: weight gain (g/day or g/kg/day), linear growth (mm/week), head growth (mm/week), and skinfold thickness growth (mm/week).

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group.

Electronic searches

An update search was carried out in September 2014 to locate randomised controlled trials of glutamine supplementation in surgical infants since the date of the last search in November 2011.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley), EMBASE (OvidSP), Maternity and Infant Care (OvidSP), MEDLINE & MEDLINE in process (OvidSP) and PubMed. We limited the searches to references added to the databases since November 2011. We limited retrieval to clinical trials using a search filter where possible. We did not apply language restrictions.

We searched for ongoing and completed trials in ClinicalTrials.gov, metaRegister of Controlled Trials (mRCT), and the World Health Orgainzation International Clinical Trials Registry Platform (ICTRP), limiting where possible to trials added or updated since November 2011.

Full search strategies with results can be found in Appendix 1.

Searching other resources

We examined the reference lists of studies identified as potentially relevant. We searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2014), the European Society for Paediatric Research (1995 to 2013), the UK Royal College of Paediatrics and Child Health (2000 to 2014), and the Perinatal Society of Australia and New Zealand (2000 to 2014). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

Two review authors screened the title and abstract of all studies identified by the above search strategy. We assessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. We discussed any disagreements until consensus was achieved.

Data extraction and management

We used a data collection form to aid extraction of relevant information from each included study. Two review authors extracted the data separately. We discussed any disagreements until consensus was achieved. We asked the investigators for further information if data from the trial reports were insufficient.

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. Additional information from the trial authors was requested to clarify methodology and results as necessary. We evaluated and reported the following issues in the 'Risk of bias' tables.

  1. Sequence generation: we categorised the method used to generate the allocation sequence as:
    1. low risk: any random process (e.g. random number table; computer random number generator);
    2. high risk: any non-random process (e.g. odd or even date of birth; patient case-record number);
    3. unclear.
  2. Allocation concealment: we categorised the method used to conceal the allocation sequence as:
    1. low risk: (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    2. high risk: open random allocation; unsealed or non-opaque envelopes, alternation; date of birth;
    3. unclear.
  3. Blinding: we assessed blinding of participants, clinicians and carers, and outcome assessors separately for different outcomes and categorised the methods as:
    1. low risk;
    2. high risk;
    3. unclear.
  4. Incomplete outcome data: we described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised completeness as:
    1. low risk: < 20% missing data;
    2. high risk: ≥ 20% missing data;
    3. unclear.

Measures of treatment effect

We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and weighted mean difference (WMD) for continuous data with respective 95% confidence intervals (CI). We determined the number needed to treat for benefit (NNTB) or harm (NNTH) for a statistically significant difference in the RD.

Unit of analysis issues

The unit of analysis is the participating infant in individually randomised trials and the neonatal unit for cluster randomised trials.

Dealing with missing data

We requested missing study data from the trial investigators.

Assessment of heterogeneity

If more than one trial was included in a meta-analysis, we examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We calculated the I² statistic for each analysis to quantify inconsistency across studies and describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error. If substantial (I² > 50%) heterogeneity was detected, we explored the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments) in sensitivity analyses.

Data synthesis

We used a fixed-effect model for meta-analyses.

Subgroup analysis and investigation of heterogeneity

We pre-specified the following subgroup analyses:

  1. trials where participants were predominantly (> 80%) term infants versus trials where participants were predominantly preterm infants;
  2. trials where participants were infants with NEC 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 g/kg/day of glutamine versus trials where less glutamine supplementation was given.

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Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies.

Results of the search

We have included a trial previously identified as ongoing in this review update (Ong 2012). The status of NCT00647036, which was also identified as ongoing in 2011, is not known.

Three trials, in which a total of 274 infants participated, fulfilled eligibility criteria (Duggan 2004; Albers 2005, Ong 2012). The abstract of another small trial (n = 13) was found by our searches in 2011 (Nolin 2001). Further searching in September 2014 identified the full-text of a master's thesis (Nolin 2000). As this study did not focus on infants undergoing gastrointestinal surgery we have now excluded it from this review.

Included studies

Two trials were single-centre studies undertaken in surgical neonatal and paediatric intensive care centres in Europe (Albers 2005) and North America (Duggan 2004). The third trial was conducted in 14 paediatric surgical units across the UK (Ong 2012). All participants were recruited between 2000 and 2005. The smallest trial was a pilot study that aimed to assess feasibility and safety (Duggan 2004).

Participants

Duggan 2004 enrolled 20 young infants with severe gastrointestinal diseases (NEC, 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.

Albers 2005 enrolled 80 children of gestational age at birth > 30 weeks and chronological age less than two years. This trial, therefore, did not strictly fulfil our a priori population criterion (infants < 3 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 most common gastrointestinal conditions affecting participants were NEC, congenital bowel atresia or obstruction, anterior abdominal wall defects, and Hirschsprung's 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.

Ong 2012 enrolled 174 young infants with severe gastrointestinal diseases (abdominal wall defect, congenital bowel obstruction, or NEC). Most participants were born at term (median gestational age at birth 37 weeks). Their median postnatal age at enrolment was five days.

Interventions

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, carers, and assessors. The intervention group received 0.08 g/kg/day of glutamine at the start of the study. This increased to 0.31 g/kg/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.

Albers 2005: On the second postoperative day, infants in the intervention group received a standard parenteral nutrition solution supplemented with L-glutamine sufficient to provide 0.4 g/kg/day. Control infants received parenteral nutrition with an iso-nitrogenous amino acid solution. The carers 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 postoperative day when enteral feeding was gradually re-introduced.

Ong 2012: From day three of parenteral nutrition, infants in the intervention group received a glutamine dipeptide supplement providing 0.4 g/kg/day of glutamine. This was continued while parenteral nutrition was administered. The control group received an isonitrogenous, isocaloric parenteral nutrition solution. The solutions were indistinguishable to parents, carers, and assessors, and nutritional information on labels did not allow identification of the solution. All study participants received only parenteral nutrition at the start of the trial and were gradually progressed to full enteral feeds. While exclusively receiving parenteral nutrition the control group did not receive any glutamine. With the introduction of enteral feeds, the control group received some naturally occurring glutamine in breast milk or formula.

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.

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 stay, and rates of nosocomial infection were reported as secondary outcomes.

Ong 2012 assessed the effect of parenteral glutamine supplementation on time required to achieve full enteral nutrition and the incidence of "sepsis" and "septicaemia". Adverse events and mortality were also reported.

Excluded studies

Three trials that appeared potentially eligible were excluded after further evaluation of the full report (Barbosa 1999; Nolin 2000, Ehrenkranz 2011). Most participants in these trials were infants with non-gastrointestinal disease.

Risk of bias in included studies

The overall methodological quality of all studies was good.

Allocation (selection bias)

All trials used methods to conceal allocation.

Blinding (performance bias and detection bias)

All trials blinded carers and assessors to the intervention.

Incomplete outcome data (attrition bias)

All trials achieved complete or near-complete follow-up.

Effects of interventions

Glutamine supplementation (parenteral or enteral) versus no supplementation

Mortality prior to hospital discharge (Outcome 1.1):

None of the trials nor a meta-analysis of data from all trials showed a statistically significant difference in mortality (typical RR 0.79, 95% CI 0.19 to 3.20; typical RD -0.01, 95% CI -0.05 to 0.03). (Figure 1; Analysis 1.1).

Neurodevelopmental outcomes

This outcome was not assessed in any trial.

Incidence of invasive infection (Outcome 1.2)

None of the trials nor a meta-analysis of data from both trials showed a statistically significant difference in infection rates (typical RR 1.37, 95% CI 0.89 to 2.11; typical RD 0.08, 95% CI -0.03 to 0.18). (Figure 2; Analysis 1.2)

Time to establish full enteral feeds

Duggan 2004 reported no statistically significant difference in the time taken to establish full enteral feeding in the intervention group (median 39 days; interquartile range 12 to 99) versus the control group (median 21 days; interquartile range 6 to 59). Similarly, Ong 2012 reported that there was no statistically significant difference in the time taken to establish full enteral feeds between the intervention group (median: 19 days; 5th to 95th centile 14.6 to 23.4) and the control group (median: 16 days; 5th to 95th centile 13.6 to 18.4). Albers 2005 did not report on this outcome.

Time to discharge from hospital

Albers 2005 did not find a statistically significant difference between the intervention group (median 32 days; interquartile range 16.8 to 44.8) and the control group (median 31.5 days; interquartile range 14 to 64). Duggan 2004 did not assess time to hospital discharge (according to personal communication from trial authors). Time to discharge was not reported by Ong 2012.

Growth during the trial period

Duggan 2004 did not find a statistically significant difference in the rate of weight gain during the study period (MD 3.80 g/day; 95% CI -6.65 to 14.25) (Figure 3; Analysis 1.3). 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. Ong 2012 reported no significant difference in weight centile change between groups and maintenance of head circumference centiles in each group. Data were not presented. Albers 2005 did not report growth during the trial period.

Subgroup analyses
Trials where participants were predominantly term infants versus trials where participants were predominantly preterm infants

Duggan 2004 recruited preterm infants predominantly - see above. For Albers 2005 and Ong 2012, subgroup data were not available.

Trials where participants were infants with NEC versus trials where participants were infants who had undergone gastrointestinal surgery for other indications

In Albers 2005, 19 of 80 participating infants had NEC. In Duggan 2004, eight of 20 participating infants had NEC. In Ong 2012, seven of 174 participating infants had NEC. Subgroup data for infants with NEC versus other surgical gastrointestinal conditions were not presented in any of the reports.

Trials where infants received enteral glutamine supplementation versus no supplementation and trials where supplemental glutamine was given parenterally versus no supplementation

Albers 2005 and Ong 2012 studied the effect of parenteral glutamine supplementation - see above. Duggan 2004 studied the effect of enteral glutamine supplementation - see above.

Trials where the aim was to give at least 0.2 g/kg/day of glutamine versus trials where less glutamine supplementation was given

All trials aimed to provide at least 0.2 g/kg/day on average of glutamine.

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Discussion

Summary of main results

Three good quality randomised controlled trials in which 274 infants with severe gastrointestinal disease participated assessed the effect of glutamine supplementation versus no glutamine. The available data do not provide evidence that supplemental glutamine affects mortality, rates of invasive infection, or other morbidity.

Overall completeness and applicability of evidence

Although methodologically sound, the included trials were too small to detect moderate but potentially important effects on the specified outcomes of this review. Based on a control event rate for invasive infection (consistent with the included trials), a single trial would need to enrol about 2500 participants (1250 in each group) to be able to detect a 25% risk reduction with 5% significance and 90% power. This optimum study size is an order of magnitude larger than the total number of participants in the trials identified in this review.

Furthermore, the included trials recruited a heterogeneous group of participants with a range of severe gastrointestinal diseases. This 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 severe NEC compared with term infants who have had reduction of an anterior abdominal wall defect but are otherwise metabolically and physiologically stable. If further data become available from ongoing trials, subgroup analyses by gestational age at birth (term versus preterm) or by type of gastrointestinal disease may be needed to define which groups of infants, if any, 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 NEC, but this may be the most appropriate route for clinically stable infants recovering from a less physiologically destabilising gastrointestinal condition.

Quality of the evidence

All three trials were of good methodological quality but were too small to detect moderate but potentially important effects (Duggan 2004; Albers 2005, Ong 2012).

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Authors' conclusions

Implications for practice

The currently available evidence from three trials does not indicate that glutamine supplementation improves important clinical outcomes for young infants with severe gastrointestinal disease.

Implications for research

A very large randomised controlled trial is required to assess whether glutamine supplementation is beneficial for young infants with severe gastrointestinal disease. Future trials may also need to be of sufficient size to allow subgroup analyses by type of gastrointestinal disease and by gestational age.

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Acknowledgements

We thank Mellisa Harden (Centre for Reviews and Dissemination, University of York) for revising and running the electronic search.

We thank Professor Christopher Duggan for supporting a previous version of 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, and Drs. Tubman and Zubin Grover for contributing to a previous iteration (Grover 2007).

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Contributions of authors

In discussion with WM, JVEB searched and screened the studies for inclusion, assessed the methodological quality of the trials, and extracted and entered the relevant information and data from each included study. WM and JVEB completed the final review.

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Declarations of interest

None.

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Differences between protocol and review

Albers 2005 enrolled 80 children of gestational age at birth > 30 weeks and chronological age less than two years. This trial therefore did not strictly fulfil our a priori population criterion (infants up to 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 up to three months old.

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Characteristics of studies

Characteristics of included studies

Albers 2005

Methods

Randomised controlled trial

Participants

80 children of gestational age > 30 weeks and chronological age < 2 years

Exclusion criteria: renal or hepatic dysfunction, an inborn error of metabolism, immunodeficiency, use of corticosteroids, pre-existent life expectancy < 6 months, and simultaneous participation in another trial
Setting: Sophia Children's Hospital/Erasmus Medical Centre, Rotterdam, the Netherlands
1 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.

Interventions

Intervention (n = 41): on the second postoperative day infants in the intervention group received a standard parenteral nutrition solution supplemented with L-glutamine sufficient to provide 0.4 g/kg/day.

Control (n = 39): infants received parenteral nutrition with an iso-nitrogenous amino acid solution.
The protocol specified that participating infants should continue to receive full parenteral nutrition until at least the 6th postoperative day when enteral feeding was gradually re-introduced.

Outcomes
  1. Intestinal permeability (sugar absorption test)
  2. Nitrogen balance
  3. Death prior to hospital discharge
  4. Length of intensive care unit and hospital stay
  5. Episodes of invasive infection
  6. Use of antibiotics
Notes

This trial did not strictly fulfil our a priori population criterion of including only infants < 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 < 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.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generated, blocks of 4

Allocation concealment (selection bias) Low risk

Randomisation schedule available only to pharmacist

Blinding of participants and personnel (performance bias) Low risk

Physicians and nurses blinded

Incomplete outcome data (attrition bias) Low risk

Data were analysed by intention-to-treat

Duggan 2004

Methods

Randomised controlled trial

Participants

20 infants with significant gastrointestinal illness including NEC requiring laparotomy and resection, intestinal atresia, omphalocoele, gastroschisis, intestinal volvulus, or malrotation

Exclusion criteria: significant hepatic, renal, or metabolic disease necessitating protein restriction < 1.0 g/kg/day; significant extra-intestinal disease (cystic fibrosis, severe hypoxic ischaemic encephalopathy); or extreme short bowel syndrome (defined as < 25 cm of residual bowel length)
Setting: Children's Hospital, Boston, USA

Interventions

Intervention (n = 9): glutamine-supplemented (up to 0.31 g/kg/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

Outcomes
  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 trial investigators)
Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random numbers list in blocks of 4

Allocation concealment (selection bias) Low risk

Sealed envelopes, opened by hospital pharmacists

Blinding of participants and personnel (performance bias) Low risk

Investigators, parents, physicians, nurses blinded

Incomplete outcome data (attrition bias) Low risk

> 80% followed up

Ong 2012

Methods

Randomised controlled trial

Participants

174 infants with significant gastrointestinal illness, including abdominal wall defect, congenital bowel obstruction, and NEC

Exclusion criteria: renal failure, inborn errors of metabolism or immune deficiency

Setting: 14 paediatric surgical units in the UK

Interventions

Intervention (n = 87): parenteral nutrition supplemented with glutamine dipeptide (0.6 g/kg/d)

Control (n = 87): isonitrogenous, isocaloric parenteral nutrition solution

Outcomes
  1. Time on parenteral nutrition
  2. Time to full enteral feeding
  3. Incidence of sepsis and septicaemia

Adverse events and mortality also reported

Notes

This trial was stopped when funding came to an end before the target of 250 participants was achieved. It was judged that there was a less than 5% chance of identifying the specified differences in the primary outcome measure (duration of parenteral nutrition), even if recruitment had continued as planned.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Methods used to generate sequence in pharmacy not stated explicitly

Allocation concealment (selection bias) Low risk

Infants allocated to groups by central pharmacy, allocation communicated to pharmacy of recruiting centre and not shared outside of pharmacy

Blinding of participants and personnel (performance bias) Low risk

Parents, nurses, physicians, surgeons, and trial coordinator blinded

Allocation was revealed in one case (control group) where clinically necessary

Incomplete outcome data (attrition bias) Low risk

> 80% followed up, any loss to follow-up explained and balanced across groups

4 infants in each group who had "intervention discontinued" were not included in final analyses by intention to treat

Footnotes

NEC: necrotising enterocolitis

Characteristics of excluded studies

Barbosa 1999

Reason for exclusion

Most participants in this small trial (n = 9) were infants with non-gastrointestinal disease

Ehrenkranz 2011

Reason for exclusion

Did not focus on infants with gastrointestinal disease

Nolin 2000

Reason for exclusion

Did not focus on infants with gastrointestinal disease

Characteristics of studies awaiting classification

NCT00647036

Methods

Randomised controlled trial

Participants

Surgical infants requiring total parenteral nutrition

Interventions  
Outcomes  
Notes  

Characteristics of ongoing studies

None noted.

[top]

References to studies

Included studies

Albers 2005

Albers MJ, Steyerberg EW, Hazebroek FW, Mourik M, Borsboom GJ, Rietveld T, et al. 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(4):599-606. [PubMed: 15798461]

Duggan 2004

Duggan C, Stark AR, Auestad N, Collier S, Fulhan J, Gura K, et al. Glutamine supplementation in infants with gastrointestinal disease: a randomized, placebo-controlled pilot trial. Nutrition 2004;20(9):752-6. [PubMed: 15325681]

Ong 2012

Published and unpublished data

Ong EG, Eaton S, Wade AM, Horn V, Losty PD, Curry JI, et al. Randomised clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease. British Journal of Surgery 2012;99(7):929-38. [DOI: 10.1002/bjs.8750; PubMed: 22513659]

Excluded studies

Barbosa 1999

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(1):21-4. [PubMed: 10488597]

Ehrenkranz 2011

Ehrenkranz RA, Das A, Wrage LA, Poindexter BB, Higgins RD, Stoll BJ, et al. Early nutrition mediates the influence of severity of illness on extremely LBW infants. Pediatric Research 2011;69(6):522-9. [DOI: 10.1203/PDR.0b013e318217f4f1; PubMed: 21378596]

Nolin 2000

Unpublished data only

Nolin F. Parenteral glutamine supplementation in neonates following surgical stress. http://digitool.library.mcgill.ca/R/?func=dbin-jump-full&object_id=31281&local_base=GEN01-MCG02 2000.

Studies awaiting classification

NCT00647036

[ClinicalTrials.gov: NCT00647036]

Ongoing studies

None noted.

[top]

Other references

Additional references

Abdullah 2007

Abdullah F, Arnold MA, Nabaweesi R, Fischer AC, Colombani PM, Anderson KD, et al. Gastroschisis in the United States 1988-2003: analysis and risk categorization of 4344 patients. Journal of Perinatology 2007;27(1):50-5. [PubMed: 17036030]

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(4):434-8. [PubMed: 10963461]

Andrews 2011

Andrews PJ, Avenell A, Noble DW, Campbell MK, Croal BL, Simpson WG, et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ 2011;342:d1542. [DOI: 10.1136/bmj.d1542; PubMed: 21415104]

Avenell 2009

Avenell A. Hot topics in parenteral nutrition. Current evidence and ongoing trials on the use of glutamine in critically-ill patients and patients undergoing surgery. The Proceedings of the Nutrition Society 2009;68(3):261-8. [DOI: 10.1017/S0029665109001372; PubMed: 19490739]

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):1-7. [PubMed: 413500]

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(3):182-5. [PubMed: 12757111]

Dalla Vecchia 1998

Dalla Vecchia LK, Grosfeld JL, West KW, Rescorla FJ, Scherer LR, Engum SA. Intestinal atresia and stenosis: a 25-year experience with 277 cases. Archives of Surgery 1998;133(5):490-6. [PubMed: 9605910]

Donnell 2002

Donnell SC, Taylor N, van Saene HK, Magnall VL, Pierro A, Lloyd DA. Infection rates in surgical neonates and infants receiving parenteral nutrition: a five-year prospective study. The Journal of Hospital Infection 2002;52(4):273-80. [PubMed: 12473472]

Estivariz 2008

Estivariz CF, Griffith DP, Luo M, Szeszycki EE, Bazargan N, Dave N, et al. Efficacy of parenteral nutrition supplemented with glutamine dipeptide to decrease hospital infections in critically ill surgical patients. Journal of Parenteral and Enteral Nutrition 2008;32(4):389-402. [DOI: 10.1177/0148607108317880; PubMed: 18596310]

Furst 1997

Furst P, Pogan K, Stehle P. Glutamine dipeptides in clinical nutrition. Nutrition 1997;13(7-8):731-7. [PubMed: 9263278]

Garlick 2001

Garlick PJ. Assessment of the safety of glutamine and other amino acids. Journal of Nutrition 2001;131(9 Suppl):2556S-61S. [PubMed: 11533313]

Hajivassiliou 2003

Hajivassiliou CA. Intestinal obstruction in neonatal/pediatric surgery. Seminars in Pediatric Surgery 2003;12(4):241-53. [PubMed: 14655163]

Kalhan 2005

Kalhan SC, Parimi PS, Gruca LL, Hanson RW. Glutamine supplement with parenteral nutrition decreases whole body proteolysis in low birth weight infants. Journal of Pediatrics 2005;146(5):642-7. [PubMed: 15870668]

Kays 1996

Kays DW. Surgical conditions of the neonatal intestinal tract. Clinics in Perinatology 1996;23(2):353-75. [PubMed: 8780909]

Khan 1991

Khan K, Hardy G, McElroy B, Elia M. The stability of L-glutamine in total parenteral nutrition solutions. Clinical Nutrition 1991;10(4):193-8. [PubMed: 16839918]

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(8):1040-5. [PubMed: 2378557]

Lacey 1990

Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutrition Reviews 1990;48(8):297-309. [PubMed: 2080048]

Lefebvre 2008

Lefebvre C, Eisinga A, McDonald S, Paul N. Enhancing access to reports of randomised trials published world-wide - the contribution of EMBASE records to the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library. Emerging Themes in Epidemiology 2008;5:13. [DOI: 10.1186/1742-7622-5-13]

Lefebvre 2011

Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions. 5.1.0 (updated March 2011) edition. The Cochrane Collaboration, 2011.

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(4):437-9. [PubMed: 1910108]

Moe-Byrne 2012

Moe-Byrne T, Wagner JVE, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD001457. DOI: 10.1002/14651858.CD001457.pub4.

Murray 2009

Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD002920. DOI: 10.1002/14651858.CD002920.pub3.

Newsholme 1999

Newsholme P, Curi R, Pithon Curi TC, Murphy CJ, Garcia C, Pires de Melo M. Glutamine metabolism by lymphocytes, macrophages, and neutrophils: its importance in health and disease. Journal of Nutritional Biochemistry 1999;10(6):316-24. [PubMed: 15539305]

Newsholme 2001

Newsholme P. Why Is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? Journal of Nutrition 2001;131(9 Suppl):2515S-22S. [PubMed: 11533304]

Nolin 2001

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

Novak 2002

Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Critical Care Medicine 2002;30(9):2022-9. [PubMed: 12352035]

Panigrahi 1997

Panigrahi P, Gewolb IH, Bamford P, Horvath K. Role of glutamine in bacterial transcytosis and epithelial cell injury. Journal of Parenteral and Enteral Nutrition 1997;21(2):75-80. [PubMed: 9084009]

Parimi 2004

Parimi PS, Devapatla S, Gruca LL, Amini SB, Hanson RW, Kalhan SC. Effect of enteral glutamine or glycine on whole-body nitrogen kinetics in very-low-birth-weight infants. American Journal of Clinical Nutrition 2004;79(3):402-9. [PubMed: 14985214]

Parry-Billings 1990

Parry-Billings M, Evans J, Calder PC, Newsholme EA. Does glutamine contribute to immunosuppression after major burns? Lancet 1990;336(8714):523-5. [PubMed: 1975037]

Parry-Billings 1992

Parry-Billings M, Baigrie RJ, Lamont PM, Morris PJ, Newsholme EA. Effects of major and minor surgery on plasma glutamine and cytokine levels. Archives of Surgery 1992;127(10):1237-40. [PubMed: 1358047]

Pierro 2002

Pierro A. Metabolism and nutritional support in the surgical neonate. Journal of Pediatric Surgery 2002;37(6):811-22. [PubMed: 12037742]

Rees 2007

Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Archives of Disease in Childhood. Fetal and Neonatal Edition 2007;92(3):F193-8. [PubMed: 16984980]

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(4 Suppl):100S-5S. [PubMed: 2119454]

Stoll 2004

Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292(19):2357-65. [PubMed: 15547163]

Van der Hulst 1993

van der Hulst RR, van Kreel BK, von Meyenfeldt MF, Brummer RJ, Arends JW, Deutz NE, et al. Glutamine and the preservation of gut integrity. Lancet 1993;341(8857):1363-5. [PubMed: 8098788]

Walsh 1986

Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatric Clinics of North America 1986;33(1):179-201. [PubMed: 3081865]

Windmueller 1980

Windmueller HG, Spaeth AE. Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. Quantitative importance of glutamine, glutamate, and aspartate. Journal of Biological Chemistry 1980;255(1):107-12. [PubMed: 7350142]

Other published versions of this review

Brown 2012

Brown JVE, Moe-Byrne T, Grover Z, McGuire W. Glutamine supplementation for young infants with severe gastrointestinal disease. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD005947. DOI: 10.1002/14651858.CD005947.pub3.

Grover 2007

Grover Z, Tubman R, McGuire W. Glutamine supplementation for young infants with severe gastrointestinal disease. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD005947. DOI: 10.1002/14651858.CD005947.pub2.

Classification pending references

None noted.

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Data and analyses

1 Glutamine supplementation (parenteral or enteral) versus no supplementation

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Death prior to hospital discharge 3 263 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.19, 3.20]
1.2 Incidence of invasive infection 3 263 Risk Ratio (M-H, Fixed, 95% CI) 1.37 [0.89, 2.11]
1.3 Weight gain during trial period (g/day) 1 20 Mean Difference (IV, Fixed, 95% CI) 3.80 [-6.65, 14.25]
 

[top]

Figures

Figure 1 (Analysis 1.1)

Refer to figure 1 caption below.

Forest plot of comparison 1: glutamine supplementation (parenteral or enteral) versus no supplementation, outcome 1.1: death prior to hospital discharge (Figure 1 description).

Figure 2 (Analysis 1.2)

Refer to figure 2 caption below.

Forest plot of comparison 1: glutamine supplementation (parenteral or enteral) versus no supplementation, outcome 1.2: incidence of invasive infection (Figure 2 description).

Figure 3 (Analysis 1.3)

Refer to figure 3 caption below

Forest plot of comparison 1: glutamine supplementation (parenteral or enteral) versus no supplementation, outcome 1.3: weight gain during trial period (g/day) (Figure 3 description).

[top]

Sources of support

Internal sources

  • University of York, UK

External sources

  • National Institute for Health Research (NIHR), UK
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

[top]

Appendices

1 Electronic search strategy

Database searches

Cochrane Central Register of Controlled Trials (CENTRAL)

Wiley Wiley Online Library External Web Site Policy

Issue 8 of 12, August 2014

Searched on 22nd September 2014. 70 records were retrieved.

  1. MeSH descriptor: [Infant, Newborn] explode all trees 13194
  2. MeSH descriptor: [Premature Birth] this term only 397
  3. (neonat* or neo next nat*):ti,ab,kw 10126
  4. (newborn* or new next born* or newly next born*):ti,ab,kw 16527
  5. (preterm or preterms or pre next term or pre next terms):ti,ab,kw 6017
  6. (preemie* or premie or premies):ti,ab,kw 14
  7. (prematur* near/3 (birth* or born or deliver*)):ti,ab,kw 1126
  8. (low near/3 (birthweight* or birth next weight*)):ti,ab,kw 3243
  9. (lbw or vlbw or elbw):ti,ab,kw 887
  10. infan*:ti,ab,kw 36861
  11. (baby or babies):ti,ab,kw 3163
  12. MeSH descriptor: [Enterocolitis, Necrotizing] this term only 121
  13. enterocolitis:ti,ab,kw 683
  14. NEC:ti,ab,kw 173
  15. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 43510
  16. MeSH descriptor: [Glutamine] this term only 491
  17. glutam*:ti,ab,kw 3181
  18. levoglutam*:ti,ab,kw 0
  19. #16 or #17 or #18 3181
  20. #15 and #19 189
  21. #15 and #19 in Trials 186
  22. #15 and #19 Publication Year from 2007 to 2014, in Trials 70
Key

MeSH descriptor = indexing term (MeSH heading)

* = truncation

:ti,ab,kw = terms in either title or abstract or keyword fields

near/3 = terms within three words of each other (any order)

next = terms are next to each other

EMBASE

OvidSP http://ovidsp.ovid.com/ External Web Site Policy

1980 to 2014 Week 38

Searched on 22nd September 2014. 87 records were retrieved. A search strategy developed by Lefebvre 2008 to identify randomised trials in EMBASE was used to limit retrieval to clinical trials (lines 22-36).

  1. exp infant/ (841476)
  2. prematurity/ (70117)
  3. premature labor/ (29157)
  4. exp low birth weight/ (39329)
  5. (neonat$ or neo nat$).ti,ab. (229859)
  6. (newborn$ or new born$ or newly born$).ti,ab. (143427)
  7. (preterm or preterms or pre term or pre terms).ti,ab. (60787)
  8. (preemie$ or premie or premies).ti,ab. (154)
  9. (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (14127)
  10. (low adj3 (birthweight$ or birth weight$)).ti,ab. (29286)
  11. (lbw or vlbw or elbw).ti,ab. (6941)
  12. infan$.ti,ab. (364930)
  13. (baby or babies).ti,ab. (64354)
  14. necrotizing enterocolitis/ (6320)
  15. enterocolitis.ti,ab. (9685)
  16. NEC.ti,ab. (4115)
  17. or/1-16 (1134787)
  18. glutamine/ (28305)
  19. glutam$.ti,ab. (162556)
  20. levoglutam$.ti,ab. (3)
  21. 18 or 19 or 20 (173526)
  22. random$.ti,ab. (900117)
  23. factorial$.ti,ab. (23315)
  24. crossover$.ti,ab. (49098)
  25. cross-over$.ti,ab. (21608)
  26. placebo$.ti,ab. (202020)
  27. (doubl$ adj blind$).ti,ab. (143459)
  28. (singl$ adj blind$).ti,ab. (14632)
  29. assign$.ti,ab. (242053)
  30. allocat$.ti,ab. (85229)
  31. volunteer$.ti,ab. (177796)
  32. Crossover Procedure/ (40222)
  33. double blind procedure/ (115438)
  34. Randomized Controlled Trial/ (350056)
  35. single blind procedure/ (18827)
  36. or/22-35 (1432268)
  37. 17 and 21 and 36 (364)
  38. animal/ (1570185)
  39. exp animal experiment/ (1697956)
  40. Nonhuman/ (4374620)
  41. (rat or rats or mouse or mice or hamster or hamsters or animal or animals or dog or dogs or cat or cats or bovine or sheep).ti,ab,sh. (4568271)
  42. 38 or 39 or 40 or 41 (6746352)
  43. exp human/ (15016996)
  44. human experiment/ (329080)
  45. 43 or 44 (15018382)
  46. 42 not (42 and 45) (5182957)
  47. 37 not 46 (225)
  48. limit 47 to em=201100-201438 (87)
Key:

/ = indexing term (EMTREE heading)

$ = truncation

.ti,ab. = terms in either title or abstract fields

adj3 = terms within three words of each other (any order)

.sh.= subject heading field

.em. = entry date – date added to database

Maternity and Infant Care

OvidSP http://ovidsp.ovid.com/ External Web Site Policy

1971 to August 2014

Searched on 22nd September 2014. 59 records were retrieved.

  1. Infant.de. (7384)
  2. Infant - newborn.de. (23849)
  3. Infant - premature.de. (7331)
  4. infant - very premature.de. (753)
  5. Infant - low birth weight.de. (2367)
  6. Infant - very low birth weight.de. (2147)
  7. Premature birth.de. (1625)
  8. Infant - small for gestational age.de. (887)
  9. (neonat$ or neo nat$).ti,ab. (32059)
  10. (newborn$ or new born$ or newly born$).ti,ab. (14916)
  11. (preterm or preterms or pre term or pre terms).ti,ab. (18476)
  12. (preemie$ or premie or premies).ti,ab. (41)
  13. (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (3141)
  14. (low adj3 (birthweight$ or birth weight$)).ti,ab. (8455)
  15. (lbw or vlbw or elbw).ti,ab. (2237)
  16. infan$.ti,ab. (48220)
  17. (baby or babies).ti,ab. (23514)
  18. Enterocolitis.de. (8)
  19. enterocolitis.ti,ab. (1349)
  20. NEC.ti,ab. (493)
  21. or/1-20 (94518)
  22. Glutamine.de. (16)
  23. glutam$.ti,ab. (161)
  24. levoglutam$.ti,ab. (0)
  25. 22 or 23 or 24 (162)
  26. 21 and 25 (108)
  27. limit 26 to yr="2007 -Current" (59)
Key

.de. = indexing term

$ = truncation

.ti,ab. = terms in either title or abstract fields

adj3 = terms within three words of each other (any order)

yr = year published

MEDLINE

OvidSP http://ovidsp.ovid.com/ External Web Site Policy

1946 to September week 2 2014

Searched on 22nd September 2014. 61 records were retrieved. The Cochrane highly sensitive search strategy for identifying randomized trials in MEDLINE (sensitivity-maximizing version) was used to limit retrieval to clinical trials (lines 21-31) (Lefebvre 2011).

  1. exp Infant, Newborn/ (504876)
  2. Premature Birth/ (6949)
  3. (neonat$ or neo nat$).ti,ab. (189942)
  4. (newborn$ or new born$ or newly born$).ti,ab. (128353)
  5. (preterm or preterms or pre term or pre terms).ti,ab. (45250)
  6. (preemie$ or premie or premies).ti,ab. (106)
  7. (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (11353)
  8. (low adj3 (birthweight$ or birth weight$)).ti,ab. (24580)
  9. (lbw or vlbw or elbw).ti,ab. (5285)
  10. infan$.ti,ab. (323868)
  11. (baby or babies).ti,ab. (50568)
  12. Enterocolitis, Necrotizing/ (2030)
  13. enterocolitis.ti,ab. (7862)
  14. NEC.ti,ab. (2655)
  15. or/1-14 (818716)
  16. Glutamine/ (15076)
  17. glutam$.ti,ab. (145071)
  18. levoglutam$.ti,ab. (4)
  19. 16 or 17 or 18 (149488)
  20. 15 and 19 (5020)
  21. randomized controlled trial.pt. (388375)
  22. controlled clinical trial.pt. (89809)
  23. randomized.ab. (284414)
  24. placebo.ab. (150745)
  25. drug therapy.fs. (1744932)
  26. randomly.ab. (201022)
  27. trial.ab. (295504)
  28. groups.ab. (1282228)
  29. or/21-28 (3283677)
  30. exp animals/ not humans.sh. (4011372)
  31. 29 not 30 (2797292)
  32. 15 and 19 and 31 (437)
  33. limit 32 to ed=20111101-20140911 (61)
Key

/ = indexing term (MeSH heading)

exp = exploded MeSH heading

$ = truncation

.ti,ab. = terms in either title or abstract fields

adj3 = terms within three words of each other (any order)

.pt. = publication type

.fs. = floating subheading

.sh.= subject heading

.ed. = entry date - date added to the database

MEDLINE In-Process & Other Non-Indexed Citations

OvidSP http://ovidsp.ovid.com/ External Web Site Policy

September 19, 2014

Searched on 22nd September 2014. 60 records were retrieved.

  1. exp Infant, Newborn/ (0)
  2. Premature Birth/ (0)
  3. (neonat$ or neo nat$).ti,ab. (10428)
  4. (newborn$ or new born$ or newly born$).ti,ab. (5627)
  5. (preterm or preterms or pre term or pre terms).ti,ab. (3486)
  6. (preemie$ or premie or premies).ti,ab. (11)
  7. (prematur$ adj3 (birth$ or born or deliver$)).ti,ab. (623)
  8. (low adj3 (birthweight$ or birth weight$)).ti,ab. (1523)
  9. (lbw or vlbw or elbw).ti,ab. (432)
  10. infan$.ti,ab. (16416)
  11. (baby or babies).ti,ab. (3393)
  12. Enterocolitis, Necrotizing/ (0)
  13. enterocolitis.ti,ab. (468)
  14. NEC.ti,ab. (298)
  15. or/1-14 (30053)
  16. Glutamine/ (0)
  17. glutam$.ti,ab. (8117)
  18. levoglutam$.ti,ab. (0)
  19. 16 or 17 or 18 (8117)
  20. 15 and 19 (176)
  21. limit 20 to ed=20111101-20140918 (60)
Key

/ = indexing term (MeSH heading)

exp = exploded MeSH heading

$ = truncation

.ti,ab. = terms in either title or abstract fields

adj3 = terms within three words of each other (any order)

ed = entry date - date added to the database

PubMed

http://www.ncbi.nlm.nih.gov/pubmed/

Searched on 23rd September 2014. 82 records were retrieved. The Cochrane highly sensitive search strategy for identifying randomized trials in PubMed (sensitivity-maximizing version) was used to limit retrieval to clinical trials (Lefebvre 2011).

Search (((((((((((((((((((((("Infant, Newborn"[Mesh])) OR ("Premature Birth"[Mesh])) OR (((neonat*[Title/Abstract]) OR neo nat*[Title/Abstract]) OR neo-nat*[Title/Abstract])) OR (((((newborn*[Title/Abstract]) OR new born*[Title/Abstract]) OR new-born*[Title/Abstract]) OR newly born*[Title/Abstract]) OR newly-born*[Title/Abstract])) OR ((((((preterm[Title/Abstract]) OR preterms[Title/Abstract]) OR pre term[Title/Abstract]) OR pre-term[Title/Abstract]) OR pre terms[Title/Abstract]) OR pre-terms[Title/Abstract])) OR (((preemie*[Title/Abstract]) OR premie[Title/Abstract]) OR premies[Title/Abstract])) OR ((prematur*[Title/Abstract]) AND birth*[Title/Abstract])) OR ((prematur*[Title/Abstract]) AND born[Title/Abstract])) OR ((prematur*[Title/Abstract]) AND deliver*[Title/Abstract])) OR ((low[Title/Abstract]) AND birthweight*[Title/Abstract])) OR ((low[Title/Abstract]) AND birth weight*[Title/Abstract])) OR ((low[Title/Abstract]) AND birth-weight*[Title/Abstract])) OR (((lbw[Title/Abstract]) OR vlbw[Title/Abstract]) OR elbw[Title/Abstract])) OR (infan*[Title/Abstract])) OR ((baby[Title/Abstract]) OR babies[Title/Abstract])) OR ("Enterocolitis, Necrotizing"[Mesh:noexp]) OR (enterocolitis[Title/Abstract]) OR (NEC[Title/Abstract]))) AND (((levoglutam*[Title/Abstract]) OR glutam*[Title/Abstract]) OR "Glutamine"[Mesh:noexp]))) AND (((((((((((randomized controlled trial[Publication Type])) OR (controlled clinical trial[Publication Type])) OR (randomized[Title/Abstract])) OR (placebo[Title/Abstract])) OR (drug therapy[MeSH Subheading])) OR (randomly[Title/Abstract])) OR (trial[Title/Abstract])) OR (groups[Title/Abstract]))) NOT (animals[mh] NOT humans[mh])))) AND ("2011/11/01"[Date - Entrez] : "3000"[Date - Entrez])

Key

[Mesh] = exploded Medical Subject heading (MeSH)

[mh] = exploded MeSH

[Mesh:noexp] = MeSH not exploded

* = truncation

[Title/Abstract] = terms in either title or abstract fields

[Date - Entrez] = entry date - date added to the database

Trial register searches

Clinical Trials.gov

http://clinicaltrials.gov/

Searched on 23rd September 2014. 17 records were retrieved in total using the following search strategies:

4 studies found for: Glutamine AND (infant OR infants OR newborn OR newborns OR premature OR prematurity OR neonate OR neonates OR neonatal OR preterm OR preterms OR preemie OR preemies OR premie OR premies OR birthweight OR baby OR babies) | received on or after 11/01/2011 | updated on or after 11/01/2011

1 study found for: Glutamine AND (NEC OR enterocolitis) | received on or after 11/01/2011 | updated on or after 11/01/2011

12 studies found for: "Glutamine" | Child | received on or after 11/01/2011 | updated on or after 11/01/2011

metaRegister of Controlled Trials (mRCT)

http://www.controlled-trials.com/mrct/searchform

Searched on 23rd September 2014. 18 trials were retrieved.

(Glutamine AND (infant OR infants OR newborn OR newborns OR premature OR prematurity OR neonate OR neonates or neonatal OR preterm OR preterms OR preemie OR preemies OR premie OR premies OR birthweight OR baby OR babies OR enterocolitis or NEC))

WHO International Clinical Trials Registry Platform

http://apps.who.int/trialsearch/AdvSearch.aspx External Web Site Policy

Searched on 23rd September 2014. 21 trials were retrieved in total using the following search strategies:

  1. glutam* in title, clinical trials in children – 11 trials.
  2. glutam* in intervention field, clinical trials in children – 10 trials.

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This review is published as a Cochrane review in The Cochrane Library, Issue 12, 2014 (see http://www.thecochranelibrary.com External Web Site Policy 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.