Meta-analysis of the initial randomized controlled trials of parenteral GLN supplementation suggested outcome benefits in the six early trials examining critical illness [45]. Since that time an additional 22 randomized clinical trials have been performed in over 2,000 patients receiving GLN as a component of complete nutrition support, primarily given as PN (85% of trials). In addition, we have a much greater understanding of the potential beneficial mechanisms of GLN in critical illness as summarized in recent reviews [1, 46].

Early trials of GLN were primarily focused on patients receiving full nutrition support primarily by PN at doses falling within the approved prescribing indications for dose in commercially available GLN preparations. Further, as shown in Table 1, patients in these traditional trials were commonly excluded from enrollment if they had pre-existing renal or liver failure. These traditional nutritionally oriented (or non-pharmaconutrition based) GLN supplementation trials have shown a consistent reduction of mortality and benefit on other outcomes as suggested by the 2009 update of the Canadian Critical Care Nutrition Guidelines [47]. However, given the publication of 11 new randomized controlled trials examining the traditional parenteral use of GLN as a component of nutrition support (predominantly PN) since 2009, a new systematic review is indicated.

This need for a new systematic review is further driven by the results of the REDOXS trial, a 1,200-patient, 40-center randomized controlled trial of ‘pharmacologically dosed’ parenteral and enteral GLN (approximately 0.6 to 0.8 g/kg/day) factorialized with antioxidant supplementation [6]. This trial was distinct from any of the previously published parenteral GLN trials supplementing PN or EN in ICU patients as GLN (and a cocktail of antioxidants) were administered independent of any concomitant nutrition support. In contrast to the design of studies reported in this analysis, the nutritional delivery of energy and protein in the REDOXS trial averaged less than 50% of that prescribed for the patient, and thus was quite insufficient in meeting patient needs. In addition, all patients in the REDOXS trial had documented multi-system organ failure at enrollment, which is a common exclusion criteria in the trials reported in this analysis using parenteral GLN as a supplement to nutrition support. Further, more than 30% of REDOXS patients were found to have baseline renal failure at admission, which was a very common exclusion criteria in the trials reported in the analysis (Table 1). As stated, this is a key difference of REDOXS from all other GLN trials.

Thus, given the many differences in fundamental trial design between REDOXS and traditional GLN supplementation trials, the REDOXS trial has not been included in this systematic review focused on GLN supplementation of nutrition support. However, the publication of the REDOXS trial necessitates a close examination of the many new GLN supplementation trials published recently to examine if there has been a change in the fundamental signal of benefit of GLN supplementation of PN seen in historical trials in the recent era of critical care practice. This was the primary aim of this systematic review.

Overall, our results reveal that GLN supplementation continues to show a significant reduction in hospital mortality. In addition, GLN supplementation of complete nutrition was found to be associated with a strong trend towards a reduction in infectious complications, ICU LOS and a significant reduction in hospital LOS. GLN supplementation as part of nutrition support also continues to show a trend towards reduction of overall mortality in all trials examining both PN and EN nutrition delivery. The signal may be stronger for trials that utilize GLN supplementation as part of PN nutrition delivery. Importantly, no statistically significant signal of publication bias was observed in any of our tests for asymmetry as shown in the funnel plots in Figure 7.

A number of high-quality multi-center trials of parenteral GLN supplementation have been published recently, driving the need for this new critical care focused systematic review. A number of these key trials have strengths and weaknesses that are in some cases not reflected in the trial quality scoring utilized by this and other systematic reviews. Thus, a brief discussion of some of these key trials is useful. In short, these trials include the Scandinavian GLN trial [39], which examined 413 patients in multiple centers and demonstrated a benefit on ICU survival rates with parenteral GLN. A limitation of this trial was that it was stopped prior to achievement of its predefined enrollment goal due to slow enrollment. Another multi-center trial, the SIGNET trial, showed no benefit of short-term (approximately ≤4 days), low-dose GLN (approximately 0.2 g/kg/d) given parenterally to ICU patients on parenteral feeding [20]. Some concerns with this trial included lack of availability of some key data including issues regarding missing values, dropouts, protocol violations, and complete follow-up data. The actual values for GLN doses based on body weight have not been published and this has been viewed as a significant limitation of the trial. In an attempt to address the effect of quality of the trials and single-center versus multi-center trials included in the systematic review, we performed subgroup analyses to examine the role of these factors. We observed a more significant signal for parenteral GLN supplementation reducing mortality in the higher quality studies versus the lower quality trials. Single-center trials showed a greater benefit of GLN supplementation on mortality and overall infectious morbidity, although no signals of harm were observed in the multi-center trials of GLN on mortality. Interestingly, the beneficial effect of GLN on VAP was greater in the multi-center trials then the single-center trials. This is an endpoint that may deserve more focused examination in future trials of GLN supplementation in the ICU.

A number of other systematic reviews of GLN supplementation in either much broader populations, including noncritically ill patients, or specific populations (pancreatitis, burn injury, or elective surgery) have been published recently [11–14]. To our knowledge, our systematic analysis is the first to focus on the parenteral use of GLN supplementation of standard nutrition support in which all subjects are critically ill. When compared to the largest recent meta-analysis in a broader mixed elective surgery and critical care population many similarities with our data are observed [11]. First, with regard to mortality this recent analysis of GLN showed a very similar trend towards reduction of mortality (RR = 0.89; 95% CI, 0.77 to 1.04 versus RR 0.88, 95% CI 0.75, 1.03, in our analysis) in a patient population with a lower illness severity (where an effect on mortality would be less likely to be observed). No analysis of hospital mortality was reported in this previous analysis. With regard to infectious morbidity, this earlier meta-analysis showed a stronger statistically significant reduction of infectious morbidity (RR = 0.83; 95% CI, 0.72 to 0.95) compared to our data where a nonsignificant trend of similar magnitude for a benefit on infection was observed (RR 0.86, 95% CI 0.73, 1.02). Both the previous and current systematic reviews reported significant reductions on hospital LOSs of approximately 2.5 days (-2.35; 95%, -3.68 to -1.02 versus -2.56, 95% CI -4.71, -0.42 in our analysis). Other key differences of our analysis versus the earlier report was that no direct industry funding was involved in support of our analysis (partial funding by an unrestricted industry grant was used to support this previous analysis), we included all of the world literature (including non-English trials) in our search, and we successfully attempted in all cases to contact the original authors when any questions of missing data or actual ICU patient inclusion was in question. For the first time we also examined the effect of GLN supplementation on VAP. We were also able to incorporate original source data from the unpublished multi-center American ‘GLND’ trial of GLN-supplementation of PN published in abstract form [44]. Finally, we performed funnel plots for all primary and key secondary endpoints examined by this analysis to examine possible publication bias associated with these endpoints.

The strength of our meta-analysis includes the use of several methods to reduce bias (comprehensive literature search, duplicate data abstraction, specific criteria for searching and analysis) and focus on clinically important primary outcomes. Notwithstanding, we are aware that our meta-analysis has several limitations. The major limitation is the small number of trials included in certain subgroup analyses such as PN-supplementation of EN. We also unfortunately could not perform subgroup analysis for all endpoints due to limited numbers of trials examining the particular endpoints. Another potential weakness of any systematic review of randomized controlled nutrition trials has been pointed out by Vincent et al. recently [48]. This is the potential inability of a controlled nutrition trial to recreate ‘real-life’ patient conditions in the controlled setting of a trial (that is due to many patient exclusions). That said, we feel this systematic review best reflects all existing data in a wide variety of critical care settings of parenteral GLN supplementation to provide clinicians with most complete data to assist in making clinical decisions. Further, despite our attempts to be fully comprehensive in our search for all available trials we may not have been to include all available trials.

In spite of these limitations, we have demonstrated that traditional GLN supplementation used in the context of standard (predominantly parenteral) nutrition support in the critically ill may significantly reduce hospital mortality and shorten hospital LOS with a trend towards reduction in overall mortality and infectious complications, including VAP, and ICU LOS. Nonetheless, many questions on the ideal dose and timing of GLN supplementation in the ICU still remain unanswered. Further research is warranted to define the optimal dose and timing of supplementation of GLN in patients receiving full nutrition support. Recent data from REDOXS and other trials suggest that parenteral GLN should not be given in patients early in the acute phase of critical illness, in patients with multiple organ failure or in patients with unresuscitated shock requiring significant vasopressor support. Finally, based on the results of the REDOXS trial [6], we believe that high-dose parenteral or parenteral + enteral GLN (doses >0.5 g/kg/d) should not be used during the acute phase of critical illness.