A situation in which mechanism of action is not understood makes the meta-analysis technique particularly hazardous. The impact of route of administration, dosing, combination with other nutrients, definition of shortage, and time course of treatment all call for subgroup analyses in which the individual studies in the end will stand quite alone with their specific treatment protocols. Meta-analyses may be a useful tool when the mechanism of action is known and the peculiarities of the individual studies can be evaluated in that context. When the mechanism is obscure, results become much more speculative, and the value of combining studies into a meta-analysis is discounted and may even become confusing.
Until today, only one study provides plasma glutamine concentration at the time of study start [1]. It is unfortunate that the study protocol did not select the patients with hypoglutaminemia to randomization. Another unfortunate factor is that the intervention was not confined to glutamine supplementation but also included omega-3 fatty acids, and therefore post hoc subgroup analyses of the hypoglutaminemic subject did not shed any light on the effect of glutamine supplementation in that particular group. So to summarize, the hypothesis that glutamine supplementation may be beneficial in critically ill patients with hypoglutaminemia is still not addressed.