November 2015 E-Journal Club

Mountains 8-15 (2)Greetings,
We did not host a traineeship program in November, but we still managed to find time for journal club before everyone became preoccupied with Thanksgiving festivities. Our topic this month was the use of glutamine-supplemented parenteral nutrition in surgical ICU patients.

November Citation:
Ziegler TR, May AK, Hebbar G, et al. Efficacy and Safety of Glutamine-supplemented Parenteral Nutrition in Surgical ICU Patients: An American Multicenter Randomized Controlled Trial. Ann Surg. 2015 Oct 22. [Epub ahead of print]

This was a multicenter double-blind randomized study to determine the safety and clinical efficacy of glutamine-dipeptide supplemented parenteral nutrition (PN) in ICU patients after cardiac, vascular, or intestinal surgery. In consideration of the results of the REDOXS study, which revealed increased mortality in patients who received combined enteral and parenteral glutamine, particularly in patients with renal failure, this study was designed to provide only parenteral glutamine to a carefully selected population free of sepsis and renal or hepatic failure.

Patients who were expected to require parenteral nutrition for at least 7 days were randomized to receive either glutamine dipeptide (alanyl-glutamine) 0.5 g/kg/day (GLN) or an equivalent amount of 15% parenteral amino acid added to PN (STD) for a maximum of 28 days, or until enteral nutrition (EN) or an oral diet could be provided that met 50% of nutrition needs. Patients received total calories of estimated REE X 1.3 and protein of 1.5 gm/kg/day, and when EN and oral diet were started, the PN was decreased to maintain nutrition goals.

Patients were followed for a maximum of 6 months and were contacted by phone at 2, 4, and 6 months after randomization. The primary study outcomes were hospital mortality and hospital-acquired infections. Study size was established to detect a 25% difference in mortality (with 90% power) and a 25% change in hospital-acquired infections (90% power).

Inclusion and Exclusion Criteria:
Inclusion criteria:
Patients who required admission to the SICU after non-laparoscopic cardiac, non-neurologic vascular, esophageal, gastric, or intestinal surgery or after exploratory laparotomy who were deemed to require PN at least 7 days, age 18-90 years, BMI <40 kg/m2 before surgery, and attending MD would allow the investigators to manage nutrition support during the study.

Exclusion criteria:
Pregnancy, sepsis, malignant disease, history of seizures or seizure disorder, current encephalopathy, cirrhosis or total bilirubin ≥10.0 mg/dL, renal failure or creatinine > 2.5 mg/dl, concomitant burn or trauma, organ transplant, HIV/AIDS, received an investigational drug within 60 days, received arginine or glutamineenriched EN or PN within 30 days, unable or unwilling to participate in study procedures.

Major Results:
Of a total of 1247 patients screened, 150 were randomized with 75 patients in each group. Forty-five patients died and 100 patients were available for the 6-month follow up (1 withdrew consent, others lost to F/U). Baseline characteristics were similar between the groups after randomization. The most common surgery was intestinal resection (50 GLN, 52 STD). Patients were randomized into their study nutrition groups approximately 4 days post-surgery and ultimately received Std PN for 10.6 ± 5.2 days and GLN-PN for 11.0 ± 5 days.

Both the amount of nutrition received (average of 26.7 kcals/kg and 1.5 gm protein/kg in both groups) and the advancement of enteral nutrition during the first 14 days of the study were similar between the groups. Plasma glutamine at study entry was in the normal to low range for both groups.

There were no significant differences between the 2 groups in infectious complications, mortality at any time point (overall, or for any subgroup), ventilator days, renal or hepatic labs, or adverse events. There was no significant difference in morning blood glucose, afternoon blood glucose, evening blood glucose, hypoglycemia incidence, or hyperglycemia incidence > 180 mg/dl. There was a statistically significant increase in the number of hyperglycemia events > 250 mg/dl in the STD group compared to the GLN group (59 STD, 24 GLN, p = 0.04).

Author’s Conclusions:
“… in a rigorous, multicenter, Phase III American trial, complete PN supplemented with alanyl-GLN dipeptide at a dose of 0.5 g/kg/d was safe, but did not impact clinical outcomes in SICU patients deemed to require PN after intestinal, vascular, or cardiac surgery.”

This was a high quality, double-blind, multicenter randomized trial, with intention to treat analysis. However, any take home conclusions are limited because the study simply enrolled too few patients to adequately study safety and outcomes in the ICU. Undoubtedly, the goal to study glutamine in patients who required parenteral nutrition but without organ failure limited the number who could be enrolled, which is evidenced by the fact that only 12% of those evaluated were enrolled.

The power calculations for this study were based on an optimistic expectation of reducing hospital mortality and new infections by 25%. Although these numbers were derived from pilot data, there are few single interventions that can reduce hospital mortality, or even hospital-acquired infections, to this degree. To illustrate, recall that recombinant activated protein-C (Drotrecogin alfa/Xigris) was hailed as a “breakthrough” in the fight against sepsis when a study with 1690 patients reported a 19.4% decrease in the relative risk of 28-day mortality (1).  More to the point, it required further studies that ultimately enrolled over 6000 adult patients before it was clear that mortality was not improved, and some adverse effects (“non-serious bleeding”) were increased (2).  Also, consider that a previous study of early enteral and parenteral glutamine in 1223 patients passed through 2 interim analyses and was allowed to continue until completion before it was evident that there was a significant increase in hospital and 6-month mortality in the patients with organ failure who had received glutamine (3).  The point is that 150 patients is far too few to be able to detect potential harm that occurs infrequently.

A substantial number of outcomes, subgroups, and labs were compared between the GLN and STD group, so it is actually surprising that there were not more statistical differences by chance alone. The fact that were 5 indices of glucose control that were not significantly different between the groups tends to relegate the difference in hyperglycemia events > 250 mg/dl between groups to that of a chance occurrence.

It is possible that supplemental glutamine may have benefits with a different timing, dose, or patient population, but at present supplemental glutamine in adult ICU patients would be an area for research, and not routine clinical use.

Our Take Home Message(s)
1. This study enrolled too few patients to reliably study safety or outcomes in the ICU.
2. Parenteral glutamine, or any supplemental nutrients, should be studied in adequately powered clinical studies before they are routinely used in critically ill patients.

1. Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.

2. Cochrane Database of Systematic Reviews: Human recombinant activated protein C for severe sepsis and septic shock in adult and paediatric patients. Accessed 11/24/15.

3. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013; 368(16):1489-1497.

Other News on the UVAHS GI Nutrition Website: (

Upcoming Webinars 2016:
• Wed, January 20th—Medical and Nutritional Management of Inflammatory Bowel Disease
• Tues, February 9th—The Malabsorption Work Up
• March—Enhanced Recovery After Surgery (ERAS) Protocol
• April—Hypoglycemia Following Gastric Bypass Surgery
• May—Meeting Calorie Needs in the ICU—Should We?
• June—Micronutrient Deficiencies After Gastric Bypass

Latest Practical Gastroenterology article:
• Foster M, Philips W, Parrish CR. Transition to Ready to Hang Enteral Feeding System: One Institution’s Experience. Practical Gastroenterology 2015;XXXIX(12):28.


Joe Krenitsky MS, RDN
Bethany Blalock, RDN, CNSC

PS – Please feel free to forward on to friends and colleagues.