University of Virginia Health System
Nutrition Support E-Journal Club
Spring has finally arrived in Charlottesville, and our trainees from Berkeley, California and Boone, North Carolina were able to enjoy the daffodils and first blooms and blossoms opening around town.
Gianotti L, Braga M, Biffi R, et al. GlutamItaly Research Group of the Italian Society of Parenteral, and Enteral Nutrition. Perioperative intravenous glutamine supplementation in major abdominal surgery for cancer: a randomized multicenter trial. Ann Surg. 2009;250:684-690.
This was a prospective, randomized, multicenter, non-blinded study that investigated the effects of intravenous l-alanine-L-glutamine dipeptide (0.4 g/kg/day = 0.25 g/kg/day free glutamine) compared to no treatment in 428 well-nourished adult patients with cancer of the GI tract scheduled for elective major surgery. Patients received either alanine-glutamine dipeptide in 500mL 5% dextrose, or the 5% dextrose alone over 20 hours starting the morning before surgery and continuing for at least 5 days postoperatively. Patients did not received enteral or parenteral nutrition (PN) support unless they could not start oral intake within 7 days post-op.
The primary endpoint was the reduction of the postoperative complication rate in the treated group. The secondary outcomes were the length of hospitalization, and the need of postoperative nutrition support.
Inclusion and Exclusion Criteria were:
Inclusion criteria: Adult, well-nourished (preoperative weight loss <10% with respect to usual body weight), with cancer of the GI tract, and scheduled to receive major surgery.
Exclusion criteria: Patients who refused to participate, advanced liver disease (Child-Pugh class C), heart failure (NYHA >3), renal insufficiency (hemodialysis, plasma creatinine >3 mg/dL, or both), respiratory insufficiency (arterial blood PaO2 <70 mm Hg), Karnofsky performance status <80, American Society of Anesthesiology score >3, ongoing infection, immunosuppressive diseases (including steroid use), emergency operation, or pregnancy.
Major Results reported by authors:
The investigators identified 555 patients that were eligible for the study; 428 met inclusion criteria, were randomized (212 glutamine, 216 control) and analyzed by intention-to-treat. One patient was not able to complete the protocol due to cutaneous symptoms with the first glutamine infusion. The mean duration of glutamine treatment was 7.1+/- 1.8 days. There was no significant difference in the overall rate of postoperative complications between groups (RR = 1.06; 0.81-1.38, 95% CI: P = 0.65), or in any of the secondary outcomes. The lack of statistical difference between groups persisted even when analyzed for major and minor complications, infectious and non infectious complications, stratified by amount of weight loss or type of operation. Mortality rate was 1.9% (4/212) in the Ala-Glu group and 1.4% (3/216) in the control group (-1.92 to 2.92, 95% CI: P = 0.98).
The authors concluded that their results do not support "the routine use of intravenous glutamine dipeptide in patients with no, or mild preoperative weight loss or surgical stress undergoing elective surgery for GI cancer."
Positive aspects of this study include relatively large group sizes, randomized design and analyzed by intention to treat. The glutamine group received more than the 0.2 g glutamine/kg identified by meta-analysis as the threshold where benefit has been demonstrated in some other studies (1). One obvious limitation of this study is a lack of double-blind methodology. It is unclear why the study was not blinded, especially when the control group received the same "vehicle" used to provide the glutamine to the study group. The lack of double-blind design may mean that these results are excluded from some meta-analysis in the future.
Although the dose of glutamine used was above the threshold identified in previous meta-analysis, it is possible that an even higher glutamine dose may be necessary to achieve clinically evident results in some populations. The authors point out that they did not normalize serum glutamine in the treated group until day 3 of therapy.
One aspect of this study that should be considered is that the glutamine was not provided as part of a PN regimen. The authors correctly pointed out that in those patients without significant malnutrition, who are expected to resume oral intake in 7-10 days, that PN would not provide net benefit, and only increase complications. However, it is possible that glutamine may only provide benefits in the setting of PN. Standard PN not only lacks glutamine, but it will reduce the breakdown of lean muscle mass that would normally liberate large amounts of amino acids, including glutamine, under catabolic conditions. We could consider the possibility that parenteral glutamine may make PN less detrimental, but may not possess therapeutic advantage when provided alone.
However, the most evident reason why there was no outcome benefits of parenteral glutamine in this study may rest with the fact that these were well nourished patients with a relatively uncomplicated post-op course. It is possible that the relatively modest rate of infectious complications can not be expected to be reduced further by glutamine. The authors do point out that these results should not necessarily be extrapolated to a malnourished, more severely ill, or extended stay population.
Our Take Home message:
This study suggests that perioperative intravenous glutamine dipeptide at 0.4gm/kg did not provide benefits to well-nourished patients with elective procedures for GI malignancy. Further studies will be required to determine if a different dose of glutamine may have benefits, or if parenteral glutamine may provide outcome benefits, to malnourished or more severely ill patients.
- 1. Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002 Sep;30(9):2022-9.
Check out the full schedule of webinar programs at: http://www.healthsystem.virginia.edudh/webinars.html
- April 14: Update on Nutrition in End-Stage Renal Failure andIntradialytic Parenteral Nutrition (IDPN)--Mitch Rosner, MD
- May 18: Practical Nutrition Assessment of the Hospitalized Patient: Dogma, Data and Future Directions--Joe Krenitsky, MS, RD
- June 15:ChyleLeaks--Carol Parrish, MS, RD
See the latest Practical Gastroenterology articles:
- We took the month of March off :)
Joe Krenitsky MS, RD
Carol Rees Parrish MS, RD
PS - Please feel free to forward this on to friends and colleagues.