ORIGINAL ARTICLE
Effect of Oral Glutamine Supplementation on Gut Permeability and Endotoxemia in Patients With Severe Acute Pancreatitis A Randomized Controlled Trial Namrata Singh, MSc, RD,* Sushil Kumar Mishra, DM,* Vikas Sachdev, MSc,* Hanish Sharma, DM,* Ashish Datt Upadhyay, MA,Þ Indu Arora, MSc,* and Anoop Saraya, DM*
Objective: The aim of this study is to evaluate the effect of oral glutamine (GL) supplementation on gut permeability and endotoxemia (surrogate end point) in patients with severe acute pancreatitis. Methods: In a randomized controlled trial, patients were randomized to be given placebo or GL for 7 days. The primary outcome measures include the effect on gut permeability (assessed by lactulose/mannitol excretion in urine and endotoxemia assessed by endotoxin core antibodies type IgG and IgM (EndoCab IgG and IgM). The secondary outcome measures include infectious complications, mortality, total hospital/intensive care unit stay, C-reactive protein, and prealbumin levels. Results: Patients were assigned to GL (n = 41) and placebo (n = 39) groups. There was no change in gut permeability after the intervention. However, the EndoCab IgM levels increased significantly (33 [4, 175] to 40 [8, 350] GMU/mL; P = 0.0164) and the C-reactive protein levels decreased significantly (133 [1, 287] to 88 [1, 267] ng/mL; P = 0.0236) in the GL group. No difference was observed in infectious complication, prealbumin value, hospital/intensive care unit stay, and mortality in both groups. Conclusions: No significant trend was identified for an effect of GL on gut permeability. Decreased inflammation and endotoxemia did not translate into reduced infectious complications in severe acute pancreatitis. However, the study was underpowered to detect the aforementioned difference (trial registration: CTRI/2009/000945). Key Words: glutamine, intestinal permeability, endotoxemia, severe acute pancreatitis (Pancreas 2014;43: 867Y873)
A
cute pancreatitis (AP) is a common abdominal emergency with pancreatic necrosis complicating severe attacks. The overall mortality of patients with acute necrotizing pancreatitis is in the range of 10% to 15%. Secondary pancreatic infection and sepsis develop in 40% to 70% of patients with 80% mortality.1 Small bowel bacterial overgrowth and subsequent bacterial translocation (BT) may be responsible for most of these infections.2 The breakdown of intestinal mucosal integrity alters
From the Departments of *Gastroenterology and Human Nutrition, and †Biostatistics, All India Institute of Medical Sciences, New Delhi, India. Received for publication June 10, 2013; accepted January 28, 2014. Reprints: Anoop Saraya, DM, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-29, India (e and nitric oxide play an important role. Experimental studies have shown that intravenous administration of endotoxin is associated with hyperdynamic circulatory changes and the increase in the production of IL-2, IL-6, and prostaglandin E2. Endotoxemia has been shown to be directly related to the severity of episodes of AP, being more relevant in patients with SAP. The IgM antibody titer is an indirect marker for endotoxin levels and endotoxemia peaks coincidentally with the lower levels of EndoCab IgM antibody. We found a significant increase in IgM in the group receiving GL (suggesting decreased endotoxemia) after 7 days of intervention. Results of our study were comparable to an inconclusive study17 and a meta-analysis,35 which showed no evidence that enteral nutrition supplemented with GL, arginine, and/or omega 3 fatty acids, in comparison with standard enteral nutrition, has any beneficial effect on infectious complications, mortality, or the length of hospital stay in AP but in contrast to an earlier published report,18 which shows that enteral immunonutrition containing GL and arginine improves the gut barrier function by reducing the gut permeability and decreasing plasma endotoxin level in the early stage of SAP. We looked for methodology errors to explain these results. Dose and duration of GL were not similar to that used in this study. The results in the 2 groups were similar after supplementation possibly because of a protein supplementation (Whey) also being given to the control group. The explanation could be that the effects seen in the study were due to the increased protein in both groups rather than GL per se. There are various studies of parenteral GL supplementation in AP.8Y10,12,36 Ours was a prospective study; planning in advance ensured the collection of all required data; all patients admitted during the study period were included and followed up for the length of stay and outcome of the disease. To the best of our knowledge, there are no data available on the effect of oral GL on IP and endotoxemia. The strength of our study is that it is the first randomized controlled trial that has assessed the effect of oral GL supplementation on IP and endotoxemia. The availability of almost complete outcomes as no patient lost to follow-up is another strength of the study. Our study has a few potential limitations. It is not an adequately powered study. The hypothesized decrease in levels of primary end point was seen only in 1 marker of endotoxemia after 7 days of supplementation, and maybe a longer duration of supplementation was required to see the desired decrease. Together, the results of this pilot randomized, PL-controlled study suggest that 7 days of daily GL supplementation in AP led to a reduction in inflammation and endotoxemia, which did not translate into reduced infectious complications in SAP. No significant trend was identified for an effect of GL on gut permeability. However, an adequately powered, multicentric larger study is needed to substantiate. * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pancreas
&
Volume 43, Number 6, August 2014
ACKNOWLEDGMENT The authors thank the support of Fresenius Kabi India Pvt Ltd, India in providing the GL on a complimentary basis. REFERENCES 1. Mifkovic A, Pindak D, Daniel I, et al. Septic complications of acute pancreatitis. Bratisl Lek Listy. 2006;107:296Y313. 2. Dervenis C, Smailis D, Hatzitheoklitos E. Bacterial translocation and its prevention in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2003;10:415Y418. 3. Liu H, Li W, Wang X, et al. Early gut mucosal dysfunction in patients with acute pancreatitis. Pancreas. 2008;36:192Y196. 4. Hall JC, Heel K, McMauley R. Glutamine. Br J Surg. 1996;83:305Y312. 5. Fu¨rst P, Pogan K, Stehle P. Glutamine dipeptides in clinical nutrition. Nutrition. 1997;13:731Y737. 6. Roth E, Zo¨ch G, Schulz F, et al. Amino acid concentrations in plasma and skeletal muscle of patients with acute hemorrhagic necrotizing pancreatitis. Clin Chem. 1985;31:1305Y1309. 7. Lankisch PG, Weber-Dany B, Doobe C, et al. Plasma glutamine levels are negatively correlated with the severity of acute pancreatitis. Pancreas. 2008;36:322Y324. 8. Sahin H, Mercanligil SM, Inanc¸ N, et al. Effects of glutamine-enriched total parenteral nutrition on acute pancreatitis. Eur J Clin Nutr. 2007;61:1429Y1434. 9. Yang SQ, Xu JG. Effect of glutamine on serum interleukin-8 and tumor necrosis factor-alpha levels in patients with severe pancreatitis. Nan Fang Yi Ke Da Xue Xue Bao. 2008;28:129Y131. 10. Hajdu´ N, Bela´gyi T, Issekutz A, et al. Intravenous glutamine and early nasojejunal nutrition in severe acute pancreatitisVa prospective randomized clinical study. Magy Seb. 2012;65:44Y51. 11. Ockenga J, Borchert K, Rifal K, et al. Effect of glutamine-enriched total parenteral nutrition in patients with acute pancreatitis. Clin Nutr. 2002;21:409Y416. 12. Xue P, Deng LH, Xia Q, et al. Impact of alanyl-glutamine dipeptide on severe acute pancreatitis in early stage. World J Gastroenterol. 2008;14:474Y478. 13. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489Y1497. 14. Spanier BW, Bruno MJ, Mathus-Vliegen EM. Enteral nutrition and acute pancreatitis: a review. Gastroenterol Res Pract. 2011;2011:857949. 15. Gupta R, Patel K, Calder PC, et al. A randomised clinical trial to assess the effect of total enteral and total parenteral nutritional support on metabolic, inflammatory and oxidative markers in patients with predicted severe acute pancreatitis (APACHE II 9 6). Pancreatology. 2003;3:406Y413. 16. Hallay J, Kova´cs G, Szatmari K, et al. Early jejunal nutrition and changes in the immunological parameters of patients with acute pancreatitis. Hepatogastroenterology. 2001;48:1488Y1492. 17. Pearce CB, Sadek SA, Walters AM, et al. A double-blind, randomised, controlled trial to study the effects of an enteral feed supplemented with glutamine, arginine, and omega-3 fatty acid in predicted acute severe pancreatitis. JOP. 2006;7:361Y371.
* 2014 Lippincott Williams & Wilkins
Trial on Glutamine in Acute Pancreatitis
18. Huang XX, Wang XP, Ma JJ, et al. Effects of enteral nutrition supplemented with glutamine and arginine on gut barrier in patients with severe acute pancreatitis: a prospective randomized controlled trial. Zhonghua Yi Xue Za Zhi. 2008;88:2407Y2409. 19. Bradley EL III. A clinically based classification system for acute pancreatitis: summary of the international symposium on acute pancreatitis, Atlanta, Ga September 11 through 13, 1992. Arch Surg. 1993;128:586Y590. 20. Balthazar EJ, Robinson DL, Megibow AJ, et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology. 1990;174:331Y336. 21. Behrens RH, Docherty H, Elia M, et al. A simple enzymatic method for the assay of urinary lactulose. Clin Chim Acta. 1984;137:361Y367. 22. Corcoran AC, Page HI. Method for determination of mannitol in plasma and urine. J Biol Chem. 1947;170:165Y171. 23. Singh N, Sharma B, Sharma M, et al. Evaluation of early enteral feeding through nasogastric and nasojejunal tube in severe acute pancreatitis: a noninferiority randomized controlled trial. Pancreas. 2012;41:153Y159. 24. Sharma B, Srivastava S, Singh N, et al. Role of probiotics on gut permeability and endotoxemia in patients with acute pancreatitis: a double-blind randomized controlled trial. J Clin Gastroenterol. 2011;45:442Y448. 25. Kumar A, Singh N, Prakash S, et al. Early enteral nutrition in severe acute pancreatitis: a prospective randomized controlled trial comparing nasojejunal and nasogastric routes. J Clin Gastroenterol. 2006;40: 431Y434. 26. Sobotka L. Acute pancreatitisVpancreatic perfusion and fluid resuscitation in ICU. Nutrition. 1996;12:844. 27. Menzies IS. Absorption of intact oligosaccharide in health and disease. Biochem Soc Trans. 1974;2:1040Y1046. 28. Ryan M, Bailey SH, Carter EA, et al. Additive effects of thermal injury and infection on gut permeability. Arch Surg. 1994;129:325Y328. 29. Russell DH, Barreto JC, Klemm K, et al. Haemorrhagic shock increases gut macromolecular permeability in the rat. Shock. 1995;4:50Y55. 30. Carter EA, Tompkins RG, Schiffrin E, et al. Cutaneous thermal injury alters macromolecular permeability of rat small intestine. Surgery. 1990;107:335Y341. 31. Ammori BJ, Leeder PC, King RF. Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure and mortality. J Gastrointest Surg. 1998;2:518Y525. 32. Runkel NSF, Rodriguez LF, Moody FG. Mechanisms of sepsis in acute pancreatitis in opossums. Am J Surg. 1995;169:227Y232. 33. Wang XD, Wang Q, Anderson RI. Alterations in intestinal function in acute pancreatitis in an experimental model. Br J Surg. 1996;83: 1537Y1542. 34. Marotta F, Barreto R, Wu CC, et al. Experimental acute alcohol pancreatitis-related liver damage and endotoxemia: synbiotics but not metronidazole have a protective effect. Chin J Dig Dis. 2005;6: 193Y197. 35. Petrov MS, Atduev VA, Zagainov VE. Advanced enteral therapy in acute pancreatitis: is there a room for immunonutrition? A meta-analysis. Int J Surg. 2008;6:119Y124. 36. Fuentes-Orozco C, Cervantes-Guevara G, Mucin˜o-Herna´ndez I, et al. L-alanyl-L-glutamineYsupplemented parenteral nutrition decreases infectious morbidity rate in patients with severe acute pancreatitis. JPEN J Parenter Enteral Nutr. 2008;32:403Y411.
www.pancreasjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
873
Effect of Oral Glutamine Supplementation on Gut Permeability and Endotoxemia in Patients With Severe Acute Pancreatitis A Randomized Controlled Trial Namrata Singh, MSc, RD,* Sushil Kumar Mishra, DM,* Vikas Sachdev, MSc,* Hanish Sharma, DM,* Ashish Datt Upadhyay, MA,Þ Indu Arora, MSc,* and Anoop Saraya, DM*
Objective: The aim of this study is to evaluate the effect of oral glutamine (GL) supplementation on gut permeability and endotoxemia (surrogate end point) in patients with severe acute pancreatitis. Methods: In a randomized controlled trial, patients were randomized to be given placebo or GL for 7 days. The primary outcome measures include the effect on gut permeability (assessed by lactulose/mannitol excretion in urine and endotoxemia assessed by endotoxin core antibodies type IgG and IgM (EndoCab IgG and IgM). The secondary outcome measures include infectious complications, mortality, total hospital/intensive care unit stay, C-reactive protein, and prealbumin levels. Results: Patients were assigned to GL (n = 41) and placebo (n = 39) groups. There was no change in gut permeability after the intervention. However, the EndoCab IgM levels increased significantly (33 [4, 175] to 40 [8, 350] GMU/mL; P = 0.0164) and the C-reactive protein levels decreased significantly (133 [1, 287] to 88 [1, 267] ng/mL; P = 0.0236) in the GL group. No difference was observed in infectious complication, prealbumin value, hospital/intensive care unit stay, and mortality in both groups. Conclusions: No significant trend was identified for an effect of GL on gut permeability. Decreased inflammation and endotoxemia did not translate into reduced infectious complications in severe acute pancreatitis. However, the study was underpowered to detect the aforementioned difference (trial registration: CTRI/2009/000945). Key Words: glutamine, intestinal permeability, endotoxemia, severe acute pancreatitis (Pancreas 2014;43: 867Y873)
A
cute pancreatitis (AP) is a common abdominal emergency with pancreatic necrosis complicating severe attacks. The overall mortality of patients with acute necrotizing pancreatitis is in the range of 10% to 15%. Secondary pancreatic infection and sepsis develop in 40% to 70% of patients with 80% mortality.1 Small bowel bacterial overgrowth and subsequent bacterial translocation (BT) may be responsible for most of these infections.2 The breakdown of intestinal mucosal integrity alters
From the Departments of *Gastroenterology and Human Nutrition, and †Biostatistics, All India Institute of Medical Sciences, New Delhi, India. Received for publication June 10, 2013; accepted January 28, 2014. Reprints: Anoop Saraya, DM, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-29, India (e and nitric oxide play an important role. Experimental studies have shown that intravenous administration of endotoxin is associated with hyperdynamic circulatory changes and the increase in the production of IL-2, IL-6, and prostaglandin E2. Endotoxemia has been shown to be directly related to the severity of episodes of AP, being more relevant in patients with SAP. The IgM antibody titer is an indirect marker for endotoxin levels and endotoxemia peaks coincidentally with the lower levels of EndoCab IgM antibody. We found a significant increase in IgM in the group receiving GL (suggesting decreased endotoxemia) after 7 days of intervention. Results of our study were comparable to an inconclusive study17 and a meta-analysis,35 which showed no evidence that enteral nutrition supplemented with GL, arginine, and/or omega 3 fatty acids, in comparison with standard enteral nutrition, has any beneficial effect on infectious complications, mortality, or the length of hospital stay in AP but in contrast to an earlier published report,18 which shows that enteral immunonutrition containing GL and arginine improves the gut barrier function by reducing the gut permeability and decreasing plasma endotoxin level in the early stage of SAP. We looked for methodology errors to explain these results. Dose and duration of GL were not similar to that used in this study. The results in the 2 groups were similar after supplementation possibly because of a protein supplementation (Whey) also being given to the control group. The explanation could be that the effects seen in the study were due to the increased protein in both groups rather than GL per se. There are various studies of parenteral GL supplementation in AP.8Y10,12,36 Ours was a prospective study; planning in advance ensured the collection of all required data; all patients admitted during the study period were included and followed up for the length of stay and outcome of the disease. To the best of our knowledge, there are no data available on the effect of oral GL on IP and endotoxemia. The strength of our study is that it is the first randomized controlled trial that has assessed the effect of oral GL supplementation on IP and endotoxemia. The availability of almost complete outcomes as no patient lost to follow-up is another strength of the study. Our study has a few potential limitations. It is not an adequately powered study. The hypothesized decrease in levels of primary end point was seen only in 1 marker of endotoxemia after 7 days of supplementation, and maybe a longer duration of supplementation was required to see the desired decrease. Together, the results of this pilot randomized, PL-controlled study suggest that 7 days of daily GL supplementation in AP led to a reduction in inflammation and endotoxemia, which did not translate into reduced infectious complications in SAP. No significant trend was identified for an effect of GL on gut permeability. However, an adequately powered, multicentric larger study is needed to substantiate. * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pancreas
&
Volume 43, Number 6, August 2014
ACKNOWLEDGMENT The authors thank the support of Fresenius Kabi India Pvt Ltd, India in providing the GL on a complimentary basis. REFERENCES 1. Mifkovic A, Pindak D, Daniel I, et al. Septic complications of acute pancreatitis. Bratisl Lek Listy. 2006;107:296Y313. 2. Dervenis C, Smailis D, Hatzitheoklitos E. Bacterial translocation and its prevention in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2003;10:415Y418. 3. Liu H, Li W, Wang X, et al. Early gut mucosal dysfunction in patients with acute pancreatitis. Pancreas. 2008;36:192Y196. 4. Hall JC, Heel K, McMauley R. Glutamine. Br J Surg. 1996;83:305Y312. 5. Fu¨rst P, Pogan K, Stehle P. Glutamine dipeptides in clinical nutrition. Nutrition. 1997;13:731Y737. 6. Roth E, Zo¨ch G, Schulz F, et al. Amino acid concentrations in plasma and skeletal muscle of patients with acute hemorrhagic necrotizing pancreatitis. Clin Chem. 1985;31:1305Y1309. 7. Lankisch PG, Weber-Dany B, Doobe C, et al. Plasma glutamine levels are negatively correlated with the severity of acute pancreatitis. Pancreas. 2008;36:322Y324. 8. Sahin H, Mercanligil SM, Inanc¸ N, et al. Effects of glutamine-enriched total parenteral nutrition on acute pancreatitis. Eur J Clin Nutr. 2007;61:1429Y1434. 9. Yang SQ, Xu JG. Effect of glutamine on serum interleukin-8 and tumor necrosis factor-alpha levels in patients with severe pancreatitis. Nan Fang Yi Ke Da Xue Xue Bao. 2008;28:129Y131. 10. Hajdu´ N, Bela´gyi T, Issekutz A, et al. Intravenous glutamine and early nasojejunal nutrition in severe acute pancreatitisVa prospective randomized clinical study. Magy Seb. 2012;65:44Y51. 11. Ockenga J, Borchert K, Rifal K, et al. Effect of glutamine-enriched total parenteral nutrition in patients with acute pancreatitis. Clin Nutr. 2002;21:409Y416. 12. Xue P, Deng LH, Xia Q, et al. Impact of alanyl-glutamine dipeptide on severe acute pancreatitis in early stage. World J Gastroenterol. 2008;14:474Y478. 13. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489Y1497. 14. Spanier BW, Bruno MJ, Mathus-Vliegen EM. Enteral nutrition and acute pancreatitis: a review. Gastroenterol Res Pract. 2011;2011:857949. 15. Gupta R, Patel K, Calder PC, et al. A randomised clinical trial to assess the effect of total enteral and total parenteral nutritional support on metabolic, inflammatory and oxidative markers in patients with predicted severe acute pancreatitis (APACHE II 9 6). Pancreatology. 2003;3:406Y413. 16. Hallay J, Kova´cs G, Szatmari K, et al. Early jejunal nutrition and changes in the immunological parameters of patients with acute pancreatitis. Hepatogastroenterology. 2001;48:1488Y1492. 17. Pearce CB, Sadek SA, Walters AM, et al. A double-blind, randomised, controlled trial to study the effects of an enteral feed supplemented with glutamine, arginine, and omega-3 fatty acid in predicted acute severe pancreatitis. JOP. 2006;7:361Y371.
* 2014 Lippincott Williams & Wilkins
Trial on Glutamine in Acute Pancreatitis
18. Huang XX, Wang XP, Ma JJ, et al. Effects of enteral nutrition supplemented with glutamine and arginine on gut barrier in patients with severe acute pancreatitis: a prospective randomized controlled trial. Zhonghua Yi Xue Za Zhi. 2008;88:2407Y2409. 19. Bradley EL III. A clinically based classification system for acute pancreatitis: summary of the international symposium on acute pancreatitis, Atlanta, Ga September 11 through 13, 1992. Arch Surg. 1993;128:586Y590. 20. Balthazar EJ, Robinson DL, Megibow AJ, et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology. 1990;174:331Y336. 21. Behrens RH, Docherty H, Elia M, et al. A simple enzymatic method for the assay of urinary lactulose. Clin Chim Acta. 1984;137:361Y367. 22. Corcoran AC, Page HI. Method for determination of mannitol in plasma and urine. J Biol Chem. 1947;170:165Y171. 23. Singh N, Sharma B, Sharma M, et al. Evaluation of early enteral feeding through nasogastric and nasojejunal tube in severe acute pancreatitis: a noninferiority randomized controlled trial. Pancreas. 2012;41:153Y159. 24. Sharma B, Srivastava S, Singh N, et al. Role of probiotics on gut permeability and endotoxemia in patients with acute pancreatitis: a double-blind randomized controlled trial. J Clin Gastroenterol. 2011;45:442Y448. 25. Kumar A, Singh N, Prakash S, et al. Early enteral nutrition in severe acute pancreatitis: a prospective randomized controlled trial comparing nasojejunal and nasogastric routes. J Clin Gastroenterol. 2006;40: 431Y434. 26. Sobotka L. Acute pancreatitisVpancreatic perfusion and fluid resuscitation in ICU. Nutrition. 1996;12:844. 27. Menzies IS. Absorption of intact oligosaccharide in health and disease. Biochem Soc Trans. 1974;2:1040Y1046. 28. Ryan M, Bailey SH, Carter EA, et al. Additive effects of thermal injury and infection on gut permeability. Arch Surg. 1994;129:325Y328. 29. Russell DH, Barreto JC, Klemm K, et al. Haemorrhagic shock increases gut macromolecular permeability in the rat. Shock. 1995;4:50Y55. 30. Carter EA, Tompkins RG, Schiffrin E, et al. Cutaneous thermal injury alters macromolecular permeability of rat small intestine. Surgery. 1990;107:335Y341. 31. Ammori BJ, Leeder PC, King RF. Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure and mortality. J Gastrointest Surg. 1998;2:518Y525. 32. Runkel NSF, Rodriguez LF, Moody FG. Mechanisms of sepsis in acute pancreatitis in opossums. Am J Surg. 1995;169:227Y232. 33. Wang XD, Wang Q, Anderson RI. Alterations in intestinal function in acute pancreatitis in an experimental model. Br J Surg. 1996;83: 1537Y1542. 34. Marotta F, Barreto R, Wu CC, et al. Experimental acute alcohol pancreatitis-related liver damage and endotoxemia: synbiotics but not metronidazole have a protective effect. Chin J Dig Dis. 2005;6: 193Y197. 35. Petrov MS, Atduev VA, Zagainov VE. Advanced enteral therapy in acute pancreatitis: is there a room for immunonutrition? A meta-analysis. Int J Surg. 2008;6:119Y124. 36. Fuentes-Orozco C, Cervantes-Guevara G, Mucin˜o-Herna´ndez I, et al. L-alanyl-L-glutamineYsupplemented parenteral nutrition decreases infectious morbidity rate in patients with severe acute pancreatitis. JPEN J Parenter Enteral Nutr. 2008;32:403Y411.
www.pancreasjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
873
