591601
research-article2015
NCPXXX10.1177/0884533615591601Nutrition in Clinical PracticeYao et al
Clinical Research
Perioperative Alanyl-Glutamine–Supplemented Parenteral Nutrition in Chronic Radiation Enteritis Patients With Surgical Intestinal Obstruction: A Prospective, Randomized, Controlled Study
Nutrition in Clinical Practice Volume XX Number X Month 201X 1–7 © 2015 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533615591601 ncp.sagepub.com hosted at online.sagepub.com
Danhua Yao, MD1,*; Lei Zheng, PhD1,*; Jian Wang, MD1; Mingxiao Guo, MD1; Jianyi Yin, MD1; and Yousheng Li, MD1
Abstract Background:A prospective, randomized, controlled study was performed to evaluate the effects of perioperative alanyl-glutamine– supplemented parenteral nutrition (PN) support on the immunologic function, intestinal permeability, and nutrition status of surgical patients with chronic radiation enteritis (CRE)–induced intestinal obstruction. Methods: Patients who received 0.4 g/kg/d alanyl-glutamine and isonitrogenous PN were assigned to an alanyl-glutamine–supplemented PN (Gln-PN) group and a control group, respectively. Serum levels of alanine aminotransferase and glutamine, body fat mass (FM), immunologic function, and intestinal permeability were measured before and after surgery. Results: Serum glutamine levels of the Gln-PN group significantly exceeded that of the control group (P < .001; Gln-PN, baseline 460.7 ± 42.5 vs 523.3 ± 48.6 µmol/L on postoperative day 14 [POD14], P < .001; control, baseline 451.9 ± 44.0 vs 453.8 ± 42.3 µmol/L on POD14, P = .708). Lactulose/mannitol ratios of both groups decreased over time (Gln-PN, baseline 0.129 ± 0.0403 vs 0.024 ± 0.0107 on POD1 4; control, baseline 0.125 ± 0.0378 vs 0.044 ± 0.0126 on POD14, P < .001 in both groups). CD4/CD8-positive T-lymphocyte ratios significantly rose in both groups, with significant intergroup difference (P < .001; Gln-PN, baseline 1.36 ± 0.32 vs 1.82 ± 0.30 on POD14, P < .001; control, baseline 1.37 ± 0.25 vs 1.63 ± 0.31 on POD14, P < .001). In the Gln-PN group, FM increased from 3.68 ± 1.68 kg at baseline to 5.22 ± 1.42 kg on POD14 (P < .001). FM of control group increased from 3.84 ± 1.57 kg at baseline to 5.40 ± 1.54 kg on POD14 (P < .001). However, there were no significant intergroup differences (P = .614). Conclusion: Gln-PN significantly boosted the immune state and decreased the intestinal permeability of CRE patients. However, Gln-PN was not superior to standard PN in improving the nutrition state and intestinal motility of surgical patients with CRE-induced intestinal obstruction. (Nutr Clin Pract.XXXX;xx:xx-xx)
Keywords radiation injuries; glutamine; immune system; chronic radiation enteritis; parenteral nutrition; alanyl-glutamine; intestinal obstruction; immunologic function; intestinal permeability
Chronic radiation enteritis (CRE), as a common complication in pelvic and abdominal regions, threatens 5%–55% of the patients who receive radiotherapy1 to treat urological, gynecological, and gastrointestinal (GI) malignant tumors. Occurring 6–24 months after radiotherapy, CRE is clinically manifested as weight loss, abdominal pain, diarrhea, rectal bleeding, malabsorption, stricture, intestinal obstruction, pseudo-obstruction, nonspecific malaise, and occasionally atraumatic perforation.2 Particularly, mechanical obstruction is the most common clinical complication requiring surgery.3 Patients with CRE-induced intestinal obstruction are prone to malnutrition due to surgery, repeated radiotherapy and chemotherapy, chronic pain, recurrent obstruction crises, and tumor burden. Perioperative parenteral nutrition (PN) is most suitable for these patients because they cannot be enterally fed adequately before the operation, and their caloric requirements cannot be met within 7–10 days enterally according to the European Society for Clinical Nutrition and Metabolism (ESPEN) guideline.4 Moreover, a meta-analysis concluded that glutamine
dipeptide–supplemented PN improved some outcomes in patients undergoing abdominal surgery.5 Glutamine plays an important role in nitrogen transportation as well as purine and pyrimidine syntheses, which, however, is consumed in hypermetabolism stages under stress by producing cortisol, epinephrine, glucagon, and some cytokines.6 Adding glutamine dipeptide to PN solutions has managed to mitigate the clinical symptoms of critically ill patients, with the most striking benefits being reduced mortality and From 1Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, P. R. China. *These authors contributed equally to this study. Financial disclosure: None declared. Corresponding Author: Yousheng Li, MD, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, P. R. China. Email: [email protected]
Downloaded from ncp.sagepub.com at Bobst Library, New York University on June 24, 2015
2
Nutrition in Clinical Practice XX(X)
infection rates in the intensive care unit (ICU).7,8 Several clinical trials have demonstrated that glutamine dipeptide supplementation was capable of improving postoperative nitrogen balance and immune function.9,10 In addition, as the preferential substrate that rapidly divides cells such as enterocytes and stimulates their proliferation,6 glutamine can also inhibit the apoptosis of intestinal epithelial cells11 and maintain the integrity of the intestinal mucosal barrier.12 Glutamine may have a protective effect on patients with CRE-induced intestinal obstruction, but few randomized controlled studies have been performed to verify this hypothesis.12 We hypothesized that perioperative alanyl-glutamine–supplemented PN (Gln-PN) could enhance immunologic function, reduce intestinal permeability, and may lead to a better nutrition status in patients undergoing GI surgery. Therefore, a prospective study was conducted to evaluate the effects of perioperative Gln-PN on the immunologic function, intestinal permeability, and nutrition status of surgical patients with CRE-induced intestinal obstruction.
Table 1. Composition of Parenteral Nutrition. Concentration Nutrient a
L-alanyl-L-glutamine, g/kg 11.4% compound amino acids,b g/kg 20% MCT/LCT,c g/kg Glucose, g/kg
Gln-PN
Control
0.8 0.4
0 0.6
1–2 4–13
1–2 4–13
Gln-PN, alanyl-glutamine–supplemented parenteral nutrition; LCT, longchain triglyceride; MCT, medium-chain triglyceride. a Dipeptiven (Fresenius Kabi, Bad Homburg, Germany). b Novamin (Fresenius Kabi). c Lipovenoes (Fresenius Kabi).
who made PN prescriptions and pharmacists who prepared PN were not blinded.
Intervention Methods Study Design This was a prospective, randomized, single-blind controlled study. The study protocol has been evaluated and confirmed by the Ethic Committee of Jinling Hospital, and written informed consent was obtained from each patient.
Patients Patients admitted in our department from June 2010 to June 2013 with CRE-induced surgical intestinal obstruction were primarily considered suitable for this study, regardless of the types of tumors. Inclusion criteria were the following: (1) patients had undergone abdominal and pelvic radiotherapy, (2) patients were 20–70 years old, (3) intestinal obstruction was diagnosed, and (4) patients met indications for both nutrition support and surgical therapy. Exclusion criteria were the following: (1) acute or chronic liver disorders or renal insufficiency, (2) chronic endocrine disease (diabetes mellitus, thyroid dysfunction, etc), (3) recurrence of primary malignancy, and (4) hemorrhage or fistula besides intestinal obstruction. After signing the informed consent, all patients who met the inclusion criteria were randomly assigned to a Gln-PN group or a standard PN (control) group. They were randomized according to a computer-generated randomization list managed by an external person uninvolved in this study. After informed consent was obtained, a central venous catheter or peripherally inserted central venous catheter was placed in all patients in the 2 groups 1 day before the first dose of PN was administrated. Patients were blinded for treatment assignment and outcomes until the end of this study. However, physicians
The Gln-PN group was administered glutamine dipeptide (Dipeptiven; Fresenius-Kabi, Bad Homburg, Germany; 100 mg/mL L-alanyl-L-glutamine) from preoperative day 13 (PreOD13) in PN (0.4 g/kg/d Dipeptiven to replace equivalent amount of nitrogen in amino acid solution) daily as long as PN was supplied. The control group was administered with isonitrogenous PN solution. Each patient received 0.22 g nitrogen/kg each day in 2500– 3000 mL of PN solution. The ratio of glucose to lipid in PN solution was 1–1.5:1. The total calories given to each patient were guided and adjusted by resting energy expenditure (REE), which was detected by indirect calorimetry (Quark PFT; CosMed, Rome, Italy). Total calories provided by PN were 1.3 times that of REE. The value of REE was detected on preoperative day 14 (PreOD14) and postoperative day 3 (POD3), respectively. Multivitamins and trace elements were also included in the PN solution, in accordance with the ESPEN guideline.4 Electrolytes and the total volume of solution were adjusted according to the serum biochemical indices and total output (urine, drainage fluids, and stool in case of diarrhea) in 24 hours, respectively. The composition of PN is shown in Table 1. On the first day of this study, each patient was given half of the total calories without changing other PN ingredients. PN, which was supplied from PreOD13 to preoperative day 1 (PreOD1), was restarted on POD3. After the operation, when the total drainage from nasogastric tube was 18.5 17–18.5
research-article2015
NCPXXX10.1177/0884533615591601Nutrition in Clinical PracticeYao et al
Clinical Research
Perioperative Alanyl-Glutamine–Supplemented Parenteral Nutrition in Chronic Radiation Enteritis Patients With Surgical Intestinal Obstruction: A Prospective, Randomized, Controlled Study
Nutrition in Clinical Practice Volume XX Number X Month 201X 1–7 © 2015 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533615591601 ncp.sagepub.com hosted at online.sagepub.com
Danhua Yao, MD1,*; Lei Zheng, PhD1,*; Jian Wang, MD1; Mingxiao Guo, MD1; Jianyi Yin, MD1; and Yousheng Li, MD1
Abstract Background:A prospective, randomized, controlled study was performed to evaluate the effects of perioperative alanyl-glutamine– supplemented parenteral nutrition (PN) support on the immunologic function, intestinal permeability, and nutrition status of surgical patients with chronic radiation enteritis (CRE)–induced intestinal obstruction. Methods: Patients who received 0.4 g/kg/d alanyl-glutamine and isonitrogenous PN were assigned to an alanyl-glutamine–supplemented PN (Gln-PN) group and a control group, respectively. Serum levels of alanine aminotransferase and glutamine, body fat mass (FM), immunologic function, and intestinal permeability were measured before and after surgery. Results: Serum glutamine levels of the Gln-PN group significantly exceeded that of the control group (P < .001; Gln-PN, baseline 460.7 ± 42.5 vs 523.3 ± 48.6 µmol/L on postoperative day 14 [POD14], P < .001; control, baseline 451.9 ± 44.0 vs 453.8 ± 42.3 µmol/L on POD14, P = .708). Lactulose/mannitol ratios of both groups decreased over time (Gln-PN, baseline 0.129 ± 0.0403 vs 0.024 ± 0.0107 on POD1 4; control, baseline 0.125 ± 0.0378 vs 0.044 ± 0.0126 on POD14, P < .001 in both groups). CD4/CD8-positive T-lymphocyte ratios significantly rose in both groups, with significant intergroup difference (P < .001; Gln-PN, baseline 1.36 ± 0.32 vs 1.82 ± 0.30 on POD14, P < .001; control, baseline 1.37 ± 0.25 vs 1.63 ± 0.31 on POD14, P < .001). In the Gln-PN group, FM increased from 3.68 ± 1.68 kg at baseline to 5.22 ± 1.42 kg on POD14 (P < .001). FM of control group increased from 3.84 ± 1.57 kg at baseline to 5.40 ± 1.54 kg on POD14 (P < .001). However, there were no significant intergroup differences (P = .614). Conclusion: Gln-PN significantly boosted the immune state and decreased the intestinal permeability of CRE patients. However, Gln-PN was not superior to standard PN in improving the nutrition state and intestinal motility of surgical patients with CRE-induced intestinal obstruction. (Nutr Clin Pract.XXXX;xx:xx-xx)
Keywords radiation injuries; glutamine; immune system; chronic radiation enteritis; parenteral nutrition; alanyl-glutamine; intestinal obstruction; immunologic function; intestinal permeability
Chronic radiation enteritis (CRE), as a common complication in pelvic and abdominal regions, threatens 5%–55% of the patients who receive radiotherapy1 to treat urological, gynecological, and gastrointestinal (GI) malignant tumors. Occurring 6–24 months after radiotherapy, CRE is clinically manifested as weight loss, abdominal pain, diarrhea, rectal bleeding, malabsorption, stricture, intestinal obstruction, pseudo-obstruction, nonspecific malaise, and occasionally atraumatic perforation.2 Particularly, mechanical obstruction is the most common clinical complication requiring surgery.3 Patients with CRE-induced intestinal obstruction are prone to malnutrition due to surgery, repeated radiotherapy and chemotherapy, chronic pain, recurrent obstruction crises, and tumor burden. Perioperative parenteral nutrition (PN) is most suitable for these patients because they cannot be enterally fed adequately before the operation, and their caloric requirements cannot be met within 7–10 days enterally according to the European Society for Clinical Nutrition and Metabolism (ESPEN) guideline.4 Moreover, a meta-analysis concluded that glutamine
dipeptide–supplemented PN improved some outcomes in patients undergoing abdominal surgery.5 Glutamine plays an important role in nitrogen transportation as well as purine and pyrimidine syntheses, which, however, is consumed in hypermetabolism stages under stress by producing cortisol, epinephrine, glucagon, and some cytokines.6 Adding glutamine dipeptide to PN solutions has managed to mitigate the clinical symptoms of critically ill patients, with the most striking benefits being reduced mortality and From 1Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, P. R. China. *These authors contributed equally to this study. Financial disclosure: None declared. Corresponding Author: Yousheng Li, MD, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, P. R. China. Email: [email protected]
Downloaded from ncp.sagepub.com at Bobst Library, New York University on June 24, 2015
2
Nutrition in Clinical Practice XX(X)
infection rates in the intensive care unit (ICU).7,8 Several clinical trials have demonstrated that glutamine dipeptide supplementation was capable of improving postoperative nitrogen balance and immune function.9,10 In addition, as the preferential substrate that rapidly divides cells such as enterocytes and stimulates their proliferation,6 glutamine can also inhibit the apoptosis of intestinal epithelial cells11 and maintain the integrity of the intestinal mucosal barrier.12 Glutamine may have a protective effect on patients with CRE-induced intestinal obstruction, but few randomized controlled studies have been performed to verify this hypothesis.12 We hypothesized that perioperative alanyl-glutamine–supplemented PN (Gln-PN) could enhance immunologic function, reduce intestinal permeability, and may lead to a better nutrition status in patients undergoing GI surgery. Therefore, a prospective study was conducted to evaluate the effects of perioperative Gln-PN on the immunologic function, intestinal permeability, and nutrition status of surgical patients with CRE-induced intestinal obstruction.
Table 1. Composition of Parenteral Nutrition. Concentration Nutrient a
L-alanyl-L-glutamine, g/kg 11.4% compound amino acids,b g/kg 20% MCT/LCT,c g/kg Glucose, g/kg
Gln-PN
Control
0.8 0.4
0 0.6
1–2 4–13
1–2 4–13
Gln-PN, alanyl-glutamine–supplemented parenteral nutrition; LCT, longchain triglyceride; MCT, medium-chain triglyceride. a Dipeptiven (Fresenius Kabi, Bad Homburg, Germany). b Novamin (Fresenius Kabi). c Lipovenoes (Fresenius Kabi).
who made PN prescriptions and pharmacists who prepared PN were not blinded.
Intervention Methods Study Design This was a prospective, randomized, single-blind controlled study. The study protocol has been evaluated and confirmed by the Ethic Committee of Jinling Hospital, and written informed consent was obtained from each patient.
Patients Patients admitted in our department from June 2010 to June 2013 with CRE-induced surgical intestinal obstruction were primarily considered suitable for this study, regardless of the types of tumors. Inclusion criteria were the following: (1) patients had undergone abdominal and pelvic radiotherapy, (2) patients were 20–70 years old, (3) intestinal obstruction was diagnosed, and (4) patients met indications for both nutrition support and surgical therapy. Exclusion criteria were the following: (1) acute or chronic liver disorders or renal insufficiency, (2) chronic endocrine disease (diabetes mellitus, thyroid dysfunction, etc), (3) recurrence of primary malignancy, and (4) hemorrhage or fistula besides intestinal obstruction. After signing the informed consent, all patients who met the inclusion criteria were randomly assigned to a Gln-PN group or a standard PN (control) group. They were randomized according to a computer-generated randomization list managed by an external person uninvolved in this study. After informed consent was obtained, a central venous catheter or peripherally inserted central venous catheter was placed in all patients in the 2 groups 1 day before the first dose of PN was administrated. Patients were blinded for treatment assignment and outcomes until the end of this study. However, physicians
The Gln-PN group was administered glutamine dipeptide (Dipeptiven; Fresenius-Kabi, Bad Homburg, Germany; 100 mg/mL L-alanyl-L-glutamine) from preoperative day 13 (PreOD13) in PN (0.4 g/kg/d Dipeptiven to replace equivalent amount of nitrogen in amino acid solution) daily as long as PN was supplied. The control group was administered with isonitrogenous PN solution. Each patient received 0.22 g nitrogen/kg each day in 2500– 3000 mL of PN solution. The ratio of glucose to lipid in PN solution was 1–1.5:1. The total calories given to each patient were guided and adjusted by resting energy expenditure (REE), which was detected by indirect calorimetry (Quark PFT; CosMed, Rome, Italy). Total calories provided by PN were 1.3 times that of REE. The value of REE was detected on preoperative day 14 (PreOD14) and postoperative day 3 (POD3), respectively. Multivitamins and trace elements were also included in the PN solution, in accordance with the ESPEN guideline.4 Electrolytes and the total volume of solution were adjusted according to the serum biochemical indices and total output (urine, drainage fluids, and stool in case of diarrhea) in 24 hours, respectively. The composition of PN is shown in Table 1. On the first day of this study, each patient was given half of the total calories without changing other PN ingredients. PN, which was supplied from PreOD13 to preoperative day 1 (PreOD1), was restarted on POD3. After the operation, when the total drainage from nasogastric tube was 18.5 17–18.5
