l-Alanyl-l-glutamine-supplemented parenteral nutrition improves infectious morbidity in secondary peritonitis

Abstract

Background & aims: A growing number of randomized clinical trials suggest that glutamine (Gln) supplementation may be beneficial in a selected group of patients and conditions. However, the effects of Gln-enriched total parenteral nutrition (TPN) on recovery from acute intra-abdominal infection have not been thoroughly investigated. Therefore, the aim of this study was to investigate whether the provision of Gln-enriched TPN after surgical and medical treatment of secondary peritonitis improves infectious morbidity.

Methods: Thirty-three patients with secondary peritonitis were randomly assigned to receive either standard (n=16) TPN or l-alanyl-l-glutamine-supplemented (n=17) TPN, after medical and surgical treatment of the infectious focus. The two TPN formulae were isonitrogenous and isocaloric, which commenced the morning after surgery and ran continuously for 10 consecutive days. The control group received standard TPN, while the treatment group was given l-alanyl-l-glutamine, 0.40 g/kg/d (Dipeptiven,^® Fresenius Kabi, Bad Homburg, Germany). Infectious morbidity, nitrogen balance, leukocytes, lymphocytes, subpopulations CD₄ and CD₈, Immunoglobulin A (IgA), total proteins, albumin, hospital and intensive care unit (ICU) stays, and mortality were evaluated. Statistical analysis included one-way ANOVA, the unpaired Student's t-test, the Mann–Whitney U-test, χ² test, or Fisher's exact test.

Results: Patients in both groups were comparable prior to the operation. Nitrogen balance and the levels of albumin and IgA were significantly better than those in the control group. Also, a significant reduction in the infectious morbidity was found in the Gln-treated group. Lymphocyte counts as well as subpopulations CD₄ and CD₈, and proteins showed a propensity to improvement and a tendency to reduced rates of mortality were observed when comparing the groups. Hospital and ICU stays were similar.

Conclusion: l-alanyl-l-glutamine-supplemented TPN improved the infectious morbidity of patients with secondary peritonitis. Gln supplementation to parenteral nutrition may be an alternative for enhancing host defenses and improving infectious morbidity.

Introduction

Patients with severe sepsis demonstrate a characteristic picture in which hypermetabolism occurs, protein and fat are consumed, and body water and salt are preserved.¹ Acute peritonitis carries a mortality rate of 5–40% depending on its source of origin and whether it appears as a postoperative complication.2., 3., 4. It is managed by surgical correction of the infectious focus, broad-spectrum antibiotics and postoperative fluid and electrolyte therapy until bowel movements return and oral feeding is restarted. Postoperative fasting may be prolonged and enteral nutrition cannot be started early due to ileus. Secondary peritonitis is defined as any localized or generalized inflammation of the peritoneum caused by polymicrobial infection after either spontaneous or traumatic viscus perforation, or anastomotic dehiscence.³ Secondary peritonitis includes a large variety of different pathologic conditions ranging in severity from a local problem such as gangrenous appendicitis to a devastating disease such as diffuse postoperative peritonitis due to a dehiscence of a gastroduodenal anastomosis.3., 5. Commonly occurring secondary peritonitis can be either an acute perforation (gastrointestinal perforation, intestinal ischemia, pelviperitonitis), postoperative secondary to an anastomotic leak, accidental perforation and devascularization, or post-traumatic (blunt or penetrating abdominal trauma).³ Thus, it is always a polymicrobial infection. The flora consists of aerobic enterobacteriaeceae and anaerobes, mainly Bacteroides fragilis. These two groups of bacteria act synergistically.⁵ Optimal management of secondary peritonitis includes a timely surgical intervention to stop delivery of bacteria and adjuvants into the peritoneal cavity. All other measures are of little importance if the operation does not successfully abort the infective source and quantitatively reduce the inoculums of microorganisms and adjuvants of infection so that they can be effectively handled by the patient's defenses, supported by antibiotic therapy.3., 5. Accordingly, intensive measures to support tissue oxygenation and maintain organ function are necessary while awaiting recovery brought on through surgery and antibiotic therapy.

There is no current indication for routine administration of total parenteral nutrition (TPN) after elective major abdominal surgery in non-malnourished patients. However, in humans with ongoing infection, TPN palliates protein losses, and the supply of exogenous nutrients reduces depletion of protein and fat stores.2., 6. These benefits are more pronounced if the septic focus is controlled by appropriate surgical intervention. It is believed, however, that septic morbidity is significantly higher in patients receiving TPN.7., 8. Parenteral nutrition results in mucosal atrophy and increased intestinal permeability that reflects damage to the intestinal barrier. This pre-disposes to bacterial translocation and may be one explanation for increased rates of septic complications.7., 8. Still, TPN may be required if the patient's condition does not allow enteral nutrition (eg. paralytic ileus). Furthermore, TPN has failed to improve relevant biochemical markers and clinical outcome after laparotomy in an animal model of peritonitis.² On the other hand, glutamine (Gln) has been regarded as a conditionally essential amino acid during catabolic illnesses, such as sepsis.9., 10., 11., 12. Standard TPN formulations lack many important nutrients such as Gln and nucleotides.10., 11. Additionally, Gln augments the functions of immune cells such as lymphocytes, macrophages, and nuetrophils.9., 13. Gln increases cocanavalian A-stimulated proliferation, ribonucleic acid (RNA), and protein synthesis of lymphocytes.9., 14., 15. Gln also improves the in vitro bactericidal function of neutrophils and enhances the phagocytosis of yeast cells and sheep red blood cells and killing of Candida albicans by macrophages.9., 16., 17. Thus, Gln-supplemented nutrition may improve the ability of the host already confined to parenteral nutrition to deal with an upcoming infection.

A growing number of randomized clinical trials and experimental studies suggest that Gln supplementation may be beneficial in a selected group of patients and conditions (Table 1).¹⁸ Most studies have demonstrated that Gln (0.2 and 0.5 g/kg/d) is safe and inexpensive, and results in an improvement in nitrogen balance19., 20., 21., 22. and gut barrier function,19., 23. reduced infection rates19., 21. and diminished mortality in specific clinical settings including postoperative, intensive care unit (ICU) and bone marrow transplant (BMT)²⁴ and the number of days of ventilatory support,19., 24., 25. and a reduction of both hospital stay19., 21., 26. and expenses.19., 20., 21., 22. Careful clinical trials may identify additional groups of patients who will benefit from Gln-supplemented parenteral nutrition. The effects of Gln-enriched TPN on recovery from acute intra-abdominal infection have not been thoroughly investigated. Therefore, the aim of this study was to investigate whether the provision of Gln-enriched TPN after surgical and medical treatment of secondary peritonitis improves infectious morbidity.