L-Alanyl-L-Glutamine-Supplemented Parenteral Nutrition Decreases Infectious Morbidity Rate in Patients With Severe Acute Pancreatitis

Written By: Sam Savage

Published Date: September 4, 2008 Last Edited: September 4, 2008

By Fuentes-Orozco, Clotilde Cervantes-Guevara, Gabino; Mucino- Hernandez, Ivette; Lopez-Ortega, Alejandro; Ambriz-Gonzalez, Gabriela; Gutierrez-de-la-Rosa, Jose Luis; Gomez-Herrera, Efrain; Hermosillo-Sandoval, Jose Manuel; Gonzalez-Ojeda, Alejandro

Background: The effect of parenteral GLN on recovery from severe acute pancreatitis has not been thoroughly investigated. The aims of this study were to determine whether parenteral GLN improves nutrition status and immune function, and to determine its ability to reduce morbidity and mortality in patients with this condition. Methods: In a randomized clinical trial, 44 patients with severe acute pancreatitis were randomly assigned to receive either standard PN (n = 22) or L-alanyl-L-glutamine-supplemented PN (n = 22) after hospital admission. Nitrogen balance, counts of leukocytes, total lymphocytes, and CD4 and CD8 subpopulations, and serum levels of immunoglobulin A, total protein, albumin, C-reactive protein, and serum interleukin (IL)-6 and IL-10 were measured on days 0, 5, and 10. Hospital stay, infectious morbidity, and mortality were also evaluated. Results: Demographics, laboratory characteristics, and pancreatitis etiology and severity at entry to the study were similar between groups. The study group exhibited significant increases in serum IL-10 levels, total lymphocyte and lymphocyte subpopulation counts, and albumin serum levels. Nitrogen balance also improved to positive levels in the study group and remained negative in the control group. Infectious morbidity was more frequent in the control group than in the study group. The duration of hospital stay was similar between groups, as was mortality. Conclusion: The results suggest that treatment of patients with GLN- supplemented PN may decrease infectious morbidity rate compared with those who treated with nonenriched PN. (JPEN J Parenter Enteral Nutr. 2008;32:403-411) Keywords: severe acute pancreatitis; GLN- supplemented PN; infectious morbidity

Glutamine (GLN), which is synthesized in organs such as the skeleton, muscle, lungs, and brain, is the most abundant amino acid in the plasma and intracellular amino acid pools. Although GLN is a nonessential amino acid, it is classified as a conditionally essential amino acid because of increased demand for it in catabolic states.1-3

Support of patients with acute pancreatitis with parenteral nutrition (PN) has been suggested to improve functioning of the gastrointestinal system and the pancreas. Furthermore, long-term ileus and surgical interventions preclude oral and enteral nutrition (EN) of patients with severe acute pancreatitis. It has been suggested that PN may be useful for management of patients with acute pancreatitis by preventing exocrine secretions responsible for autodigestion of the pancreas. PN has also been used to support optimal recovery as well as for life support. 4-6

In recent years, EN has been considered the method of choice for the nutrition of patients with mild acute pancreatitis. However, PN is also useful for patients suffering from mild acute pancreatitis accompanied by nausea and vomiting.7,8 Although most patients develop the mild form of acute pancreatitis, 20% develop the severe or life-threatening form, which is characterized by local complications such as necrosis, infection, abscesses, pseudocysts, acute respiratory and renal failure, as well as an intense systemic inflammatory response accompanied by a high risk of multiple organ failure.9 Severe acute pancreatitis, like sepsis and trauma, is characterized by a marked degree of protein breakdown.10-14 Catabolism of body protein may be as high as 2% per day.15 A study using the Harris-Benedict equation to predict resting energy expenditure showed that patients with acute pancreatitis have markedly elevated metabolic rates (77%- 139% of predicted energy expenditure), especially in the presence of septic complications, which are commonly observed in acute pancreatitis.16 In patients with nausea, vomiting, and intermittent ileus secondary to intraabdominal infection or repetitive surgical debridement of necrotic and infected pancreatic and peripancreatic tissue, nutrient requirements cannot be met by EN.17

Although PN contributes to optimal recovery and pancreas function, a long period of PN (>10 days) increases the risk of an acute inflammatory response and septicemia.18,19 It has been postulated that GLN is an immunomodulatory agent, as it has beneficial effects on the cells of the immune system and their functions.20,21 Previous studies have shown that GLN-enriched PN formulas improve the prognosis of septic and surgical patients22-25 by decreasing the acute inflammatory response commonly observed in such patients.3

This study was performed to determine the effects of early administration (within the first 48 hours of the onset of severe acute pancreatitis) of GLN dipeptide-supplemented PN on the nutrition status, inflammatory response, occurrence of complications, duration of hospital stay, and mortality of patients with severe acute pancreatitis.

Patients and Methods

Patients and Study Design

The experiment was designed as a randomized, doubleblind, controlled clinical trial. The study period was from April 2003 to October 2005. Patients with suspected episodes of acute pancreatitis were studied to confirm the diagnosis. Acute pancreatitis was defined as an increase in serum amylase concentrations to a level 3- fold greater than basal levels, or abdominal pain and findings typical of acute pancreatitis upon abdominal ultrasound or computed tomography (CT). The severity of acute pancreatitis was defined using the following criteria26-28: an Acute Physiology and Chronic Health Evaluation (APACHE) II score >8, a Ranson score >4 at 48 hours, a C-reactive protein (CRP) serum level >1 50 mg/L, and CT with at least a Balthazar’s CT grade of C, D, or E at admission and a CT severity index (CT grade plus necrosis score) >/= 4.

Patients were admitted to the intensive care unit (ICU) where a subclavian central venous catheter was collocated in all cases. Intensive monitoring was performed and IV liquids were administered according to the hemodynamic state of the individual. Patients with renal failure (creatinine > 1 80 mol/L) or hepatic failure (bilirubin > 40 mol/L, alanine aminotransferase [ALT] > 100 U/L and aspartate aminotransferase [AST] > 100 U/L) were excluded from the study. Patients with severe neutropenia (

Patients satisfying the enrollment criteria received a serial number allocated in ascending order of enrollment. Based on this number, the patients were assigned to one of the study groups. The patient number appeared on the patient’s prescription and was used to prepare the all-inone bag for the patient. The blinded preparation of solutions was conducted with the help of the pharmacy. All investigators involved in the analysis, patients, and relatives of patients were blinded to the randomization until the 10- day follow-up had been completed for all subjects. Patients were randomly assigned to receive either standard PN (n = 22) or GLN- supplemented PN (n = 22), which commenced between 24 and 48 hours after admittance to the ICU. Baseline hematology and biochemistry were conducted at enrollment and on protocol days 5 and 10. Routine hematology consisted of measurement of hemoglobin levels, white blood cell counts, platelet counts, and differential with blood cell (neutrophils and lymphocytes) counts. Routine biochemistry consisted of measurements of levels of sodium, potassium, chloride, AST, ALT, glucose, cholesterol, urea, creatinine, total bilirubin, triglycerides, and bicarbonate.

Feeding Regimen

The 2 PN formulas were isonitrogenous and isocaloric. The control group received standard PN, which supplied 30 kcal/kg per day. The nonprotein calories were derived from carbohydrates (50% hypertonic glucose) and lipids (20% fatty acids) in a ratio of 60:40. The protein calories were derived from amino acids (8.5%; 1.5 g/kg per day). The treatment group was given 0.40 g/kg per day of L-alanyl-L- Glutamine (Dipeptiven, Fresenius Kabi, Bad Homburg, Germany) plus 8.5% standard amino acids (1.1 g/kg per day). For caloric estimations, adjusted body weight was considered in each patient (adjusted body weight = 0.25 x [actual body weight – ideal body weight] + ideal body weight). Nutrition support was initially infused at 80% of the calculated en ergy requirements, then increased over 48 h to achieve 100% of the target energy rate and continued until death or as long as clinically required (normal diet or full EN). The clinicians were allowed to adjust the total volume of PN delivered and the amount of water and electrolytes administered on a daily basis as judged clinically appropriate. All patients were under close metabolic control mediated by the infusion of IV crystalline insulin according to serum or capillary glucose levels. Nitrogen Balance

A fluid balance chart was maintained during the study period. Total urinary nitrogen was determined using the micro-Kjeldahl method.29 The amount of nitrogen administered via PN was determined by multiplying the volume of PN administered by the nitrogen concentration of the infusate. Insensible nitrogen losses were assumed to be 0.025 g/kg per day. Nitrogen balance was calculated from the formula: daily nitrogen balance = nitrogen administered – total urinary nitrogen loss – insensible nitrogen loss. For those patients treated surgically during the follow up period, drainage losses were taken into account when estimating nitrogen balance. For each 1000 mL/24 hours of fluid drained from open abdomen or close drains, 1 g of nitrogen was empirically added to the feeding formula. Blood and plasma transfusions were not considered.30

Endpoint Definitions

The primary efficacy variables were infectious morbidity, nitrogen balance, leukocyte, counts of leucocytes, lymphocytes and CD4 and CD8 subpopulation, and levels of immunoglobulin A (IgA), total protein, albumin, CRP, interleukin (IL)-6, and IL-10. Systemic inflammatory response syndrome, sepsis, septic shock, and multiple organ failure syndrome were defined as follows:

* Systemic inflammatory response syndrome was defined as a systemic inflammatory response to a variety of severe clinical insults manifested by at least 2 of the following conditions: (1) temperature > 38[degrees]C or

* Sepsis was defined as the systemic response to infection. Such a response is manifested by at least 2 of the following conditions as a result of infection: (1) temperature higher than 38[degrees]C or lower than 36[degrees]C; (2) heart rate faster than 90 beats/ min; (3) respiratory rate faster than 20 breaths/min or an arterial partial pressure of carbon dioxide below 4.3 kPa; and (4) white blood cell count larger than 12,000 cells/mm^sup 3^, less than 4000 cells/mm^sup 3^, or more than 1 0% of immature forms.

* Septic shock was defined as sepsis with hypotension despite adequate fluid resuscitation and the presence of perfusion abnormalities, including but not limited to lactic acidosis, oliguria, or an acute alteration in mental status. Patients on inotropic or vasopressor agents could not be hypotensive at the time that perfusion abnormalities were measured.

* Multiple organ dysfunction syndrome was defined as the presence of altered organ function in an acutely ill patient such that homeostasis could not be maintained without intervention.

Infectious morbidity included intraabdominal and extra-abdominal infections.

* Diagnosis of infected pancreatic necrosis, pancreatic abscess, or generalized peritoneal infection was based on microbiological examination (gram stain and culture for aerobic and anaerobic germs and fungi) of samples obtained by CT-guided fineneedle aspiration of pancreatic, peripancreatic, or any intra-abdominal collection and confirmed in fluid or tissue specimens obtained during surgery.

* Pneumonia was defined as a chest radiographic examination showing new or progressive infiltrate, consolidation, and cavitation (interpreted by a radiologist blinded to a patient’s treatment assignment), and at least 2 of the following: (1) temperature above 38.5[degrees]C or below 35[degrees]C, (2) a white blood cell count larger than 10 x 107L or less than 3 x 109/L, and (3) isolation of pathogens from the sputum, bronchial aspirates or bronchial brushing.

* Bacteremia was diagnosed when a pathogen was isolated from the blood with a temperature above 38.5[degrees]C or below 35[degrees]C or a white blood cell count larger than 10 x 10^sup 9^/L or less than 3 x 10^sup 9^/L, and it was not related to infection at another site.

* Urinary tract infection was defined as the isolation of at least 10^sup 5^ colonies/mL of a pathogen from the urine.

* Catheter-related sepsis was diagnosed if the patient had local signs of infection at the entry site, a temperature > 38.5[degrees]C or 10 x 109/L or

Secondary efficacy parameters included durations of hospital stay, ICU stay, ventilatory support, and the incidence of mortality.

Ethical Aspects

This study was conducted according to the principles of the Declaration of Helsinki of 1989 and the Mexican Health Guidelines. The Ethical Committee of the Western Medical Center of the Mexican Institute of Social Security approved all protocols. Full, written informed consent was obtained from all patients before their inclusion in the study.

Statistical Analysis

All quantitative values in the text refer to the mean +- standard deviation (SD). Comparison between means was assessed using ANOVA or the unpaired Student’s t test. When data were not distributed normally, comparisons were made using the Mann-Whitney U test. Qualitative values are expressed as proportions. Comparison between proportions was assessed using the chi^sup 2^ test or Fisher’s exact test. The analysis was performed using SPSS release 10.0 for Windows (SPSS Inc., Chicago, IL). A P value of

Results

Demographic and laboratory characteristics of the control (n = 22) and study (n = 22) groups were similar at entry (Table 1 ). All 44 patients had severe acute pancreatitis. The randomization process resulted in groups with similar patient characteristics. Sex distribution and body mass index (BMI) were similar between groups. The most common type of pancreatitis was biliary pancreatitis, and the second most common was alcoholic pancreatitis. The APACHE II scores of the groups were similar at the beginning of the study. The CT severity index was also similar between groups. As established by the inclusion criteria, patients presented with at least 30% necrosis of the pancreatic gland as evaluated by contrast-enhanced CT scanning.

Table 1 . Baseline Characteristics of the Patients in the Study (GLN+) and Control Group (GLN-) (mean +- SD)

Nutrient Intake

Target energy requirements were reached in the first 48 hours. Patients of the control group received initially from 1765 +- 124.97 to 2020.68 +- 207.0 calories/day in the subsequent days, and patients of the study group received 1798 +- 156.25 to 2024.81 +- 174.70 calories each day. There was no difference between the amount of initial and targeted calories requirements between groups (P = .44 and P = .99, respectively).

Patients of the control group received 105.6 +- 20.35 g of proteins/day and 16.9 +- 3.2 g of nitrogen/day, and patients of the study group received 107.9 +- 14.07 g of proteins/day and 17.2 +- 2.23 g of nitrogen/day. There was no difference in the amount of proteins and nitrogen administered in both groups (P = .66 and P = .65, respectively).

Proteins, Albumin, and Nitrogen Balance

Protein and albumin levels as well as nitrogen balance are depicted in Table 2. Protein levels increased in both groups in a similar fashion, but the increase was only significant on day 10 in favor of the study group. Albumin levels also rose in a similar fashion in both groups but serum levels remained below 3 g/dL limits. On protocol day 10, the difference between groups was significant (P = .01). During follow-up, nitrogen balance remained negative in the control group (Table 2). The patients in the study group attained a slightly positive nitrogen balance on day 10 and the difference was significant (P = .049).

Table 2. Laboratory Findings at Different Time Intervals (mean +- SD)

Total Leukocyte Counts

During follow-up, patients of the study and control group shown elevated leukocyte counts (Table 2). Basal values were not different between groups, nor were counts on day 5; on day 10, the leukocyte count of the study group was less than that of the control group (P = .04).

Total Lymphocyte Counts

Total lymphocyte counts are depicted in Table 2. Patients of the study group experienced progressive elevations of total lymphocyte counts in opposition to the control group, and the difference was not significant on days 0 and 5. At the end of the follow-up period, the total lymphocyte count was higher in the study group. The difference was significant (P = .04).

CD4 and CD 8 counts

Counts of CD4 and CD8 lymphocyte subpopulations are depicted in Table 2. Both CD4 and CD8 levels increased with time for the L- alanyl-L-glutamine- supplemented PN group relative to those of the standard PN group, and the difference was statistically significant on days 5 and 10 for CD4 count (P = .003 and P = .03, respectively) and only on day 10 for CD8 count (P = .03).

Immunoglobulin A

Average IgA levels are shown in Table 2. Patients in the study and control groups experienced a progressive elevation in IgA serum levels, but differences on days 0 and 5 were not statistically significant. In contrast, IgA serum levels on day 10 were higher in patients of the study group. This difference was significant (P – .01).

IL and CRP Levels

IL-6, IL-10, and CRP levels are depicted in Table 2. IL-6 levels decreased on day 10 in study group patients. In the control group, levels remained elevated during the followup period. The difference was statistically significant at this point (P = .03). Regarding the anti-inflammatory IL10, patients of both groups showed progressive increasing levels, but the levels were higher in the study group than in the control group on day 10 (P = .02). With reference to CRP levels, we observed a progressive reduction in both groups, but it was notably different in patients of the study group on day 10 (P = .005). Infection Rate

The number of patients with infectious morbidity was significantly different between groups. In the control group, 16 patients suffered from at least 1 infective complication, in contrast to the study group in which only 9 patients developed at least 1 infective episode (72.7% vs 40.9%, P = .03). The total number of infectious episodes is shown in Table 3.

Table 3. Infectious Complications

Table 4. Surgical Interventions

Surgical Interventions

Surgical interventions are shown in Table 4. Almost all patients with biliary pancreatitis underwent open or laparoscopic cholecystectomy during hospitalization, usually during the third or fourth week of hospital stay (21 +- 4 days). Patients with intra- abdominal septic complications were treated between the second and third week after admission (14 +- 2 days). All patients with infected necrosis required repetitive open drainage. Patients with suspected generalized intra-abdominal infection underwent laparotomy and drainage of the abdominal cavity until absolute control of the infection was attained; this required 2.3 +- 0.57 and 3.1 +- 0.47 reinterventions in the study and control groups, respectively. More reinterventions were required to treat intra-abdominal infection in the control group (P = .03).

Secondary Efficacy Parameters

There were no between-group differences in the duration of stay in the ICU or the duration of ventilatory support (Table 5). All patients required > 10 days of PN before oral or EN was commenced. Mortality was 22.7% in the control group and 9% in the study group (P = .20). To establish the clinical relevance of mortality, we calculated absolute risk reduction, 13.7%; relative risk reduction, 60%, and number needed to treat to prevent 1 death, 8 patients. In all fatal cases, the cause of death was multiple organ failure.

Table 5. Secondary Efficacy Parameters (mean +- SD)

Discussion

GLN is the most abundant amino acid in the body. Plasma levels decrease during critical illness, suggesting that GLN becomes limited.32 Parenteral GLN supplementation improves nitrogen balance.33,34 GLN is involved in interorgan nitrogen transport, functions as a nitrogen donor for nucleotides and amino sugars, and is a key substrate for renal ammonia formation.35 As the preferred fuel of enterocytes, GLN may reduce bacterial translocation across the gut wall and thus reduce the risk of sepsis.32,36 Cells of the immune system also use GLN as fuel and the amino acid contributes to antioxidant defense37 through the production of glutathione.32 GLN enhances the expression of heat shock proteins, which are important for protection against tissue damage during stress or injury.38,40

Patients with mild acute pancreatitis can begin oral feeding after 5-7 days of medical treatment with IV solutions, analgesics, and gastric drainage if necessary. For this group of patients, nutrition support with either EN or PN is considered unnecessary. However, several studies and guidelines have emphasized the superiority of EN over PN.8,41-43 Fortunately, most patients with acute pancreatitis will not develop the severe form of pancreatitis. Those who develop severe acute pancreatitis suffer intense catabolic stress with abdominal manifestations of compartmental syndrome and ileus, which precludes the use of the enteral route, at least during the first 10 days after the beginning of the catabolic state. PN is still an option for these patients if they cannot be fed orally or enterally.44-47

In the past 10 years, 6 studies that evaluated PN with or without supplemental parenteral GLN have been published.48-53 A study by Zhao et al48 compared a treatment group receiving PN with added parenteral GLN (0.22 g/kg per day) with a control group receiving conventional PN without GLN. The treatment group was transitioned to receive supplemental EN once gut paralysis was relieved. Inflammatory markers decreased faster and to a greater extent in the treatment group compared with controls at day 4, 7, and 11 as well as APACHE II score and basal Balthazar’s severity index. Unfortunately, no outcome parameters were evaluated in the 96 patients randomized in this study.

In a second study, De Beaux et al49 evaluated PN with and without supplemental parenteral GLN (0.22 g/kg per day). However, only patients receiving long-term PN who had persistent failure of the GI tract for more than 7 days after the onset of acute pancreatitis were included in the study. As a result, patients were randomized at 10-18 days after the onset of the illness. The severity of the episodes of acute pancreatitis was not described. The incidence of major pancreatic complications was observed in more than 50% of the patients of both groups. Levels of IL-8, an inflammatory cytokine released by mononuclear cells, decreased in the GLN group, whereas levels increased significantly in controls receiving PN alone (P = .045). There were no deaths in the study.

Ockenga et al50 performed a study of patients with mild to moderate pancreatitis randomly assigned to isocaloric and isonitrogenous PN with 0.3 g of L-alanyl-L-glutamine and 1.2 g/kg per day of standard amino acids vs 1.5 g/kg per day of standard amino acids in the control group. The study examined 28 patients (n = 14 in each group) with an APACHE II score of 5.7 and 5.1 and a Balthazar’s severity index of 1.9 and 2.4, respectively. They found that patients in the treatment group reduced mean hospital stay compared with controls receiving PN without supplementation and experienced significantly shorter duration of nutrition therapy. Visceral protein levels, including those of albumin, transferrin, and total protein were all significantly greater in the GLN supplementation group (P

Xian-Li et al51 studied 64 patients with severe acute pancreatitis randomized to receive traditional conservative therapy (group I, n = 23). For these patients, glucose was the major source of energy. Combined with traditional conservative therapy, 21 patients in group II and 20 cases in group III were treated by isocaloric and isonitrogenous PN and, in group III, with additional GLN dipeptide-supplementation (0.4 g/kg per day of alanyl- glutamine). PN with GLN was associated with significantly less pancreatic infection (0% vs 23.8%), fewer overall complications (20% vs 52.4%), and less mortality (0% vs 14.3%) compared with PN without supplemental GLN.51

In a recent publication by Sahin et al,52 a total of 40 patients with acute pancreatitis who had Ranson’s score between 2 and 4 were randomly assigned to receive GLN (0.3 g/kg per day) and standard amino acids (1.1 g/kg per day); the control group received 1.4 g/kg per day of standard amino acids. The lengths of PN use and hospital stays were not different between groups. The complication rates in the treatment and control groups were 10% and 40%, respectively. Mortality was 10% in the study group and 30% in the control group.52

Finally, Xue et al53 evaluated the therapeutic effect of alanyl- glutamine dipeptide (AGD) in a randomized clinical trial of 76 patients with severe acute pancreatitis in early and advance stages. Patients of the early treatment group received 100 mL/day of 20% AGD intravenously for 10 days started either on admission day or 5 days after (late treatment group) admission. The severity of the episodes were evaluated with 48-hour Ranson score (4.5 +- 1.7 vs 4.8 +- 1.6), 24-hour APACHE II score (10.8 +- 3.5 vs 10.2 +- 3.1) and CT score (5.8 +- 2.3 and 5.9 +- 2.4). As primary endpoints, the authors studied the presence and duration of organ failure. They demonstrated a significant reduction in the length of organ failure. The incidence of infection was 7.9% in the early treatment group, 5 patients required surgical interventions (13.2%), and mortality was 5.3%. In the late group, infection was observed in 26.3% of the cases, 13 required surgical interventions (34.2%), and mortality was 21.1%. The authors concluded that early treatment with AGD achieved a better clinical outcome in severe acute pancreatitis patients.53

In our study, we included patients with severe acute pancreatitis with a minimum CT severity index of 4 points. All patients developed pancreatic gland necrosis of at least 30%. Patients of the study group received 0.4 g/kg per day of L-alanyl-L-glutamine and patients of the control group received 1.5 g/kg per day of standard amino acids. The primary efficacy parameters were better in patients of the study group. We attribute our results to a reduction in the acute inflammatory response mediated by a decrease in levels of pro- inflammatory IL-6 and CRP and a progressive increase in the level of anti-inflammatory IL-10. We also observed an enhancement of immune function, as the counts of CD4 and CD8 lymphocytes and serum levels of IgA increased to a significantly greater extent in the GLN group than in the control group. In the control group, a slight increase in these parameters was also observed. The study group patients experienced rapid nutritional recovery, as evidenced by high levels of total protein and serum albumin and a slightly positive nitrogen balance on day 10. Probably it was the result ol a modulation of the inflammatory response, as well as a marked reduction in the incidence of septic intra-abdominal and extra-abdominal complications observed in the treatment group. However, albumin levels in study group patients remained below the lower normal limit, probably as a consequence of the intense catabolic state imposed by the severity of the acute pancreatitis.9,10,14 In agreement with the results of studies published by De Beaux et al,49 Ockenga et al,50 Xian-Li et al,51 Sahin et al,52 and Xue et al,53 our results indicate that overall complications, including infectious morbidity, were less frequent in patients receiving GLN- enriched PN. In our study, however, this reduction in infectious complications did not result in a reduction in mortality, duration of ICU stay, or duration of hospital stay. These may be real phenomena or may merely reflect the small sample number of this trial. A clinical trial with a large sample is necessary to resolve this.

Conclusion

Our results suggest that parenteral GLN dipeptide supplementation decreases the incidence of infectious complications. Mortality was not different between groups, but we observed a slight reduction in this secondary efficacy parameter in patients of the study group.

Acknowledgement

The authors would like to thank Rafael Montufa, MD, from Fresenius Kabi, Zapopan, Jalisco, Mexico for his technical support and for finishing this project.

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Clotilde Fuentes-Orozco, MD, PhD1; Gabino Cervantes-Guevara, MD, MSc2; Ivette Mucino-Hernandez, MD1; Alejandro Lopez-Ortega, MD1; Gabriela Ambriz-Gonzalez, MD, MSc1; Jose Luis Gutierrez-de-la-Rosa, MD3; Efrain Gomez-Herrera, MD3; Jose Manuel Hermosillo-Sandoval, MD3; and Alejandro Gonzalez-Ojeda, MD, PhD, FACS1 Financial disclosure: none declared.

From the 1 Medical Research Unit in Clinical Epidemiology, Western Medical Center, Mexican Institute of Social Security; 2 Department of Nutritional Support at Civil Hospital “Fray Antonio Alcalde,” University of Guadalajara; and 3 Department of General Surgery and Nutritional Support, Specialties Hospital at Western Medical Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico.

Received for publication April 25, 2007; accepted for publication March 10, 2008.

Address correspondence to: Alejandro Gonzalez-Ojeda, MD, Calle Jose Enrique Rodo # 2558, Colonia Prados Providencia, 44657, Guadalajara, Jalisco, Mexico; e-mail: [email protected].

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