Can Glutamine Enable the Critically Ill to Cope Better With Infection?From the Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Address correspondence to: Gil Hardy, PhD, FRSC, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand; e-mail: g.hardy{at}auckland.ac.nz.
Bloodstream infections (BSIs) are among the most dangerous complications that can occur in the hospital. According to the recent Epic2: National Evidence-Based UK Guidelines, 3 in every 1000 patients acquire a BSI.1 The incidence of septicemia ranges up to 8% in patients receiving IV therapy, and one-third of BSIs are related to central venous lines used for parenteral nutrition (PN) or other intensive care therapies. Hospital-acquired infections (HAIs) affect 10% of patients admitted to acute hospitals in the United Kingdom, with an estimated annual cost of $2 billion. Between 10% and 35% of intensive care unit (ICU) patients in the United States develop nosocomial infections, of which 10% are BSIs.2 With an attributable hospital mortality of 15%, which is rising annually,3 this represents the eighth leading cause of death.4 Extremely sick patients represent only about 10% of the ICU population but in surgical ICUs (SICUs), they exhibit the highest risk of HAI.5 BSIs worsen the severity of the patient's underlying disease, prolong hospitalization by at least 4 days,6 and are expensive to treat. Nosocomial infections are more likely in long-stay patients who are taking longer to recover before leaving the SICU. Staphylococcus epidermidis, Staphylococcus aureus, and Staphylococcus enterococci are the bacteria most frequently implicated,1 while Candida albicans is the most common fungal organism, found among normal flora of the GI tract and vagina.7 Candida infection is generally nosocomial and accounts for many infections. Almost half the patients in the ICU stay longer than 5 days and suffer from 1 or more infections, of which 17% are fungal. Infection is thus closely related to the duration of ICU stay and has long been associated with increased morbidity and mortality.8 Immunocompetent surgical patients have fewer nutrient deficiencies and only a 7% chance of developing postoperative septic complications, with 9% mortality (in contrast to a 60% chance for anergic patients).9 Glutamine (GLN) deficiency is common in those who remain critically ill for more than a few days and may result in impaired immune function, which increases susceptibility to infection. This predisposition may be due to immune and gut barrier dysfunction, facilitating infection from gut-derived microorganisms.10,11 How GLN influences nosocomial infections is unclear. It is an energy substrate for immune and gut epithelial cells, which may help to maintain gut barrier and gut mucosal function.12-18 Upregulation of the antioxidant glutathione and specific heat shock proteins may also be contributing factors.17-19 Only a small percentage of SICU patients are candidates for PN, but they have a high rate of morbidity and mortality.3 Those who undergo pancreatic debridement for severe necrotic pancreatitis usually require PN to maintain nutritional status. In a single-center pilot study,20 the large multidisciplinary group of Tom Ziegler at Emory University set out to determine whether GLN-supplemented PN influences nosocomial infection rates and postoperative complications in different subgroups of SICU patients. The double-blind, randomized controlled trial investigated patients requiring PN after pancreatic necrosis, cardiac, vascular, or colonic surgery. Thirty patients received approximately 18 g L-GLN/d as L-alanyl-L-GLN dipeptide-supplemented PN (GLN-PN), while 29 controls received isocaloric isonitrogenous PN (STD-PN). PN was administered for at least 7 days, with a maximum of 21 days, and was proportionally decreased as enteral intake increased to maintain therapeutic goals. GLN therapy did not alter infection rates following pancreatic necrosis surgery but significantly decreased infections in SICU patients after cardiac, vascular, and colonic surgery. In these non–pancreatic surgery patients, GLN-PN was associated with significantly decreased nosocomial infections (36 vs 13; P < .030), BSIs (7 vs 0; P < .01), pneumonias (16 vs 6; P < .05), and infections attributed to S aureus (P < .01), fungi, and Gram-negative bacteria (each P < .05). New nosocomial infections in all GLN patients almost halved (65 vs 38; P = .060). Moreover, GLN-PN led to a significant 3-fold decrease in the number of new infections in non–pancreatic surgery subjects. GLN patients in this cohort also demonstrated a significant decrease in the number of new nosocomial pneumonias, and none developed a BSI (P < .002). As in the recent French multicenter study,21 GLN supplementation significantly decreased the number of days patients required mechanical ventilation, perhaps because of the reduced incidence of pneumonia (21 vs 9 days). The number of patients who developed a new S aureus infection was significantly lower in the GLN-PN group (6/12 vs 1/15; P = .03). In addition, a total of 13 fungal BSIs (primarily C albicans) occurred in control patients, whereas no GLN patient developed a fungal infection. Non–pancreatic surgery patients given GLN-PN also developed fewer Gram-negative infections (0.93 vs 0.53 infections/patient). There was a trend for these patients to develop fewer nosocomial infections due to S aureus, such that when all 59 study subjects were considered, there was a 5-fold higher incidence of S aureus infection in patients receiving STD-PN vs GLN-PN. The decrease in SICU length of stay did not reach statistical significance, but this is not an especially relevant outcome measure. Non–pancreatic surgery patients at Emory University were very sick (mean APACHE II score of 15) as were patients in the earlier study by Griffiths et al (APACHE II scores of 17-18), who would have been expected to stay in the ICU for many days. Mortality was about the same in both U.K. groups for the first 20 days, but long-stay patients in the GLN group, who still had GI failure, eventually survived for longer. The rate of HAI during the study by Griffiths et al22 is related to reduced mortality from multiple-organ failure (MOF). As in the Ziegler study, GLN patients developed fewer Candida infections after a longer ICU stay, whereas STD-PN patients not only became infected earlier but also had more infections and eventually died from MOF. GLN halved the incidence of infection, and not only did it take longer for Candida infections to develop, but GLN patients were also better able to survive infection. This implies that GLN decreased the risk of dying from an infection. GLN-PN therapy in non–pancreatic surgery subgroups has been shown to significantly reduce nosocomial infections, mainly due to pneumonias and BSI attributed to S aureus, Candida, and Gram-negative bacteria. These organisms are responsible for a high percentage of nosocomial infections in immunocompromised postoperative and ICU patients.23 Unfortunately, the authors were unable to demonstrate any significant improvement in immune function tests, such as T lymphocytes, CD-4, or CD-8 T cells. Speculation that reduction in S aureus and Candida infections may be due to GLN's positive effect on neutrophil function is plausible but needs confirmation. Patients in these important surgical subgroups exhibited lower plasma GLN levels and higher APACHE II scores, and they were older and more lymphopenic. This cohort was therefore more GLN-depleted with a higher severity of illness and anticipated mortality. It is thus not surprising, and indeed encouraging, that hospital mortality significantly decreased by 35% in the GLN-PN cohort. All deaths were due to infection-associated acute respiratory distress syndrome and/or MOF. How quickly immunocompetence returns to normal after leaving the ICU is uncertain, but one might speculate that a patient's ability to survive is related not so much to the number or virulence of infections but to his or her ability to resist them (ie, the strength of their immune system). This timely study provides more evidence that GLN supplementation of PN can help fight infections and increase the ability to survive in seriously ill, elderly patients requiring prolonged intensive care. L-GLN is now widely considered a vital nutrient that becomes essential during critical illness. Provision of conventional PN (or EN) with little or no GLN cannot adequately meet immunonutritional requirements during serious illness.24 GLN-enriched PN is a clearly effective therapy for patients at risk of repeat infections, helping to reduce the chance of dying from infection and/or MOF.
Financial disclosure: none declared.
Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 4,
489-491 (2008)
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