Nutritional Support and the Surgical Patient

Yvonne Huckleberry

Disclosures

Am J Health Syst Pharm. 2004;61(7) 

In This Article

Immunonutrition

One of the most prominent areas of controversy over NS in recent years has been immune-modulating nutrients, including glutamine, arginine, omega-3 fatty acids, and nucleotides. Numerous trials have been conducted to assess the impact of products containing these ingredients on patient outcomes. However, many of these trials have been criticized for design flaws, and the results have been conflicting.

Glutamine

Glutamine has received much attention over the past decade. This amino acid serves as a nitrogen courier among organs; a fuel for lymphocytes, hepatocytes, and the intestinal mucosa; and a substrate for gluconeogenesis and protein synthesis.[78] Glutamine is typically considered nonessential, since it is synthesized by almost all body tissues. However, under conditions of catabolic stress, glutamine levels decline as glutamine consumption exceeds synthesis. Low glutamine levels have been associated with immune dysfunction and increased hospital mortality.[79,80] This finding has prompted evaluation of whether glutamine supplementation in serious injury or illness is safe and, if so, whether supplementation can improve patient outcomes.

Although short-term administration of i.v. glutamine has been suggested to be safe in healthy volunteers, some concern has been raised over its use in certain disease states and specific patient populations.[81] For example, glutamine supplementation at 0.285 g/kg/day resulted in significant elevation of liver enzymes in two of seven adult patients after four weeks of infusion with home PN.[82] In addition, one of the products of glutamine degradation is ammonia, which raises concern that excess glutamine may worsen hepatic encephalopathy.[83] There are few studies evaluating the effects of glutamine supplementation in the very young or elderly.

To evaluate both safety and efficacy, Novak and colleagues[84] performed a systematic review of 14 RCTs comparing glutamine with placebo or standard care in elective surgical or critically ill adult patients. All trials evaluated the impact of glutamine on clinically important endpoints, including complications, length of hospitalization, and mortality. Aggregate results showed no effect on patient mortality (RR, 0.78; 95% CI, 0.58 to 1.04) but did show a reduction in infectious complications in the glutamine group (RR, 0.80; 95% CI, 0.64 to 1.00). A reduction in length of stay was also observed (-2.6 days; 95% CI, -4.5 to -0.7); however, the heterogeneity between groups reporting length of stay as an endpoint was significant. Subgroup analysis of a priori hypotheses found differences in results for elective surgical patients compared with critically ill patients. For elective surgical patients, supplemental glutamine made no difference in mortality (RR, 0.99; 95% CI, 0.27 to 3.58) but did make a significant difference in complication rates (RR, 0.36; 95% CI, 0.14 to 0.92) and length of hospitalization (-3.54 days; 95% CI, -5.3 to -1.76). In critically ill patients receiving glutamine, a downward trend was observed in mortality (RR, 0.77; 95% CI, 0.57 to 1.03) and infectious complications (RR, 0.86; 95% CI, 0.68 to 1.08), but no difference wasseen in hospital stay (0.9 day; 95% CI, -4.9 to 6.8). A reduction in mortality (RR, 0.71; 95% CI, 0.51 to 0.99), hospital stay (-2.67 days; 95% CI, -4.4 to -0.9), and infectious complications (RR, 0.58; 95% CI, 0.43 to 0.80) was found with higher-dose glutamine (>0.2 g/kg/day), whereas no effect was observed with lower-dose glutamine. Parenteral glutamine significantly decreased mortality (RR, 0.71; 95% CI, 0.51 to 0.99) and length of stay (-2.8 days; 95% CI, -4.8 to -0.7); no effect was observed with enteral glutamine. The authors warned that conclusions should not be drawn based on these findings due to the small number of studies and their weaknesses. However, they suggested that parenteral glutamine is safe and potentially beneficial for surgical and critically ill patients when given in daily doses of 0.2 to 0.5 g/kg.

Arginine, Omega-3 Fatty Acids, and Nucleotides

Like glutamine, arginine is a nonessential amino acid that may be essential under conditions of metabolic stress. This amino acid, among the highest in nitrogen, has been associated with improved nitrogen balance and wound healing.[85] Arginine is believed to be immunoenhancing through the promotion of macrophage and natural killer tumor cytotoxicity, as well as T-cell proliferation and activation.[86] In addition, arginine is a precursor for nitric oxide, which is involved in the regulation of vascular tone and immune function.[78] These characteristics have made arginine attractive for potential use in surgical patients.

Few human studies have evaluated the impact of NS with arginine alone. However, several studies have evaluated arginine as a component of immunoenhancing enteral formulas that include other ingredients, such as omega-3 fatty acids and nucleotides.

Omega-3 fatty acids, derived primarily from fish oils, compete with other fatty acids for incorporation into the cell membrane. In contrast to omega-6 fatty acids typically provided as i.v. lipids, these fatty acids give rise to antiinflammatory, anti-thrombotic eicosanoids.[87,88] Among the limited trials evaluating omega-3 fatty acids and their influence on patient outcomes, a recent RCT assessed their impact on the postoperative course of patients with extended abdominal surgery.[89] Twenty-four well-nourished patients received either 10 g of fish oil infusion (Omegaven, Fresenius AG, Bad Homburg, Germany) or no fish oil infusion on perioperative days 1-5. Both groups received the same PN on days 4 and 5. There were no significant differences in characteristics between the two groups. Results showed a trend toward lower postsurgical infection rates and a significantly shorter hospital stay for patients fed omega-3 fatty acids.

Nucleotides are the structural units of DNA and RNA. Although suggested to have potential immunoenhancing effects with regard to natural killer cells and T lymphocytes, no human studies have shown beneficial effects of nucleotide supplementation.[87]

Arginine has raised the greatest concern with regard to the safety of immune-enhancing nutrients. As a major substrate for nitric oxide synthases, supplemental arginine may, it has been argued, promote excess nitric oxide production, leading to a worsening hemodynamic status and abnormalities in immune function that may be detrimental in the critically ill. Unlike general surgery patients, who may experience some degree of immunosuppression postoperatively, critical illness due to postsurgical complications may induce an amplified immune response. This may explain why immune-enhancing NS may not benefit this patient population.[90]

Three meta-analyses have been performed to evaluate the impact of immune-enhancing EN compared with standard EN on patient outcomes in critically ill and surgical patients. In the first of these, Heys et al.[91] pooled 11 trials including 1009 patients randomized to immunonutrition or a standard EN formula. The outcome measures of the trials included infectious complications, length of stay, and mortality. The authors noted that the treatment and control diets were not isonitrogenous and isocaloric in all trials. In fact, the nitrogen content of the treatment diet was markedly higher than that of the control diet in three trials. In addition, the nutritional status of patients prior to study entry was not uniformly described. However, this meta-analysis suggested a significant reduction in major infectious complications (odds ratio, 0.47; 95% CI, 0.32 to 0.70) and length of hospitalstay (-2.5 days; 95% CI, -4.0 to -1.0 days) for the treatment group compared with the controls. Subgroup analysis for surgical patients with GI cancer showed similar results for infectious complications (odds ratio, 0.47; 95% CI, 0.30 to 0.73) and length of hospitalization (-2.4 days; 95% CI, -3.9 to -1.2 days). Tests for heterogeneity between trials were consistently not significant.

Beale and colleagues[92] performed a systematic review and meta-analysis of 12 RCTs including 1482 patients with trauma, sepsis, or major surgery. All RCTs included critically ill patients fed immunonutrition or standard formulas. Trial endpoints included mortality, length of hospital stay, infection rates, and number of days of mechanical ventilation. Overall, the treatment group received significantly more nitrogen (0.04 g/kg/day; p = 0.01) and slightly fewer calories (1.6 kcal/kg/day) than the controls. These authors found a positive impact of immunonutrition in terms of relative risk of acquiring an infection (RR, 0.60; 95% CI, 0.42 to 0.86), ventilator days (2.6 days; 95% CI, 0.1 to 5.1 days), and length of hospitalization (2.9 days; 95% CI, 1.4 to 4.4 days). No heterogeneitywas observed between trials reporting these outcomes. Subgroup analysis suggested that the benefit of immunonutrition was greater in the surgical subpopulation than in the trauma and medical subgroups. Immunonutrition did not affect overall mortality (RR, 1.05; 95% CI, 0.78 to 1.41). However, >60% of all deaths were reported in one trial.

In a 2001 publication, Heyland et al.[93] reported an evaluation of 22 RCTs involving 2419 surgical and critically ill patients. Like the previous two meta-analyses, all trials compared immunoenhancing EN with standard EN formulas. Clinically important endpoints were defined as mortality, infectious complications, and length of hospitalization. Calorie and nitrogen equivalence between groups was not assessed. Aggregate results showed no impact on mortality (RR, 1.10; 95% CI, 0.93 to 1.31) but significantly fewer infectious complications (RR, 0.66; 95% CI, 0.54 to 0.80) and a shorter length ofstay (effect size, -0.63; 95% CI, -0.9 to -0.32) for patients receiving immunonutrition. However, heterogeneity across studies was significant and prompted an evaluation of a priori hypotheses that showed that patients fed formulas with a higher arginine content (Impact, Immun-Aid) fared better in terms of infectious complications (RR, 0.55; 95% CI, 0.46 to 0.67) and length of hospital stay (effect size, -0.77; 95% CI, -1.09 to -0.45) than patients given lower-arginine formulas. Infectious complications were significantly reduced in surgical patients receiving immunonutrition (RR, 0.53; 95% CI, 0.42 to 0.68), but there was no difference in critically ill patients (RR, 0.96; 95% CI, 0.77 to 1.20). The difference between these subgroups was significant (p = 0.002). Higher-quality studies of critically ill patients suggested significantly higher mortality (RR, 1.46; 95% CI, 1.01 to 2.11) and shorter length of stay (effect size, -0.48; 95% CI, -0.95 to -0.01) in patients receiving immunonutrition.

Immunonutrition may thus improve outcomes in elective surgical patients but may potentially harm the critically ill. This is supported by a recent RCT showing that patients with sepsis who were fed immunoenhancing EN had greater mortality than those prescribed PN.[94] Until further research clarifies which patients may benefit from immune-modulating NS, these products should not be routinely recommended for all postoperative patients.

Specific recommendations on the use of immune-enhancing diets have been published[95]; recommendations pertinent to surgical patients are summarized in Table .

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