Benefits of Enteral versus Parenteral Nutrition
Several prospective randomized controlled trials (PRCTs) performed in the late 1980s and early 1990s had significant impact on clinical practice in surgical, and particularly trauma ICUs. These single institutional trials all randomized trauma patients to early enteral nutrition or parenteral nutrition and all demonstrated that patients receiving early enteral nutrition had significantly fewer infectious complications (see ch66). A meta-analysis that combined data from eight PRCTs (six published, two not published) was then conducted to assess the nutritional equivalence of enteral nutrition compared to parenteral nutrition in high-risk trauma and/or postoperative patients.4 Similar to the single institutional trials, fewer infectious complications developed in patients receiving enteral nutrition. Even when patients with catheter-related sepsis were removed from the analysis, a significant difference in infections between groups remained. Taken together, these trials provide convincing evidence that enteral nutrition is preferred to parenteral nutrition in patients sustaining major torso trauma. A recent meta-analysis evaluating the effect of early versus delayed enteral nutrition in acutely ill (medical and surgical) patients also confirmed a decrease in infectious complications in patients receiving early enteral nutrition.45
Based on available data, we can now explain how enteral nutrition interrupts this sequence of events to prevent late nosocomial infections and MOF. In a variety of models (i.e., sepsis, hemorrhagic shock, and gut I/R), intraluminal nutrients have been shown to reverse shock-induced mucosal hypoperfusion.46 In the laboratory, we have also shown that enteral nutrition reverses impaired intestinal transit when given after a gut I/R insult.47 Improved transit should decrease ileus-induced bacterial colonization. Moreover, enteral nutrition attenuates the gut permeability defect that is induced by critical illness.48 Finally, and most important, the gut is a very important immunologic organ and infections may be lessened by feeding the gut. Dr. Kudsk has performed a series of laboratory studies that have nicely elucidated a mechanistic explanation of how this occurs.49 enteral nutrition supports the function of the MALT that produces 70% of the body’s secretory IgA. Naive T and B cells target and enter the gut-associated lymphoid tissue (GALT) where they are sensitized and stimulated by antigens sampled from the gut lumen and thereby become more responsive to potential pathogens in the external environment. These stimulated T and B cells then migrate via mesenteric lymph nodes to the thoracic duct and into the vascular tree for distribution to GALT and extra intestinal sites of MALT. Lack of enteral stimulation (i.e., use of TPN) causes a rapid and progressive decrease in T and B cells within GALT and simultaneous decreases in intestinal and respiratory IgA levels. Previously resistant TPN-fed laboratory animals, when challenged with pathogens via respiratory tree inoculation, succumb to overwhelming infections. These immunologic defects and susceptibility to infection are reversed within 3 to 5 days after initiating enteral nutrition.
Modified Enteral Formulas
Recent basic and clinical research suggests that the beneficial effects of enteral nutrition can be amplified by supplementing specific nutrients that exert pharmacologic immune-enhancing effects beyond the prevention of acute protein malnutrition. There are at least 18 PRCT and 3 meta-analyses where an IED is compared with a standard enteral diet or no diet and where the patient outcome was a predetermined end point. Of the 18 PRCTs, 11 trials demonstrated improved outcome, 4 trials were highly suggestive of improved outcome, and 3 trials did not demonstrate any clinical outcome advantage. The majority of trials are in trauma and cancer patients, although a few trials include mixed ICU and septic ICU patients.
The proposed immune-enhancing agents include glutamine, arginine, omega-3 polyunsaturated fatty acids (PUFAs), and nucleotides, although the individual contributions of each have not been well investigated. Glutamine is actively absorbed across the intestinal epithelium and then metabolized in the small bowel to ammonia, citrulline, alanine, and proline, and serves as an energy source for the enterocyte. Glutamine is therefore acknowledged to be the preferred fuel of the enterocyte, and stimulates lymphocyte and monocyte function. The demand for glutamine is increased during stressed states and supplementation at pharmacologic doses may be required. Glutamine also promotes protein synthesis, is a precursor for nucleotides as well as glutathione, and is thought to play a role in maintaining gut integrity. In a recent meta-analysis, glutamine (parenteral and enteral) administered to critically ill and surgical patients resulted in a lower mortality, less infectious complications, and shorter hospital stay.50 High-dose and parenteral glutamine had the greatest effect, although the study was not designed to examine these parameters. Additionally, a mixed patient population was included with limited (randomized) studies and clinical endpoints. A randomized trial of glutamine-enriched enteral nutrition in severely injured patients demonstrated a decrease in pneumonia, sepsis, and bacteremia.51 One proposed mechanism by which enteral nutrients may be beneficial is via prevention or reduction of increased intestinal permeability. Glutamine, in particular, has been suggested as an important nutritional supplement with beneficial effects related to intestinal permeability.52 Arginine is a semiessential amino acid that is important for T-cell function and wound healing. Endogenous production is insufficient during periods of metabolic stress (such as illness) and exogenous supplementation is required for maximal function of the immune system. It also is a powerful secretagogue, increasing the production of growth hormone, prolactin, somatostatin, insulin, and glucagon. Additionally, arginine is the chief precursor of nitric oxide and has been shown to increase protein synthesis and improve wound healing. It is the association with nitric oxide production that has led to speculation that arginine may enhance the systemic inflammatory response and therefore be potentially harmful, particularly in the septic patient.53 Sepsis increases levels of inducible nitric oxide synthetase (iNOS). Arginine is a substrate for iNOS and in its presence, arginine combines with molecular oxygen to produce citrulline and nitric oxide. The resulting nitric oxide could have numerous adverse effects in sepsis including vasodilation, cardiac dysfunction, and direct cytotoxic injury by generating potent reactive oxygen species. Increased mortality has been demonstrated in some critically ill septic patients when receiving an immune-enhancing diet, and arginine has been implicated as the causative agent.53 However, Ochoa and others have examined arginine metabolism in trauma patients and demonstrated induction of systemic arginase 1, an enzyme that shunts arginine away from the iNOS pathway.54 Although increased arginine at the systemic level does not appear to be problematic for trauma patients, its effects at the gut level are largely unknown.
Although traditional enteral products contain a high proportion of omega-6 PUFAs, diets with a low omega-6 PUFA and high omega-3 PUFA content more favorably alter the fatty acid composition of membrane phospholipids toward reduced inflammation. Finally, nucleotides (purines and pyrimidines) are needed for DNA and RNA synthesis and may be necessary in stressed states to maintain rapid cell proliferation and responsiveness. In the setting of increased demand, most tissues can increase intracellular de novo synthesis of nucleotides. Lymphocytes, macrophages, and enterocytes, however, rely on increased salvage from the extracellular pool that may be depleted during stress.
Enteral Glutamine during Shock Resuscitation
Shock patients are generally not given enteral nutrition. Although there is controversy over the safety of feeding the hypoperfused small bowel, evidence supports the feasibility of enteral nutrition in this setting.55 An alternative concept that we have studied in the laboratory and then pursued clinically is enteral administration of glutamine in the setting of shock.56 There are several reasons why this would be beneficial. First, intraluminal glutamine infusion reverses shock-induced splanchnic vasoconstriction. Second, glutamine is a preferred fuel source and promotes protein synthesis in the gut mucosa. Glutamine is also a preferred fuel for lymphocytes and is a precursor for glutathione and nucleotides. Glutathione protects against oxidant stress and nucleotides are required for rapid cellular proliferation of enterocytes and lymphocytes under stressful conditions. Third, glutamine induces a variety of protective mechanisms. Glutamine protects against oxidant and cytokine-induced apoptosis.57 Glutamine has also been shown to induce antioxidant enzymes (e.g., heat shock protein and heme-oxgenase-1). In our rodent gut IR model, we recently showed that intraluminal glutamine provides protection via a novel molecular mechanism of activating the anti-inflammatory transcription factor peroxisome proliferator activator receptor gamma (PPARγ).56 Of note, enteral glutamine favorably modulates SIRS. In a well-established model in which manipulation of the small bowel initiates local gut inflammation and dysfunction that ultimately causes remote lung inflammation and dysfunction, pretreatment with oral glutamine abrogates both local and remote events.58 Finally, glutamine plays a crucial regulatory role in enterocyte proliferation, which restores villous surface area. This is critical in restoring gut digestive and absorptive capacity, and the ability to tolerate enteral nutrition.
Enteral Glutamine Has Been Used in Critically Ill Patients
Of the additives in IEDs, enteral glutamine has been the most tested as monotherapy in critically ill patients. It has proven to be a safe, inexpensive intervention. In recent years, there have been eight published PRCTs that tested high-dose (0.3–0.5 g/kg) enteral glutamine in critically ill patients, the majority demonstrating improved clinical outcomes (principally decreased infection). Additionally, findings associated with enteral glutamine were decreases in (a) urinary lactulose/mannitol ratios, (b) serum diamine oxidase levels, (c) circulating endotoxin levels, and (d) gram-negative bacteremias, all of which suggest that glutamine is achieving these benefits through a gut-specific mechanism.
Because gastroparesis and ileus are commonly seen postoperatively and following resuscitation, and because they can complicate initiation of enteral feeding, agents to restore motility have been sought. Evaluation of such prokinetic agents is difficult because it is not enough to just stimulate contractions, but contractions at adjacent sites must be coordinated in order for normal digestion, absorption, and transit to take place. Coordinated contractions are under the control of hormonal and neural, both central and peripheral, pathways and it is these pathways that are affected by the cytokines and other mediators that are upregulated following a traumatic insult. Prokinetic strategies are aimed at either blocking these mediators or overriding them by stimulating normal pathways.
Agents such as erythromycin that act on receptors for motilin, the naturally occurring hormone responsible in part for regulating normal GI motility, have been shown to enhance gastric emptying and intestinal transit in animal models and in some clinical trials. Although clinical studies have documented their effectiveness in promoting gastric emptying their effectiveness in reducing postoperative ileus has been disappointing.59 A promising new peptide, ghrelin, has been shown in a rodent model to not only accelerate gastric emptying and small intestinal transit in unoperated animals but also reverse postoperative gastric ileus.60 Clinical trials examining the efficacy in postoperative and critically injured patients have yet to be performed. A recent Cochrane review of systemic acting prokinetic agents to treat postoperative ileus after abdominal surgery failed to recommend any of the currently available agents.61 Erythromycin showed uniform absence of effect while there was insufficient evidence to recommend cholecystokinin-like drugs, dopamine-antagonists, propanolol, or vasopressin. Most trials had small sample size and inadequate reporting of methods to draw meaningful conclusions.
One of the major transmitters within the enteric nervous system is serotonin. By acting at various serotonin receptors, serotonin can either enhance or inhibit intestinal contractions and transit. Although studies were never overwhelmingly convincing or consistent that serotonin antagonists enhanced motility, a few agents have been used in clinical situations. Side effects, however, have resulted in their being removed from the market. This may be an area for future research.
The cycle of organ hypoperfusion during shock followed by reperfusion during resuscitation results in the formation of detrimental reactive oxygen species. Thus, it is logical to propose that administration of antioxidants could prove beneficial. In many animal models, administration of agents such as superoxide dismutase, ethyl pyruvate, and melatonin limit damage induced by ischemia/reperfusion.29 In a recent animal study, administration of alpha-melanocyte-stimulating hormone preserved both the function and the structural integrity of the intestine following mesenteric ischemia/reperfusion.29
Clinically, antioxidant replacement strategies have demonstrated overall reduction in mortality and specific end-organ protection. A randomized, prospective trial of antioxidant supplementation with vitamins C and E to critically ill surgical patients, primarily trauma patients, demonstrated a significant reduction in organ failure.62
Likewise, Collier et al. demonstrated a significant risk reduction in mortality in severely injured patients who received high-dose antioxidants compared to historical controls.63 A systemic review of aggregated clinical trials in critically ill patients demonstrated an overall reduction in mortality with antioxidant supplementation.64 After subgroup analysis, selenium appeared to be the predominant antioxidant responsible for the positive effects.
The REDOX trial is a large prospective, randomized, double blinded multicenter trial currently in progress that is designed to evaluate mortality in critically ill patients with evidence of hypoperfusion receiving supplementation with antioxidants alone, glutamine alone, or a combination of glutamine and antioxidants. Results of the phase I dose-escalating study failed to show any adverse effect on organ function from the nutrients but did show a reduction in markers of oxidative stress, greater preservation of glutathione levels, and an improvement in mitochondrial function.65 This important study should provide definitive data on the efficacy of glutamine and antioxidant supplementation in critically ill patients.
Probiotics and Prebiotics
A probiotic is defined as a live microbial feed supplement that improves the host’s intestinal microbial balance. Commonly utilized probiotics include lactobacilli, bifidobacteria, and saccharomyces. A prebiotic is defined as a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of specific bacteria in the colon. Probiotics are usually nondigestible oligosaccharides. The most extensively studied are the fructooligosaccharides (FOS) such as oligofructose. FOS are fermented in the colon, which promotes the proliferation of bifidobacteria with a reduction in clostridia and fusobacteria. Manipulation of the colonic microflora may reduce the incidence of enteral nutrition-associated diarrhea by suppressing enteropathogens.
Clinically, enteric formulas containing probiotics have shown a significant reduction in a variety of postoperative complications. A recent randomized clinical trials have demonstrated a significant decrease in postoperative infections in patients who have undergone major abdominal surgery and received postoperative enteral formulas containing probiotics.66
Results of recent clinical trials employing probiotics, prebiotics, or a combination, in critically ill and burn patients, however, have been disappointing.67
Synbiotics are a combination of pro- and prebiotics, and the combination is postulated to improve the survival of the probiotic organism by having a specific substrate readily available for probiotic fermentation. In a study in trauma patients receiving symbiotic supplementation had decreased intestinal permeability and lower combined infection rates than those receiving other immunomodulating formulas. The authors postulated that the presence of synbiotics in the GI tract reduced pathogenic flora and thereby decreased the incidence of pneumonia.68 These findings represent the immunomodulatory potential for synbiotic enteral formulas in the setting of severe systemic inflammation. However, a meta-analysis failed to demonstrate sufficient evidence to recommend prebiotic, probiotics, or synbiotics to critically ill patients.69
In summary, ACS and nonocclusive bowel necrosis are two extreme outcomes of gut dysfunction that can directly contribute to MOF and mortality. Newer modalities to monitor and modulate gut dysfunction need to be developed and appropriate measures taken to reduce its occurrence. The use gut-specific resuscitants, opioid antagonists, alternative sedatives, and early use of enteral nutrients with select supplements such as glutamine or antioxidants, may all assist in preventing the untoward effects of gut dysfunction in critically injured patients.