Rosemary A. Kozar and Frederick A. Moore
For patients who survive the first 48 hours of intensive care, sepsis-related multiple organ failure (MOF) is the leading cause for prolonged intensive care unit (ICU) stays and deaths. Several lines of clinical evidence convincingly link gut injury and subsequent dysfunction to MOF.1 First, patients who experience persistent gut hypoperfusion after resuscitation are at high risk for abdominal compartment syndrome (ACS), MOF, and death.2 Second, epidemiologic studies have consistently shown that the normally sterile proximal gut becomes heavily colonized with a variety of organisms. These same organisms have been identified to be pathogens that cause late nosocomial infections. Third, gut-specific therapies (selective gut decontamination, early enteral nutrition, and most recently immune-enhancing enteral diets [IEDs]) have been shown to reduce these nosocomial infections.3–5 The purpose of this chapter will be to first provide a brief overview of why critically injured trauma patients develop gut dysfunction and how gut dysfunction contributes to adverse outcomes. The discussion will then focus on the pathogenesis and clinical monitoring of specific gut dysfunctions. Based on this information, potential therapeutic strategies to prevent and/or treat gut dysfunction to enhance patient outcome will be discussed.
HOW GUT DYSFUNCTION CONTRIBUTES TO ADVERSE PATIENT OUTCOME
Multiple Organ Failure
MOF occurs as a result of a dysfunctional inflammatory response and in two different patterns (i.e., early vs. late) (see Chapter 55). After a traumatic insult, patients are resuscitated into a state of systemic hyperinflammation, now referred to as the systemic inflammatory response syndrome (SIRS). The intensity of SIRS is dependent upon (1) inherent host factors, (2) the degree of shock, and (3) the amount of tissue injured. Of the three, shock is the predominant factor.6 Mild-to-moderate SIRS is most likely beneficial, whereas severe SIRS can result in early MOF. As time proceeds, negative feedback systems downregulate certain aspects of acute SIRS to restore homeostasis and limit potential autodestructive inflammation (see Chapter 67). This latter response has been dubbed the compensatory anti-inflammatory response syndrome (CARS) and results in delayed immunosuppression.7 Mild-to-moderate delayed immunosuppression is clinically insignificant, but severe immunosuppression is associated with late infections. These late infections can worsen early MOF or precipitate late MOF. Over the last decade, late CARS was characterized to include (a) apoptotic loss of intestinal lymphocytes and epithelial cells, (b) PMN and monocytic deactivation, (c) anergy characterized by suppressed T-cell proliferative responses, and (d) a shift from a TH1 to a TH2 phenotype.8,9
More recently, it has been hypothesized that SIRS and CARS are present concurrently following injury. With time though, SIRS ceases to exist and CARS is the predominant force. Debate exists over whether CARS is truly a compensatory response. In the laboratory, CARS does not occur unless preceded by SIRS.10 However, although the intensity of SIRS predicts early adverse outcomes, it does not predict late adverse outcome. CARS appears to occur in response to the injury (not to SIRS) (Fig. 58-1). This is consistent with clinical observations that early MOF and late MOF have different early clinical predictors and biomarkers.11 Additionally, shock insults have been shown to initiate simultaneous proinflammation and anti-inflammation.12 We believe that the balance of proinflammation versus anti-inflammation determine clinical trajectory.13 We still see shock-induced severe SIRS that causes fuminant proinflammatory MOF and death. We believe patients are genetically preprogramed for this trajectory or alternatively have been exposed to appropriately timed second hits. Fortunately, most patients survive early SIRS but some appear to be protected (i.e., preconditioned) against further insult and recover while others develop unbalanced anti-inflammation. They progress into severe CARS associated with apoptosis and depression in adaptive immunity. This sets the stage for immunoparalysis, poor nutrition status, impaired wound healing, recurrent nosocomial infections, late MOF, and an indolent death. The gut is believed to be both an instigator and victim of this dysfunctional inflammatory response.1 Shock is associated with obligatory gut ischemia. With resuscitation, reperfusion results in a local inflammatory response that can injure the gut, setting the stage for ACS. Additionally, the reperfused gut releases mediators, including proteins such as cytokines and lipid such as those derived from phospholipase A2, via the mesenteric lymph, that amplify SIRS.14 Moreover, for patients undergoing laparotomy, bowel manipulation and anesthetics cause further gut dysfunction.15 Finally, standard ICU therapies (morphine, H2-antagonists, catecholamines, and broad-spectrum antibiotics) and intentional disuse (use of total parenteral nutrition rather than enteral nutrition) promote additional gut dysfunction. The end result is progressive dysfunction (Table 58-1) characterized by gastroesophageal reflux (GER), gastroparesis, duodenogastric reflux, gastric alkalinization, decreased mucosal perfusion, impaired intestinal transit, impaired absorptive capacity, increased permeability, decreased mucosal immunity, increased colonization, and gut edema. As time proceeds, the normally sterile upper gut becomes heavily colonized, mucosal permeability increases, and local mucosal immunity decreases. Intraluminal contents (e.g., bacteria and their toxic products) then disseminate by aspiration or translocation to cause systemic sepsis, which then promotes further gut dysfunction.
FIGURE 58-1 Role of compensatory anti-inflammatory response syndrome (CARS) after injury.
TABLE 58-1 Progressive Gut Dysfunction in Critically Injured Patients
Abdominal Compartment Syndrome
Intra-abdominal pressure (IAP) is monitored by urinary bladder pressure measurements. When these pressures exceed 25 cm H2O, extra-abdominal organ functions may become impaired (see Chapter 41). By definition, this is ACS. There are two types of ACS: primary (1°) and secondary (2°).2 Primary ACS occurs in patients with abdominal injuries that typically have undergone “damage control” laparotomy (where obvious bleeding is rapidly controlled and the abdomen is packed) and have entered the “bloody viscus cycle” of coagulopathy, acidosis, and hypothermia, which promotes ongoing bleeding (see Chapter 61). Accumulation of blood, worsening bowel edema from resuscitation, and the presence of intra-abdominal packs all contribute to increasing IAP that causes ACS. Secondary ACS occurs when extra-abdominal bleeding (e.g., mangled extremity or pulmonary hilar gun shot wound) requires massive resuscitation that causes bowel edema, thus increasing IAP and eventually ACS. Markedly elevated IAP also decreases gut perfusion that may adversely affect a variety of gut functions. Clinical studies have clearly documented the poor outcome of patients developing ACS and the frequent association of ACS and MOF.16
Nonocclusive Small Bowel Necrosis (NOBN)
NOBN is a relatively rare, but frequently fatal, entity that is associated with the use of enteral nutrition in critically ill patients.17 Patients typically present with complaints of cramping abdominal pain and progressive abdominal distention associated with SIRS. Computed tomography (CT) may reveal pneumatosis intestinalis or thickened dilated bowel in more advanced stages. For those who progress and require exploratory celiotomy, extensive patchy necrosis of the small bowel is found. Pathologic analysis of the resected specimens yields a spectrum of findings from acute inflammation with mucosal ulceration to transmural necrosis and multiple perforations. The consistent association with enteral nutrition indicates that inappropriate administration of nutrients into a dysfunctional gut plays a pathogenic role. There are three popular hypotheses (Fig. 58-2).17 First, metabolically compromised enterocytes become ATP depleted as a result of increased energy demands induced by the absorption of intraluminal nutrients, leading to hypoperfusion and subsequent NOBN.18 The second hypothesis is that when nutrients are delivered into the dysmotile small bowel, fluid shifts into the lumen as a result of the presence of hyperosmolar enteral formula, leading to abdominal distention, which when severe progresses to NOBN. Third, bacterial colonization leads to intraluminal toxin accumulation, which can result in mucosal injury and inflammation, and if significant, NOBN.
FIGURE 58-2 Proposed pathogenesis of nonocclusive bowel necrosis (NOBN).
SPECIFIC GUT DYSFUNCTIONS
The gut is a complex organ that performs a variety of functions, some of which are vital for ultimate survival of critically ill patients (e.g., barrier function, immune competence, and metabolic regulation). Unfortunately, gut dysfunction in critically injured patients is poorly characterized and routine monitoring of gut function is crude. Currently, the best parameter of gut function is tolerance to enteral nutrition (see Chapter 66). For several reasons, this is an attractive parameter to monitor and potentially modulate. First, tolerance to enteral nutrition requires integrative gut functioning (e.g., secretion, digestion, motility, and absorption). Second, locally administered nutrients may improve perfusion and optimize the recovery of other vital gut functions (e.g., motility, barrier function, mucosal immunity). Third, tolerance correlates with patient outcome and improving tolerance will likely improve patient outcome. Fourth, refined therapeutic interventions to improve enteral nutrition tolerance will lessen the need to use parenteral nutrition and decrease its associated complications (see Chapter 61).
Parameters of gut dysfunctions are outlined in Table 58-1 and are likely contributors to intolerance to enteral nutrition. A brief overview of the pathogenesis of each of these dysfunctions and how they are monitored clinically will be reviewed to provide the rationale for proposed therapeutic strategies to improve tolerance to enteral nutrition.
GER is an important contributing factor to aspiration of enteral feedings, which is a common cause of pneumonia in ICU patients. Reflux will occur whenever the pressure difference between the stomach and esophagus is great enough to overcome the resistance offered by the lower esophageal sphincter. Increases in gastric pressure can be due to distention with fluids and failure of the stomach to relax to accommodate fluid. Decreases in resistance at the lower esophageal sphincter can be due to relaxation of the sphincter muscle in response to many stimuli including mediators released during injury and resuscitation. Additional contributing factors include (a) forced supine position, (b) the presence of a nasoenteric tube, (c) hyperglycemia, and (d) morphine.
Commonly used clinical monitors include laboratory testing for presence of glucose in tracheal secretions or by observing blue food dye, which has been added to the enteral formula in tracheal aspirates. Detection of glucose lacks specificity. False-positive results can occur with high serum glucose levels or presence of blood in tracheal secretions. The use of blue food dye is poorly standardized and lacks sensitivity. More importantly, however, several reports document absorption of blue food dye in critically ill patients that is associated with death. This is presumably due to a toxic effect that blue food dye has on mitochondrial function. A recent consensus conference recommended that both these techniques be abandoned.19 Unfortunately, there are no simple monitors of GER other than observing for vomiting or regurgitation, which are not very sensitive. The head of the bed should be elevated 30° to 45° to decrease the risk that when GER occurs that it is less likely to result in pulmonary aspiration (see Chapter 60). Gastric residual volumes (GRVs) should be monitored with the presumption that a distended stomach will lead to higher volume GER (see Chapter 66).
Gastroparesis and Duodenogastric Reflux
Gastroparesis is common in ICU patients and predisposes to increased duodenogastric reflux (a potential contributing factor for gastric alkalinization) and GER (a contributing factor for aspiration). The mechanisms responsible for gastroparesis in critical illness have not been well studied. Potential factors include (a) medications (e.g., morphine, dopamine), (b) sepsis mediators (e.g., nitric oxide), (c) hyperglycemia, and (d) increased intracranial pressure.
The common clinical monitors for gastroparesis are intermittent measurement of GRVs when feeding into the stomach or measurement of continuous suction nasogastric tube output when feeding postpyloric. The practice of using GRV is poorly standardized and is a major obstacle to advancing the rate of enteral nutrition.20 GRVs appear to correlate poorly with gastric function and GRVs <200 cc generally are well tolerated. GRVs of 200–500 cc should prompt careful clinical assessment and the initiation of a prokinetic agent. With GRVs >500 cc, enteral nutrition should be stopped. After clinical assessment excludes small bowel ileus or obstruction, placement of a postligament of Treitz feeding tube should be considered (see Chapter 66).
Although not well studied in trauma specifically, critically ill patients are known to have a high incidence of gastroduodenal reflux. In a study of antral, duodenal, and proximal jejunal motility, Tournadre et al. demonstrated that postoperative gastroparesis occurs after major abdominal surgery and is associated with discoordinated duodenal contractions of which 20% migrated in a retrograde fashion.21 Heyland et al. administered radio-labeled enteral formulas through a standard postpyloric nasoenteric feeding tube in ventilated ICU patients and documented an 80% rate of radio isotope label reflux into the stomach, 25% reflux rate into the esophagus, and a 4% reflux rate into the lung.22 Finally, Wilmer et al. reported monitoring bile reflux in the esophagus of ventilated ICU patients using a fiberoptic spectrophotometer that detects and quantifies bilirubin concentration.23 Endoscopy was performed and documented erosive esophagitis in half of the patients of which 15% had pathologic acid reflux and 100% had pathologic bile reflux. These studies provide convincing evidence that duodenogastric reflux is a common event in ICU patients.
The stomach, through secretion of hydrochloric acid, normally has a pH below 4.0. This acid environment has been correlated with the relatively low bacterial counts found in the stomach. Reviews of several studies have shown that alkalinization of the stomach through the use of antacids, H2 antagonists, and proton pump inhibitors results in gastric colonization by bacteria not normally found in the stomach; and several, but not all, studies have shown that gastric colonization predispose patients to ventilator-associated pneumonia,24 and can increase the risk of community-acquired Clostridium difficile–associated disease.25
Several animal studies conducted recently by our group have shown that both lipopolysaccharide administration and mesenteric ischemia/reperfusion result in the gastric accumulation of an alkaline fluid.26This most likely results from a decrease in gastric acid secretion with continued gastric bicarbonate secretion and the reflux of duodenal contents into the stomach. Even more recently, we have reported that the pH of gastric contents in trauma patients also is elevated, possibly due to similar events.27 Thus, even without the administration of antacids or inhibitors of acid secretion, gastric alkalinization and bacterial colonization of the stomach are likely in this group of patients. When this is combined with the gastroparesis often seen in these patients (see above), it is easy to envision the stomach becoming a major source of bacteria for ventilator-assisted pneumonia and perhaps translocation to other organs.
Impaired Mucosal Perfusion
Shock results in disproportionate splanchnic vasoconstriction. The gut mucosa appears to be especially vulnerable to injury during hypoperfusion. The arterioles and venules in the small bowel mucosal villi form “hairpin loops.” This anatomic arrangement improves absorptive function, but it also permits a countercurrent exchange of oxygen from the arterioles to the venules in the proximal villus. Under hypoperfused conditions, a proximal “steal” of oxygen is believed to reduce the pO2 at the tip of the villi to zero. The gut mucosa is further injured during reperfusion by reactive oxygen metabolites and recruitment of activated neutrophils (see Chapter 67). This mucosal injury, however, appears to quickly repair. Mucosal blood flow does not always, though, return to baseline with resuscitation and this is in part due to defective vasorelaxation. The gut mucosa is also vulnerable to recurrent episodes of hypoperfusion from ACS, sepsis, and use of vasoactive drugs. Whether recurrent hypoperfusion results in additional ischemia/reperfusion injury is not known, but it is reasonable to assume that hypoperfusion would decrease gut nutrient absorption and render the patient more susceptible to NOBN.
Monitoring gastric mucosal perfusion in the clinical setting can be done by gastric tonometry. With hypoperfusion, intramucosal CO2 increases due to insufficient clearance of CO2 produced by aerobic metabolism or due to buffering of extra hydrogen ions produced in anaerobic metabolism. As intramucosal CO2 accumulates, it diffuses into the lumen of the stomach. The tonometer measures the CO2 that equilibrates in a saline filled balloon (newer monitor uses air filled balloon) that sits in the stomach. This is the regional CO2 tension (PrCO2) and is assumed to equal the intramucosal CO2 tension. Using this measured PrCO2 and assuming that arterial bicarbonate equals intramucosal bicarbonate, the intramucosal pH (pHi) is calculated by using the Henderson–Hasselbalch equation. Numerous studies have documented that a persistently low pHi (or high PrCO2 level) despite effective systemic resuscitation predicts adverse outcomes and that attempts to resuscitate to correct a low pHi do not favorably influence mortality.28 Unfortunately, alternative resuscitation strategies have not been able to increase pHi to improve outcome and thus this monitoring tool is in search of a novel application (see Chapter 60).
Impaired Intestinal Transit
Laboratory models of shock, bowel manipulation, and sepsis demonstrate that small bowel transit is impaired.29 This impairment in turn is expressed as a decrease in the number and/or force of contractions, or as an abnormal pattern of contractions. Although the results in animal models are convincing, surprisingly, clinical studies indicate that small bowel motility and transit are more often than not well preserved after major elective and emergency laparotomies.30 This observation coupled with the observation that small bowel absorption of simple nutrients is relatively intact provided the rationale for early jejunal feeding.
Clinical studies have documented that the majority of critically ill patients tolerate early jejunal feeding.31 In a recent study, severely injured patients had jejunal manometers and feeding tubes placed at secondary laparotomy.30Surprisingly, 50% had fasting patterns of motility that included components of the normal migrating motor complexes (MMCs). These patients tolerated advancements of enteral nutrition without problems. The other 50% who did not have fasting MMCs did not tolerate early advancement of enteral nutrition. Of note, none of the patients converted to a normal-fed pattern of motility once they reached full-dose enteral feeding. This could be due to infusion of caloric loads insufficient to bring about conversion. On the other hand, the failure to develop fed activity, a pattern of motility promoting mixing and absorption, might explain why diarrhea is a common problem in this patient group.
Although manometry can be used to monitor motility, it is not practical. Unfortunately, simpler indicators of motility such as the presence of bowel sounds or the passing of flatus are unreliable. Other minimally invasive methods to monitor transit are needed. Contrast studies through the feeding tubes are relatively simple, but not validated.
Impaired Gut Absorptive Capacity (GAC)
Small bowel absorption of glucose and amino acids is depressed after trauma and sepsis. Multiple factors have been identified including (a) cytosolic calcium overload, (b) ATP depletion, (c) diminished brush border enzyme activity, (d) decreased carrier activity, (e) decreased absorptive epithelial surface area, and (f) hypoalbuminemia. In a recent animal study, intestinal ischemia/reperfusion caused significant mucosal injury and significant depletion of mucosal ATP.18 When this was combined with exposure of the bowel to a nonmetabolizable nutrient, the damage and ATP depletion were more severe and the absorption of glucose was impaired. In contrast, exposure of the bowel to metabolizable nutrients preserved ATP levels, protected against mucosal injury, and improved GAC.
The clinical significance of these observations remains unclear because most patients tolerate enteral nutrition when delivered into the small bowel. However, decreased GAC may be a cause for diarrhea and may explain why patients commonly experience diarrhea with reinstitution of enteral nutrition after prolonged bowel rest. Unfortunately, there are no easily performed clinical monitors for GAC. D-Xylose absorption is clinically available but is used most frequently to diagnose chronic malabsorption.
Diarrhea may be indicative of depressed GAC, but there are other causes for diarrhea in the critically ill including impaired transit, bacterial overgrowth (e.g., presence of C. difficile), contaminated enteral formulas, abnormal colonic responses to enteral nutrition (e.g., ascending colon secretion rather than absorption, or impaired distal colon motor activity), and administration of drugs, which contain sorbitol (e.g., medication elixirs) or magnesium (e.g., antacids).
Increased Gut Permeability
Enhanced paracellular permeability represents a type of barrier dysfunction that allows increased passage between viable cells and may induce an inflammatory cascade. The major components of the epithelial barrier are tight junctions, which bind cells together and serve as the gateways to the underlying paracellular spaces. The integrity of the tight junctions is modulated by the actin cytoskeleton. Under conditions of ATP depletion, such as would occur during shock, disruption of the actin cytoskeleton with consequent opening of the tight junctions and loss of the integrity of the permeability barrier can occur.18
Intestinal barrier dysfunction has been suggested as a means by which inflammatory cytokines can lead to the SIRS and MOF. Additionally, increased intestinal permeability has been documented in high-risk patients after burns, sepsis, and shock, in most but not all studies.32
Decreased Gut Mucosal Immunity
During periods of intestinal disuse, critically injured patients are subject to a reduction in gut mucosal immunity. Lack of enteral stimulation (such as during starvation or with use of parenteral nutrition) quickly leads to lack of immunologic protection by mucosal-associated lymphoid tissue (MALT), which normally provides protection for both the gastrointestinal (GI) and respiratory tracts against microbial flora and infectious pathogens. Kudsk has demonstrated a link between intestinal IgA, intestinal cytokine production, and the vascular endothelium of the GI tract. With enteral stimulation, IL-4 and IL-10 production from the lamina propria of the small intestine stimulate production of IgA on the mucosal surface and inhibit intracellular adhesion molecule-1 (ICAM-1) of the vascular endothelium and subsequent neutrophil-associated inflammation and injury.33
Increased Gut Colonization
With progressive gut dysfunction, the normally sterile upper GI tract becomes colonized with organisms that become pathogens in nosocomial infections. Gastric alkalinization, paralytic ileus, loss of colonization resistance due to broad-spectrum antibiotics, and decreased local gut immunity have all been proposed mechanisms by which the upper GI tract becomes colonized. In an effort to decrease the incidence of infectious complications, selective digestive decontamination (SDD) has been proposed. SDD generally consists of topical nonabsorbed antibiotics along with a short course of parenteral antibiotics. There have been numerous clinical trials and at least six meta-analyses addressing this practice. Most studies have examined the incidence of ventilator-associated pneumonias and mortality and, in general, have demonstrated a decrease in both. Despite rather impressive results of these trials, most of which have been performed in Europe, intensivists in the United States have generally avoided use of SDD due to reports of antimicrobial resistance.34
Aggressive fluid resuscitation can result in significant bowel edema and altered intestinal function. Both in the laboratory and clinically, significant bowel edema following resuscitation can lead to elevated intra-abdominal pressure and potentially to ACS. The precise mechanisms by which bowel edema adversely effects bowel function, however, have not been fully elucidated. Laboratory investigations by Moore-Olufemi et al. have shown that bowel edema alone (not associated with gut ischemia/reperfusion or hemorrhagic shock) is associated with impaired intestinal transit and this can be reversed with enteral feeding.35 A number of clinical studies, even though not in resuscitated trauma patients, have demonstrated the benefit of fluid restriction on postoperative bowel function and complications.36
STRATEGIES TO IMPROVE GUT DYSFUNCTION
Gut-specific Resuscitation and Monitoring for Abdominal Compartment Syndrome
If shock-induced gut hypoperfusion is assumed to be a prime-inciting event for gut dysfunction, then resuscitation protocols need to be devised to optimize early gut perfusion and prevent reperfusion injury. Traditional resuscitation is aimed at optimizing systemic perfusion, and the standard of care is to first administer 2 L of isotonic crystalloids and then add packed red blood cells to the regimen at a ratio of 3 to 1 crystalloid to blood (see Chapter 13). Although this approach is effective in most patients, it is associated with problematic bowel edema in patients at high risk for MOF. As edema worsens and intra-abdominal pressure increases, bowel perfusion becomes impaired, setting up a vicious cycle that leads to ACS (Fig. 58-3).37 The hypovolemic trauma patient is volume loaded with crystalloid infusions that decrease intravascular colloid oncotic pressure, increase hydrostatic pressure, and increase capillary leak. Although this intervention can be beneficial in increasing cardiac output through increased preload, it can also have a detrimental effect through increased edema of the reperfused gut. Bowel edema causes intra-abdominal pressure to increase, which impairs venous return and may further worsen bowel edema. As abdominal pressures increase, cardiac output is impeded and patients can enter the futile crystalloid preloading cycle, during which further crystalloid infusion worsens bowel edema, and increases intra-abdominal pressure until full-blown ACS has developed.
FIGURE 58-3 Crystalloid viscious cycle leading to abdominal compartment syndrome. ACS, abdominal compartment syndrome; CO, cardiac output; IAP, intra-abdominal pressure; IV, intravenous; UO, urine output.
Intra-abdominal pressures should be measured routinely in patients in whom significant resuscitation is anticipated as ACS can be predicted early in at-risk patients.2 A high index of suspicion and knowledge of these predictors is warranted. In the past, surgeons have not decompressed the abdomen until clear signs of organ dysfunction were present (e.g., decreased urine output, decreased PaO2/FIO2 ratio, decreased cardiac output despite volume loading) in part because of fear of creating an open abdomen with consequent need for planned ventral hernia and delayed reconstruction (see Chapter 41). However, with the advent of vacuum-assisted wound closure of open abdomens this long-term problem is unlikely. As IAP approaches 25 mm Hg, the abdomen is on the steep portion of its compliance curve and additional fluid pushes IAP into pathologic ranges. Thus, based on prediction models,2 those patients who meet defined high-risk criteria and are requiring ongoing aggressive resuscitation may be considered for a “presumptive” decompressive laparotomy. In fact, a recent prospective study demonstrated that early decompression in at-risk patients reduced mortality from intra-abdominal hypertension/ACS.38
Alternative resuscitation strategies are under investigation, which may lessen bowel edema and therefore reduce the incidence of ACS and include the earlier use of blood products and more aggressive use of coagulation products.39
Analgesics and Sedatives
There are three types of opioid receptors, δ, κ, μ, and all have been identified as having GI side effects including delayed gastric emptying and delayed transit time in both the small bowel and colon. One major cause of ileus is stress-related stimulation of opioid receptors. In animal models and humans, both endogenously released and exogenously administered opioids act on receptors in both the central nervous system and in the enteric nervous system to alter intestinal function, especially motility. Although actions at both the central nervous system and enteric nervous system are involved, recent studies indicate that if opioid actions at the enteric nervous system are blocked, ileus may be prevented or resolved without interfering with the desired opioid actions on the central nervous system and other systems. An investigational opioid receptor antagonist that has limited systemic absorption after oral administration and minimal access to the central nervous system has been shown to speed recovery of bowel function and shorten the duration of hospitalization after surgery.40 There is also a peripherally acting μ-receptor antagonist, alvimopan, that has recently been shown in a prospective, randomized controlled trial to accelerate time to recovery of GI function in patients undergoing elective major abdominal surgery.41 μ-Receptor antagonists are attractive agents for postoperative patients in that they are peripherally acting (gut specific), thereby maintaining centrally mediated pain reduction. A recent Cochrane review on μ-opioid antagonists for opioid-induced bowel dysfunction concluded that both alvimopan and methylnaltrexone were effective in reversing increased transit time and constipation. Additionally, alvimopan is safe and efficacious in treating postoperative ileus.42 However, long-term data are lacking and further studies are indicated. Both these agents need to be studied in patients at high risk for postoperative bowel dysfunction, particularly patients who have undergone major resuscitation from shock.
Ketamine, an antagonist of the N-methyl-D-aspartate receptor, combines both analgesic and sedative effects and may represent an alternative to benzodiazepines for sedation and opioids for pain control in ICU patients. There are reports in burn patients of the opiate-sparing effect of ketamine minimizing prolonged gut dysfunction and ileus.43 Additionally, both proinflammatory cytokines and mediators have been suppressed in laboratory models of sepsis following ketamine administration.44
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 Chapter 66). 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.4Similar 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.50High-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.61Erythromycin 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.
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