Chapter 58: Gastrointestinal Failure

For patients who survive the first 48 hours of intensive care, multiple organ failure (MOF) is the leading cause of death among patients in the intensive care unit (ICU) (see Chapter 61). 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), which can lead to early MOF, and even death.^2,3 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 after the ischemia–reperfusion insult weakens the gut barriers.^{4,5,6,7,8,9,10,11,12} 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.^{13,14,15,16,17,18,19} 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 overall morbidity and mortality. 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.

Multiple Organ Failure

Multiple organ failure results from a dysfunctional, hyperinflammatory response producing two distinct patterns (ie, early vs late) (see Chapter 55). Soon after a traumatic insult, patients are found to be in a state of systemic hyperinflammation, now referred to as the systemic inflammatory response syndrome (SIRS).^20,21,22 The intensity of SIRS is dependent upon (1) innate host factors, (2) the degree of shock, and (3) the amount of tissue injured. Of the three, shock is the predominant factor that produces a maladaptive, over exuberant SIRS response.^23,24 Mild-to-moderate SIRS is most likely beneficial, whereas severe SIRS can result in early organ failure and death. As time proceeds, negative feedback systems down regulate certain aspects of acute SIRS to restore homeostasis and limit potential auto-destructive inflammation (see Chapter 61).

Reiterated in a recently published Glue Grant Study by Tompkins et al, they took blood samples of 167 patients at varying time intervals to better understand the genomic make-up after severe trauma or burn using microarray analysis. They referred to what they found as “genomic storm” in that “circulating white cells of the 167 patients studied when compared with those of the 35 normal volunteers, more than 80% of the WBC genes changed significantly.²⁵ Tompkins et al further described the genomic patterns of complicated patients (thus that got MOF or nosocomial infections) as demonstrating higher levels of deviation from normal gene expression, and these changes quantitatively persisted longer than those same genes in the uncomplicated patients. They concluded, there were 5136 genes changed at a twofold level in the circulating WBCs of patients compared with normal volunteers. These changes were long-lasting, and in the complicated patients, more than 50% of these genes remained abnormal even at 28 days after injury.”²⁶ The question remains what drives the inflammatory response after the acute insult to potentially cause MOF or death?

All throughout these three phenotypes of MOF (SIRS/CARS/PICS) it is hypothesized that the gut can be both an instigator and victim of the characteristic dysfunctional inflammatory response.^{1,6,7,9,12,18,27,28} Shock is associated with obligatory gut ischemia leading to integral damage.⁸ With a robust resuscitation, reperfusion results in a local intense inflammatory response that can further injure the gut, setting the stage for ACS or MOF.^2,3 Additionally, the reperfused gut releases inflammatory mediators, including proteins such as cytokines and lipid such as those derived from phospholipase A2, via the mesenteric lymph, that amplify SIRS.²⁹ Moreover, for patients undergoing laparotomy, bowel manipulation and anesthetics cause further gut dysfunction.³⁰ 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 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 (eg, bacteria and their toxic products) then disseminate by aspiration or translocation to cause systemic sepsis, which then promotes further gut dysfunction.

If this dysfunction goes unchecked long enough a certain threshold is reached which propels a patient into a vicious cycle of persistent inflammatory, immunosuppressive, and catabolic state (PICS). This persistent inflammation is characterized by increased production of IL-6, a persistent acute phase response, neutrophilia with increased immature granulocyte count, anemia, lymphopenia, and, often, tachycardia.^4,5 Unfortunately, this deranged inflammatory, immunosuppressive state consumes large amount of energy derived from protein catabolism. The catabolic state gives way to the new phenotype that produces substantial lean body mass loss and proportional decrease in functional status, despite aggressive nutritional support.^31,32 It is the PICS phenotype that clinically depicts chronic critical illness (CCI—defined as requiring >14 days ICU care).^33,34,35

A patient meets PICS criteria if he or she is residing in the ICU more than 14 days with evidence of organ dysfunction and has persistent inflammation, defined by C-reactive protein (CRP) concentration greater than 150 Hg/dL and retinol binding protein concentrations less than 1 mg/dL, immunosuppression crudely defined by a total lymphocyte count less than 0.80 × 10⁹/L, and a catabolic state defined by serum albumin concentrations less than 3.0 g/dL, creatinine height index less than 80%, and weight loss more than 10% or body mass index less than 18 during the current hospitalization.^4,5 Although these clinical markers are not direct measurements of inflammation, immunosuppression, or protein catabolism, they can serve as surrogates that are readily available in most critical care settings.

We think PICS is the new phenotype that has replaced late-appearing MOF. The major challenges for this new paradigm are: (1) to identify PICS early in its course, (2) to understand its underlying pathophysiology, and (3) to initiate appropriate multimodal therapies that target specific components of the syndrome. Medical care resource consumption associated with PICS has yet to be measured, but is likely to be a large multiple of the costs associated with the short-term treatment of trauma, severe sepsis, and septic shock.³⁶ The incidence of PICS will likely increase, as our population ages and our ICU technology improves.³⁷ Characterization and management of PICS will require technologies for direct monitoring and modulation of the patient’s nutritional status and immune responses. We believe that PICS is the new horizon for surgical intensive care.

To re-emphasize, after the initial insult, there is a simultaneous SIRS/CARS response. Some patients develop severe SIRS and precede to the early MOF and fulminant early death trajectory. Modern ICUs, however, are becoming increasingly effective in preventing the full expression of this phenotype (ie, early death). Some patients rapidly recover, but most patients linger in the ICU with manageable organ dysfunctions for prolonged periods, and develop CCI. A substantial portion of these CCI patients (40–60%) exhibit ongoing protein catabolism with poor nutritional status, poor wound healing, and recurrent infections.^4,5 In addition, they have persistent low-grade inflammation, with defects in innate and adaptive immunity. We believe this is driven in large part by bone marrow dysfunction, with expansion and release of the myeloid derived suppressor cells (MDSCs).³⁸

Although expansion of the MDSC population can be explained in part by increased myelopoiesis, defects in the maturation and differentiation of this cell lineage render them ineffective at fighting infections, and are responsible for producing a persistent low level inflammatory state through cytokine secretion. Through the University of Florida, Health Sepsis and Critical Illness Research Center (UF SCIRC) we will be investigating the genomic make up of PICS, trying to predict patients at high-risk of developing PICS, elucidate the role of MDSC’s, and recommend possible interventions. With a recently awarded a P50 grant by NIGMS entitled, “PICS: A New Horizon for Surgical Critical Care” the funding will provide a strong foundation to make this achievement possible. As we believe these PICS patients are ultimately discharged to LTAC facilities, rarely rehabilitate, hardly ever return to functional life, and usually experience prolonged decline and an indolent death.^{34,36,39,40,41,42,43,44,45,46,47,48}

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°).^2,3,49,50 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 vicious cycle” of coagulopathy, acidosis, and hypothermia, which promotes ongoing bleeding (see Chapter 13). 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 (eg, mangled extremity or pulmonary hilar gunshot 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.²

Nonocclusive Small Bowel Necrosis

Nonocclusive small bowel necrosis (NOBN) is a relatively rare, but frequently fatal, entity that is associated with the use of enteral nutrition in critically ill patients.⁵¹ 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. 58-1).⁵¹ 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.⁵² 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 intestinal 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.

The gut is a complex organ that performs a variety of functions, some of which are vital for ultimate survival of critically ill patients (eg, 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 60). For several reasons, this is an attractive parameter to monitor and potentially modulate. First, tolerance to enteral nutrition requires integrative gut functioning (eg, secretion, digestion, motility, and absorption). Second, locally administered nutrients may improve perfusion and optimize the recovery of other vital gut functions (eg, 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 60).

Gut dysfunction certainly contributors to enteral feeding intolerance. Thus, 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.

Gastroesophageal Reflux

Gastroesophageal reflux 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 (1) forced supine position, (2) the presence of a nasoenteric tube, (3) hyperglycemia, and (4) 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.⁵³ 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 57). 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 (1) medications (eg, morphine, dopamine), (2) sepsis mediators (eg, nitric oxide), (3) hyperglycemia, and (4) 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.⁵⁴ GRVs appear to correlate poorly with gastric function and GRVs less than 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 more than 500 cc, enteral nutrition traditionally was stopped. After clinical assessment excludes small bowel ileus or obstruction, placement of a postligament of Treitz feeding tube should be considered (see Chapter 60). However, a study by Reignier et al, in JAMA should that not monitoring GVR and allowing patients to advance to goal tube feed rates for adequate nutritional supplementation was not inferior to checking GVR in preventing ventilator associated pneumonia.⁵⁵

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.⁵⁶ 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.⁵⁷ 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.⁵⁸ 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.

Gastric Alkalinization

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,⁵⁹ and can increase the risk of community-acquired Clostridium difficile–associated disease.⁶⁰

Several animal studies conducted by our group have shown that both lipopolysaccharide administration and mesenteric ischemia/reperfusion result in the gastric accumulation of an alkaline fluid.⁶¹ This 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.⁶² 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 61). 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.⁶³ 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 55).

Impaired Intestinal Transit

Laboratory models of shock, bowel manipulation, and sepsis demonstrate that small bowel transit is impaired.⁶⁴ 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.⁶⁵ This observation coupled with the observation that small bowel absorption of simple nutrients is relatively intact provided the rationale for early jejunal feeding (see Chapter 60).

Clinical studies have documented that the majority of critically ill patients tolerate early jejunal feeding.⁶⁶ In a recent study, severely injured patients had jejunal manometers and feeding tubes placed at secondary laparotomy.⁶⁵ Surprisingly, 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

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 an animal study, intestinal ischemia/reperfusion caused significant mucosal injury and significant depletion of mucosal ATP.⁵² 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 (such as glucose) preserved ATP levels, protected against mucosal injury, and improved gut absorptive capacity (GAC).⁶⁷

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 (eg, presence of C. difficile), contaminated enteral formulas, abnormal colonic responses to enteral nutrition (eg, ascending colon secretion rather than absorption, or impaired distal colon motor activity), and administration of drugs, which contain sorbitol (eg, medication elixirs) or magnesium (eg, 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.⁵²

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.⁶⁸

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.⁶⁹

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 concerns of inducing antimicrobial resistance.⁷⁰

Gut Edema

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.⁷¹ 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.⁷²

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 3:1 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. 58-2).⁵⁰ 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.

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.³ 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 (eg, 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 38). 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,³ 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.⁷³

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.⁷⁴

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.⁷⁵ 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.⁷⁶ 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.⁷⁷ 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.⁷⁸ Additionally, both proinflammatory cytokines and mediators have been suppressed in laboratory models of sepsis following ketamine administration.⁷⁹

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 60). A meta-analysis that combined data from eight PRCTs (six published, two unpublished) 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.⁸⁰

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 (ie, sepsis, hemorrhagic shock, and gut I/R), intraluminal nutrients have been shown to reverse shock-induced mucosal hypoperfusion.⁸¹ In the laboratory, we have also shown that enteral nutrition reverses impaired intestinal transit when given after a gut I/R insult.⁸² Improved transit should decrease ileus-induced bacterial colonization. Moreover, enteral nutrition attenuates the gut permeability defect that is induced by critical illness.⁸³ Finally, and most important, the gut is a very important immunologic organ and infections may be lessened by feeding the gut. Kudsk et al has performed a series of laboratory studies that have nicely elucidated a mechanistic explanation of how this occurs.⁸⁴ 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 (ie, 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 3–5 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. 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.⁸⁵ 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.⁸⁶ Although little controversy exists over the potential benefits of glutamine in surgical patients, some doubt still exists about the need for routine supplementation in this patient population.⁸⁷ Recent data would suggest that supplemental glutamine in high doses may, in fact, be toxic and detrimental in patients with acute renal injury and MOF.⁸⁸

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.⁸⁹ An alternative concept that we have studied in the laboratory and then pursued clinically is enteral administration of glutamine in the setting of shock.⁹⁰ 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.⁹¹ Glutamine has also been shown to induce antioxidant enzymes (eg, heat shock protein and heme oxygenase-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).⁹⁰ 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.⁹² 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 (1) urinary lactulose/mannitol ratios, (2) serum diamine oxidase levels, (3) circulating endotoxin levels, and (4) gram-negative bacteremias, all of which suggest that glutamine is achieving these benefits through a gut-specific mechanism.

Prokinetic Agents

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.⁹³ 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.⁹⁴ 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.⁹⁵ 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.

Serotonin Antagonists

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.

Antioxidants

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.⁶⁴ In an animal study, administration of alpha-melanocyte-stimulating hormone preserved both the function and the structural integrity of the intestine following mesenteric ischemia/reperfusion.⁶⁴

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.⁹⁶

Likewise, Collier et al demonstrated a significant risk reduction in mortality in severely injured patients who received high-dose antioxidants compared to historical controls.⁹⁷ A systemic review of aggregated clinical trials in critically ill patients demonstrated an overall reduction in mortality with antioxidant supplementation.⁹⁸ 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.⁹⁹ 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.¹⁰⁰

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.¹⁰¹

Results of recent clinical trials employing probiotics, prebiotics, or a combination, in critically ill and burn patients, however, have been disappointing.¹⁰²

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.¹⁰³ 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.¹⁰⁴