Chapter 81. Gut and Hepatobiliary Dysfunction

• Alterations in gastrointestinal motility occur commonly in critically ill patients.
• The small intestine is the site of obstruction in 90% of cases of mechanical bowel obstruction. Pelvic adhesions are the most common cause. Thirty percent of cases require surgery.
• Intestinal pseudo-obstruction (nonmechanical bowel obstruction) may present with clinical symptoms that are similar to mechanical obstruction. Treatment includes nasogastric suction, rehydration, and correction of causative factors.
• Ogilvie's syndrome (colonic pseudo-obstruction) is characterized by abdominal distension and marked dilation of the cecum and right colon on abdominal x-rays. Treatment with colonoscopic decompression of the right colon is successful in about 60% of patients. Intravenous neostigmine is also effective.
• The incidence of diarrhea in the critically ill is greater than 40% and is up to 60% in patients receiving enteral feedings.
• Clostridium difficile infections are generally acquired in the hospital in patients receiving broad-spectrum antibiotics. Measurement of C. difficile toxin A or B in the stool by rapid enzyme-linked immunosorbent assay (ELISA) is the most practical method for diagnosis. Treatment consists of metronidazole or vancomycin for 7 to 14 days.
• Hyperbilirubinemia is frequently seen in patients with sepsis; cytokines along with bacterial endotoxins impair transport of bile acids at the sinusoidal and canalicular membranes, resulting in cholestasis.
• The etiology of total parenteral nutrition (TPN)-associated liver dysfunction appears to be multifactorial. The diagnosis is often made after the exclusion of other causes such as the concurrent use of potentially hepatotoxic medications, biliary obstruction, infections, and underlying intrinsic liver disease.
• Critically ill patients have multiple risk factors that predispose to acalculous cholecystitis. Patients often present atypically; unexplained fever and evidence of occult infection may frequently be the only manifestations. Ultrasonography alone is of limited value in diagnosis.
• Strong clinical suspicion and early recognition of acalculous cholecystitis are essential. Because of delays in diagnosis, more than 40% of patients develop complicated disease with gangrene, abscess, or perforation of the gallbladder.

Gastrointestinal (GI) and hepatic dysfunction are common in the critically ill patient, particularly in the setting of multiple organ system failure (MOSF) and the systemic inflammatory response syndrome (SIRS). Many factors are responsible for the pathophysiologic derangements of the GI tract and liver in critically ill patients. Disordered function may be directly related to the precipitating illness of the patient, which can lead to additive morbidity, thus perpetuating a vicious cycle. Management of disordered GI and hepatic function often necessitates aggressive and sometimes invasive diagnostic and therapeutic maneuvers, placing critically ill patients at risk for iatrogenic complications. These conditions may create vexing problems in the ongoing care of patients in the intensive care unit. It is therefore imperative for the clinician to develop a thorough understanding of the pathophysiology of GI and hepatic dysfunction in the critical care patient. This knowledge will permit identification of these conditions and allow for management decisions that are appropriate and timely.

In this chapter, we review the physiology of intestinal motility, and the pathophysiology and clinical features of intestinal obstruction and pseudo-obstruction. We also review the various causes of diarrhea in the critically ill patient, as well as the pathophysiology of bacterial translocation. In addition, the relationship between hepatic dysfunction in the critically ill patient as related to infection and parenteral nutrition will be discussed. The diagnosis and management of acalculous cholecystitis will also be reviewed.

Alterations of intestinal motility are common in the critically ill patient. The following discussion will be restricted to small intestinal and colonic motility, since these are the GI organs most subject to dysfunction in the intensive care setting.

Normal Function of the Small Intestine and Colon

The contents of the small intestine and colon are subject to complex processing prior to their excretion from the rectum. As GI contents are moved through the stomach and small intestine, mixing and churning result in the reduction in size of individual particles. These smaller particles allow increased exposure of nutrients to the small intestinal mucosa. The contents of the small intestine subsequently undergo nutrient and electrolyte absorption with a net secretion of fluid. The normal transit time of a liquid bolus from the mouth to the ileocecal valve is less than 2 hours, whereas solid substances take up to 8 hours to reach the cecum.1 The colon functions as a storage organ, with solid contents remaining within the colon for an average of 35 hours prior to excretion.2 Intraluminal contents undergo solidification as they move from the proximal to distal colon as marked reabsorption of water, sodium, and chloride, and net secretion of potassium, takes place. These processes occur through highly coordinated events with regional differences within portions of the small and large intestine. The control of luminal fluid and electrolyte balance, as well as motility of the small intestine and colon, requires the integration of neuronal, muscular, and endocrine components of these organs.

Neuroanatomy of the Small Intestine and Colon

The complexity of intestinal neuroanatomy can be appreciated by the fact that the neuronal density of the gut is approximately equivalent to that of the spinal cord. This network of neuronal pathways has been described as the “brain of the gut.”3 The small and large intestine have both intrinsic and extrinsic neuronal components. The intrinsic neurons of the small intestine and colon consist of cell bodies which are located in either the submucosa (Meissner's plexus) or the intermuscular region between the circular and longitudinal muscles of the gut wall (Auerbach's plexus) (Fig. 81-1). Submucosal nerve cell bodies are most prominent in the duodenum and decrease in density in a caudal direction; intermuscular nerve cell bodies are more evenly distributed throughout the GI tract.

The extrinsic intestinal nervous system makes up a significant portion of the autonomic nervous system and consists of parasympathetic and sympathetic branches. The distributions of these pathways are markedly different.4,5 Parasympathetic motor fibers originating from the medulla coalesce along the vagus nerve. Additional parasympathetic motor axons arise from the sacral portion of the spinal cord and join as the pelvic nerves and hypogastric plexus. The axons of these vagal and sacral parasympathetic plexuses advance directly to the GI tract, where they synapse with cell bodies in the submucosa or intermuscular areas as previously described. Sensory fibers arising from the GI tract that synapse with central nervous system (CNS) ganglia are also present in these plexuses.

Adrenergic pathways start at the thoracolumbar region of the spinal cord. These neurons synapse with ganglia which are located outside the GI tract called the paravertebral ganglia. Sympathetic neurons synapse within or pass beyond these ganglia and then form several nerve bundles termed the splanchnic nerves. The splanchnic nerves advance to prevertebral ganglia and plexuses located on the aorta and its branches. The prevertebral ganglia include the celiac, superior mesenteric, inferior mesenteric, intermesenteric, and hypogastric plexuses. Postganglionic axons from these ganglia then travel along the blood vessels to the submucosal and intermuscular plexuses as previously described. Sensory fibers arising from the GI tract are also found within the thoracolumbar sympathetic system (Fig. 81-2). Cholinergic neurons result in stimulation of gut motility by a direct effect on the enteric smooth muscle. Adrenergic neurons cause gut relaxation, primarily by inhibition of cholinergic neurons.6 Other important enteric neurotransmitters include serotonin, somatostatin, and vasoactive intestinal peptide. For example, stimulation of 5-HT4 (serotonin) receptors promotes intestinal motility and decreases noxious sensations from the gastrointestinal tract.7 Opioid receptor inhibition also stimulates small intestinal motility and decreases oral-cecal transit time.8

Muscular Anatomy of the Small Intestine and Colon

Small intestinal and colonic motility are accomplished by contraction of the smooth muscles that make up a portion of the walls of these organs. The muscular portion of the small intestine is divided into an inner circular layer and outer longitudinal layer. In the small intestine and rectum, the longitudinal muscular layer consists of a thick coat which surrounds the entire circumference of these organs. In the colon, the longitudinal muscles are arranged in three bundles, called teniae coli, which traverse the colon and then fan out in the rectum. The presence of circular and longitudinal muscle layers in the small and large intestines allows for shortening of intestinal segments when the longitudinal musculature contracts, and narrowing of the intestinal lumen when circular muscles contract.

Classification of Muscular Contractions of the Gut

Two main forms of contractions occur in the small intestine. These are called ring contractions and sleeve contractions. Ring contractions are contractions of circular muscle and result in narrowing of the small intestine lumen. These occur continuously in the fed state, but are intermittent in the fasted state and result in the caudad movement of the intestinal contents. Sleeve contractions are caused by longitudinal muscle contraction. Their primary function is the mixing of small intestinal contents.5

Normal motor activity in the small intestine is highly organized. In the fed state, ring contractions moving from the proximal to distal small intestine result in the caudad movement of its contents. Motility in the fasted state is quite complex.9 The fasted motility pattern occurs 4 to 6 hours after completion of a meal. This pattern consists of three phases (Fig. 81-3). Phase I is a rest phase which makes up about 80% of the entire cycle. Phase II is the beginning of rhythmic ring contractions, which may be solitary or clustered. Phase III consists of maximum ring contractions, also called the migrating motor complex (MMC), which begin in the proximal portion of the intestine and move in a distal direction. It is evident that the MMC causes a wave of contractions that sweep along the small intestine.10 The function of the MMC is the emptying of food particles that remain in the small intestine after completion of the fed pattern of motility.

Ring contractions also occur in the colon; sleeve contractions do not. Colonic ring contractions are subdivided into tonic ring contractions and rhythmic ring contractions. Tonic ring contractions are sustained contractions of the circular musculature which form the haustral markings of the colon. The haustra, which divide the colon into individual segments, are stable for long periods. They disappear when mass movement of feces occurs on a periodic basis, then subsequently reappear. Rhythmic ring contractions cause mass movements of fecal material every few hours, as well as continuous caudad and cephalad motion of fecal material. Rhythmic ring contractions cause mixing of the colonic contents.5

Unlike the detailed information available on small intestinal motility, the motility patterns of the colon in the fed and fasted state have not been fully elucidated.

One of the most common GI abnormalities encountered in the critical care setting is the disruption of normal intestinal motility. Loss of motor function may occur in the small intestine as well as the colon. A variety of terminologies have been used to describe disrupted intestinal motility. Ileus is a physiologic term referring to the complete discontinuation of neuromuscular function in the small and large intestine. The term acute intestinal pseudo-obstruction refers to nonmechanical causes of small intestinal and colonic dysfunction. Intestinal obstruction describes a mechanical blockade of the small or large intestine. Postoperative ileus is a term for the normal gut response that occurs for up to 72 hours following abdominal and other types of surgery. Often the clinician will be faced with a diagnostic dilemma in differentiating between mechanical intestinal obstruction, which may require surgical intervention, and pseudo-obstruction, which generally responds to medical therapy.

Acute Intestinal Obstruction in the Critically Ill

More than 90% of all cases of mechanical obstruction of the intestine involve the small intestine alone. Intestinal obstruction is generally caused by adhesions within the abdominal and pelvic cavities; hernias, carcinoma, and intestinal volvulus are other less common causes. Intestinal obstruction may also occur as a consequence of congenital anomalies such as intestinal malrotation; inflammatory bowel disease, especially Crohn's disease; intestinal ischemia; or impaction of the intestinal lumen by foreign bodies such as gallstones.11

Adhesions develop after abdominal surgery and following prior intra-abdominal sepsis.12 Intestinal obstruction secondary to adhesions may occur as early as 3 days after the original surgery. However, delayed effects of adhesive small bowel disease are common, with some patients having recurrent bouts of small intestinal obstruction up to 20 years after their initial surgery.13

The pathophysiologic consequence of a mechanical small intestinal obstruction is distention of the region of the small intestine proximal to the blockade. High pressures develop within the intestinal lumen that may ultimately compromise the blood flow to affected areas. Bowel edema with fluid secretion into the small intestinal lumen occurs as well. This phenomenon, in conjunction with fluid losses secondary to vomiting, causes fluid and electrolyte derangements. As luminal pressure increases, strangulation of the bowel may occur. Bacterial translocation into the circulatory system with resulting bacteremia as well as perforation, peritonitis, and shock are the sources of mortality associated with this condition.

The clinical presentation of patients with acute intestinal obstruction includes intermittent abdominal pain, nausea, and vomiting. Fever, leukocytosis, and electrolyte disturbances commonly occur. Colicky abdominal pain, distension, and abnormal bowel sounds in a patient with previous abdominal surgery are highly sensitive and specific for the presence of mechanical small intestinal obstruction.14

Radiographs of the abdomen with supine and upright views as well as an upright chest x-ray are commonly used to confirm the diagnosis of small intestinal obstruction. Whereas dilated loops of small intestine and colon with the presence of air in the rectum are seen in acute intestinal pseudo-obstruction, mechanical intestinal obstruction is characterized by small intestinal dilation alone without much air in the colon or rectum. Air-fluid levels may be present and represent separation of gas and fluid within fluid-filled, static portions of the small intestine (Fig. 81-4). Absence of air beyond a dilated segment of the small intestine is seen in a complete small intestinal obstruction. Air under the diaphragm on the upright chest x-ray is indicative of an intestinal perforation.

Computed tomography (CT) scanning with oral contrast has been demonstrated to have better sensitivity in diagnosing complete small intestinal obstruction than plain abdominal radiography.15 CT with contrast may also be used to pinpoint the location of a mechanical small intestinal obstruction by identifying decompressed bowel that is distal to the obstruction and may be used to diagnose the presence of intestinal ischemia.16 CT scanning is also used to identify the source of obstruction such as an intra-abdominal or pelvic mass. Small intestinal radiography with contrast may be used to differentiate intestinal obstruction from pseudo-obstruction and for cases not resolving with conservative management. Caution is advised with the use of contrast studies, since barium entering the abdominal cavity through a perforated organ may cause a chemical peritonitis, whereas aspirated water-soluble contrast can result in pneumonitis. The therapeutic role of water-soluble contrast agents for the relief of intestinal obstruction has been investigated and remains controversial.17

Partial small intestinal obstruction is initially treated conservatively with nasogastric suction, administration of intravenous fluids, and correction of electrolyte abnormalities. Nasogastric suction is used for bowel decompression. Serial abdominal examinations and x-rays are vital in the ongoing management of partial intestinal obstruction. The development of sepsis, complete obstruction, or clinical signs of perforation are indications for immediate surgery. Nonresolution of partial mechanical small bowel obstruction is another indication for surgery.18

Conservative management for partial small intestinal obstruction is effective in about 70% of patients. Patients failing conservative management require laparotomy and lysis of adhesions with resection of nonviable intestine. Hospital mortality for small intestinal obstruction is about 10%. Recurrences are common, and more than 50% of patients undergoing surgery for intestinal obstruction can expect a recurrence during their lifetime.13

Intestinal Pseudo-Obstruction

Intestinal pseudo-obstruction results from disruption of the extrinsic or intrinsic neuronal pathways of the intestine. The mechanism for the development of this disruption varies. In some patients, such as those who have recently undergone abdominal surgery, sympathetic overdrive is present, thus diminishing cholinergic output to the intestine. In others, the direct anticholinergic activity of drugs and neurohumoral mediators inhibits gut function.19 A variety of conditions may result in acute intestinal pseudo-obstruction (Table 81-1). Small intestinal motility in patients with acute idiopathic intestinal pseudo-obstruction is markedly reduced. For example, manometric studies performed in patients with these disorders show marked abnormalities of the fasted motility pattern, including the MMC.20

The clinical symptoms of acute intestinal pseudo-obstruction closely resemble those of mechanical small intestinal obstruction. Most patients have abdominal distention and absence of bowel sounds. Abdominal pain is usual but may not be recognized in the patient who is sedated, delirious, or encephalopathic. Vomiting may also be present, placing patients with this condition at risk for aspiration pneumonia.

Treatment consists of correction of electrolyte abnormalities and administration of intravenous fluid. Pharmacologic agents that may be causing or aggravating the condition should be discontinued. Nasogastric suctioning may result in symptomatic improvement and may alter the pathophysiologic consequences of bowel distention in these patients. Limited therapeutic trials of pharmacologic agents for acute intestinal pseudo-obstruction or prolonged postoperative ileus with metoclopramide and erythromycin have shown few beneficial effects.20 Recent studies of opiate antagonists including methylnaltrexone and alvimopan21,22 have shown promise as potential therapies for postoperative ileus. Movement of the patient and ambulation when possible are encouraged.

Ogilvie's Syndrome: Acute Colonic Pseudo-Obstruction

This syndrome, first described by Sir Heneag Ogilvie in 1948, is generally seen in the ICU or in postoperative patients. It is characterized by abdominal distention accompanied by colonic dilation, particularly involving the cecum and right colon. A variety of medical conditions are associated with the development of Ogilvie's syndrome. It is generally accepted that this disorder results from decreased parasympathetic tone to the distal colon from the sacral nerves with normal vagal impulses to the right side of the colon resulting in a pseudo-obstruction of the distal colon with associated proximal colonic dilation.23 Sympathetic hyperactivity of the right colon has also been postulated as a potential mechanism for the development of this disorder.

The most common medical conditions associated with Ogilvie's syndrome include sepsis, respiratory failure, organic brain disorders, and malignancy. Trauma to the spine, retroperitoneum, and pelvis, as well as burns, may also result in the development of Oglivie's syndrome.24,25 Electrolyte disturbances, including hyponatremia, hypernatremia, hypokalemia, and hypocalcemia, are seen in the majority of patients.26 A variety of medications have been implicated as potential etiologic agents in Ogilvie's syndrome, including narcotics, phenothiazines, calcium channel blockers, and cyclic antidepressants. For example, in one review of Ogilvie's syndrome, 56% of patients had received opiates on the day of diagnosis, 42% had received phenothiazines, and 15% ingested cyclic antidepressants.27 Other medications associated with the development of Ogilvie's syndrome include clonidine and anticholinergic agents. Ogilvie's syndrome may also occur in the postoperative period, most commonly after cesarean sections, orthopedic surgery, and urologic procedures.24

Physical examination of patients with Ogilvie's syndrome always reveals abdominal distention. Bowel sounds remain present in most patients, but may be hypoactive or high pitched. Leukocytosis may be seen in up to 30% of patients, even prior to the development of associated bowel ischemia or perforation. Abdominal x-rays are the diagnostic test of choice, showing dilation of the cecum, usually with associated dilation of the right colon (Fig. 81-5). A decrease in the gas pattern of the left colon is often seen. At the time of diagnosis of colonic pseudo-obstruction, the transverse diameter of the cecum often measures 9 cm or greater on an unmagnified abdominal film.28

Ogilvie's syndrome may be complicated by ischemia and perforation of the distended cecum. As the colon becomes increasingly enlarged (and its radius of curvature increases), less additional pressure is needed to further distend it, and its wall tension rises dangerously (as described by the law of Laplace).28 Case series have shown that the spontaneous cecal perforation rate in Ogilvie's syndrome is approximately 13%, and mortality from this occurrence is 43%. However, the absolute cecal diameter does not correlate specifically with the risk of perforation. The duration of cecal dilation and the rate at which it dilates appear to be the most important factors related to perforation.29

The goal of therapy for Ogilvie's syndrome is decompression of the colon. Some have advocated an initial conservative approach, including nasogastric suction, intravenous hydration, correction of electrolyte abnormalities, discontinuation of offending medications, and treatment of predisposing medical or surgical conditions.27 Others suggest early colonoscopic decompression of the cecum and right colon as an effective and safe therapy for the disorder.26 The colonoscope is advanced to the cecum or the right colon, an often technically challenging procedure because no colonic cleansing preparation is used. Minimal air is insufflated during the procedure to prevent iatrogenic cecal perforation. The reported success rate for initial colonoscopic decompression ranges from 61% to 76%.23,26 The success rate increases after repeat colonoscopic decompression which is required in 20% to 50% of cases. Complication rates for colonoscopic decompression in Ogilvie's syndrome are modest and range from 0% to 3% in published series. Overall the condition carries a mortality rate of approximately 15% in uncomplicated cases, with patients generally dying from their underlying condition. If bowel becomes ischemic or perforates, mortality increases to about 40% as previously described.27

A variety of pharmacologic treatments have been attempted for Ogilvie's syndrome, including cisapride and erythromycin.30,31 These treatments have been reported as case studies only. Neostigmine, a cholinesterase inhibitor, stimulates neuromuscular activity. Several case studies involving a total of 58 patients have demonstrated the efficacy of neostigmine administered slowly by the intravenous route.32–34 Most recently, Trevisani and associates treated 28 patients with 2.5 mg neostigmine administered over 3 minutes. Twenty-six patients (93%) had resolution of the condition with therapy.34 Abdominal cramping, nausea, and diaphoresis were common side effects, although no patients experienced severe bradycardia or cardiovascular collapse, complications that have been described with the use of neostigmine.

Colonoscopic decompression fails in approximately 15% to 20% of patients, even after multiple attempts. These patients require surgical decompression, generally accomplished with a cecostomy and placement of a catheter. A 50% morbidity and 15% mortality is anticipated following cecostomy placement for Ogilvie's syndrome.29 Complications include pericatheter leakage, superficial wound infections, catheter herniation, catheter dislodgment, and prolonged cecal-cutaneous fistula. Nonetheless, this procedure is reportedly successful in 96% of patients. Occasionally patients will require a colonic resection for treatment of this disorder, with an expected 30% surgical mortality.27

The incidence of diarrhea in critically ill patients is greater than 40%.35 Differentiating between potential causes of diarrhea in these patients is necessary for optimal management of these disorders (Table 81-2). The following discussion will focus on the most common of these conditions.

Clostridium Difficile Colitis

Clostridium difficile is a fastidious gram-positive spore-forming anaerobe that is toxin-producing. C. difficile is found in the colonic flora in up to 3% of the general population. The organism is readily acquired from the environment, and studies have shown that bathrooms, sinks, and floors of hospitals and chronic care facilities often harbor colonies of C. difficile.36 It may persist in the rooms of infected individuals for up to 40 days.37 Patients are at high risk of developing C. difficile colitis after receiving broad-spectrum antibiotics, particularly those with activity against anaerobic organisms. Clindamycin and broad-spectrum cephalosporins are often implicated, but symptomatic C. difficile colitis has been described following the administration of almost all currently used antibiotics. Broad-spectrum antibiotics eliminate the normal colonic flora, the majority of which are anaerobic organisms. Preexisting carriage, or more commonly, exposure to environmentally-acquired C. difficile results in subsequent colonization, overgrowth, and infection with the toxin-producing organism. Immunosuppressed patients are at particular risk for the development of severe toxic colitis secondary to C. difficile. Such patients may develop diffuse colonic involvement with bowel ischemia and perforation.

Symptoms of C. difficile colitis include abdominal pain, diarrhea, and fever. Some patients may have neither abdominal pain nor diarrhea, so C. difficile colitis should always be considered in the differential diagnosis of patients with occult sepsis.38 Leukocytosis, electrolyte abnormalities, and hypoalbuminemia may also be present.39C. difficile is diagnosed by stool examination. Fecal leukocytes are often present. Culturing of C. difficile is the gold standard for diagnosing this disorder, but is technically difficult to perform. Measurement for the presence of C. difficile toxin A or B by rapid ELISA is the most common method of diagnosis. It has a sensitivity of 86% and specificity of 100%. The cytotoxic assay for toxin B is more sensitive (94% to 100%), but requires a tissue culture laboratory to perform and takes up to 48 hours.37 Plain radiography or CT imaging may provide clues to the diagnosis (Fig. 81-6A and B). A bedside sigmoidoscopy is useful for identifying the presence of colitis. If the patient is infected with C. difficile, typical pseudomembranes will be seen about 60% of the time (Fig. 81-7).

Treatment for C. difficile colitis should be initiated in all patients in whom the toxin has been identified or in whom endoscopic findings suggest this disorder. Broad-spectrum antibiotics should be discontinued if possible. Metronidazole 250 to 500 mg PO qid for 7 to 14 days or vancomycin 125 to 250 mg PO tid for 7 to 14 days is used to eradicate the organism. A high response rate is expected with oral antibiotic therapy, although relapse rates of 15% to 20% following treatment can be expected.40 Intravenous metronidazole 500 to 750 mg q6h may be used in those patients who cannot tolerate oral antibiotic therapy, but this may not be as effective as oral therapy. For patients who are critically ill due to C. difficile colitis, combined therapy with intravenous metronidazole and oral vancomycin may be indicated.41

Miscellaneous Causes of Diarrhea

Patients receiving enteral tube feedings commonly develop diarrhea; the published incidence ranges from 5% to greater than 60%.31 Diarrhea in these patients can often be attributed to the osmolarity of the feeding solutions. When the rate of administration of enteral feeding is high, the normal mechanisms for fluid and electrolyte reabsorption in the small intestine and colon may be overwhelmed. In other critically ill patients, intestinal wall edema and villous atrophy may be present, resulting in nutrient malabsorption and increased osmotic load to the colon. A number of studies have shown that patients with low serum albumin levels, particularly levels below 2.6 g/dL, are at risk for diarrhea.42 Finally, altered colonic flora following the administration of broad-spectrum antibiotics results in decreased colonic reabsorption of carbohydrates, which produces an osmotic type of diarrhea as well.

A variety of methods have been suggested to lessen the diarrhea associated with enteral feeding, but these have met with variable success.43 Current recommendations include decreasing the infusion rate of enteral feedings, adding fiber to enteral formulas, decreasing the osmolality of the feeding solution by diluting it with water, and adding dipeptides and predigested proteins to standard enteral formulas.44 Lactose-free or reduced-fat-content formulas may benefit occasional patients.

Sorbitol, a common additive in medications that are administered in a liquid or syrup form, may also cause diarrhea. Since sorbitol, a sugar alcohol, is not absorbed in the small intestine, it functions as an osmotic agent in the colon, increasing intraluminal fluid and electrolytes. The sorbitol content of administered medications should be checked in all patients with unexplained diarrhea who are receiving medications in a suspension or syrup form.45 Magnesium, a common ingredient in antacid preparations, also causes diarrhea. It should also be remembered that many different medications may cause diarrhea in individual patients by a variety of mechanisms. Medications should therefore always be included in the differential diagnosis of diarrhea.

Patients in the ICU may also have diarrhea owing to the presence of preexisting GI illnesses, such as intestinal ischemia, inflammatory bowel disease, small intestinal diseases, and pancreatic insufficiency. Following gastric or small intestinal resections, patients commonly develop diarrhea due to stasis of bowel contents and subsequent bacterial overgrowth, as well as to malabsorption occurring as a direct result of the surgery. Bacterial overgrowth may also occur following prolonged ileus and loss of the MMC, combined with a loss of local immunoglobulin production in the small intestine.

The gut normally functions as an effective barrier against bacteria and endotoxin present in the intestinal lumen. Some migration of bacteria across the GI mucosa occurs in health, likely contributing to the regulation of local and systemic immunity against the innumerable antigens that contact the intestinal epithelium.46 In the critically ill patient, however, abnormal intestinal barrier function results in greater transmucosal passage of bacteria and endotoxin. In addition to being a potential source of infection, this bacterial translocation appears to serve as a trigger for the release of cytokines and other cellular mediators that may in turn activate or further perpetuate the inflammatory and hypermetabolic responses to injury. Thus gut dysfunction may play a major role in the initiation and propagation of MOSF.47

Components of the physiologic gut barrier include the normal microbial flora, bile salts within the intestinal lumen, the epithelial mucous layer, peristalsis, and an intact local and systemic immune system.46,48 Normal microbial flora occupy the space closest to the intestinal epithelial cells, thereby limiting attachment to the enterocytes of potentially pathogenic gram-negative enteric bacteria. Oral antibiotics eliminate indigenous microflora and increase the risk of bacterial translocation, an effect which may be seen for prolonged periods following cessation of antibiotic therapy. Enterococcus faecalis, Pseudomonas aeruginosa, and the Enterobacteriaceae appear to translocate in the greatest numbers. H2 blockers and proton pump inhibitors facilitate upper GI tract bacterial colonization, which may also predispose to translocation. Finally, ileus, hyperosmolar enteral feeding, and TPN all disrupt the normal intestinal microbial flora.49

Small amounts of endotoxin normally enter the circulation and appear to play a role in maintaining the reticuloendothelial system in a primed state.50 Bile salts within the intestinal lumen normally limit endotoxemia by binding intraluminal endotoxin. Loss of bile salts associated with critical illness may allow more endotoxin to reach the portal circulation. In animal models of obstructive jaundice, bacterial overgrowth, which occurs as a consequence of the absence of enteric bile salts, appears to promote bacterial translocation.

Further defense against translocation is provided by the normal mucus layer, which contains immunoglobulin A and other protective substances, as well as normal gut peristalsis, which impedes bacterial penetration of the protective layer of mucus. Translocation appears to become clinically relevant only with failure of local and systemic immunity. Immunosuppressive drugs increase bacterial translocation in animals, indirect evidence that intact systemic immunity may itself limit translocation.51

Mucosal atrophy, particularly when it occurs as a consequence of luminal nutrient deprivation, is another predisposing factor. TPN is associated with thinning of the gut mucosa and increased translocation, a consequence that can be prevented by providing nutrition via an enteral rather than intravenous route. Bacterial translocation also more readily occurs in a gut mucosal barrier compromised by ischemia.52 Hypotension and shock may significantly decrease splanchnic perfusion, resulting in reduced oxygen delivery to the intestinal mucosa and accelerated free radical generation.46 Lipid peroxidation and cell membrane injury result, leading to ischemia and increased mucosal permeability. Even short periods of hypotension can result in splanchnic ischemia, since splanchnic blood flow is reduced out of proportion to systemic blood flow in models of hypovolemia. This splanchnic ischemia has recently been shown to contribute to the hepatic dysfunction that ultimately occurs over time in critically ill patients. A mismatch between hepatic metabolic demand that appears to be significantly increased in MOSF, and hepatic blood flow may be at the root of this problem.53

Protein malnutrition, burns, pancreatitis, inflammatory bowel disease, hemorrhage, systemic infection, any form of shock, abdominal surgery, radiation, trauma, intestinal obstruction, advanced liver disease, and obstructive jaundice all promote bacterial translocation.52,54–58 Several of these features may interact in critically ill patients to cause infection remote from the GI tract, enteric bacteremia without an identified infectious source, or propagation of systemic inflammation. The presence of two predisposing factors (e.g., treatment with antibiotics in combination with immunosuppressive drugs) appears to synergistically promote systemic spread of translocating bacteria. Intestinal barrier dysfunction and bacterial translocation may thus play a central role in MOSF.47

Although it seems clear that the critically ill are predisposed to bacterial translocation, preventive therapy has not been particularly beneficial. Aggressive resuscitation from shock may decrease the chances for translocation. Although TPN has not been proven to predispose to bacterial translocation in humans, enteral feeding is more physiologic and could offset gut barrier failure and thus is always preferred over TPN56 (see Chap. 11). In rats, use of glutamine in TPN has been shown to minimize intestinal permeability and bacterial translocation caused by trauma and endotoxemia.59 Selective decontamination of the digestive tract with nonabsorbable antibiotics may decrease bacterial translocation by suppressing potentially pathogenic microorganisms in the oropharynx and upper GI tract. Whereas selective gut decontamination appears to reduce nosocomial colonization, it may or may not have a significant effect on mortality and length of ICU stay.60–62 In addition, selective gut decontamination may predispose to the development of resistant organisms (see Chap. 43). Improved delineation of the role of bacterial translocation in human critical illness is anticipated.

Patients in the intensive care unit present a difficult challenge when diagnosing and treating complications related to the biliary tract.63 Laboratory data are often nonspecific in diagnosing biliary tract complications. Gallbladder abnormalities are frequently seen on imaging studies in intensive care patients; therefore their presence does not necessarily indicate acute disease.64 Because there is often a delay in diagnosing biliary tract disease in these patients, intervention is associated with high morbidity and mortality when compared to the ambulatory setting. Hepatic dysfunction significantly prolongs length of hospital stay and increases mortality in critically ill patients.65

Cholestasis of Sepsis

Cholestasis results from impaired bile formation or obstruction to bile flow. Biochemically, cholestasis is characterized by a disproportionate increase in serum alkaline phosphatase or bilirubin concentrations relative to aminotransferase elevations. Cholestasis is classified as intrahepatic when there is a defect in bile formation at the level of the hepatocyte or extrahepatic when there is structural or mechanical impairment to bile flow66 (Table 81-3).

In the critically ill, cholestasis is at times a manifestation of underlying hepatobiliary disease. Most cholestasis seen in the ICU, however, occurs in the absence of any intrinsic liver disease. Cholestatic jaundice occurring in infected and bacteremic patients, termed the cholestasis of sepsis, has been a well-recognized clinical syndrome for two decades.67,68 Bilirubin levels range typically from 5 to 10 mg/dL, with the conjugated fraction predominating. This suggests that the hyperbilirubinemia seen in sepsis results from impaired bile canalicular secretion.69,70 Liver biopsy characteristically shows retained bile concretions within bile ductules (Fig. 81-8A and 8B). This histology differs from that seen in patients with biliary obstruction in whom cholestasis is present within both hepatocytes and bile ductules; bile ductular proliferation also occurs in obstructive jaundice (Fig. 81-8C).

Bile formation depends in large part on the ability of hepatocytes to transport bile acids from sinusoidal blood into bile canaliculi against a steep concentration gradient. The initial step is mediated in part by an active, sodium-driven bile acid uptake system across the sinusoid. An hepatocyte sodium-taurocholate-transporting polypeptide appears to be the major sinusoidal sodium-bile acid cotransporter. Efflux across the canalicular membrane represents the rate-limiting step in the overall transport of bile acids and depends both on a negative membrane potential and on adenosine triphosphate (ATP) hydrolysis.71 There also appear to be ATP-dependent canalicular transport proteins; endotoxin and certain cytokines released in response to endotoxin may selectively impair these bile acid transporters. Endotoxemia severely impairs the transport of certain bile acids and organic anions at both the sinusoidal and canalicular membranes. As a result of this impaired hepatic bile acid and organic anion transport, bile flow is decreased.72

Cholestasis is not restricted to gram-negative sepsis alone, suggesting that nonendotoxin mediators may also impair bile secretion. Tumor necrosis factor-α (TNF-α) inhibits bile acid transport at both the sinusoidal and canalicular membranes. In vivo administration of anti-TNF-α antibody has been shown to prevent endotoxin-induced cholestasis. The end result of this inhibition of bile acid and organic anion transport is that sinusoidal transport may exceed canalicular transport, and potentially toxic compounds may accumulate intracellularly.73 Impaired canalicular bile formation and resulting bile stasis, along with decreased intestinal luminal bile acid concentration, appear to perpetuate a vicious cycle by predisposing to bacterial translocation and further endotoxin absorption.70,74,75

When critically ill patients develop elevated serum bilirubin levels, biliary obstruction, viral hepatitis, and drug toxicity66 should be excluded. As with cases of postoperative jaundice,76 the etiology of cholestasis is often multifactorial. Hematologic causes of unconjugated hyperbilirubinemia such as hemolysis, multiple blood transfusions, and hematoma resorption should also be sought. Gilbert's syndrome affects approximately 10% of the general population and can present with an isolated unconjugated hyperbilirubinemia.77 If all these conditions are excluded, infection, whether documented or occult, should be suspected as the cause of hyperbilirubinemia.

Hepatobiliary Complications of Total Parenteral Nutrition

Total parenteral nutrition (TPN) is associated with various catheter-related and metabolic complications (see Chap. 11). In addition, hepatic dysfunction is a common occurrence in many patients.78 This may result in abnormal liver chemistry tests, and less frequently, in hepatomegaly or jaundice. It is often unclear to what extent other factors such as infection, malnutrition, the concurrent use of potentially hepatotoxic medications, alcoholism, or underlying intrinsic liver disease may contribute to the liver dysfunction.79

In adults, modest elevation of serum aminotransferase levels occurs within the first 2 to 3 weeks of initiating TPN. These abnormalities are usually mild and reverse within 10 to 14 days of cessation of TPN. Elevations of serum alkaline phosphatase and bilirubin can occur with more prolonged parenteral nutrition. Since these abnormalities may normalize despite continuance of TPN, they should not be interpreted as evidence of permanent hepatic dysfunction or histologic damage. The early predominant histologic abnormality of the liver is steatosis, which is almost always clinically asymptomatic (Fig. 81-9). Long-term administration of TPN in infants may be accompanied by the development of cirrhosis and chronic liver disease.78–80 In these infants, chronic liver disease appears to be a direct consequence of prolonged cholestasis. Though once thought to be a rare occurrence, recent studies have shown more adults developing advanced liver disease from long-term TPN use.81 Thus once significant cholestasis has developed, even in adults, TPN should generally be discontinued.

The exact mechanism of TPN-induced liver dysfunction remains unknown but is probably multifactorial in nature. Possible contributing factors are listed in Table 81-4.78–80 The development of steatosis during TPN appears primarily to be related to the combined effects of excess glucose calories and impaired hepatic triglyceride secretion.79,82 In addition, lipoprotein synthesis may become impaired and hepatic triglyceride secretion limited when amino acid supplementation is inadequate. Although essential fatty acid deficiency may similarly cause hepatic steatosis, most standard TPN solutions contain all essential amino acids, vitamins, and trace elements, so deficiency states are unlikely to be major contributors to TPN-associated hepatic dysfunction. Bacterial translocation and prolonged fasting may contribute to cholestasis by upsetting the enterohepatic bile salt circulation and affecting biliary secretory capacity. The cholestasis resulting from sepsis itself may be an additive or complicating factor.72 Patients with TPN-related hepatic dysfunction appear predisposed to infection.

The development of biliary sludge, cholelithiasis, and calculous and acalculous cholecystitis are all increased in patients receiving TPN. Gallbladder sludge is detected in half of patients receiving TPN for a total of 4 to 6 weeks, and in almost 100% of patients after 8 to 13 weeks. TPN-induced gallstones are pigmented and composed primarily of calcium bilirubinate. Gallstone formation may partly relate to prolonged fasting; reduced gallbladder contractility and impaired bile flow result from prolonged use of TPN and may contribute to stone formation. Loss of normal enteral stimulation by oral nutrients also plays a role. Disease or resection of the terminal ileum further promotes the development of cholelithiasis in some patients.78–80

Proving TPN-induced hepatobiliary disease is challenging, since this is usually a diagnosis of exclusion. Evaluation in the ICU should include assessment of hepatitis viral serologies; radiologic studies looking for signs of biliary obstruction, liver abscess, or cholecystitis; and a search for systemic infection or hepatotoxic medications. There may be a high incidence of false-positive (nonvisualization) hepato-iminodiacetic acid (HIDA) or diisopropyl iminodiacetic acid (DISIDA) scans related to impaired gallbladder emptying in patients receiving TPN.78 Liver biopsy may be useful to delineate any intrinsic liver disease contributing to hepatic dysfunction in the critically ill patient, but generally is not required.

If TPN-related liver chemistry abnormalities occur, they will usually normalize with discontinuation of TPN.78–80 Physicians should avoid using an excess of glucose (>4 to 5 g/kg body weight) or an excess of total calories in TPN. Concurrent use of oral or enteral feeding or discontinuation of TPN may improve gallbladder contractility and decrease the risk of gallstone formation or cholecystitis. Cholecystokinin has been administered periodically to promote gallbladder contractility, though this has not been shown to reliably decrease the formation of gallstones.78–80 Studies are currently examining the efficacy of ursodiol in preventing the cholestasis associated with prolonged TPN use.83

Acalculous Cholecystitis

Acute cholecystitis may occur at any time in a patient with gallstones but is especially dangerous in patients with chronic debilitating conditions or intercurrent critical illness. Though acalculous cholecystitis comprises only 2% to 15% of all cases of acute cholecystitis, the critically ill appear to be at much greater risk. More than 50% of postoperative cases of acute cholecystitis are of the acalculous form. Risk factors are prevalent in ICU patients and include mechanical ventilation, TPN use, dehydration, use of narcotics, hypotension, chronic renal failure, and massive blood transfusion. Diabetes mellitus, human immunodeficiency virus infection, abdominal vasculitis (such as polyarteritis nodosa), and cardiac surgery are also associated with acalculous cholecystitis. This condition may also occur in trauma and burn patients and following bone marrow transplantation.63,84–86

Most patients developing acalculous cholecystitis have no previous history of gallbladder disease and present with atypical clinical manifestations. Abdominal examination is often unreliable owing to the presence of altered mental status, concomitant systemic illness, or recent abdominal surgery. Leukocytosis and hyperbilirubinemia occur commonly but are nonspecific in the setting of critical illness. Unexplained fever or evidence of infection may frequently be the only manifestations of acalculous cholecystitis. Because of the extremely high morbidity and mortality associated with acute acalculous cholecystitis, a high index of suspicion as well as early recognition are of paramount importance. Acalculous cholecystitis occurs commonly enough in critically ill patients that it should be in the differential diagnosis in any septic patient without a clear focus of infection.(63,84)

The etiology of acalculous cholecystitis is not completely understood; one major predisposing factor appears to be biliary stasis. Stasis and gallbladder dysmotility can be precipitated by prolonged fasting, general anesthesia, dehydration, and the use of narcotics. The resultant increase in bile viscosity has been postulated to produce functional cystic duct obstruction, increasing intraluminal gallbladder pressure; it may also render the gallbladder mucosa more susceptible to local injury. Gallbladder ischemia has also been implicated in the development of acalculous cholecystitis. This is supported by the high incidence of gallbladder mucosal necrosis, endothelial dissection, arteriolar thrombosis, gangrene, and perforation noted in autopsy studies. Gallbladder ischemia may occur as a result of low flow states in shock, systemic infection, dehydration, and hypercoagulable disorders. Prolonged mechanical ventilation with positive end-expiratory pressure may result in ischemia by decreasing portal perfusion and by raising hepatic venous and common bile duct pressures.63,86

Bedside abdominal ultrasonography is an unreliable routine screening tool for acute acalculous cholecystitis.87 When present, characteristic findings include pericholecystic fluid, a gallbladder wall thickness greater than 4 mm, subserosal edema, and intramural gas. However, there can be a high false-positive rate in patients receiving TPN and in those with ascites or hypoalbuminemia. HIDA and DISIDA scanning may fail to visualize the gallbladder, implying cystic duct obstruction (Fig. 81-10). False-negative gallbladder scintigraphy is unusual. Neither scintigraphy nor ultrasound can differentiate between calculous and acalculous cholecystitis. Morphine cholescintigraphy is superior to ultrasonography in making a diagnosis. Mariat and associates performed bedside ultrasonography and morphine cholescintigraphy in 28 patients suspected of having acalculous cholecystitis. Sensitivity of ultrasound and scintigraphy was 50% and 67%, specificity was 94% and 100%, positive predictive value was 86% and 100%, and negative predictive value was 71% and 80%, respectively. The probability of disease was 100% with a positive scintiscan regardless of ultrasound results. A positive ultrasound finding was associated with an 86% probability of disease, but with a probability of only 66% with negative scintigraphy results.88 Diagnostic laparoscopy or laparotomy is a more definitive method of diagnosing cholecystitis but has obvious attendant risks.89 In some centers, percutaneous cholecystostomy performed by an interventional radiologist provides a less risky means for obtaining bile fluid cultures and decompressing the biliary system,90 but these microbiologic studies may not be sensitive or specific (see Chaps. 89 and 101).

Because of delays in making a diagnosis, more than 40% of patients with acalculous cholecystitis develop complicated disease characterized by gangrene, pericholecystic abscess, or gallbladder perforation. In one series, 40% of patients with acalculous cholecystitis who underwent surgery more than 48 hours after symptom onset developed gallbladder perforation.63,84–85 The mortality in complicated acalculous cholecystitis may be as high as 75%, with death usually due to MOSF. Once acalculous cholecystitis is recognized, cholecystectomy is the mainstay of treatment. The high incidence of gangrene and perforation makes inspection of the entire gallbladder very important. Cholecystostomy is an option in the critically ill, but this approach risks missing complicated disease and fails to adequately drain the common bile duct in cases of concomitant cholangitis. A cholecystostomy drainage catheter should remain in place for 10 to 14 days to allow maturation of the tract between the gallbladder and the abdominal wall.90 If rapid clinical improvement does not ensue, open cholecystectomy is indicated. Laparoscopic cholecystostomy and transpapillary endoscopic cholecystostomy have proved to be effective treatment options in some patients.89,91