CHAPTER 104: Jaundice, Diarrhea, Obstruction, and Pseudoobstruction

• Jaundice (hyperbilirubinemia) is seen in critically ill patients and can occur due to prehepatic, intrahepatic, or posthepatic causes.

• Biliary obstruction and acalculous cholecystitis are two common surgical problems requiring urgent intervention.

• For acalculous or calculous cholecystitis, cholecystectomy removes the inflamed and ischemic gallbladder and prevents recurrence and thus is preferred in those able to tolerate the procedure. A cholecystostomy tube is indicated for nonsurgical candidates.

• Diarrhea commonly occurs in critical illness (up to 60% of those on enteral feeds) and may be related to infection, medications, malabsorption, composition of the enteral feeds, or gastrointestinal disease.

• Clostridium difficile should be ruled out as the cause of diarrhea in the ICU or any patient with risk factors (particularly antibiotics or contact) as morbidity and mortality increase with delay in treatment.

• Fulminant Clostridium difficile can present as an ileus or with diarrhea in a toxic patient, and is associated with high mortality and frequent need for surgical intervention.

• Studies are ongoing to determine the optimal medical and surgical management of Clostridium difficile. Currently for severe cases enteral vancomycin plus intravenous metronidazole is suggested ± subtotal colectomy or ileostomy with colon lavage.

• Bowel obstruction should be ruled out prior to managing as pseudoobstruction.

• Commonest causes of adult small bowel obstruction are adhesions and hernia, whereas commonest causes of adult large bowel obstruction are colon cancer, sigmoid volvulus, and stricture from diverticulitis.

• Pseudoobstruction (nonmechanical obstruction) is managed by resuscitation, removing or limiting precipitants, using nasogastric or rectal tubes to relieve overdistension, and occasional endoscopic decompression or use of neostigmine in appropriate patients.

OVERVIEW

Jaundice is characterized by yellow discoloration of the skin, conjunctivae, and mucous membranes as a result of widespread tissue deposition of the pigmented metabolite bilirubin. It can present as an isolated abnormality, or associated with specific hepatic and/or pancreatic dysfunction, or associated with multisystem organ dysfunction.

In the intensive care setting, jaundice may be an important sign of a condition that requires ICU admission, such as acute cholangitis, or a new development in an already admitted patient, such as one with septic shock. Patient history, laboratory evaluation, appropriate imaging investigations, and a thorough understanding of those conditions that place a patient at increased risk for the development of hyperbilirubinemia will help narrow the broad differential diagnosis of jaundice and identify those conditions that require specific therapy.

METABOLISM AND MEASUREMENT OF BILIRUBIN

Bilirubin is a hydrophobic and potentially toxic compound that is an end product of heme degradation (Fig. 104-1 depicts bilirubin metabolism and excretion).¹ The majority of bilirubin (70%-80%) is derived from degradation of hemoglobin from senescent erythrocytes, with a minor component of this being premature destruction of newly formed erythrocytes. The remaining 20% to 30% is mostly formed from breakdown of hemoproteins, such as catalase and cytochrome (CYP family) oxidases, in hepatocytes.

Bilirubin circulates in plasma tightly, but noncovalently, bound to albumin. To be excreted, bilirubin must be converted to water-soluble conjugates by hepatocytes and subsequently secreted in a multistep process. Bilirubin is taken up across the sinusoidal membrane of hepatocytes and conjugated with uridine diphosphate (UDP)-glucuronic acid by the enzyme bilirubin UDP-glucuronyl transferase (B-UGT). This converts the hydrophobic bilirubin into a water-soluble form that can be excreted into the bile canaliculus. Any conjugated bilirubin in plasma undergoes renal elimination and this pathway may be upregulated in disorders characterized by cholestasis. With prolonged cholestasis, a large proportion of conjugated bilirubin in plasma becomes covalently bound to albumin (referred to as delta bilirubin) which cannot be excreted into urine. Of note, this delta bilirubin will take longer to resolve than typical hyperbilirubinemias as its half-life becomes that of albumin, which is 14 to 21 days. Approximately 80% of bilirubin in bile is in the form of diglucuronides, with the rest being in the form of monoglucuronides and only trace amounts being unconjugated.

Normal serum bilirubin concentration in adults is less than 1.2 mg/dL or <20 µmol/L. Jaundice is generally not evident until serum concentrations exceed 3 mg/dL or 50 µmol/L. In healthy adults, <5% circulates in its unconjugated form.

Depending on the laboratory method of measurement, bilirubin concentration may be reported as total and conjugated, or potentially as total, direct, and indirect. Indirect bilirubin is not directly equivalent to unconjugated bilirubin and reliance on direct and indirect measurements can lead to errors in the diagnosis of isolated disorders of bilirubin metabolism. Measurement of the total and conjugated fraction is more useful. However, in disorders with prolonged cholestasis such assays may underestimate the conjugated bilirubin concentration because they do not accurately detect albumin-bound conjugated bilirubin (delta bilirubin). Even with modern assay techniques, the levels of total and conjugated bilirubin are often not able to distinguish hepatic disorders from biliary obstruction. Nevertheless, when combined with history and physical examination, jaundice can be characterized as obstructive or nonobstructive in over 75% of cases.

ETIOLOGY OF JAUNDICE

Table 104-1 lists possible causes of jaundice. The key step to determine management relies on differentiating whether the cause of hyperbilirubinemia is due to biliary obstruction or not.

Nonobstructive jaundice is often due to global hepatic or systemic disease for which the treatment is supportive and directed at the underlying disease. However, drugs and hepatotoxins as causative agents should be ruled out as specific time-sensitive antidotes exist (eg, n-acetyl-cysteine for acetaminophen toxicity).²

The common causes of obstructive jaundice in patients requiring ICU care include choledocholithiasis (stones in the common bile duct) with cholangitis,³ Mirizzi syndrome (cholecystitis with extrinsic compression of the common bile duct),⁴ biliary or pancreatic malignancies, severe pancreatitis, and postsurgical biliary strictures or complications. The importance in recognizing these causes is that many of them require surgical or urgent invasive therapies for effective treatment.

INVESTIGATION OF JAUNDICE

The patient’s history and physical examination provide important clues regarding the cause of jaundice. Important aspects of the history include presence of biliary and/or systemic symptoms, previous biliary tract disease or procedures such as ERCP, and previous biliary or intestinal surgery that may have resulted in altered biliary anatomy (eg, Whipple, Billroth II, bariatric procedures). The patient’s risk factors for viral infections should be assessed including any history of travel or blood transfusions. A history of alcohol use and/or abuse as well as exposure to hepatic toxins or recreational drugs is important. Any family history of hepatic or biliary disease, Gilbert syndrome, or hemoglobinopathy should be sought out. Physical examination may reveal abdominal scars, masses, areas of tenderness, or signs of existing liver disease. Laboratory investigation should begin with obtaining a CBC, alkaline phosphatase, serum transaminases (ALT and AST), bilirubin, lipase, albumin, and coagulation profile. Use of diagnostic imaging and modality will be guided by the clinician’s assessment of the most likely etiologies, but an abdominal ultrasound is a useful and common initial investigation. An algorithm for the investigation of jaundice is depicted in Figure 104-2.

TREATMENT

Treatment of obstructive jaundice generally involves relief of the obstruction with invasive endoscopic, interventional radiologic, or surgical therapies. Nonobstructive causes largely require supportive therapy although specific medical therapies do exist for some diseases. Below we discuss several select causes of jaundice seen in the ICU setting.

Cholangitis: Acute cholangitis, also known as ascending cholangitis, is a bacterial infection of the biliary tract that occurs in an obstructed system and leads to systemic signs of infection.⁵ The leading cause of cholangitis is choledocholithiasis (common bile duct stones). The prevalence of gallstones (cholelithiasis) is estimated to be 10% to 20% in Western populations,^6-8 with approximately one-quarter of these patients becoming symptomatic during their lifetime. Choledocholithiasis occurs in 10% to 20% of patients with symptomatic gallstone disease, and it’s these patients who are at risk for the development of acute cholangitis.⁵

The clinical diagnosis of acute cholangitis was first described by Charcot in 1877 and consists of the triad of fever, jaundice, and right upper quadrant pain. In 1959, Reynolds and Dargan added two other worrisome clinical findings (mental confusion and hypotension) associated with worse outcomes and this constellation of signs was subsequently termed Reynold pentad.⁹ The gold standard method of diagnosis is confirmation of biliary infection as the source of systemic illness by aspiration of purulent bile. However, this procedure is seldom done for diagnostic purposes, and thus the diagnosis of acute cholangitis continues to be made clinically. The diagnostic criteria developed by the Tokyo international consensus conference in 2006 are listed in Table 104-2.¹⁰

Diagnostic imaging in patients with cholangitis can serve to make the diagnosis as well as reveal the etiology of the biliary obstruction. Abdominal ultrasound, historically the first imaging test used in the investigation for biliary obstruction, continues to be extremely useful in the ICU setting. Its advantages include being able to be performed at a patient’s bedside, not requiring the use of intravenous nephrotoxic radiocontrast dye, being noninvasive, and widely available. Although obscuration of the distal common bile duct by overlying bowel gas is not uncommon and contributes to its lack of sensitivity for visualizing stones, it provides excellent visualization of the intrahepatic and proximal biliary tree and gallbladder, thereby allowing a diagnosis of biliary dilation to be made and the level of biliary obstruction (intrahepatic, proximal extrahepatic, or distal extrahepatic) to be determined. More recently, studies have demonstrated favorable accuracy of endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP) when compared to endoscopic retrograde cholangiopancreatography (ERCP),¹¹ as well as favorable accuracy of computed tomographic cholangiography (CTC) when compared to EUS in the diagnosis of choledocholithiasis.¹² EUS has been recently recommended by the American Society for Gastrointestinal Endoscopy as being highly accurate with fewer complications than ERCP in the detection of choledocholithiasis.¹³ Computed tomography provides imaging of not just the biliary system but the surrounding liver, pancreas, and foregut as well, making it an important investigative technique in determining the etiology of the biliary obstruction. ERCP is generally reserved as a primarily therapeutic procedure,³ although it may be used for diagnosis in centers without the availability of other noninvasive modalities.

Treatment of acute cholangitis depends on its severity and response to supportive therapies. Supportive care with early intravenous fluid resuscitation and broad-spectrum antibiotics is standard. The most common bacterial pathogens include Escherichia coli, Klebsiella, Enterobacter, Streptococcus, and Enterococcus,^14,15 with Clostridium being the most common anaerobe. Patients with biliary stents in situ have a higher rate of polymicrobial infection (90% vs 45% of those without stents).¹⁵ Although no specific guidelines for antibiotic therapy exist, broad-spectrum coverage for the above listed common organisms including anaerobic coverage should be used, with definitive antimicrobial therapy based on the culture and sensitivity results obtained from blood if bacteremia is present and otherwise from bile cultures. However, the most important therapy is providing expeditious and effective biliary drainage. Without drainage the increased pressure in the biliary system creates ongoing cholangiovenous reflux of bacteria with resultant bacteremia and sepsis, as well as preventing effective secretion of antibiotics into the biliary system.¹⁴ A Cochrane review summarizes the superiority of ERCP compared to open surgery in the treatment of bile duct stones and cholangitis.¹⁶ Surgical and percutaneous biliary drainage is reserved for those cases where ERCP is unsuccessful or contraindicated such as some patients with a Roux-en-Y biliary-enteric anastomosis, bariatric procedures such as gastric bypass or duodenal switch, or a Billroth II reconstruction.¹⁷ Of note, removal of stones, if the causative etiology, is not necessary in the acute setting and can be performed electively at a later time so long as a stent can be successfully placed acutely.¹⁸ Patients admitted to the ICU with cholangitis are most likely to have a severe form and require early supportive therapy as outlined above as well as emergent biliary drainage.^10,19 Patients without organ failure who respond to antibiotic therapy may be treated by ERCP within 24 to 48 hours.⁵

Patients who develop cholangitis as a complication of biliary stone disease should be referred for eventual elective cholecystectomy.¹⁹ These patients are at risk of recurrent cholangitis and other biliary complications (Fig. 104-3 illustrates biliary obstruction due to choledocholithiasis). A Cochrane review of over 600 patients randomized to endoscopic sphincterotomy or cholecystectomy for the treatment of choledocholithiasis demonstrated significantly reduced complication rates in the group that received an elective cholecystectomy as definitive treatment.²⁰

Acalculous Cholecystitis: Acalculous cholecystitis is an acute inflammatory disease of the gallbladder that frequently presents in the ICU as fever or an elevated white count of unknown origin, or right upper quadrant pain.²¹ It is associated with elevated liver enzymes and jaundice in up to 20%. The pathophysiology is thought to be due to gallbladder stasis, endothelial injury, and ischemia leading to inflammation and necrosis of the gallbladder. A number of infections (eg, Epstein-Barr, cytomegalovirus, Campylobacter jejuni, Vibrio cholera) are also associated with development of acalculous cholecystitis, along with more commonly seen ICU risk factors such as prolonged lack of enteral feeds, total parenteral nutrition, mechanical ventilation, burns, shock, sepsis, massive transfusion, diabetes, renal failure, and cardiovascular disease.

Ultrasound is the investigation of choice, although the diagnosis can also be made by CT. Management consists of appropriate resuscitation, broad-spectrum intravenous antibiotics (covering enteric bacteria such as E Coli, Enterococcus, Klebsiella, Pseudomonas, Proteus, and Bacteroides), and prompt surgery consultation. For those able to tolerate the operative procedure without undue risk, laparoscopic cholecystectomy provides definitive source control and prevents recurrence. In those deemed not an appropriate candidate for surgery, a percutaneous drain placed by interventional radiology has been shown to be almost as effective as surgery in most patients.²² Providing the patient recovers, studies have shown that subsequent cholecystectomy is not needed in all patients.²³ In such cases, the percutaneous drain is left in place for several weeks to ensure development of a fibrous tract, and a cholangiogram is done via the tube to ensure the absence of persistent gallbladder or biliary obstruction or leak, prior to drain removal.

Morbidity and mortality of acalculous cholecystitis increases with delay in diagnosis and management, with mortality as high as 75% having been reported in critically ill patients. As such, a high index of suspicion and early diagnosis plus surgery consultation are recommended.

Parenteral Nutrition–Associated Cholestasis: Total parenteral nutrition (TPN) is associated with a number of significant side effects including steatosis, lipidosis, and cholestasis.²⁴ The mechanisms are multifactorial, with TPN promoting bacterial overgrowth in enterally unstimulated bowel, which in turn favors conditions known to induce cholestasis such as translocation of intestinal endotoxins into the portal venous system, bacterial sepsis, and formation of lithogenic bile acids.²⁵ Long-term TPN therapy results in gallbladder akinesis, biliary stasis, and biliary sludge that promotes the formation of gallstones, which in turn contribute to obstructive forms of jaundice as well as acalculous cholecystitis. Persistent parenteral nutrition–associated cholestasis (PNAC) can progress to cirrhosis and eventual liver failure.²⁵ Efforts to treat PNAC include cyclical TPN, decreasing dextrose and fat amounts, promoting enteral nutrition, treating bacterial overgrowth, and discontinuation of TPN altogether.²⁵

Postsurgical, Trauma, and Other: Jaundice is a common postoperative complication of surgery, most commonly occurring in cardiac surgery,²⁶ hepatobiliary surgery including liver transplantation, and surgery complicated by, or for the treatment, of sepsis.²⁷ Not unexpectedly, hepatobiliary and pancreatic surgeries are associated with multiple potential complications (vascular thrombosis, strictures, leaks, hepatic insufficiency), and thus in such patients, early surgical consultation is advised.^28,29

Bile leakage into the peritoneal cavity may be reabsorbed by the peritoneal lining and manifest as hyperbilirubinemia, such as in a post-laparoscopic cholecystectomy missed bile duct injury, perforated acalculous cholecystitis, or severe liver trauma. Another interesting but rare cause of jaundice in postoperative or trauma patients is hematobilia which often presents as jaundice, severe right upper quadrant pain, and melena. Hemolysis can also occur in the postoperative setting especially in patients who received large amounts of red blood cell transfusions, those with hemoglobinopathies including sickle cell disease, and those susceptible to any pro-oxidant medications (eg, patients with glucose-6-phosphate dehydrogenase deficiency) that may have been given perioperatively.

Severe hypotension and ischemia can also produce a condition termed “shock liver”³⁰ with a clinical pattern of a rapid rise in serum aminotransferases to levels 10 to 100 times the upper limit of normal, along with delayed and less significant rises in bilirubin. Levels subsequently plateau within a few days and the fall steadily with return to normal levels.²⁴ Gilbert syndrome, characterized by a relative deficiency of hepatic UDP-glucuronyl transferase, may also become unmasked by the stress of surgery or infection and a self-limited asymptomatic rise in bilirubin may occur. There are also many drugs that can cause injury to the liver and an examination of the patient’s medications and doses, including any herbal or recreational agents used, is important when searching for an etiology of jaundice.

INTRODUCTION

The occurrence of gastrointestinal complications in the critically ill patient is common.³¹ A multicenter study of 400 patients conducted in Spain in 1999 found that diarrhea complicated 15% of patients admitted to the ICU.³² A similar study of over 1300 ICU patients published 10 years later reported a 14% incidence of diarrhea.³³ The occurrence of diarrhea continues to complicate the care of ICU patients and its management is an ongoing challenge, especially in the face of recommendations for earlier and more aggressive enteral feeding.^34,35 This section will discuss the approach and management to diarrhea that develops in the critical care patient, followed by a separate discussion of Clostridium difficile.

CAUSES OF DIARRHEA IN CRITICAL CARE

While diarrhea can be classified into osmotic, secretory, infectious, or noninfectious, the causes of diarrhea in the critically ill patient can be simplified to those due to infection, medication, oral or enteral feeds, or preexisting intestinal disorders of absorption or motility. Most diarrhea in the ICU is acute in onset (<14 days) as opposed to persistent ≥14 days or chronic ≥4 weeks.³⁶ Infection must always be considered and ruled out in any new-onset diarrhea (see Fig. 104-4 and Tables 104-3 and 104-4). A careful history including any collateral information from the patient’s family or close associates may reveal a preexisting condition such as lactose intolerance, celiac disease, inflammatory bowel disease, or irritable bowel syndrome. Investigation generally involves fecal specimen analysis for common bacterial and viral pathogens, and assessment for the presence of fecal toxins when infection with C difficile or enterotoxigenic/enterohemorrhagic bacteria is suspected. Routine testing for ova and parasites is not cost-effective for the majority of patients,³⁷ but should be considered in the setting of persistent diarrhea, patients with a history of travel to a high risk area, and immunocompromised patients.³⁶

Medications are another cause of diarrhea by a variety of mechanisms. Antibiotics are frequently associated with diarrhea by altering the colonic flora, and laxatives and prokinetics increase intestinal motility. Acid-suppressive medications also have an inherent propensity to cause diarrhea (up to 7% of proton-pump inhibitors) and many oral electrolyte formulations or antacids are known irritants to the gastrointestinal mucosa (magnesium, phosphates). A study of 27 ICU patients treated for constipation showed 70% of them subsequently developed diarrhea,³⁸ and another study showed diarrhea resolved in over 25% of patients following the discontinuation of laxative therapy.³⁹ Many oral medications are hyperosmolar and/or contain sorbitol which can cause GI intolerance especially when given in large volumes. Sorbitol is a sugar alcohol that is used as a sweetener in many oral liquid medications and is known to cause osmotic diarrhea and cramping when ingested in amounts over 10 to 20 g in healthy volunteers.⁴⁰ The amount of sorbitol is often not specified on medication labels as it is an inactive ingredient, and thus the amount of sorbitol being delivered to a patient is often difficult to determine.

MANAGEMENT OF DIARRHEA IN CRITICAL CARE

Fluid and electrolyte repletion is an important initial therapy as large-volume diarrhea can quickly lead to significant fluid, electrolyte, and acid-base disturbances; repletion should be accomplished via the intravenous route until the etiology of the diarrhea is determined.

The patient’s medication list should be examined for causative agents and these should be discontinued or substituted with alternative medications or routes of administration when appropriate. Sorbitol-containing liquid medications should be discontinued and sorbitol-free formulations or crushed tablets used when available. Dilution of any necessary hyperosmolar medications should be considered.^41,42

Antimotility and antidiarrheal agents should be reserved for those patients whose diarrhea persists despite the identification and treatment of the underlying cause. C difficile infection should specifically be ruled out as antimotility agents in this setting can precipitate the development of a toxic megacolon.⁴³ Antimotility agents include loperamide, diphenoxylate/atropine, and oral narcotic derivatives. Loperamide is advocated as the medication of choice as it has the lowest risk of central nervous system adverse effects.⁴² Bismuth subsalicylate is less effective than loperamide and lacks supporting data to recommend its use.⁴⁴ Cholestyramine is effective in the treatment of diarrhea caused by bile acid malabsorption (eg, patients with short bowel syndrome, terminal ileum resection, postcholecystectomy) but given concerns about binding to other medications—most notably oral vancomycin⁴⁵—and the lack of data outside of these specific patient populations, its general application is not recommended.

The composition of enteral nutrition formulas (ENF) can also be responsible for diarrhea and modification of these components can bring resolution.³¹ ENF with high osmolality may cause diarrhea, especially when being fed directly into the small bowel, and changing to a lower osmolality formula may alleviate diarrhea.^46,47 Some ENF may contain poorly absorbed and rapidly fermentable short-chain carbohydrates collectively termed FODMAPs (fermentable, oligo-, di-, monosaccharides, and polyols).^41,48 These act similarly to undigested lactose and include fructooligosaccharides (FOS), galactooligosaccharides (GOS), and fructose. FODMAPs significantly increase output from the small bowel due to osmotic effects and present rapidly fermentable substrates to colonic bacteria with subsequent excessive and ongoing gas production. Dietary FODMAPs have even been shown to induce symptoms in healthy volunteers,^49,50 and their role in intestinal dysmotility in the ICU is an area of active research.

Fiber is also often incorporated into the ENF or be added as a supplement. Fiber can be classified as soluble or insoluble, and each has different effects. Soluble fibers, typically found in fruits and vegetables⁵¹ (eg, partially hydrolyzed guar gum, fructooligosaccharides, pectin, inulin, psyllium), are fermented by colonic anaerobic bacteria to short-chain fatty acids.⁴² These fatty acids are a preferred fuel for colonocytes and may mitigate diarrhea by improving sodium and water reabsorption in the colon.⁵² Insoluble fibers, typically found in whole grains (eg, cellulose and hemicellulose) may decrease diarrhea by increasing stool bulk and absorbing water.^42,51 Many types of fiber have been studied in the prevention and treatment of diarrhea in patients. Conflicting meta-analyses have been published^53,54 although the more recent analysis including over 1700 patients in 51 studies showed a reduction in the incidence of diarrhea with fiber supplementation of enteral feeds.⁵³ The SCCM and ASPEN guidelines state that the use of soluble (but not insoluble fiber) may be useful in patients who develop diarrhea while receiving enteral nutrition.³⁴

Modification of the microflora of the gastrointestinal tract is another area of active investigation and its role in the ICU has yet to be determined. Probiotics are a preparation or product containing viable defined microorganisms in sufficient numbers which alter the microflora by implantation or colonization in a compartment of the host and that exert beneficial effects in the host. Prebiotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of one or a limited number of bacteria in the colon, and thus improve the health of the host. Synbiotics are a combination of prebiotics and probiotics able to modulate gut immunity and facilitate nutrient/factor interaction necessary for gut recovery.⁵⁵ A review of the literature by Isakow in 2007 found no evidence for the use of probiotics in critically ill patients.⁵⁶ The SCCM/ASPEN Clinical Practice Guidelines published in 2009 state there exist insufficient data to make recommendations for general usage in the ICU population.³⁴ There are currently a number of active trials investigating their use in the ICU population.

Finally, the method of delivering enteral feeds can also cause diarrhea with continuous feeding potentially having a lower incidence compared with intermittent feeding.^57,58 Bacterial contamination of enteral feeds has also been postulated as a cause of diarrhea although data for this are lacking.³⁴

CLOSTRIDIUM DIFFICILE

The Clostridium difficile bacillus was first described in 1935, although its association with disease was not identified until 1978.⁵⁹Clostridium difficile infection (CDI) has become an increasingly common cause of health care–associated diarrhea and an increasingly common reason for admission to the intensive care unit (ICU).^60-63

The prevalence of asymptomatic colonization with C difficile is 7% to 26% among adult inpatients in acute care facilities.⁴³ The primary reservoirs of C difficile are colonized or infected patients and contaminated environments and surfaces within hospitals.⁶⁴ Recently, there have been major outbreaks of CDI in North America, England, Europe, and Asia, and the emergence of more virulent strains is leading to greater numbers of infected patients with greater disease severity and mortality.^63,65-67

Pathogenesis of Clostridium Difficile: C difficile is an anaerobic gram-positive spore-forming bacillus that most commonly exists in a vegetative form that is readily killed by even brief exposures to oxygen.⁶⁸ When in its spore form, it is heat stable and resistant to gastric acid and many ethanol-based disinfectants. It is transmitted via the fecal-oral route, from person to person and fomite to person.

In healthy adults, the colon contains more than 500 species of bacteria,⁶⁹ some of which antagonize the adherence and proliferation of C difficile in the colonic crypts. Creation of a suitable local environment allows C difficile reproduction and the generation of toxins, thereby establishing CDI. The pathogenesis of CDI is dependent on the three events: alteration of normal fecal flora, colonic colonization with toxigenic C difficile, and growth of the organism and elaboration of its toxins.⁶⁴

C difficile toxin A (enterotoxin) and B (cytotoxin) are both exotoxins. Toxin B is more potent (up to 10×) than toxin A and demonstrates cytotoxic effects,⁶⁸ but both cause increased vascular permeability by opening tight junctions between cells. They both induce the production of TNF-α and proinflammatory cytokines which contribute to the associated inflammatory response and formation of colonic pseudomembranes. The majority of toxigenic C difficile strains produce both toxins, but approximately 1% to 2% of strains in the USA are negative for toxin A.⁴³

In 2002, hospitals in Quebec, Canada, began experiencing an epidemic of CDI with over 14,000 nosocomial cases reported between 2003 and 2004 with a mortality rate of almost 14% (historic controls had 2% mortality).^43,66 Similar outbreaks were also reported in a handful of US states. In 2005, the NAP1/B1/027 epidemic strain of C difficile was reported as the causative strain in these outbreaks with its increased virulence traced to its ability to produce 16 × more toxin A and 23 × more toxin B than control strains, as well as uniformly carrying the gene for binary toxin.⁶⁶ Further studies demonstrated this strain to have resistance to fluoroquinolone antibiotics that was new when compared to historic isolates.⁶⁵ A recent assessment shows this strain has now spread to over 40 US states and 7 Canadian provinces, and caused outbreaks in England, Europe, and Asia.^43,62,63 Infection with this strain may mean a reduced time from the development of symptoms to severe disease and thus require more aggressive therapy and monitoring.^70,71

Identified risk factors for the development of CDI include age ≥65 years, increased duration of hospitalization, exposure to antimicrobial agents (with longer exposure and exposure to multiple antimicrobials increasing this risk), cancer chemotherapy, gastrointestinal surgery, and gastric acid suppression.^43,68 Prognostic factors for poor outcome following CDI include advanced age, comorbidities, decreased antibody response to the infection, gastric acid suppressants, the need to prolong inciting antibiotic therapy, immunodeficiency, and ICU admission.^62,71

Clinical Presentation of Clostridium Difficile: CDI symptoms present at a median of 2 to 3 days after colonization. Typical clinical features consist of watery, grossly nonbloody diarrhea and abdominal pain. Systemic features can include fever, anorexia, nausea, malaise, and a leukocytosis. Severe disease can develop a colonic ileus and toxic dilation with minimal or no diarrhea. Complications of CDI include dehydration, electrolyte imbalances, hypoalbuminemia, renal failure, toxic megacolon, colonic perforation, SIRS, sepsis, shock, and death. Fulminant colitis occurs in 1% to 3% of patients and the hospital mortality associated with toxic megacolon is reported as 24% to 38%.^64,72

Diagnosis of Clostridium Difficile: Diagnosis is made based on a combination of clinical and laboratory information. Recently published US and European guidelines have better defined this disease and its treatment.^43,71,73 CDI is defined by the presence of symptoms (usually diarrhea) and either a stool test positive for C difficile toxins or toxigenic C difficile, or colonoscopic or histopathologic findings revealing pseudomembranous colitis. Laboratory testing should only be performed on diarrheal stool unless ileus due to CDI is suspected, and it is not recommended to test asymptomatic patients or use as a test of cure.⁶⁸ Although stool culture is the most sensitive test, it requires 2 to 3 days for results. Enzyme immunoassays (EIA) for toxin are rapid but have historically had poor sensitivity. However, newer EIA and polymerase chain reaction tests for toxin have high sensitivity and specificity rates.⁷⁴ Since no testing strategy is 100% sensitive and specific, clinical suspicion and consideration of patient risk factors remain important in making clinical decisions about treatment.^43,71 This is particularly important for the up to 37% of fulminant CDI that present with ileus rather than diarrhea.

In CDI patients with ileus, and some with diarrhea, the diagnosis can sometimes be made endoscopically. Pseudomembranes are islands of neutrophils, fibrin, mucin, and cellular debris that can be appreciated histologically or on direct visualization via endoscopy.⁶⁴ Of the patients who are diagnosed with combined laboratory and clinical criteria, approximately 50% of these cases will have pseudomembranes on direct visualization or on histopathologic examination, but the percentage with pseudomembranes in severe disease can be as high as 85%. Thus, although endoscopy is not a sensitive test, the visualization of pseudomembranes is sufficiently specific to confirm the diagnosis of CDI.

Radiographic imaging may also provide information suggestive of CDI. Abdominal x-ray may show “thumbprinting” which is representative of colonic haustral thickening that can be seen in any form of colitis. Abdominal computed tomography (CT) is a more sensitive test to assess for radiographic features of colitis (see Fig. 104-5).⁶¹ In the authors’ experience, an advantage of CT lies in its ability to help identify the etiology of undifferentiated severe abdominal sepsis while confirmatory laboratory testing is pending. A patient hospitalized with new onset abdominal sepsis, diarrhea, and pancolitis on CT scan has CDI until proven otherwise and requires immediate empiric therapy.

Treatment of Clostridium Difficile

Medical Medical therapy for CDI largely revolves around antibiotic therapy and supportive care. The various society guidelines vary depending on the severity of disease, with most recommending for severe cases the use of oral vancomycin alone or in combination with intravenous metronidazole. There are also a number of other important aspects for CDI management. First, the inciting antibiotics should be discontinued if possible. In severe cases, empiric therapy should be initiated as soon as the diagnosis is suspected and not delayed for laboratory confirmation. Antiperistaltic agents should be avoided as they may obscure symptoms and precipitate toxic megacolon. Also, appropriate infection control measures including glove and gown contact precautions for the duration of the diarrhea, hand hygiene compliance, and private rooms for CDI patients should be instituted.

In addition to these standard therapies, multiple adjunctive therapies have been proposed but generally lack sufficient evidence to recommend. For example, both the US and European guidelines state there is no role for the use of probiotics in the treatment or prevention of CDI.^43,71 Similarly the data on the effectiveness of IVIG are not particularly compelling and until sufficient evidence is available its use is not recommended. In vitro and animal data showed that both cholestyramine and colestipol bind the toxins produced by C difficile.⁴⁵ Unfortunately, these agents also bind vancomycin, thereby decreasing the amount of active drug available. Given the lack of evidence and the current recommendation for vancomycin as first-line therapy for severe CDI, anion-exchange resins are not recommended. Fecal transplantation is another treatment that has recently shown promise for recurrent CDI, but it similarly at present has no role in acute severe CDI.

There are a number of antibiotics whose role in CDI is evolving.⁷⁵ Nitazoxanide, an antiprotozoal drug, has been shown to be at least as effective as both metronidazole and vancomycin in small randomized controlled trials.^73,76 Although not available in the United States, the use of teicoplanin is endorsed by both US and European guidelines as being equally efficacious to vancomycin and metronidazole. Rifaximin is an antibiotic with minimal absorption in the gastrointestinal tract after oral administration that has been reported to be effective against C difficile.⁷⁷ Fidaxomicin is a new nonabsorbed macrocyclic antibiotic that has recently has been approved by the US Food and Drug Administration for treatment of C difficile, with studies suggest it is noninferior to oral vancomycin in mild to moderate CDI cases.⁷⁸

Surgical Surgical therapy for CDI is indicated for toxic megacolon, perforation, failure of medical therapy, and fulminant disease. While the former two indications are relatively easy to identify, the latter two can be more difficult. Clinical response to medical therapy may take 48 to 72 hours to manifest.⁷⁹ Multiple retrospective series have sought to identify predictive factors that could be applied to decide when such patients would benefit from an early colectomy.^61,80-82 Certain factors such as lactate level of 5.0 mmol/L or greater,⁶¹ WBC >37⁸⁰ or >50,⁶¹ use of preoperative vasopressors, preoperative single or multiorgan failure, and immunosuppression have been identified as predictive of mortality. While there are no prospectively validated data to confirm the clinical utility of these factors, it is the opinion of the authors that after the initial resuscitation and institution of antibiotic therapy of patients with CDI admitted to the ICU, any new onset or worsening of existing organ failure, increasing lactic acidosis, increasing WBC, or the requirement for vasoconstrictor medications for support should prompt consideration of surgical therapy, with a lower threshold applied to those who are immunocompromised.

The gold standard surgical treatment for severe CDI currently is a total abdominal colectomy with sparing of the rectum and creation of an end ileostomy.⁸³ Unfortunately, this operation is associated with high mortality and morbidity. In a retrospective analysis of the Quebec 2003-2005 CDI outbreak series, following adjustment for several confounders, the group undergoing this surgery had lower mortality (adjusted odds ratio of 0.22; 95% CI, 0.07-0.67; p = 0.008) versus those managed nonoperatively⁶¹; but the 30-day mortality for the surgical group was 34%! A recent long-term follow-up study of patients treated with colectomy for CDI found 1-year, 2-year, 5–year, and 7-year mortality of 68.5%, 79.6%, 88.9%, and 90.7%.⁷² In an effort to improve outcomes, another surgical technique—a diverting loop ileostomy and colonic lavage—has recently gained favor. A preliminary study using this new approach suggested a much lower early mortality of only 19%.⁸⁴ Further studies are ongoing to better define the optimal surgical approach.⁸³

Intestinal obstruction develops when air and secretions are prevented from passing normally as the result of mechanical blockage. Mechanical blockage can occur due to extrinsic compression of the bowel, or intrinsic obstruction from an abnormality of the bowel wall or intraluminally (see Tables 104-5 and 104-6).

Obstruction can occur at any point along the entire gastrointestinal tract from oropharynx to anus. It is classified in a number of important ways that direct management:

• Anatomical location (ie, esophageal, gastric, small bowel, colonic)

• Complete or incomplete

• Mechanism (ie, adhesions, masses, hernia, volvulus)

Additionally, for obstruction caused by hernias, it is important to determine whether the contents of the hernia (ie, the portion of the intestine stuck in the hernia sac) are incarcerated (cannot be reduced to their normal anatomical location with physical manipulation) or strangulated (compromised blood flow resulting in bowel ischemia). Obstruction can occur at a single point in the bowel or at two points in a loop, termed a closed-loop obstruction. A closed-loop obstruction can occur (1) within hernias where the bowel is obstructed at the entrance and exit point of the hernia, (2) with adhesive obstructions where the bowel twists around a fixed point, (3) with any volvulus (colonic, gastric, small bowel), (4) and potentially with colonic obstruction in a person with a competent ileocecal valve that will not allow the colonic contents to reflux and decompress in a retrograde fashion into the small bowel. The importance in classifying the nature of the obstruction is to assess for the presence of, and determine the risk of, bowel ischemia. Conditions that result in compromised viability of the bowel or those that have no meaningful chance of spontaneous resolution require emergent operation. Obstruction that does not result in immediate or impending bowel ischemia can be given a trial of nonoperative management depending on the likely underlying etiology.

WORKUP OF BOWEL OBSTRUCTION AND MANAGEMENT

The investigation of intestinal obstruction depends on important clues from the history if available, physical examination, and appropriate radiologic imaging. A history of clinical obstructive features (vomiting, obstipation, bloating) can make the diagnosis, and history of previous malignancies and abdominal operations can provide clues regarding the etiology and location of the obstruction along the gastrointestinal tract. A physical examination is essential to exclude hernias or rectal obstruction as an etiology, as well as to assess for any signs of peritoneal irritation that may indicate complications of obstruction such as ischemia or perforation. An approach to the evaluation of ileus with or without abdominal distension is presented in Figure 104-6. Although many modalities for imaging intestinal obstruction exist, none is as singularly useful as a CT scan of the abdomen.

SMALL BOWEL OBSTRUCTION

Small bowel obstruction (SBO) is a common clinical problem (see Table 104-5 for causes) and is due to adhesions from previous surgery in 60% of cases, and may occur in up to one-third of all patients who have abdominal surgery.⁸⁵ The Eastern Association for the Surgery of Trauma Practice Management Guidelines for the Management of Small Bowel Obstruction state that all patients being evaluated for SBO should have plain abdominal films to differentiate obstruction from nonobstruction, and inconclusive plain films for complete or high-grade obstruction should have a CT of the abdomen.⁸⁶ In detecting a high-grade small bowel obstruction, abdominal plain films are as sensitive as CT.⁸⁶ The American College of Radiology guidelines corroborate this approach, as it lists CT of the abdomen (with intravenous contrast but not oral contrast) as the most appropriate radiologic investigation of a suspected complete or high-grade partial small bowel obstruction. CT can provide information regarding the presence or absence of obstruction, its anatomical location, the degree of the obstruction, the presence of complicating features such as ischemia or perforation, as well as if any other intra-abdominal cause of ileus is present should no obstruction be found. Recent studies have demonstrated CT to have an accuracy of 85% to 100%^86,87 in diagnosing strangulation, with accuracy increased when combined with classical clinical criteria such as the presence of tachycardia, fever, abdominal tenderness, and leukocytosis.⁸⁷ CT findings suggestive of ischemia include mesenteric haziness, reduced wall enhancement, wall thickening, mesenteric fluid, mesenteric venous congestion, and ascites.

A partial small bowel obstruction can be treated successfully with nonoperative management in over 80% of cases, with a risk of progression to strangulation in 3% to 6%. As the vast majority of patients being treated nonoperatively improve within 48 hours, those that do not improve after such a trial should with rare exception be taken for surgery. Patients with complete small bowel obstruction require surgery with resection of compromised bowel in approximately 30% of cases.⁸⁶ As mortality is increased by up to sevenfold when an operation is performed for intestinal strangulation compared with simple obstruction, earlier surgery is preferred. Of note, there is no evidence supporting the use of routine antibiotics as adjunctive therapy in the nonoperative treatment of small bowel obstruction, and as such, antibiotics should only be used for patients with signs of intestinal compromise who are on their way to the operating theatre. There is also no evidence of benefit of long intestinal tubes over conventional oro- or nasogastric tubes.⁸⁶

LARGE BOWEL OBSTRUCTION

The investigation and management of large bowel obstruction have evolved considerably over the last decade. Etiologies of large bowel obstruction are listed in Table 104-6, with the most common causes in North America being malignancy (60%), volvulus (10%-15% of which 75% are sigmoidal and 20% cecal),⁸⁸ and strictures (10%). Large bowel obstruction can be diagnosed on plain abdominal x-rays with a sensitivity of 84%,⁸⁹ although differentiation from acute colonic pseudoobstruction may require additional imaging. When differentiating acute colonic pseudoobstruction from true obstruction, the use of a rectal contrast study is recommended. This may be in the form of a water-soluble enema or potentially CT scan with rectal contrast. Use of barium contrast is contraindicated in an obstructed colon as it is not necessary to make the diagnosis of obstruction, it can precipitate barium peritonitis in the setting of compromised bowel at risk of perforation, and its retention in the bowel will hamper any future radiographic imaging as it is extremely radiodense and causes significant artifact. A water-soluble contrast enema may be used in the investigation of volvulus where plain abdominal films are not diagnostic, but CT scan (± rectal contrast) is being increasingly used to diagnose these conditions.⁹⁰

Management of volvulus of the sigmoid colon is emergent endoscopic detorsion and elective resection to prevent recurrence, or emergent surgical exploration in the setting of bowel compromise.⁹¹ Cecal volvulus generally does not respond to endoscopic therapy and thus emergent surgery is the procedure of choice. Similarly, malignant colonic obstruction generally requires surgical resection for definitive management, although sometimes either endoscopy or interventional radiology can place stents in nonoperative candidates.^92,93

AN APPROACH TO ILEUS AND/OR FEED INTOLERANCE IN THE ICU

Unfortunately, up to 60% of ICU patients will experience gastrointestinal symptoms during their stay.^31-33 Both surgical and nonsurgical ICU patients often have multiple causes for ileus or pseudoobstruction (Table 104-7), in addition to being at risk for mechanical bowel obstructions. An algorithm for assessing ileus and/or abdominal distension is provided in Figure 104-6. In the case of a likely mechanical obstruction, remember that delay in surgical management increases morbidity and mortality.⁹⁴ Indeed, even experienced surgeons have been shown to be able to accurately predict the development of intestinal ischemia in only 50% of cases of complete small bowel obstruction.⁹⁵ Thus, if mechanical obstruction is high on the differential, early surgical consultation should be obtained.

Paralysis of the gastrointestinal tract, or ileus, is a common response in patients undergoing abdominal surgery, but it can also develop in response to a number of acute extra-abdominal and intra-abdominal conditions (see Table 104-7). Studies have demonstrated that ileus complicates up to 40% of ICU patients who have not had antecedent abdominal surgery.^32,33

The pathophysiology of ileus is incompletely understood, although is best described as multifactorial, involving abnormalities of the enteric nervous system, autonomic nervous system, neurohormonal pathways, and local and systemic inflammatory processes.^96-98 Vasoactive intestinal peptide, substance P, and nitric oxide have all been shown to play a role in the development of postoperative ileus. The body’s inflammatory response, whether as a result of direct intestinal manipulation by surgeons or from systemic illness, also plays a significant role in the development of ileus and helps explain the frequent occurrence of this condition in nonsurgical ICU patients.^32,98

Postoperative ileus is manifested by atony of the stomach, small bowel, and colon that usually resolves spontaneously within a few days. Typically the small bowel regains motility first, followed by the stomach then colon. Initial therapy is directed at identifying and correctly reversible causes (see Table 104-7) and providing relief of symptoms such as distension, nausea, or vomiting. Many studies have investigated methods of preventing or shortening the duration of postoperative ileus. While no such methods are universally accepted nor employed, the following have support for their use in the literature: laparoscopic surgical technique,⁹⁸ postoperative gum chewing,^99,100 judicious perioperative intravenous fluid administration,^101-103 nonopioid pain control medications (eg, NSAIDS),⁹⁸ use of local anesthetic epidural anesthesia instead of epidural or systemic narcotics,¹⁰⁴ and most recently, alvimopan¹⁰⁵ and methylnaltrexone.¹⁰⁶ Use of promotility agents such as erythromycin¹⁰⁷ or metoclopramide have not been shown to decrease postoperative ileus,^108,109 although they are useful in assisting with enteral feed tolerance in ICU patients and diabetic gastroparesis.³⁴ It is important to note that according to the SCCM/ASPEN guidelines, in the ICU setting the resolution of clinical ileus is not required in order to initiate enteral nutrition, and in fact, NPO status may prolong ileus.³⁴

Ileus without antecedent abdominal operation also commonly occurs in the ICU. Although the treatment of ileus in these patients is the same, it is important that the etiology is clarified sufficiently to exclude anything more ominous that may require surgery or other interventions. Similarly, when an ileus persists for an inappropriate length of time, investigation for an underlying obstructive or otherwise sinister etiology (eg, such as an intra-abdominal abscess) should be considered.

ACUTE COLONIC PSEUDOOBSTRUCTION

In 1948, Sir William Heneage Ogilvie described two cases of colonic dilation without obstruction,¹¹⁰ a phenomenon which was subsequently called Ogilvie syndrome. In the early 1980s, the term acute colonic pseudoobstruction (ACPO) was introduced.¹¹¹

ACPO is characterized by massive colonic dilation with symptoms and signs of colonic obstruction without mechanical blockage.¹¹² Although its exact prevalence is unknown, it most often affects those in their sixth decade of life with a slight male predominance (60% males).¹¹³ It is reported to occur in approximately 1% of orthopedic procedures,¹¹⁴ but is almost exclusively restricted to hospitalized or institutionalized patients with serious underlying medical and/or surgical conditions. Complications occur in 3% to 15% of patients and mortality rate can be up to 50%.^113,115,116

PATHOGENESIS OF OGILVIE SYNDROME

The exact mechanism of the development of ACPO has not been determined, but the most accepted theory is an imbalance in autonomic output to the colon, produced by a variety of factors, leading to excessive parasympathetic suppression or sympathetic stimulation.^112,116 Most patients who develop ACPO have multiple predisposing factors that include certain drugs, recent trauma or operation, infections, and metabolic disturbances (see Table 104-7).

CLINICAL PRESENTATION OF ACPO

ACPO is characterized by abdominal distension, pain, nausea ± vomiting, with variable passage of flatus or stools. On examination, the abdomen is tympanitic and bowel sounds are typically present. Abdominal distension usually develops over 3 to 7 days but can occur as rapidly as within 24 hours.¹¹³ The presence of marked abdominal tenderness, fever, and leukocytosis raises the suspicion of ischemia or perforation, although these findings are neither specific nor reliably sensitive for such complications. Radiographically, plain abdominal x-rays show colonic dilation primarily involving the proximal colon. Concomitant dilation of the small bowel suggests an ileus or distal colonic obstruction with an incompetent ileocecal valve. A reduction in distal colonic diameter or “cutoff sign” may be present, the presence of which begs the dilemma of whether there is an actual mechanical obstruction or not.

DIAGNOSIS OF ACPO

The differential diagnosis of ACPO includes mechanical colonic obstruction and toxic megacolon. As the name suggests, this disease presents with clinical and/or radiographic evidence of obstruction, and thus mechanical obstruction must always be ruled out before ascribing the patient’s condition to ACPO.

Distal mechanical colonic obstruction can be investigated with rectal examination, careful colonoscopy, CT (with IV and/or oral or rectal contrast),¹¹⁷ or with a water-soluble (never barium) contrast enema. The ASGE guidelines suggest the use of a water-soluble contrast enema to rule out obstruction which is reported to have a sensitivity of 96% and specificity of 98%.⁸⁹ Recently, CT with a sensitivity and specificity of at least 91% for determining the etiology of large bowel obstruction, while simultaneously ruling out complications such as ischemia and perforation, or other etiologies for the ileus (eg, tumors, intra-abdominal abscesses) has become the most frequently used test. Colonoscopy can be diagnostic and therapeutic, but is often contraindicated when ischemia or perforation is suspected and can be challenging to perform as the bowel is unprepared and insufflation must be kept to a minimum.¹¹⁶

TREATMENT OF COLONIC PSEUDOOBSTRUCTION

Once mechanical colonic obstruction and the presence of any complicating features such as ischemia or perforation have been ruled out, the initial therapy of ACPO is supportive and aimed at alleviating any predisposing factors and encouraging spontaneous resolution (see Fig. 104-7). The major risk factors for complications and poor outcome are the amount and duration of colonic distension.^113,118 By Laplace law, tension in the wall of the cecum is proportional to its radius. When the cecal wall tension exceeds that of capillary perfusion pressure, ischemia results and this can progress to infarction and perforation. Retrospective analysis of over 400 reported cases in the literature has shown that the risk of cecal perforation is negligible when its diameter is <12 cm, but increases steadily with increasing diameter.^113,116 Although duration of distension >6 days has been listed as a risk factor in some reviews,^112,119 examination of the primary literature reveals this number is based on a series of only 25 patients, five of which perforated, and of note, all patients who had cecal dilation for 4 days or less survived.¹¹⁸

Initial therapy includes giving the patient nothing per mouth, placing a nasogastric suction catheter to limit swallowed air from contributing further to colonic distension, intravenous correction of any fluid or electrolyte imbalances (Na, K, Ca, PO₄, Mg), investigation for contributing etiologies such as hypothyroidism and infection, discontinuation of any possibly offending medications, and mobilization as much as possible. Oral laxatives are avoided, particularly lactulose which results in further gas production via colonic bacterial fermentation.¹¹² Placement of a rectal tube ± tap water enemas may be included. Patients should be followed with serial physical examinations, plain abdominal radiographs every 12 to 24 hours, and serial laboratory tests including complete blood cell count and electrolytes. The reported success rates for this approach varies widely from 20% to 92%.¹²⁰

It is important to note that if at any point during treatment the patient’s condition deteriorates, investigation for ischemia and perforation should be undertaking immediately. Patients who fail to improve after 24 to 48 hours of conservative therapy should be considered for pharmacological therapy with neostigmine.

Neostigmine is an acetylcholinesterase inhibitor that works by increasing the amount of acetylcholine at the muscarinic receptors in the bowel (and elsewhere), thereby enhancing colonic motor activity. The onset of action is within a few minutes and lasts 1 to 2 hours when given intravenously. The typical dose is 2 mg IV given over 3 to 5 minutes and may be repeated once. Contraindications included hypersensitivity to the drug and gastrointestinal or genitourinary mechanical obstruction. Caution should be exercised administering neostigmine to patients with recent myocardial infarction, asthma, bradycardia, or renal failure. The most common side effects are abdominal cramping, excessive salivation, and bradycardia.¹²¹ Administration of neostigmine should only be done with cardiac monitoring and atropine available at the bedside. Of note, the administration of neostigmine to a patient with a mechanical colonic obstruction can also precipitate bowel perforation. To date, neostigmine use for ACPO has been reported in over 140 patients, with a pooled success rate of 87% and recurrence rate of 10%.¹¹² A randomized controlled study of 24 patients by van der Spoel et al examined the use of an IV infusion of 0.4 to 0.8 mg/h of neostigmine to treat colonic ileus in mechanically ventilated critically ill patients.¹²² The study found significant success in obtaining stool passage, but an exclusion criterion of the study was Ogilvie syndrome, and thus these results are not immediately generalizable to critical care patients with ACPO.

Sgouros et al performed a randomized controlled trial investigating the effect of administration of polyethylene glycol (PEG) solution after decompression of ACPO with the aim of decreasing recurrence rates.¹²³ Their study of 30 patients revealed a significant reduction in relapse (0 of 15 as compared with 5 of 15 patients) after the daily administration of 29.5 g of PEG in 500 mL of water in two divided doses for 1 week.¹²³

The use of lidocaine infusions to reduce the duration of postoperative ileus is also an area of active investigation.^124,125 Success with treatment of colonic pseudoobstruction with IV naloxone has also been reported.¹²⁶ Methylnaltrexone and alvimopan, both peripherally acting opioid antagonists, have recently been introduced to clinical practice and although they have not yet been reported to help with ACPO, their utility in treating opioid-induced bowel dysfunction is a promising area of investigation^106,127 and studies for ACPO are underway.

Endoscopic decompression for ACPO is now mainly used only in those patients who fail neostigmine or have a contraindication to its use. Success rates in large retrospective series approach 80% with recurrence rates of 20% to 40%.^115,116,128 The difficulty in negotiating an unprepared bowel with minimal insufflation contributes to the reported perforation rate of 2%.¹²⁰ Placement of a decompression tube has been shown to reduce the recurrence rate in some small studies and as such, is recommended.^112,129,130 Of note, if colonoscopy demonstrates ischemia, discontinuation of the procedure and immediate surgical consultation are advised.

Surgical management of ACPO is reserved for bowel ischemia or perforation. Historical use of surgical management of ACPO resulted in mortality rates double that of medical or endoscopic management (10%-14% vs 30%-35%).^113,115 Thus, surgery is only used for patients who fail endoscopic and pharmacologic efforts, and for those in whom another indication for surgery exists.

Finally, although percutaneous cecostomy—placed either radiologically or endoscopically—has been reported for the treatment of refractory cases, experience with this technique is limited. Less than 25 cases have been reported for the treatment of colonic pseudoobstruction, and many of these were patients with chronic bowel conditions.^131-137 Reported complications of this procedure include fecal peritonitis and death,¹³¹ and as such, this procedure is not currently recommended for ACPO.