107 Toxic Megacolon and Ogilvie’s Syndrome
Acute megacolon refers to a syndrome presenting as marked colonic distension in the absence of mechanical obstruction. It results from disturbed colonic motility1,2 and may be a manifestation of Ogilvie’s syndrome or toxic megacolon. Ogilvie’s syndrome, or acute colonic pseudo-obstruction (or its precursor, critical illness–related colonic ileus [CIRCI]),3 is a disease of seriously ill hospitalized patients and associated with myriad hemodynamic, metabolic, pharmacologic, inflammatory, and postoperative conditions. In toxic megacolon, distension is caused by severe colitis and is associated with systemic toxicity. Toxic megacolon is classically described as a complication of inflammatory bowel disease (IBD), usually ulcerative colitis, but in the critically ill, toxic megacolon mostly occurs as a complication of severe infectious colitis generally caused by Clostridium difficile. Whether secondary to IBD or C. difficile colitis, progressive colonic distension can lead to gut barrier failure, sepsis, ischemia, perforation, and multiple organ dysfunction. These potentially life-threatening complications must be prevented. This chapter focuses on toxic megacolon and Ogilvie’s syndrome in critically ill patients admitted to the intensive care unit (ICU) and proposes prevention strategies.
Clinical Features
Ogilvie’s Syndrome or Acute Colonic Pseudo-Obstruction
The hallmark of Ogilvie’s syndrome is abdominal distension with or without tenderness in hospitalized patients with serious comorbid disease.4–6 Patients may present with constipation, but flatus or stools may pass as well. Bowel sounds are normal, diminished, or high, and percussion is hypertympanic. Tenderness is most pronounced over the cecum. Nausea and vomiting may occur, but gastric retention is often minimal, and enteral feeding may be tolerated. If diagnosis and treatment are delayed, progressive distension may cause peritoneal signs, respiratory compromise, nutritional depletion, sepsis, multiple organ failure, ischemia, and perforation. Perforation most commonly occurs in the cecum. The risk of perforation is unlikely when cecal diameter is less than 12 cm but increases sharply when cecal diameter is 12 cm or more. CIRCI is characterized by constipation for many days without marked colonic distension. This syndrome may herald development of Ogilvie’s syndrome.3
Toxic Megacolon
Toxic megacolon is a serious complication of colitis. Patients present with fever, abdominal tenderness, and distension or even with an acute abdomen. IBD or infectious colitis commonly present with diarrhea, but a decrease in stool frequency may herald the onset of megacolon and delay diagnosis.2,7 Altered consciousness, dehydration, hypotension, tachycardia, leukocytosis, thrombocytopenia, low albumin, and electrolyte disturbances are common. In severe cases, systemic toxicity leads to septic shock and multiple organ failure.8–10 Ascending pylephlebitis and septic emboli in the superior mesenteric vein and liver are rare complications. Patients with ulcerative colitis are at highest risk of developing toxic megacolon early in their disease.11 Factors that may trigger toxic megacolon are early discontinuation or decrease in medications, use of antidiarrheal agents such as loperamide or opioids, severe hypokalemia, barium enema, and colonoscopy.
Gastrointestinal Motility
Intestinal motility is mainly under control of the enteric nervous system, an independently functioning complex network regulated by entero-enteric reflex pathways, the so-called enteric minibrain.12
Several types of motor activity are involved in intestinal propulsion; local reflex peristalsis after feeding and the migrating motor complex (MMC) during fasting are the most important.13 Local reflex peristalsis is activated by intraluminal distension (food), which stimulates the release of the neurotransmitter, serotonin. Release of serotonin triggers afferent neurons that activate excitatory motor neurons proximal to the site of the stimulus to release acetylcholine and substance P, resulting in contraction. Distal to the site of distension, inhibitory neurons are activated to release nitric oxide (NO) and vasoactive intestinal peptide (VIP), leading to relaxation.14 This nonadrenergic, noncholinergic, intrinsic inhibitory innervation (NANCI) is more pronounced in organs with a reservoir function, explaining why the stomach and proximal colon are more susceptible to distension than the small intestine.15
The MMC or interdigestive motility pattern is initiated by the hormone, motilin. The motilin receptor is expressed on enteric neurons of the human duodenum and colon.16 Many peptides, autacoids, and hormones influence MMC activity, including insulin, cholecystokinin, serotonin, opioids, dopamine, norepinephrine, somatostatin, and NO.17–19
The enteric nervous system is modulated by the central autonomic nervous system; the parasympathetic nerves promote and the sympathetic nerves suppress motility.20,21 Parasympathetic nerves to the right and transverse colon originate from the vagal nerve and those to the distal colon from the spinal cord (S2-4); they release acetylcholine. Sympathetic innervation of the colon runs through the spinal cord and the celiac and mesenteric ganglia. Sympathetic activations suppress contractions via the release of norepinephrine, causing a presynaptic inhibition of acetylcholine release from enteric neurons and also the release of other excitatory neurotransmitters such as serotonin from enteric nerve cells.22,23 Apart from inhibiting motility, sympathetic activation contracts the sphincters by a direct effect of norepinephrine on the smooth muscle; norepinephrine released by sympathetic neurons also affects vascular tone.
Pathogenesis of Megacolon
Colonic Ileus and Ogilvie’s Syndrome
The pathophysiology of Ogilvie’s syndrome is not fully understood. Increased sympathetic and suppressed or interrupted parasympathetic activity play a role. In addition, neurotransmitters, inflammatory mediators, metabolic derangement and pharmacologic interventions are directly or indirectly involved.20,21
Abdominal surgery induces hypomotility by a complex interaction of neurogenic and inflammatory mechanisms. Intestinal manipulation initiates norepinephrine release via sympathetic nerves from the spinal cord, as well as NO and VIP release via vagal nerve stimulation, causing inhibition of contractile activity and relaxation.21 Prolonged postoperative ileus involves inflammation of the intestinal muscularis, initiated by activation of peritoneal mast cells and resident macrophages. Activated mast cells release histamine and proteases, which recruit leukocytes and temporarily increase intestinal permeability with translocation of bacteria and bacterial products. Activated mast cells also stimulate resident macrophages to release cytokines such as tumor necrosis factor (TNF) and up-regulate inducible nitric oxide synthetase (iNOS) and cyclooxygenase (COX-2) expression; collectively, all of these factors inhibit motility. Local inflammation by influx of leukocytes in the muscularis mucosa and circulating cytokines subsequently activate neurogenic inhibitory adrenergic pathways, causing generalized hypomotility.21 In addition, activation of peripheral opioid receptors in the gastrointestinal (GI) tract inhibits acetylcholine release from motor neurons and promotes transmitter release from inhibitory neurons.24 Opioid receptors are stimulated by endogenous opioids, which are locally secreted upon surgical stress. Exogenous opioids used for analgesia also act on peripheral opioid receptors in the GI tract, inhibiting motility. Peritonitis and pain cause a generalized inhibition of motility via spinal afferents that connect in the spinal cord to sympathetic efferents.20
Colonic hypomotility in critically ill patients may be related to circulating bacterial products and/or proinflammatory cytokines (e.g., lipopolysaccharide or TNF), leading to increased expression of iNOS and COX-2.25,26 Colonic hypomotility also may be related to ischemia and reperfusion, causing an energy deficit, functio laesa, and oxidant-mediated tissue damage. Finally, distal colonic distension induces inhibition of proximal colonic motility, the so-called colo-colonic reflex, which passes by the paravertebral ganglia and activates inhibitory sympathetic nerves.22 In this way, colonic dilation perpetuates itself.
Predisposing Factors
Ogilvie’s Syndrome
Clinical factors predisposing to Ogilvie’s syndrome are summarized in Box 107-1.5,27,28 The syndrome was first described by Sir William Heneage Ogilvie (1887-1971) in two patients with malignant infiltration of the celiac plexus.29 After surgery and trauma of spine, hip, and pelvis, dysfunction of the sacral parasympathetic nerves may impair motility of the distal colon, causing atony with functional obstruction.30 In a series reporting 400 patients with Ogilvie’s syndrome, the most common underlying conditions were trauma, cardiovascular disease, and infections.5 In another series, the majority of patients had cardiovascular disease.31 Both drugs and ischemia may play a role in cardiovascular disease. Exogenous catecholamines have dose-dependent effects on intestinal motility; low doses promote and high doses suppress motility.18,32 α-Adrenergic agonists are stronger inhibitors of acetylcholine release than β-adrenergic agents. Dobutamine and dopexamine have little effect on intestinal peristalsis. Dopamine not only inhibits upper GI motility but also distal colonic motility.17,19,33 The use of dopamine is associated with late defecation.34 Clonidine and dexmedetomidine, central α2-adrenergic receptor agonists, decrease fasting colonic smooth muscle tone35 and are associated with Ogilvie’s syndrome.36 Opioids suppress the phase III migrating motor contractions.37 This inhibiting effect on gut motility is mediated by activation of mu-opioid receptors in the GI tract, reducing the release of acetylcholine from the myenteric plexus.38 Ogilvie’s syndrome with life-threatening complications is reported with the use of antipsychotic agents such as clozapine that cause generalized GI hypomotility by anticholinergic and antiserotonergic mechanisms.39,40 In patients with sepsis, bacterial products (e.g., lipopolysaccharide), proinflammatory cytokines (e.g., TNF) and NO produced by the inducible enzyme, iNOS, suppress intestinal motility.25,41,42
Toxic Megacolon
The incidence of toxic megacolon in IBD has substantially decreased with better management of severe colitis.43 The most common cause of toxic megacolon in the critically ill is pseudomembranous colitis caused by overgrowth of C. difficile.44 However, other pathogens such as enterotoxin-producing strains of Clostridium perfringens, Staphylococcus aureus, and Klebsiella oxytoca can cause colitis after antibiotic use.45 Sporadic cases of megacolon due to infections caused by Salmonella spp.,46 Shigella spp., Amoeba, herpesvirus, or cytomegalovirus (CMV) have also been described.11 In patients with human immunodeficiency virus (HIV), toxic megacolon may be a primary manifestation of the HIV infection or be related to infection with C. difficile or CMV.47 Causes of toxic megacolon are summarized in Box 107-2.
The pathogenesis of toxic megacolon is not well understood.2,11 In infectious colitis, inflammation extends into the deeper layers of the colonic wall, whereas the inflammation in ulcerative colitis is typically limited to the mucosa. Deep infiltration, microabscesses, edema, and necrosis may paralyze colonic smooth muscle and lead to dilatation. Bacterial toxins permeating through ulcerations activate the release of cytokines, with subsequent systemic toxicity. NO, locally generated in excessive amounts secondary to increased expression of iNOS in inflammatory and smooth muscle cells, is the key mediator of diminished smooth muscle function in toxic megacolon.48,49
Clostridium Difficile Infection
Clostridium difficile is a gram-positive spore-forming rod. Pathogenic strains produce two major exotoxins: A and B. Both activate cell-signaling molecules including the transcription factor, nuclear factor-κB, and mitogen-activated protein kinases in monocytes, leading to the production and release of proinflammatory cytokines. Both toxins induce colitis in humans.50 Colonic injury results from alterations of the enterocyte cytoskeleton, with disruption of tight junction function and marked inflammation in the lamina propria. Severe pseudomembranous colitis occurs in 3% to 5% of carriers. Recurrent sepsis or toxic megacolon are rare but severe complications.
Colonization with C. difficile results from alterations in the composition of the indigenous colonic microflora. Enemas containing normal human feces appear to be effective in the treatment of infected patients.51,52 Mechanisms of suppression include the production of volatile acids, hydrogen sulfide, and secondary bile acids.53 The most frequently identified clinical risk factor for C. difficile–associated diarrhea is the antecedent use of antibiotics affecting indigenous colonic microflora.54 The opportunity to acquire the organism increases with prolonged hospital stay,55 and it may spread by nosocomial transmission.56 Whether a person remains an asymptomatic carrier or develops colitis depends on the size of the C. difficile population, toxigenicity of the strain, toxin-neutralizing effects of the indigenous gut flora, and underlying disease (Box 107-3).53,57,58 Susceptibility is further increased by poor GI defense mechanisms resulting from the use of gastric acid–inhibiting drugs that facilitate intestinal transit of the bacteria,54,55 total parenteral nutrition, postpyloric enteral feeding, or recent GI surgery.59–61 A combination of factors increases the risk.
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