Toxic Megacolon: A Review for Emergency Department Clinicians

CLINICAL

TOXIC MEGACOLON: A REVIEW FOR EMERGENCY DEPARTMENT CLINICIANS Author: Erik Woodhouse, DNPc, RN, CEN, Madison, WI

oxic megacolon is an infrequently occurring but severe and potentially fatal complication of colitis. First recognized as a clinical entity in 1950, 1 toxic megacolon is defined as segmental or total colonic dilation of greater than 6 cm in the presence of acute colitis and signs of systemic toxicity. 2 Toxic megacolon is demarcated from other types of colonic dilation such as Ogilvie syndrome and Hirschsprung disease by the additional presence of systemic toxicity and the inflammatory or infectious etiology of the underlying disease. Although toxic megacolon may be considered rare, incidence is expected to increase because of the rapidly increasing prevalence of pseudomembranous colitis. 3–5 Because early detection and intervention have a profound impact on survival, it is imperative that clinicians be aware of this potentially fatal complication to attenuate morbidity and mortality. This article will review the epidemiology, etiology, pathophysiology, clinical manifestations, emergency management, and prognosis of toxic megacolon in adults.

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Epidemiology

Toxic megacolon can occur in any patient with colitis, and there appears to be no predilection in any particular age group, gender, or race. The incidence varies depending on etiology and has been most extensively studied in persons with inflammatory bowel disease (IBD). Toxic megacolon has been reported in up to 10% of patients admitted with ulcerative colitis 6 and in 1% to 5% of patients with Crohn disease. 7 Patients with ulcerative colitis are reported to have a 6 times higher rate of toxic megacolon than do patients with Crohn disease, 3,8 and they have an estimated lifetime

Erik Woodhouse is Staff Registered Nurse, Emergency Department, William S. Middleton Memorial Veterans Hospital, Madison, WI. For correspondence, write: Erik Woodhouse, DNPc, RN, CEN, 418 S Livingston St, Madison, WI 53703; E-mail: [email protected]. J Emerg Nurs ■. 0099-1767 Copyright © 2016 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jen.2016.04.007

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incidence of 1% to 2.5%. 2 Mortality rates range from 19% up to 45% and are markedly higher among patients in whom perforation develops. 2 The incidence of toxic megacolon in persons with pseudomembranous colitis is reported to be 0.4% to 3%. 4 During the past decade, however, major changes in the epidemiology of Clostridium difficile infections (CDIs) have been observed. 9 Whereas other hospital-associated infections have decreased since 2001, the incidence of CDI has increased. 10 In the United States, hospitalizations for CDI doubled between 2000 and 2010, 9 and CDI-related deaths increased 400% between 2000 and 2007. 11 These changes are attributed to more indiscriminate use of broad-spectrum antibiotics and the emergence of a hypervirulent C difficile strain (BI/NAP1/027). 3,7 Once toxic megacolon develops in the setting of pseudomembranous colitis, the associated mortality rate is significant, varying from 38% to 80%. 2,4 Etiology

Historically, toxic megacolon was thought to be a complication solely of ulcerative colitis. Crohn disease was then recognized as a cause, and gradually it became evident that almost any inflammatory condition of the colon can predispose patients to toxic dilation. 2 Recent research has drawn attention to a demographic shift from chronic inflammatory causes to infectious causes associated with the development of toxic megacolon. 3,6 Current data suggest that toxic megacolon is more often caused by pseudomembranous colitis than by ulcerative colitis. 12 As the prevalence of CDI increases and treatments become more refractory, clinicians can expect to encounter more patients with CDI-associated toxic megacolon in the future. 13 Toxic megacolon also plays a role in immunocompromised patients. Cytomegalovirus and CDI are the predominant causes of toxic megacolon in patients with human immunodeficiency virus (HIV). 14 In the setting of underlying inflammation of infectious colitis, additional risk factors for the occurrence of toxic megacolon include discontinuation of steroids, use of barium enemas, and medications that slow colonic motility such as narcotics and antidiarrheal or anticholinergic drugs. 2 Potential triggers and exacerbating factors are listed in Table 1. Etiologic factors associated with toxic megacolon are listed in Table 2.

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TABLE 1

Potential triggers and exacerbating factors of toxic megacolon Chemotherapy Discontinuation of steroids Barium enema Colonoscopy Drugs: antidiarrheal agents, narcotics, and anticholinergic drugs

Pathophysiology

The exact pathologic mechanism of toxic megacolon is not yet clearly understood, although most investigators agree that several pathologic mechanisms likely contribute to the development of this phenomenon. The progression from uncomplicated ulcerative colitis to toxic megacolon is best studied to date. 3 Whereas in typical ulcerative colitis the inflammatory response is limited to the superficial mucosa, toxic megacolon is characterized by severe inflammation extending into the smooth muscle layer. 15 One of the most important contributing factors in the development of toxic megacolon is the progression of inflammation beyond the submucosa into the muscularis and serosa. As inflammation progresses, neutrophils invade the muscle layer and cause further damage by release of proteolytic enzymes, cytokines, and leukotriene B4, resulting in dysmotility, which leads to dilation. 8,15 The depth of inflammation appears to be correlated with the extent of colonic dilation. 3 In infectious causes such as pseudomembranous colitis, C. difficile toxins A and B disrupt the epithelial barrier and cause epithelial cell necrosis and electrophysiologic changes in the colonic mucosa, leading to marked colonic inflammation. 16 Inflammation of the bowel alters the normal absorptive function, causing water, sodium, and potassium to be

trapped in the colonic lumen. Resultant hypokalemia and other electrolyte abnormalities decrease the ability of the bowel to contract. 2 The barrier mechanism of the colon is lost, which permits the absorption of toxins, microbes, and toxic wastes, leading to systemic toxicity. 2 The systemic symptoms associated with toxic megacolon are not directly related to bacteremia, colonic perforation, or ischemia but to oxide-induced inflammatory mediators such as interleukin-8, macrophage inflammatory protein–2, substance P, and tumor necrosis factor–α, released in the colon. 7 The gross pathologic features of toxic megacolon are similar to both ulcerative colitis and Crohn disease with pronounced dilation of the colon, thinning of the bowel wall, and deep ulcers. 15 Nitric oxide, a strong inhibitor of smooth muscle tone, has been postulated to play a role in the pathogenesis of toxic megacolon. Nitric oxide is generated in the macrophages and smooth muscle cells of the inflamed colon and is a nonadrenergic, noncholinergic neurotransmitter. 15 Nitric oxide, released by invading neutrophils, may paralyze muscle cells and lead to colonic dilation. 5 In a study of colon segments removed during surgery from patients with toxic megacolon, severe nontoxic ulcerative colitis, and nonobstructive colon cancer, investigators reported higher levels of inducible nitric oxide synthase in the muscle samples of persons with toxic megacolon than in the other 2 groups. 17 Because nitric oxide is also a marker of inflammation, its true involvement in the pathogenesis of toxic megacolon remains unclear.

Clinical Manifestations

Patients often present during a relapse of established IBD, but a substantial number present during their first flare or within 2 to 3 months of diagnosis. 2 Patients with IBD are at highest risk of the development of toxic megacolon early in their disease. Up to 30% of patients present within 3

TABLE 2

Etiologic factors of toxic megacolon

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Inflammatory

Infectious

Ulcerative colitis Crohn disease Behçet disease

Bacterial Clostridium difficile Salmonella Shigella Yersinia Campylobacter Escherichia coli

Viral Cytomegalovirus Rotavirus

Parasitic Entamoeba Cryptosporidium

Ischemia

Malignancy

Ischemic colitis

Kaposi sarcoma

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months of being diagnosed with IBD, and about 60% of cases occur within the first 3 years. 15 Patients typically present to the emergency department in the midst of an ongoing bout of severe colitis, and signs and symptoms are typically present for a week or more before the onset of acute dilation. 2,5 These symptoms include diarrhea (often bloody), fevers, chills, and abdominal cramping. The onset of toxic megacolon is inconsistent but may be heralded by abdominal distention, improvement in diarrhea, constipation, obstipation, diminished bowel sounds, and constitutional symptoms such as fever, tachycardia, and hypotension. 2,15 The abdomen can be extremely tender either locally or diffusely, but these signs may be masked by high-dose corticosteroids or a decreased level of consciousness.

Diagnosis

Toxic megacolon is a diagnosis based on clinical signs of systemic toxicity in combination with radiographic evidence of colonic dilation greater than 6 cm. 3 Toxic megacolon should be considered in all patients who present to the emergency department with abdominal distention and acute or chronic diarrhea. 15 The clinical criteria for toxic megacolon diagnosis, initially described by Jalan et al 18 in 1969, remains the most widely accepted criteria and includes any 3 of the following: (1) fever N 38.6°C (101.5°F); (2) heart rate N 120 beats/min; (3) white blood cell count N 10.5/μL; or (4) anemia. Patients also should have one of the following criteria: dehydration, hypotension, electrolyte disturbances, or mental status changes (Table 3). 18

The radiologic diagnosis is made using plain abdominal films. Colonic dilation N 6 cm is suggestive of the diagnosis, although dilations of as much as 15 cm are not uncommon. 2 The transverse and ascending colon are most prone to dilation. 3 Fig. 1 shows an example of classic radiograph findings consistent with toxic megacolon. Further radiographic features include colonic air-fluid levels and loss of colonic haustra. Ultrasonography (US) also may be a valuable diagnostic tool. Consistent US findings among patients with toxic megacolon are thin colonic walls, loss of colonic haustra, and dilation N 6 cm with gaseous content, similar to features found on plain abdominal radiographs. 19 Although it is difficult to differentiate between other causes of colonic dilation using US, because of its wide availability, it may be a valuable diagnostic tool in early recognition or suspicion of toxic megacolon. 3 In Fig. 2, normal colonic haustra US findings are compared with expected toxic megacolon haustra findings. Toxic megacolon features found by radiograph or US indicate the need for abdominal computed tomography (CT). A CT scan is useful in determining the cause and is an important tool in the diagnosis of abdominal complications such as perforation or ascending pyelophlebitis. 3,4 Laboratory studies in patients with toxic megacolon may represent several nonspecific abnormalities and reflect systemic toxicity and the severity of the colitis. Anemia and leukocytosis with left shift is a common feature, and the leukocyte count may reach as high as 40,000/μL. 8 Neutropenia, not leukocytosis, may be observed among patients with HIV or those receiving chemotherapy. 15 Metabolic acidosis and electrolyte imbalances such as low potassium, calcium, chloride, phosphate, and magnesium may occur from prolonged diarrhea. Electrolyte

TABLE 3

Diagnosing toxic megacolon Clinical manifestation

Clinical criteria (any 3)

At least one of the following criteria

Radiographic criteria

Diarrhea (often bloody)

Temperature N 38.6°C (101.5°F) Heart rate N 120 bpm White blood cell count N 10.5 μL

Dehydration

Dilation of ascending or transverse colon N 6 cm

Hypotension Electrolyte imbalance(s)

Anemia

Mental status changes

Constipation, obstipation Abdominal pain (local or diffuse) Abdominal cramping Abdominal distention Reduced bowel sounds Fever, chills

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Stool samples should be sent for culture, sensitivity, and C difficile toxin A and B assay in patients with a history of antibiotic use or chemotherapy. Ova and parasite infection should be considered in patients with HIV. 8

Emergency Management

FIG. 1 Abdominal radiograph demonstrating severe colonic dilation.

disturbances, especially hypokalemia, have been reported in more than 50% of patients. 8 Hypokalemia and hypoalbuminemia are associated with severe diarrhea, volume loss, and a poor prognosis in general. 3 Elevated inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein are often seen and are useful when observing the progression of the disease. 3 Blood cultures should be obtained to rule out bacteremia because sepsis occurs in up to 25% of patients with toxic megacolon. 2

Toxic megacolon is a life-threatening emergency. The ED clinician’s first priority is the detection and management of life-threatening complications such as septic shock, hypovolemic shock, severe anemia, and dehydration. 20 Central components of emergency management include fluid resuscitation, electrolyte correction, decompression, administration of antibiotics, and surgical consultation. Anemia, dehydration, and electrolyte deficits, particularly hypokalemia, aggravate colonic dysmotility and should be aggressively treated. 3 Intravenous crystalloids should be used for fluid resuscitation unless the patient is in a severe state of shock or hypoalbuminemia, in which case colloids should be used. 8 Blood products may be required to correct severe anemia. All medications that impair gastric motility should be stopped immediately, including anticholinergic medications, antidiarrheal drugs, and narcotics. 4 Nasogastric or long tube suction should be used for decompression. 15 Long tubes are more effective for colonic decompression than are nasogastric tubes; however, they must be placed in the ileum under fluoroscopic guidance. 2 Administration of broad-spectrum antibiotics is recommended, not as primary therapy for IBD or for toxic dilation, but rather to reduce septic complications and mortality should perforation occur. 2 Broad-spectrum intravenous antibiotics with coverage equivalent to ampicillin or cephalosporin, plus gentamicin and metronidazole, is an appropriate regimen. 8

FIG. 2 Normal versus abnormal ultrasound findings. The ultrasound image on the left demonstrates the ascending colon with normal haustra (curved arrows) and alternating haustral clefts (black arrows). The ultrasound image on the right demonstrates complete loss of colonic haustra (arrows), an expected finding in a patient with toxic megacolon.

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The mainstay of medical therapy for patients with toxic megacolon caused by ulcerative colitis is high-dose intravenous steroids. Steroid therapy should be started immediately and should not be delayed by pending microbiological results. 3 Most authors recommend a daily dose of either 400 mg hydrocortisone (100 mg every 6 hours) or 60 mg methylprednisolone given intravenously for 5 days. 3 If steroid treatment does not induce remission, rescue therapy with cyclosporine should be considered. 16 In patients with toxic megacolon caused by pseudomembranous colitis, offending antibiotics should be withdrawn. The most common antibiotics associated with CDI are clindamycin, cephalosporins, and fluoroquinalones. 21 Vancomycin should be administered as first-line therapy according to current guidelines issued by the Society for Healthcare Epidemiology of America and the Infectious Disease Society of America. 22 Pain management is challenging in patients with toxic megacolon because nonsteroidal anti-inflammatory drugs may exacerbate bleeding and opioids adversely affect bowel peristalsis, causing an increased risk of colonic perforation. Opioids should be used with caution, although tramadol may have less effect on motility when used on a short-term basis. 20 One study 23 has demonstrated that low-dose ketamine is a safe and effective analgesic in children with toxic megacolon, although reports of effectiveness among adults were absent from the literature. A surgical consultation should be obtained as soon as possible. Successful medical therapy circumvents the need for surgery in 50% of patients who experience toxic megacolon 15; however, surgical intervention may be necessary in up to 80% of patients with toxic megacolon resulting from C. difficile colitis. 13 Absolute indications for surgery include signs of organ failure, shock, uncontrollable hemorrhage, perforation, and progressive dilation after 24 to 72 hours of medical therapy. 6 In urgent situations, most surgeons favor a subtotal colectomy, mucous fistula, and ileostomy because this procedure is associated with a lower morbidity and mortality compared with a total proctocolectomy. 3 Early surgical consultation is critical to improving outcomes, because surgery in patients without evidence of perforation results in much lower mortality (2% to 8%) than does a colectomy after perforation has occurred (40% or more). 15 The fear in delaying surgery is that the surgeon will then be dealing with an acutely ill patient with a friable colon that tends to tear at the splenic flexure. 8 The patient should be admitted to the intensive care unit for hemodynamic monitoring with frequent examinations by nursing and medical staff for signs of deterioration. Any sign of complication, worsening, or failure to improve should be considered an indication for a colectomy. 2

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Excessive delays will likely lead to unnecessary morbidity and mortality. The central components of toxic megacolon management are listed in Table 4.

Prognosis

Morbidity and mortality are high among patients in whom toxic megacolon develops. For patients who survive an episode of toxic megacolon with medical management alone, the long-term prognosis is poor, with high rates of eventual colectomy and recurrence. 2 Among patients with ulcerative colitis who initially respond to medical therapy, 60% will require a colectomy within the next 12 months, and 80% will require a colectomy within 5 years. 16 The development of toxic megacolon in persons with pseudomembranous colitis is often devastating, with reported mortality as high as 80%. 2,24 The rate of colectomy and mortality from pseudomembranous colitis has increased at an alarming rate, mostly as a result of the development of

TABLE 4

Toxic megacolon management General

Intravenous fluid support Complete bowel rest Correct electrolyte abnormalities Discontinue antidiarrheal agents, anticholinergic drugs, narcotics, and antidepressants Rule out an infectious etiology Daily laboratory tests (complete blood cell count, electrolytes, chemistry, and albumin) Medical care Intravenous corticosteroids for inflammatory bowel disease Specific treatment for infectious causes Broad-spectrum antibiotics Decompression Nasogastric or long intestinal tube Repositioning maneuvers Imaging Frequent assessment with plain abdominal films Computed tomography Surgical intervention Indications: perforation, uncontrolled hemorrhage, progressive dilation, or toxicity Failed medical care (typically after 24 to 72 hours)

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toxic megacolon. 2 Early recognition and treatment have decreased the number of deaths from this diagnosis.

11. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/pdf/arthreats-2013-508.pdf. Published April 2013. Accessed April 21, 2016.

Conclusion

Toxic megacolon is a well-recognized and highly lethal complication of acute colitis. Clinicians can expect to see an increase in toxic megacolon cases because of the increasing prevalence of pseudomembranous colitis associated with broad-spectrum antibiotic use and hypervirulent C difficile strains. It is essential that patients with toxic megacolon be diagnosed rapidly and correctly to decrease morbidity and mortality. ED clinicians can minimize excessive treatment delays by suspecting toxic megacolon in all patients who present with abdominal distention and acute or chronic diarrhea.

12. Maddu KK, Mittal P, Shuaib W, Tewari A, Ibraheem O, Khosa F. Colorectal emergencies and related complications: a comprehensive imaging review—imaging of colitis and complications. AJR Am J Roentgenol. 2014;203(6):1205-1216. 13. Sayedy L, Kothari D, Richards RJ. Toxic megacolon associated Clostridium difficile colitis. World J Gastrointest Endosc. 2010;2(8):293-297. 14. Beaugerie L, Ngo Y, Goujard F, et al. Etiology and management of toxic megacolon in patients human immunodeficiency virus infection. Gastroenterology. 1994;107:858-863. 15. Sheth SG, LaMont JT. Toxic megacolon. Lancet. 1998;351:509-513. 16. Halaweish I, Alam HB. Surgical management of severe ulcerative colitis in the intensive care unit. J Intensive Care Med. 2015;30(8):451-461. 17. Mourelle M, Casellas F, Guarner F, et al. Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon. Gastroenterology. 1995;109:1497-1502.

REFERENCES 1. Marshak RH, Friedmann AI. Megalcolon, a complication of ulcerative colitis. Gastroenterology. 1950;16:768-772. 2. Gan SI, Beck PL. A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management. Am J Gastroenterol. 2003;98(11):2363-2371.

18. Jalan KN, Sircus W, Card WI, et al. An experience of ulcerative colitis: toxic dilation in 55 cases. Gastroenterology. 1969;57:68-82. 19. Maconi G, Sampietro GM, Adrizzone S, et al. Ultrasonographic detection of toxic megacolon in inflammatory bowel diseases. Dig Dis Sci. 2004;49(1):138-142.

3. Autenrieth DM, Baumgart DC. Toxic megacolon. Inflamm Bowel Dis. 2012;18(3):584-591.

20. Cameron P, Jelinek G, Kelly A, Brown A, Little M. Textbook of Adult Emergency Medicine. 4th ed. London: Churchill Livingstone Elsevier; 2015.

4. Earhart MM. The identification and treatment of toxic megacolon secondary to pseudomembranous colitis. Dimens Crit Care Nurs. 2008; 27(6):249-254.

21. Yu S, Abdelkarim A, Nawras A, et al. Fecal transplant for treatment of toxic megacolon associated with Clostridium difficile colitis in a patient with Duchenne muscular dystrophy. Am J Ther. 2016;23(2):e609-e613.

5. Ausch C, Madoff RD, Gnant M, et al. Aetiology and surgical management of toxic megacolon. Colorectal Dis. 2005;8:195-201. 6. Tapani MK, Olavi KH. Surgical management of toxic megacolon. Hepatogastroenterology. 2014;61(131):638-641. 7. Ferri FF. Ferri’s Clinical Advisor. 1st ed. Philadelphia, PA: Elsevier; 2016.

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10. Walters PR, Zuckerbraun BS. Clostridium difficile infection: clinical challenges and management strategies. Crit Care Nurse. 2014; 34(4):24-34.

22. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 updated by the Society for Healthcare Epidemiology of America and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5): 431-455.

8. Levine CD. Toxic megacolon: diagnosis and treatment challenges. AACN Clin Issues. 1999;10(4):492-499.

23. White M, Shah N, Lindley K, Lloyd-Thomas A, Thomas M. Pain mangement in fulminating ulcerative colitis. Paediatr Anaesth. 2006; 16(11):1148-1152.

9. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infections in the United States. N Engl J Med. 2015;372:825-834.

24. Hall JF, Berger D. Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management. Am J Surg. 2008;196:384-388.

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