In view of the above data and previously described diagnostic options, this guideline proposes redefining disease severity to guide treatment (Table 6 and Figure 1). This is currently a nonvalidated guide to rating disease severity but incorporates the most up-to-date knowledge of risk factors for disease severity. Patients with mild disease are those who have typical symptoms of CI with a segmental colitis not isolated to the right colon and with none of the commonly associated risk factors for poorer outcome that are seen in moderate disease. Moderate disease includes any patient with up to three of the following factors: male gender, hypotension (systolic blood pressure <90 mm Hg), tachycardia (heart rate >100 beats/min), abdominal pain without rectal bleeding, blood urea nitrogen >20 mg/dl, Hgb <12 g/dl, LDH >350 U/l, serum sodium <136 mEq/l (mmol/l), WBC >15 × 109/l, or colonoscopically identified mucosal ulceration. Severe disease is defined by more than three of the previously listed criteria or any of the following: peritoneal signs on physical examination, pneumatosis on CT, gangrene on colonoscopy, and a pancolonic distribution or IRCI on CT or colonoscopy.
Treatment of CI varies with the severity of the disease and its presentation. In general, many patients have a benign, self-limited episode of CI that is neither diagnosed nor treated or is managed in the outpatient setting. Most cases of CI resolve spontaneously and do not require specific therapy; such patients have reversible ischemic colopathy or transient ischemic colitis (91). Patients with more significant symptoms or findings require hospitalization to enable observation for complications or signs of irreversible disease. Initial medical management most commonly includes general supportive measures, bowel rest, intravenous hydration, and correction of possible precipitating conditions. Parenteral nutrition may be indicated if a protracted course is anticipated. No therapeutic modality has ever been tested in a rigorous clinical trial and the mostly benign nature of CI has led to a shortage of trials assessing various therapies. It is also important to consider that the currently available literature for the management of CI focuses on hospitalized patients who have complicated disease with less emphasis on the milder cases that are not hospitalized. The recommendations presented in this guideline are mostly based on small retrospective studies that lack control groups. Most guideline statements are based upon extrapolation from the available literature and expert opinion.
One systematic review of the management of CI included 10 retrospective studies comprising 841 patients (145). Within these studies there was no standard protocol for management; however, nonsurgical treatment usually included bowel rest, intravenous fluid, electrolyte repletion, and antibiotic usage with occasional administration of total parenteral nutrition. All articles reviewed did agree that surgery was indicated for patients with peritonitis or those who were hemodynamically unstable (145). This systematic review had significant limitations including methodologic anomalies such as excluding some well-structured publications and also including three studies with patients who had CI as a complication of vascular procedures despite methodology stating this as a criterion for exclusion. In addition, the study included some patients without pathologically confirmed disease. This lack of uniformity characterizes the CI management literature, but the abstract’s conclusion reads “There is very little evidence base for the management of this condition” (145). We believe this statement is accurate.
Indication and timing for antimicrobial use in CI remains untested. There is no clinical evidence to show beneficial effects of such therapy and it is unlikely that a randomized controlled trial will be forthcoming; because the prognosis of CI is excellent in most cases, the number of patients in such a trial needed to show benefit (or to disprove a lack of benefit) would have to be immense. Previous recommendations for antibiotic usage were based on experimental studies that showed reduction in the severity and extent of bowel damage when antibiotics were given before or during an ischemic event, with the majority of these trials being several decades old (140, 146, 147, 149, 150). Yoshiya et al. (140) pretreated mice with ampicillin, vancomycin, neomycin, and metronidazole, and subsequently induced intestinal ischemia with reperfusion by ligating the SMA for 30 min. These mice were then compared with control mice that also underwent intestinal ischemia but did not receive antimicrobial therapy. In the mice pretreated with antibiotic therapy, the expression of Toll-like receptors 2 and 4 was decreased as was expression of inflammatory markers (e.g., tumor necrosis factor, interleukin-6, and cyclo-oxygenase-2). As Toll-like receptors normally bind Gram-positive and Gram-negative bacteria to stimulate inflammatory responses, the study supports the theory that antimicrobial therapy decreases the overall inflammatory response to ischemic injury. Intestinal injury resulting from ischemia and reperfusion is also believed to be stimulated by ischemic cells presenting neoantigens that bind natural immunoglobulins to activate the complement pathway. Yoshiya et al. (140) also showed decreased complement (C3), IgM, and IgA in ischemic tissue of mice pretreated with antimicrobials compared with the ischemic tissues of mice not exposed to antimicrobial therapy.
Antimicrobial therapy is also believed to prevent poor outcome through decreased bacterial translocation in the setting of acute ischemia and reperfusion injury. The loss of mucosal integrity as a result of vigorous inflammation has been shown in mouse models to facilitate bacterial translocation and resulting bacteremia (151, 152, 153). Luo et al. (153) studied mice that had ischemia induced by SMA occlusion for 30, 60, or 90 min followed by reperfusion for 30 min. These mice were given varying oral doses of bacteria after the ischemic episode and had blood cultures drawn immediately and 15 min after reperfusion. A control group of mice was fed the same bacteria but did not have any ischemic episode. Control mice showed no translocation of bacteria, whereas the mice that were exposed to even 30 min of ischemia and a low bacterial inoculum developed bacteremia (153). The studies of Yoshiya et al. (140) and Luo et al. (153) reinforce the theories behind antimicrobial therapy in the setting of CI in mouse models. Antibiotics are believed to improve outcome in CI by reducing inflammatory responses stimulated by the normal fecal microbiome, reducing the antigens that prompt innate immune response and minimizing bacterial translocation through compromised colonic mucosa.
Available human studies of antimicrobial treatment in CI are few in number, heterogeneous in design, and do not directly address antimicrobial use for a specific therapeutic benefit. Three studies have presented data regarding broad-spectrum antimicrobial therapy of CI and associated outcomes (107, 108, 139). Añón et al. (108) looked at 85 consecutive patients, of whom 69 had “mild disease” that was treated with fluid and electrolyte correction and “wide-spectrum antibiotics”; all but 1 patient survived (98.6%) and another 16 patients had severe disease that was initially treated medically, but subsequently required surgery. Mosele et al. (107) retrospectively assessed 46 patients who were at least 65 years of age, of whom 67.4% clinically improved with only medical therapy consisting of intestinal rest, total parenteral nutrition, and broad-spectrum antibiotics; 6 of the original cohort received medical therapy and subsequently died (13.0%), whereas another 9 would ultimately require surgical intervention (19.6%). Matsumoto et al. (139) retrospectively assessed 41 patients with CI, with 31.7% of patients receiving a “combination of antibiotics” along with fasting, bowel rest, and fluid replacement; none of these patients required surgery or died. These studies are similar as they were all small, not designed to assess the effect of antimicrobial therapy on outcome, mentioned antimicrobial therapy as part of the medical treatment regimen but mostly did not detail the number of patients within the “medical therapy” cohort who received antibiotics, and did not delineate the specific antibiotics used or the duration of therapy. Perhaps most importantly, there were no comparator groups of patients who did not receive antimicrobials.
By performing multivariate analysis on 401 consecutive patients, Longstreth and Yao (9) found that antimicrobial therapy was associated with a 3.94 (confidence interval: 1.23–164, P<0.05)-fold increased risk of severe disease as defined by need for surgery or mortality. This finding speaks to one of the major weaknesses of all available treatment data, namely that this statistical association is likely the result of a selection bias by which patients with the most severe disease are those receiving antimicrobial therapy, most of whom are most at risk for poor outcomes regardless of therapy.
Because there is a shortage of clinical trials of antimicrobial therapy in CI and there is experimental evidence that these medications should be beneficial, this guideline recommends antimicrobial therapy for CI patients who have either “moderate” or “severe” disease as newly classified in a previous section of this guideline (see also Figure 1). The criteria for classification are based upon risk factors for poor outcome in CI that is believed to be mediated through a vigorous inflammatory response, bacterial translocation, and extensive damage to the large bowel. Mouse models have shown antimicrobial use moderates these processes and we believe these will improve outcome in the appropriate clinical setting. This recommendation is based upon expert opinion considering the murine models, retrospective human studies, and personal experience. As previously discussed, it is highly unlikely that a properly designed randomized control trial of antibiotics in humans stratified for mild, moderate, and severe CI will ever be performed.
The question of which antimicrobial agents are most efficacious in patients with CI is also unanswered. Plonka et al. (154) transected the vascular supply to the colon in mice and then treated them with saline, gentamicin alone, metronidazole alone, or gentamicin plus metronidazole. Mice receiving metronidazole alone or gentamicin plus metronidazole showed improved survival. This study supports the role of anaerobic bacteria as a contributing factor to poor outcome. Because of the risks of bacterial translocation across compromised colonic mucosa, with inflammatory and innate immunologic reactions that are stimulated by the colonic microbiota, we recommend a broad antimicrobial regimen to “cover” these organisms. Possible antimicrobial regimens include an anti-anaerobic agent plus a fluoroquinolone or an aminoglycoside or a third-generation cephalosporin.
The optimal duration of antimicrobial therapy is unclear and studies to date have not addressed this issue. Once therapy has been initiated, this guideline recommends that antimicrobials be continued for at least 72 h, at which time the patient’s clinical status should be reevaluated. If the patient has not clinically improved, one should consider consultation with an infectious disease expert to help define the antimicrobial regimen. If the patient is symptomatically improved after 72 h, a 7-day course of therapy should be considered.
Glucocorticoids are not recommended for CI, except when it is a complication of a vasculitis. In such cases, the steroids are used to treat the vasculitis and not the CI. The only potential role for these agents or others used in the treatment of IBD might be in patients with chronic CI (see above), but there is no published experience to support the use of local or systemic glucocorticoids, sulfasalazine, aminosalicylates, or fatty acid enemas to treat CI. Indeed, there are numerous reports implicating these drugs as a cause of CI and, in one experimental study using Fischer rats, azathioprine and methylprednisolone augmented the damage of intestinal ischemia (155). Nonsteroidal anti-inflammatory drugs are generally accepted to be a cause of colonic ulcerations, but one large trial of patients with CI showed that a lack of nonsteroidal anti-inflammatory drug use at the time of diagnosis was independently associated with severe disease (e.g., surgery and/or death) (9). This potentially protective effect of nonsteroidal anti-inflammatory drugs was an indirect observation with no further trials to date (9). Anecdotal evidence has shown that fatty acid enemas have helped to heal the necrotic mucosa of two patients with otherwise unresponsive CI, although there are no formalized publications supporting this intervention (LJ Brandt and SJ Boley, unpublished).
Surgical intervention for patients with CI is required in its most severe presentations. The O’Neill et al. (148) review of 11 studies comprising 1,049 patients showed that 19.6% of pooled patients required surgical intervention and had a mortality rate of 39.3%. Published data have wide ranges for the need for surgery and vary with the study population (e.g., surgical service vs. general population; age >65 vs. <65 years); 8–19.8% of large, broad populations with biopsy-proven CI have been estimated to require surgical intervention, whereas the need for surgery in patients admitted to surgical services is as high as 45.2% (7, 9, 94). The requirement of biopsy-proven disease in some studies mandates endoscopic evaluation, thereby perhaps excluding patients not sick enough to warrant colonoscopy, biasing the study population to patients who are more acutely ill, and overestimating the true need for surgical intervention. Inclusion of patients on a surgical service is not representational of a general population and cannot be applied to all patients with CI. Given the mostly benign course of CI, and the fact that many patients with CI do not present to medical attention, estimates of the frequency of surgery in hospitalized patients with CI is likely a significant overestimation. We recommend considering surgical consultation if patients fulfill the risk stratification for moderate or severe disease as these factors are associated with need for surgery and/or mortality.
There are several indications for surgery in acute CI, but the most common is the presence of signs of necrotic bowel (Table 9). These might include peritoneal signs on physical examination, pneumatosis or portal venous gas on radiologic imaging, or gangrene on colonoscopic examination. Without surgical intervention, mortality from necrotic bowel approaches 100%. Following the new classification scheme proposed here, patients with “severe disease” would require emergent surgical consultation. The current literature does not clarify surgical indications or optimal timing for surgical intervention. Huguier et al. (94) assessed 33 patients who underwent surgery for CI, 13 of whom had immediate surgery (i.e., <12 h after admission) for “abdominal tenderness,” with 5 having peritonitis upon surgical inspection and 8 expiring; 20 patients had delayed surgical treatment (i.e., days 2–7 of hospitalization) for clinical deterioration after admission, with 6 subsequently dying from complications of CI. Patients who develop a segmental colitis pattern during the evolution of their disease and whose symptoms persist for more than 2–3 weeks or who have a continuing protein-losing colopathy for several weeks usually are best treated by segmental colectomy. A less-recognized indication for surgery is the development of recurrent sepsis in a patient who has symptomatically recovered from an acute episode of CI. Such patients usually have a short segment of unhealed bowel that, via bacterial translocation, is the source of the sepsis; resection of this segment is curative.
The surgical procedure patients undergo for CI depends upon the affected segment of colon, but most commonly include total or subtotal colectomy, right hemicolectomy, or segmental colectomy with either a primary anastomosis or diverting stoma (Table 10). Antolovic et al. (156) prospectively collected data on patients requiring surgical intervention at the University of Heidelberg between 2001 and 2004. Of the 85 consecutive patients undergoing surgery, 56 (66.7%) required procedures within 24 h of presentation to the surgical service. Left hemicolectomy was performed in 8%, right hemicolectomy in 26%, sigmoid resection in 5%, and total colectomy in 49%, with the remainder having other segmental resections; 42% had a Hartmann procedure and another 38% had a diverting stoma created in addition to bowel resection (156). Castleberry et al. (141) retrospectively assessed 115 consecutive patients undergoing surgery for acute CI: segmental colon resection was most common (53%), with right hemicolectomy (49%) being the predominant segmental resection performed; 26% had subtotal or total colectomy, 10% had ileocecectomy, and 10% had a Hartmann procedure; 87% of patients also required an ileostomy or colostomy. Reissfelder et al. (142) prospectively assessed 177 consecutive patients undergoing surgical management for acute CI between 2002 and 2008. Subtotal colectomy was performed in 54%, right hemicolectomy in 38%, and left hemicolectomy in 8%; 61% of their patients had a stoma placed (142). These studies provide a cross-sectional view of surgical treatment patterns for CI, but of course do not assess which surgical procedure is most efficacious for which presentation. The choice of surgical procedure is influenced by a number of factors including the training of the surgeon and his or her practice patterns.
Colon stricture after an episode of CI may be asymptomatic or even resolve over months to years. Surgery is indicated only when an ischemic stricture produces symptoms; in such cases, segmental resection is adequate. Transendoscopic dilation of an ischemic stricture is an alternative to surgery, although an unproven one. Chronic segmental CI is a more controversial indication for surgery and, as with other colitides, the decision to abandon medical therapy is a complex one that must be individualized for each case. Recurrent CI is uncommon and resection of the involved segment of colon, while usually curative, does not necessarily protect against recurrent CI in other areas of the colon. There are no published data on the frequency of such recurrence following surgery for recurrence.
This guideline was produced in collaboration with the Practice Parameters Committee of the American College of Gastroenterology. The Committee gives special thanks to Fouad J. Moawad, MD, FACG, who served as guideline monitor for this document.
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