The American Journal of Surgery (2014) 207, 533-539
Clinical Science
Life after colectomy for fulminant Clostridium difficile colitis: a 7-year follow up study Kai B. Dallas, B.S., Audree Condren, M.D., Celia M. Divino, M.D.* Department of Surgery, The Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1259, New York, NY 10029, USA
KEYWORDS: Surgery; Fulminant Clostridium difficile colitis; Survival; Prognosis; Colectomy
Abstract BACKGROUND: The long-term prognosis of patients undergoing colectomy for fulminant Clostridium difficile colitis has not been well studied. The authors present 7-year survival trends in such patients. METHODS: Patients were identified through a pathologic database. Medical records were reviewed and follow-up phone calls made to determine relevant patient history, longevity, and quality of life. RESULTS: The 61 patients identified had mean and median survival of 18.1 and 3.2 months, respectively, and 1-year, 2-year, 5-year, and 7-year mortality of 68.5%, 79.6%, 88.9%, and 90.7%, respectively. Previous C difficile infection, hypotension, requirement of vasopressors, mental status changes, elevated arterial lactate, decreased platelet counts, intubation, and longer duration on nonoperative therapy were associated with in-hospital mortality. There were no factors correlated with longterm survival. CONCLUSIONS: Patients who require colectomy for fulminant C difficile colitis have a poor prognosis with poor long-term survival and significant morbidity. Although there are several factors associated with in-hospital mortality, there were no factors correlated with long-term survival. Ó 2014 Elsevier Inc. All rights reserved.
Clostridium difficile is a gram-positive, spore-forming, anaerobic rod well known for causing antibioticassociated diarrhea.1 Infection ranges from asymptomatic carriage to severe fulminant disease requiring emergent surgical intervention if there is any hope for survival.1,2 It is estimated that 3% to 8% of infected patients will develop fulminant colitis, with approximately 20% of these patients requiring surgical intervention.1,3–5 Complications of fulminant colitis include prolonged ileus, perforation, toxic
The authors declare no conflicts of interest. * Corresponding author. Tel.: 11-212-241-5499; fax: 11-212-4100111. E-mail address: [email protected] Manuscript received August 10, 2012; revised manuscript April 19, 2013 0002-9610/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2013.04.008
megacolon, and death.3 Surgical intervention is most appropriate for patients with the most severe fulminant disease who fail to respond to optimal medical treatment, display signs of systemic toxicity, have toxic colonic dilatation, or have bowel perforation.5,6 Fulminant colitis is a progression of severe colitis marked by a systemic inflammatory response to bacterial toxin, which may result in multipleorgan dysfunction.7,8 Although there has been much research involving the immediate surgical management of fulminant C difficile colitis, there is limited literature exploring the long-term prognosis of these patients. The aims of the present study were to explore the long-term survival of patients who required colectomy for fulminant C difficile infection, determine patient factors that are correlated with inferior or superior survival, and assess quality of life in surviving patients.
534 Table 1
The American Journal of Surgery, Vol 207, No 4, April 2014 Demographics and hospital course
Variable
Value
Percentage of total (denominator 5 61)
Age (y) Men DM CAD COPD HTN ESRD Previous Clostridium difficile infection Immunosuppression Abdominal pain Diarrhea Ileus ABX in previous 2 mo IVIG Metronidazole only Vancomycin only Combination (metronidazole and vancomycin) No antibiotics CT imaging Endoscopy Duration of symptoms (d) Duration of trial of medical treatment (days) ASA score Peak WBC count
71.9 (range, 29–95) 29 19 23 6 36 5 10 20 45 50 10 58 8 22 4 2 8 35 42 6.9 (95% CI, 5.5–8.3) 4.2 (95% CI, 2.9–5.5) 4.1 (95% CI, 4.0–4.2) 38.1 (95% CI, 32.2–44.0)
NA 47.5 31.1 37.7 9.8 59.0 8.2 6.4 32.8 73.8 82.0 16.4 95.1 13.1 35.0 6.6 45.9 13.1 57.4 68.9 NA NA NA NA
ABX 5 antibiotics; ASA 5 American Society of Anesthesiologists; CAD 5 coronary artery disease; CI 5 confidence interval; COPD 5 chronic obstructive pulmonary disease; CT 5 computed tomographic; DM 5 diabetes mellitus; ESRD 5 end-stage renal disease; HTN 5 hypertension; IVIG 5 intravenous immunoglobulin; NA 5 not applicable; WBC 5 white blood cell.
Methods After receiving approval from the Mount Sinai institutional review board, patients for our study were identified with an institutional pathologic specimen database (Tamtron Power-Path system; IMPAC, Columbus OH). A total of 73 colectomy specimens were identified with the pathologic diagnosis of C difficile–associated colitis. In our study, we defined fulminant colitis as we have in our previous studies: as the requirement for surgical intervention after failed medical management in addition to a pathologic diagnosis of either pseudomembranes or pseudomembranous colitis.9
Table 2
Surgical aspects
Variable Subtotal colectomy Left hemicolectomy Right hemicolectomy Ileocolic resection with anastomosis Perforation Necrosis Intraoperative mortality
Number of patients
Percentage of total (denominator 5 61)
51 5 4 1
83.6 8.2 6.6 1.6
3 7 1
4.9 11.5 1.6
The dates of hospital admission ranged from 1994 to 2006. Twelve patients were excluded because of histories of inflammatory bowel disease, leaving a total of 61 patients eligible for our study. Medical records of these patients were reviewed for basic demographic information, medical comorbidities, details of their hospital course, and operative reports. Specifically, to determine factors that affected survival, several variables were explored with relation to in-hospital mortality. Variables included patient demographics, common comorbidities, and prior C difficile infection. Variables involving hospital course included antibiotic treatment, vital signs, requirement of vasopressors or intubation, length of hospital stay, duration of symptoms, mental status changes, type and duration of surgery, estimate blood loss, American Society of Anesthesiologists score, use and findings of imaging studies, use and findings of endoscopic studies, and common laboratory data (arterial lactate, pH, prothrombin time, partial thromboplastin time, international normalized ratio, basic metabolic panel, and complete blood count). To determine which patients were still living, follow-up phone calls were made to all patients who were discharged from the hospital. If the patient could not be reached, a family member was contacted. To assess the quality of life in surviving patients, a survey regarding abilities to perform activities of daily living (ADLs) and instrumental ADLs
K.B. Dallas et al.
Life after colectomy for Clostridium difficile
535 version 18.0.0 (SPSS, Inc, Chicago, IL), and all analysis was reviewed by a statistician. P values ,.05 were taken to indicate significance.
Results
Figure 1 Kaplan-Meier survival curve of all patients. Cum 5 cumulative.
(IADLs) was administered over the phone. ADLs were defined as the ability to dress, bathe, feed oneself, ambulate, and toilet. IADLs were defined as the ability to shop, keep house, manage finances, prepare meals, use the telephone, and manage transportation.
Statistical analysis Mean and median survival were estimated using KaplanMeier analysis. Chi-square tests and independent-samples t tests were used to correlate categorical and continuous patient factors, respectively, with survival. To determine independent factors associated with survival, multivariate analysis was performed using a binary logistical regression model. All analysis was performed using PASW Statistics
Figure 2 Kaplan-Meier survival curve of patients who survived initial hospitalization. Cum 5 cumulative.
A total of 61 patients were identified as having received colectomy for fulminant C difficile colitis with no history of inflammatory bowel disease. The mean age of these patients was 72 years at the time of surgery. A large proportion of patients had severe comorbid disease, with 37.7%, 31.3%, and 32.8% of patients having histories of coronary artery disease, diabetes mellitus, and immunosuppression, respectively. In the 2 months before surgery, 95.1% of patients had histories of antibiotic use, and 16.4% had histories of prior C difficile infection (Table 1). In addition to surgery, most patients were treated with a combination of metronidazole and vancomycin (45.9%). However 35.0%, 6.6%, and 13.1% received only metronidazole, only vancomycin, and no antibiotics, respectively. A total of 57.4% of patients underwent computed tomographic imaging, and 68.9% of patients underwent endoscopy. The mean duration of symptoms before surgery was 6.9 days, and the average length of medical trial in these patients was 4.2 days (Table 1). Most patients (83.6%) underwent subtotal colectomy, while 8.8%, 6.6%, and 1.6% of patients underwent left hemicolectomy, right hemicolectomy and ileocolic resection with anastomosis, respectively (Table 2). A total of 25 of the 61 patients (41.5%) expired in the hospital. A total of 7 patients (11.5%) were lost to follow-up. The estimated mean and median survival times overall were 18.1 months (95% confidence interval [CI], 10.6 to 25.7 months) and 3.2 months (95% CI, 1.6 to 4.8 months), respectively, indicating a minority of individuals with high longevity (Fig. 1). The estimated mean and median survival times for patients who survived hospitalization and were discharged were 32.4 months (95% CI, 20.6 to 44.2 months) and 20.1 months (95% CI, 10.5 to 29.7) months, respectively, also indicating a minority of individuals with high longevity (Fig. 2). The highest rate of mortality was within the first 6 months after surgery, after which there was a leveling off of mortality. Overall, the survival rate was poor (Table 3, Fig. 1). The longest time to censor or death was observed to be 8.3 years in 1 patient, who was still alive at follow-up. Of the patient factors explored, only prior C difficile infection, systolic blood pressure ,100 mm Hg, the requirement of vasopressors, mental status change, intubation, elevated arterial lactate, lower platelet count, and longer duration of medical therapy before surgical intervention were correlated with increased likelihood of in-hospital mortality (Table 4, Fig. 3). Interestingly, the diagnosis of type 2 diabetes mellitus was associated with a decreased likelihood of in-hospital mortality. Multivariate analysis, however, revealed that only intubation and increased duration of nonoperative treatment were independent risk
536
The American Journal of Surgery, Vol 207, No 4, April 2014
Table 3
Survival trends
Variable
All patients
In-hospital mortality Loss to follow-up Overall morality to date Mean survival time (mo) Median survival time (mo) 1-y mortality 2-y mortality 5-y mortality 7-y mortality
25/61 7/61 52/54 18.1(95% CI, 10.6–25.7) 3.2 (95% CI, 1.6–4.8) 37/54 43/54 48/54 49/54
Percentage of all patients
Patients discharged
41.0 11.5 96.0
NA 7/36 27/29 32.4 (95% CI, 20.6–44.2) 20.1(95% CI, 10.5–29.7) 12/29 18/29 23/29 24/29
68.5 79.6 88.9 90.7
Percentage of discharged patients 19.4 93.1
41.4 62.1 79.3 82.8
CI 5 confidence interval; NA 5 not applicable.
factors of in-hospital mortality (P 5 .016 and P 5 .009, respectively). To explore which patients had superior long-term outcomes, the patients who were discharged from the hospital were included in a separate analysis to determine what, if any, of the factors outlined above were associated with longer survival. This analysis was performed by dividing the patients who survived initial hospitalization into a short-term survival group (mortality within 1 year) and a long-term survival group (.1-year survival). None of the factors described above was significantly associated with a patient’s being either a short-term or a long-term survivor. Of the 2 patients who were still living at the time of the interview (average, 7.5 years after surgery), only 1 patient was able to perform all IADLs and ADLs independently with the other patient being completely dependent on others for care. A total of 4 of the 29 patients (13.8%) who were discharged and not lost to follow-up had gastrointestinal continuity restored.
Comments It is extremely important to understand the natural history of C difficile infection because it is the most common nosocomial infection of the gastrointestinal tract, affecting .3 million patients per year in the United States
alone.4 Studying the surgical outcomes of fulminant infection is imperative not only because of the rising incidence of C difficile infection in general but also because of the increasing proportion of patients requiring surgery as hypervirulent antibiotic resistant strains become more common.1,2,10,11 In our series, we found in-hospital mortality after surgical intervention to be 41%, which is consistent with the literature, in which mortality ranges from 35% to 80%.3,10,12–14 Patients in our study had lower-thanaverage life spans compared to the overall US life expectancy of 77.7 years (80.2 years in women, 75.1 years in men) in 2006.15 The average age for patients in our study was 71.9 years, with a mean survival time after C difficile infection of 18.1 months. Thus, in our study, C difficile infection lowered life expectancy by 4.3 years on average. This difference is likely to be even greater for women, as their life expectancy in known to be longer. The most common surgical intervention in our patients was subtotal colectomy with end ileostomy, which is also consistent with prior studies.3,6,12 Our patients were extremely ill at the time of surgery, with many having risk factors that have been associated with the development of fulminant infection and need for surgical intervention including leukocytosis, immunosuppression, recent intravenous immunoglobulin therapy, hypotension, and tachycardia.3,6,10,16 Our patients had the characteristics of
Table 4 Factors correlated with in-hospital mortality of patients who underwent colectomy for treatment of fulminant Clostridium difficile colitis Variable
In-hospital mortality
Percentage
Discharged
Percentage
P
DM (n 5 17) Previous C difficile infection (n 5 9) SBP , 100 mm Hg (n 5 23) Required pressors (n 5 20) Mental status change (n 5 33) Intubation (n 5 27) Arterial lactate (mmol/L) Platelet count (! 103/mL) Duration of medical therapy before surgery (d)
3 7 15 14 21 17 1.545 237 6.42
17.6 77.8 65.2 70.0 63.6 63.0 NA NA NA
14 2 8 6 12 10 3.032 168 2.29
82.4 22.2 34.8 30.0 36.4 37.0 NA NA NS
.004 .038 .016 .007 .001 .01 .004 .034 .007
DM 5 diabetes mellitus; NA 5 not applicable; SBP 5 systolic blood pressure.
K.B. Dallas et al.
Life after colectomy for Clostridium difficile
Figure 3
537
Individual survival curves by individual comorbidity. Cum 5 cumulative.
the patient group explored in Lamontagne et al,16 and the mortality rate would have likely been much higher if any of the patients had received nonoperative therapy only.
It was discovered that certain variables, such a previous C difficile infection, hypotension, the requirement of vasopressors, mental status changes, intubation, elevated
538 arterial lactate, low platelet count, and longer duration of nonoperative therapy, were positively associated with increased in-hospital mortality. This is consistent with prior studies at separate institutions that identified factors such as the use of vasopressors, hypotension, and intubation as being associated with increased mortality after colectomy for fulminant C difficile colitis.5,10,13,16–19 Our finding of only intubation and increased duration of nonoperative therapy being predictive of in-hospital mortality with multivariate analysis is logical given the collinearity of many of the significant factors with univariate analysis. Although diabetes was correlated with increased survival only in the univariate analysis and not the multivariate analysis, it is interesting to note that the protective effect of diabetes mellitus in sepsis has been studied and is theorized to be a result of the effect of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and the interactions of agents used to treat diabetes.20 Mean survival in patients was higher than the median, indicating that a minority of patients experienced increased longevity and that the highest rate of death is in the hospital. Although in-hospital mortality was 41%, after 1 year, the yearly mortality rate dropped to 11.1% between years 1 and 2 and about 3% per year thereafter. Between the 5-year and 7-year follow-up, there was only 1 mortality. Despite this leveling off, all but 5 patients (11.1%) were dead by 5-year follow-up. This is comparable with the 5year survival rate of stage IV colon cancer, with only a handful of patients surviving long term.21 Attempts were made to identify factors predictive of long-term survival, but of patients who were successfully discharged from the hospital, there were no factors unique to patients with .1-year survival. This means that although there are several predictors of survival of hospitalization, it remains unclear exactly which patients will have superior outcomes once discharged successfully. In light of our findings, it is important to note when discussing the possibility of surgery in these patients that in addition to both a high in-hospital mortality rate and poor long-term survival, there is significant morbidity associated with surgical intervention. We found that of the 2 patients still living at follow-up, only 1 was able to perform IADLs and ADLs, indicating that severe disability is likely common. Contributing to this morbidity is that fact that in our series of the patients followed up, only 13.8% had gastrointestinal continuity restored. There are a few limitations to our findings. The first is we excluded patients with histories of inflammatory bowel disease, because we felt that these patients represented a different population than the one we were interested in studying. In fact, it has been shown that patients with inflammatory bowel disease who require surgery for fulminant C difficile colitis are usually younger and healthier than those without and have improved prognosis.22 In addition, although this is the largest cohort of patients followed for this extended period of time, the size of the population
The American Journal of Surgery, Vol 207, No 4, April 2014 was still small. Finally, the staggered nature of the followup made it difficult to assess quality-of-life parameters in these patients, because only those patients at the later end of the cohort would likely be living at the time of followup. In the future, we could provide valuable information to the critical care provider by expanding our definition of fulminate colitis to include the patients who have a systemic inflammatory response to C difficile but are not operative candidates because of comorbidities. A comparison of operative versus nonoperative treatment could then be made. However, our current acquisition of specimens is limited to surgical specimens and does not include postmortem specimens from nonoperative patients with fulminant C difficile. Despite these limitations, this study provides an excellent survey of the long-term survival trends of patients who required surgery for fulminant C difficile colitis and details the extremely grim prognosis these patients face.
References 1. Kachrimanidou M, Malisiovas N. Clostridium difficile infection: a comprehensive review. Critical Reviews in Microbiology 2011;37: 178–87. 2. Hookman P, Barkin JS. Clostridium difficile associated infection, diarrhea and colitis. World J Gastroenterol 2009;15:1554–80. 3. Sailhamer EA, Carson K, Chang Y, et al. Fulminant clostridium difficile colitis patterns of care and predictors of mortality. Arch Surg 2009;144:433–9. 4. Miller AT, Tabrizian P, Greenstein AJ, et al. Long-term follow-up of patients with fulminant clostridium difficile colitis. J Gastrointest Surg 2009;13:956–9. 5. Koss K, Clark MA, Sanders DS, et al. The outcome of surgery in fulminant clostridium difficile colitis. Colorectal Dis 2005;8:149–54. 6. Noblett SE, Welfare M, Seymour K. The role of surgery in clostridium difficile colitis. BMJ 2009;33:1196–200. 7. Adams SD, Mercer DW. Fulminant Clostridium difficile colitis. Curr Opin Crit Care 2007;13:450–5. 8. Koss K, Clark MA, Sander DSA, et al. The outcome of surgery in fulminant Clostridium difficile colitis. Colorectal Dis 2005;8:149–54. 9. Bym JC, Maun DC, Gingold DS, et al. Predictors of mortality after colectomy for fulminant Clostridium difficile colitis. Arch Surg 2008;143:150–4. 10. Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg 2009;235:363–72. 11. Shah D, Dang M, Hasbun R, et al. Clostridium difficile infection: update on emerging antibiotic treatment options and antibiotic resistance. Expert Rev Anti Infect Ther 2010;8:555–64. 12. Longo WE, Mazuski JE, Virgo KS, et al. Outcome after colectomy for clostridium difficile colitis. Dis Colon Rectum 2004;47:1620–6. 13. Hall JF, Berger D. The role of surgery in clostridium difficile colitis. Am J Surg 2008;338:384–8. 14. Gash K, Brown E, Pullyblank A. Emergency subtotal colectomy for fulminant clostridium difficile colitis – is a surgical solution considered for all patients? Ann R Coll Surg Engl 2003;92:56–60. 15. Heron MP, Hoyert DL, Murphy SL, et al. Deaths: Final data for 2006. Natl Vital Stat Rep 2009;57:1–134. 16. Lamontagne F, Labbe´ AC, Haeck O, et al. Early surgical intervention for fulminant pseudomembranous colitis. Ann Surg 2007;245: 267–72.
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17. Markelov A, Livert D, Kohli H. Predictors of fatal outcome after colectomy for fulminant clostridium difficile colitis: a 10-year experience. Am Surg 2011;77:977–8. 18. Ali SO, Welch JP, Dring RJ. Early surgical intervention for fulminant pseudomembranous colitis. Am Surg 2008 Jan;74:20–6. 19. Seder CW, Villalba MR, Robbins J, et al. Early colectomy may be associated with improved survival in fulminant Clostridium difficile colitis: an 8-year experience. Am J Surg 2009;197: 302–7.
539 20. Yang Y, Salam ZH, Ong BC, et al. Respiratory dysfunction in patients with sepsis: protective effect of diabetes mellitus. Am J Crit Care 2011;20:e41–7. 21. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96:1420–5. 22. Byrn JC, Maun DC, Gingold DS, et al. Predictors of mortality after colectomy for fulminant Clostridiumdifficile colitis. Arch Surg 2008; 143:150–4.
Clinical Science
Life after colectomy for fulminant Clostridium difficile colitis: a 7-year follow up study Kai B. Dallas, B.S., Audree Condren, M.D., Celia M. Divino, M.D.* Department of Surgery, The Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1259, New York, NY 10029, USA
KEYWORDS: Surgery; Fulminant Clostridium difficile colitis; Survival; Prognosis; Colectomy
Abstract BACKGROUND: The long-term prognosis of patients undergoing colectomy for fulminant Clostridium difficile colitis has not been well studied. The authors present 7-year survival trends in such patients. METHODS: Patients were identified through a pathologic database. Medical records were reviewed and follow-up phone calls made to determine relevant patient history, longevity, and quality of life. RESULTS: The 61 patients identified had mean and median survival of 18.1 and 3.2 months, respectively, and 1-year, 2-year, 5-year, and 7-year mortality of 68.5%, 79.6%, 88.9%, and 90.7%, respectively. Previous C difficile infection, hypotension, requirement of vasopressors, mental status changes, elevated arterial lactate, decreased platelet counts, intubation, and longer duration on nonoperative therapy were associated with in-hospital mortality. There were no factors correlated with longterm survival. CONCLUSIONS: Patients who require colectomy for fulminant C difficile colitis have a poor prognosis with poor long-term survival and significant morbidity. Although there are several factors associated with in-hospital mortality, there were no factors correlated with long-term survival. Ó 2014 Elsevier Inc. All rights reserved.
Clostridium difficile is a gram-positive, spore-forming, anaerobic rod well known for causing antibioticassociated diarrhea.1 Infection ranges from asymptomatic carriage to severe fulminant disease requiring emergent surgical intervention if there is any hope for survival.1,2 It is estimated that 3% to 8% of infected patients will develop fulminant colitis, with approximately 20% of these patients requiring surgical intervention.1,3–5 Complications of fulminant colitis include prolonged ileus, perforation, toxic
The authors declare no conflicts of interest. * Corresponding author. Tel.: 11-212-241-5499; fax: 11-212-4100111. E-mail address: [email protected] Manuscript received August 10, 2012; revised manuscript April 19, 2013 0002-9610/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2013.04.008
megacolon, and death.3 Surgical intervention is most appropriate for patients with the most severe fulminant disease who fail to respond to optimal medical treatment, display signs of systemic toxicity, have toxic colonic dilatation, or have bowel perforation.5,6 Fulminant colitis is a progression of severe colitis marked by a systemic inflammatory response to bacterial toxin, which may result in multipleorgan dysfunction.7,8 Although there has been much research involving the immediate surgical management of fulminant C difficile colitis, there is limited literature exploring the long-term prognosis of these patients. The aims of the present study were to explore the long-term survival of patients who required colectomy for fulminant C difficile infection, determine patient factors that are correlated with inferior or superior survival, and assess quality of life in surviving patients.
534 Table 1
The American Journal of Surgery, Vol 207, No 4, April 2014 Demographics and hospital course
Variable
Value
Percentage of total (denominator 5 61)
Age (y) Men DM CAD COPD HTN ESRD Previous Clostridium difficile infection Immunosuppression Abdominal pain Diarrhea Ileus ABX in previous 2 mo IVIG Metronidazole only Vancomycin only Combination (metronidazole and vancomycin) No antibiotics CT imaging Endoscopy Duration of symptoms (d) Duration of trial of medical treatment (days) ASA score Peak WBC count
71.9 (range, 29–95) 29 19 23 6 36 5 10 20 45 50 10 58 8 22 4 2 8 35 42 6.9 (95% CI, 5.5–8.3) 4.2 (95% CI, 2.9–5.5) 4.1 (95% CI, 4.0–4.2) 38.1 (95% CI, 32.2–44.0)
NA 47.5 31.1 37.7 9.8 59.0 8.2 6.4 32.8 73.8 82.0 16.4 95.1 13.1 35.0 6.6 45.9 13.1 57.4 68.9 NA NA NA NA
ABX 5 antibiotics; ASA 5 American Society of Anesthesiologists; CAD 5 coronary artery disease; CI 5 confidence interval; COPD 5 chronic obstructive pulmonary disease; CT 5 computed tomographic; DM 5 diabetes mellitus; ESRD 5 end-stage renal disease; HTN 5 hypertension; IVIG 5 intravenous immunoglobulin; NA 5 not applicable; WBC 5 white blood cell.
Methods After receiving approval from the Mount Sinai institutional review board, patients for our study were identified with an institutional pathologic specimen database (Tamtron Power-Path system; IMPAC, Columbus OH). A total of 73 colectomy specimens were identified with the pathologic diagnosis of C difficile–associated colitis. In our study, we defined fulminant colitis as we have in our previous studies: as the requirement for surgical intervention after failed medical management in addition to a pathologic diagnosis of either pseudomembranes or pseudomembranous colitis.9
Table 2
Surgical aspects
Variable Subtotal colectomy Left hemicolectomy Right hemicolectomy Ileocolic resection with anastomosis Perforation Necrosis Intraoperative mortality
Number of patients
Percentage of total (denominator 5 61)
51 5 4 1
83.6 8.2 6.6 1.6
3 7 1
4.9 11.5 1.6
The dates of hospital admission ranged from 1994 to 2006. Twelve patients were excluded because of histories of inflammatory bowel disease, leaving a total of 61 patients eligible for our study. Medical records of these patients were reviewed for basic demographic information, medical comorbidities, details of their hospital course, and operative reports. Specifically, to determine factors that affected survival, several variables were explored with relation to in-hospital mortality. Variables included patient demographics, common comorbidities, and prior C difficile infection. Variables involving hospital course included antibiotic treatment, vital signs, requirement of vasopressors or intubation, length of hospital stay, duration of symptoms, mental status changes, type and duration of surgery, estimate blood loss, American Society of Anesthesiologists score, use and findings of imaging studies, use and findings of endoscopic studies, and common laboratory data (arterial lactate, pH, prothrombin time, partial thromboplastin time, international normalized ratio, basic metabolic panel, and complete blood count). To determine which patients were still living, follow-up phone calls were made to all patients who were discharged from the hospital. If the patient could not be reached, a family member was contacted. To assess the quality of life in surviving patients, a survey regarding abilities to perform activities of daily living (ADLs) and instrumental ADLs
K.B. Dallas et al.
Life after colectomy for Clostridium difficile
535 version 18.0.0 (SPSS, Inc, Chicago, IL), and all analysis was reviewed by a statistician. P values ,.05 were taken to indicate significance.
Results
Figure 1 Kaplan-Meier survival curve of all patients. Cum 5 cumulative.
(IADLs) was administered over the phone. ADLs were defined as the ability to dress, bathe, feed oneself, ambulate, and toilet. IADLs were defined as the ability to shop, keep house, manage finances, prepare meals, use the telephone, and manage transportation.
Statistical analysis Mean and median survival were estimated using KaplanMeier analysis. Chi-square tests and independent-samples t tests were used to correlate categorical and continuous patient factors, respectively, with survival. To determine independent factors associated with survival, multivariate analysis was performed using a binary logistical regression model. All analysis was performed using PASW Statistics
Figure 2 Kaplan-Meier survival curve of patients who survived initial hospitalization. Cum 5 cumulative.
A total of 61 patients were identified as having received colectomy for fulminant C difficile colitis with no history of inflammatory bowel disease. The mean age of these patients was 72 years at the time of surgery. A large proportion of patients had severe comorbid disease, with 37.7%, 31.3%, and 32.8% of patients having histories of coronary artery disease, diabetes mellitus, and immunosuppression, respectively. In the 2 months before surgery, 95.1% of patients had histories of antibiotic use, and 16.4% had histories of prior C difficile infection (Table 1). In addition to surgery, most patients were treated with a combination of metronidazole and vancomycin (45.9%). However 35.0%, 6.6%, and 13.1% received only metronidazole, only vancomycin, and no antibiotics, respectively. A total of 57.4% of patients underwent computed tomographic imaging, and 68.9% of patients underwent endoscopy. The mean duration of symptoms before surgery was 6.9 days, and the average length of medical trial in these patients was 4.2 days (Table 1). Most patients (83.6%) underwent subtotal colectomy, while 8.8%, 6.6%, and 1.6% of patients underwent left hemicolectomy, right hemicolectomy and ileocolic resection with anastomosis, respectively (Table 2). A total of 25 of the 61 patients (41.5%) expired in the hospital. A total of 7 patients (11.5%) were lost to follow-up. The estimated mean and median survival times overall were 18.1 months (95% confidence interval [CI], 10.6 to 25.7 months) and 3.2 months (95% CI, 1.6 to 4.8 months), respectively, indicating a minority of individuals with high longevity (Fig. 1). The estimated mean and median survival times for patients who survived hospitalization and were discharged were 32.4 months (95% CI, 20.6 to 44.2 months) and 20.1 months (95% CI, 10.5 to 29.7) months, respectively, also indicating a minority of individuals with high longevity (Fig. 2). The highest rate of mortality was within the first 6 months after surgery, after which there was a leveling off of mortality. Overall, the survival rate was poor (Table 3, Fig. 1). The longest time to censor or death was observed to be 8.3 years in 1 patient, who was still alive at follow-up. Of the patient factors explored, only prior C difficile infection, systolic blood pressure ,100 mm Hg, the requirement of vasopressors, mental status change, intubation, elevated arterial lactate, lower platelet count, and longer duration of medical therapy before surgical intervention were correlated with increased likelihood of in-hospital mortality (Table 4, Fig. 3). Interestingly, the diagnosis of type 2 diabetes mellitus was associated with a decreased likelihood of in-hospital mortality. Multivariate analysis, however, revealed that only intubation and increased duration of nonoperative treatment were independent risk
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The American Journal of Surgery, Vol 207, No 4, April 2014
Table 3
Survival trends
Variable
All patients
In-hospital mortality Loss to follow-up Overall morality to date Mean survival time (mo) Median survival time (mo) 1-y mortality 2-y mortality 5-y mortality 7-y mortality
25/61 7/61 52/54 18.1(95% CI, 10.6–25.7) 3.2 (95% CI, 1.6–4.8) 37/54 43/54 48/54 49/54
Percentage of all patients
Patients discharged
41.0 11.5 96.0
NA 7/36 27/29 32.4 (95% CI, 20.6–44.2) 20.1(95% CI, 10.5–29.7) 12/29 18/29 23/29 24/29
68.5 79.6 88.9 90.7
Percentage of discharged patients 19.4 93.1
41.4 62.1 79.3 82.8
CI 5 confidence interval; NA 5 not applicable.
factors of in-hospital mortality (P 5 .016 and P 5 .009, respectively). To explore which patients had superior long-term outcomes, the patients who were discharged from the hospital were included in a separate analysis to determine what, if any, of the factors outlined above were associated with longer survival. This analysis was performed by dividing the patients who survived initial hospitalization into a short-term survival group (mortality within 1 year) and a long-term survival group (.1-year survival). None of the factors described above was significantly associated with a patient’s being either a short-term or a long-term survivor. Of the 2 patients who were still living at the time of the interview (average, 7.5 years after surgery), only 1 patient was able to perform all IADLs and ADLs independently with the other patient being completely dependent on others for care. A total of 4 of the 29 patients (13.8%) who were discharged and not lost to follow-up had gastrointestinal continuity restored.
Comments It is extremely important to understand the natural history of C difficile infection because it is the most common nosocomial infection of the gastrointestinal tract, affecting .3 million patients per year in the United States
alone.4 Studying the surgical outcomes of fulminant infection is imperative not only because of the rising incidence of C difficile infection in general but also because of the increasing proportion of patients requiring surgery as hypervirulent antibiotic resistant strains become more common.1,2,10,11 In our series, we found in-hospital mortality after surgical intervention to be 41%, which is consistent with the literature, in which mortality ranges from 35% to 80%.3,10,12–14 Patients in our study had lower-thanaverage life spans compared to the overall US life expectancy of 77.7 years (80.2 years in women, 75.1 years in men) in 2006.15 The average age for patients in our study was 71.9 years, with a mean survival time after C difficile infection of 18.1 months. Thus, in our study, C difficile infection lowered life expectancy by 4.3 years on average. This difference is likely to be even greater for women, as their life expectancy in known to be longer. The most common surgical intervention in our patients was subtotal colectomy with end ileostomy, which is also consistent with prior studies.3,6,12 Our patients were extremely ill at the time of surgery, with many having risk factors that have been associated with the development of fulminant infection and need for surgical intervention including leukocytosis, immunosuppression, recent intravenous immunoglobulin therapy, hypotension, and tachycardia.3,6,10,16 Our patients had the characteristics of
Table 4 Factors correlated with in-hospital mortality of patients who underwent colectomy for treatment of fulminant Clostridium difficile colitis Variable
In-hospital mortality
Percentage
Discharged
Percentage
P
DM (n 5 17) Previous C difficile infection (n 5 9) SBP , 100 mm Hg (n 5 23) Required pressors (n 5 20) Mental status change (n 5 33) Intubation (n 5 27) Arterial lactate (mmol/L) Platelet count (! 103/mL) Duration of medical therapy before surgery (d)
3 7 15 14 21 17 1.545 237 6.42
17.6 77.8 65.2 70.0 63.6 63.0 NA NA NA
14 2 8 6 12 10 3.032 168 2.29
82.4 22.2 34.8 30.0 36.4 37.0 NA NA NS
.004 .038 .016 .007 .001 .01 .004 .034 .007
DM 5 diabetes mellitus; NA 5 not applicable; SBP 5 systolic blood pressure.
K.B. Dallas et al.
Life after colectomy for Clostridium difficile
Figure 3
537
Individual survival curves by individual comorbidity. Cum 5 cumulative.
the patient group explored in Lamontagne et al,16 and the mortality rate would have likely been much higher if any of the patients had received nonoperative therapy only.
It was discovered that certain variables, such a previous C difficile infection, hypotension, the requirement of vasopressors, mental status changes, intubation, elevated
538 arterial lactate, low platelet count, and longer duration of nonoperative therapy, were positively associated with increased in-hospital mortality. This is consistent with prior studies at separate institutions that identified factors such as the use of vasopressors, hypotension, and intubation as being associated with increased mortality after colectomy for fulminant C difficile colitis.5,10,13,16–19 Our finding of only intubation and increased duration of nonoperative therapy being predictive of in-hospital mortality with multivariate analysis is logical given the collinearity of many of the significant factors with univariate analysis. Although diabetes was correlated with increased survival only in the univariate analysis and not the multivariate analysis, it is interesting to note that the protective effect of diabetes mellitus in sepsis has been studied and is theorized to be a result of the effect of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and the interactions of agents used to treat diabetes.20 Mean survival in patients was higher than the median, indicating that a minority of patients experienced increased longevity and that the highest rate of death is in the hospital. Although in-hospital mortality was 41%, after 1 year, the yearly mortality rate dropped to 11.1% between years 1 and 2 and about 3% per year thereafter. Between the 5-year and 7-year follow-up, there was only 1 mortality. Despite this leveling off, all but 5 patients (11.1%) were dead by 5-year follow-up. This is comparable with the 5year survival rate of stage IV colon cancer, with only a handful of patients surviving long term.21 Attempts were made to identify factors predictive of long-term survival, but of patients who were successfully discharged from the hospital, there were no factors unique to patients with .1-year survival. This means that although there are several predictors of survival of hospitalization, it remains unclear exactly which patients will have superior outcomes once discharged successfully. In light of our findings, it is important to note when discussing the possibility of surgery in these patients that in addition to both a high in-hospital mortality rate and poor long-term survival, there is significant morbidity associated with surgical intervention. We found that of the 2 patients still living at follow-up, only 1 was able to perform IADLs and ADLs, indicating that severe disability is likely common. Contributing to this morbidity is that fact that in our series of the patients followed up, only 13.8% had gastrointestinal continuity restored. There are a few limitations to our findings. The first is we excluded patients with histories of inflammatory bowel disease, because we felt that these patients represented a different population than the one we were interested in studying. In fact, it has been shown that patients with inflammatory bowel disease who require surgery for fulminant C difficile colitis are usually younger and healthier than those without and have improved prognosis.22 In addition, although this is the largest cohort of patients followed for this extended period of time, the size of the population
The American Journal of Surgery, Vol 207, No 4, April 2014 was still small. Finally, the staggered nature of the followup made it difficult to assess quality-of-life parameters in these patients, because only those patients at the later end of the cohort would likely be living at the time of followup. In the future, we could provide valuable information to the critical care provider by expanding our definition of fulminate colitis to include the patients who have a systemic inflammatory response to C difficile but are not operative candidates because of comorbidities. A comparison of operative versus nonoperative treatment could then be made. However, our current acquisition of specimens is limited to surgical specimens and does not include postmortem specimens from nonoperative patients with fulminant C difficile. Despite these limitations, this study provides an excellent survey of the long-term survival trends of patients who required surgery for fulminant C difficile colitis and details the extremely grim prognosis these patients face.
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