Ann Thorac Surg 2007;83:1396-1402
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Clostridium Difficile in Cardiac Surgery: Risk Factors and Impact on Postoperative Outcome
Traves Crabtree, MDa,*,
Doug Aitchison, MDa,
Bryan F. Meyers, MDa,
Heidi Tymkew, MHSa,
Jennifer R. Smith, PharmDb,
Tracey J. Guthrie, BSNa,
Nabil Munfakh, MDa,
Marc R. Moon, MDa,
Michael K. Pasque, MDa,
Jennifer Lawton, MDa,
Nader Moazami, MDa,
Ralph J. Damiano, Jr, MDa
a Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri
b Department of Pharmacy, Barnes-Jewish Hospital, St. Louis, Missouri
Accepted for publication October 24, 2006.
* Address correspondence to Dr Crabtree, Washington University School of Medicine, Division of Cardiothoracic Surgery, 660 S Euclid Ave, Campus Box 8234, St. Louis, MO 63110 (Email: crabtreet{at}wustl.edu).
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Abstract
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Background: Clostridium difficile–associated diarrhea (CDAD) is a potentially preventable and often troublesome gastrointestinal complication after cardiac surgery.
Methods: A retrospective study was performed of 8,405 cardiac surgery patients at two institutions between January 1997 and August 2004. Preoperative cardiac risk factors, perioperative factors including blood product transfusion, antibiotic utilization, and postoperative morbidity and mortality were recorded. Univariate and multivariate analyses were performed comparing C difficile patients with a control group matched by date of surgery and institution.
Results: Sixty-six of the 8,405 patients identified with toxin-positive CDAD produced an overall incidence of 0.79% (0.70% at institution A and 1.09% at institution B), with a peak overall incidence of 5.45% in June 2003. Independent prognostic factors for CDAD by multivariate analysis included advancing age (odds ratio [OR] 1.028, 95% confidence interval [CI]: 1.001 to 1.056; p = 0.034), female sex (OR 2.026, 95% CI: 1.102 to 3.722; p = 0.022), blood product transfusion (OR 3.277, 95% CI: 1.292 to 8.311; p = 0.006), and increasing cumulative days of antibiotic administration (OR 1.046, 95% CI: 1.014 to 1.080; p = 0.004). There were no differences in the proportion of fluoroquinolones, cephalosporins, or penicillin derivatives administered between groups. The diagnosis of CDAD was associated with a greater median length of mechanical ventilation (25 hours versus 12 hours, p < 0.001), longer intensive care unit stay (5 days versus 2 days, p < 0.001), and extended hospital stay (21 days versus 7 days, p < 0.001), with no difference in 30-day mortality (7.6% versus 9.5%, p = 0.80).
Conclusions: Although the overall incidence of CDAD was low, alteration in transfusion practices and antibiotic utilization may impact the development of CDAD among cardiac surgical patients.
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Introduction
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Infection or colonization with Clostridium difficile is an increasingly significant public health problem, with recently reported outbreaks in the United States and United Kingdom [1]. Clostridium difficile is a frequently identified pathogen within the large bowel that may be carried asymptomatically in 3% of the general (nonhospital) population. The rates of asymptomatic carriage increase to more than 20% in hospital populations, particularly the elderly [2].
For patients undergoing surgery, Clostridium difficile–associated diarrhea (CDAD) has remained a significant complication. The reported incidence of CDAD is 0.2% to 8.4% depending on the surgical population studied [3–9]. It is particularly common after major surgery, where the risk factors of frequent antibiotic usage, increasing age, and comorbidity are associated with increased incidence [3, 5, 10]. Other recently identified risk factors include nonsurgical gastrointestinal procedures including bowel preparation and nasogastric tubes, ulcer medication, increasing length of intensive care unit stay, and increasing length and number of courses of antibiotics [2, 3, 5, 6, 10].
Complications related to CDAD are generally rare, although its persistence in the inpatient setting and transmissibility remain a significant problem in the hospital environment. The incidence of CDAD and CDAD-related complications are increased by the production of the protein toxins A and B. Toxin production may be asymptomatic in many, particularly those with a strong antitoxin immunoglobulin A antibody response. Presence of the toxin may lead to the development of potentially serious large bowel complications, ranging from diarrhea, pseudo-obstruction, pseudomembranous colitis, toxic megacolon, and large bowel perforation. Mortality ranges from 6% in patients with diarrhea to approximately 30% for patients in whom pseudomembranous colitis develops [1]. Hospital stay and other complications are known to be increased, resulting in significant outcome, resource, and financial implications. Unfortunately, there are limited data in the literature examining the characteristics of C difficile infection in the cardiac surgical population. One study of a mixed population of cardiac and vascular patients randomly assigned to surgical prophylaxis with cefuroxime or ceftriaxone demonstrated an incidence of all infections of 4.7%, with only 1 case of C difficile infection (0.2%) [4].
Cardiac surgical populations have been increasing steadily in age and levels of other comorbidity over time. Antibiotic usage and prolonged intensive care unit stays are common among older patients. Prevalence of peripheral vascular disease, postoperative gastrointestinal stasis, and the relative immunosuppressant effect of cardiopulmonary bypass may increase the risks of bowel ischemia in this group, and hence the potential risk of complications of CDAD. The objectives of this study were to document the incidence and explore changes over time of CDAD and colitis in a defined cardiac surgical population. The study also aimed to explore identifiable risk factors for postoperative CDAD, and to determine the impact of C difficile infection on postoperative mortality and hospital length of stay.
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Material and Methods
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Using data from our institutional Society of Thoracic Surgeons (STS) database, all patients (N = 8,405) undergoing cardiopulmonary bypass at Barnes-Jewish Hospital and at Christian Hospital Northeast between January 1997 and August 2004 were screened for CDAD. This study was reviewed and approved by the Washington University School of Medicine Human Research Protection Office on November 10, 2004, and waiver of consent was obtained. Preoperative demographics, operative characteristics, and postoperative complications were obtained from the database. Clinical charts were also reviewed to confirm the diagnosis of CDAD and to collect data on antibiotic administration. Patients with symptoms of diarrhea and confirmation of the presence of C difficile toxin on stool assays were included. Patients empirically treated for C difficile colitis without confirmation of toxin were not included in the study group. In addition, a control group was identified and matched to the C difficile study group by date of surgery and institution where the surgery was performed. The matched control group to C difficile group ratio was 3:1 and chosen in a random fashion.
Clinical characteristics obtained from our institutional STS database included age, sex, body mass index, preoperative left ventricular ejection fraction, hypercholesterolemia, smoking history, chronic lung disease, diabetes mellitus, congestive heart failure, hypertension, vascular disease, renal failure, New York Heart Association (NYHA) heart failure classification, cross-clamp time, bypass time, and type of procedure performed. Postoperative variables included blood product administration, concomitant infections (ie, skin, urinary tract, pulmonary, sternal, bloodstream), renal failure, cerebrovascular accident, hospital length of stay and intensive care unit length of stay, length of mechanical ventilation, and 30-day mortality. The total number of days of antibiotics administered before the diagnosis of CDAD was recorded. For the control group, the total number of days of antibiotics administered during their hospitalization was recorded. The time interval from the initiation of antibiotic therapy to the diagnosis of CDAD and the time interval from the last administered dose of antibiotics to the diagnosis of CDAD were also recorded.
Statistical analyses were performed with SPSS 11.0 software (SPSS, Chicago, Illinois). Univariate analyses were performed for all relevant categoric variables by using contingency tables (
2 or Fisher exact tests for variables with small expected cell numbers) and t tests or the Mann-Whitney U test for continuous variables. Continuous data are reported as the median with the interquartile range (Q25 to Q75). Multivariate analyses were performed by using a stepwise logistic regression, in which all variables with a p value of less than 0.10 in the univariate analyses were included in the initial full models. A p value of less than 0.05 was considered significant.
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Results
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Of the 8,405 patients, there were 66 identified with toxin-positive C difficile colitis, for an overall incidence of 0.79% (46 of 6,575 [0.70%] at institution A and 20 of 1,830 [1.09%] at institution B). Figure 1
outlines the incidence of C difficile colitis over the designated time period overall and at each institution. The peak overall incidence of 5.45% occurred in June 2003. The peak incidence was 8.89% at institution A in June 2003 and 5.66% at institution B in May 2003. There was minimal cross coverage with faculty and staff between the two institutions.
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Fig 1. Overall incidence of Clostridium difficile colitis at each institution during the designated time period. (Diamonds = total; triangles = institution A; squares = institution B.)
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Demographic data and preoperative comorbidities for C difficile patients and the matched control group are included in Table 1. Patients with CDAD were older and more likely to be female. Congestive heart failure, peripheral vascular disease, history of cerebrovascular accident, and renal failure were more common among patients with CDAD than in the matched control group.
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Table 1 Preoperative Characteristics of Patients With Subsequent Clostridium Difficile Colitis Versus Matched Control Group by Univariate Analysis
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There were no differences between groups in the type of surgery performed (ie, coronary revascularization versus valve surgery, and so forth; p = 0.068). Total aortic cross-clamp time was 95 ± 62 for C difficile patients and 98 ± 54 minutes for the control group (p = 0.723). Total bypass time was 151 ± 71 minutes in the C difficile group versus 142 ± 78 minutes in the control group (p = 0.409).
Table 2
outlines postoperative variables including postoperative complications and infections that occurred before or concomitantly to the development of CDAD. Concomitant or preceding infections occurred more frequently in the C difficile than in the study group, with urinary tract and pulmonary infections occurring most often. In the C difficile group, 91% received blood product transfusion in the perioperative period versus only 68% in the control group (p < 0.001).
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Table 2 Perioperative Characteristics of Patients With Subsequent Clostridium Difficile Colitis Versus Matched Control Group by Univariate Analysis
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The mean number of days the patients received antibiotics before the diagnosis of CDAD was 12.0 ± 10.4 compared with 6.8 ± 8.0 days in the control group (p < 0.001). That included perioperative antibiotic prophylaxis. When examining each antibiotic class as a percentage of all antibiotics administered, there were no differences in the proportion of fluoroquinolones (15.4% [C difficile] versus 12.4% [controls]), cephalosporins (37.8% versus 45.4%), or penicillin derivatives (5.8% versus 2.8%) administered between groups. The average number of days from the initiation of antibiotics to the diagnosis of CDAD was 14.5 ± 13.8 days. This value accounts for gaps in antibiotic therapy and for days between completion of antibiotics to diagnosis of CDAD. The mean number of days from completion of antibiotic therapy to the diagnosis of CDAD was 1.7 ± 4.2 days.
Table 3
outlines the significant predictors of the development of CDAD upon multivariate regression analysis. Independent prognostic factors for CDAD by multivariate analysis included advancing age (odds ratio [OR] 1.028, 95% confidence interval [CI]: 1.001 to 1.056; p = 0.034), female sex (OR 2.026, 95% CI: 1.102 to 3.722; p = 0.022), blood product transfusion (OR 3.277, 95% CI: 1.292 to 8.311; p = 0.006), and increasing cumulative days of antibiotic administration (OR 1.046, 95% CI: 1.014 to 1.080; p = 0.004).
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Table 3 Results of Multivariate Analysis of Prognostic Factors for the Diagnosis of Clostridium Difficile in Cardiac Surgery Patients
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Table 4
outlines outcome variables for the C difficile patients and the control group. Patients with CDAD had a greater median length of mechanical ventilation (25 hours versus 12 hours, p < 0.001), longer intensive care unit stay (5 days versus 2 days, p < 0.001), and extended hospital stay (21 days versus 7 days, p < 0.001), with no difference in 30-day mortality (7.6% versus 9.5%, p = 0.80). Three patients of 66 with CDAD (4.5%) required colectomy, with 1 death (33%).
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Table 4 Outcome Characteristics of Patients With Subsequent Clostridium Difficile Colitis Versus Matched Control Group by Univariate Analysis
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Comment
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The overall incidence of 0.79% in this study is within the range of other published rates of C difficile infection occurring in postsurgical patients although there is significant variability, ranging from 0.2% to 8.4% [3–9]. In a prospective randomized study of surgical patients undergoing cardiac and vascular procedures, the incidence of CDAD was 0.2% [4]. Others have demonstrated wide discrepancy in the incidence of C difficile infection based upon the retrospective or prospective nature of the study in the same surgical populations [6, 11]. Thus, while the diversity of a mixed surgical population may contribute to the variability in the reported incidence of CDAD, selection bias may also play a role in nonrandomized trials, which make up the majority of reports on C difficile. In the only prospective study limited to cardiac surgical patients, Gelfand and colleagues [11] reported an incidence of CDAD of 5% among patients randomly assigned to prophylaxis with cefamandole or cefonicid. Other studies examining specific antibiotic classes have implicated broader spectrum second- and third-generation cephalosporins as independent risk factors for the development of CDAD, and that may account for the higher reported rate in this randomized trial [5, 12, 13]. One limitation of the current study is that it is limited to a retrospective review of inpatient records for cardiac patients in the perioperative period. Therefore, the true incidence of CDAD may be higher given the potential for development of infection after hospital discharge. Furthermore, the false negative rate for C difficile toxin assay is estimated to be 10% to 20%, which may also contribute to a higher actual incidence of C difficile in all populations [14–16]. This false negative rate may be decreased by performing the assay on more than one stool specimen [17].
While the overall incidence of CDAD was less than 1% over the entire period of this study, the majority of cases were identified in the later years of the study. Such an increase in the incidence of CDAD has also been documented worldwide in mixed populations of both medical and surgical patients, with endemics developing in some countries [2]. The recent increase in the incidence of CDAD is likely multifactorial, with increasing acuity of illness in surgical populations potentially playing a significant role. In the current study, that may also be related to improved surveillance in patients with postoperative diarrhea in more recent years and to alterations in antibiotic selection and utilization over time. Future studies should focus on the appropriateness of initiation of antibiotics and antibiotic selection in postsurgical patients, given the concern over the potential rising incidence of C difficile infections nationally.
Among patients undergoing cardiopulmonary bypass, advancing age, female sex, blood product transfusion, and increasing cumulative days of antibiotic administration were found to be associated with the development of CDAD. Other reported risk factors for the development of CDAD include longer postoperative hospital stay, renal impairment, chronic obstructive pulmonary disease, and preoperative bowel preparation [2, 3, 5, 6, 10]. Advancing age and increasing cumulative antibiotic use have been universally reported risk factors for CDAD. Thus, while the overall incidence is low, the increasing age of the cardiac surgical population may lead to an increased risk of C difficile in the future. The identification of female sex as a risk factor in the regression analysis came as a surprise, as sex has not previously been specifically identified as a risk factor for CDAD. Among patients having CDAD, the total number of antibiotic days was not different between males and females, and the incidence of urinary tract infections was similar between the sexes. While this question remains unanswered, gender differences in the immune response or gender variability in the response to administered antibiotics should be considered as potential factors.
Transfusion of blood products has been shown to be associated with an increased risk of postoperative infections among surgical patients, and that may also impact antibiotic utilization [18–21]. Despite multivariate analysis, the debate continues whether transfusion is a true risk factor for infection or if it is simply a marker of increasing severity of illness. One cannot exclude, however, the possible contribution of alterations in the immune response secondary to blood product transfusion impacting the body’s response to C difficile. Perhaps the more prudent use of blood products and antibiotics may decrease the risk of CDAD and its associated complications. Recently, we have made an effort to establish stricter guidelines regarding blood transfusion. We have attempted to implement evidence-based algorithms outlining transfusion criteria for postoperative patients including separate criteria for administration of packed red blood cells and for utilization of other products such as fresh frozen plasma, platelets, and cryoprecipitate. Currently, these algorithms are designated as guidelines for the practicing physicians, and cooperation and compliance at a large institution remain key obstacles to impacting transfusion rates.
The mean time from initiation of antibiotics for treatment of other infections to the time of initiation of treatment of CDAD was 14.5 days. The mean length of stay for the matched control group was 7 days, again suggesting that the actual incidence of CDAD may be higher given that patients started on antibiotics before discharge for trivial infections (ie, for urinary tract infection) may not be diagnosed until some time after discharge. The mean number of days from completion of antibiotic therapy to the initiation of treatment of CDAD was 1.7 ± 4.2 days, demonstrating that most patients were diagnosed with CDAD while concomitantly receiving antibiotics for other infections. Antibiotic therapy for C difficile infection was initiated at the time of diagnosis or empirically after the onset of diarrhea and after stool samples had been sent to the laboratory. No patients with CDAD received perioperative antibiotic prophylaxis alone without receiving other additional antibiotics. Therefore, the impact of perioperative antibiotic prophylaxis cannot be adequately measured in this study. Within a general surgical population, CDAD has been shown to develop in 16% to 20% of patients receiving isolated perioperative antibiotic prophylaxis [5, 11, 13, 22, 23]. Working with the epidemiology division at each institution, we have attempted to monitor adherence to recommendations of limiting perioperative antibiotic prophylaxis to no more than 24 hours without specific documentation of why antibiotics should be continued beyond this time period. This information is tracked, and variations in utilization are reviewed on a monthly basis. Therapeutic utilization of antibiotics remains at the discretion of the treating physician, and altering practices has proved to be difficult. In parallel with the issues regarding transfusion, the increasing number of comorbidities in the cardiac surgical population also impacts their risk of infection and thus antibiotic utilization.
The outbreak of CDAD in the summer of 2003 also suggests a role of cross contamination between patients. It is interesting, however, that this peak occurred at two separate institutions with minimal cross coverage. That would suggest a possible seasonal impact related to such outbreaks or perhaps an unidentified systemwide change, as the two institutions are part of the same hospital organization. Such outbreaks may be prevented with more strict isolation policies, aggressive hand cleansing, and healthcare staff education and awareness, which have been shown to decrease the rate of C difficile infections in medical models [2]. It has been suggested that the recently instituted alcohol gels often found at the bedside have decreased transmission of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus organisms, but may not be as effective at preventing the spread of C difficile [24, 25]. The mechanical action of routine hand washing with soap and water may be more effective at eliminating C difficile spores found in the oil surface of the skin [26]. That may be another factor in preventing outbreaks of C difficile infection when it is diagnosed in individual patients. While sporadic cases do contribute to the overall incidence of CDAD, a significant decrease in the overall incidence may be impacted by preventing such endemics.
The diagnosis of CDAD was associated with a greater median length of mechanical ventilation and a longer intensive care unit stay, which have been described as risk factors for C difficile infections in other populations. Despite the efforts to match the control group to the C difficile group, patients with CDAD were more likely to have congestive heart failure, peripheral vascular disease, cerebrovascular disease, and renal failure preoperatively. Relatively healthy patients undergoing elective uncomplicated bypass surgery should be at low risk for postoperative infection and therefore generally receive minimal antibiotics. For this study, the control group was matched to the C difficile study group by date of surgery and institution where the surgery was performed. In our control group, 30% were urgent or emergent cases, 70% were smokers, 16% had chronic lung disease, 32% were diabetic, 9.5% had preoperative renal failure, and 60% had unstable angina. Furthermore, within the control group, 9% had postoperative urinary tract infections, 1.5% had leg infections, 11.4% had pneumonia, and 7% had sepsis. Thus, the significant comorbidities and postoperative infections among our control patients contribute to a higher overall risk and antibiotic utilization in our control group than one might expect in an otherwise healthy cardiac patient undergoing elective surgery. Despite C difficile being associated with an extended hospital stay compared with controls, there was no difference in 30-day mortality. This finding would suggest that the presence of CDAD is a marker of increasing severity of illness and postoperative morbidity, but is usually not specifically a causative agent in postoperative mortality if managed appropriately.
As cardiac surgeons are faced with an older population of patients with more comorbid conditions, more prudent criteria for antibiotic initiation and selection, more judicious use of blood product transfusions, and closer attention to basic measures for the prevention of outbreaks may ameliorate the anticipated rise in CDAD in the future.
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Abstract
Introduction
