LIVER TRANSPLANTATION 20:930–936, 2014
ORIGINAL ARTICLE
Surgical Site Infections After Liver Retransplantation: Incidence and Risk Factors Harshal Shah,1,5 Walter C. Hellinger,1 Michael G. Heckman,2 Nancy Diehl,2 Jefree A. Shalev,3 Darrin L. Willingham,4 C. Burcin Taner,4 Dana K. Perry,4 and Justin Nguyen4 1 Division of Infectious Disease; 2Section of Biostatistics; 3Division of Transplant Medicine, 4Division of Transplant Surgery, Mayo Clinic, Jacksonville, FL; and 5Parkview Medical Center, Pueblo, CO
Surgical site infections (SSIs) after liver transplantation (LT) are associated with an increased risk of graft loss and death. The incidence of SSIs after LT and their risk factors have been determined for first LT but not for second LT. The importance of reporting the incidence of SSIs risk-stratified by first LT versus second LT is not known. All patients undergoing second LT at a single institution between 2003 and 2011 (n 5 152) were reviewed. The Kaplan-Meier method was used to estimate the cumulative SSI incidence. Relative risks (RRs) and 95% confidence intervals (CIs) from Cox proportional hazards regression models were used to evaluate associations of potential risk factors with SSIs after second LT. Thirty-one patients developed SSIs (6 superficial SSIs, 1 deep SSI, and 24 organ/space SSIs). The cumulative incidence of SSIs 30 days after LT was 20.8% (95% CI 5 14%-27%), which was slightly but not significantly higher than the previously reported incidence of SSIs after first LT at our institution between 2003 and 2008 (16%, RR 5 1.32, 95% CI 5 0.90-1.93, P 5.16). Units of transfused red blood cells [RR (doubling) 5 1.38, 95% CI 5 1.02-1.86, P 5.04] and hepaticojejunostomy (RR 5 2.22, 95% CI 5 1.05-4.72, P 5.04) were the only factors associated with SSIs after second LT in single-variable analysis. The associations weakened in a multivariate analysis (P 5.07 and P 5.07, respectively), potentially because of the correlation of red blood cell transfusions and hepaticojejunostomy (P 5.08). In conclusion, the incidence of SSIs after second LT was slightly higher but not significantly different than the published incidence of SSIs (16%) after first LT at the same institution. Significant independent risk factors for SSIs after second LT were not identified. Risk stratification for retransplantation may C 2014 not be necessary when the incidence of SSIs after LT is being reported. Liver Transpl 20:930-936, 2014. V AASLD. Received December 13, 2013; accepted April 11, 2014.
The operative site is the leading anatomic site of infections in recipients of liver transplantation (LT).1 Surgical site infections (SSIs), as defined by the Centers for Disease Control and Prevention, have been reported to follow 11% to 34% of LT procedures,2-5 and they have been associated with an increased risk of graft loss and death.6 Risk factors associated with SSIs in these investigations have included pretransplant antibiotic therapy, pretransplant mechanical ventilation, intraoperative hyperglycemia, intraoperative administration of vasopressors, need for intraoperative red
blood cell transfusions, surgeons, and operative times.2,3,5,6 Feedback about benchmarked, risk-adjusted rates of SSIs to surgeons has been associated with declines in the rates of these infections in nontransplant surgeries.7-10 An appropriate risk adjustment of SSI incidence is required for the identification of modifiable factors that are associated with the development of SSIs and for the feedback of credible information to surgeons. Published reports of SSI incidence after LT have been derived from cohorts including either
Abbreviations: ASA, American Society of Anesthesiologists; CI, confidence interval; CMV, cytomegalovirus; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NHSN, National Healthcare Safety Network; RR, relative risk; SSI, surgical site infection. The authors report no grants or other financial support, and they have no conflicts of interest to declare. Address reprint requests to Walter C. Hellinger, M.D., Division of Infectious Disease, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224. Telephone: 904-953-2419; FAX: 904-953-0017; E-mail: [email protected] DOI 10.1002/lt.23890 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
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exclusively or predominantly patients undergoing LT for the first time. The incidence of SSIs after liver retransplantation and their risk factors have not been assessed. Liver retransplantation is considered a higher risk procedure than primary transplantation11; therefore, differences in the incidence of SSIs and their risk factors between first LT and second LT would not be surprising. Whether and how the incidence of SSIs after LT should be adjusted for retransplantation is not known. Thus, the aim of this investigation was to determine the incidence of SSIs after second LT and their risk factors.
PATIENTS AND METHODS A retrospective analysis of all 152 patients undergoing second LT between 2003 and 2011 at Mayo Clinic in Florida was performed. Patients undergoing subsequent retransplants (eg, third and fourth transplants) were excluded to improve the homogeneity of the study population and to avoid correlation of the data. Medical records and prospectively maintained local transplant databases were reviewed for patient, donor, and operative characteristics that could be associated with SSIs, graft loss, or death after second LT. The study protocol was reviewed and approved by the Mayo Clinic institutional review board. SSIs were identified with standardized definitions and surveillance methodology that were developed by the National Healthcare Safety Network (NHSN) of the Centers for Disease Control and Prevention.12 SSIs were classified as superficial, deep, or organ/space infections on the basis of findings within 30 days of the second transplant surgery. A superficial SSI was recorded if an infection involved only the skin and subcutaneous tissues of the incision and 1 or more of the following were documented: purulent drainage from the superficial incision; organisms isolated from an aseptically obtained culture of fluid or tissue from the incision; a tender, swollen, red or warm superficial incision deliberately opened by the surgeon or his or her designee; and a superficial SSI diagnosed by the surgeon or his or her designee. A deep SSI was recorded if an infection involved the fascial and muscle layers of the incision and 1 or more of the following were documented: purulent drainage from the incision; spontaneous dehiscence of the deep incision or deliberate opening of the deep incision by the surgeon or his or her designee in the presence of fever (>38 C) or incisional pain; and an abscess or other evidence of infection involving the deep incision that was detected on direct examination, during an invasive procedure, or by histopathological examination or imaging. An organ/space SSI was recorded if an infection involved the space (peritoneum) or organ (liver) contiguous to the plane of the incision and 1 or more of the following were documented: purulent drainage from a drain placed in the organ or space; organisms recovered in an aseptically obtained culture of fluid or tissue of the organ or space; and an abscess or other evidence of infection involving the organ or space that
SHAH ET AL. 931
was detected on direct examination, during an invasive procedure, or by histopathological examination or imaging. Surgical wounds were classified in accordance with NHSN definitions as clean but contaminated (type II: controlled incision of a mucosal surface colonized with microorganisms below the level of the skin), contaminated (type III: unintended contamination of the surgical site; eg, by spillage of the contents of a gastrointestinal viscus), or infected (type IV: infection of the surgical site at the time of transplantation).7 All retransplants were performed with the piggyback technique without venovenous bypass, portocaval shunts, or caval clamping. All liver grafts were reperfused with portal flow, which was then followed by arterial flow. During retransplantation, the previous bile duct anastomosis was resected. The recipient bile duct was mobilized with minimal dissection of the pericholedochal tissue. The viability of the recipient bile duct was assessed by the presence of bleeding from the cut edge of the duct. If the recipient duct was found to be well vascularized, then duct-to-duct biliary reconstruction was performed.13 Patients without a penicillin allergy received 1 g of intravenous cefotaxime every 8 hours for 48 hours as perioperative antibiotic prophylaxis; patients with a penicillin allergy received 1 g of intravenous vancomycin every 12 hours and 1 g of intravenous aztreonam every 8 hours for 48 hours. Anti-Candida antifungal prophylaxis in the form of fluconazole or caspofungin was added when the operative time was longer than 6 hours or operative red blood cell transfusions were greater than 8 U; antimold prophylaxis in the form of caspofungin or liposomal amphotericin was added in lieu of anti-Candida prophylaxis when renal replacement therapy was required for second LT or when there was renal failure (serum creatinine level off renal replacement therapy > 2 mg/dL) or allograft insufficiency extending beyond day 7 after second LT in accordance with previously reported risk stratification for invasive fungal infections at this center.14
Statistical Analysis Continuous variables were summarized as sample medians, minima, and maxima. Categorical variables were summarized as numbers and percentages. The Kaplan-Meier method was used to estimate the cumulative incidence of SSIs after LT; censoring was performed on the date of graft loss or death for patients who experienced these outcomes on or before post-LT day 30 and who did not experience SSIs before these events. Cox proportional hazards regression models were used to compare the risk of SSIs between first LT and second LT; previously published data for SSIs involving 1036 patients who underwent first LT at our institution between 2003 and 20083 were used, and we accounted for the correlation between patients who underwent both first LT and second LT (n 5 84) with a marginal models approach.15 Cox proportional hazards regression
932 SHAH ET AL.
LIVER TRANSPLANTATION, August 2014
TABLE 1. Baseline Patient Characteristics, Donor Information, and Operative Information at LT
Variables Baseline patient characteristics Age at second transplant (years)† Sex: male [n (%)] Body mass index (kg/m2)† Diabetes [n (%)] MELD score† MELD score > 35 [n (%)] Prednisone [n (%)] Mycophenolate [n (%)] Solumedrol 90 days before second transplant [n (%)] Pretransplant hospital length of stay (days)† Principal liver disease diagnosis [n (%)] Chronic hepatitis C Alcohol cirrhosis Cryptogenic cirrhosis Primary sclerosing cholangitis Other Re-LT indication [n (%)] Recurrent hepatitis C Primary nonfunction Biliary necrosis/strictures Hepatic artery thrombosis Chronic rejection Other ASA classification [n (%)] 2 3 4 5 CMV positivity [n (%)] Biliary anastomosis at first LT: Roux-en-Y [n (%)] Location on day of transplant [n (%)] Hospital Hospital: intensive care unit Mechanical ventilation on day of transplant [n (%)] Malignancy in explant [n (%)] Status 1 [n (%)] Operative information Wound classification [n (%)] II (clean but contaminated) III (contaminated) IV (infected) Surgeon [n (%)] 1 2 3 4 5 6 7 8 9 Time between first LT and second LT (days)† 30 days [n (%)] Active infection on day of transplant [n (%)] Renal replacement therapy on day of transplant [n (%)] Operative time (minutes)† Red blood cells (U)† Biliary anastomosis: Roux-en-Y [n (%)] Donor information and post-LT complications Age (years)†
Second LT: 2003-2011
First LT: 2003-2008
(n 5 152)
(n 5 1036)*
54 (20-72) 109 (72) 26 (17-61) 50 (33) 25 (6-49) 32 (21) 64 (42) 32 (21) 54 (36) 1 (0-75)
56 (16-81) 701 (68) 28 (16-61) 264 (25) 17 (6-51) 44 (4) Not applicable Not applicable Not applicable Not applicable
77 (51) 15 (10) 17 (11) 14 (9) 29 (19)
393 (38) 146 (14) 165 (16) 72 (7) 260 (25)
46 (30) 13 (9) 34 (22) 22 (14) 6 (4) 31 (20)
Not Not Not Not Not Not
applicable applicable applicable applicable applicable applicable
1 (1) 27 (18) 113 (74) 11 (7) 118 (78) 22 (16)
10 (1) 301 (29) 703 (68) 22 (2) 710 (69) Not applicable
65 (43) 33 (22) 19 (12) 3 (2) 13 (9)
146 (14) Not available 43 (4) 274 (26) 13 (1)
132 (87) 1 (1) 19 (12)
1033 (99.7) 3 (0.3) 0
36 (24) 25 (16) 23 (15) 22 (14) 18 (12) 10 (7) 8 (5) 6 (4) 4 (3) 318 (2-5879) 30 (20) 28 (18) 20 (13) 278 (137-633) 13 (0-120) 77 (51)
205 (20) 230 (22) 173 (17) 149 (14) 114 (11) Not applicable 52 (5) 113 (11) Not applicable Not applicable Not applicable Not available Not available 241 (100-745) 8 (0-103) 108 (10)
33 (6-70)
49 (7-88)
LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014
SHAH ET AL. 933
TABLE 1. Continued
Variables Sex: male Donor/recipient sex incompatibility Liver mass (g)† Donor risk index† Donor liver mass/recipient body mass < 0.01 [n (%)] CMV seropositivity [n (%)] Donor/recipient CMV combination [n (%)] Positive/positive Positive/negative Negative/positive Negative/negative
Second LT: 2003-2011 (n 5 152)
First LT: 2003-2008 (n 5 1036)*
81 (53) 76 (50) 1449 (613-2300) 1.46 (0.83-2.68) 6 (4) 101 (66)
576 (56) 623 (60) 1480 (570-3620) 1.68 (0.88-4.30) 44 (4) 699 (67)
79 (52) 39 (26) 22 (14) 12 (8)
466 (45) 244 (24) 233 (22) 93 (9)
NOTE: For some patients in the second LT cohort, information was unavailable for the biliary anastomosis at first transplant (n 5 14), the donor liver mass (n 5 1), a donor liver mass/recipient body mass < 0.01 (n 5 1), and the donor risk index (n 5 1). *The data have been taken from Hellinger et al.3 † The data for continuous variables are presented as sample medians (with minima and maxima in parentheses).
TABLE 2. Pathogens Recovered From Cultures of SSIs
Pathogens
SSIs After Second LT (n 5 31)
SSIs After First LT (n 5 166)*
15 (48) 11 (35) 8 (26) 7 (23) 5 (16) 5 (16) 5 (16) 3 (10) 3 (10) 2 (6) 1 (3) 0 0 0
45 (27) 42 (25) 17 (10) 19 (11) 30 (18) 50 (30) 12 (7) 12 (7) 4 (2) 0 0 13 (8) 7 (4) 1 (0.6)
Polymicrobial Enterococci Aerobic gram-negative bacilli, not Pseudomonas Vancomycin-resistant Enterococcus Methicillin-resistant Staphylococcus aureus Coagulase-negative Staphylococcus Candida Pseudomonas aeruginosa Streptococcus viridans Bacillus species, not anthracis Group B Streptococcus Methicillin-sensitive Staphylococcus aureus Anaerobes Lactobacillus NOTE: The data are presented as numbers and percentages. *The data have been taken from Hellinger et al.3
models were used to evaluate associations of patient, operative, and donor characteristics with the development of SSIs after LT. Single-variable models were used, as were multivariate models adjusted for variables associated with SSIs with a P value of .05 or less in the single-variable analysis. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated. No adjustment for multiple testing was made in these exploratory analyses, and P values of .05 or less were considered statistically significant. Statistical analyses were performed with SAS 9.2 (SAS Institute, Inc., Cary, NC) and R 2.11.0 statistical software (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS A summary of baseline patient, donor, and operative information is provided in Table 1 for the cohort of 152 second LT recipients. The median age at the time of second LT was 54 years (range 5 20-72 years), and 109 patients (72%) were male. The median body mass index was 26 kg/m2 (range 5 17-61 kg/m2), and the median Model for End-Stage Liver Disease (MELD) score was 25 (range 5 6-49). The most common principal liver disease diagnosis was chronic hepatitis C (51%). The majority of wound classifications were class II (87%), the median operative time was 278 minutes (range 5 137-633 minutes), the median
934 SHAH ET AL.
Figure 1.
LIVER TRANSPLANTATION, August 2014
Cumulative incidence of SSIs. The data for first LT have been taken from Hellinger et al.3
number of red blood cell units received was 13 (range 5 0-120), and biliary anastomoses were most commonly Roux-en-Y (51%). The median donor age was 33 years (range 5 6-70 years), and 81 donors (53%) were male. Thirty-one of the 152 patients who underwent LT for a second time developed an SSI. One of these 31 patients (3%) developed a deep SSI, 24 (77%) developed an organ or space SSI, and 6 (19%) developed a superficial SSI. The pathogens recovered from cultures of wound specimens of the SSIs are provided in Table 2. The cumulative incidence of SSIs after second LT is displayed in Fig. 1. Thirty days after second LT, the cumulative incidence of SSIs was 20.8% (95% CI 5 14.0%-27.1%). When we compared this incidence to the previously published incidence of 16% for SSIs after first LT at our institution from 2003 to 2008 (1036 patients),3 which is also displayed in Fig. 1, we did not observe a statistically significant difference (RR 5 1.32, 95% CI 5 0.90-1.93, P 5 .16). This lack of a difference was also observed when we considered only second LT procedures that occurred between 2003 and 2008 so that the time periods would match exactly for the first LT patient cohort and the second LT patient cohort (RR 5 1.35, 95% CI 5 0.87-2.10, P 5 .18). As indicated in Table 1, despite the similar incidences of SSIs in the 2 cohorts, the patients undergoing second LT had higher MELD scores, a greater frequency of status 1 listing, a higher likelihood of hospitalization and mechanical ventilation at the time of transplantation, a greater frequency of active infections at the operative site at transplant (type IV surgical wounds), longer operative times, more intraoperative red blood cell transfusions, and a greater likelihood of hepaticojejunostomy at trans-
plant. The distribution of pathogens recovered from the cultures of surgical wound specimens after first LT and second LT are provided in Table 2. Greater proportions of SSIs were caused by multiple pathogens, aerobic gram-negative bacilli, and Candida, and staphylococci and enterococci were more likely to be methicillin- and vancomycin-resistant, respectively, in patients who underwent LT for a second time. Patient, operative, and donor characteristics associated with the development of SSIs after second LT are shown in Table 3, where, for simplicity, only associations with a P value .20 in the single-variable analysis are displayed. In all, 51 different characteristics were evaluated for an association with SSIs. The only 2 of these that were significantly associated with SSIs in the single-variable analysis were increased units of red blood cells received [RR (doubling) 5 1.38, 95% CI 5 1.02-1.86, P 5 .04] and Roux-en-Y biliary anastomosis (RR 5 2.22, 95% CI 5 1.05-4.72, P 5 .04). In the multivariate analysis, which included both of these variables in the same model, the associations weakened slightly [RR for units of red blood cells received (doubling) 5 1.30, 95% CI 5 0.98-1.74, P 5 .07; RR for Roux-en-Y biliary anastomosis 5 2.04, 95% CI 5 0.95-4.39, P 5 .07]. The weakening of the strength of these associations was perhaps due to the degree of correlation between the units of red blood cells received and the biliary anastomosis for the second transplant (P 5 .08): the median number of units of red blood cells received for the second transplant was 11 (range 5 0-80) for duct-to-duct patients and 15 (range 5 0-120) for Roux-en-Y patients. Additionally, in the multivariate analysis, which was adjusted for the units of red blood cells received and the biliary anastomosis for second LT, the association of a variable donor liver mass/recipient body mass
LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014
SHAH ET AL. 935
TABLE 3. Baseline Patient Characteristics, Donor Information, and Operative Information Associated With the Development of SSIs After Second LT Single-Variable Analysis Variables Baseline patient characteristics Pretransplant hospital length of stay: doubling (days) ASA classification: 5 Operative information Biliary anastomosis at first LT: Roux-en-Y Other Operative time: 60-minute increase Units of red blood cells received: doubling Biliary anastomosis: Roux-en-Y Donor information Donor liver mass/recipient body mass < 0.01
Multivariate Analysis
RR (95% CI)
P Value
RR (95% CI)
P Value
1.14 (0.94-1.37)
.19
1.11 (0.93-1.34)
.25
1.99 (0.70-5.68)
.20
2.10 (0.73-6.05)
.17
1.90 2.15 1.12 1.38 2.22
.14
1.84 1.58 0.92 1.30 2.04
.17
(0.81-4.48) (0.70-6.56) (0.95-1.31) (1.02-1.86) (1.05-4.72)
.18 .04 .04
2.61 (0.62-10.95)
.19
(0.77-4.35) (0.51-4.96) (0.74-1.15) (0.98-1.74) (0.95-4.39)
.48 .07 .07
4.33 (0.95-19.64)
.06
NOTE: Associations from the single-variable analysis with P values .20 are shown. Multivariate models were adjusted for variables associated with SSIs with P values of 0.05 or less in the single-variable analysis (ie, units of red blood cells received and biliary anastomosis at secondary LT). RRs and P values resulted from Cox proportional hazards regression models.
ratio < 0.01 with SSIs was strengthened, and it was almost significant (RR 5 4.33, 95% CI 5 0.95-19.64, P 5 .06). However, this finding should be interpreted with caution because there were only 6 patients with a donor liver mass/recipient body mass ratio < 0.01 (Table 1).
DISCUSSION The incidence of SSIs after second LT was found to be 20.8% in our cohort of 152 patients. This incidence was slightly but not significantly higher than the previously reported incidence of SSIs after first LT over the same time period at our institution, and it was within the 11% to 34% range of SSI incidences reported by other studies that used the same surveillance methodologies for the identification of SSIs and that investigated cohorts of patients exclusively or predominantly undergoing first LT.2-5 Although an increased number of units of red blood cells transfused intraoperatively and Roux-en-Y biliary anastomosis were associated with SSIs in the single-variable analysis, they were not independently associated with SSIs in the multivariate analysis. Additionally, because of the relatively small sample size and the exploratory nature of the study, we made no adjustment for multiple testing; had such an adjustment been made, the associations of transfused red blood cells and biliary anastomosis with SSIs would not have approached statistical significance. Therefore, we did not identify risk factors for SSIs after second LT. Concluding that an adjustment for second LT is not necessary for risk-stratified reporting of SSI rates and for investigations of modifiable risk factors for SSIs after LT may be premature. Notably, the separate inci-
dences of SSIs in patients predominantly undergoing first LT were 11%,2 13%,4 16%,3 and 34%.5 Furthermore, because the respective cohort sizes for these studies were 680, 1036, 800, and 167, the pooled SSI incidence was 15%. Also, when the cohort of patients undergoing second LT in this investigation was compared to the cohort of patients undergoing first LT at the same institution between 2003 and 2008,3 we found that those undergoing second LT were more likely to be on mechanical ventilation at transplant, received larger quantities of red blood cell transfusions intraoperatively, and had longer operative times; all of these factors have been associated with a risk for SSIs after LT.2,3,5,6 Finally, the surgical wound classification for 13% of this cohort was class IV, and this indicated the presence of an infection at the operative site at the time of transplantation, which is a powerful predictor of a subsequent wound infection in nontransplant surgery.16 Studies of larger cohorts of patients undergoing first LT and second LT will be needed to determine whether the probability of subsequent SSIs after each procedure is significantly different. Interestingly, factors that have been associated with a reduced risk of survival after liver retransplantation, including recipient age, MELD score, serum creatinine level, need for mechanical ventilation, time of first graft failure with respect to retransplantation, intraoperative red blood cell transfusions, and donor age,17-20 were not associated with SSIs after a second transplant. The lack of an association of these factors with SSIs may have been due to the influence of variables that were not measured (eg, intraoperative hyperglycemia and intraoperative vasopressor administration) or could not be assessed (ie surgeon) because of the large number of categories with respect to the number of
936 SHAH ET AL.
patients who developed an SSI. Alternatively, the lack of an association of factors associated with a reduced risk of survival after liver retransplantation with SSIs after second LT may have been due to the cohort size and the lack of power. Although no association of risk factors for reduced survival after liver retransplantation with SSIs after second LT was observed, the possibility of a type II error (ie, a false-negative association) is important to consider. The limitations of this study include its completion at a single center and the retrospective collection of some of its data. Also, the period of time during which data were collected for patients undergoing LT for the first time (2003-2008) did not fully overlap with the period of time during which second LT was performed (2003-2011). The relatively small sample size led to an imprecise estimate of the incidence of SSIs (as indicated by the wide 95% confidence limits) and a limited ability to identify patient, operative, and donor factors associated with SSIs. Finally, the study was confined to patients undergoing second LT, and the association between SSIs and graft loss or death, which has been demonstrated for SSIs after first LT,6 was not examined. In conclusion, the results of this study provide evidence that the incidence of SSIs after second LT is similar to the incidence of SSIs after first LT and that unique risk factors for SSIs after second LT are not readily apparent. The pooling of data on the incidence of SSIs after LT in a single repository such as the NHSN21 would create opportunities to better characterize the incidence of SSIs after liver retransplantation and their risk factors. Meanwhile, risk stratification for retransplantation may not be necessary when the incidence of SSIs after LT is being reported.
REFERENCES 1. Dummer JS. Infections in solid organ transplant recipients. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, vol. 2 [ed. 6], Philadelphia, Elsevier 2005, p3501. 2. Park C, Hsu C, Neelakanta G, Nourmand H, Braunfeld M, Wray C, et al. Severe intraoperative hyperglycemia is independently associated with surgical site infection after liver transplantation. Transplantation 2009;87:10311036. 3. Hellinger WC, Heckman MG, Crook JE, Taner CB, Willingham DL, Diehl NN, et al. Association of surgeon with surgical site infection after liver transplantation. Am J Transplant 2011;11:1877-1884. 4. Mu Y, Edwards JR, Horan TC, Berrios-Torres SI, Fridkin SK. Improving risk-adjusted measures of surgical site infection for the National Healthcare Safety Network. Infect Control Hosp Epidemiol 2011;32:970-986. 5. Garcıa Prado ME, Matia EC, Ciuro FP, Dıez-Canedo JS, Sousa Martın JM, Porras L opez FM, et al. Surgical site infection in liver transplant recipients: impact of the type
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of perioperative prophylaxis. Transplantation 2008;85: 1849-1854. 6. Hellinger WC, Crook JE, Heckman MG, Diehl NN, Shalev JA, Zubair AC, et al. Surgical site infection after liver transplantation: risk factors and association with graft loss or death. Transplantation 2009;87:1387-1393. 7. Consensus paper on the surveillance of surgical wound infections. The Society for Hospital Epidemiology of America; the Association for Practitioners in Infection Control; the Centers for Disease Control; the Surgical Infection Society. Infect Control Hosp Epidemiol 1992;13: 599-605. 8. Cruse PJ, Foord R. The epidemiology of wound infection: a 10-year prospective study of 62,939 wounds. Surg Clin North Am 1980;60:27-40. 9. Condon RE, Schulte WJ, Malangoni MA, AndersonTeschendorf MJ. Effectiveness of a surgical wound surveillance program. Arch Surg 1983;118:303-307. 10. Haley RW, Culver DH, White JW, Morgan WM, Emori TG, Munn VP, Hooton TM. The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals. Am J Epidemiol 1985;121: 182-205. 11. Zarrinpar A, Hong JC. What is the prognosis after retransplantation of the liver? Adv Surg 2012;46:87-100. 12. Centers for Disease Control and Prevention. CDC/NHSN surveillance definitions for specific types of infections. http://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdf. Accessed January 2014. 13. Sibulesky L, Heckman MG, Perry DK, Taner CB, Willingham DL, Nguyen JH. A single-center experience with biliary reconstruction in retransplantation: duct-toduct or Roux-en-Y choledochojejunostomy. Liver Transpl 2011;17:710-716. 14. Hellinger WC, Bonatti H, Yao JD, Alvarez S, Brumble LM, Keating MR, et al. Risk stratification and targeted antifungal prophylaxis for prevention of aspergillosis and other invasive mod infections after liver transplantation. Liver Transpl 2005;11:656-662. 15. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer; 2001: 169-171. 16. Haley RW, Culver DH, Morgan WM, White JW, Emori TG, Hooton TM. Identifying patients at high risk of surgical wound infection. A simple multivariate index of patient susceptibility and wound contamination. Am J Epidemiol 1985;121:206-215. 17. Yao FY, Saab S, Bass NM, Hirose R, Ly D, Terrault N, et al. Prediction of survival after liver retransplantation for late graft failure based on preoperative prognostic scores. Hepatology 2004;39:230-238. 18. Linhares MM, Azoulay D, Matos D, Castelo-Filho A, ~ o T, Goldenberg A, et al. Liver retransplantation: a Trivin model for determining long-term survival. Transplantation 2006;81:1016-1021. 19. Bilbao I, Figueras J, Grande L, Cle`ries M, Jaurrieta E, Visa J, Margarit C. Risk factors for death following liver retransplantation. Transplant Proc 2003;35:1871-1873. 20. Hong JC, Kaldas FM, Kositamongkol P, Petrowsky H, Farmer DG, Markovic D, et al. Predictive index for longterm survival after retransplantation of the liver in adult recipients: analysis of a 26-year experience in a single center. Ann Surg 2011;254:444-448. 21. Centers for Disease Control and Prevention. National Healthcare Safety Network (NHSN). http://www.cdc.gov/ nhsn/about.html. Accessed October 2013.
ORIGINAL ARTICLE
Surgical Site Infections After Liver Retransplantation: Incidence and Risk Factors Harshal Shah,1,5 Walter C. Hellinger,1 Michael G. Heckman,2 Nancy Diehl,2 Jefree A. Shalev,3 Darrin L. Willingham,4 C. Burcin Taner,4 Dana K. Perry,4 and Justin Nguyen4 1 Division of Infectious Disease; 2Section of Biostatistics; 3Division of Transplant Medicine, 4Division of Transplant Surgery, Mayo Clinic, Jacksonville, FL; and 5Parkview Medical Center, Pueblo, CO
Surgical site infections (SSIs) after liver transplantation (LT) are associated with an increased risk of graft loss and death. The incidence of SSIs after LT and their risk factors have been determined for first LT but not for second LT. The importance of reporting the incidence of SSIs risk-stratified by first LT versus second LT is not known. All patients undergoing second LT at a single institution between 2003 and 2011 (n 5 152) were reviewed. The Kaplan-Meier method was used to estimate the cumulative SSI incidence. Relative risks (RRs) and 95% confidence intervals (CIs) from Cox proportional hazards regression models were used to evaluate associations of potential risk factors with SSIs after second LT. Thirty-one patients developed SSIs (6 superficial SSIs, 1 deep SSI, and 24 organ/space SSIs). The cumulative incidence of SSIs 30 days after LT was 20.8% (95% CI 5 14%-27%), which was slightly but not significantly higher than the previously reported incidence of SSIs after first LT at our institution between 2003 and 2008 (16%, RR 5 1.32, 95% CI 5 0.90-1.93, P 5.16). Units of transfused red blood cells [RR (doubling) 5 1.38, 95% CI 5 1.02-1.86, P 5.04] and hepaticojejunostomy (RR 5 2.22, 95% CI 5 1.05-4.72, P 5.04) were the only factors associated with SSIs after second LT in single-variable analysis. The associations weakened in a multivariate analysis (P 5.07 and P 5.07, respectively), potentially because of the correlation of red blood cell transfusions and hepaticojejunostomy (P 5.08). In conclusion, the incidence of SSIs after second LT was slightly higher but not significantly different than the published incidence of SSIs (16%) after first LT at the same institution. Significant independent risk factors for SSIs after second LT were not identified. Risk stratification for retransplantation may C 2014 not be necessary when the incidence of SSIs after LT is being reported. Liver Transpl 20:930-936, 2014. V AASLD. Received December 13, 2013; accepted April 11, 2014.
The operative site is the leading anatomic site of infections in recipients of liver transplantation (LT).1 Surgical site infections (SSIs), as defined by the Centers for Disease Control and Prevention, have been reported to follow 11% to 34% of LT procedures,2-5 and they have been associated with an increased risk of graft loss and death.6 Risk factors associated with SSIs in these investigations have included pretransplant antibiotic therapy, pretransplant mechanical ventilation, intraoperative hyperglycemia, intraoperative administration of vasopressors, need for intraoperative red
blood cell transfusions, surgeons, and operative times.2,3,5,6 Feedback about benchmarked, risk-adjusted rates of SSIs to surgeons has been associated with declines in the rates of these infections in nontransplant surgeries.7-10 An appropriate risk adjustment of SSI incidence is required for the identification of modifiable factors that are associated with the development of SSIs and for the feedback of credible information to surgeons. Published reports of SSI incidence after LT have been derived from cohorts including either
Abbreviations: ASA, American Society of Anesthesiologists; CI, confidence interval; CMV, cytomegalovirus; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NHSN, National Healthcare Safety Network; RR, relative risk; SSI, surgical site infection. The authors report no grants or other financial support, and they have no conflicts of interest to declare. Address reprint requests to Walter C. Hellinger, M.D., Division of Infectious Disease, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224. Telephone: 904-953-2419; FAX: 904-953-0017; E-mail: [email protected] DOI 10.1002/lt.23890 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
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exclusively or predominantly patients undergoing LT for the first time. The incidence of SSIs after liver retransplantation and their risk factors have not been assessed. Liver retransplantation is considered a higher risk procedure than primary transplantation11; therefore, differences in the incidence of SSIs and their risk factors between first LT and second LT would not be surprising. Whether and how the incidence of SSIs after LT should be adjusted for retransplantation is not known. Thus, the aim of this investigation was to determine the incidence of SSIs after second LT and their risk factors.
PATIENTS AND METHODS A retrospective analysis of all 152 patients undergoing second LT between 2003 and 2011 at Mayo Clinic in Florida was performed. Patients undergoing subsequent retransplants (eg, third and fourth transplants) were excluded to improve the homogeneity of the study population and to avoid correlation of the data. Medical records and prospectively maintained local transplant databases were reviewed for patient, donor, and operative characteristics that could be associated with SSIs, graft loss, or death after second LT. The study protocol was reviewed and approved by the Mayo Clinic institutional review board. SSIs were identified with standardized definitions and surveillance methodology that were developed by the National Healthcare Safety Network (NHSN) of the Centers for Disease Control and Prevention.12 SSIs were classified as superficial, deep, or organ/space infections on the basis of findings within 30 days of the second transplant surgery. A superficial SSI was recorded if an infection involved only the skin and subcutaneous tissues of the incision and 1 or more of the following were documented: purulent drainage from the superficial incision; organisms isolated from an aseptically obtained culture of fluid or tissue from the incision; a tender, swollen, red or warm superficial incision deliberately opened by the surgeon or his or her designee; and a superficial SSI diagnosed by the surgeon or his or her designee. A deep SSI was recorded if an infection involved the fascial and muscle layers of the incision and 1 or more of the following were documented: purulent drainage from the incision; spontaneous dehiscence of the deep incision or deliberate opening of the deep incision by the surgeon or his or her designee in the presence of fever (>38 C) or incisional pain; and an abscess or other evidence of infection involving the deep incision that was detected on direct examination, during an invasive procedure, or by histopathological examination or imaging. An organ/space SSI was recorded if an infection involved the space (peritoneum) or organ (liver) contiguous to the plane of the incision and 1 or more of the following were documented: purulent drainage from a drain placed in the organ or space; organisms recovered in an aseptically obtained culture of fluid or tissue of the organ or space; and an abscess or other evidence of infection involving the organ or space that
SHAH ET AL. 931
was detected on direct examination, during an invasive procedure, or by histopathological examination or imaging. Surgical wounds were classified in accordance with NHSN definitions as clean but contaminated (type II: controlled incision of a mucosal surface colonized with microorganisms below the level of the skin), contaminated (type III: unintended contamination of the surgical site; eg, by spillage of the contents of a gastrointestinal viscus), or infected (type IV: infection of the surgical site at the time of transplantation).7 All retransplants were performed with the piggyback technique without venovenous bypass, portocaval shunts, or caval clamping. All liver grafts were reperfused with portal flow, which was then followed by arterial flow. During retransplantation, the previous bile duct anastomosis was resected. The recipient bile duct was mobilized with minimal dissection of the pericholedochal tissue. The viability of the recipient bile duct was assessed by the presence of bleeding from the cut edge of the duct. If the recipient duct was found to be well vascularized, then duct-to-duct biliary reconstruction was performed.13 Patients without a penicillin allergy received 1 g of intravenous cefotaxime every 8 hours for 48 hours as perioperative antibiotic prophylaxis; patients with a penicillin allergy received 1 g of intravenous vancomycin every 12 hours and 1 g of intravenous aztreonam every 8 hours for 48 hours. Anti-Candida antifungal prophylaxis in the form of fluconazole or caspofungin was added when the operative time was longer than 6 hours or operative red blood cell transfusions were greater than 8 U; antimold prophylaxis in the form of caspofungin or liposomal amphotericin was added in lieu of anti-Candida prophylaxis when renal replacement therapy was required for second LT or when there was renal failure (serum creatinine level off renal replacement therapy > 2 mg/dL) or allograft insufficiency extending beyond day 7 after second LT in accordance with previously reported risk stratification for invasive fungal infections at this center.14
Statistical Analysis Continuous variables were summarized as sample medians, minima, and maxima. Categorical variables were summarized as numbers and percentages. The Kaplan-Meier method was used to estimate the cumulative incidence of SSIs after LT; censoring was performed on the date of graft loss or death for patients who experienced these outcomes on or before post-LT day 30 and who did not experience SSIs before these events. Cox proportional hazards regression models were used to compare the risk of SSIs between first LT and second LT; previously published data for SSIs involving 1036 patients who underwent first LT at our institution between 2003 and 20083 were used, and we accounted for the correlation between patients who underwent both first LT and second LT (n 5 84) with a marginal models approach.15 Cox proportional hazards regression
932 SHAH ET AL.
LIVER TRANSPLANTATION, August 2014
TABLE 1. Baseline Patient Characteristics, Donor Information, and Operative Information at LT
Variables Baseline patient characteristics Age at second transplant (years)† Sex: male [n (%)] Body mass index (kg/m2)† Diabetes [n (%)] MELD score† MELD score > 35 [n (%)] Prednisone [n (%)] Mycophenolate [n (%)] Solumedrol 90 days before second transplant [n (%)] Pretransplant hospital length of stay (days)† Principal liver disease diagnosis [n (%)] Chronic hepatitis C Alcohol cirrhosis Cryptogenic cirrhosis Primary sclerosing cholangitis Other Re-LT indication [n (%)] Recurrent hepatitis C Primary nonfunction Biliary necrosis/strictures Hepatic artery thrombosis Chronic rejection Other ASA classification [n (%)] 2 3 4 5 CMV positivity [n (%)] Biliary anastomosis at first LT: Roux-en-Y [n (%)] Location on day of transplant [n (%)] Hospital Hospital: intensive care unit Mechanical ventilation on day of transplant [n (%)] Malignancy in explant [n (%)] Status 1 [n (%)] Operative information Wound classification [n (%)] II (clean but contaminated) III (contaminated) IV (infected) Surgeon [n (%)] 1 2 3 4 5 6 7 8 9 Time between first LT and second LT (days)† 30 days [n (%)] Active infection on day of transplant [n (%)] Renal replacement therapy on day of transplant [n (%)] Operative time (minutes)† Red blood cells (U)† Biliary anastomosis: Roux-en-Y [n (%)] Donor information and post-LT complications Age (years)†
Second LT: 2003-2011
First LT: 2003-2008
(n 5 152)
(n 5 1036)*
54 (20-72) 109 (72) 26 (17-61) 50 (33) 25 (6-49) 32 (21) 64 (42) 32 (21) 54 (36) 1 (0-75)
56 (16-81) 701 (68) 28 (16-61) 264 (25) 17 (6-51) 44 (4) Not applicable Not applicable Not applicable Not applicable
77 (51) 15 (10) 17 (11) 14 (9) 29 (19)
393 (38) 146 (14) 165 (16) 72 (7) 260 (25)
46 (30) 13 (9) 34 (22) 22 (14) 6 (4) 31 (20)
Not Not Not Not Not Not
applicable applicable applicable applicable applicable applicable
1 (1) 27 (18) 113 (74) 11 (7) 118 (78) 22 (16)
10 (1) 301 (29) 703 (68) 22 (2) 710 (69) Not applicable
65 (43) 33 (22) 19 (12) 3 (2) 13 (9)
146 (14) Not available 43 (4) 274 (26) 13 (1)
132 (87) 1 (1) 19 (12)
1033 (99.7) 3 (0.3) 0
36 (24) 25 (16) 23 (15) 22 (14) 18 (12) 10 (7) 8 (5) 6 (4) 4 (3) 318 (2-5879) 30 (20) 28 (18) 20 (13) 278 (137-633) 13 (0-120) 77 (51)
205 (20) 230 (22) 173 (17) 149 (14) 114 (11) Not applicable 52 (5) 113 (11) Not applicable Not applicable Not applicable Not available Not available 241 (100-745) 8 (0-103) 108 (10)
33 (6-70)
49 (7-88)
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SHAH ET AL. 933
TABLE 1. Continued
Variables Sex: male Donor/recipient sex incompatibility Liver mass (g)† Donor risk index† Donor liver mass/recipient body mass < 0.01 [n (%)] CMV seropositivity [n (%)] Donor/recipient CMV combination [n (%)] Positive/positive Positive/negative Negative/positive Negative/negative
Second LT: 2003-2011 (n 5 152)
First LT: 2003-2008 (n 5 1036)*
81 (53) 76 (50) 1449 (613-2300) 1.46 (0.83-2.68) 6 (4) 101 (66)
576 (56) 623 (60) 1480 (570-3620) 1.68 (0.88-4.30) 44 (4) 699 (67)
79 (52) 39 (26) 22 (14) 12 (8)
466 (45) 244 (24) 233 (22) 93 (9)
NOTE: For some patients in the second LT cohort, information was unavailable for the biliary anastomosis at first transplant (n 5 14), the donor liver mass (n 5 1), a donor liver mass/recipient body mass < 0.01 (n 5 1), and the donor risk index (n 5 1). *The data have been taken from Hellinger et al.3 † The data for continuous variables are presented as sample medians (with minima and maxima in parentheses).
TABLE 2. Pathogens Recovered From Cultures of SSIs
Pathogens
SSIs After Second LT (n 5 31)
SSIs After First LT (n 5 166)*
15 (48) 11 (35) 8 (26) 7 (23) 5 (16) 5 (16) 5 (16) 3 (10) 3 (10) 2 (6) 1 (3) 0 0 0
45 (27) 42 (25) 17 (10) 19 (11) 30 (18) 50 (30) 12 (7) 12 (7) 4 (2) 0 0 13 (8) 7 (4) 1 (0.6)
Polymicrobial Enterococci Aerobic gram-negative bacilli, not Pseudomonas Vancomycin-resistant Enterococcus Methicillin-resistant Staphylococcus aureus Coagulase-negative Staphylococcus Candida Pseudomonas aeruginosa Streptococcus viridans Bacillus species, not anthracis Group B Streptococcus Methicillin-sensitive Staphylococcus aureus Anaerobes Lactobacillus NOTE: The data are presented as numbers and percentages. *The data have been taken from Hellinger et al.3
models were used to evaluate associations of patient, operative, and donor characteristics with the development of SSIs after LT. Single-variable models were used, as were multivariate models adjusted for variables associated with SSIs with a P value of .05 or less in the single-variable analysis. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated. No adjustment for multiple testing was made in these exploratory analyses, and P values of .05 or less were considered statistically significant. Statistical analyses were performed with SAS 9.2 (SAS Institute, Inc., Cary, NC) and R 2.11.0 statistical software (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS A summary of baseline patient, donor, and operative information is provided in Table 1 for the cohort of 152 second LT recipients. The median age at the time of second LT was 54 years (range 5 20-72 years), and 109 patients (72%) were male. The median body mass index was 26 kg/m2 (range 5 17-61 kg/m2), and the median Model for End-Stage Liver Disease (MELD) score was 25 (range 5 6-49). The most common principal liver disease diagnosis was chronic hepatitis C (51%). The majority of wound classifications were class II (87%), the median operative time was 278 minutes (range 5 137-633 minutes), the median
934 SHAH ET AL.
Figure 1.
LIVER TRANSPLANTATION, August 2014
Cumulative incidence of SSIs. The data for first LT have been taken from Hellinger et al.3
number of red blood cell units received was 13 (range 5 0-120), and biliary anastomoses were most commonly Roux-en-Y (51%). The median donor age was 33 years (range 5 6-70 years), and 81 donors (53%) were male. Thirty-one of the 152 patients who underwent LT for a second time developed an SSI. One of these 31 patients (3%) developed a deep SSI, 24 (77%) developed an organ or space SSI, and 6 (19%) developed a superficial SSI. The pathogens recovered from cultures of wound specimens of the SSIs are provided in Table 2. The cumulative incidence of SSIs after second LT is displayed in Fig. 1. Thirty days after second LT, the cumulative incidence of SSIs was 20.8% (95% CI 5 14.0%-27.1%). When we compared this incidence to the previously published incidence of 16% for SSIs after first LT at our institution from 2003 to 2008 (1036 patients),3 which is also displayed in Fig. 1, we did not observe a statistically significant difference (RR 5 1.32, 95% CI 5 0.90-1.93, P 5 .16). This lack of a difference was also observed when we considered only second LT procedures that occurred between 2003 and 2008 so that the time periods would match exactly for the first LT patient cohort and the second LT patient cohort (RR 5 1.35, 95% CI 5 0.87-2.10, P 5 .18). As indicated in Table 1, despite the similar incidences of SSIs in the 2 cohorts, the patients undergoing second LT had higher MELD scores, a greater frequency of status 1 listing, a higher likelihood of hospitalization and mechanical ventilation at the time of transplantation, a greater frequency of active infections at the operative site at transplant (type IV surgical wounds), longer operative times, more intraoperative red blood cell transfusions, and a greater likelihood of hepaticojejunostomy at trans-
plant. The distribution of pathogens recovered from the cultures of surgical wound specimens after first LT and second LT are provided in Table 2. Greater proportions of SSIs were caused by multiple pathogens, aerobic gram-negative bacilli, and Candida, and staphylococci and enterococci were more likely to be methicillin- and vancomycin-resistant, respectively, in patients who underwent LT for a second time. Patient, operative, and donor characteristics associated with the development of SSIs after second LT are shown in Table 3, where, for simplicity, only associations with a P value .20 in the single-variable analysis are displayed. In all, 51 different characteristics were evaluated for an association with SSIs. The only 2 of these that were significantly associated with SSIs in the single-variable analysis were increased units of red blood cells received [RR (doubling) 5 1.38, 95% CI 5 1.02-1.86, P 5 .04] and Roux-en-Y biliary anastomosis (RR 5 2.22, 95% CI 5 1.05-4.72, P 5 .04). In the multivariate analysis, which included both of these variables in the same model, the associations weakened slightly [RR for units of red blood cells received (doubling) 5 1.30, 95% CI 5 0.98-1.74, P 5 .07; RR for Roux-en-Y biliary anastomosis 5 2.04, 95% CI 5 0.95-4.39, P 5 .07]. The weakening of the strength of these associations was perhaps due to the degree of correlation between the units of red blood cells received and the biliary anastomosis for the second transplant (P 5 .08): the median number of units of red blood cells received for the second transplant was 11 (range 5 0-80) for duct-to-duct patients and 15 (range 5 0-120) for Roux-en-Y patients. Additionally, in the multivariate analysis, which was adjusted for the units of red blood cells received and the biliary anastomosis for second LT, the association of a variable donor liver mass/recipient body mass
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SHAH ET AL. 935
TABLE 3. Baseline Patient Characteristics, Donor Information, and Operative Information Associated With the Development of SSIs After Second LT Single-Variable Analysis Variables Baseline patient characteristics Pretransplant hospital length of stay: doubling (days) ASA classification: 5 Operative information Biliary anastomosis at first LT: Roux-en-Y Other Operative time: 60-minute increase Units of red blood cells received: doubling Biliary anastomosis: Roux-en-Y Donor information Donor liver mass/recipient body mass < 0.01
Multivariate Analysis
RR (95% CI)
P Value
RR (95% CI)
P Value
1.14 (0.94-1.37)
.19
1.11 (0.93-1.34)
.25
1.99 (0.70-5.68)
.20
2.10 (0.73-6.05)
.17
1.90 2.15 1.12 1.38 2.22
.14
1.84 1.58 0.92 1.30 2.04
.17
(0.81-4.48) (0.70-6.56) (0.95-1.31) (1.02-1.86) (1.05-4.72)
.18 .04 .04
2.61 (0.62-10.95)
.19
(0.77-4.35) (0.51-4.96) (0.74-1.15) (0.98-1.74) (0.95-4.39)
.48 .07 .07
4.33 (0.95-19.64)
.06
NOTE: Associations from the single-variable analysis with P values .20 are shown. Multivariate models were adjusted for variables associated with SSIs with P values of 0.05 or less in the single-variable analysis (ie, units of red blood cells received and biliary anastomosis at secondary LT). RRs and P values resulted from Cox proportional hazards regression models.
ratio < 0.01 with SSIs was strengthened, and it was almost significant (RR 5 4.33, 95% CI 5 0.95-19.64, P 5 .06). However, this finding should be interpreted with caution because there were only 6 patients with a donor liver mass/recipient body mass ratio < 0.01 (Table 1).
DISCUSSION The incidence of SSIs after second LT was found to be 20.8% in our cohort of 152 patients. This incidence was slightly but not significantly higher than the previously reported incidence of SSIs after first LT over the same time period at our institution, and it was within the 11% to 34% range of SSI incidences reported by other studies that used the same surveillance methodologies for the identification of SSIs and that investigated cohorts of patients exclusively or predominantly undergoing first LT.2-5 Although an increased number of units of red blood cells transfused intraoperatively and Roux-en-Y biliary anastomosis were associated with SSIs in the single-variable analysis, they were not independently associated with SSIs in the multivariate analysis. Additionally, because of the relatively small sample size and the exploratory nature of the study, we made no adjustment for multiple testing; had such an adjustment been made, the associations of transfused red blood cells and biliary anastomosis with SSIs would not have approached statistical significance. Therefore, we did not identify risk factors for SSIs after second LT. Concluding that an adjustment for second LT is not necessary for risk-stratified reporting of SSI rates and for investigations of modifiable risk factors for SSIs after LT may be premature. Notably, the separate inci-
dences of SSIs in patients predominantly undergoing first LT were 11%,2 13%,4 16%,3 and 34%.5 Furthermore, because the respective cohort sizes for these studies were 680, 1036, 800, and 167, the pooled SSI incidence was 15%. Also, when the cohort of patients undergoing second LT in this investigation was compared to the cohort of patients undergoing first LT at the same institution between 2003 and 2008,3 we found that those undergoing second LT were more likely to be on mechanical ventilation at transplant, received larger quantities of red blood cell transfusions intraoperatively, and had longer operative times; all of these factors have been associated with a risk for SSIs after LT.2,3,5,6 Finally, the surgical wound classification for 13% of this cohort was class IV, and this indicated the presence of an infection at the operative site at the time of transplantation, which is a powerful predictor of a subsequent wound infection in nontransplant surgery.16 Studies of larger cohorts of patients undergoing first LT and second LT will be needed to determine whether the probability of subsequent SSIs after each procedure is significantly different. Interestingly, factors that have been associated with a reduced risk of survival after liver retransplantation, including recipient age, MELD score, serum creatinine level, need for mechanical ventilation, time of first graft failure with respect to retransplantation, intraoperative red blood cell transfusions, and donor age,17-20 were not associated with SSIs after a second transplant. The lack of an association of these factors with SSIs may have been due to the influence of variables that were not measured (eg, intraoperative hyperglycemia and intraoperative vasopressor administration) or could not be assessed (ie surgeon) because of the large number of categories with respect to the number of
936 SHAH ET AL.
patients who developed an SSI. Alternatively, the lack of an association of factors associated with a reduced risk of survival after liver retransplantation with SSIs after second LT may have been due to the cohort size and the lack of power. Although no association of risk factors for reduced survival after liver retransplantation with SSIs after second LT was observed, the possibility of a type II error (ie, a false-negative association) is important to consider. The limitations of this study include its completion at a single center and the retrospective collection of some of its data. Also, the period of time during which data were collected for patients undergoing LT for the first time (2003-2008) did not fully overlap with the period of time during which second LT was performed (2003-2011). The relatively small sample size led to an imprecise estimate of the incidence of SSIs (as indicated by the wide 95% confidence limits) and a limited ability to identify patient, operative, and donor factors associated with SSIs. Finally, the study was confined to patients undergoing second LT, and the association between SSIs and graft loss or death, which has been demonstrated for SSIs after first LT,6 was not examined. In conclusion, the results of this study provide evidence that the incidence of SSIs after second LT is similar to the incidence of SSIs after first LT and that unique risk factors for SSIs after second LT are not readily apparent. The pooling of data on the incidence of SSIs after LT in a single repository such as the NHSN21 would create opportunities to better characterize the incidence of SSIs after liver retransplantation and their risk factors. Meanwhile, risk stratification for retransplantation may not be necessary when the incidence of SSIs after LT is being reported.
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of perioperative prophylaxis. Transplantation 2008;85: 1849-1854. 6. Hellinger WC, Crook JE, Heckman MG, Diehl NN, Shalev JA, Zubair AC, et al. Surgical site infection after liver transplantation: risk factors and association with graft loss or death. Transplantation 2009;87:1387-1393. 7. Consensus paper on the surveillance of surgical wound infections. The Society for Hospital Epidemiology of America; the Association for Practitioners in Infection Control; the Centers for Disease Control; the Surgical Infection Society. Infect Control Hosp Epidemiol 1992;13: 599-605. 8. Cruse PJ, Foord R. The epidemiology of wound infection: a 10-year prospective study of 62,939 wounds. Surg Clin North Am 1980;60:27-40. 9. Condon RE, Schulte WJ, Malangoni MA, AndersonTeschendorf MJ. Effectiveness of a surgical wound surveillance program. Arch Surg 1983;118:303-307. 10. Haley RW, Culver DH, White JW, Morgan WM, Emori TG, Munn VP, Hooton TM. The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals. Am J Epidemiol 1985;121: 182-205. 11. Zarrinpar A, Hong JC. What is the prognosis after retransplantation of the liver? Adv Surg 2012;46:87-100. 12. Centers for Disease Control and Prevention. CDC/NHSN surveillance definitions for specific types of infections. http://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdf. Accessed January 2014. 13. Sibulesky L, Heckman MG, Perry DK, Taner CB, Willingham DL, Nguyen JH. A single-center experience with biliary reconstruction in retransplantation: duct-toduct or Roux-en-Y choledochojejunostomy. Liver Transpl 2011;17:710-716. 14. Hellinger WC, Bonatti H, Yao JD, Alvarez S, Brumble LM, Keating MR, et al. Risk stratification and targeted antifungal prophylaxis for prevention of aspergillosis and other invasive mod infections after liver transplantation. Liver Transpl 2005;11:656-662. 15. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer; 2001: 169-171. 16. Haley RW, Culver DH, Morgan WM, White JW, Emori TG, Hooton TM. Identifying patients at high risk of surgical wound infection. A simple multivariate index of patient susceptibility and wound contamination. Am J Epidemiol 1985;121:206-215. 17. Yao FY, Saab S, Bass NM, Hirose R, Ly D, Terrault N, et al. Prediction of survival after liver retransplantation for late graft failure based on preoperative prognostic scores. Hepatology 2004;39:230-238. 18. Linhares MM, Azoulay D, Matos D, Castelo-Filho A, ~ o T, Goldenberg A, et al. Liver retransplantation: a Trivin model for determining long-term survival. Transplantation 2006;81:1016-1021. 19. Bilbao I, Figueras J, Grande L, Cle`ries M, Jaurrieta E, Visa J, Margarit C. Risk factors for death following liver retransplantation. Transplant Proc 2003;35:1871-1873. 20. Hong JC, Kaldas FM, Kositamongkol P, Petrowsky H, Farmer DG, Markovic D, et al. Predictive index for longterm survival after retransplantation of the liver in adult recipients: analysis of a 26-year experience in a single center. Ann Surg 2011;254:444-448. 21. Centers for Disease Control and Prevention. National Healthcare Safety Network (NHSN). http://www.cdc.gov/ nhsn/about.html. Accessed October 2013.
