223 C OPYRIGHT Ó 2014
BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
Surgical Site Infection in Orthopaedic Oncology Gertraud Gradl, MD, Pieter Bas de Witte, MD, BSc, Brady T. Evans, MD, MBA, Francis Hornicek, MD, PhD, Kevin Raskin, MD, and David Ring, MD, PhD Investigation performed at Massachusetts General Hospital, Boston, Massachusetts
Background: This study addressed risk factors for surgical site infection in patients who had undergone orthopaedic oncology surgical procedures. Methods: We retrospectively reviewed data on 1521 orthopaedic oncologic surgical procedures in 1304 patients. We assessed patient demographics, updated Charlson comorbidity index, surgery-specific data, and treatment-related data and attempted to identify predictors of surgical site infection with bivariate and multivariable analysis. Results: Eight factors independently predicted surgical site infection: body mass index (odds ratio [OR]:, 1.03, 95% confidence interval [CI]: 1.00 to 1.07), age (OR: 1.18, 95% CI: 1.05 to 1.33), total number of preceding procedures (OR: 1.19, 95% CI: 1.07 to 1.34), preexisting implants (OR: 1.94, 95% CI: 1.17 to 3.21), infection at another site on the date of the surgery (OR: 4.13, 95% CI: 1.57 to 10.85), malignant disease (OR: 1.46, 95% CI: 0.94 to 2.26), hip region affected (OR: 1.96, 95% CI: 1.35 to 2.84), and duration of the procedure (OR: 1.16, 95% CI: 1.07 to 1.25). Conclusions: These factors can inform patients and surgeons of the probability of surgical site infection after orthopaedic oncologic surgery. While most risk factors are unmodifiable or related to the complexity of the case, infection at another site on the date of the surgery is one factor amenable to intervention. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.
R
eported prevalences of surgical site infection after orthopaedic surgery range from 0.7% to 22.7%1,2. Surgical site infection has a substantial impact on health-related quality of life, is associated with additional complications, and affects long-term clinical outcomes. Furthermore, patients with surgical site infection spend more time in the hospital, are readmitted more frequently, and may require a reoperation, increasing costs by more than 300%3. Surgical site infection associated with prostheses or allografts can be particularly severe4, and the rates of surgical site infection may be relatively higher in orthopaedic oncology compared with other orthopaedic subspecialties5. Several investigators have examined surgical site infections after spine surgery6-8 and joint arthroplasty9-11 and some have assessed these infections after orthopaedic fracture care1,12, but there is relatively little information on surgical site infections in patients treated for musculoskeletal tumors5,13,14. The available
data indicate that these patients have relatively high rates of surgical site infection, but little is known about the risk factors5. The objectives of this study were (1) to determine the prevalence of surgical site infections after surgery for musculoskeletal tumors, and (2) to determine risk factors associated with the development of surgical site infections and incorporate these variables in a prediction model. Materials and Methods
T
his was a single-center retrospective case study. Using local billing records under an institutional review board-approved protocol, we identified 1977 orthopaedic oncologic surgical procedures performed in 1705 patients between August 15, 2001, and December 9, 2009. Inclusion criteria were an age of eighteen years or older and final evaluation at a minimum of thirty days after surgery (or one year, for patients who had received a plate and screws, a prosthesis, or an allograft). Exclusion criteria were no confirmed benign or malignant neoplasm at the surgical site and any procedure for treatment of a
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
J Bone Joint Surg Am. 2014;96:223-30
d
http://dx.doi.org/10.2106/JBJS.L.01514
224 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG V O LU M E 96-A N U M B E R 3 F E B R UA RY 5, 2 014 d
d
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IN
O R T H O PA E D I C O N C O L O G Y
d
surgical site infection. Multiple surgical procedures per patient were included in the analyses as long as eligibility criteria were met and there was a minimal duration of one month between surgical procedures without an implant (plate, prosthesis, or allograft) or one year between surgical procedures with an implant. Preoperative needle biopsies were not considered prior surgical procedures and were accounted for as a separate potential risk factor for surgical site infection in the analyses. Of the 1705 patients (1977 procedures), 401 (456 procedures) were excluded because of insufficient follow-up (n = 275), an age under eighteen years (n = 122), or no neoplasm or the performance of a surgical procedure for a surgical site infection (n = 4), leaving a final data set of 1521 procedures in 1304 patients. The following patient-related variables were recorded: age, sex, body mass index (BMI), diabetes (as reported in index or previous admission records), smoking status, American College of Surgeons (ACS) wound classification (clean, clean/contaminated, contaminated, and dirty/infected), diagnosis, side, soft-tissue tumor (yes/no), presence of preexisting implants at the surgical site (including allograft or autograft bone, plates, and prostheses), number of previous procedures at the same site, preceding needle biopsy at the same site, infection at another site on the date of surgery (e.g., urinary tract infections, upper respiratory infections, and gastrointestinal infections), malignant disease (yes/no), metastasis (yes/no), and the Charlson comorbidity index. This index is a predictor of one-year mortality of patients based on classifying or weighting comorbid conditions including congestive heart failure; dementia; mild, moderate, or severe liver disease; diabetes with chronic complications; renal disease; AIDS/HIV; chronic pulmonary disease; rheumatologic disease; hemiplegia or paraplegia; any malignant disease; and metastatic solid 15,16 tumor . If the surgery was performed on an osseous lesion, including metastases and osseous ingrowth, the surgical indication was considered to be a bone tumor. Otherwise, the surgical indication was regarded as a soft-tissue tumor. Surgical sites were defined as the shoulder/clavicle (including the humeral head, proximal part of the humerus, and scapula), upper arm (including the humeral shaft), elbow (including the proximal part of the forearm and distal part of the humerus), forearm, wrist (including the distal parts of the radius and ulna, the carpal bones, and the hand), pelvis, hip/proximal part of the femur (intertrochanteric, pertrochanteric, subtrochanteric, and femoral neck and head), proximal part of the lower limb (including the thigh and femoral shaft), knee (including the distal part of the femur, the proximal part of the tibia, and the fibula), distal part of the lower limb (including the tibial and fibular shafts), ankle (including the malleoli, distal part of the tibia, and talus), foot, head/neck, spine/back, and trunk. The following treatment-related variables were recorded: preoperative length of hospital stay (days), postoperative length of hospital stay (days), attending surgeon, duration of procedure (hours), hair removal (no, shaved, or removed with clippers), preparation solution, muscle flap (no, local, or free), number of intraoperative blood transfusion units, skin graft, new structural allograft or autograft, new prosthesis, new (other) implant, bone packing (the application of polymethylmethacrylate bone cement, or autograft or allograft bone in [postsurgical] bone cavities), wound packing, and vacuum-assisted closure dressing (both wound packing and vacuum-assisted closure used for infection, staged coverage, or secondary wound-healing). Drains are generally used for radiated wounds or large defects and are generally removed as drainage levels off. Antibiotic therapy is discontinued when the drain is removed. The antibiotic protocol is not altered for radiation or allograft. The duration of the procedure time was defined as the number of hours between the start of the incision and the end of wound closure. The preparation solution was recorded as triple (soap, povidone-iodine [Betadine; Purdue Products, Stamford, Connecticut], and alcohol), DuraPrep (3M; St. Paul, Minnesota), or other. All patients received prophylactic antibiotics (cefazolin, clindamycin, or vancomycin) within one hour prior to the incision. With regard to oncologic treatment, we recorded neoadjuvant chemotherapy, chemotherapy within one month postoperatively, immediate preoperative radiation therapy to the surgical site, radiation therapy to the surgical site within ten days after the surgery, a remote history of radiation therapy to the surgical site, immediate preoperative or intraoperative radiation therapy with use of implanted catheters (brachytherapy), and brachytherapy within one month postoperatively.
Surgical site infections were classified according to the definition of the 17 Centers for Disease Control and Prevention (CDC) , which is an infection that develops within thirty days after an operative procedure if no implant is left in place, or within one year if an implant is in place, and that appears to be related to the operative procedure and involves deep soft-tissues (e.g., fascial and muscle layers) of the incision. All surgical site infections were confirmed with positive cultures and/or treatment with antibiotics.
Data Analysis Bivariate analyses, by means of binary logistic regression analyses for each variable, were used to compare all patient-related and treatment-related variables between patients who developed a surgical site infection and those who did not. We used similar methods to compare the application of oncologic treatment methods between these groups. We employed the chisquare test to compare proportions of each recorded site between the groups. To obtain a prediction model for the association of potential risk factors with surgical site infection after orthopaedic oncology procedures, a multivariable logistic regression model was constructed, with use of a generalized estimating equations (GEE) approach to account for multiple surgical procedures for the same patient. We followed the general rule of thumb of entering a maximum number of covariates equaling approximately 10% of the number of events simultaneously in the model in order to avoid overfitting. The first selection of variables was based on the results of the bivariate analyses, with use of variables that had significant (p < 0.05) effects and clinical relevance. Additionally, the overall multivariable prognostic prediction model included age, BMI, and sex. Malignant status was entered into the overall model as a proxy for oncologic treatments, to limit the number of entered variables. For multivariable model reduction, we applied stepwise backward elimination, excluding non-contributing variables with a p value of >0.10. The likelihood ratio test and Hosmer-Lemeshow goodnessof-fit test were applied for model calibration, to obtain a reliable prediction model with odds ratios (ORs) and confidence intervals (CIs) for evaluating infection risk on the basis of the final included variables. The accuracy of the model was assessed with the area under the curve (AUC, or c-statistic) of the receiver operating characteristic (ROC) curve. For further model validation, internal validation by means of cross-validation (fivefold) was applied. With this method, the model is repeatedly constructed on a randomly drawn 80% of the sample and tested on the other 20%. This procedure is then repeated five times in such a way that all subjects are used for model testing once. The average c-statistic of the five validations is an estimate of performance. We had insufficient power to test for two-way interactions. Per definition, the prediction model was constructed to predict chances of surgical site infection based on variables in a predefined set of covariates and not to assess etiologic relationships and interactions. Furthermore, there is general consensus that, in order to increase statistical efficiency and constrain bias, it is better to impute missing values instead of performing a complete case analy18 sis . Accordingly, before analyses, multiple imputation (ten sets, with use of sex, diabetic status, and age as predictors) was applied on the variable BMI, as this value was missing for 576 patients.
Sources of Funding No funding was received in direct support of this study.
Results he final data set included 1521 procedures in 1304 patients (655 men and 649 women) with a mean age of 48.1 years. Of these 1521 procedures, 747 (49.1%) were for osseous lesions, 458 (30.1% of 1521) of which were primary bone tumors. Four hundred and thirty-five procedures (28.6%) were for a benign soft-tissue tumor, 295 (19.4%) were for a soft-tissue sarcoma, and forty-four were for other types of soft-tissue tumors.
T
225 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG V O LU M E 96-A N U M B E R 3 F E B R UA RY 5, 2 014 d
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IN
O R T H O PA E D I C O N C O L O G Y
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TABLE I Bivariate Analyses of Association of Patient-Related Factors with Surgical Site Infection
Variable BMI† (kg/m2)
No Surgical Site Infection* (N = 1368)
Surgical Site Infection* (N = 153)
Difference (OR)
95% CI
27.5 ± 5.7
29.1 ± 6.2
1.0
1.0-1.1
0.002
1.2
1.1-1.3
BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
Surgical Site Infection in Orthopaedic Oncology Gertraud Gradl, MD, Pieter Bas de Witte, MD, BSc, Brady T. Evans, MD, MBA, Francis Hornicek, MD, PhD, Kevin Raskin, MD, and David Ring, MD, PhD Investigation performed at Massachusetts General Hospital, Boston, Massachusetts
Background: This study addressed risk factors for surgical site infection in patients who had undergone orthopaedic oncology surgical procedures. Methods: We retrospectively reviewed data on 1521 orthopaedic oncologic surgical procedures in 1304 patients. We assessed patient demographics, updated Charlson comorbidity index, surgery-specific data, and treatment-related data and attempted to identify predictors of surgical site infection with bivariate and multivariable analysis. Results: Eight factors independently predicted surgical site infection: body mass index (odds ratio [OR]:, 1.03, 95% confidence interval [CI]: 1.00 to 1.07), age (OR: 1.18, 95% CI: 1.05 to 1.33), total number of preceding procedures (OR: 1.19, 95% CI: 1.07 to 1.34), preexisting implants (OR: 1.94, 95% CI: 1.17 to 3.21), infection at another site on the date of the surgery (OR: 4.13, 95% CI: 1.57 to 10.85), malignant disease (OR: 1.46, 95% CI: 0.94 to 2.26), hip region affected (OR: 1.96, 95% CI: 1.35 to 2.84), and duration of the procedure (OR: 1.16, 95% CI: 1.07 to 1.25). Conclusions: These factors can inform patients and surgeons of the probability of surgical site infection after orthopaedic oncologic surgery. While most risk factors are unmodifiable or related to the complexity of the case, infection at another site on the date of the surgery is one factor amenable to intervention. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.
R
eported prevalences of surgical site infection after orthopaedic surgery range from 0.7% to 22.7%1,2. Surgical site infection has a substantial impact on health-related quality of life, is associated with additional complications, and affects long-term clinical outcomes. Furthermore, patients with surgical site infection spend more time in the hospital, are readmitted more frequently, and may require a reoperation, increasing costs by more than 300%3. Surgical site infection associated with prostheses or allografts can be particularly severe4, and the rates of surgical site infection may be relatively higher in orthopaedic oncology compared with other orthopaedic subspecialties5. Several investigators have examined surgical site infections after spine surgery6-8 and joint arthroplasty9-11 and some have assessed these infections after orthopaedic fracture care1,12, but there is relatively little information on surgical site infections in patients treated for musculoskeletal tumors5,13,14. The available
data indicate that these patients have relatively high rates of surgical site infection, but little is known about the risk factors5. The objectives of this study were (1) to determine the prevalence of surgical site infections after surgery for musculoskeletal tumors, and (2) to determine risk factors associated with the development of surgical site infections and incorporate these variables in a prediction model. Materials and Methods
T
his was a single-center retrospective case study. Using local billing records under an institutional review board-approved protocol, we identified 1977 orthopaedic oncologic surgical procedures performed in 1705 patients between August 15, 2001, and December 9, 2009. Inclusion criteria were an age of eighteen years or older and final evaluation at a minimum of thirty days after surgery (or one year, for patients who had received a plate and screws, a prosthesis, or an allograft). Exclusion criteria were no confirmed benign or malignant neoplasm at the surgical site and any procedure for treatment of a
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
J Bone Joint Surg Am. 2014;96:223-30
d
http://dx.doi.org/10.2106/JBJS.L.01514
224 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG V O LU M E 96-A N U M B E R 3 F E B R UA RY 5, 2 014 d
d
SURGICAL SITE INFECTION
IN
O R T H O PA E D I C O N C O L O G Y
d
surgical site infection. Multiple surgical procedures per patient were included in the analyses as long as eligibility criteria were met and there was a minimal duration of one month between surgical procedures without an implant (plate, prosthesis, or allograft) or one year between surgical procedures with an implant. Preoperative needle biopsies were not considered prior surgical procedures and were accounted for as a separate potential risk factor for surgical site infection in the analyses. Of the 1705 patients (1977 procedures), 401 (456 procedures) were excluded because of insufficient follow-up (n = 275), an age under eighteen years (n = 122), or no neoplasm or the performance of a surgical procedure for a surgical site infection (n = 4), leaving a final data set of 1521 procedures in 1304 patients. The following patient-related variables were recorded: age, sex, body mass index (BMI), diabetes (as reported in index or previous admission records), smoking status, American College of Surgeons (ACS) wound classification (clean, clean/contaminated, contaminated, and dirty/infected), diagnosis, side, soft-tissue tumor (yes/no), presence of preexisting implants at the surgical site (including allograft or autograft bone, plates, and prostheses), number of previous procedures at the same site, preceding needle biopsy at the same site, infection at another site on the date of surgery (e.g., urinary tract infections, upper respiratory infections, and gastrointestinal infections), malignant disease (yes/no), metastasis (yes/no), and the Charlson comorbidity index. This index is a predictor of one-year mortality of patients based on classifying or weighting comorbid conditions including congestive heart failure; dementia; mild, moderate, or severe liver disease; diabetes with chronic complications; renal disease; AIDS/HIV; chronic pulmonary disease; rheumatologic disease; hemiplegia or paraplegia; any malignant disease; and metastatic solid 15,16 tumor . If the surgery was performed on an osseous lesion, including metastases and osseous ingrowth, the surgical indication was considered to be a bone tumor. Otherwise, the surgical indication was regarded as a soft-tissue tumor. Surgical sites were defined as the shoulder/clavicle (including the humeral head, proximal part of the humerus, and scapula), upper arm (including the humeral shaft), elbow (including the proximal part of the forearm and distal part of the humerus), forearm, wrist (including the distal parts of the radius and ulna, the carpal bones, and the hand), pelvis, hip/proximal part of the femur (intertrochanteric, pertrochanteric, subtrochanteric, and femoral neck and head), proximal part of the lower limb (including the thigh and femoral shaft), knee (including the distal part of the femur, the proximal part of the tibia, and the fibula), distal part of the lower limb (including the tibial and fibular shafts), ankle (including the malleoli, distal part of the tibia, and talus), foot, head/neck, spine/back, and trunk. The following treatment-related variables were recorded: preoperative length of hospital stay (days), postoperative length of hospital stay (days), attending surgeon, duration of procedure (hours), hair removal (no, shaved, or removed with clippers), preparation solution, muscle flap (no, local, or free), number of intraoperative blood transfusion units, skin graft, new structural allograft or autograft, new prosthesis, new (other) implant, bone packing (the application of polymethylmethacrylate bone cement, or autograft or allograft bone in [postsurgical] bone cavities), wound packing, and vacuum-assisted closure dressing (both wound packing and vacuum-assisted closure used for infection, staged coverage, or secondary wound-healing). Drains are generally used for radiated wounds or large defects and are generally removed as drainage levels off. Antibiotic therapy is discontinued when the drain is removed. The antibiotic protocol is not altered for radiation or allograft. The duration of the procedure time was defined as the number of hours between the start of the incision and the end of wound closure. The preparation solution was recorded as triple (soap, povidone-iodine [Betadine; Purdue Products, Stamford, Connecticut], and alcohol), DuraPrep (3M; St. Paul, Minnesota), or other. All patients received prophylactic antibiotics (cefazolin, clindamycin, or vancomycin) within one hour prior to the incision. With regard to oncologic treatment, we recorded neoadjuvant chemotherapy, chemotherapy within one month postoperatively, immediate preoperative radiation therapy to the surgical site, radiation therapy to the surgical site within ten days after the surgery, a remote history of radiation therapy to the surgical site, immediate preoperative or intraoperative radiation therapy with use of implanted catheters (brachytherapy), and brachytherapy within one month postoperatively.
Surgical site infections were classified according to the definition of the 17 Centers for Disease Control and Prevention (CDC) , which is an infection that develops within thirty days after an operative procedure if no implant is left in place, or within one year if an implant is in place, and that appears to be related to the operative procedure and involves deep soft-tissues (e.g., fascial and muscle layers) of the incision. All surgical site infections were confirmed with positive cultures and/or treatment with antibiotics.
Data Analysis Bivariate analyses, by means of binary logistic regression analyses for each variable, were used to compare all patient-related and treatment-related variables between patients who developed a surgical site infection and those who did not. We used similar methods to compare the application of oncologic treatment methods between these groups. We employed the chisquare test to compare proportions of each recorded site between the groups. To obtain a prediction model for the association of potential risk factors with surgical site infection after orthopaedic oncology procedures, a multivariable logistic regression model was constructed, with use of a generalized estimating equations (GEE) approach to account for multiple surgical procedures for the same patient. We followed the general rule of thumb of entering a maximum number of covariates equaling approximately 10% of the number of events simultaneously in the model in order to avoid overfitting. The first selection of variables was based on the results of the bivariate analyses, with use of variables that had significant (p < 0.05) effects and clinical relevance. Additionally, the overall multivariable prognostic prediction model included age, BMI, and sex. Malignant status was entered into the overall model as a proxy for oncologic treatments, to limit the number of entered variables. For multivariable model reduction, we applied stepwise backward elimination, excluding non-contributing variables with a p value of >0.10. The likelihood ratio test and Hosmer-Lemeshow goodnessof-fit test were applied for model calibration, to obtain a reliable prediction model with odds ratios (ORs) and confidence intervals (CIs) for evaluating infection risk on the basis of the final included variables. The accuracy of the model was assessed with the area under the curve (AUC, or c-statistic) of the receiver operating characteristic (ROC) curve. For further model validation, internal validation by means of cross-validation (fivefold) was applied. With this method, the model is repeatedly constructed on a randomly drawn 80% of the sample and tested on the other 20%. This procedure is then repeated five times in such a way that all subjects are used for model testing once. The average c-statistic of the five validations is an estimate of performance. We had insufficient power to test for two-way interactions. Per definition, the prediction model was constructed to predict chances of surgical site infection based on variables in a predefined set of covariates and not to assess etiologic relationships and interactions. Furthermore, there is general consensus that, in order to increase statistical efficiency and constrain bias, it is better to impute missing values instead of performing a complete case analy18 sis . Accordingly, before analyses, multiple imputation (ten sets, with use of sex, diabetic status, and age as predictors) was applied on the variable BMI, as this value was missing for 576 patients.
Sources of Funding No funding was received in direct support of this study.
Results he final data set included 1521 procedures in 1304 patients (655 men and 649 women) with a mean age of 48.1 years. Of these 1521 procedures, 747 (49.1%) were for osseous lesions, 458 (30.1% of 1521) of which were primary bone tumors. Four hundred and thirty-five procedures (28.6%) were for a benign soft-tissue tumor, 295 (19.4%) were for a soft-tissue sarcoma, and forty-four were for other types of soft-tissue tumors.
T
225 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG V O LU M E 96-A N U M B E R 3 F E B R UA RY 5, 2 014 d
d
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IN
O R T H O PA E D I C O N C O L O G Y
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TABLE I Bivariate Analyses of Association of Patient-Related Factors with Surgical Site Infection
Variable BMI† (kg/m2)
No Surgical Site Infection* (N = 1368)
Surgical Site Infection* (N = 153)
Difference (OR)
95% CI
27.5 ± 5.7
29.1 ± 6.2
1.0
1.0-1.1
0.002
1.2
1.1-1.3
