The Spine Journal 15 (2015) 901–909
Clinical Study
Allogeneic blood transfusions and postoperative infections after lumbar spine surgery Stein J. Janssen, MD*, Yvonne Braun, MD, Kirkham B. Wood, MD, Thomas D. Cha, MD, MBA, Joseph H. Schwab, MD, MS Department of Orthopaedic Surgery, Spine Service, Massachusetts General Hospital, Harvard Medical School, Rm 3.946, Yawkey Bldg, 55 Fruit St, Boston, MA 02114, USA Received 5 September 2014; revised 24 December 2014; accepted 3 February 2015
Abstract
BACKGROUND CONTEXT: Allogeneic blood transfusions have an immunomodulating effect, and the previous studies in other fields of medicine demonstrated an increased risk of infections after administration of allogeneic blood transfusions. PURPOSE: Our primary null hypothesis is that exposure to allogeneic blood transfusion in patients undergoing lumbar spine surgery is not associated with postoperative infections after controlling for patient and treatment characteristics. Second, we assessed if there was a dose-response relationship per unit of blood transfused. STUDY DESIGN/SETTING: This is a retrospective cohort study from a tertiary care spine referral center. PATIENT SAMPLE: A total of 3,721 patients underwent laminectomy and/or arthrodesis of the lumbar spine. OUTCOMES MEASURES: Postoperative infections, pneumonia, endocarditis, meningitis, urinary tract infection, central venous line infection, surgical site infection, and sepsis, within 90 days after lumbar spine surgery were included. METHODS: Multivariable logistic regression analyses were used to assess the relationship of perioperative allogeneic blood transfusion with specific and overall postoperative infections accounting for age, duration of surgery, duration of hospital stay, comorbidity status, preoperative hemoglobin, sex, type of operation, multilevel treatment, operative approach, and year of surgery. RESULTS: The adjusted odds ratio for exposure to allogeneic blood transfusion from multivariable logistic regression analysis was 2.6 for any postoperative infection (95% confidence interval [CI]: 1.7–3.9, p!.001); 2.2 for urinary tract infections (95% CI: 1.3–3.9, p5.004); 2.3 for pneumonia (95% CI: 0.96–5.3, p5.062); and 2.6 for surgical site infection requiring incision and drainage (95% CI: 1.3–5.3, p5.007). Secondary analyses demonstrated no dose-response relationship between the number of blood units transfused and any of the postoperative infections. Because of the low number of endocarditis (1 case, 0.031%), meningitis (1 case, 0.031%), central venous line infection (1 case, 0.031%), and sepsis (14 cases, 0.43%), we abstained from multivariable analysis. CONCLUSIONS: Conscious of the limitations of this retrospective study, our data suggest an increased risk of surgical site infection, urinary tract infection, and overall postoperative infections, but not pneumonia, after exposure to allogeneic blood transfusion in patients undergoing lumbar
FDA device/drug status: Not applicable. Author disclosures: SJJ: Grant: Anna Foundation (B), Michael van Vloten Foundation (B), De Drie Lichten Foundation (B), KWF Kankerbestrijding (B). YB: Nothing to disclose. KBW: Other: OREF (E, Fellowship Support), AO Spine NA (E, Fellowship Support), Depuy Spine (E, Fellowship Support), K2M, Inc.: (C, Fellowship Support), TranS1 (C, Stock Options). TDC: Grant: North American Spine Society (D), Gordon and Betty Moore Foundation (B); Personnel Fees: Bio2 (B); Other: OREF (E, Institutional Fellowship Support), K2M (E, Institutional Fellowship Support), AO http://dx.doi.org/10.1016/j.spinee.2015.02.010 1529-9430/Ó 2015 Elsevier Inc. All rights reserved.
Spine (E, Institutional Fellowship Support). JHS: Other: Stryker (B, Consulting fees), Biom’up (B, Consulting fees). The disclosure key can be found on the Table of Contents and at www. TheSpineJournalOnline.com. * Corresponding author. Department of Orthopaedic Surgery, Spine Service, Massachusetts General Hospital, Harvard Medical School, Rm 3.946, Yawkey Bldg, 55 Fruit St, Boston, MA 02114, USA. Tel.: (617) 726-1569; fax: (617) 643-1274. E-mail address: [email protected] (S.J. Janssen)
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spine surgery. These findings should be taken into account when considering blood transfusion and developing transfusion policies for patients undergoing lumbar spine procedures. Ó 2015 Elsevier Inc. All rights reserved. Keywords:
Transfusion; Infection; Lumbar; Surgery; Guideline; Policy; Immunomodulation
Introduction Approximately 85 million units of packed red blood cells are transfused annually worldwide [1,2]. However, blood transfusion policies became more restrictive over the past decade [3] as there is growing evidence that allogeneic blood transfusions (i.e., blood from a genetically nonidentical donor) are associated with an increased risk of postoperative infections [4], cancer recurrences, decreased survival in cancer patients [5–7], and other direct transfusion-associated risks (e.g., transfusion-transmissible infections and transfusion errors) [1]. The increased risk of postoperative infections is explained by the immunomodulating effects of allogeneic blood transfusions [4,8–10]. This effect was first hypothesized in 1973 in a study demonstrating improved graft survival of patients who received allogeneic blood transfusion before kidney transplantation [11]. Although the exact mechanism is still unclear [4,12], many subsequent clinical and laboratory studies confirmed the immunosuppressive effect of blood transfusions [9,12]. Blood transfusion is commonly (20–36%) used in spine surgery and aims to improve the oxygen transport capacity of the blood and, therefore, tissue oxygenation [13,14]. The number of units transfused perioperatively is associated with the age of the patient, comorbidities, number of levels instrumented, preoperative hemoglobin, duration of surgery, and complexity of the operation [14–16]. The untoward effects of blood transfusion specifically on surgical site infections after spine surgery have previously been demonstrated in two relatively small case-control studies [17,18]. However, the influence of allogeneic blood transfusion on other postoperative infections, such as urinary tract infection and pneumonia, has not been studied. Understanding the association of blood transfusion with postoperative infections can help guide future transfusion policies and the management of blood loss during spine surgery. Alternative measures to reduce the need for allogeneic blood transfusions include methods to minimize blood loss, preoperative blood donation, reinfusion, and cell salvage techniques, and the use of erythropoietin and antifibrinolytic agents [17]. This study aims to assess whether perioperative allogeneic blood transfusion is associated with a higher rate of postoperative infections within 90 days after lumbar spine surgery. Our primary null hypothesis is that exposure to allogeneic blood transfusion is not independently associated with specific and overall postoperative infections in multivariable logistic regression analyses accounting for patient and operative treatment characteristics. Second,
we assessed if there was a dose-response relationship between the number of blood units transfused and postoperative infections. Material and methods Study design and participants This retrospective study was approved by the institutional review board, and a waiver of informed consent was granted. We used five Current Procedural Terminology (CPT) codes to identify patients who underwent a laminectomy and/or arthrodesis of the lumbar spine (Appendix 1). Medical record data of patients with one of these CPT codes were retrieved through our Research Patient Data Registry. This is a centralized clinical data registry covering patients from a tertiary care referral center. It comprises diagnostic codes (International Classification of Diseases, ninth revision [ICD9] code), billing (CPT) codes, demographic information (e.g. sex, date of birth, and race), clinical encounters, transfusion data, laboratory values, and operative and radiology reports. We included patients older than 18 years who underwent operative treatment between 2001 and 2013 at our institution with one of the five aforementioned CPT codes. Exclusion criteria were cervical or thoracic procedures; clinical follow-up less than 90 days; preexisting infection of the spine; and lumbar spine procedure for a fracture, pseudarthrosis, malignancy, or scoliosis. Presence of a preexisting infection, fracture, pseudarthrosis, malignancy, and scoliosis was based on the operative report. Only the first spine procedure was included when a patient had multiple lumbar spine procedures at our institution. Outcome measures and explanatory variables Our primary outcomes were postoperative infections, including pneumonia, endocarditis, meningitis, urinary tract infection, central venous line infection, surgical site infection, and sepsis, within 90 days after lumbar spine surgery. These infections were identified through infection-specific ICD9 codes (Appendix 2). Medical records of patients with one of these ICD9 codes were reviewed by two research fellows (SJ, YB), blinded for the explanatory variable allogeneic blood transfusion, to assess if the infection fulfilled the predefined criteria: pneumonia is defined as symptoms clinically consistent with pneumonia and with a positive sputum culture or with empirical start of antibiotics; endocarditis is defined as symptoms, electrocardiography and/or
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ultrasonography, consistent with endocarditis; meningitis is defined as positive cerebrospinal fluid culture; urinary tract infection is defined as positive urine culture or empirical start of antibiotics for symptoms clinically consistent with urinary tract infection; central venous line infection is defined as symptoms clinically consistent with central venous line infection with a positive culture or with empirical start of antibiotics; surgical site infection is defined as symptoms clinically consistent with a postoperative surgical site infection mandating incision and drainage; and sepsis is defined as an infection not attributable to any of the previously mentioned infections with systemic inflammatory response syndrome requiring intensive care unit admission and a positive culture. We defined allogeneic blood transfusion as perioperative when transfused 7 days before and up to 30 days after the day of operative treatment. The ‘‘no transfusion group’’ had either no perioperative blood transfusion or only autologous blood transfusion. The blood transfusion thresholds at our institution during the 12-year study period were hematocrit less than 24% for patients younger than 40 years, less than 27% for patients between 40 and 60 years, and less than 30% for patients older than 60 years. We included the following explanatory variables: age at the time of operative treatment, sex, race, comorbidity status, tobacco use, obesity, chronic pulmonary disease, chronic diabetes, renal disease, congestive heart failure, duration of surgery in minutes, duration of hospital admission in days, preoperative hemoglobin level in grams per deciliter, type of operative treatment (laminectomy and/or arthrodesis), single-level or multilevel treatment, anterior and/or posterior operative approach, and year of surgery. The comorbidity status was determined using the modified Charlson Comorbidity Index originally developed in 1984 to predict in-hospital mortality based on 17 comorbidities [19]. The scoring algorithm was updated in 2011 to the modified Charlson Comorbidity Index, a score ranging from 0 to 24 based on 12 weighted comorbidities [20]. A higher score indicates more severe comorbidity status. Previous studies found that the modified Charlson Comorbidity Index is associated with postoperative infections. We determined the modified Charlson Comorbidity Index through a previously described algorithm based on the ICD9 codes [21,22] (Appendix 3). Patients were considered obese when they had a body mass index more than 30 recorded in their medical record in the year before surgery or had an ICD9 code for obesity (278.0x). We used the ICD9 code 305.1 to determine if patients used tobacco in the year before surgery. Preoperative hemoglobin, in grams per deciliter, was obtained when measured within 14 days before operative treatment. The operative treatment characteristics, laminectomy and/or arthrodesis, single-level or multilevel treatment, and anterior and/or posterior operative approach, were based on the combinations of CPT codes (Appendix 1).
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Context There is a concern that the immunomodulating effects of allogeneic transfusion can increase the risk of infection following surgery. The authors sought to evaluate this phenomenon in a large series of patients treated at a single center. Contribution Among 3,721 patients treated surgically for lumbar spinal disorders, the authors found that the odds of exposure to allogeneic transfusion was increased by more than a factor of two for patients with urinary tract infections, surgical site infections and any post-operative infection. Implications As a retrospective study, this work is incapable of demonstrating causation, but rather can only highlight the association between allogeneic transfusion and the development of certain infections following surgery. As a retrospective work, gleaned from a single center, this study can be impaired by selection, indication and information bias, and its findings may not be translatable to experiences at other centers. For example, as an academic tertiary care facility that treats a high number of patients with complex medical issues, spinal disorders and oncologic processes, the findings inherent to Massachusetts General Hospital may not be akin to the experience of smaller non-specialty hospitals or community centers. While the information presented here can be used to inform preoperative discussions and the consent process around blood transfusion, the results are not robust enough to inform institutional policies. Further prospective study is clearly warranted. —The Editors
Statistical analyses Variables were presented with frequencies and percentages for categorical variables and as mean with standard deviation (SD) for continuous variables. The difference in explanatory variables among the allogeneic blood transfusion and no transfusion groups was assessed using a Fisher exact test for dichotomous and categorical variables and an unpaired t test for continuous variables. Specific and overall postoperative infection rates were determined in the allogeneic blood transfusion (exposure) and no transfusion (nonexposure) groups. Unadjusted odds ratios with 95% confidence intervals (CIs) were presented to quantify the association between allogeneic blood transfusion and postoperative infections without controlling for other explanatory variables. We calculated odds ratios for the exposure versus the nonexposure group and assessed a
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dose-response relationship with an odds ratio per unit of blood transfused. Multivariable logistic regression analyses were used to assess if allogeneic blood transfusion was independently associated with postoperative infections after accounting for explanatory variables. All explanatory variables with a p value less than .05 in baseline analysis were included except for chronic pulmonary disease, chronic diabetes, renal disease, and congestive heart failure. We excluded these to preclude overfitting because of the relatively low number of postoperative infections and because these comorbidities were already captured in the modified Charlson Comorbidity Index. Adjusted odds ratios derived from multivariable analyses were presented for specific and overall postoperative infections. Cases with missing values were excluded from logistic regression analyses (13% [502 of 3,721]). A two-sided p value less than .05 was considered to indicate statistical significance. p Values were not adjusted for multiple testing. Stata 13.0 (StataCorp LP, College Station, TX, USA) was used for statistical analyses.
Results Baseline characteristics Among the 3,721 included cases, 1,978 (53%) were men, and the mean age was 56 years (Table 1). Most patients were white (88% [3,256 of 3,721]). Mean modified Charlson Comorbidity Index was 1.2 (SD62.0). The average preoperative hemoglobin, available in 3,328 (89%) cases, was 13 (SD61.9) g/dL. The mean duration of surgery, available in 3,669 (99%) cases, was 168 (SD695) minutes. The mean duration of admission was 3.7 (SD63.7) days. Two hundred ninety-three of 3,721 (7.9%) patients had a perioperative allogeneic blood transfusion. The mean number of units transfused in the perioperative allogeneic blood transfusion group was 2.9. Of the 841 units transfused, 276 (33%) were leukoreduced (i.e., leucocytes were removed from packed red blood cells). Patients who received allogeneic blood transfusion were older (p!.001), had more severe comorbidity status (p!.001), had a lower preoperative hemoglobin (p!.001), and were more often women (p!.001). Furthermore, perioperative allogeneic blood transfusions were more often given in patients who underwent surgeries that took longer (p!.001), patients who were admitted longer (p!.001), arthrodesis procedures (p!.001), multilevel treatments (p!.001), and a combined anterior and posterior approaches (p5.001). Blood transfusions were more common in patients undergoing surgery between 2001 and 2007 compared with those undergoing surgery between 2008 and 2013 (p5.006) (Table 1). Overall postoperative infections Two hundred thirty-two (7.2%) of the 3,219 cases with no missing values had 265 postoperative infections within
90 days after lumbar spine surgery: pneumonia (43 cases, 1.3%), endocarditis (1 case, 0.031%), meningitis (1 case, 0.031%), urinary tract infection (122 cases, 3.8%), central venous line infection (1 case, 0.031%), surgical site infection (83 cases, 2.6%), and sepsis (14 cases, 0.43%). Odds ratios for postoperative infections after allogeneic blood transfusion Twenty-two percent of the patients (62 of 280) in the allogeneic blood transfusion group and 5.8% (170 of 2,939) in the no transfusion group had one or more of the specified postoperative infections; the unadjusted odds ratio for the exposure versus the nonexposure group was 4.6 (95% CI: 3.4– 6.4, p!.001). After controlling for explanatory variables, the adjusted odds ratio for any of the infections was 2.6 (95% CI: 1.7–3.9, p!.001). This indicates that the odds of having any postoperative infection is 2.6 times higher in the exposure group versus the nonexposure group. The adjusted odds ratio per unit of blood transfused was 1.1 (95% CI: 0.97–1.2, p5.17) (Table 2), indicating no dose-response relationship. Thirteen percent of the patients (36 of 280) in the allogeneic blood transfusion group and 2.9% (86 of 2,939) in the no transfusion group had a postoperative urinary tract infection; the adjusted odds ratio was 2.2 (95% CI: 1.3– 3.9, p5.004). The adjusted odds ratio per unit of blood transfused was 1.1 (95% CI: 0.98–1.3, p5.088) (Table 2). This indicates that there is an association between blood transfusion exposure and urinary tract infections; however, there is no dose-response relationship. Almost 6% of the patients (16 of 280) in the allogeneic blood transfusion group and 0.97% (27 of 2,939) in the no transfusion group had a postoperative pneumonia; the adjusted odds ratio was 2.3 (95% CI: 0.96–5.3, p5.062). The adjusted odds ratio per unit of blood transfused was 1.1 (95% CI: 0.94–1.3, p5.25) (Table 2). This indicates no association of blood transfusion with pneumonia. More than 6% of the patients (18 of 280) in the allogeneic blood transfusion group and 2.2% (65 of 2,939) in the no transfusion group had a postoperative surgical site infection requiring incision and drainage; the adjusted odds ratio was 2.6 (95% CI: 1.3–5.3, p5.007). The adjusted odds ratio per unit of blood transfused was 0.96 (95% CI: 0.82–1.1, p5.59) (Table 2). This indicates that there is an association between blood transfusion exposure and surgical site infections; however, there is no dose-response relationship. The endocarditis case and the central venous line infection case were in the allogeneic blood transfusion group (both 0.36%, 1 of 280). The meningitis case was in the no transfusion group (0.034%, 1 of 2,939). Four sepsis cases (1.4%, 4 of 280) were in the allogeneic blood transfusion group and 10 (0.34%, 10 of 2,939) in the no transfusion group. We abstained from separate multivariable logistic regression analysis for endocarditis, meningitis, central venous line infection, and sepsis because of the low number of these infections.
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Table 1 Baseline analysis: patient and treatment characteristics for transfusion and no transfusion groups (n53,721)
Baseline characteristics Age (y) Duration of surgery (min)y Modified Charlson Comorbidity Index Preoperative hemoglobin level (g/dL)y Duration of hospital admission (d)y Sex, n (%) M F Race White Hispanic Black Asian Other Unknown Tobacco use Yes No Obesity Yes No Chronic pulmonary disease Yes No Chronic diabetes Yes No Renal disease Yes No Congestive heart failure Yes No Operation Laminectomy Arthrodesis Laminectomy with arthrodesis Multilevel treatment Yes No Operative approach Anterior Posterior Anterior and posterior Year 2001–2007 2008–2013 Units transfused
No transfusion (n53,428)
Perioperative allogeneic blood transfusion* (n5293)
Mean (6SD)
Mean (6SD)
p Value
64 269 2.1 11 8.5
!.001 !.001 !.001 !.001 !.001
54 159 1.1 13 3.3
(16) (87) (2.0) (1.7) (2.7)
(14) (120) (2.7) (1.6) (8.0)
1,865 (54) 1,563 (46)
113 (39) 180 (61)
2,999 126 102 61 26 114
257 8 10 8 3 7
(87) (3.7) (2.98) (1.8) (0.76) (3.3)
(88) (2.7) (3.4) (2.7) (1.02) (2.4)
!.001
.64
437 (13) 2,991 (87)
31 (11) 262 (89)
.31
793 (23) 2,635 (77)
80 (27) 213 (73)
.11
483 (14) 2,945 (86)
59 (20) 234 (80)
.007
159 (4.6) 3,269 (95)
39 (13) 254 (87)
!.001
177 (5.2) 3,251 (95)
33 (11) 260 (89)
!.001
258 (7.5) 3,170 (92)
65 (22) 228 (78)
!.001
2,555 (75) 456 (13) 417 (12)
99 (34) 95 (32) 99 (34)
!.001
432 (13) 2,996 (87)
112 (38) 181 (62)
!.001
229 (6.7) 3,108 (91) 91 (2.7)
23 (7.8) 250 (85) 20 (6.8)
.001
1,817 (53) 1,611 (47) 0
180 (61) 113 (39) 2.9 (62.8)
.006 NA
F, female; M, male; NA, not applicable; SD, standard deviation. Note: Values in italics indicate significance (p value less than .05). * Allogeneic blood transfusion within 7 days before and up to 30 days after surgery. y Duration of surgery was available in 3,669 patients: 287 who had a perioperative transfusion and 3,382 with no transfusion. Preoperative hemoglobin was available in 3,328 patients: 287 who had a perioperative transfusion and in 3,041 with no transfusion. Duration of hospital admission was available in 3,636 patients: 292 who had a perioperative transfusion and 3,344 with no transfusion.
Discussion The association of perioperative blood transfusion with surgical site infection after spine surgery has previously been demonstrated in relatively small case-control studies [17,18],
and these studies did not address the influence of perioperative blood transfusions on other postoperative infections. We found that exposure to allogeneic blood transfusion was independently associated with a higher rate of urinary tract infections,
CI, confidence interval; OR, odds ratio. Note: Values in italics indicate significance (p value less than .05). * Only cases with no missing values for all included explanatory variables (n53,219) were included in the multivariable logistic regression analyses. y Perioperative allogeneic blood transfusion within 7 days before and up to 30 days after surgery. z Odds ratios from multivariable logistic regression analyses were adjusted for age, duration of surgery, duration of hospital admission, modified Charlson Comorbidity Index, preoperative hemoglobin, sex, operation, multilevel treatment, operative approach, and year of surgery. x Pneumonia, endocarditis, meningitis, urinary tract infection, central venous line infection, surgical site infection, and sepsis.
(0.98–1.3) (0.94–1.3) (0.82–1.1) (0.97–1.2) 1.1 1.1 0.96 1.1 !.001 !.001 .13 !.001 (2.9%) (0.97%) (2.2%) (5.8%) 86 27 65 170 Urinary tract infection Pneumonia Surgical site infection Any infectionx
36 16 18 62
(13%) (5.7%) (6.4%) (22%)
4.9 6.5 3.0 4.6
(3.2–7.4) (3.5–12) (1.8–5.2) (3.4–6.4)
(1.3–3.9) (0.96–5.3) (1.3–5.3) (1.7–3.9)
.004 .062 .007 !.001
1.3 1.3 1.1 1.3 2.2 2.3 2.6 2.6 !.001 !.001 !.001 !.001
(1.2–1.4) (1.2–1.4) (0.97–1.2) (1.2–1.4)
OR (95% CI) OR (95% CI) No transfusion (n52,939) Type of infection
Blood transfusiony (n5280)
OR (95% CI)
p Value OR (95% CI) p Value
p Value
Adjustedz Unadjusted
Blood transfusion (per unit transfused)y
Adjustedz Unadjusted
Blood transfusion (exposure/nonexposure)y Table 2 Odds ratios for 90-day health-care–associated infections (n53,219*)
.088 .25 .59 .17
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906
surgical site infections, and overall postoperative infections but not with pneumonia. There does not seem to be a doseresponse relationship between the number of blood units transfused and any of the postoperative infections. The limitations of this study should be kept in mind when interpreting our results. First, there were no uniform criteria for operative treatment because of the retrospective nature of this study. This might have resulted in selection bias. Second, billing and diagnostic codes were used to define the patient cohort, identify comorbidities, and to determine smoking status and obesity. There might have been inaccuracies in coding; however, we expect this to be limited. Third, adjustments in multivariable logistic regression analysis could only be made for the variables included in the model. Because of complexity of pathophysiology, and the limit of variables we could include in our multivariable model, it is possible that not all existing confounders are adjusted for in multivariable analysis. However, we included risk factors previously found to be associated with blood transfusion and infections in spine surgery [14,17,23–29]. The use of a urinary catheter is not included and might have affected our results. However, use of a urinary catheter is probably captured by the duration of surgery and/or duration of hospital admission as a catheter is routinely placed in anticipated prolonged duration of surgery (O120 minutes). The difference in infection rates between patients exposed to allogeneic blood transfusion and those who were not exposed might also be explained by a difference in blood loss itself. However, we were not able to account for intraoperative blood loss. Our finding that exposure to allogeneic blood transfusion is associated with surgical site infection (adjusted odds ratio of 2.6, 95% CI: 1.3–5.3, p5.007) after lumbar spine surgery is in line with the previously published studies [17,18]. Schwarzkopf et al. [17] included 132 patients undergoing a thoracic or lumbar spine procedure in a retrospective case-control study and found an odds ratio of 8.02 (95% CI: 2.28–28.2, p5.001). A study by Woods et al. [18] demonstrated an odds ratio of 4.00 per unit of blood transfused (95% CI: 1.96–8.15) using a logistic regression analysis based on a retrospective matched case-control cohort including 147 patients. Our study also demonstrated that blood transfusion is independently associated with a 2.2 times higher odds of postoperative urinary tract infection (95% CI: 1.3–3.9, p5.004) and a 2.6 times higher odds of any postoperative infection (95% CI: 1.7–3.9, p!.001). This association of blood transfusion with other postoperative infections has not been demonstrated in spine surgery. These results are supported by studies in other fields of medicine demonstrating an increased risk of infections after allogeneic blood transfusions [4,5,26,30]. We did not find an association of blood transfusion with pneumonia after accounting for patient and treatment characteristics (odds ratio 2.3, 95% CI: 0.96–5.3, p5.062); this might have been a result of insufficient power because of the relatively low pneumonia rate in our cohort (1.3% [43 of the 3,219 cases]). The low number of
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endocarditis, meningitis, central venous line infection, and sepsis in our study did not allow for multivariable analysis. The increased risk of infections after blood transfusion is thought to be a result of transfusion-related immunosuppression [4,8–10,12]. Although the exact mechanism is still unclear [12], many subsequent studies confirmed this immunosuppressive effect [4,9,12,31,32]. Other transfusionassociated risks are transfusion errors (i.e., receiving the wrong blood) and transfusion-transmissible infections [12,33]. Transfusion errors, although entirely preventable, remain the most commonly reported adverse event with an incidence of 1 in 10,000–30,000 units transfused [33,34]. The incidence of transfusion-transmissible infections is low (e.g., 1 in 6.7 million for human immunodeficiency virus and 1 in 1.3 million for Hepatitis B) but causes a serious risk [5,12,33]. Increased evidence and awareness of risks associated with blood transfusions led to more restrictive transfusion policies (i.e., transfusion at lower hemoglobin thresholds) in many fields of medicine and the use of leukoreduced blood [1]. Leukoreduction is the removal of white blood cells from the blood and might reduce the transfusion-transmissible infections and transfusion-related immunomodulation [4,12,31]. Optimal use of blood transfusions would be administering enough to maximize clinical outcome while avoiding unnecessary exposure to the risks [1]. The use of blood transfusions in spine surgery might be reduced by adhering to more restrictive transfusion policies or by reducing the need for perioperative allogeneic blood transfusions. General guidelines by the American Association of Blood Banks recommend consideration of transfusion in hospitalized, stable patients with a hemoglobin concentration less than 7 g/dL, or less than 8 g/dL in postoperative surgical patients, or for symptoms (chest pain, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or congestive heart failure) [1]. Future studies should assess the value of perioperative restrictive and liberal transfusion policies in the field of spine surgery. Alternative measures to reduce the need for perioperative allogeneic blood transfusions include methods to minimize blood loss, preoperative blood donation, reinfusion, and cell salvage techniques, and the use of erythropoietin antifibrinolytic agents [17]. In conclusion, these data support the influence of allogeneic blood transfusion on both surgical site infections and other postoperative infections after lumbar spine surgery. These findings should be taken into account when considering blood transfusion and developing transfusion policies for spine procedures. Randomized controlled trials should be conducted to assess the influence of transfusion threshold on postoperative infections after spine surgery.
References [1] Carson JL, Grossman BJ, Kleinman S, Tinmouth AT, Marques MB, Fung MK, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med 2012;157:49–58.
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[24] Cizik AM, Lee MJ, Martin BI, Bransford RJ, Bellabarba C, Chapman JR, et al. Using the spine surgical invasiveness index to identify risk of surgical site infection: a multivariate analysis. J Bone Joint Surg Am 2012;94:335–42. [25] Fang A, Hu SS, Endres N, Bradford DS. Risk factors for infection after spinal surgery. Spine 2005;30:1460–5. [26] Friedman R, Homering M, Holberg G, Berkowitz SD. Allogeneic blood transfusions and postoperative infections after total hip or knee arthroplasty. J Bone Joint Surg Am 2014;96:272–8. [27] Lau D, Chou D, Ziewacz JE, Mummaneni PV. The effects of smoking on perioperative outcomes and pseudarthrosis following anterior cervical corpectomy: clinical article. J Neurosurg Spine 2014;21: 547–58. [28] Lim S, Edelstein AI, Patel AA, Kim BD, Kim JY. Risk factors for postoperative infections following single level lumbar fusion surgery. Spine 2014 Sep 29. [Epub ahead of print]. [29] Olsen MA, Nepple JJ, Riew KD, Lenke LG, Bridwell KH, Mayfield J, et al. Risk factors for surgical site infection following
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Appendix 1 Current Procedural Terminology codes to identify cohort and define type of operative treatment, levels, and operative approach CPT code
Description of CPT code
CPT codes defining cohort and indicating type of operative treatment 63,047 Laminectomy, facetectomy and foraminotomy, single vertebral segment; lumbar 63,030 Laminotomy, including partial facetectomy, foraminotomy, and/or excision of disc; one interspace, lumbar 22,612 Arthrodesis, posterior or posterolateral technique, single level; lumbar 22,558 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; lumbar 22,630 Arthrodesis, posterior interbody technique, including laminectomy and/or discectomy to prepare interspace, single interspace; lumbar CPT codes indicating multilevel operation 22,614 Arthrodesis, posterior or posterolateral technique, single level; each additional vertebral segment 22,585 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; each additional interspace 22,842 Posterior segmental instrumentation; 3 to 6 vertebral segments 22,843 Posterior segmental instrumentation; 7 to 12 vertebral segments 22,844 Posterior segmental instrumentation; $13 vertebral segments 22,845 Anterior instrumentation; 2 to 3 vertebral segments 22,846 Anterior instrumentation; 4 to 7 vertebral segments 22,847 Anterior instrumentation; $8 vertebral segments CPT codes indicating approach 63,047 Laminectomy, facetectomy and foraminotomy, single vertebral segment; lumbar 63,030 Laminotomy, including partial facetectomy, foraminotomy, and/or excision of disc; one interspace, lumbar 22,612 Arthrodesis, posterior or posterolateral technique, single level; lumbar 22,630 Arthrodesis, posterior interbody technique, including laminectomy and/or discectomy to prepare interspace, single interspace; lumbar 22,614 Arthrodesis, posterior or posterolateral technique, single level; each additional vertebral segment 63,035 Laminotomy, including partial facetectomy, foraminotomy, and/or excision of herniated intervertebral disc; each additional interspace, cervical or lumbar 22,842 Posterior segmental instrumentation; 3 to 6 vertebral segments 22,843 Posterior segmental instrumentation; 7 to 12 vertebral segments 22,844 Posterior segmental instrumentation; $13 vertebral segments 22,558 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; lumbar 22,585 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; each additional interspace 22,845 Anterior instrumentation; 2 to 3 vertebral segments 22,846 Anterior instrumentation; 4 to 7 vertebral segments 22,847 Anterior instrumentation; $8 vertebral segments
Treatment type Type of operative treatment* Laminectomy Laminectomy Arthrodesis Arthrodesis Arthrodesis and Laminectomy Multilevely Multilevel Multilevel Multilevel Multilevel Multilevel Multilevel Multilevel Multilevel Operative approachz Posterior Posterior Posterior Posterior Posterior Posterior Posterior Posterior Posterior Anterior Anterior Anterior Anterior Anterior
CPT, Current Procedural Terminology. * A combined procedure (i.e., laminectomy and arthrodesis) is defined based on a combination of a laminectomy and arthrodesis code. y Operative treatment is done on a single level when none of the multilevel additional codes are given. z A combined approach (i.e., anterior and posterior) is defined based on a combination of an anterior and posterior approach codes.
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Appendix 2 International Classification of Diseases, ninth revision codes used to identify 90-day postoperative infections Postoperative infection
ICD9 codes
Pneumonia
481, 482.xx, 483.8, 485, 486, 495.7, 507 421.x, 424.xx 320.xx, 321.3 590.1x, 590.3, 590.8x, 590.9, 595, 595.9, 599 999.31, 999.32, 999.33, 999.39 998.5x, 996.66, 996.67, 683 38.xx, 790.7
Endocarditis Meningitis Urinary tract infection Central venous line infection Surgical site infection Sepsis
Note: An x indicates a number from 0 to 9 or no character.
Appendix 3 International Classification of Diseases, ninth revision codes for modified Charlson Comorbidity Index algorithm Comorbidities in modified Charlson Comorbidity Index
ICD9 codes
Congestive heart failure
398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4425.9, 428-428.43 290, 290.0, 290.3, 290.8-290.43, 294.1, 294.11-294.21, 331.2 416.8, 416.9, 490-491.0, 491.2-495.2, 495.4-505, 506.4, 508.1, 508.8 466.5, 710.0-710.4, 714.0-714.2, 714.8, 725 070.22, 070.23, 070.32, 070.33, 070.44, 070.54, 070.6, 070.9, 570, 570.1, 573.3, 573.4, 573.8, 753.9, V42.7 249.40-249.91, 250.40-250.90 342.00-342.92, 344.00-344.5, 344.89-344.9 403.01, 403.11, 403.91, 404.02, 404.03, 404.12, 404.13, 404.92, 404.93, 582-583.7, 585586, 588.0, V42.0, V45.1, V56-V56.8 150.0-159.0, 162-173.59, 173.70-175.9, 180.0-183.9, 185-186.9, 188.0-188.6, 188.8189.4, 189.9, 191.0-192.3, 192.9-194.4, 200.2-202.38, 202.70-202.81, 203.0-204.22, 204.90-208.22, 208.90-209.36, 209.70, 209.72-209.79, 230.2-230.6, 230.8, 231.2, 231.9, 232.5-232.7, 233.0, 233.1, 233.31, 233.32, 233.4, 233.7, 235.2-235.4, 235.7, 235.8, 236.2, 236.4, 236.5, 236.7-236.91, 237.1-237.4, 237.6, 238.0-238.3, 238.79, 239.0-239.4, 239.6, 239.7, 239.89, 239.9 456.0-456.2, 572.2-572.8 197.0-198.7, 198.81-190.9, 192.0-196.9, 199.0 042
Dementia Chronic pulmonary disease Rheumatologic disease Mild liver disease* Diabetes with chronic complications Hemiplegia or paraplegia Renal disease Any malignancy, including leukemia and lymphoma*
Moderate or severe liver disease* Metastatic solid tumor* AIDS/HIV
HIV, human immunodeficiency virus. * The following comorbidities were mutually exclusive: mild and moderate or severe liver disease and any malignancy and metastatic solid tumor.
Clinical Study
Allogeneic blood transfusions and postoperative infections after lumbar spine surgery Stein J. Janssen, MD*, Yvonne Braun, MD, Kirkham B. Wood, MD, Thomas D. Cha, MD, MBA, Joseph H. Schwab, MD, MS Department of Orthopaedic Surgery, Spine Service, Massachusetts General Hospital, Harvard Medical School, Rm 3.946, Yawkey Bldg, 55 Fruit St, Boston, MA 02114, USA Received 5 September 2014; revised 24 December 2014; accepted 3 February 2015
Abstract
BACKGROUND CONTEXT: Allogeneic blood transfusions have an immunomodulating effect, and the previous studies in other fields of medicine demonstrated an increased risk of infections after administration of allogeneic blood transfusions. PURPOSE: Our primary null hypothesis is that exposure to allogeneic blood transfusion in patients undergoing lumbar spine surgery is not associated with postoperative infections after controlling for patient and treatment characteristics. Second, we assessed if there was a dose-response relationship per unit of blood transfused. STUDY DESIGN/SETTING: This is a retrospective cohort study from a tertiary care spine referral center. PATIENT SAMPLE: A total of 3,721 patients underwent laminectomy and/or arthrodesis of the lumbar spine. OUTCOMES MEASURES: Postoperative infections, pneumonia, endocarditis, meningitis, urinary tract infection, central venous line infection, surgical site infection, and sepsis, within 90 days after lumbar spine surgery were included. METHODS: Multivariable logistic regression analyses were used to assess the relationship of perioperative allogeneic blood transfusion with specific and overall postoperative infections accounting for age, duration of surgery, duration of hospital stay, comorbidity status, preoperative hemoglobin, sex, type of operation, multilevel treatment, operative approach, and year of surgery. RESULTS: The adjusted odds ratio for exposure to allogeneic blood transfusion from multivariable logistic regression analysis was 2.6 for any postoperative infection (95% confidence interval [CI]: 1.7–3.9, p!.001); 2.2 for urinary tract infections (95% CI: 1.3–3.9, p5.004); 2.3 for pneumonia (95% CI: 0.96–5.3, p5.062); and 2.6 for surgical site infection requiring incision and drainage (95% CI: 1.3–5.3, p5.007). Secondary analyses demonstrated no dose-response relationship between the number of blood units transfused and any of the postoperative infections. Because of the low number of endocarditis (1 case, 0.031%), meningitis (1 case, 0.031%), central venous line infection (1 case, 0.031%), and sepsis (14 cases, 0.43%), we abstained from multivariable analysis. CONCLUSIONS: Conscious of the limitations of this retrospective study, our data suggest an increased risk of surgical site infection, urinary tract infection, and overall postoperative infections, but not pneumonia, after exposure to allogeneic blood transfusion in patients undergoing lumbar
FDA device/drug status: Not applicable. Author disclosures: SJJ: Grant: Anna Foundation (B), Michael van Vloten Foundation (B), De Drie Lichten Foundation (B), KWF Kankerbestrijding (B). YB: Nothing to disclose. KBW: Other: OREF (E, Fellowship Support), AO Spine NA (E, Fellowship Support), Depuy Spine (E, Fellowship Support), K2M, Inc.: (C, Fellowship Support), TranS1 (C, Stock Options). TDC: Grant: North American Spine Society (D), Gordon and Betty Moore Foundation (B); Personnel Fees: Bio2 (B); Other: OREF (E, Institutional Fellowship Support), K2M (E, Institutional Fellowship Support), AO http://dx.doi.org/10.1016/j.spinee.2015.02.010 1529-9430/Ó 2015 Elsevier Inc. All rights reserved.
Spine (E, Institutional Fellowship Support). JHS: Other: Stryker (B, Consulting fees), Biom’up (B, Consulting fees). The disclosure key can be found on the Table of Contents and at www. TheSpineJournalOnline.com. * Corresponding author. Department of Orthopaedic Surgery, Spine Service, Massachusetts General Hospital, Harvard Medical School, Rm 3.946, Yawkey Bldg, 55 Fruit St, Boston, MA 02114, USA. Tel.: (617) 726-1569; fax: (617) 643-1274. E-mail address: [email protected] (S.J. Janssen)
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spine surgery. These findings should be taken into account when considering blood transfusion and developing transfusion policies for patients undergoing lumbar spine procedures. Ó 2015 Elsevier Inc. All rights reserved. Keywords:
Transfusion; Infection; Lumbar; Surgery; Guideline; Policy; Immunomodulation
Introduction Approximately 85 million units of packed red blood cells are transfused annually worldwide [1,2]. However, blood transfusion policies became more restrictive over the past decade [3] as there is growing evidence that allogeneic blood transfusions (i.e., blood from a genetically nonidentical donor) are associated with an increased risk of postoperative infections [4], cancer recurrences, decreased survival in cancer patients [5–7], and other direct transfusion-associated risks (e.g., transfusion-transmissible infections and transfusion errors) [1]. The increased risk of postoperative infections is explained by the immunomodulating effects of allogeneic blood transfusions [4,8–10]. This effect was first hypothesized in 1973 in a study demonstrating improved graft survival of patients who received allogeneic blood transfusion before kidney transplantation [11]. Although the exact mechanism is still unclear [4,12], many subsequent clinical and laboratory studies confirmed the immunosuppressive effect of blood transfusions [9,12]. Blood transfusion is commonly (20–36%) used in spine surgery and aims to improve the oxygen transport capacity of the blood and, therefore, tissue oxygenation [13,14]. The number of units transfused perioperatively is associated with the age of the patient, comorbidities, number of levels instrumented, preoperative hemoglobin, duration of surgery, and complexity of the operation [14–16]. The untoward effects of blood transfusion specifically on surgical site infections after spine surgery have previously been demonstrated in two relatively small case-control studies [17,18]. However, the influence of allogeneic blood transfusion on other postoperative infections, such as urinary tract infection and pneumonia, has not been studied. Understanding the association of blood transfusion with postoperative infections can help guide future transfusion policies and the management of blood loss during spine surgery. Alternative measures to reduce the need for allogeneic blood transfusions include methods to minimize blood loss, preoperative blood donation, reinfusion, and cell salvage techniques, and the use of erythropoietin and antifibrinolytic agents [17]. This study aims to assess whether perioperative allogeneic blood transfusion is associated with a higher rate of postoperative infections within 90 days after lumbar spine surgery. Our primary null hypothesis is that exposure to allogeneic blood transfusion is not independently associated with specific and overall postoperative infections in multivariable logistic regression analyses accounting for patient and operative treatment characteristics. Second,
we assessed if there was a dose-response relationship between the number of blood units transfused and postoperative infections. Material and methods Study design and participants This retrospective study was approved by the institutional review board, and a waiver of informed consent was granted. We used five Current Procedural Terminology (CPT) codes to identify patients who underwent a laminectomy and/or arthrodesis of the lumbar spine (Appendix 1). Medical record data of patients with one of these CPT codes were retrieved through our Research Patient Data Registry. This is a centralized clinical data registry covering patients from a tertiary care referral center. It comprises diagnostic codes (International Classification of Diseases, ninth revision [ICD9] code), billing (CPT) codes, demographic information (e.g. sex, date of birth, and race), clinical encounters, transfusion data, laboratory values, and operative and radiology reports. We included patients older than 18 years who underwent operative treatment between 2001 and 2013 at our institution with one of the five aforementioned CPT codes. Exclusion criteria were cervical or thoracic procedures; clinical follow-up less than 90 days; preexisting infection of the spine; and lumbar spine procedure for a fracture, pseudarthrosis, malignancy, or scoliosis. Presence of a preexisting infection, fracture, pseudarthrosis, malignancy, and scoliosis was based on the operative report. Only the first spine procedure was included when a patient had multiple lumbar spine procedures at our institution. Outcome measures and explanatory variables Our primary outcomes were postoperative infections, including pneumonia, endocarditis, meningitis, urinary tract infection, central venous line infection, surgical site infection, and sepsis, within 90 days after lumbar spine surgery. These infections were identified through infection-specific ICD9 codes (Appendix 2). Medical records of patients with one of these ICD9 codes were reviewed by two research fellows (SJ, YB), blinded for the explanatory variable allogeneic blood transfusion, to assess if the infection fulfilled the predefined criteria: pneumonia is defined as symptoms clinically consistent with pneumonia and with a positive sputum culture or with empirical start of antibiotics; endocarditis is defined as symptoms, electrocardiography and/or
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ultrasonography, consistent with endocarditis; meningitis is defined as positive cerebrospinal fluid culture; urinary tract infection is defined as positive urine culture or empirical start of antibiotics for symptoms clinically consistent with urinary tract infection; central venous line infection is defined as symptoms clinically consistent with central venous line infection with a positive culture or with empirical start of antibiotics; surgical site infection is defined as symptoms clinically consistent with a postoperative surgical site infection mandating incision and drainage; and sepsis is defined as an infection not attributable to any of the previously mentioned infections with systemic inflammatory response syndrome requiring intensive care unit admission and a positive culture. We defined allogeneic blood transfusion as perioperative when transfused 7 days before and up to 30 days after the day of operative treatment. The ‘‘no transfusion group’’ had either no perioperative blood transfusion or only autologous blood transfusion. The blood transfusion thresholds at our institution during the 12-year study period were hematocrit less than 24% for patients younger than 40 years, less than 27% for patients between 40 and 60 years, and less than 30% for patients older than 60 years. We included the following explanatory variables: age at the time of operative treatment, sex, race, comorbidity status, tobacco use, obesity, chronic pulmonary disease, chronic diabetes, renal disease, congestive heart failure, duration of surgery in minutes, duration of hospital admission in days, preoperative hemoglobin level in grams per deciliter, type of operative treatment (laminectomy and/or arthrodesis), single-level or multilevel treatment, anterior and/or posterior operative approach, and year of surgery. The comorbidity status was determined using the modified Charlson Comorbidity Index originally developed in 1984 to predict in-hospital mortality based on 17 comorbidities [19]. The scoring algorithm was updated in 2011 to the modified Charlson Comorbidity Index, a score ranging from 0 to 24 based on 12 weighted comorbidities [20]. A higher score indicates more severe comorbidity status. Previous studies found that the modified Charlson Comorbidity Index is associated with postoperative infections. We determined the modified Charlson Comorbidity Index through a previously described algorithm based on the ICD9 codes [21,22] (Appendix 3). Patients were considered obese when they had a body mass index more than 30 recorded in their medical record in the year before surgery or had an ICD9 code for obesity (278.0x). We used the ICD9 code 305.1 to determine if patients used tobacco in the year before surgery. Preoperative hemoglobin, in grams per deciliter, was obtained when measured within 14 days before operative treatment. The operative treatment characteristics, laminectomy and/or arthrodesis, single-level or multilevel treatment, and anterior and/or posterior operative approach, were based on the combinations of CPT codes (Appendix 1).
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Context There is a concern that the immunomodulating effects of allogeneic transfusion can increase the risk of infection following surgery. The authors sought to evaluate this phenomenon in a large series of patients treated at a single center. Contribution Among 3,721 patients treated surgically for lumbar spinal disorders, the authors found that the odds of exposure to allogeneic transfusion was increased by more than a factor of two for patients with urinary tract infections, surgical site infections and any post-operative infection. Implications As a retrospective study, this work is incapable of demonstrating causation, but rather can only highlight the association between allogeneic transfusion and the development of certain infections following surgery. As a retrospective work, gleaned from a single center, this study can be impaired by selection, indication and information bias, and its findings may not be translatable to experiences at other centers. For example, as an academic tertiary care facility that treats a high number of patients with complex medical issues, spinal disorders and oncologic processes, the findings inherent to Massachusetts General Hospital may not be akin to the experience of smaller non-specialty hospitals or community centers. While the information presented here can be used to inform preoperative discussions and the consent process around blood transfusion, the results are not robust enough to inform institutional policies. Further prospective study is clearly warranted. —The Editors
Statistical analyses Variables were presented with frequencies and percentages for categorical variables and as mean with standard deviation (SD) for continuous variables. The difference in explanatory variables among the allogeneic blood transfusion and no transfusion groups was assessed using a Fisher exact test for dichotomous and categorical variables and an unpaired t test for continuous variables. Specific and overall postoperative infection rates were determined in the allogeneic blood transfusion (exposure) and no transfusion (nonexposure) groups. Unadjusted odds ratios with 95% confidence intervals (CIs) were presented to quantify the association between allogeneic blood transfusion and postoperative infections without controlling for other explanatory variables. We calculated odds ratios for the exposure versus the nonexposure group and assessed a
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dose-response relationship with an odds ratio per unit of blood transfused. Multivariable logistic regression analyses were used to assess if allogeneic blood transfusion was independently associated with postoperative infections after accounting for explanatory variables. All explanatory variables with a p value less than .05 in baseline analysis were included except for chronic pulmonary disease, chronic diabetes, renal disease, and congestive heart failure. We excluded these to preclude overfitting because of the relatively low number of postoperative infections and because these comorbidities were already captured in the modified Charlson Comorbidity Index. Adjusted odds ratios derived from multivariable analyses were presented for specific and overall postoperative infections. Cases with missing values were excluded from logistic regression analyses (13% [502 of 3,721]). A two-sided p value less than .05 was considered to indicate statistical significance. p Values were not adjusted for multiple testing. Stata 13.0 (StataCorp LP, College Station, TX, USA) was used for statistical analyses.
Results Baseline characteristics Among the 3,721 included cases, 1,978 (53%) were men, and the mean age was 56 years (Table 1). Most patients were white (88% [3,256 of 3,721]). Mean modified Charlson Comorbidity Index was 1.2 (SD62.0). The average preoperative hemoglobin, available in 3,328 (89%) cases, was 13 (SD61.9) g/dL. The mean duration of surgery, available in 3,669 (99%) cases, was 168 (SD695) minutes. The mean duration of admission was 3.7 (SD63.7) days. Two hundred ninety-three of 3,721 (7.9%) patients had a perioperative allogeneic blood transfusion. The mean number of units transfused in the perioperative allogeneic blood transfusion group was 2.9. Of the 841 units transfused, 276 (33%) were leukoreduced (i.e., leucocytes were removed from packed red blood cells). Patients who received allogeneic blood transfusion were older (p!.001), had more severe comorbidity status (p!.001), had a lower preoperative hemoglobin (p!.001), and were more often women (p!.001). Furthermore, perioperative allogeneic blood transfusions were more often given in patients who underwent surgeries that took longer (p!.001), patients who were admitted longer (p!.001), arthrodesis procedures (p!.001), multilevel treatments (p!.001), and a combined anterior and posterior approaches (p5.001). Blood transfusions were more common in patients undergoing surgery between 2001 and 2007 compared with those undergoing surgery between 2008 and 2013 (p5.006) (Table 1). Overall postoperative infections Two hundred thirty-two (7.2%) of the 3,219 cases with no missing values had 265 postoperative infections within
90 days after lumbar spine surgery: pneumonia (43 cases, 1.3%), endocarditis (1 case, 0.031%), meningitis (1 case, 0.031%), urinary tract infection (122 cases, 3.8%), central venous line infection (1 case, 0.031%), surgical site infection (83 cases, 2.6%), and sepsis (14 cases, 0.43%). Odds ratios for postoperative infections after allogeneic blood transfusion Twenty-two percent of the patients (62 of 280) in the allogeneic blood transfusion group and 5.8% (170 of 2,939) in the no transfusion group had one or more of the specified postoperative infections; the unadjusted odds ratio for the exposure versus the nonexposure group was 4.6 (95% CI: 3.4– 6.4, p!.001). After controlling for explanatory variables, the adjusted odds ratio for any of the infections was 2.6 (95% CI: 1.7–3.9, p!.001). This indicates that the odds of having any postoperative infection is 2.6 times higher in the exposure group versus the nonexposure group. The adjusted odds ratio per unit of blood transfused was 1.1 (95% CI: 0.97–1.2, p5.17) (Table 2), indicating no dose-response relationship. Thirteen percent of the patients (36 of 280) in the allogeneic blood transfusion group and 2.9% (86 of 2,939) in the no transfusion group had a postoperative urinary tract infection; the adjusted odds ratio was 2.2 (95% CI: 1.3– 3.9, p5.004). The adjusted odds ratio per unit of blood transfused was 1.1 (95% CI: 0.98–1.3, p5.088) (Table 2). This indicates that there is an association between blood transfusion exposure and urinary tract infections; however, there is no dose-response relationship. Almost 6% of the patients (16 of 280) in the allogeneic blood transfusion group and 0.97% (27 of 2,939) in the no transfusion group had a postoperative pneumonia; the adjusted odds ratio was 2.3 (95% CI: 0.96–5.3, p5.062). The adjusted odds ratio per unit of blood transfused was 1.1 (95% CI: 0.94–1.3, p5.25) (Table 2). This indicates no association of blood transfusion with pneumonia. More than 6% of the patients (18 of 280) in the allogeneic blood transfusion group and 2.2% (65 of 2,939) in the no transfusion group had a postoperative surgical site infection requiring incision and drainage; the adjusted odds ratio was 2.6 (95% CI: 1.3–5.3, p5.007). The adjusted odds ratio per unit of blood transfused was 0.96 (95% CI: 0.82–1.1, p5.59) (Table 2). This indicates that there is an association between blood transfusion exposure and surgical site infections; however, there is no dose-response relationship. The endocarditis case and the central venous line infection case were in the allogeneic blood transfusion group (both 0.36%, 1 of 280). The meningitis case was in the no transfusion group (0.034%, 1 of 2,939). Four sepsis cases (1.4%, 4 of 280) were in the allogeneic blood transfusion group and 10 (0.34%, 10 of 2,939) in the no transfusion group. We abstained from separate multivariable logistic regression analysis for endocarditis, meningitis, central venous line infection, and sepsis because of the low number of these infections.
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Table 1 Baseline analysis: patient and treatment characteristics for transfusion and no transfusion groups (n53,721)
Baseline characteristics Age (y) Duration of surgery (min)y Modified Charlson Comorbidity Index Preoperative hemoglobin level (g/dL)y Duration of hospital admission (d)y Sex, n (%) M F Race White Hispanic Black Asian Other Unknown Tobacco use Yes No Obesity Yes No Chronic pulmonary disease Yes No Chronic diabetes Yes No Renal disease Yes No Congestive heart failure Yes No Operation Laminectomy Arthrodesis Laminectomy with arthrodesis Multilevel treatment Yes No Operative approach Anterior Posterior Anterior and posterior Year 2001–2007 2008–2013 Units transfused
No transfusion (n53,428)
Perioperative allogeneic blood transfusion* (n5293)
Mean (6SD)
Mean (6SD)
p Value
64 269 2.1 11 8.5
!.001 !.001 !.001 !.001 !.001
54 159 1.1 13 3.3
(16) (87) (2.0) (1.7) (2.7)
(14) (120) (2.7) (1.6) (8.0)
1,865 (54) 1,563 (46)
113 (39) 180 (61)
2,999 126 102 61 26 114
257 8 10 8 3 7
(87) (3.7) (2.98) (1.8) (0.76) (3.3)
(88) (2.7) (3.4) (2.7) (1.02) (2.4)
!.001
.64
437 (13) 2,991 (87)
31 (11) 262 (89)
.31
793 (23) 2,635 (77)
80 (27) 213 (73)
.11
483 (14) 2,945 (86)
59 (20) 234 (80)
.007
159 (4.6) 3,269 (95)
39 (13) 254 (87)
!.001
177 (5.2) 3,251 (95)
33 (11) 260 (89)
!.001
258 (7.5) 3,170 (92)
65 (22) 228 (78)
!.001
2,555 (75) 456 (13) 417 (12)
99 (34) 95 (32) 99 (34)
!.001
432 (13) 2,996 (87)
112 (38) 181 (62)
!.001
229 (6.7) 3,108 (91) 91 (2.7)
23 (7.8) 250 (85) 20 (6.8)
.001
1,817 (53) 1,611 (47) 0
180 (61) 113 (39) 2.9 (62.8)
.006 NA
F, female; M, male; NA, not applicable; SD, standard deviation. Note: Values in italics indicate significance (p value less than .05). * Allogeneic blood transfusion within 7 days before and up to 30 days after surgery. y Duration of surgery was available in 3,669 patients: 287 who had a perioperative transfusion and 3,382 with no transfusion. Preoperative hemoglobin was available in 3,328 patients: 287 who had a perioperative transfusion and in 3,041 with no transfusion. Duration of hospital admission was available in 3,636 patients: 292 who had a perioperative transfusion and 3,344 with no transfusion.
Discussion The association of perioperative blood transfusion with surgical site infection after spine surgery has previously been demonstrated in relatively small case-control studies [17,18],
and these studies did not address the influence of perioperative blood transfusions on other postoperative infections. We found that exposure to allogeneic blood transfusion was independently associated with a higher rate of urinary tract infections,
CI, confidence interval; OR, odds ratio. Note: Values in italics indicate significance (p value less than .05). * Only cases with no missing values for all included explanatory variables (n53,219) were included in the multivariable logistic regression analyses. y Perioperative allogeneic blood transfusion within 7 days before and up to 30 days after surgery. z Odds ratios from multivariable logistic regression analyses were adjusted for age, duration of surgery, duration of hospital admission, modified Charlson Comorbidity Index, preoperative hemoglobin, sex, operation, multilevel treatment, operative approach, and year of surgery. x Pneumonia, endocarditis, meningitis, urinary tract infection, central venous line infection, surgical site infection, and sepsis.
(0.98–1.3) (0.94–1.3) (0.82–1.1) (0.97–1.2) 1.1 1.1 0.96 1.1 !.001 !.001 .13 !.001 (2.9%) (0.97%) (2.2%) (5.8%) 86 27 65 170 Urinary tract infection Pneumonia Surgical site infection Any infectionx
36 16 18 62
(13%) (5.7%) (6.4%) (22%)
4.9 6.5 3.0 4.6
(3.2–7.4) (3.5–12) (1.8–5.2) (3.4–6.4)
(1.3–3.9) (0.96–5.3) (1.3–5.3) (1.7–3.9)
.004 .062 .007 !.001
1.3 1.3 1.1 1.3 2.2 2.3 2.6 2.6 !.001 !.001 !.001 !.001
(1.2–1.4) (1.2–1.4) (0.97–1.2) (1.2–1.4)
OR (95% CI) OR (95% CI) No transfusion (n52,939) Type of infection
Blood transfusiony (n5280)
OR (95% CI)
p Value OR (95% CI) p Value
p Value
Adjustedz Unadjusted
Blood transfusion (per unit transfused)y
Adjustedz Unadjusted
Blood transfusion (exposure/nonexposure)y Table 2 Odds ratios for 90-day health-care–associated infections (n53,219*)
.088 .25 .59 .17
S.J. Janssen et al. / The Spine Journal 15 (2015) 901–909 p Value
906
surgical site infections, and overall postoperative infections but not with pneumonia. There does not seem to be a doseresponse relationship between the number of blood units transfused and any of the postoperative infections. The limitations of this study should be kept in mind when interpreting our results. First, there were no uniform criteria for operative treatment because of the retrospective nature of this study. This might have resulted in selection bias. Second, billing and diagnostic codes were used to define the patient cohort, identify comorbidities, and to determine smoking status and obesity. There might have been inaccuracies in coding; however, we expect this to be limited. Third, adjustments in multivariable logistic regression analysis could only be made for the variables included in the model. Because of complexity of pathophysiology, and the limit of variables we could include in our multivariable model, it is possible that not all existing confounders are adjusted for in multivariable analysis. However, we included risk factors previously found to be associated with blood transfusion and infections in spine surgery [14,17,23–29]. The use of a urinary catheter is not included and might have affected our results. However, use of a urinary catheter is probably captured by the duration of surgery and/or duration of hospital admission as a catheter is routinely placed in anticipated prolonged duration of surgery (O120 minutes). The difference in infection rates between patients exposed to allogeneic blood transfusion and those who were not exposed might also be explained by a difference in blood loss itself. However, we were not able to account for intraoperative blood loss. Our finding that exposure to allogeneic blood transfusion is associated with surgical site infection (adjusted odds ratio of 2.6, 95% CI: 1.3–5.3, p5.007) after lumbar spine surgery is in line with the previously published studies [17,18]. Schwarzkopf et al. [17] included 132 patients undergoing a thoracic or lumbar spine procedure in a retrospective case-control study and found an odds ratio of 8.02 (95% CI: 2.28–28.2, p5.001). A study by Woods et al. [18] demonstrated an odds ratio of 4.00 per unit of blood transfused (95% CI: 1.96–8.15) using a logistic regression analysis based on a retrospective matched case-control cohort including 147 patients. Our study also demonstrated that blood transfusion is independently associated with a 2.2 times higher odds of postoperative urinary tract infection (95% CI: 1.3–3.9, p5.004) and a 2.6 times higher odds of any postoperative infection (95% CI: 1.7–3.9, p!.001). This association of blood transfusion with other postoperative infections has not been demonstrated in spine surgery. These results are supported by studies in other fields of medicine demonstrating an increased risk of infections after allogeneic blood transfusions [4,5,26,30]. We did not find an association of blood transfusion with pneumonia after accounting for patient and treatment characteristics (odds ratio 2.3, 95% CI: 0.96–5.3, p5.062); this might have been a result of insufficient power because of the relatively low pneumonia rate in our cohort (1.3% [43 of the 3,219 cases]). The low number of
S.J. Janssen et al. / The Spine Journal 15 (2015) 901–909
endocarditis, meningitis, central venous line infection, and sepsis in our study did not allow for multivariable analysis. The increased risk of infections after blood transfusion is thought to be a result of transfusion-related immunosuppression [4,8–10,12]. Although the exact mechanism is still unclear [12], many subsequent studies confirmed this immunosuppressive effect [4,9,12,31,32]. Other transfusionassociated risks are transfusion errors (i.e., receiving the wrong blood) and transfusion-transmissible infections [12,33]. Transfusion errors, although entirely preventable, remain the most commonly reported adverse event with an incidence of 1 in 10,000–30,000 units transfused [33,34]. The incidence of transfusion-transmissible infections is low (e.g., 1 in 6.7 million for human immunodeficiency virus and 1 in 1.3 million for Hepatitis B) but causes a serious risk [5,12,33]. Increased evidence and awareness of risks associated with blood transfusions led to more restrictive transfusion policies (i.e., transfusion at lower hemoglobin thresholds) in many fields of medicine and the use of leukoreduced blood [1]. Leukoreduction is the removal of white blood cells from the blood and might reduce the transfusion-transmissible infections and transfusion-related immunomodulation [4,12,31]. Optimal use of blood transfusions would be administering enough to maximize clinical outcome while avoiding unnecessary exposure to the risks [1]. The use of blood transfusions in spine surgery might be reduced by adhering to more restrictive transfusion policies or by reducing the need for perioperative allogeneic blood transfusions. General guidelines by the American Association of Blood Banks recommend consideration of transfusion in hospitalized, stable patients with a hemoglobin concentration less than 7 g/dL, or less than 8 g/dL in postoperative surgical patients, or for symptoms (chest pain, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or congestive heart failure) [1]. Future studies should assess the value of perioperative restrictive and liberal transfusion policies in the field of spine surgery. Alternative measures to reduce the need for perioperative allogeneic blood transfusions include methods to minimize blood loss, preoperative blood donation, reinfusion, and cell salvage techniques, and the use of erythropoietin antifibrinolytic agents [17]. In conclusion, these data support the influence of allogeneic blood transfusion on both surgical site infections and other postoperative infections after lumbar spine surgery. These findings should be taken into account when considering blood transfusion and developing transfusion policies for spine procedures. Randomized controlled trials should be conducted to assess the influence of transfusion threshold on postoperative infections after spine surgery.
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Appendix 1 Current Procedural Terminology codes to identify cohort and define type of operative treatment, levels, and operative approach CPT code
Description of CPT code
CPT codes defining cohort and indicating type of operative treatment 63,047 Laminectomy, facetectomy and foraminotomy, single vertebral segment; lumbar 63,030 Laminotomy, including partial facetectomy, foraminotomy, and/or excision of disc; one interspace, lumbar 22,612 Arthrodesis, posterior or posterolateral technique, single level; lumbar 22,558 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; lumbar 22,630 Arthrodesis, posterior interbody technique, including laminectomy and/or discectomy to prepare interspace, single interspace; lumbar CPT codes indicating multilevel operation 22,614 Arthrodesis, posterior or posterolateral technique, single level; each additional vertebral segment 22,585 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; each additional interspace 22,842 Posterior segmental instrumentation; 3 to 6 vertebral segments 22,843 Posterior segmental instrumentation; 7 to 12 vertebral segments 22,844 Posterior segmental instrumentation; $13 vertebral segments 22,845 Anterior instrumentation; 2 to 3 vertebral segments 22,846 Anterior instrumentation; 4 to 7 vertebral segments 22,847 Anterior instrumentation; $8 vertebral segments CPT codes indicating approach 63,047 Laminectomy, facetectomy and foraminotomy, single vertebral segment; lumbar 63,030 Laminotomy, including partial facetectomy, foraminotomy, and/or excision of disc; one interspace, lumbar 22,612 Arthrodesis, posterior or posterolateral technique, single level; lumbar 22,630 Arthrodesis, posterior interbody technique, including laminectomy and/or discectomy to prepare interspace, single interspace; lumbar 22,614 Arthrodesis, posterior or posterolateral technique, single level; each additional vertebral segment 63,035 Laminotomy, including partial facetectomy, foraminotomy, and/or excision of herniated intervertebral disc; each additional interspace, cervical or lumbar 22,842 Posterior segmental instrumentation; 3 to 6 vertebral segments 22,843 Posterior segmental instrumentation; 7 to 12 vertebral segments 22,844 Posterior segmental instrumentation; $13 vertebral segments 22,558 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; lumbar 22,585 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace; each additional interspace 22,845 Anterior instrumentation; 2 to 3 vertebral segments 22,846 Anterior instrumentation; 4 to 7 vertebral segments 22,847 Anterior instrumentation; $8 vertebral segments
Treatment type Type of operative treatment* Laminectomy Laminectomy Arthrodesis Arthrodesis Arthrodesis and Laminectomy Multilevely Multilevel Multilevel Multilevel Multilevel Multilevel Multilevel Multilevel Multilevel Operative approachz Posterior Posterior Posterior Posterior Posterior Posterior Posterior Posterior Posterior Anterior Anterior Anterior Anterior Anterior
CPT, Current Procedural Terminology. * A combined procedure (i.e., laminectomy and arthrodesis) is defined based on a combination of a laminectomy and arthrodesis code. y Operative treatment is done on a single level when none of the multilevel additional codes are given. z A combined approach (i.e., anterior and posterior) is defined based on a combination of an anterior and posterior approach codes.
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909
Appendix 2 International Classification of Diseases, ninth revision codes used to identify 90-day postoperative infections Postoperative infection
ICD9 codes
Pneumonia
481, 482.xx, 483.8, 485, 486, 495.7, 507 421.x, 424.xx 320.xx, 321.3 590.1x, 590.3, 590.8x, 590.9, 595, 595.9, 599 999.31, 999.32, 999.33, 999.39 998.5x, 996.66, 996.67, 683 38.xx, 790.7
Endocarditis Meningitis Urinary tract infection Central venous line infection Surgical site infection Sepsis
Note: An x indicates a number from 0 to 9 or no character.
Appendix 3 International Classification of Diseases, ninth revision codes for modified Charlson Comorbidity Index algorithm Comorbidities in modified Charlson Comorbidity Index
ICD9 codes
Congestive heart failure
398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4425.9, 428-428.43 290, 290.0, 290.3, 290.8-290.43, 294.1, 294.11-294.21, 331.2 416.8, 416.9, 490-491.0, 491.2-495.2, 495.4-505, 506.4, 508.1, 508.8 466.5, 710.0-710.4, 714.0-714.2, 714.8, 725 070.22, 070.23, 070.32, 070.33, 070.44, 070.54, 070.6, 070.9, 570, 570.1, 573.3, 573.4, 573.8, 753.9, V42.7 249.40-249.91, 250.40-250.90 342.00-342.92, 344.00-344.5, 344.89-344.9 403.01, 403.11, 403.91, 404.02, 404.03, 404.12, 404.13, 404.92, 404.93, 582-583.7, 585586, 588.0, V42.0, V45.1, V56-V56.8 150.0-159.0, 162-173.59, 173.70-175.9, 180.0-183.9, 185-186.9, 188.0-188.6, 188.8189.4, 189.9, 191.0-192.3, 192.9-194.4, 200.2-202.38, 202.70-202.81, 203.0-204.22, 204.90-208.22, 208.90-209.36, 209.70, 209.72-209.79, 230.2-230.6, 230.8, 231.2, 231.9, 232.5-232.7, 233.0, 233.1, 233.31, 233.32, 233.4, 233.7, 235.2-235.4, 235.7, 235.8, 236.2, 236.4, 236.5, 236.7-236.91, 237.1-237.4, 237.6, 238.0-238.3, 238.79, 239.0-239.4, 239.6, 239.7, 239.89, 239.9 456.0-456.2, 572.2-572.8 197.0-198.7, 198.81-190.9, 192.0-196.9, 199.0 042
Dementia Chronic pulmonary disease Rheumatologic disease Mild liver disease* Diabetes with chronic complications Hemiplegia or paraplegia Renal disease Any malignancy, including leukemia and lymphoma*
Moderate or severe liver disease* Metastatic solid tumor* AIDS/HIV
HIV, human immunodeficiency virus. * The following comorbidities were mutually exclusive: mild and moderate or severe liver disease and any malignancy and metastatic solid tumor.
