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Clinical research study| Volume 129, ISSUE 3, P315-323.e2, March 2016

Association Between Anemia, Bleeding, and Transfusion with Long-term Mortality Following Noncardiac Surgery

Published:October 30, 2015DOI:https://doi.org/10.1016/j.amjmed.2015.10.012

      Abstract

      Background

      Preoperative anemia is a well-established risk factor for short-term mortality in patients undergoing noncardiac surgery, but appropriate thresholds for transfusion remain uncertain. The objective of this study was to determine long-term outcomes associated with anemia, hemorrhage, and red blood cell transfusion in patients undergoing noncardiac surgery.

      Methods

      We performed a long-term follow-up study of consecutive subjects undergoing hip, knee, and spine surgery between November 1, 2008 and December 31, 2009. Clinical data were obtained from administrative and laboratory databases, and retrospective record review. Preoperative anemia was defined as baseline hemoglobin < 13 g/dL for men and < 12 g/dL for women. Hemorrhage was defined by International Classification of Diseases, Ninth Revision coding. Data on long-term survival were collected from the Social Security Death Index database. Logistic regression models were used to identify factors associated with long-term mortality.

      Results

      There were 3050 subjects who underwent orthopedic surgery. Preoperative anemia was present in 17.6% (537) of subjects, hemorrhage occurred in 33 (1%), and 766 (25%) received at least one red blood cell transfusion. Over 9015 patient-years of follow-up, 111 deaths occurred. Anemia (hazard ratio [HR] 3.91; confidence interval [CI], 2.49-6.15) and hemorrhage (HR 5.28; 95% CI, 2.20-12.67) were independently associated with long-term mortality after multivariable adjustment. Red blood cell transfusion during the surgical hospitalization was associated with long-term mortality (HR 3.96; 95% CI, 2.47-6.34), which was attenuated by severity of anemia (no anemia [HR 4.39], mild anemia [HR 2.27], and moderate/severe anemia [HR 0.81]; P for trend .0015).

      Conclusions

      Preoperative anemia, perioperative bleeding, and red blood cell transfusion are associated with increased mortality at long-term follow-up after noncardiac surgery. Strategies to minimize anemia and bleeding should be considered for all patients, and restrictive transfusion strategies may be advisable. Further investigation into mechanisms of these adverse events is warranted.

      Keywords

      Clinical Significance
      • Preoperative anemia and perioperative bleeding are associated with increased mortality at long-term follow-up after major noncardiac surgery.
      • Red blood cell transfusion during hospitalization for noncardiac surgery was associated with long-term mortality, but the association was attenuated by the severity of preoperative anemia.
      Orthopedic surgery accounts for nearly one quarter of all operating room procedures in the US, with more than 1.5 million hip, knee, and spine surgeries performed each year.

      Steiner C, Andrews R, Barrett M, Weiss A. HCUP projections: mobility/orthopedic procedures 2003 to 2012. Report # 2012-03. U.S. Agency for Healthcare Research and Quality. Published September 20, 2012. Available at: http://www.hcup-us.ahrq.gov/reports/projections/2012-03.pdf. Accessed November 1, 2014.

      • Haralson 3rd, R.H.
      • Zuckerman J.D.
      Prevalence, health care expenditures, and orthopedic surgery workforce for musculoskeletal conditions.
      • Weiss A.J.
      • Elixhauseer A.
      Trends in Operating Room Procedures in US Hospitals, 2001–2011. HCUP Statistical Brief #171.
      Up to a third of patients undergoing orthopedic surgery have preoperative anemia,
      • Seicean A.
      • Seicean S.
      • Alan N.
      • et al.
      Preoperative anemia and perioperative outcomes in patients who undergo elective spine surgery.
      • Bierbaum B.E.
      • Callaghan J.J.
      • Galante J.O.
      • Rubash H.E.
      • Tooms R.E.
      • Welch R.B.
      An analysis of blood management in patients having a total hip or knee arthroplasty.
      a well-established risk factor for short-term mortality and cardiovascular complications in patients undergoing noncardiac surgery.
      • Seicean A.
      • Seicean S.
      • Alan N.
      • et al.
      Preoperative anemia and perioperative outcomes in patients who undergo elective spine surgery.
      • Carson J.L.
      • Duff A.
      • Poses R.M.
      • et al.
      Effect of anaemia and cardiovascular disease on surgical mortality and morbidity.
      • Carson J.L.
      • Noveck H.
      • Berlin J.A.
      • Gould S.A.
      Mortality and morbidity in patients with very low postoperative hb levels who decline blood transfusion.
      • Wu W.C.
      • Schifftner T.L.
      • Henderson W.G.
      • et al.
      Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery.
      • Beattie W.S.
      • Karkouti K.
      • Wijeysundera D.N.
      • Tait G.
      Risk associated with preoperative anemia in noncardiac surgery: a single-center cohort study.
      • Musallam K.M.
      • Tamim H.M.
      • Richards T.
      • et al.
      Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study.
      • Saager L.
      • Turan A.
      • Reynolds L.F.
      • Dalton J.E.
      • Mascha E.J.
      • Kurz A.
      The association between preoperative anemia and 30-day mortality and morbidity in noncardiac surgical patients.
      Red blood cell transfusion remains the cornerstone of treatment for anemia, and approximately one-third of orthopedic patients receive an allogeneic blood transfusion in the perioperative period.
      • Bierbaum B.E.
      • Callaghan J.J.
      • Galante J.O.
      • Rubash H.E.
      • Tooms R.E.
      • Welch R.B.
      An analysis of blood management in patients having a total hip or knee arthroplasty.
      • Vuille-Lessard E.
      • Boudreault D.
      • Girard F.
      • Ruel M.
      • Chagnon M.
      • Hardy J.F.
      Red blood cell transfusion practice in elective orthopedic surgery: a multicenter cohort study.
      • Audet A.M.
      • Andrzejewski C.
      • Popovsky M.A.
      Red blood cell transfusion practices in patients undergoing orthopedic surgery: a multi-institutional analysis.
      Despite the theoretical advantages of perioperative red blood cell transfusion, the benefits of this practice remain unproven for patients without life-threatening hemorrhage or symptomatic anemia. In a randomized trial of older patients with hip fractures and anemia, a liberal transfusion strategy using a hemoglobin threshold of <10 g/dL did not reduce the frequency of in-hospital acute coronary syndrome or death compared with a restrictive strategy using a threshold of <8 g/dL.
      • Carson J.L.
      • Terrin M.L.
      • Noveck H.
      • et al.
      FOCUS Investigators
      Liberal or restrictive transfusion in high-risk patients after hip surgery.
      Retrospective studies of red blood cell transfusion in orthopedic surgery have reported conflicting short-term findings.
      • Carson J.L.
      • Duff A.
      • Berlin J.A.
      • et al.
      Perioperative blood transfusion and postoperative mortality.
      • Pedersen A.B.
      • Mehnert F.
      • Overgaard S.
      • Johnsen S.P.
      Allogeneic blood transfusion and prognosis following total hip replacement: a population-based follow up study.
      • Glance L.G.
      • Dick A.W.
      • Mukamel D.B.
      • et al.
      Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery.
      Appropriate thresholds for perioperative transfusion in orthopedic surgery remain uncertain. Moreover, long-term outcomes associated with anemia and red blood cell transfusion following orthopedic surgery remain poorly characterized. We investigated the association between anemia, bleeding, and transfusion on long-term mortality in a large, retrospective study of patients undergoing major orthopedic surgery.

      Methods

      Study Design

      We performed a retrospective cohort study of consecutive adults undergoing knee, hip, or spine surgery between November 1, 2008 and December 31, 2009 at 2 hospitals within a large tertiary care academic medical center. The full methods have been described previously.
      • Oberweis B.S.
      • Nukala S.
      • Rosenberg A.
      • et al.
      Thrombotic and bleeding complications after orthopedic surgery.
      Clinical data were obtained from administrative, blood bank, and laboratory databases, and retrospective record review. The study was approved by the Institutional Review Board with an informed consent waiver.

      Patients and Outcomes

      Patient demographics, clinical history, and baseline comorbidities were evaluated using a hospital administrative dataset. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to identify spinal fusion (81.0x), refusion of spine (81.3x), joint replacement of lower extremity (81.5x), and other procedures on spine (81.6x). Comorbidities present on admission were determined using ICD-9 diagnosis codes, including diabetes mellitus (250.x), stroke (V12.54, 438.0-438.9), heart failure (402.01, 402.11, 402.91, 428, 428.1, 428.2, 428.22, 428.23, 428.3, 428.32, 428.33, 428.4, 428.42, 428.43, 428.9), or coronary artery disease (412, 414.x).
      Complete blood counts obtained before surgery were reviewed. Preoperative anemia was defined as baseline hemoglobin < 13 g/dL for men and < 12 g/dL for women, according to the World Health Organization definition.
      World Health Organization (WHO)
      Nutritional Anaemias. Report of a WHO Scientific Group.
      Anemia was sub-classified as mild (Hgb ≥11 g/dL), moderate (9-11 g/dL), and severe (<9 g/dL). Red blood cell transfusion during the surgical admission was abstracted from a hospital blood bank dataset. Leukocyte-reduced units of packed red blood cells comprised approximately 50% of all transfusions during the study period, but patient-level data on leukocyte reduction were not available for analysis. Postoperative hemorrhage was identified by discharge diagnosis code (998.11). Long-term mortality was determined from the Social Security Death Index database, with a query performed on July 13, 2012. Long-term survival was not available for 32 (1.0%) subjects; 7 subjects had birth dates incongruent with data from the Social Security Death Index, and 25 lacked social security numbers. These patients were excluded from the present analysis.

      Statistical Analysis

      Normally distributed continuous variables were displayed as means ± standard deviation and were compared using the Student's t test. Categorical variables were displayed as frequencies and percentages and were compared by chi-squared and Fisher's exact tests. Baseline characteristics associated with outcomes were estimated with univariate logistic regression models and reported as hazard ratios (HR) with 95% confidence intervals (CI). Time-to-event Cox proportional hazards analyses were used to examine the association among anemia, hemorrhage, transfusion, and mortality, while controlling for potential demographic, clinical, and procedural confounders. Associations between red blood cell transfusion and long-term mortality were performed with anemia as a dichotomous variable and stratified by severity. A sensitivity analysis was performed after excluding patients with hemorrhage. The likelihood ratio test was used to compare HRs for equality. Kaplan-Meier plots were generated for long-term mortality stratified by the presence of preoperative anemia and perioperative red blood cell transfusion.
      In order to control for treatment-selection bias for red blood cell transfusion, we assembled 2 equal-sized cohorts of patients with similar baseline characteristics, one with and one without perioperative red blood cell transfusion, using propensity-score matching. The propensity score is the conditional probability of a particular exposure given a set of covariates measured at baseline. Propensity scores were determined for patients who had complete data, including baseline hemoglobin values, using a logistic regression model with demographic, clinical, and procedural covariates. Matching was performed using a 1:1 protocol without replacement, with a caliper width equal to 0.2 of the standard deviation of the log odds of the estimated propensity score. Two-tailed P-values <.05 were considered to be statistically significant for all tests. Statistics were calculated using SPSS 20 (IBM SPSS Statistics, Armonk, NY) and R version 3.2.0 (R Foundation for Statistical Computing, Vienna, Austria).

      Results

      There were 3050 subjects who underwent orthopedic surgery of the spine, hip, or knee during the study period and were included in the analysis. Mean age was 60.8 years; 59% of subjects were female. Coronary artery disease was present in 10.7% of patients. Full demographic, clinical, and procedural characteristics are displayed in Table 1.
      • Lee T.H.
      • Marcantonio E.R.
      • Mangione C.M.
      • et al.
      Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery.
      Mean preoperative hemoglobin (Hgb) concentration was 13.4 ± 1.6 g/dL. Hemorrhage was coded in 33 patients (1.07%). Perioperative red blood cell transfusion was administered in 766 (25.1%) subjects. A complete blood count was obtained in 2722 subjects (89.2%) before surgery. Patients with and without preoperative hemoglobin measurements had similar postoperative bleeding, transfusion, and mortality (Supplementary Table 1, Appendix, available online).
      Table 1Baseline Characteristics
      Overall Population (n = 3050)
      Age (y), mean60.84 ± 13.25
      Female1806 (59.2)
      Race
       White1986 (65.1)
       Black433 (14.2)
       Hispanic414 (13.6)
       Other217 (7.1)
      Admission type
       Elective2876 (94.3)
       Emergency or urgent surgery174 (5.7)
      Procedure
       Spine1144 (37.5)
       Knee992 (32.5)
       Hip914 (30.0)
      RCRI score
      • Lee T.H.
      • Marcantonio E.R.
      • Mangione C.M.
      • et al.
      Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery.
       Coronary artery disease326 (10.7)
       Heart failure86 (2.8)
       Stroke/transient ischemic attack18 (0.6)
       Creatinine > 2 mg/dL15 (0.6)
       Diabetes mellitus445 (14.6)
      Hemoglobin, mean (SD)13.4 ± 1.6
      Anemia537 (17.6)
      RCRI = Revised Cardiac Risk Index.
      Mean follow-up was 3.0 ± 0.5 years following surgery. During 9015 patient-years of follow-up, 111 (3.6%) deaths occurred, with 53 (48%) deaths within 12 months of surgery and 37 (33%) deaths between 12 and 24 months. Subjects who died during follow-up were older, more likely to be male, had lower body mass index, greater burden of cardiovascular risk factors, and were more likely to have undergone urgent or emergent surgery. Univariate associations with mortality are displayed in Table 2.
      Table 2Univariate Analysis of Baseline Characteristics, Procedural Risk Factors, and Long-Term Mortality
      Death (n = 111)No Death (n = 2939)Univariate Analysis
      Odds Ratio (95% CI)P-Value
      Age (y), mean69.71 ± 15.460.51 ± 13.01.06 (1.04-1.08)<.001
      Female54 (48.6)1752 (59.6)0.64 (0.44-0.94).014
      Race
       White82 (73.9)1904 (64.8)1
       Black8 (7.2)425 (14.5)0.44 (0.21-0.91).03
       Hispanic12 (10.8)402 (13.7)0.69 (0.38-1.28).39
       Other9 (8.1)208 (7.1)1.01 (0.50-2.03).68
      Admission type
       Elective65 (58.6)2811 (95.6)1
       Emergency or urgent surgery46 (41.4)128 (4.4)15.54 (10.24-23.59)<.001
      Procedure
       Spine50 (45.0)1094 (37.2)1
       Knee19 (17.1)973 (33.1)0.43 (0.25-0.73).002
       Hip42 (37.8)872 (29.7)1.05 (0.69-1.60).81
      RCRI score
       Coronary artery disease27 (24.3)299 (10.2)2.84 (1.81-4.45)<.001
       Heart failure18 (16.2)68 (2.3)8.17 (4.67-14.29)<.001
       Stroke/transient ischemic attack2 (1.8)16 (0.5)3.35 (0.76-14.7).14
       Creatinine > 2 mg/dL3 (2.7)12 (0.4)6.95 (1.93-25.08).015
       Diabetes mellitus26 (23.4)419 (14.3)1.84 (1.17-2.90).01
      Hemoglobin (g/dL)11.9 ± 1.913.5 ± 1.50.53 (0.47-0.60)<.001
      Preoperative anemia
       None38 (40.0%)2147 (81.7%)1
       Mild anemia27 (28.4%)373 (14.2%)4.09 (2.47-6.78)<.001
       Moderate anemia25 (26.3%)96 (3.7%)14.71 (8.54-25.36)<.001
       Severe anemia5 (5.3%)11 (0.4%)25.68 (8.51-77.52)<.001
       Baseline Hgb not available16 (14.4%)312 (10.6%)
      Blood transfusion (any)71 (64.0)695 (23.6)5.57 (3.78-8.20)<.001
      Blood transfusion (within 48 h of surgery)
       None51 (45.9)2414 (81.4)1
       1U Packed red blood cells21 (18.9)198 (6.7)4.87 (2.93-8.09)<.001
       2U Packed red blood cells15 (13.5)173 (5.9)4.00 (2.25-7.11)<.001
       3+U packed red blood cells24 (21.6)179 (6.0)6.10 (3.75-9.90)<.001
      Hemorrhage (ICD-9 coded)7 (6.3)26 (0.9)7.27 (3.38-15.64)<.001
      CI = confidence interval; ICD-9 = International Classification of Diseases, Ninth Revision; RCRI = Revised Cardiac Risk Index.
      Preoperative anemia was present in 17.6% (537) of subjects overall (19.7% of subjects with preoperative hemoglobin measurements recorded). Age, sex, and multiple cardiovascular risk factors were significantly associated with baseline anemia in multivariable analysis (Table 3). Among patients with anemia at baseline, long-term mortality was higher than in those without preoperative anemia (10.6% vs 1.7%, P < .001). After adjusting for demographic and clinical variables in multivariable models, anemia at baseline remained independently associated with long-term mortality (HR 3.91; 95% CI, 2.49-6.15). The severity of preoperative anemia was also associated with long-term mortality, with mild (6.8%, adjusted HR 3.30; 95% CI, 1.97-5.53), moderate (20.7%, adjusted HR 4.63; 95% CI, 2.52-8.49), and severe (31.3%, adjusted HR 9.15; 95% CI, 3.37-25.82) anemia demonstrating an incremental hazard for mortality after multivariable adjustment (P for trend ≤ .001) (Table 4). Kaplan-Meier curves of long-term survival by degree of preoperative anemia are shown in Figure 1.
      Table 3Multivariate Odds of Anemia, Hemorrhage, and Transfusion Adjusted for Baseline Cardiovascular Risk Factors
      Odds Ratio (95% Confidence Interval)
      AnemiaP-ValueMajor BleedingP-ValueTransfusionP-Value
      Age (y), mean1.02 (1.01-1.03)<.0011.01 (0.98-1.04).531.02 (1.01-1.03)<.001
      Female1.39 (1.12-1.73).0031.10 (0.51-2.37).791.84 (1.50-2.25)<.001
      Admission type
       Urgent or emergent3.07 (2.14-4.40)<.0011.49 (0.50-4.41).473.06 (2.13-4.40)<.001
      Procedure
       Spine111
       Knee0.92 (0.72-1.18).300.07 (0.01-0.55).011.00 (0.80-1.28).99
       Hip0.89 (0.69-1.15).420.81 (0.37-1.78).591.56 (1.24-1.96)<.001
      RCRI
       Coronary artery disease1.97 (1.47-2.66)<.0015.70 (2.40-13.60)<.0012.33 (1.76-3.10)<.001
       Heart failure1.70 (0.99-2.93).064.05 (1.22-13.39).012.04 (1.18-3.52).01
       Stroke/transient ischemic attack1.81 (0.58-5.65).31-1.004.64 (1.35-15.97).02
       CKD (Cr > 2 mg/dL)9.09 (2.96-27.90)<.001-1.008.60 (2.61-28.28)<.001
       Diabetes mellitus1.77 (1.36 -2.29)<.0010.38 (0.11-1.36).141.13 (0.88-1.46).34
      CKD = chronic kidney disease; RCRI = Revised Cardiac Risk Index.
      Table 4Multivariate Cox Proportional Hazards Regression Analysis of Anemia and Long-Term Mortality
      Mild AnemiaModerate AnemiaSevere AnemiaAny Anemia
      Hazard Ratio (95% CI)P-ValueHazard Ratio (95% CI)P-ValueHazard Ratio (95% CI)P-ValueHazard Ratio (95% CI)P-Value
      Unadjusted3.97 (2.43-6.51)<.00113.39 (8.08-22.18)<.00124.64 (9.70-62.63)<.0016.43 (4.26-9.69)<.001
      Adjusted for age, sex, race3.33 (2.02-5.48)<.0019.96 (5.86-16.91)<.00121.53 (8.38-55.27)<.0015.13 (3.37-7.82)<.001
      Adjusted for age, sex, race, admission type, procedure3.13 (1.90-5.16)<.0014.95 (2.78-8.84)<.0019.10 (3.39-24.40)<.0013.82 (2.48-5.89)<.001
      Multivariable adjusted
      Adjusted for age, sex, race, admission type (elective vs emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      3.30 (1.97-5.53).0014.63 (2.52-8.49)<.0019.15 (3.37-24.81)<.0013.91 (2.49-6.15)<.001
      Adjusted for age, sex, race, admission type (elective vs emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      Figure thumbnail gr1
      Figure 1Preoperative anemia and long-term mortality following surgery.
      Perioperative hemorrhage occurred in 33 subjects (1.1%), and was more common among patients with preoperative anemia (2.8% vs 0.6%, P < .001; multivariable adjusted HR 3.29; 95% CI, 1.45-7.46). Perioperative hemorrhage was associated with substantially higher long-term mortality than subjects without hemorrhage (21.2% vs 3.4%, P < .001), and a significant hazard for mortality after multivariable adjustment (HR 5.28; 95% CI, 2.20-12.67) (Table 5).
      Table 5Association Between Anemia, Bleeding, Transfusion and Long-Term Mortality
      n (%)Long-Term MortalityMultivariate Analysis
      Multivariate Cox proportional hazards regression analysis adjusted for age, sex, race, admission type (elective vs emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/ transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      Hazard Ratio (95% CI)P-Value
      Anemia537 (19.7%
      Excluding patients without preoperative hemoglobin values.
      /17.6%)
      57 (10.6%)3.91 (2.49-6.15)<.001
      No anemia2185 (80.3%
      Excluding patients without preoperative hemoglobin values.
      /71.6%)
      38 (1.7%)
      Hemorrhage33 (1.1%)7 (21.2%)5.28 (2.20-12.66)<.001
      No hemorrhage3017 (98.9%)104 (3.4%)
      Transfusion766 (25.1%)71 (9.3%)3.96 (2.47-6.34)<.001
      No transfusion2284 (74.9%)40 (1.8%)
      Multivariate Cox proportional hazards regression analysis adjusted for age, sex, race, admission type (elective vs emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/ transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      Excluding patients without preoperative hemoglobin values.
      During the surgical hospitalization, 766 (25.1%) subjects received at least one red blood cell transfusion, with 606 subjects transfused within the first 48 hours of surgery. Patients who required red blood cell transfusion during their hospitalization had an increased long-term mortality (9.3% vs 1.8%, P < .001 for transfusion overall), and red blood cell transfusion was more common in those who died during follow-up (64.0% vs 23.7%, P < .001 for transfusion overall). Findings were similar for patients who received red blood cell transfusion within 48 hours of surgery. Kaplan-Meier curves of long-term survival by red blood cell transfusion are shown in Figure 2. Red blood cell transfusion was associated with a significant hazard for mortality after multivariable adjustment (HR 3.96; 95% CI, 2.47-6.34) (Table 5). When stratified by severity of anemia at baseline, red blood cell transfusion in patients with the highest preoperative hemoglobin was associated with the greatest degree of hazard for mortality after multivariable adjustment. The association between red blood cell transfusion and long-term mortality was attenuated by the severity of anemia (Table 6). Similar findings were observed for red blood cell transfusion administered within 48 hours of surgery (data not shown) and after the exclusion of patients with hemorrhage (Supplementary Table 2, Appendix, available online). In the propensity-matched cohort of 1108 patients, red blood cell transfusion was also associated with significantly higher 1-year (3.2% vs 0.4%, P = .0007) and long-term mortality (6.3% vs 2.5%, P = .002) (Supplementary Table 3, Supplementary Figure [Appendix, available online]).
      Figure thumbnail gr2
      Figure 2Red blood cell transfusion (RBCT) and long-term mortality following surgery.
      Table 6Association Between Red Blood Cell Transfusion and Long-Term Mortality Stratified by Severity of Baseline Anemia
      Long-Term Mortality n (%)Multivariate Analysis
      Adjusted for age, sex, race, admission type (elective vs emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      Hazard Ratio (95% CI)
      P for trend = .0015.
      P-Value
      Moderate/Severe anemia
       Red blood cell transfusion26/105 (24.8%)0.81 (0.24-2.73)0.73
       No transfusion4/32 (12.5%)
      Mild anemia
       Red blood cell transfusion20/185 (10.8%)2.27 (0.86-6.04)0.10
       No transfusion7/215 (3.3%)
      No anemia
       Red blood cell transfusion18/400 (4.5%)4.39 (2.14-8.98)<.001
       No transfusion20/1785 (1.1%)
      Adjusted for age, sex, race, admission type (elective vs emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      P for trend = .0015.

      Discussion

      In this large, retrospective study of patients undergoing orthopedic surgery, we demonstrate a strong association between preoperative hemoglobin, anemia, and long-term mortality that persisted after adjustment for demographic and clinical variables. Even mild anemia was associated with a threefold increased hazard for long-term mortality. In multivariable adjusted models, red blood cell transfusion was associated with long-term mortality, with the greatest hazard among patients with higher preoperative hemoglobin values. In contrast, red blood cell transfusion was not associated with mortality in patients with the lowest preoperative hemoglobin levels.
      The findings of the present study are consistent with data on the risks of preoperative anemia and in-hospital and 30-day outcomes. In a retrospective study of 1958 patients undergoing noncardiac surgery who refused transfusion, there was a strong association between preoperative hemoglobin and 30-day mortality, with substantially greater risks in patients with comorbid cardiovascular disease.
      • Carson J.L.
      • Duff A.
      • Poses R.M.
      • et al.
      Effect of anaemia and cardiovascular disease on surgical mortality and morbidity.
      Subsequent large retrospective studies of patients undergoing major noncardiac surgery confirmed these findings.
      • Seicean A.
      • Seicean S.
      • Alan N.
      • et al.
      Preoperative anemia and perioperative outcomes in patients who undergo elective spine surgery.
      • Carson J.L.
      • Noveck H.
      • Berlin J.A.
      • Gould S.A.
      Mortality and morbidity in patients with very low postoperative hb levels who decline blood transfusion.
      • Wu W.C.
      • Schifftner T.L.
      • Henderson W.G.
      • et al.
      Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery.
      • Beattie W.S.
      • Karkouti K.
      • Wijeysundera D.N.
      • Tait G.
      Risk associated with preoperative anemia in noncardiac surgery: a single-center cohort study.
      • Musallam K.M.
      • Tamim H.M.
      • Richards T.
      • et al.
      Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study.
      • Saager L.
      • Turan A.
      • Reynolds L.F.
      • Dalton J.E.
      • Mascha E.J.
      • Kurz A.
      The association between preoperative anemia and 30-day mortality and morbidity in noncardiac surgical patients.
      In an analysis of noncardiac surgery from the Department of Veterans Affairs National Surgical Quality Improvement Program database, a 1.6% increase in 30-day mortality was associated with each percentage point deviation of hematocrit below the normal range.
      • Wu W.C.
      • Schifftner T.L.
      • Henderson W.G.
      • et al.
      Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery.
      In the subgroup of patients who underwent orthopedic surgery, anemia was associated with an even greater short-term mortality. Thus, even mild preoperative anemia is implicated in adverse outcomes after surgery. In the present study, we demonstrate durable associations between preoperative anemia and mortality at 3 years of follow-up. The mechanism of this association remains uncertain, although it may be related to underlying systemic disease, inflammation, inadequate oxygen delivery leading to organ dysfunction during periods of stress, or a combination of factors.
      The effect of perioperative transfusion and outcomes has been subject to much controversy. Since the first successful human blood transfusion in 1818, red blood cell transfusions have become the standard of care in the management of anemia in patients undergoing surgery.
      • Blundell J.
      Experiments on the transfusion of blood by the syringe.
      In fact, 40%-70% of all red cell units are transfused in the perioperative setting given the prevalence of anemia and the risks of bleeding after surgery.
      • Wells A.W.
      • Mounter P.J.
      • Chapman C.E.
      • Stainsby D.
      • Wallis J.P.
      Where does blood go? Prospective observational study of red cell transfusion in north england.
      • Whitaker B.
      • Schlumpf K.
      • Schulman J.
      • Green J.
      Report of the US Department of Health and Human Services. The 2009 National Blood Collection and Utilization Survey Report.
      Still, transfusion targets and the effects of allogeneic red blood cells in the perioperative period remain uncertain. To date, only one large randomized trial of patients undergoing noncardiac surgery has been powered to evaluate the effect of optimal transfusion targets on mortality. The Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial randomized 2016 older patients (mean age 81.6 years) undergoing hip fracture repair with anemia (Hgb < 10 g/dL) and cardiovascular disease or risk factors to a liberal (Hgb < 10 g/dL) or restrictive (Hgb < 8 g/dL) transfusion strategy.
      • Carson J.L.
      • Terrin M.L.
      • Noveck H.
      • et al.
      FOCUS Investigators
      Liberal or restrictive transfusion in high-risk patients after hip surgery.
      Although patients in the liberal transfusion arm were more likely to receive red blood cell transfusion (96.7% vs 41.0%), there were no differences in the occurrence of acute coronary syndrome or short-term mortality between the 2 groups, and there was no compelling evidence to support higher transfusion targets.
      • Carson J.L.
      • Terrin M.L.
      • Noveck H.
      • et al.
      FOCUS Investigators
      Liberal or restrictive transfusion in high-risk patients after hip surgery.
      These findings are consistent with large randomized trials of transfusion targets in critically ill, nonsurgical populations.
      • Hebert P.C.
      • Wells G.
      • Blajchman M.A.
      • et al.
      A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion requirements in critical care investigators, canadian critical care trials group.
      • Holst L.B.
      • Haase N.
      • Wetterslev J.
      • et al.
      The TRISS Trial Group, Scandinavian Critical Care Trials Group
      Lower versus higher hemoglobin threshold for transfusion in septic shock.
      Observational studies of the effects of transfusion in patients undergoing noncardiac surgery have reported conflicting findings. Multiple orthopedic surgery studies report that red blood cell transfusions are associated with approximately twofold higher short-term mortality compared with nontransfused patients.
      • Pedersen A.B.
      • Mehnert F.
      • Overgaard S.
      • Johnsen S.P.
      Allogeneic blood transfusion and prognosis following total hip replacement: a population-based follow up study.
      • Glance L.G.
      • Dick A.W.
      • Mukamel D.B.
      • et al.
      Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery.
      • Karkouti K.
      • Stukel T.A.
      • Beattie W.S.
      • et al.
      Relationship of erythrocyte transfusion with short- and long-term mortality in a population-based surgical cohort.
      In a propensity-matched analysis of a large claims database of patients undergoing noncardiac surgery, red blood cell transfusion was also associated with a greater-than twofold increase in 30-day perioperative stroke and myocardial infarction.
      • Whitlock E.L.
      • Kim H.
      • Auerbach A.D.
      Harms associated with single unit perioperative transfusion: retrospective population based analysis.
      A large, retrospective multicenter study of 162,190 patients undergoing orthopedic procedures demonstrated that patients who received perioperative transfusion had higher 30-day (HR 2.32; 95% CI, 1.91-2.83) and 1-year (HR 1.75; 95% CI, 1.60-1.91) mortality after multivariable adjustment.
      • Karkouti K.
      • Stukel T.A.
      • Beattie W.S.
      • et al.
      Relationship of erythrocyte transfusion with short- and long-term mortality in a population-based surgical cohort.
      However, when participating hospitals were categorized by hospital-specific rates of perioperative transfusion (ranging from 10.3% to 57.9%), surgeries performed at centers with the highest transfusion rates were not associated with an increased mortality after multivariable adjustment, raising questions as to whether anemia requiring transfusion is simply a proxy for the burden of unmeasured confounders that may underlie observed associations between transfusion and mortality. Furthermore, a separate retrospective cohort study of 8787 older adults undergoing orthopedic surgery for hip fracture found no association between perioperative transfusion in patients with hemoglobin levels ≥ 8 g/dL and 30- or 90-day mortality after adjusting for nadir hemoglobin and other risk factors.
      • Carson J.L.
      • Duff A.
      • Berlin J.A.
      • et al.
      Perioperative blood transfusion and postoperative mortality.
      Based on the totality of data from studies of perioperative and critically ill populations, current guidelines recommend lower hemoglobin values (6-8 g/dL) as thresholds for red blood cell transfusion.
      American Society of Anesthesiologists Task Force on Perioperative Blood T, Adjuvant T
      Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American society of anesthesiologists task force on perioperative blood transfusion and adjuvant therapies.
      • Carson J.L.
      • Grossman B.J.
      • Kleinman S.
      • et al.
      Clinical Transfusion Medicine Committee of the AABB
      Red blood cell transfusion: a clinical practice guideline from the AABB*.
      The findings of the present study are consistent with previous reports that red blood cell transfusion has a narrow therapeutic window and may be independently associated with an increased hazard for perioperative stroke, myocardial infarction, and mortality. We identified the greatest hazard for mortality associated with transfusions in patients who had the highest preoperative hemoglobin levels. Red blood cell transfusion had no significant effect on mortality among patients with baseline anemia. Thus, restrictive transfusion strategies may be most appropriate for patients without preoperative anemia who undergo orthopedic surgery.
      Plausible mechanisms exist to explain the observed hazard associated with transfusion. Red blood cell transfusion can result in transfusion-induced immunomodulation related to the infusion of cytokines, allogeneic leukocytes, and other bioactive compounds. Immunomodulation has been postulated to cause aberrant immune activity that may be detrimental.
      • Vamvakas E.C.
      • Blajchman M.A.
      Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction?.
      Transfusion has been associated with an increased risk of serious infection in multiple clinical settings. In a systematic review of randomized trials of patients undergoing orthopedic surgery, restrictive red blood cell transfusion strategies were associated with a reduced hazard for acute health care-associated infections (HR 0.70; 95% CI, 0.54-0.91).
      • Rohde J.M.
      • Dimcheff D.E.
      • Blumberg N.
      • et al.
      Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis.
      Platelet aggregation may be another unintended consequence of transfusion.
      • Silvain J.
      • Abtan J.
      • Kerneis M.
      • et al.
      Impact of red blood cell transfusion on platelet aggregation and inflammatory response in anemic coronary and noncoronary patients: the transfusion-2 study (impact of transfusion of red blood cell on platelet activation and aggregation studied with flow cytometry use and light transmission aggregometry).
      Administration of packed red blood cells is associated with increased platelet reactivity in healthy volunteers, although increased incidence of thrombotic events has not been observed in randomized trials of transfusion targets.
      • Silvain J.
      • Abtan J.
      • Kerneis M.
      • et al.
      Impact of red blood cell transfusion on platelet aggregation and inflammatory response in anemic coronary and noncoronary patients: the transfusion-2 study (impact of transfusion of red blood cell on platelet activation and aggregation studied with flow cytometry use and light transmission aggregometry).
      Finally, risks of transfusion may not be uniform among all units of blood. Stored red cells undergo structural and functional changes over time, with nitric oxide depletion and increased adhesion to the vascular endothelium potentially impairing microvascular function.
      • Rao S.V.
      • Califf R.M.
      Is old blood bad blood?.
      • Koch C.G.
      • Li L.
      • Sessler D.I.
      • et al.
      Duration of red-cell storage and complications after cardiac surgery.
      Further studies are necessary to fully understand the mechanisms of adverse outcomes associated with red blood cell transfusions.
      There are a number of limitations to this study. First, this is a retrospective observational study of consecutive orthopedic surgeries. All surgeries were conducted over a short 1-year time period, minimizing the effect of changes to routine health care practices. Medical comorbidities and clinical variables were identified through hospital databases, and unmeasured confounders and misclassification bias cannot be excluded. Second, preoperative hemoglobin measurements were performed at the discretion of providers, and data were available for 89.3% of patients. Nonetheless, outcomes of hemorrhage, transfusion, and mortality were similar between the groups. Nadir hemoglobin levels and estimates of intraoperative blood losses were not evaluated. Prior studies suggest that the benefits of perioperative transfusion may be limited to patients with > 500 mL of operative blood loss.
      • Wu W.C.
      • Smith T.S.
      • Henderson W.G.
      • et al.
      Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery.
      Third, the administration of red blood cell transfusion was determined by the treating physicians. Standardized transfusion thresholds were not enforced. Distinctions between allogeneic and autologous red blood cells were not available, nor was the duration of blood cell storage before transfusion. Fourth, medical management therapy was not recorded. Therefore, the long-term impact of bleeding and transfusion on antiplatelet or anticoagulant therapy prescribing could not be assessed. Fifth, hemoglobin values were not available during follow-up, and the association between long-term hemoglobin trends and mortality could not be assessed. Consequently, we were unable to identify the precise mechanisms through which preoperative anemia was associated with long-term adverse outcomes. However, worsening anemia during long-term follow-up may have impaired the function of other organ systems or adversely impacted the delivery of life-saving medical and surgical interventions during follow-up. Finally, causes of death were not available for analysis and adjudication of outcomes was not performed.
      In conclusion, among patients undergoing major noncardiac surgery, preoperative anemia, bleeding, and red blood cell transfusion are associated with increased mortality at long-term follow-up. Strategies to minimize preoperative anemia and surgical bleeding should be considered for all patients. Restrictive transfusion strategies may be advisable in the absence of a compelling clinical indication for transfusion. Further investigation into mechanisms of adverse events associated with erythrocyte transfusion and trials to improve perioperative outcomes are needed.

      Acknowledgment

      Berger was partially funded by Grant RO1HL114978 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, and Grant 13CRP14410042 from the American Heart Association Clinical Research Program. The authors report no relevant disclosures or conflicts of interest.

      Appendix

      Supplementary Table 1The Association Between Preoperative Hemoglobin Measurement and Bleeding, Transfusion, and Mortality
      Overall Population (n = 3050)Preoperative Hemoglobin Measured (n = 2722)No Preoperative Hemoglobin Measured (n = 328)P-Value
      Outcomes
       Hemorrhage33 (1.1)29 (1.1)4 (1.2).79
       Transfusion766 (25.0)694 (25.3)76 (23.2).37
       Death111 (3.6)95 (3.5)16 (4.8).20
      Supplementary Table 2Association Between Red Blood Cell Transfusion and Long-Term Mortality Stratified by Severity of Anemia, Excluding Patients with Hemorrhage
      Long-Term Mortality, n (%)Multivariate Analysis
      Adjusted for age, sex, race, admission type (elective vs. emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      Hazard Ratio (95% CI)P-Value
      Moderate/severe anemia
       Red blood cell transfusion25/102 (24.5%)1.96 (0.61-5.05).16
       No red blood cell transfusion3/31 (9.7%)
      Mild anemia
       Red blood cell transfusion17/176 (9.7%)2.29 (0.91-5.75).08
       No red blood cell transfusion7/214 (3.3%)
      No anemia
       Red blood cell transfusion18/390 (4.6%)4.17 (2.05-8.48)<.001
       No red blood cell transfusion20/1781 (1.1%)
      Adjusted for age, sex, race, admission type (elective vs. emergency/urgent surgery), procedure, coronary artery disease, heart failure, stroke/transient ischemic attack, creatinine > 2 mg/dL, diabetes mellitus.
      Supplementary Table 3Baseline Characteristics of Patients with and Without Perioperative RBCT, Pre- and Postpropensity Score Matching
      PrematchingPostmatching
      No RBCT (n = 2284)RBCT (n = 766)P-ValueNo RBCT (n = 554)RBCT (n = 554)P-Value
      Age (y), mean59.4 ± 12.865.3 ± 13.6<.00164.1 ± 12.463.3 ± 13.4.26
      Female1280 (56.0)526 (68.7)<.001373 (67.3)370 (66.8).85
      Race
       White1470 (64.4)516 (67.4).03370 (66.8)373 (67.3).12
       Black327 (14.3)106 (13.8)72 (13.0)83 (15.0)
       Hispanic336 (14.7)78 (10.2)74 (13.4)47 (8.5)
       Other151 (6.6)66 (8.6)38 (6.9)51 (9.2)
      Admission type
       Elective2206 (96.6)670 (87.5)<.001511 (92.2)506 (91.3).58
       Emergency or urgent surgery78 (3.4)96 (12.5)43 (7.8)48 (8.7)
      Procedure
       Spine908 (39.8)236 (30.8)<.001169 (30.5)189 (34.1).27
       Knee757 (33.1)325 (30.7)194 (35.0)171 (30.9)
       Hip619 (27.1)295 (38.5)191 (34.5)194 (35.0)
      RCRI score
       Coronary artery disease182 (8.0%)144 (18.8)<.00184 (15.2)85 (15.3).93
       Heart failure35 (1.5)51 (6.7)<.00120 (3.6)21 (3.8).87
       Stroke/transient ischemic attack6 (0.3)12 (1.6)<.0014 (0.7)5 (0.9).74
       Creatinine > 2 mg/dL4 (0.2)11 (1.6)<.0014 (0.7)3 (0.5).71
       Diabetes mellitus300 (13.1)145 (18.9)<.00190 (16.2)92 (16.6).87
      Anemia247 (12.2)290 (42.0)<.001152 (27.4)176 (31.8).11
      Perioperative hemorrhage7 (0.3)26 (3.4)<.0015 (0.9)9 (1.6).28
      RBCT = red blood cell transfusion; RCRI = Revised Cardiac Risk Index.
      Figure thumbnail fx1
      Supplementary FigureRed blood cell transfusion (RBCT) and long-term mortality following surgery in the propensity-matched cohort.

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      Linked Article

      • Assessing Association Among Anemia, Bleeding, and Transfusion with Long-Term Mortality
        The American Journal of MedicineVol. 129Issue 9
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          In the recent article by Smilowitz et al,1 the multivariate Cox proportional hazards regression analysis shows that preoperative anemia, perioperative bleeding, and red blood cell transfusion are associated with increased long-term mortality after orthopedic surgery. The available literature suggests that postoperative long-term mortality of patients undergoing orthopedic surgery primarily represents the natural history of aging and comorbidities.2 This study adjusted several comorbidities included in the revised cardiac risk index, but other preoperative comorbidities affecting postoperative mortality, such as hypertension, peripheral vascular disease, chronic obstructive pulmonary disease, liver disease, dementia, and malignant disease, were not included in adjusted confounders.
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