Morbidity of Bleeding After Cardiac Surgery: Is It Blood Transfusion, Reoperation for Bleeding, or Both?

ORIGINAL ARTICLES: ADULT CARDIAC

ADULT CARDIAC SURGERY: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. ADULT CARDIAC

Morbidity of Bleeding After Cardiac Surgery: Is It Blood Transfusion, Reoperation for Bleeding, or Both? Alessandro Vivacqua, MD, Colleen G. Koch, MD, MBA, Arshad M. Yousuf, MD, Edward R. Nowicki, MD, MS, Penny L. Houghtaling, MS, Eugene H. Blackstone, MD, and Joseph F. Sabik III, MD Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Department of Cardiothoracic Anesthesiology and Outcomes Research, Anesthesiology Institute, and Department of Quantitative Health Sciences, Research Institute, Cleveland Clinic, Cleveland, Ohio

Background. Etiology for increased morbidity in patients (2% to 8%) undergoing reoperation for bleeding after cardiac surgery is unclear. Recent work suggests that it may be related to red-cell transfusion, but what role does reoperation itself play? We sought to determine prevalence of and risk factors for reoperation for bleeding, separate the effect of reoperation from that of transfusion on hospital mortality and major morbidity, and identify the source of bleeding. Methods. From January 1, 2000 to January 1, 2010, 18,891 primary and repeat coronary artery bypass grafting, valve, or combined operations were performed. Risk factors for reoperation were identified by multivariable logistic regression. Hospital mortality and major morbidity were compared in propensity-matched patients requiring reoperation and not. Medical records from 2005 to 2010 were reviewed to determine bleeding source. Results. A total of 566 patients (3.0%) underwent reoperation for bleeding, with considerable variability over

time. Risk factors included older age, higher acuity, greater comorbidity, aortic valve surgery, longer myocardial ischemic and cardiopulmonary bypass durations, and surgeon. Mortality was higher for propensitymatched patients requiring reoperation; 8.5% (68% confidence interval [CI] 7.3% to 9.9%) versus 1.8% (CI 1.2% to 2.5%). Both greater transfusion and reoperation were independently associated with increased risk of mortality and major morbidity. At reoperation, technical factors (74%), coagulopathy (13%), both (10%), or other (3.3%) causes were responsible for bleeding. Conclusions. Transfusion and reoperation for bleeding both contribute to postoperative mortality and morbidity. Technical reasons are at the root of most bleeding, emphasizing a major focus for process improvement to minimize need for reoperation and blood use.

R

Therefore, primary objectives of this investigation were to determine time-related prevalence of reoperation for bleeding after cardiac surgery, to identify its risk factors, and to assess its association with postoperative morbidity while considering the concomitant risks of transfusion. Our secondary objective was to review source of postoperative bleeding found at reoperation.

eoperation for bleeding, estimated to occur in 2% to 8% of cardiac surgical patients, is an undesirable event associated with increased patient morbidity, mortality, and resource utilization [1– 6]. A recent investigation in coronary artery bypass grafting (CABG) revealed a 2.4% prevalence of reoperation for bleeding with an associated risk-adjusted mortality of 5.9%, compared with 2.0% for patients not returning to the operating room. Not surprisingly, those requiring reoperation received substantially more red blood cell (RBC) transfusions and component therapy [1]. Because of this linkage between reoperation and transfusion requirements, quantifying separate effects on outcomes is challenging.

Accepted for publication March 15, 2011. Address correspondence to Dr Koch, Cleveland Clinic, 9500 Euclid Ave/J4-245, Cleveland, OH 44195; e-mail: [email protected].

© 2011 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2011;91:1780 –90) © 2011 by The Society of Thoracic Surgeons

Patients and Methods Patients and Data From January 2000 to January 2010, 18,752 patients underwent 18,891 CABG, isolated valve, or combined CABG Dr Sabik discloses that he has financial relationships with Edwards Lifesciences, Medtronic, and ValvExchange.

0003-4975/$36.00 doi:10.1016/j.athoracsur.2011.03.105

and valve operations (primary and reoperation) at Cleveland Clinic. Demographics, comorbidities, and perioperative variables were prospectively abstracted into the Cardiovascular Information Registry, which is approved for use in research by our Institutional Review Board, with patient consent waived. Operative notes for each reoperation for bleeding were reviewed for the most recent 5-year cohort (January 1, 2005 to January 1, 2010) to identify the source of bleeding. Bleeding was defined as surgical if a localized source was identified.

Endpoints Reoperation for bleeding was defined as return to the operating room for bleeding or tamponade after admission to the intensive care unit (ICU) after surgery. Decision to reoperate was made by staff surgeons and generally depended on chest tube drainage rate, sudden increase in chest tube output, total drainage, and hemodynamic status. Outcomes included hospital mortality, prolonged postoperative ventilatory support greater than 24 hours, renal failure requiring hemodialysis, stroke, and deep sternal wound infection as defined by the Society of Thoracic Surgeons National Adult Cardiac Surgery Database; http:// www.ctsnet.org/file/rptDataSpecifications252_1_For VendorsPGS.pdf. Major morbidity composite endpoint included these morbidities (other than death) plus deep sternal wound infection and reoperation for nonbleeding indication. Resource utilization was characterized by length of ICU and postoperative stay.

Statistical Methods PREVALENCE AND TRENDS. Temporal trend of reoperation for bleeding used Loess nonparametric regression [7]. RISK FACTORS FOR REOPERATION. Multivariable logistic regression analysis using variables listed in Table 1 was performed to identify risk factors for reoperation for bleeding. Variable selection used bagging with automated analysis of 500 resampled datasets, stepwise variable entry, and retention criterion of p ⫽ 0.05 [8]. Variables appearing in 50% or more of these analyses were considered reliable risk factors at p (2-sided) are equal to 0.05 or less. OUTCOMES COMPARISON. This parsimonious risk-factor model was augmented with variables identified in Table 1 (propensity model) and a propensity score calculated for each patient. Patients undergoing reoperation for bleeding were propensity matched to patients who did not [9], yielding 566 pairs (Fig 1). These were representative across the entire study group (Fig 2). RISK OF TRANSFUSION VERSUS REOPERATION. Concurrent effects of RBC transfusion and reoperation for bleeding on outcomes were examined by logistic regression models for mortality and major morbidity. These models were developed using bagging, as described in the preceding text, with reoperation for bleeding, propensity for reoperation, and transfused blood products forced into the models. Procedural interactions with New York Heart

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Association functional class, extent of coronary artery disease, and ejection fraction were tested, as were interactions between age and number of previous cardiac operations, and urgent and emergency status. SOURCE OF BLEEDING. Source of bleeding was tabulated from operative note abstraction. MISSING DATA MANAGEMENT. Mean imputation was used to impute missing data for a few variables where 10% or less of the data were missing. Missing value indicator variables were used in models to account for possibly informative missingness. PRESENTATION. Continuous variables are summarized by mean and standard deviation and categoric variables by frequency and percentage. Uncertainty is expressed by asymmetric 68% confidence intervals (CI) equivalent to ⫾1 standard error. All analyses utilized SAS statistical software (SAS v9.1; Cary, NC).

Results Prevalence and Trends Overall, 566 (3.0%; CI 2.9% to 3.1%) patients underwent reoperation for bleeding. Year-to-year prevalence varied from 2.3% in 2000 to 4.0% in 2006. A downward trend was noted in 2009, with prevalence falling to less than 2.5%.

Risk Factors for Reoperation Patients who underwent reoperation for bleeding differed considerably in demographics, acuity, noncardiac comorbidity, and operative characteristics from those who did not (Table 1). Differences included smaller body size, higher acuity, longer cardiopulmonary bypass time, certain surgeons, and operations other than isolated CABG and isolated mitral valve repair, but predictability was poor (C-statistic ⫽ 0.66; Table 2). Age was not an independent risk factor for reoperation for bleeding; however, older patients with higher acuity were more likely to require it (p ⫽ 0.006). Gender and body size interactions were found not significant (p ⬎ 0.05).

Outcomes Hospital mortality was 8.5% (CI 7.3% to 9.9%) among patients undergoing reoperation for bleeding and 1.0% (CI 0.90% to 1.1%) for those who did not. Among 566 propensity-matched patient pairs, hospital mortality, prolonged ventilation, renal failure, and postoperative length of stay were all greater for patients who underwent reoperation for bleeding than for those who did not (p ⬍ 0.0001; Table 3), but prevalences of stroke and deep sternal wound infection were similar. Intraoperative transfusion of RBCs and component therapy was similar among propensity-matched pairs; however, patients who underwent reoperation received more blood products postoperatively.

Transfusion Versus Reoperation for Bleeding Patients who received blood and underwent reoperation for bleeding had higher mortality than those

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Table 1. Patient Characteristics and Operative Details Reoperation for Bleeding Variable ADULT CARDIAC

Demography Age (years) with reoperation Without reoperation Gender male Female Race Caucasian Other BMI (kg/m⫺2) with reoperation Without reoperation Acuity NYHA functional class I II III IV Heart failure No Cardiogenic shock No Operative status Emergency Urgent Elective Inotropes No Cardiac comorbidity Coronary artery diseasec LMT disease No LAD disease No LCx disease No RCA disease No LV ejection fraction with reoperation Without reoperation Previous MI No Preoperative AF No Hypertension No Peripheral arterial disease No Reoperation No Noncardiac comorbidity Stroke No Smoking No

No. (%) or Mean ⫾ SD

p Value

566 18,325 13,351 5,540

66 ⫾ 13 65 ⫾ 12 397 (3.0) 169 (3.1)

0.0007b

16,495 2,176 539 16,711

494 (3.0) 65 (3.0) 27 ⫾ 6.1 29 ⫾ 6.1

3,320 7,762 3,151 956 4,275 14,616 150 18,741

91 (2.7) 232 (3.0) 113 (3.6) 41 (4.3) 163 (3.8) 403 (2.8) 9 (6.0) 557 (3.0)

161 5,979 12,748 951 17,939

7 (4.3) 223 (3.7) 559 (2.6) 47 (4.9) 519 (2.9)

3,144 12,778 8,014 8,684 9,544 7,040 9,832 6,788 508 16,431 7,380 11,511 603 16,476 13,640 5,251 7,661 11,230 3,672 15,219

86 (2.1) 395 (3.1) 234 (2.9) 264 (3.0) 262 (2.7) 227 (3.2) 287 (2.9) 205 (3.0) 51 ⫾ 13 50 ⫾ 12 215 (2.9) 351 (3.0) 26 (4.3) 502 (3.0) 419 (3.1) 147 (2.8) 251 (3.3) 315 (2.8) 125 (3.4) 441 (2.9)

1,512 17,379 10,728 8,045

48 (3.2) 518 (3.0) 313 (2.9) 251 (3.1)

n

a

0.8 0.9

⬍0.0001

0.04

0.0004 0.03

⬍0.0001

0.001

0.3 0.7 0.07 0.7 0.02 0.6 0.08 0.3 0.06 0.11

0.7 0.4

Continued

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Table 1. Continued Reoperation for Bleeding

COPD No Treated diabetes No Insulin-treated diabetes No Total cholesterol (mg/dL⫺1) with reoperation Without reoperation Renal disease No BUN (mg/dL⫺1) with reoperation Without reoperation Bilirubin (mg/dL⫺1) with reoperation Without reoperation Cholesterol (mg/dL⫺1) with reoperation Without reoperation Creatinine (mg/dL⫺1) with reoperation Without reoperation Creatinine clearance (mg/dL⫺1)d with reoperation Without reoperation Hematocrit (%) with reoperation Without reoperation Operative factors Procedure Isolated CABG Isolated AVR Isolated MVR Isolated MV repair AVR⫹CABG MVR⫹CABG MV repair⫹CABG Myocardial ischemic time (min) with reoperation Without reoperation CPB duration (minutes) with reoperation Without reoperation ITA use No Surgeon A B C D E F G H I J K Transfusion: intraoperative RBC No

No. (%) or Mean ⫾ SD

p Value

2,698 16,193 4,768 13,855 1,898 16,704 480 15,318 873 18,018 565 18,293 552 17,772 480 15,318 565 18,294 539 16,703 566 18,319

93 (3.4) 473 (2.9) 138 (2.9) 417 (3.0) 53 (2.8) 500 (3.0) 172 ⫾ 46 178 ⫾ 44 31 (3.6) 535 (3.0) 22 ⫾ 12 21 ⫾ 12 0.68 ⫾ 0.44 0.63 ⫾ 0.37 172 ⫾ 46 178 ⫾ 44 1.3 ⫾ 1.2 1.1 ⫾ 0.84 77 ⫾ 36 86 ⫾ 37 38 ⫾ 6.0 38 ⫾ 5.7

0.14

8,692 2,660 714 3,068 2,311 326 1,120 566 18,325 566 18,324 10,184 8,707

206 (2.4) 95 (3.6) 31 (4.3) 89 (2.9) 90 (3.9) 13 (4.0) 42 (3.8) 71 ⫾ 36 65 ⫾ 33 93 ⫾ 44 84 ⫾ 41 284 (2.8) 282 (3.2)

1,817 2,099 1,405 1,499 1,497 2,656 2,070 683 2,190 1,172 436

39 (2.1) 45 (2.1) 33 (2.3) 36 (2.4) 37 (2.5) 76 (2.9) 64 (3.1) 26 (3.8) 84 (3.8) 59 (5.0) 28 (6.4)

0.02 0.7 0.14 0.16 0.2 0.01 0.8 0.2 0.01 ⬍0.0001 ⬍0.0001

4,704 14,100

204 (4.3) 359 (2.5)

⬍0.0001

n

ADULT CARDIAC

Variable

a

0.7 0.6 0.0015 0.3 0.0004 0.007 0.001 0.005 ⬍0.0001 0.5

⬍0.0001 0.06 0.03 0.7 0.007 0.3 0.13 0.001 ⬍0.0001 0.07

Continued

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Table 1. Continued Reoperation for Bleeding Variable FFP No Platelets No Cryoprecipitate No Experience Date of operatione With reoperation Without reoperation

p Value

530 16,507 1,489 17,316 51 16,986

47 (8.9) 465 (2.8) 108 (7.3) 456 (2.6) 7 (14) 505 (3.0)

⬍0.0001

566 18,325

5.1 ⫾ 2.8 4.6 ⫾ 2.9

⬍0.0001 ⬍0.0001

0.003

a b Data available. p value refers to differences in occurrence of reoperation for categoric variables and to differences in mean values for continuous c d e ⱖ50% stenosis. Cockcroft-Gault. Years from January 1, 2000. variables.

AF ⫽ atrial fibrillation; AVR ⫽ aortic valve replacement; BMI ⫽ body mass index; BUN ⫽ blood urea nitrogen; CABG ⫽ coronary artery bypass grafting; COPD ⫽ chronic obstructive pulmonary disease; CPB ⫽ cardiopulmonary bypass; FFP ⫽ fresh frozen plasma; ITA ⫽ internal thoracic artery; LAD ⫽ left anterior descending; LCx ⫽ left circumflex; LMT ⫽ left main trunk; LV ⫽ left ventricular; MI ⫽ myocardial infarction; MV ⫽ mitral valve; MVR ⫽ mitral valve replacement; NYHA ⫽ New York Heart Association; RBC ⫽ red blood cell; RCA ⫽ right coronary artery; SD ⫽ standard deviation.

Fig 1. Mirrored histogram of propensity matched scores for reoperation for bleeding versus no reoperation for bleeding. Reoperation is displayed beneath the baseline in dark green and no reoperation above the baseline in light green. Inset: Scale reduced to depict details.

1750 1000

1500 Number of Subjects

750

1250

Number of Subjects

ADULT CARDIAC

No. (%) or Mean ⫾ SD

n

a

500 No reoperation 250

0

1000 Reoperation 250 0

3

6

9

12

15

Propensity Score (%)

750

500

250

No reoperation

0

Reoperation 0

1

2

3

4

5

6

7

8

9

10 11 12 13 14 15

Propensity Score (%)

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Fig 2. Standardized differences before and after matching for patients who underwent reoperation for bleeding versus those who did not. (AV any ⫽ aortic valve repair or replacement; AVR ⫽ aortic valve replacement; BMI ⫽ body mass index; BUN ⫽ blood urea nitrogen; CABG ⫽ coronary artery bypass grafting; COPD ⫽ chronic obstructive pulmonary disease; FFP ⫽ fresh frozen plasma; LVEF ⫽ left ventricular ejection fraction; LCx ⫽ left circumflex coronary artery; MVR ⫽ mitral valve replacement; NYHA ⫽ New York Heart Association; PAD ⫽ peripheral arterial disease; RBC ⫽ red blood cells; reop ⫽ reoperation.)

Table 2. Incremental Risk Factors for Reoperation for Bleeding Factor Demographics Older age (years) in urgent casesb Lower BMI (kg/m⫺2)c Acuity Higher NYHA class Noncardiac comorbidities Lower cholesterol (mg/dL⫺1)d Higher BUN (mg/dL⫺1)e Higher bilirubin (mg/dL⫺1) Operative Longer CPB time (min) Surgeon J B C D Procedure Off-pump CABG Isolated AVR Isolated MVR Isolated MV repair AVR CABG MVR⫹CABG MV repair⫹CABG Intercept

Estimate ⫾ SE

p Value

Reliability (%)a

0.0038 ⫾ 0.00136 0.83 ⫾ 0.12

0.006 ⬍.0001

64 92

0.12 ⫾ 0.060

0.04

56

0.34 ⫾ 0.14 0.31 ⫾ 0.11 0.23 ⫾ 0.096

0.01 0.003 0.02

72 56 63

0.0060 ⫾ 0.0013

⬍0.0001

71

0.80 ⫾ 0.15 0.96 ⫾ 0.21 0.50 ⫾ 0.13 0.48 ⫾ 0.16

⬍0.0001 ⬍0.0001 0.0001 0.003

84 86 68 58

0.68 ⫾ 0.22 0.47 ⫾ 0.13 0.26 ⫾ 0.21 0.0029 ⫾ 0.15 0.30 ⫾ 0.14 ⫺0.0045 ⫾ 0.31 0.12⫾0.18 ⫺7.0⫾0.40

0.002 0.0006 0.2 0.9 0.03 0.9 0.5 ⬍0.0001

55 81f 81 81 81 81 81

a

b Percent of times factor appeared in 500 bootstrap models. Interaction, age in nonelective cases. d e (200/cholesterol), inverse transformation. Log(BUN), natural logarithmic transformation. tion. as a reference.

f

c (25/BMI)2, inverse squared transformaCluster of operations with isolated CABG

C-statistic ⫽ .66. AVR ⫽ aortic valve replacement; BMI ⫽ body mass index; BUN ⫽ blood urea nitrogen; CABG ⫽ coronary artery bypass grafting; CPB ⫽ cardiopulmonary bypass; MV ⫽ mitral valve; MVR ⫽ mitral valve replacement; NYHA ⫽ New York Heart Association; SE ⫽ standard error.

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Table 3. Morbidity and Mortality Associated With Reoperation for Bleeding in Matched Patients Reoperation for Bleeding (n ⫽ 566) No. (%); 68% CI

Variable ADULT CARDIAC

Operative mortality Morbidity Perioperative myocardial infarction Stroke Renal failure Renal failure requiring hemodialysis Prolonged ventilation (⬎24 hours) Deep sternal wound infection Reoperation for valve dysfunction Reoperation for exclusion of valve dysfunction/graft occlusion Other noncardiac reoperation Length of stay ⬎14 days Transfusion Any intraoperative blood use RBC FFP Platelets Cryoprecipitate Any postoperative blood use RBC 0 1 2 3 ⱖ4 FFP Platelets Cryoprecipitate CI ⫽ confidence interval;

FFP ⫽ fresh frozen plasma;

No Reoperation for Bleeding (n ⫽ 566) No. (%); 68% CI

p Value

10 (1.8); 1.2–2.5

⬍0.0001

4 (0.71); 0.37–1.3 11 (1.9); 1.4–2.7 79 (14); 12–16 38 (6.7); 5.7–7.9 196 (42); 40–45 9 (1.6); 1.1–2.3 7 (1.2); 0.78–1.9 57 (10); 8.8–11

1 (0.18); 0.03–0.58 11 (1.9); 1.4–2.7 31 (5.5); 4.5–6.6 11 (1.9); 1.4–2.7 55 (12); 11–14 4 (0.71); 0.37–1.3 1 (0.18); 0.03–0.58 2 (0.35); 0.13–0.82

0.18 ⬎0.9 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.16 0.03 ⬍0.0001

65 (14); 12–16 145 (26); 24–27

6 (1.4); 0.82–2.1 67 (12); 10–13

⬍0.0001 ⬍0.0001

241 (46); 44–48 215 (38); 36–40 46 (9.0); 7.8–10 113 (20); 18–22 7 (1.4); 0.87–2.1 226 (40); 38–42 215 (38); 36–40 351 (62) 73 (13) 80 (14) 15 (2.6) 47 (8.3) 54 (9.5); 8.3–11 64 (11); 10–13 8 (1.4); 0.93–2.1

0.6 0.5 0.9 0.7 ⬎0.9 ⬍0.0001 ⬍0.0001

48 (8.5); 7.3–9.8

234 (45); 42–47 204 (36); 34–38 47 (9.2); 7.9–11 108 (19); 17–21 7 (1.4); 0.87–2.1 495 (87); 86–89 476 (84); 82–86 90 (16) 33 (5.8) 87 (15) 65 (11) 291 (51) 271 (48); 46–50 317 (56); 54–58 102 (18); 16–20

⬍0.0001 ⬍0.0001 ⬍0.0001

RBC ⫽ red blood cell.

receiving blood but not undergoing reoperation (Table 4); mortality among patients not receiving blood but undergoing reoperation was also higher than that of patients not receiving blood or undergoing a reoperation. Major morbidity occurred more frequently in patients who were transfused and returned to the operating room for bleeding than in those transfused but not returning to the operating room. Renal failure was higher, as was prolonged postoperative ventilation and hospital stay, for patients receiving blood products and undergoing reoperation for bleeding. All these outcomes followed the same general pattern; they were lowest in patients who received no blood and had no reoperation for bleeding, somewhat higher for patients receiving blood but having no reoperation, higher still for those receiving a reoperation but no blood, and highest among those receiving blood and a reoperation. Demographics, comorbidities, lower ejection fraction, and higher New York Heart Association functional class were significantly associated with death (Table 5), as was RBC transfusion and reoperation for bleeding. Hence, after

risk adjustment for comorbidity, both RBC transfusion and reoperation were associated with increased mortality. A number of risk factors, such as demographics and comorbidities, were also associated with postoperative morbidity (Table 6). Similar to mortality, RBC transfusion and reoperation for bleeding were both associated with poorer postoperative outcomes. Both mortality and major morbidity were higher in patients who underwent reoperation for bleeding even after adjusting for number of RBCs transfused (Figs 3 and 4).

Source of Bleeding Of 294 reoperations for bleeding from 2005 to 2010, interpretable data were obtained on 285 patients regarding reason (6 uncertain, 3 lost charts) and 253 for site of bleeding (38 uncertain, 3 lost charts). Bleeding was related to surgical technique in 200 of 285 (70%), coagulopathy in 34 (12%), both in 27 (9.5%), and other (tamponade, clot) in 24 (8.5%). The sternum (n ⫽ 77, 30%), mediastinum (n ⫽ 61 of 253, 24%), internal thoracic artery bed (n ⫽ 40, 16%), and coronary anastomosis site (n ⫽ 29, 11%) were the most

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Table 4. Morbidity and Mortality Associated With Blood Use With and Without Reoperation for Bleeding No Blood Used No Reop. for Bleeding (Total n ⫽ 10,056) Variable

a

Reop. for Bleeding (Total n ⫽ 61)

No Reop. for Bleeding (Total n ⫽ 8,269)

na

No. (%)

na

No. (%)

p

na

10,056 10,056 10,056 10,056 10,056 10,056

10 (0.099) 559 (5.6) 16 (0.16) 81 (0.81) 165 (1.6) 8 (0.08)

61 61 61 61 61 61

4 (6.6) 22 (36) 1 (1.6) 0 (0) 5 (8.2) 1 (1.6)

⬍0.0001 ⬍0.0001 0.005 0.5 ⬍0.0001 ⬍0.0001

8,269 8,269 8,269 8,269 8,269 8,269

7,785 10,056 10,056 10,056

215 (2.8) 83 (0.83) 30 (0.30) 24 (0.24)

56 61 61 61

5 (8.9) 0 (0) 0 (0) 5(8.2)

0.005 0.5 0.7 ⬍0.0001

6,033 8,269 8,269 8,269

7,785 10,056 10,056

35 (0.45) 4,705 (47) 194 (1.9)

56 61 61

15 (27) 18 (30) 3 (4.9)

⬍0.0001 0.007 0.09

6,033 8,269 8,269

Reop. for Bleeding (Total n ⫽ 505) na

No. (%)

173 (2.1) 1,666 (20) 43 (0.52) 160 (1.9) 723 (8.7) 198 (2.4)

505 505 505 505 505 505

44 (8.7) 245 (49) 3 (0.59) 11 (2.2) 74 (15) 37 (7.3)

⬍0.0001 ⬍0.0001 0.8 0.7 ⬍0.0001 ⬍0.0001

970 (16) 111 (1.3) 16 (0.19) 75 (0.91)

408 505 505 505

191 (47) 9 (1.8) 7 (1.4) 52 (10)

⬍0.0001 0.4 ⬍0.0001 ⬍0.0001

408 505 505

50 (12) 42 (8.3) 142 (28)

⬍0.0001 ⬍0.0001 ⬍0.0001

No. (%)

155 (2.6) 1,471 (18) 1,129 (14)

Data available.

Reop ⫽ reoperation.

p

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Operative mortality Major morbidity Perioperative myocardial infarction Stroke Renal failure Renal failure requiring hemodialysis Prolonged ventilation (⬎24 hours) Deep sternal wound infection Reoperation for valve dysfunction Reoperation for exclusion of valve dysfunction/graft Occlusion Other noncardiac reoperation Stay ⬍6 days Stay ⬎14 days

Blood Given

1787

ADULT CARDIAC

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Table 5. Incremental Risk Factors for Mortality (n ⫽ 18,891)a Factor ADULT CARDIAC

Demographics Older age (years) Height (cm)b Acuity Higher NYHA class Cardiac comorbidity Lower LV ejection fraction (%) Complete heart block Noncardiac comorbidity COPD Renal disease Higher creatinine (mg·dL⫺1)c Higher bilirubin (mg·dL⫺1) Operative Longer CPB time (minutes) Nonelective status Surgeon D E Reoperation for bleeding Transfusion Total number of RBC units transfusedd FFP used Platelets used Cryoprecipitate used

Estimate ⫾ SE

p

0.42 ⫾ 0.097 1.07 ⫾ 0.38

⬍0.0001 0.005

0.015 ⫾ 0.0047

0.001

⫺0.012 ⫾ 0.0055

0.02

0.54 ⫾ 0.27

0.04

0.57 ⫾ 0.16 0.55 ⫾ 0.22 0.015 ⫾ 0.0041 0.44 ⫾ 0.13

0.0004 0.01 0.0005 0.0007

0.0036 ⫾ 0.0016 0.37 ⫾ 0.17

0.03 0.03

0.65 ⫾ 0.33 ⫺0.61 ⫾ 0.29 0.70 ⫾ 0.21

0.05 0.03 0.001

1.8 ⫾ 0.13 ⫺0.21 ⫾ 0.21 0.32 ⫾ 0.21 ⫺0.79 ⫾ 0.32

⬍0.0001 0.3 .12 .01

a

Adjusted with propensity score and blood products forced into modb c (180/height)2 inverse squared transformation. Creatinine2, el. d Intercept adjustment term: -0.45 ⫾ 0.55 squared transformation. (p ⫽ 0.2). C-statistic ⫽ 0.92. COPD ⫽ chronic obstructive pulmonary disease; monary bypass; FFP ⫽ fresh frozen plasma; lar; NYHA ⫽ New York Heart Association; cell; SE ⫽ standard error.

CPB ⫽ cardiopulLV ⫽ left ventricuRBC ⫽ red blood

common sites of bleeding (69%; sites not mutually exclusive).

Comment Principal Findings Reoperation for bleeding and transfusion increased risk of poor outcomes after surgery. Patients requiring reoperation had higher mortality, more renal failure, prolonged ventilatory support, and increased resource utilization, with more blood transfused and longer overall hospital stay. Understanding that RBC transfusion is associated with greater risk of complications [10 –14], we performed analyses to better discern whether risk was isolated transfusion, reoperation for bleeding, or both. We found that increased risk for patients undergoing reoperation for bleeding was related to both greater transfusion requirements and reoperation. Transfused

patients had higher morbidity and mortality, and reoperation for bleeding further heightened the risk of adverse outcomes. Ranucci and colleagues [15] reported that the main determinant of morbidity after reoperation for bleeding was amount of RBCs transfused, and delaying reoperation was related to risk only if it involved excess use of blood products. Dacey and colleagues [6] reported nearly 3 times higher in-hospital mortality and longer length of stay for patients who underwent reoperation for bleeding. In addition to mortality, reoperation for bleeding is reportedly associated with more postoperative complications and longer ICU stay [3, 4, 16, 17]. In our experience, prevalence of reoperation for bleeding varied considerably over time. Munoz and colleagues [18] examined time-related trends in reexploration for bleeding with the Northern New England Cardiovascular Disease Study Group. They reported a 46% decline in reoperation for bleeding between 2 time periods, 1992 to 1994 and 1995 to 1997, despite a higher prevalence of risk factors for reoperation for bleeding in the later period, but increased use of antifibrinolytics. Routine use of epsilon aminocaproic acid was consistent throughout our entire study period despite variable trends in prevalence of reoperation. Table 6. Incremental Risk Factors for Major Morbidity (n ⫽ 18,891)a Factor Acuity Higher NYHA class Cardiac comorbidity Lower LV ejection fraction Noncardiac comorbidity COPD Peripheral arterial disease Stroke Insulin-treated diabetes Renal disease Higher BUN (mg/dL⫺1)b Operative Nonelective status Longer CPB time (minutes) Reoperation for bleeding Transfusion Total number of RBC units transfusedc Platelets used FFP used Cryoprecipitate used

Estimate ⫾ SE

p

0.013 ⫾ 0.0019

⬍0.0001

⫺0.0077 ⫾ 0.0020

0.0001

0.31 ⫾ 0.061 0.16 ⫾ 0.051 0.27 ⫾ 0.076 0.37 ⫾ 0.069 0.27 ⫾ 0.094 0.61 ⫾ 0.064

⬍0.0001 0.002 0.0003 ⬍0.0001 0.003 ⬍0.0001

0.24 ⫾ 0.052 0.0026 ⫾ 0.00058

⬍0.0001 ⬍0.0001

1.01 ⫾ 0.11

⬍0.0001

1.065 ⫾ 0.052

⬍0.0001

⫺0.069 ⫾ 0.077 0.19 ⫾ 0.091 0.0027 ⫾ 0.15

0.4 0.03 0.9

a Adjusted with propensity score and blood products forced into modb c Log(BUN), logarithmic transformation. Intercept adjustel. ment term: -0.16 ⫾ 0.76 (p ⫽ 0.04).

C-statistic ⫽ 0.79. BUN ⫽ blood urea nitrogen; COPD ⫽ chronic obstructive pulmonary disease; CPB ⫽ cardiopulmonary bypass; FFP ⫽ fresh frozen plasma; LV ⫽ left ventricular; NYHA ⫽ New York Heart Association; RBC ⫽ red blood cell ; SE ⫽ standard error.

VIVACQUA ET AL REOPERATION, TRANSFUSION, AND OUTCOMES

Reoperation for bleeding

No reoperation for bleeding

Incremental risk factors for reoperation for bleeding were related to patient factors such as older age and comorbidity, and processes-of-care factors such as longer cardiopulmonary bypass duration and surgeon. These were similar to those identified by others [3, 4, 6]. Of note, the C-statistic for our risk-factor model had poor predictability, likely reflecting an inability to predict bleeding due to technical factors. A majority of these reoperations were found to be due to technical factors, suggesting a role for process improvements to minimize need for reoperation and decrease blood use. Hall and colleagues [2] also found that in 66% of reoperations for bleeding, a surgical source was identified. These were primarily from the chest wall, internal thoracic artery bed, and side branches of bypass grafts, as we found. Karthik and colleagues [3] examined risk factors and effect of time delay on reoperation for bleeding after CABG. A surgical site for bleeding was identified in 82% of reoperations. Higher risk of complications was noted when patients waited more than 12 hours to reoperation. The authors concluded that because reoperation for bleeding contributed to patient morbidity and most cases of bleeding after CABG had a surgical

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Fig 3. Predicted probability of operative mortality from multivariable model (Table 5) stratified on reoperation for bleeding and depicted for number of red blood cell (RBC) units transfused. The nomogram was solved for a 65-year-old patient with no chronic obstructive pulmonary disease or heart block, ejection fraction of 0.50, height of 170 cm, creatinine level of 1.4 mg/dL⫺1, and bilirubin level of 0.6 mg/dL⫺1 undergoing a 1-component elective operation with a cardiopulmonary bypass time of 95 minutes and myocardial ischemic time of 65 minutes.

cause, there was a strong case for policies promoting early reoperation in response to excess bleeding in the ICU. In a similar investigation, Choong and colleagues [5] reported delayed reoperation led to increased mortality (29% vs 7%) if delay was greater than 12 hours after surgery.

Limitations This is a prospective cohort investigation with natural imbalances in variables between groups. Randomizing patients to reoperation and transfusion is not possible. Therefore, multivariable regression and propensity methodology were used to reduce confounding; however, there may be unaccounted for imbalances in unmeasured confounding variables. We did not measure hemodynamic variables surrounding reoperations for bleeding, nor duration of hemodynamic instability. Timing for reoperation was not examined; however, some of that risk is captured by increased transfusion requirements.

Conclusions Both reoperation for bleeding and higher transfusion requirements independently contribute to increased

Reoperation for bleeding No reoperation for bleeding

Fig 4. Predicted probability of major morbidity from multivariable model (Table 6) stratified on reoperation for bleeding and depicted for number of red blood cell (RBC) units transfused. The nomogram was solved for the same patient characteristics as in Figure 3.

ADULT CARDIAC

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VIVACQUA ET AL REOPERATION, TRANSFUSION, AND OUTCOMES

ADULT CARDIAC

morbidity and mortality risk after cardiac surgery. Technical reasons were the primary reason for bleeding after surgery. Greater attention to surgical techniques that control and decrease bleeding is likely to lower morbidity and mortality by reducing the prevalence of both reoperation for bleeding and transfusion requirements.

References 1. Mehta RH, Sheng S, O’Brien SM, et al. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes 2009;2:583–90. 2. Hall TS, Brevetti GR, Skoultchi AJ, Sines JC, Gregory P, Spotnitz AJ. Re-exploration for hemorrhage following open heart surgery differentiation on the causes of bleeding and the impact on patient outcomes. Ann Thorac Cardiovasc Surg 2001;7:352–7. 3. Karthik S, Grayson AD, McCarron EE, Pullan DM, Desmond MJ. Reexploration for bleeding after coronary artery bypass surgery: risk factors, outcomes, and the effect of time delay. Ann Thorac Surg 2004;78:527–34. 4. Moulton MJ, Creswell LL, Mackey ME, Cox JL, Rosenbloom M. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg 1996;111:1037– 46. 5. Choong CK, Gerrard C, Goldsmith KA, Dunningham H, Vuylsteke A. Delayed re-exploration for bleeding after coronary artery bypass surgery results in adverse outcomes. Eur J Cardiothorac Surg 2007;31:834 – 8. 6. Dacey LJ, Munoz JJ, Baribeau YR, et al. Reexploration for hemorrhage following coronary artery bypass grafting: incidence and risk factors. Northern New England Cardiovascular Disease Study Group. Arch Surg 1998;133:442–7.

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7. Cleveland WS, Devlin SJ. Locally weighted regression: an approach to regression analysis by local fitting. J Am Stat Assoc 1988;83:596 – 610. 8. Breiman L. Bagging predictors. Machine Learning 1996;24: 123– 40. 9. Bergstralh EJ, Konsanke JL. Computerized matching of cases to controls. In. Technical report No. 56. Department of Health Science Research. Rochester, MN: Mayo Clinic; 1995. 10. Koch C, Li L, Figueroa P, Mihaljevic T, Svensson L, Blackstone EH. Transfusion and pulmonary morbidity after cardiac surgery. Ann Thorac Surg 2009;88:1410 – 8. 11. Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006;34:1608 –16. 12. Koch CG, Li L, Duncan AI, et al. Transfusion in coronary artery bypass grafting is associated with reduced long-term survival. Ann Thorac Surg 2006;81:1650 –7. 13. Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008;358:1229 –39. 14. Koch CG, Li L, Van Wagoner DR, Duncan AI, Gillinov AM, Blackstone EH. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 2006;82:1747–56. 15. Ranucci M, Bozzetti G, Ditta A, Cotza M, Carboni G, Ballotta A. Surgical reexploration after cardiac operations: why a worse outcome? Ann Thorac Surg 2008;86:1557– 62. 16. Sellman M, Intonti MA, Ivert T. Reoperations for bleeding after coronary artery bypass procedures during 25 years. Eur J Cardiothorac Surg 1997;11:521–7. 17. Christensen MC, Krapf S, Kempel A, von Heymann C. Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc Surg 2009;138:687–93. 18. Munoz JJ, Birkmeyer NJ, Dacey LJ, et al. Trends in rates of reexploration for hemorrhage after coronary artery bypass surgery. Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg 1999;68:1321–5.