1. M Ruel, V Chan, M Boodhwani, B McDonald, X Ni, G Gill, K Lam, F Rubens, P Hendry, R Masters, T Mesana Ottawa, Canada How Detrimental is Re-Exploration for Bleeding after Cardiac Surgery? Analysis from 16,793 Cases

2. DISCLOSURES: none

3. Introduction & Objectives -Re-exploration for bleeding (REFB) rates are ~2-6% -Previous groups suggest mortality due to transfusions not REFB (Ranucci et al, Ann Thorac Surg 2008) -Others promote earlier re-intervention as less risky (Karthik et al, Ann Thorac Surg 2004; Haneya et al, Thorac Cardiovasc Surg 2015) -No large single-center series encompasses all cases -How intrinsically detrimental is REFB?

4. Elective priority (N=9,162) Discharged to ICU (N=16,749) Discharged home (N=16,254) Adult Cardiac Surgical Procedure (N=16,793) CABG*Valve*Valve+CABGArrhythmia*Heart Failure § CongenitalAorticOthers † (N=9,214)(N=3,906)(N=2,198)(N=48)(N=335)(N=157)(N=627)(N=308) Not discharged to ICU (N=44) In-hospital death (N=539) * Denotes isolated CABG, isolated valve replacement/repair, or isolated arrhythmia surgery § Denotes heart transplantation, mechanical heart assistance, or other operations for cardiomyopathy † Denotes pericardiectomy, cardiac tumor resection, pulmonary thromboendarterctomy or embolectomy, or other non-categorized operations Urgent priority (N=6,302) Emergency priority (N=1,329) July 2002 - September 2014 Not re-explored for bleeding (N=16,132) or Re-explored for bleeding (N=661) Not readmitted to hospital (N=15,196) Readmitted to hospital (N=1,058)

5. Patients were operated on CPB unless noted Crystalloid cardioplegia until June 2005 LV grades 1, 2, 3 and 4 = LVEF ≥50%, 35-49%, 20-34%, and <20 Increase in serum creatinine defined as highest serum creatinine value minus preoperative Mortality defined as hospital mortality at any time prior to discharge Surgical site infections monitored during hospitalization and after discharge by dedicated staff

6. Comparisons between patients who were not REFB and REFB with T test/Mann- Whitney U test for continuous variables; Chi-square with Yate’s for categorical For clinical outcomes logistic (REFB, mortality, other morbidity and readmission) and linear (increases in creatinine and length of stay) models included: age gender body surface area preoperative atrial fibrillation preoperative LV grade preoperative serum creatinine operative priority redo status type of operation lowest hematocrit on CPB aortic cross-clamp and CPB durations number of blood product units transfused postoperative increase in serum creatinine new onset atrial fibrillation Regression models underwent 50 bootstrap resampling estimations Optimal cut-off values set by receiver operating characteristics

8. Re-exploration after the index procedure occurred in 710 (4.2%) patients The first episode of REFB occurred on pod 0 in 358 (54.2%), on pod 1 in 169 (25.6%), on pod 2 in 19 (2.9%), on pod 3-7 in 47 (7.1%), later in 68 (10.3%) Thirteen patients (2.0% of REFB patients) were re-explored for bleeding more than once Of these, 661 (3.9%) were REFB

9. Coefficient [95% CI]P value Body surface area (per m 2 ) 0.6±0.1 [0.4, 0.9]0.02 Emergency status 1.7±0.4 [1.1, 2.6]0.03 Redo status 1.5±0.3 [1.1, 2.1]0.02 On-pump vs. off-pump CABG 1.7±0.1 [1.1, 2.5]0.01 Aortic dissection repair 3.0±1.0 [1.6, 5.6]0.001 Tricuspid valve repair 2.6±0.1 [1.9, 3.6]<0.001 Lowest CPB hematocrit (per %) 0.97±0.01 [0.94, 0.99]0.02 Ao clamp duration (per min) 1.003±0.001 [1.000, 1.006]0.04 CPB duration (per min) 1.005±0.001 [1.003, 1.006]<0.001

10. ROC curves revealed the best cut-off of lowest CPB hematocrit to be 27% (c-statistic=0.614) However, specificity was increased in patients with lowest CPB hematocrit < 24%, in whom the risk of re-exploration was independently increased by two-thirds (odds ratio 1.7±0.2; P<0.001)

11. Perioperative mortality was 458/16,132 (2.8%) in those who did not undergo REFB versus 81/661 (12.0%) in those who had REFB 4.1±0.5 odds ratio (P<.001) for perioperative death, which was additive to other mortality determinants, including the number of blood products unit transfused Timing of REFB did not significantly impact mortality in patients who had REFB: within REFB patients, the OR for death was 1.06±0.4 (P=0.1) per incremental day after the index surgical procedure

12. Coefficient [95% CI]P value Female gender 1.6±0.1 [1.4, 1.8] <0.001 Age (per year) 1.04±0.04 [1.03, 1.05] <0.001 Left ventricular grade (per grade) 1.6±0.1 [1.4, 1.8] <0.001 Creatinine (preoperative, /umol/L) 1.002±0.0006 [1.001, 1.003] 0.001 Emergency status 4.3±0.8 [3.1, 6.2] <0.001 Redo status 1.5±0.3 [1.1, 2.1] 0.02 Aortic dissection 9.9±5.3 [3.5, 28.0] <0.001 Mitral valve repair 0.6±0.1 [0.4, 0.9] 0.007 Tricuspid valve repair 1.9±0.4 [1.3, 2.8] 0.001 Lowest CPB hematocrit (per %) 0.97±0.01 [0.94, 0.99] 0.02 Ao clamp duration (per min) 1.01±0.002 [1.01, 1.02] <0.001 CPB duration (per min) 1.01±0.002 [1.01, 1.02] <0.001 Total blood products transfused (/u) 1.04±0.003 [1.03, 1.04] <0.001 Re-exploration for bleeding 4.1±0.5 [3.2, 5.3]<0.001

13. Not REFB (N=16,132) REFB (N=661) Multivariable coefficient (Coef) or odds ratio (OR)* P value ICU LOS, median days [IQR]1 [1]3 [5] Coef: 6.1±1.1<0.001 ICU readmission, n (%)453 (2.8%)80 (12.1%) OR: 3.6±0.8<0.001 New atrial fibrillation, n (%)4,194 (26.0%)240 (36.3%) OR: 1.5±0.20.006 † Increase in creatinine, umol/L 25.9±48.551.0±49.6 Coef: 17.9±3.2<0.001 Hospital LOS, median days [IQR]7 [6]12 [20] Coef: 6.8±0.8<0.001 Hospital readmission, n (%)1,011 (6.3%)47 (7.1%) OR: 1.02±0.30.9 Surgical site infection, n (%)1,055 (6.5%)84 (12.7%) OR: 2.0±0.40.001

14. Single center experience No economic analysis No perioperative medications effect No individual surgeon association No differentiation between surgical and medical bleeding

15. Re-exploration for bleeding (REFB) is a: non-infrequent lethal potentially modifiable complication of cardiac surgery In a large contemporary series: the impact of REFB adds to that of other well known risk factors for mortality and morbidity, including transfusions avoiding nadir hematocrits of less than 24% during CPB may help avoid REFB the present findings strongly justify continued quality improvement and research efforts to minimize the occurrence and negative impacts of REFB.