Thrombosis Research 134 (2014) 346–353
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
The prothrombotic paradox of severe obesity after cardiac surgery under cardiopulmonary bypass Michel Kindo a,⁎, Tam Hoang Minh a, Sébastien Gerelli a, Nicolas Meyer b, Mickaël Schaeffer b, Stéphanie Perrier a, Jonathan Bentz a, Tarek Announe a, Arnaud Mommerot a, Olivier Collange c, Sandrine Marguerite c, Adrien Thibaud c, Hubert Gros c, Philippe Billaud a, Jean-Philippe Mazzucotelli a a b c
Department of Cardiovascular Surgery, University Hospitals of Strasbourg, France Department of Public Health, University Hospitals of Strasbourg, France Department of Surgical Intensive Care Unit and Anesthesiology, University Hospitals of Strasbourg, France
a r t i c l e
i n f o
Article history: Received 17 March 2014 Received in revised form 27 May 2014 Accepted 5 June 2014 Available online 12 June 2014 Keywords: Obesity Cardiopulmonary bypass Blood coagulation Hemorrhage Fibrinogen
a b s t r a c t Background: Obesity is suggested to reduce postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) but perioperative hemostasis variations have not been studied. Therefore, we investigated the effects of severe obesity (body mass index [BMI] ≥35 kg/m2) on chest tube output (CTO) and hemostasis in patients undergoing cardiac surgery with CPB. Materials and Methods: We prospectively investigated 2799 consecutive patients who underwent coronary and/ or valve surgery using CPB between 2008 and 2012. 204 patients (7.3%) presented a severe obesity. Results: In the severe obesity group, the 6-h and 24-h CTO were significantly reduced by -21.8% and -14.8% respectively (P b 0.0001) compared with the control group. A significant reduction of the mean number of red blood cell units transfused at 24 h was observed in the severe obesity groups (P = 0.01). On admission to the intensive care unit, a significant increase of platelet count (+ 9.2%; P b 0.0001), fibrinogen level (+ 12.2%; P b 0.0001) and prothrombin time (+4.1%; P b 0.01) and a significant decrease of the activated partial thromboplastin time (-4.2%; P b 0.01) were observed in the severe obesity group compared with the control group. In multivariate analysis, severe obesity was significantly associated to a decreased risk of excessive bleeding (24-h CTO N 90th percentile; Odds ratio: 0.37, 95% CI: 0.17 to 0.82). No significant differences were observed regarding postoperative thromboembolic events between the two groups. Conclusions: Severe obesity is associated with a prothrombotic postoperative state that leads to a reduction of postoperative blood loss in patients undergoing cardiac surgery with CPB. © 2014 Elsevier Ltd. All rights reserved.
Introduction Incidence of obesity (body mass index [BMI] ≥30 kg/m2) is increasing and is actually a major health problem [1]. Obesity is an independent risk factor for mortality mainly correlated to the high prevalence of diabetes mellitus and cardiovascular diseases in obese patients [1]. Hence among patients referred for cardiac surgery, the proportion of obese patients is increasing. Cardiac surgery with CPB induces coagulation activation, hemodilution, platelet dysfunction, fibrinolysis, endothelial dysfunction and proinflammatory state [2,3]. With some preoperative conditions, as antiplatelet and/or anticoagulant therapies, there is a high risk for patients
⁎ Corresponding author at: Department of Cardiovascular Surgery, NHC, 1 Place de l’Hôpital, BP 426, 67091 Strasbourg Cedex, France. Tel.: +33 3 69 55 08 11; fax: +33 3 69 55 18 87. E-mail address: [email protected] (M. Kindo).
http://dx.doi.org/10.1016/j.thromres.2014.06.008 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
undergoing cardiac surgery of postoperative bleeding and so the need of allogeneic blood product transfusions [2–4]. Red blood cells (RBC) transfusion and/or excessive postoperative blood loss increase mortality and morbidity after cardiac surgery [2,5–7]. For this reason, during the early postoperative course, the hemostasis control is a challenge with the need to control bleeding without the induction of pathologic thrombotic events [3]. Obesity is associated to a prothrombotic state due to increased thrombin formation, platelet hyperactivity and decreased fibrinolysis [1,8]. There are open issues and gaps in knowledge regarding the impact of this prothrombotic state on postoperative blood loss after cardiac surgery. Some studies have reported a significant reduction of reoperation for bleeding or RBC transfusion in obese patients [9–16]. Only three studies analyzed the mean chest tube output (CTO) after coronary artery bypass graft (CABG) surgery in obese patients with conflicting results [12,17,18]. Furthermore the effects of obesity on the coagulation cascade, platelet and fibrinolysis have not been yet explored in patients undergoing cardiac surgery with CPB.
M. Kindo et al. / Thrombosis Research 134 (2014) 346–353
The current study was, therefore, designed to determine the impact of BMI on postoperative blood loss and its effects on hemostasis after CABG and/or valvular surgeries under CPB. Methods Patients and Study Design A prospective cohort study of all consecutive patients undergoing cardiac surgery with CPB between October 1, 2008 and December 1, 2012, in our institution was performed. Inclusion criteria were age ≥18-years, valve and/or CABG surgeries. Exclusion criteria were surgery on the thoracic aorta, septal defect repair, ventricular aneurysm resection and perioperative need of ventricular assist device or extracorporeal life support. 2799 patients met the inclusion and exclusion criteria and were enrolled in this prospective, single-center, observational study. Perioperative data and outcomes were prospectively collected and validated. Study procedures were approved by the Institutional Review Board. Obesity was assessed by the BMI. Patients were classified into 2 groups: control group with a BMI b 35 kg/m2 (n = 2595; 92.7%) and severe obesity group with a BMI ≥35 kg/m2 (n = 204 patients; 7.3%; obese classes II and III of the International Classification of the World Health Organization). Unfractionated heparin anticoagulation to maintain an activated coagulation time (ACT) above 400 seconds was used during cardiopulmonary bypass (CPB). Patients received systematically intraoperative tranexamic acid infusion. At the end of CPB, protamine sulfate (dose/
347
dose) was given to reverse anticoagulation. Pericardial and/or pleural cavities were drained with small surgical drains (8 to 14 drains, each 9 mm diameter, Peters Surgical, France). Blood samples were harvested preoperatively, on admission to the intensive care unit (ICU) or postoperative day 0 (POD 0) and on the morning of the first postoperative day (POD 1). When postoperative anticoagulation was indicated unfractionated heparin or low molecular weight heparin was used as reported elsewhere [19]. All the patients had systematic deep venous thrombosis prevention with mechanical prophylaxis and low molecular weight heparin or low-dose unfractionated heparin. End-Points The primary end-point was the postoperative blood loss. It was defined by the mean CTO at 6 h and 24 h and the occurrence of an excessive bleeding defined as a mean CTO exceeding the 90th percentile of distribution at 6 h and 24 h after the end of the surgery. This threshold was chosen based on clinical experience at our institution. The 6-h and 24-h CTO values were missing for 3.5% and 3.7% patients respectively. The secondary end-points included perioperative variations of standard coagulation tests, in-hospital mortality from any cause and postoperative morbidities as: new atrial fibrillation, postoperative thromboembolic events (myocardial infarction, stroke, transient ischemic attack, acute mesenteric ischemia, acute limb ischemia, deep venous thrombosis), sternal complications (deep sternal wound infection, superficial sternal wound infection and sternal dehiscence requiring reoperation), postoperative infection (bronchopneumopathy,
Table 1 Preoperative characteristics.
Age (years) Female gender BMI (kg/m2) Smoker Diabetes Hypertension Hyperlipidemia Kidney failure Preoperative dialysis Chronic lung disease Stroke history Previous myocardial infarction Previous PCI Peripheral vascular disease Prior heart failure Previous cardiovascular surgery Preoperative atrial fibrillation Emergency surgery Logistic EuroSCORE (%) Antiplatelet and/or anticoagulant therapies Antiplatelet therapy Heparin Vitamin K antagonist Echocardiography data Left ventricular ejection fraction (%) Biological data Hemoglobin (g/dL) White blood cell count (109/L) Platelet count (103/mm3) Prothrombin time (%) Activated partial thromboplastin time (sec) Fibrinogen (g/L) GFR (ml/min/1.73 m2) Troponin I (μg/L)
Overall (n = 2799)
Control (n = 2595)
Severe obesity (n = 204)
P-value
67.5 ± 11.6 867 (31.0) 27.6 ± 4.9 1326 (47.4) 894 (31.9) 1914 (68.4) 1759 (62.8) 665 (23.8) 38 (1.4) 240 (8.6) 199 (7.1) 388 (13.9) 485 (17.3) 480 (17.1) 295 (10.5) 314 (11.2) 302 (10.8) 219 (7.8) 6.4 ± 7.9
67.6 ± 11.8 773 (29.8) 26.7 ± 3.8 1238 (47.7) 772 (29.7) 1744 (67.2) 1604 (61.8) 620 (24.9) 37 (1.4) 208 (8.0) 190 (7.3) 360 (13.9) 442 (17.0) 450 (17.3) 279 (10.8) 305 (11.8) 277 (10.7) 202 (7.8) 6.5 ± 8.1
66.6 ± 9.4 94 (46.1) 38.5 ± 3.7 88 (43.1) 122 (59.8) 170 (83.3) 155 (76.0) 45 (22.7) 1 (0.5) 32 (15.7) 9 (4.4) 28 (13.7) 43 (21.1) 30 (14.7) 16 (7.8) 9 (4.4) 25 (12.3) 17 (8.3) 5.4 ± 6.0
0.232 b0.0001 b0.0001 0.208 b0.0001 b0.0001 b0.0001 0.455 0.521 b0.0001 0.119 0.953 0.142 0.336 0.193 0.001 0.484 0.779 0.057
1722 (61.5) 130 (4.6) 435 (15.5)
1582 (61.0) 120 (4.6) 406 (15.6)
140 (68.6) 10 (4.9) 29 (14.2)
0.030 0.856 0.587
59.6 ± 11.7
59.6 ± 11.7
59.5 ± 12.1
0.957
13.4 ± 1.7 7.2 ± 2.6 232.4 ± 76.3 86.2 ± 20.3 36.2 ± 12.1 3.9 ± 1.1 76.9 ± 26.3 0.9 ± 16.6
13.4 ± 1.7 7.2 ± 2.6 232.4 ± 76.3 86.2 ± 20.3 36.3 ± 12.2 3.9 ± 1.1 76.8 ± 26.3 0.9 ± 16.6
13.3 ± 2.6 7.5 ± 2.6 232.6 ± 76.8 86.3 ± 19.5 35.0 ± 10.6 4.2 ± 1.2 77.9 ± 25.5 0.8 ± 3.7
0.332 0.087 0.968 0.949 0.185 b0.0001 0.551 0.863
The plus-minus values are the mean ± SD, and the others are no. (%). P-value, control group versus severe obesity group. Kidney failure, glomerular filtration rate (GFR) b60 mL/min/1.73 m2 determined with the MDRD equation; FVC, forced vital capacity; FEV, forced expiration volume in 1 second; PCI, percutaneous coronary intervention; Logistic EuroSCORE, 30-day operative mortality predicted by EuroSCORE I; GFR, glomerular filtration rate determined with the MDRD equation; Antiplatelet therapy, aspirin and/or clopidogrel treatment.
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M. Kindo et al. / Thrombosis Research 134 (2014) 346–353
urinary infection, endocarditis), renal failure, dialysis, bleeding requiring reoperation and RBC transfusion. Ventilation time, ICU stay and inhospital stay were also collected. Statistical Analysis The date are presented are mean ± standard deviation (SD). Differences between the categorical variables were tested using chi-square or Fisher’ exact tests, depending on the expected values. Differences between continuous variables were tested using the Student’s test or the Mann-Whitney test, depending on whether there was a Gaussian distribution. The link between BMI and perioperative variables was studied by non parametric tests (Mann-Whitney U test and Spearman’s rankorder correlation coefficient). Potential risk factors for significant postoperative bleeding (excessive bleeding group) were first tested using a univariate analysis. After performing a univariate analysis, only the variables with a P-value less than 0.150, which were determined using a 2-tailed t-test, were used in a multivariate logistic regression analysis (with a backward, stepwise method based on the likelihood ratio test). The odds ratios and their corresponding 95% confidence intervals are reported in addition to their associated p-values. The sample size was estimated as follows: for a type I error risk of 5%, a group ratio of 1/9 and a total sample size of 3000, a loss of 300 ± 250 ml at 6 h and a 15% decrease in blood loss for the obese group would achieve an 83% power. A 24 h blood loss of 700 ± 350 mL with a loss decrease of 10% in the obese group would achieve 90% power
with the same sample size of 3000. Different scenarios gave sample size estimates of around 2600 to 3000 subjects with power ranging from 80 to 90%. We thus considered that our data base would be large enough to show clinically relevant as well as statistically significant differences. The statistical computations were performed using R software (version 2.15.3) and SPSS (SPSS®, version 17.0, Chicago, IL). Results Preoperative and Operative Characteristics Preoperative characteristics in control and severe obesity groups are reported in Table 1. The patients in severe obesity group were younger, more likely to be female, and had an increased prevalence of diabetes, hypertension, hyperlipidemia and chronic lung disease (chronic obstructive pulmonary disease or restrictive lung disease) than in the control group. Previous cardiac surgery was more frequent in the control group. The preoperative used of anticoagulant (heparin or vitamin K antagonist used) did not significantly differ between the 2 groups. Antiplatelet therapies (aspirin and/or clopidogrel) were more often preoperatively used in severe obesity group than control group. Table 2 lists operative characteristics in the 2 groups. Aortic valve replacement was significantly more frequent in the severe obesity group whereas mitral valve repair and mitral valve replacement was significantly more frequent in the control group. For CABG surgery (isolated or combined to valvular surgery), no differences were observed between the 2 groups regarding the total number of distal anastomoses,
Table 2 Intraoperative data. Overall (n = 2799)
Control (n = 2595)
Severe obesity (n = 204)
Type of surgery Valvular surgery Isolated valvular surgery CABG Isolated CABG Valvular surgery and CABG Redo surgery
1577 (56.3) 1196 (42.7) 1603 (57.3) 1222 (43.7) 381 (13.6) 171 (6.1)
1468 (56.6) 1113 (42.9) 1482 (57.1) 1127 (43.4) 355 (13.7) 167 (6.4)
109 (53.4) 83 (40.7) 121 (59.3) 95 (46.6) 26 (12.7) 4 (2.0)
Valvular surgery Aortic valve replacement Aortic valve repair Mitral valve replacement Mitral valve repair Tricuspid valve replacement Tricuspid valve repair Mechanical valve replacement Biologic valve replacement
1155 (41.3) 18 (0.6) 241 (8.6) 247 (8.8) 9 (0.3) 79 (2.8) 432 (15.4) 906 (32.4)
1056 (40.7) 17 (0.7) 232 (8.6) 243 (9.4) 9 (0.3) 74 (2.9) 391 (15.1) 842 (32.4)
99 (48.5) 1 (0.5) 9 (4.4) 4 (2.0) 0 5 (2.5) 41 (20.1) 64 (31.4)
0.029 0.777 0.026 b0.001 1.000 0.739 0.055 0.752
CABG Total no. distal anastomoses Arterial no. distal anastomoses Venous no. distal anastomoses
2.7 ± 1.1 2.2 ± 1.0 0.5 ± 0.8
2.7 ± 1.1 2.2 ± 1.0 0.5 ± 0.8
2.7 ± 1.1 2.3 ± 0.9 0.4 ± 0.6
0.678 0.112 0.544
Cardiopulmonary bypass Cross clamp time (min) CPB time (min) Warm blood cardioplegia Residual blood processing by cell savage
89.1 ± 35.6 122.2 ± 45.6 730 (26.1) 1618 (57.8)
89.1 ± 35.5 122.3 ± 45.7 680 (26.2) 1499 (57.8)
89.1 ± 36.7 120.7 ± 44.2 50 (24.5) 119 (58.3)
0.980 0.625 0.596 0.874
Operative transfusion Red blood cells Fresh frozen plasma Platelet Albumin Fibrinogen concentrate Prothrombin complex concentrate Human antithrombin
1284 (45.9) 310 (11.1) 588 (21.0) 1025 (36.6) 104 (3.7) 167 (6.0) 87 (3.1)
1199 (46.3) 290 (11.2) 544 (21.0) 945 (36.5) 101 (3.9) 159 (6.1) 84 (3.2)
85 (41.6) 20 (9.8) 44 (21.5) 80 (39.2) 3 (1.4) 8 (3.9) 3 (1.4)
0.218 0.553 0.828 0.410 0.083 0.202 0.162
The plus-minus values are the mean ± SD, and the others are no. (%). P-value, control group versus severe obesity group. CPB, cardiopulmonary bypass; CABG, coronary artery bypass grafting; LITA, left internal thoracic artery; RITA, right internal thoracic artery.
P-value
0.384 0.540 0.540 0.384 0.708 0.006
M. Kindo et al. / Thrombosis Research 134 (2014) 346–353
the used of arterial grafts and the used of bilateral internal thoracic arteries. No differences were found regarding the used of warm cardioplegia among the 2 groups. The cross clamp and CPB times were similar in the 2 groups.
Postoperative Bleeding Mean CTO at 6 h and 24 h were significantly lower in the severe obesity group than in the control group (-21.8%, P b 0.0001 and -14.8%, P b 0.0001, respectively; Table 3). Excessive bleeding at 6 h and 24 h were defined as a mean CTO exceeding the 90th percentile (575.0 mL and 1160.0 mL, respectively). Severe obesity was associated with a significant reduction of excessive bleeding at 6 h and 24 h (P b 0.01, Table 3). The incidence of bleeding requiring reoperation did not differed significantly between the 2 groups (Table 3). Regarding the mean number of RBC transfused, a significant reduction was observed at 24 hours in severe obesity group (P = 0.01) but not intraoperatively (Table 3). The need to transfuse 5 or more RBC units during the first 24 h did not differ between the two groups (Table 3). There were a significant inverse correlation between BMI and CTO at 6 h (r2 = 0.0009; rho = -0.094; P b 0.0001) and 24 h (r2 = 0.008; rho = -0.087; P b 0.0001).
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Perioperative Variations of Standard Coagulation Tests, Hematocrit and Hemoglobin Regarding the preoperative standard coagulation tests as namely, platelet count, activated partial thromboplastin time (APTT) and prothrombin time (PT), no differences were found between the 2 groups (Fig. 1 and Table 1). Only the preoperative fibrinogen level was significantly higher in the severe obesity group than in the control group (P b 0.0001; Fig. 1B and Table 1). Preoperative fibrinogen level was significantly correlated to the BMI (r2 = 0.008; rho = 0.098; P b 0.0001). The baseline ACT performed in the operating room before heparinization was significantly higher in the obese group compared with the control group (120.2 ± 16.7 versus 117.3 ± 16.2 sec; P = 0.01; respectively). No significant differences of the operative ACT at the beginning of CPB, before the completion of CPB, at the end of the surgery and the lowest value during the CPB were observed between the 2 groups. Operative hematocrit levels presented no significant differences between the 2 groups at the different time points. On POD 0, a significant increased of platelet count (+ 9.2%; P b 0.0001), fibrinogen level (+ 12.2%; P b 0.0001) and PT (+ 4.1%; P b 0.01) and a significant decreased of the APTT (-4.2%; P b 0.01) were observed in the severe obesity group compared with the control group (Fig. 1). Fibrinogen level on POD 0 was significantly correlated to the BMI (r2 = 0.013; rho = 0.130; P b 0.0001). On POD 1, platelet count
Table 3 Endpoints.
Primary end-points CTO at 6 h (mL) CTO at 24 h (mL) Excessive bleeding at 6 h Excessive bleeding at 24 h Secondary endpoints Hospital mortality Atrial fibrillation Thromboembolic events MI Peak troponin I (μg/L) Stroke Transient ischemic attack Acute limb ischemia Acute mesenteric ischemia Sternal complications Deep infection Superficial infection Aseptic dehiscence Postoperative infection Bronchopneumopathy Urinary infection Endocarditis Renal function GFR on POD 0 GFR on POD 1 GFR at discharge Renal failure Dialysis Bleeding requiring reoperation Red blood cells transfusion Intraoperative (unit/patient) First 24 h (unit/patient) N4 units during the first 24 h Ventilation time (h) Ventilation b24 h ICU stay (days) ICU stay b2 days In-hospital stay (days)
Overall (n = 2799)
Control (n = 2595)
Severe obesity (n = 204)
P-value
330.1 ± 246.7 716.5 ± 406.9 279 (10.2) 275 (10.1)
335.5 ± 251.5 724.4 ± 414.9 270 (10.6) 267 (10.5)
262.1 ± 160.5 617.1 ± 267.6 9 (4.5) 8 (4.0)
b0.0001 b0.0001 0.005 0.003
70 (2.5) 773 (27.6) 80 (2.8) 22 (0.8) 13.9 ± 37.8 20 (0.7) 19 (0.6) 11 (0.4) 11 (0.4) 56 (2.0) 18 (0.6) 23 (0.8) 15 (0.5) 497 (17.7) 425 (15.9) 61 (2.1) 3 (0.1)
64 (2.5) 713 (27.5) 75 (2.9) 21 (0.8) 14.1 ± 38.6 17 (0.7) 18 (0.5) 11 (0.4) 11 (0.4) 48 (1.8) 16 (0.6) 22 (0.8) 10 (0.4) 456 (17.6) 388 (15.0) 53 (2.0) 3 (0.1)
6 (2.9) 60 (29.4) 5 (2.5) 1 (0.5) 11.8 ± 25.4 3 (1.5) 1 (0.5) 0 0 8 (3.9) 2 (1.0) 1 (0.5) 5 (2.5) 41 (20.1) 37 (18.1) 8 (3.9) 0
0.676 0.552 0.717 1.000 0.408 0.183 1.000 1.000 1.000 0.042
78.6 ± 25.8 78.0 ± 42.5 84.9 ± 32.1 279 (9.9 88 (3.1) 96 (3.4)
78.9 ± 25.9 78.7 ± 43.3 85.0 ± 31.5 258 (9.9) 80 (3.1) 92 (3.5)
75.2 ± 24.6 69.5 ± 28.3 83.8 ± 38.7 21 (10.3) 8 (3.9) 4 (2.0)
0.053 0.003 0.606 0.872 0.509 0.316
1.4 ± 1.8 1.9 ± 2.5 376 (13.4) 24.0 ± 76.3 2363 (84.4) 3.9 ± 6.6 1505 (59.4) 10.7 ± 8.8
1.4 ± 1.8 2.0 ± 2.5 357 (12.7) 23.6 ± 75.6 2191 (85.5) 3.9 ± 6.3 1393 (59.3) 10.7 ± 8.6
1.2 ± 1.6 1.5 ± 1.9 22 (10.7) 28.7 ± 84.4 172 (84.7) 4.2 ± 8.9 112 (60.5) 11.8 ± 10.6
0.180 0.014 0.253 0.357 0.779 0.500 0.736 0.075
0.363 0.222 0.077 1.000
CTO, chest tube output; excessive bleeding, mean CTO exceeding the 90th percentile of distribution; MI, transmural myocardial infarction; GFR, glomerular filtration rate determined by the MDRD equation (mL/min/1.73 m2); POD 0, postoperative day 0 or admission to the intensive care unit (ICU); POD 1, first postoperative date; Renal failure, a twofold increase in creatinine compared to the preoperative value.
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M. Kindo et al. / Thrombosis Research 134 (2014) 346–353
A
500
B
Control
6
P
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
The prothrombotic paradox of severe obesity after cardiac surgery under cardiopulmonary bypass Michel Kindo a,⁎, Tam Hoang Minh a, Sébastien Gerelli a, Nicolas Meyer b, Mickaël Schaeffer b, Stéphanie Perrier a, Jonathan Bentz a, Tarek Announe a, Arnaud Mommerot a, Olivier Collange c, Sandrine Marguerite c, Adrien Thibaud c, Hubert Gros c, Philippe Billaud a, Jean-Philippe Mazzucotelli a a b c
Department of Cardiovascular Surgery, University Hospitals of Strasbourg, France Department of Public Health, University Hospitals of Strasbourg, France Department of Surgical Intensive Care Unit and Anesthesiology, University Hospitals of Strasbourg, France
a r t i c l e
i n f o
Article history: Received 17 March 2014 Received in revised form 27 May 2014 Accepted 5 June 2014 Available online 12 June 2014 Keywords: Obesity Cardiopulmonary bypass Blood coagulation Hemorrhage Fibrinogen
a b s t r a c t Background: Obesity is suggested to reduce postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) but perioperative hemostasis variations have not been studied. Therefore, we investigated the effects of severe obesity (body mass index [BMI] ≥35 kg/m2) on chest tube output (CTO) and hemostasis in patients undergoing cardiac surgery with CPB. Materials and Methods: We prospectively investigated 2799 consecutive patients who underwent coronary and/ or valve surgery using CPB between 2008 and 2012. 204 patients (7.3%) presented a severe obesity. Results: In the severe obesity group, the 6-h and 24-h CTO were significantly reduced by -21.8% and -14.8% respectively (P b 0.0001) compared with the control group. A significant reduction of the mean number of red blood cell units transfused at 24 h was observed in the severe obesity groups (P = 0.01). On admission to the intensive care unit, a significant increase of platelet count (+ 9.2%; P b 0.0001), fibrinogen level (+ 12.2%; P b 0.0001) and prothrombin time (+4.1%; P b 0.01) and a significant decrease of the activated partial thromboplastin time (-4.2%; P b 0.01) were observed in the severe obesity group compared with the control group. In multivariate analysis, severe obesity was significantly associated to a decreased risk of excessive bleeding (24-h CTO N 90th percentile; Odds ratio: 0.37, 95% CI: 0.17 to 0.82). No significant differences were observed regarding postoperative thromboembolic events between the two groups. Conclusions: Severe obesity is associated with a prothrombotic postoperative state that leads to a reduction of postoperative blood loss in patients undergoing cardiac surgery with CPB. © 2014 Elsevier Ltd. All rights reserved.
Introduction Incidence of obesity (body mass index [BMI] ≥30 kg/m2) is increasing and is actually a major health problem [1]. Obesity is an independent risk factor for mortality mainly correlated to the high prevalence of diabetes mellitus and cardiovascular diseases in obese patients [1]. Hence among patients referred for cardiac surgery, the proportion of obese patients is increasing. Cardiac surgery with CPB induces coagulation activation, hemodilution, platelet dysfunction, fibrinolysis, endothelial dysfunction and proinflammatory state [2,3]. With some preoperative conditions, as antiplatelet and/or anticoagulant therapies, there is a high risk for patients
⁎ Corresponding author at: Department of Cardiovascular Surgery, NHC, 1 Place de l’Hôpital, BP 426, 67091 Strasbourg Cedex, France. Tel.: +33 3 69 55 08 11; fax: +33 3 69 55 18 87. E-mail address: [email protected] (M. Kindo).
http://dx.doi.org/10.1016/j.thromres.2014.06.008 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
undergoing cardiac surgery of postoperative bleeding and so the need of allogeneic blood product transfusions [2–4]. Red blood cells (RBC) transfusion and/or excessive postoperative blood loss increase mortality and morbidity after cardiac surgery [2,5–7]. For this reason, during the early postoperative course, the hemostasis control is a challenge with the need to control bleeding without the induction of pathologic thrombotic events [3]. Obesity is associated to a prothrombotic state due to increased thrombin formation, platelet hyperactivity and decreased fibrinolysis [1,8]. There are open issues and gaps in knowledge regarding the impact of this prothrombotic state on postoperative blood loss after cardiac surgery. Some studies have reported a significant reduction of reoperation for bleeding or RBC transfusion in obese patients [9–16]. Only three studies analyzed the mean chest tube output (CTO) after coronary artery bypass graft (CABG) surgery in obese patients with conflicting results [12,17,18]. Furthermore the effects of obesity on the coagulation cascade, platelet and fibrinolysis have not been yet explored in patients undergoing cardiac surgery with CPB.
M. Kindo et al. / Thrombosis Research 134 (2014) 346–353
The current study was, therefore, designed to determine the impact of BMI on postoperative blood loss and its effects on hemostasis after CABG and/or valvular surgeries under CPB. Methods Patients and Study Design A prospective cohort study of all consecutive patients undergoing cardiac surgery with CPB between October 1, 2008 and December 1, 2012, in our institution was performed. Inclusion criteria were age ≥18-years, valve and/or CABG surgeries. Exclusion criteria were surgery on the thoracic aorta, septal defect repair, ventricular aneurysm resection and perioperative need of ventricular assist device or extracorporeal life support. 2799 patients met the inclusion and exclusion criteria and were enrolled in this prospective, single-center, observational study. Perioperative data and outcomes were prospectively collected and validated. Study procedures were approved by the Institutional Review Board. Obesity was assessed by the BMI. Patients were classified into 2 groups: control group with a BMI b 35 kg/m2 (n = 2595; 92.7%) and severe obesity group with a BMI ≥35 kg/m2 (n = 204 patients; 7.3%; obese classes II and III of the International Classification of the World Health Organization). Unfractionated heparin anticoagulation to maintain an activated coagulation time (ACT) above 400 seconds was used during cardiopulmonary bypass (CPB). Patients received systematically intraoperative tranexamic acid infusion. At the end of CPB, protamine sulfate (dose/
347
dose) was given to reverse anticoagulation. Pericardial and/or pleural cavities were drained with small surgical drains (8 to 14 drains, each 9 mm diameter, Peters Surgical, France). Blood samples were harvested preoperatively, on admission to the intensive care unit (ICU) or postoperative day 0 (POD 0) and on the morning of the first postoperative day (POD 1). When postoperative anticoagulation was indicated unfractionated heparin or low molecular weight heparin was used as reported elsewhere [19]. All the patients had systematic deep venous thrombosis prevention with mechanical prophylaxis and low molecular weight heparin or low-dose unfractionated heparin. End-Points The primary end-point was the postoperative blood loss. It was defined by the mean CTO at 6 h and 24 h and the occurrence of an excessive bleeding defined as a mean CTO exceeding the 90th percentile of distribution at 6 h and 24 h after the end of the surgery. This threshold was chosen based on clinical experience at our institution. The 6-h and 24-h CTO values were missing for 3.5% and 3.7% patients respectively. The secondary end-points included perioperative variations of standard coagulation tests, in-hospital mortality from any cause and postoperative morbidities as: new atrial fibrillation, postoperative thromboembolic events (myocardial infarction, stroke, transient ischemic attack, acute mesenteric ischemia, acute limb ischemia, deep venous thrombosis), sternal complications (deep sternal wound infection, superficial sternal wound infection and sternal dehiscence requiring reoperation), postoperative infection (bronchopneumopathy,
Table 1 Preoperative characteristics.
Age (years) Female gender BMI (kg/m2) Smoker Diabetes Hypertension Hyperlipidemia Kidney failure Preoperative dialysis Chronic lung disease Stroke history Previous myocardial infarction Previous PCI Peripheral vascular disease Prior heart failure Previous cardiovascular surgery Preoperative atrial fibrillation Emergency surgery Logistic EuroSCORE (%) Antiplatelet and/or anticoagulant therapies Antiplatelet therapy Heparin Vitamin K antagonist Echocardiography data Left ventricular ejection fraction (%) Biological data Hemoglobin (g/dL) White blood cell count (109/L) Platelet count (103/mm3) Prothrombin time (%) Activated partial thromboplastin time (sec) Fibrinogen (g/L) GFR (ml/min/1.73 m2) Troponin I (μg/L)
Overall (n = 2799)
Control (n = 2595)
Severe obesity (n = 204)
P-value
67.5 ± 11.6 867 (31.0) 27.6 ± 4.9 1326 (47.4) 894 (31.9) 1914 (68.4) 1759 (62.8) 665 (23.8) 38 (1.4) 240 (8.6) 199 (7.1) 388 (13.9) 485 (17.3) 480 (17.1) 295 (10.5) 314 (11.2) 302 (10.8) 219 (7.8) 6.4 ± 7.9
67.6 ± 11.8 773 (29.8) 26.7 ± 3.8 1238 (47.7) 772 (29.7) 1744 (67.2) 1604 (61.8) 620 (24.9) 37 (1.4) 208 (8.0) 190 (7.3) 360 (13.9) 442 (17.0) 450 (17.3) 279 (10.8) 305 (11.8) 277 (10.7) 202 (7.8) 6.5 ± 8.1
66.6 ± 9.4 94 (46.1) 38.5 ± 3.7 88 (43.1) 122 (59.8) 170 (83.3) 155 (76.0) 45 (22.7) 1 (0.5) 32 (15.7) 9 (4.4) 28 (13.7) 43 (21.1) 30 (14.7) 16 (7.8) 9 (4.4) 25 (12.3) 17 (8.3) 5.4 ± 6.0
0.232 b0.0001 b0.0001 0.208 b0.0001 b0.0001 b0.0001 0.455 0.521 b0.0001 0.119 0.953 0.142 0.336 0.193 0.001 0.484 0.779 0.057
1722 (61.5) 130 (4.6) 435 (15.5)
1582 (61.0) 120 (4.6) 406 (15.6)
140 (68.6) 10 (4.9) 29 (14.2)
0.030 0.856 0.587
59.6 ± 11.7
59.6 ± 11.7
59.5 ± 12.1
0.957
13.4 ± 1.7 7.2 ± 2.6 232.4 ± 76.3 86.2 ± 20.3 36.2 ± 12.1 3.9 ± 1.1 76.9 ± 26.3 0.9 ± 16.6
13.4 ± 1.7 7.2 ± 2.6 232.4 ± 76.3 86.2 ± 20.3 36.3 ± 12.2 3.9 ± 1.1 76.8 ± 26.3 0.9 ± 16.6
13.3 ± 2.6 7.5 ± 2.6 232.6 ± 76.8 86.3 ± 19.5 35.0 ± 10.6 4.2 ± 1.2 77.9 ± 25.5 0.8 ± 3.7
0.332 0.087 0.968 0.949 0.185 b0.0001 0.551 0.863
The plus-minus values are the mean ± SD, and the others are no. (%). P-value, control group versus severe obesity group. Kidney failure, glomerular filtration rate (GFR) b60 mL/min/1.73 m2 determined with the MDRD equation; FVC, forced vital capacity; FEV, forced expiration volume in 1 second; PCI, percutaneous coronary intervention; Logistic EuroSCORE, 30-day operative mortality predicted by EuroSCORE I; GFR, glomerular filtration rate determined with the MDRD equation; Antiplatelet therapy, aspirin and/or clopidogrel treatment.
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urinary infection, endocarditis), renal failure, dialysis, bleeding requiring reoperation and RBC transfusion. Ventilation time, ICU stay and inhospital stay were also collected. Statistical Analysis The date are presented are mean ± standard deviation (SD). Differences between the categorical variables were tested using chi-square or Fisher’ exact tests, depending on the expected values. Differences between continuous variables were tested using the Student’s test or the Mann-Whitney test, depending on whether there was a Gaussian distribution. The link between BMI and perioperative variables was studied by non parametric tests (Mann-Whitney U test and Spearman’s rankorder correlation coefficient). Potential risk factors for significant postoperative bleeding (excessive bleeding group) were first tested using a univariate analysis. After performing a univariate analysis, only the variables with a P-value less than 0.150, which were determined using a 2-tailed t-test, were used in a multivariate logistic regression analysis (with a backward, stepwise method based on the likelihood ratio test). The odds ratios and their corresponding 95% confidence intervals are reported in addition to their associated p-values. The sample size was estimated as follows: for a type I error risk of 5%, a group ratio of 1/9 and a total sample size of 3000, a loss of 300 ± 250 ml at 6 h and a 15% decrease in blood loss for the obese group would achieve an 83% power. A 24 h blood loss of 700 ± 350 mL with a loss decrease of 10% in the obese group would achieve 90% power
with the same sample size of 3000. Different scenarios gave sample size estimates of around 2600 to 3000 subjects with power ranging from 80 to 90%. We thus considered that our data base would be large enough to show clinically relevant as well as statistically significant differences. The statistical computations were performed using R software (version 2.15.3) and SPSS (SPSS®, version 17.0, Chicago, IL). Results Preoperative and Operative Characteristics Preoperative characteristics in control and severe obesity groups are reported in Table 1. The patients in severe obesity group were younger, more likely to be female, and had an increased prevalence of diabetes, hypertension, hyperlipidemia and chronic lung disease (chronic obstructive pulmonary disease or restrictive lung disease) than in the control group. Previous cardiac surgery was more frequent in the control group. The preoperative used of anticoagulant (heparin or vitamin K antagonist used) did not significantly differ between the 2 groups. Antiplatelet therapies (aspirin and/or clopidogrel) were more often preoperatively used in severe obesity group than control group. Table 2 lists operative characteristics in the 2 groups. Aortic valve replacement was significantly more frequent in the severe obesity group whereas mitral valve repair and mitral valve replacement was significantly more frequent in the control group. For CABG surgery (isolated or combined to valvular surgery), no differences were observed between the 2 groups regarding the total number of distal anastomoses,
Table 2 Intraoperative data. Overall (n = 2799)
Control (n = 2595)
Severe obesity (n = 204)
Type of surgery Valvular surgery Isolated valvular surgery CABG Isolated CABG Valvular surgery and CABG Redo surgery
1577 (56.3) 1196 (42.7) 1603 (57.3) 1222 (43.7) 381 (13.6) 171 (6.1)
1468 (56.6) 1113 (42.9) 1482 (57.1) 1127 (43.4) 355 (13.7) 167 (6.4)
109 (53.4) 83 (40.7) 121 (59.3) 95 (46.6) 26 (12.7) 4 (2.0)
Valvular surgery Aortic valve replacement Aortic valve repair Mitral valve replacement Mitral valve repair Tricuspid valve replacement Tricuspid valve repair Mechanical valve replacement Biologic valve replacement
1155 (41.3) 18 (0.6) 241 (8.6) 247 (8.8) 9 (0.3) 79 (2.8) 432 (15.4) 906 (32.4)
1056 (40.7) 17 (0.7) 232 (8.6) 243 (9.4) 9 (0.3) 74 (2.9) 391 (15.1) 842 (32.4)
99 (48.5) 1 (0.5) 9 (4.4) 4 (2.0) 0 5 (2.5) 41 (20.1) 64 (31.4)
0.029 0.777 0.026 b0.001 1.000 0.739 0.055 0.752
CABG Total no. distal anastomoses Arterial no. distal anastomoses Venous no. distal anastomoses
2.7 ± 1.1 2.2 ± 1.0 0.5 ± 0.8
2.7 ± 1.1 2.2 ± 1.0 0.5 ± 0.8
2.7 ± 1.1 2.3 ± 0.9 0.4 ± 0.6
0.678 0.112 0.544
Cardiopulmonary bypass Cross clamp time (min) CPB time (min) Warm blood cardioplegia Residual blood processing by cell savage
89.1 ± 35.6 122.2 ± 45.6 730 (26.1) 1618 (57.8)
89.1 ± 35.5 122.3 ± 45.7 680 (26.2) 1499 (57.8)
89.1 ± 36.7 120.7 ± 44.2 50 (24.5) 119 (58.3)
0.980 0.625 0.596 0.874
Operative transfusion Red blood cells Fresh frozen plasma Platelet Albumin Fibrinogen concentrate Prothrombin complex concentrate Human antithrombin
1284 (45.9) 310 (11.1) 588 (21.0) 1025 (36.6) 104 (3.7) 167 (6.0) 87 (3.1)
1199 (46.3) 290 (11.2) 544 (21.0) 945 (36.5) 101 (3.9) 159 (6.1) 84 (3.2)
85 (41.6) 20 (9.8) 44 (21.5) 80 (39.2) 3 (1.4) 8 (3.9) 3 (1.4)
0.218 0.553 0.828 0.410 0.083 0.202 0.162
The plus-minus values are the mean ± SD, and the others are no. (%). P-value, control group versus severe obesity group. CPB, cardiopulmonary bypass; CABG, coronary artery bypass grafting; LITA, left internal thoracic artery; RITA, right internal thoracic artery.
P-value
0.384 0.540 0.540 0.384 0.708 0.006
M. Kindo et al. / Thrombosis Research 134 (2014) 346–353
the used of arterial grafts and the used of bilateral internal thoracic arteries. No differences were found regarding the used of warm cardioplegia among the 2 groups. The cross clamp and CPB times were similar in the 2 groups.
Postoperative Bleeding Mean CTO at 6 h and 24 h were significantly lower in the severe obesity group than in the control group (-21.8%, P b 0.0001 and -14.8%, P b 0.0001, respectively; Table 3). Excessive bleeding at 6 h and 24 h were defined as a mean CTO exceeding the 90th percentile (575.0 mL and 1160.0 mL, respectively). Severe obesity was associated with a significant reduction of excessive bleeding at 6 h and 24 h (P b 0.01, Table 3). The incidence of bleeding requiring reoperation did not differed significantly between the 2 groups (Table 3). Regarding the mean number of RBC transfused, a significant reduction was observed at 24 hours in severe obesity group (P = 0.01) but not intraoperatively (Table 3). The need to transfuse 5 or more RBC units during the first 24 h did not differ between the two groups (Table 3). There were a significant inverse correlation between BMI and CTO at 6 h (r2 = 0.0009; rho = -0.094; P b 0.0001) and 24 h (r2 = 0.008; rho = -0.087; P b 0.0001).
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Perioperative Variations of Standard Coagulation Tests, Hematocrit and Hemoglobin Regarding the preoperative standard coagulation tests as namely, platelet count, activated partial thromboplastin time (APTT) and prothrombin time (PT), no differences were found between the 2 groups (Fig. 1 and Table 1). Only the preoperative fibrinogen level was significantly higher in the severe obesity group than in the control group (P b 0.0001; Fig. 1B and Table 1). Preoperative fibrinogen level was significantly correlated to the BMI (r2 = 0.008; rho = 0.098; P b 0.0001). The baseline ACT performed in the operating room before heparinization was significantly higher in the obese group compared with the control group (120.2 ± 16.7 versus 117.3 ± 16.2 sec; P = 0.01; respectively). No significant differences of the operative ACT at the beginning of CPB, before the completion of CPB, at the end of the surgery and the lowest value during the CPB were observed between the 2 groups. Operative hematocrit levels presented no significant differences between the 2 groups at the different time points. On POD 0, a significant increased of platelet count (+ 9.2%; P b 0.0001), fibrinogen level (+ 12.2%; P b 0.0001) and PT (+ 4.1%; P b 0.01) and a significant decreased of the APTT (-4.2%; P b 0.01) were observed in the severe obesity group compared with the control group (Fig. 1). Fibrinogen level on POD 0 was significantly correlated to the BMI (r2 = 0.013; rho = 0.130; P b 0.0001). On POD 1, platelet count
Table 3 Endpoints.
Primary end-points CTO at 6 h (mL) CTO at 24 h (mL) Excessive bleeding at 6 h Excessive bleeding at 24 h Secondary endpoints Hospital mortality Atrial fibrillation Thromboembolic events MI Peak troponin I (μg/L) Stroke Transient ischemic attack Acute limb ischemia Acute mesenteric ischemia Sternal complications Deep infection Superficial infection Aseptic dehiscence Postoperative infection Bronchopneumopathy Urinary infection Endocarditis Renal function GFR on POD 0 GFR on POD 1 GFR at discharge Renal failure Dialysis Bleeding requiring reoperation Red blood cells transfusion Intraoperative (unit/patient) First 24 h (unit/patient) N4 units during the first 24 h Ventilation time (h) Ventilation b24 h ICU stay (days) ICU stay b2 days In-hospital stay (days)
Overall (n = 2799)
Control (n = 2595)
Severe obesity (n = 204)
P-value
330.1 ± 246.7 716.5 ± 406.9 279 (10.2) 275 (10.1)
335.5 ± 251.5 724.4 ± 414.9 270 (10.6) 267 (10.5)
262.1 ± 160.5 617.1 ± 267.6 9 (4.5) 8 (4.0)
b0.0001 b0.0001 0.005 0.003
70 (2.5) 773 (27.6) 80 (2.8) 22 (0.8) 13.9 ± 37.8 20 (0.7) 19 (0.6) 11 (0.4) 11 (0.4) 56 (2.0) 18 (0.6) 23 (0.8) 15 (0.5) 497 (17.7) 425 (15.9) 61 (2.1) 3 (0.1)
64 (2.5) 713 (27.5) 75 (2.9) 21 (0.8) 14.1 ± 38.6 17 (0.7) 18 (0.5) 11 (0.4) 11 (0.4) 48 (1.8) 16 (0.6) 22 (0.8) 10 (0.4) 456 (17.6) 388 (15.0) 53 (2.0) 3 (0.1)
6 (2.9) 60 (29.4) 5 (2.5) 1 (0.5) 11.8 ± 25.4 3 (1.5) 1 (0.5) 0 0 8 (3.9) 2 (1.0) 1 (0.5) 5 (2.5) 41 (20.1) 37 (18.1) 8 (3.9) 0
0.676 0.552 0.717 1.000 0.408 0.183 1.000 1.000 1.000 0.042
78.6 ± 25.8 78.0 ± 42.5 84.9 ± 32.1 279 (9.9 88 (3.1) 96 (3.4)
78.9 ± 25.9 78.7 ± 43.3 85.0 ± 31.5 258 (9.9) 80 (3.1) 92 (3.5)
75.2 ± 24.6 69.5 ± 28.3 83.8 ± 38.7 21 (10.3) 8 (3.9) 4 (2.0)
0.053 0.003 0.606 0.872 0.509 0.316
1.4 ± 1.8 1.9 ± 2.5 376 (13.4) 24.0 ± 76.3 2363 (84.4) 3.9 ± 6.6 1505 (59.4) 10.7 ± 8.8
1.4 ± 1.8 2.0 ± 2.5 357 (12.7) 23.6 ± 75.6 2191 (85.5) 3.9 ± 6.3 1393 (59.3) 10.7 ± 8.6
1.2 ± 1.6 1.5 ± 1.9 22 (10.7) 28.7 ± 84.4 172 (84.7) 4.2 ± 8.9 112 (60.5) 11.8 ± 10.6
0.180 0.014 0.253 0.357 0.779 0.500 0.736 0.075
0.363 0.222 0.077 1.000
CTO, chest tube output; excessive bleeding, mean CTO exceeding the 90th percentile of distribution; MI, transmural myocardial infarction; GFR, glomerular filtration rate determined by the MDRD equation (mL/min/1.73 m2); POD 0, postoperative day 0 or admission to the intensive care unit (ICU); POD 1, first postoperative date; Renal failure, a twofold increase in creatinine compared to the preoperative value.
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A
500
B
Control
6
P
