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  • Research article
  • Open Access
  • Open Peer Review

Six-years survival and predictors of mortality after CABG using cold vs. warm blood cardioplegia in elective and emergent settings

  • 1Email author,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 2,
  • 3,
  • 4,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 1
Contributed equally
Journal of Cardiothoracic Surgery201510:180

https://doi.org/10.1186/s13019-015-0384-9

  • Received: 16 February 2015
  • Accepted: 18 November 2015
  • Published:
Open Peer Review reports

Abstract

Background

The aim of this study was to determine whether intermittent warm blood cardioplegia (IWC) is associated with comparable myocardial protection compared to cold blood cardioplegia (ICC) in patients undergoing elective vs. emergent CABG procedures.

Methods

Out of 2292 consecutive patients who underwent isolated on-pump CABG surgery using cardioplegic arrest either with ICC or IWC between January 2008 and December 2010, 247 consecutive emergent patients were identified and consecutively matched 1:2 with elective patients based on gender, age (<50 years, 50–70 years, >70 years) and ejection fraction (<40 %, 40–50 %, >50 %). Perioperative outcomes and long-term mortality were compared between ICC and IWC strategies and predictors for 30-day mortality and perioperative myocardial injury were identified in both elective and emergent subgroups of patients.

Results

Preoperative demographics and baseline characteristics, logistic Euroscore, CPB-time, number of distal anastomoses and LIMA-use were comparable. Aortic cross clamp time was significantly longer in the IWC-group regardless of the urgency of the procedure (p = 0.05 and p = 0.015 for emergent and elective settings). There were no significant differences regarding ICU-stay, ventilation time, total blood loss and need for dialysis. The overall 30-day, 1-, 3- and 6-year survival of the entire patient cohort was 93.7, 91.8, 90.4 and 89.1 %, respectively, with significantly better outcomes when operated electively (p < 0.001) but no differences between ICC and IWC both in elective (p = 0.857) and emergent (p = 0.741) subgroups. Multivariate analysis did not identify the type of cardioplegia as a predictor for 30-day mortality and for perioperative myocardial injury. However, independent factors predictive of 30-day mortality were: EF < 40 % (OR 3.66; 95 % CI: 1.79–7.52; p < 0.001), atrial fibrillation (OR 3.33; 95 % CI: 1.49-7.47; p < 0.003), peripheral artery disease (OR 2.51; 95 % CI: 1.13–5.55; p < 0.023) and COPD (OR 0.26; 95 % CI: 1.05–6.21; p < 0.038); predictors for perioperative myocardial infarction were EF < 40 % (OR 2.04; 95 % CI: 1.32–3.15; p < 0.001), preoperative IABP support (OR 3.68; 95 % CI: 1.34-10.13; p < 0.012), and hemofiltration (OR 3.61; 95 % CI: 2.22–5.87; p < 0.001).

Conclusion

Although the aortic cross clamp time was prolonged in the IWC group our results confirm effective myocardial protection under IWC, regardless of the urgency of the procedure. We suggest that intermittent warm cardioplegia in emergent CABG setting is a low-cost alternative and safe. It is associated with similar long-term outcomes both in elective and emergent settings compared to intermittent cold cardioplegia.

Keywords

  • Coronary Artery Bypass Grafting
  • Myocardial Protection
  • Blood Cardioplegia
  • Coronary Artery Bypass Grafting Patient
  • Aortic Cross Clamp Time

Background

The concept of myocardial protection during cardiac surgery have been already described in detail in the 1950s by Bigelow, who proposed to use hypothermia as a strategy to protect the myocardium in heart surgery [1]. In this respect, a reduction in myocardial oxygen consumption up to 80 % can be achieved by lowering the blood temperature up to 20 °C. However, the disadvantage of the isolated hypothermia without an additional usage of cardioplegia results in an incomplete electromechanical cardiac arrest with ventricular fibrillation. Therefore, subsequent studies by Gay and Ebert support the use of potassium-rich solution for the induction of diastolic cardiac arrest by depolarization [2]. In addition, further development of blood cardioplegia by Follette and Buckberg as a composition of blood and crystalloid solution improved myocardial protection enormously [2, 3]. Finally, the next breakthrough was the development of normothermic blood cardioplegia in which Calafiore has set new standards in myocardial protection during cardiac surgery [4, 5].

Currently, a large variety of techniques for myocardial protection is available in cardiac surgery. Most surgical centers in the USA and west european countries preferably apply blood cardioplegia as several studies indicated superiority of blood cardioplegia over crystalloid solutions [6]. Nevertheless, the debate over the optimal cardioplegia strategy, the way of application and temperature is still under discussion [7]. Moreover, other additional potentially cardioprotective effects on ischemic myocardium are discussed in the literature [8]. In our institution intermittent blood cardioplegia is used in coronary artery bypass grafting (CABG) patients and is administered antegradely either as intermittent normothermic cardioplegia (IWC) according to Calafiore’s warm blood cardioplegia or intermittent hypothermic cardioplegia (ICC) according to Buckberg’s cold blood cardioplegia. Nowadays, the IWC as a simple and cost-effective method is in widespread use throughout the world. Whereas several studies have been focused on differences and similarities in blood cardioplegia in elective CABG patients, there has been a lack of evidence in terms of applicability of different cardioplegia in emergent settings. The aim of the present study was to critically examine both myocardial protection strategies in patients undergoing emergent CABG and patients receiving elective CABG.

Methods

Patients

This was a retrospective study at the Heart Center of the University of Cologne with a cohort consisting of a total of 2292 patients who underwent isolated CABG from January 2008 to December 2010. Of them 247 consecutive patients were treated as an emergency and were consecutively matched 1:2 with elective coronary bypass patients based on age (<50, 50–70 or >70 years), gender and ejection fraction (<40 %, 40–50 % or >50 %). Due to several missing values in terms of preoperative patient characteristics and differences regarding baseline data between elective and emergent patients, the number of elective patients with exact matching criteria reached 448. In total, we explored two groups with a total number of 695 patients, subsequently dividing them depending on the blood cardioplegia strategy, with 176 patients (25.3 %) receiving ICC versus 506 patients (72.8 %) receiving IWC. A total of 13 patients were excluded after matching due to missing variables of interest. A subgroup analysis for each urgency status was performed. Furthermore, factors associated with early mortality as well as independent factors predictive of 30-day mortality in elective and emergent settings were evaluated.

Operation technique

CABG was standardized in terms of surgical technique and perioperative management. In brief, all operations were performed with cardiopulmonary bypass (CPB) via median sternotomy. CPB was implemented with arterial cannulation of the ascending aorta and venous drainage which was connected to the right atrium with a two-stage venous cannula. A root suction was always placed in the aortic root. Left and/or right internal mammary arteries (LIMA and RIMA) and/or venous grafts were used as graft material. Distal anastomoses were connected during the total aortic cross clamp time. Proximal anastomoses were performed within reperfusion time using a partial clamping technique of the ascending aorta. Finally, after decannulation, insertion of chest drains and sternal closure intubated patients were transferred to the intensive care unit (ICU).

Application of cardioplegia

In terms of cardioplegia protocol in our institution, the so called „cold induction“ and „cold reinfusion“ Buckberg cardioplegia is normally used. The components are supplied separately in two bottles (400 mL and 100 mL) and are first mixed together when needed. The induction cardioplegia solution contains: 400 mL of high potassium concentration with KCl 34 mmol, THAM 17.45 mmol and NaCl 16.12 mmol; following substances are added with the second 100 mL bottle: citric acid 0.45 mmol x H2O, sodium citrate 2.60 mmol x 2 H2O, sodium hydrogen phosphate 0.47 mmol x 2 H2O and glucose 92.42 mmol x H2O. For the reinfusion cardioplegia there are also two bottles that are first mixed when needed: 400 mL low potassium concentration of KCl 16.90 mmol, THAM 18.30 mmol and NaCl 16.90 mmol. As with induction cardioplegia, additional substances are added from the 100 mL bottle: citric acid 0.48 mmol, sodium citrate 2.73 mmol, sodium hydrogen phosphate 0.49 mmol and glucose 96.93 mmol. This concentrated solution is diluted in a ratio 1:4 with blood to provide oxygen, the desired pH and osmolarity. The cardioplegic induction solution with high potassium concentration is delivered over 4 min to initiate cardiac arrest whereas the following reinfusion solution with lower potassium concentration is delivered over 2 min to maintain cardiac arrest every 15–20 min.

Cardioplegia was delivered into the aortic root immediately after cross clamping ascending aorta and re-infused into vein grafts after completion of the distal anastomosis in patients with severely obstructed or occluded coronary arteries. In the ICC group, cardiac arrest was initiated by cold induction using a mixture of the patient’s own blood with the crystalloid Buckberg solution (Dr. Franz Köhler Chemie GmbH, Germany) at a ratio of 1 to 4 and blood flow rate of 200–300 mL/min. Patients were receiving cold (4–6 °C) blood cardioplegia for 4 min aiming for a potassium target dose of 20 mmol/L. In the ICC group the body temperature was routinely cooled down to 34 °C. According to our institutional policy there was no additional topical cooling. While the aorta was cross clamped, intermittent re-infusions for 2–4 min each with ICC were applied at intervals of 15–20 min. Despite recommendations by the Buckberg protocol warm terminal reperfusion (‘hot shot’) was not infused prior to aortic unclamping in our center. Over the study period a total of 8 surgeons were performing elective and emergent CABG. Whereas 3 surgeons were advocates of Buckberg cardioplegia (ICC), other 5 surgeons were proponents of Calafiore cardioplegia (IWC). There were no surgeons who had used both types of cardioplegia dependent on clinical factors. Also, as it is a retrospective analysis, the choice of cardioplegia could not be influenced.

According to our institutional policy the body temperature using IWC was maintained between 36 °C and 37 °C. In the IWC group, infusion of normothermic (37 °C) oxygenated blood was administered to the aortic root using a standardized setup. A syringe pump was connected to the extracorporeal circulation containing a modified mixture of 30 mL of KCl (2 mmol/L) and 10 ml of MgSO4 (2 mmol/L). Cardiac arrest was induced by a syringe pump with the flow rate of 150 mL/h at a blood flow rate of 200–300 mL/min for approximately 2 min with the aim to achieve potassium concentration of 20 mmol/L and magnesium target dose of 5 mmol/L. In cases when cardiac arrest was not achieved immediately, an additional bolus injection of 3–4 ml cardioplegia was infused. Thereafter, the cardioplegic solution was repeatedly administered every 15 min or after completion of each distal anastomosis, whereby the flow rate of the syringe pumps was reduced (120-90-60 mL/h) according the protocol of Calafiore et al. [5].

Data collection

All data were collected from our institutional database. The Electronic Patient Record of our department contains all patient data, such as demographics, preoperative risk factors, intra- and postoperative data. Moreover, the preoperative medication, especially the use of aspirin and clopidogrel and their discontinuation were recorded. In addition, laboratory values were obtained from the institutional database.

Definitions

Thirty day mortality was defined as death of any cause within 30 days after CABG. Perioperative myocardial infarction (PMI) was defined as the combination of the two following criteria proposed by Liakopoulos et al. [8] higher than fivefold increase in creatine kinase MB (CK-MB >120 U/L) including CK-MB fraction range of 6–25 % and an increase in Troponin T over 1.5 ng/mL within 72 h after surgery. Further studies have also shown that those laboratory tests are qualified for the diagnostics of PMI in patients undergoing cardiac surgery, especially Troponin T [1012].

Statistical analysis

Statistical analysis was performed using the IBM SPSS statistics version 19 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation and categorical variables given as absolute values and percentages. A comparison of the two groups was done using ANOVA for continuous variables and Chi square test or Fisher exact test for categorical variables. P values of < 0.05 were considered statistically significant. Univariate analysis was executed to demonstrate associations between outcome and perioperative variables. Binary logistic regression analysis was performed to detect independent predictors for 30-day mortality. Kaplan-Meier Survival analysis was performed with the view to presenting long-term outcomes of the entire patient cohort as wall as comparing outcomes in subgroups.

Results

Patient demographics and preoperative baseline characteristics are listed in Table 1. There were no statistically significant differences between ICC and IWC groups except for proportion of patients on regular statin medication (66.7 % in the ICC group vs. 80.7 % in the IWC group, p = 0.035) in the emergent subgroup and with the presence of left main disease with more than 50 % stenosis (34.5 % in the ICC group vs. 23.5 % in the IWC group, p = 0.026) in the elective subgroup. Patients were comparable in terms of past medical history, cardiac risk factors, preoperative medication and logistic Euroscore.
Table 1

Preoperative data, emergent vs. elective CABG devided in ICC and IWC

 

Emergent CABG

Elective CABG

 

ICC

IWC

 

ICC

IWC

 
 

n

%

n

%

p-Wert

n

%

n

%

p-Wert

Age > 70

23

36.5

63

36.2

 

45

39.8

117

35.2

 

Female gender

14

22.2

36

20.7

0.857

24

21.2

71

21.4

1.000

HT

49

27.8

142

28.2

0.450

105

59.7

295

58.3

0.279

Pulm. HT

6

9.5

11

6.5

0.410

4

3.5

12

3.6

1.000

Hyperlipidemia

46

73.0

12

65.1

0.276

92

81.4

261

78.6

0.592

Diab. mellitus

16

25.4

58

33.5

0.269

38

33.6

134

40.4

0.220

BMI > 30

14

22.2

43

24.7

0.734

42

37.2

98

29.5

0.159

AF

14

23.7

33

22.2

0.857

5

4.4

20

6.0

0.641

3 V-CAD

50

79.4

136

78.2

1.000

97

85.8

274

82.5

0.467

LMS

31

49.2

81

47.1

0.883

39

34.5

78

23.5

0.026

COPD

4

6.3

20

11.6

0.332

15

13.3

35

10.5

0.490

PAD

10

15.9

31

17.9

0.847

20

17.7

52

15.7

0.658

Smoker

30

47.6

91

52.9

0.556

46

40.7

137

41.3

1.000

Crea >2

5

7.9

11

6.3

0.770

2

1.8

11

3.3

0.317

CVA

8

12.7

31

18.0

0.429

12

13.3

57

17.2

0.377

Beta-blocker

48

76.2

139

81.3

0.462

86

76.1

274

82.5

0.165

Statin

42

66.7

138

80.7

0.035

92

81.4

256

77.1

0.359

Antiplatel.

55

91.7

156

94.5

0.532

26

23.0

54

16.3

0.120

EF < 40 %

23

36.5

48

27.6

 

33

29.2

97

29.2

 

Euroscore Logistic

29.82 ± 27.14

25.09 ± 23.95

0.214

7.26 ± 10.91

7.20 ± 9.48

0.953

Preoperative Data: emergent- vs. elective CABG devided in intermittent cold cardioplegia (ICC) and intermittent warm cardioplegia (IWC) accordingto Buckberg and Calafiore, respectively. Arterial fibrillation (AF), 3 vessel-coronary artery disease (3 V-CAD), cerebrovascular accident(CVA), Hypertension (HT), left main stenosis (LMS), peripherial artery disease (PAD)

Table 2 represents intra-operative patient data for both groups. In the emergent subgroup, patients receiving IWC had longer cross clamp time (41.1 ± 13.9 vs. 35.4 ± 12.2 min, p = 0.005), whereas patients receiving ICC were associated with significantly longer administration time (5.9 ± 2,2 vs. 5.0 ± 2.7 min, p = 0.017) and amount (329 ± 155 vs. 18.5 ± 5.6 ml, p < 0.001) of cardioplegia compared to IWC group. Similar associations were also found within the elective subgroup. In terms of intraoperative data within both subgroups there were no statistically significant differences in CPB, operation and, reperfusion time, and the usage of IMA. Groups were also comparable regarding phosphodiesterase-III-inhibitor usage, and the need for hemofiltration.
Table 2

Intraoperative data, emergent vs. elective CABG devided in ICC and IWC

 

Emergent CABG

Elective CABG

 

ICC

IWC

 

ICC

IWC

 
 

n

%

n

%

p-Wert

n

%

n

%

p-Wert

AOX (min)

35.38 ± 12.16

41.05 ± 13.91

0.005

39.92 ± 12.65

43.96 ± 15.85

0.015

CBP (min)

81.81 ± 37.75

90.50 ± 38.68

0.121

77.96 ± 25.20

82.93 ± 32.25

0.138

OP-time (min)

182.03 ± 46.10

198.52 ± 64.67

0.064

184.39 ± 46.24

201.31 ± 95.14

0.092

Number of distal grafts

2.94 ± 0.76

3.09 ± 0.91

0.245

3.01 ± 0.84

2.93 ± 0.78

0.386

LIMA use

58

92.1

158

90

1.000

107

94.7

315

94.9

1.000

RIMA use

7

11.1

27

15.5

0.530

28

24.8

83

25.0

1.000

Reperfusion time (min)

34.87 ± 22.05

38.35 ± 27.35

0.366

28.54 ± 12.69

30.72 ± 17.55

0.225

Cardioplegia time (min)

5.91 ± 2.22

5.01 ± 2.68

0.017

7.03 ± 3.05

5.08 ± 2.73

0.000

Cardioplegia in (mL)

329.02 ± 155.43

18.54 ± 5.6

0.000

370 ± 125.60

19.15 ± 21.51

0.000

Hemofiltration

22

34.9

48

27.6

0.333

13

11.5

37

11.1

1.000

PDI (Corotrop)

21

34.4

63

36.4

0.877

13

15.9

75

22.6

0.143

Intraoperative patients data: emergent- vs. elective CABG devided in intermittent cold cardioplegia (ICC) and intermittent warm cardioplegia (IWC). Aortic clamp time (AOX), cardiopumonary bybass (CBP), LIMA (left internal mammary artery), RIMA (right internal mammary artery), phospodiesterase inhibitor (PDI)

Postoperative patients’ characteristics are presented in Table 3. The mean number of platelet units transfused in the elective subgroup was 0.62 ± 1.43 in the ICC group and 0.31 ± 0.72 in the IWC group (p = 0.003). The 30-day all cause mortality in the elective subgroup tended to be increased in the IWC group with 2 % in contrast to 0 % in ICC group, however it did not reach statistical significance (p = 0.072). Similarly, in the emergent subgroup, the 30-day mortality was 5,1 % in the ICC group vs. 4,2 % in the IWC group not reaching statistical significance. During cardiac surgery in the emergent subgroup 10.8 % patients of the ICC group received an intra-aortic balloon pump (IABP) compared to 6.5 % of the IWC group also not reaching statistical significance (p = 0.077). Further outcome variables, such as PMI, length of hospital and ICU stay, ventilation duration, extracorporeal membrane oxygenation (ECMO), dialysis, inotropic support, blood transfusion and total blood loss were also not statistically different. Long-term outcomes in terms of overall cumulative survival are presented in Figure 1. The overall 30-day, 1-, 3- and 6-year survival of the entire patient cohort was 93.7, 91.8, 90.4 and 89.1 %, respectively, with significantly better outcomes when operated electively (p < 0.001) but no differences between ICC and IWC both in elective (p = 0.857) and emergent (p = 0.741) subgroups.
Table 3

Postoperative data, emergent vs. elective CABG devided in ICC and IWC

 

Emergent CABG

Elective CABG

 

ICC

IWC

 

ICC

IWC

 
 

n

%

n

%

p-value

n

%

n

%

p-value

30 day mortality

9

5.1

31

4.7

0.661

0

0.0

10

2.0

0.072

PMI

12

6.8

28

U

0.563

13

7.4

31

6.1

0.584

ICU(d)

6.44 ± 11.80

5.73 ± 5.70

0.536

3.83 ± 4.15

4.01 ± 4.50

0.708

Hospital (d)

13.19 ± 12.77

13.53 ± 9.39

0.825

12.98 ± 7.21

13.05 ± 6.20

0.979

Duration of ventilation (h)

109.85 ± 171.87

76.85 ± 150.32

0.194

44.45 ± 168.25

30.97 ± 73.03

0.24/

IABP

 - preop

10

5.7

19

3.8

0.370

1

0.6

2

0.4

1.000

 - intraop

19

10.8

33

6.5

0.077

2

1.1

8

1.6

1.000

 - postop

3

1.7

9

1.8

1.000

1

0.6

5

1.0

1.000

ECMO

5

2.8

11

2.2

0.770

0

0.0

0

0.0

 

Blood transfusion

 - RBC

7.76 ± 12.92

5.96 ± 7.30

0.183

3.93 ± 5.79

3.45 ± 5.07

0.401

 - FFP

4.43 ± 6.8

2.79 ± 4.21

0.210

1.50 ± 3.95

1.19 ± 3.29

0.411

 - Platelets

1.46 ± 1.45

1.05 ± 1.10

0.220

0.62 ± 1.43

0.31 ± 0.72

0.003

Total blood loss (ml)

1537.81 ± 1049.81

1400.17 ± 1019.14

0.425

1085.00 ± 715.66

962.03 ± 622.91

0.084

Dialysis

3

1.7

21

4.2

0.142

3

1.7

11

2.2

1.000

Inotropie support > 24 h

14

8.9

48

10.1

0.858

23

14.6

56

11.7

0.390

Inotropie support > 48 h

17

10.8

58

12.2

0.734

12

7.6

52

10.9

0.274

Postoperative patients data: emergent- vs. elective CABO devided in intermittent cold cardioplegia (ICC) and Intermittent warm cardioplegia (IWC). Extra Corporeal Mrrubianr Onygrri.ition (ECMO), inti.i aortic balloon pump countrrpuKation (IABP), prfimycK.irdi.il infarction (PMI)

Fig. 1
Fig. 1

Long-term overall cumulative survival of the entire patient cohort with 30-day, 1-, 3- and 6-year survival of 93.7, 91.8, 90.4 and 89.1 %, respectively (left upper graph); significantly better outcomes when operated electively (p < 0.001, right upper graph); no differences between ICC and IWC groups both in elective (p = 0.857, left lower graph) and emergent (p = 0.741, right lower graph) subgroups

Univariate regression analysis was executed (Tables 4 and 5), in order to show possible associations of early clinical outcome with determined variables. There were no associations found between each clinical endpoint and the application of IWC or ICC.
Table 4

Univariate analysis, primary endpoint: 30-days mortality

Univariate analysis, primary endpoint: 30-days mortality (n = 45)

Variable

Yes

No

O.R.

95 %-C.I.

p-value

 

n

%

n

%

Age > 70 y

17

37.8

28

6.4

1.04

(0.56 – 1.95)

0.875

Female

13

28.9

32

5.9

1.55

(0.79 – 3.03)

0.192

HT

35

79.5

9

9.9

0.55

(0.26 – 1.22)

0.163

pulmonal. HT

7

16.3

36

5.5

4.44

(1.81 – 10.89)

0.003

HLP

21

47.7

23

13.4

0.27

(0.15 – 0.51)

<0,001

Diab. mellitus

18

40.0

27

6.1

1.18

(0.64 – 2.19)

0.632

BMI > 30

13

28.9

32

6.5

1.01

(0.52 – 1.96)

1.000

AF

15

34.1

29

4.8

4.60

(2.34 – 9.03)

<0,001

3 V–CAD

32

71.1

13

10.1

0.54

(0.27 – 1.05)

0.074

LMS

20

44.4

25

5.4

1.63

(0.89 – 3.00)

0.141

COPD

9

20.0

36

5.8

2.13

(0.99 – 4.62)

0.080

PAD

15

33.3

30

5.2

2.62

(1.36 – 5.03)

0.007

Smoker

22

50.0

22

5.7

1.27

(0.59 – 2.33)

0.531

Crea >2

6

14.0

37

5.7

4.32

(1.66 – 11.24)

0.007

Renal insuff. preop. Crea <2

23

51.1

22

4.7

2.25

(1.23 – 4.14)

0.013

CVA

6

13.6

38

6.6

0.79

(0.33 – 1.91)

0.333

Beta–blocker

27

62.8

16

11.8

0.38

(0.20 – 0.73)

0.005

Statin

22

51.2

21

13.6

0.27

(0.14 – 0.51)

<0,001

Antiplatelet

29

67.4

14

3.6

2.90

(1.50 – 5.59)

<0,001

EF < 40 %

30

66.7

15

3.1

5.36

(2.82 – 10.21)

<0,001

EF 40–50 %

8

17.8

37

7.0

0.70

(0.32 – 1.53)

0.466

EF >50 %

7

15.6

38

10.4

0.19

(0.08 – 0.43)

<0,001

Euroscore > =6

40

95.2

2

0.6

16.98

(4.07 – 70.85)

<0,001

IABP preop.

6

13.3

39

5.9

3.68

(1.43 – 9.45)

0.013

NYHA III + IV

34

75.6

11

3.3

2.96

(1.48 – 5.94)

0.002

Emergent CABG

34

75.6

11

2.5

6.43

(3.15 – 12.76)

<0,001

preop. myocardial infarction

22

50.0

22

4.4

3.26

(1.76 – 6.06)

<0,001

Time between angiography and operation:

<3d

27

65.9

14

3.2

4.41

(2.26 – 8.60)

<0,001

<24 h

26

63.4

15

3.1

5.79

(2.99 – 11.24)

<0,001

OP–time after 08.00 pm

6

13.3

39

6.2

1.57

(0.64 – 3.86)

0.292

ICC cardioplegia

10

23.8

32

6.3

0.89

(0.43 – 1.86)

0.857

IWC cardioplegia

31

73.8

11

6.2

0.99

(0.48 – 2.00)

1.000

AoX < 80 min

37

88.1

5

35.7

0.11

(0.03 0.33)

0.001

AoX > 60 min

6

14.3

36

5.9

1.39

(0.57 – 3.43)

0.444

AoX >45 min

13

31.0

29

6.3

0.91

(0.46 – 1.78)

0.866

CPB >180 min

10

22.7

34

5.0

37.82

(12.25 116.80)

<0,001

CPB > 120 min

20

45.5

24

3.9

9.36

(4.85 – 18.04)

<0,001

OP–time > 180 min

33

73.3

12

3.9

2.47

(1.25 – 4.88)

0.008

Reperfusion time > 60 min

17

39.5

26

4.1

13.40

(6.57 – 27.34)

<0,001

Hemofiltration

27

60.0

IS

3.2

8.54

(4.53 – 16.10)

<0,001

PDI (Corotrop)

24

54.5

20

2.9

3.71

(2.00 – 6.90)

<0,001

PMI

36

80.0

9

1.7

14.71

(6.92 – 31.26)

<0,001

ICU > 3d

29

69.0

13

3.3

3.28

(1.67 – 6.43)

<0,001

ICU > 5d

19

45.2

23

4.6

2.52

(8.83 – 34.82)

0.006

ICU > 7d

16

38.1

26

4.8

2.59

(1.35 – 4.97)

0.005

ICU > 10d

12

28.6

30

5.1

3.13

(1.53 – 6.38)

0.003

Hospital stay > 15 d

10

22.7

34

6.3

1.07

(0.51 – 2.21)

0.851

Ventilation time >48 h

23

62.2

14

2.6

11.23

(5.54 – 22.73)

<0,001

IABP preop.

27

60.0

18

2.9

15.91

(8.25 – 30.67)

<0,001

ECMO

15

33.3

30

4.4

107.83

(29.61 – 392.72)

<0,001

Blood transfusion

43

100.0

0

0.0

0.92

(0.90 – 0.94)

0.068

RBC Unit >5

31

68.9

14

2.7

8.48

(4.39 – 16.39)

<0,001

Total blood loss >1l

19

65.6

10

2.7

2.62

(1.20 – 5.73)

0.020

Total blood loss >2l

12

41.4

17

3.0

6.17

(2.82 – 13.52)

<0,001

Dialysis

12

26.7

33

5.0

8.08

(3.77 – 12.30)

<0,001

Inotropie support >48 h

26

89.7

3

0.8

12.19

(3.65 40.70)

<0,001

ACT > 150 sec

10

41.7

14

3.1

4.33

(1.85 – 10.10)

<0,001

Pneumonia

10

22.7

34

5.1

12.39

(5.19 – 29.62)

<0,001

Wound infection

3

6.8

41

6.5

0.77

(0.23 – 2.57)

1.000

Operative re–exploration

13

29.5

31

4.8

6.91

(3.34 – 14.31)

<0,001

Pre-rintra- and postoperative data in univariate analysis. The nominal variables are shown in absolute and percentage figures. Cerebrovascular accident (CVA), 3 vessel coronary artery disease (3-V CAD), left main stenosis (LMS), Red blood cells (RBC)

Table 5

Univariate analysis, primary endpoint: Perimyocardial Infarction (PMI)

Univariate analysis, primary endpoint: PMI (n = 175)

Variable

Yes

No

O.R.

95 %-C.I.

p-value

n

%

n

%

 

Age > 70 years

66

(37.7)

109

(24.8)

1.05

(0.74 – 1.50)

0.786

Female

36

(20.6)

139

(25.4)

0.94

(0.62 – 1.44)

0.832

HT

141

(S1.0)

33

(35.3)

0.54

(0.34 – 0.85)

0.013

pulmonal HT

14

(8.1)

158

(24–2)

2.19

(1.08 – 4.44)

0.040

HLP

122

(70.1)

52

(30.2)

0.71

(0.48 – 1.04)

0.085

Diab. mellitus

63

(36.0)

112

(25.4)

0.98

(0.69 – 1.40)

0.928

BMI >30

50

(2S.6)

125

(25.3)

0.99

(0.68 – 1.44)

1.000

AF

39

(22.9)

131

(21.6)

3.46

(2.14 – 5.58)

<0,001

3 V–CAD

140

(SO.O)

35

(27.1)

0.88

(0.57 – 1.36)

0.575

LMS

73

(42–5)

100

(21.8)

1.67

(1.17 – 2.38)

0.005

COPD

20

(H–4)

155

(25.2)

1.04

(0.61 – 1.79)

0.890

PAD

39

(22.3)

136

(23.7)

1.57

(1.02 – 2.41)

0.048

Smoker

84

(48.3)

90

(23.4)

1.23

(0.87 – 1.73)

0.253

Crea >2

14

(8–5)

151

(23.3)

3.08

(1.45 – 6.52)

0.006

Renal insuff. preop Crea <2

78

(44.6)

97

(20.8)

1.97

(1.38 – 2.80)

<0,001

CVA

36

(20.7)

138

(23.9)

1.47

(0.95 – 2.28)

0.098

Beta–blocker

127

(73.4)

46

(33.3)

0.58

(0.39 – 0.87)

0.011

Statin

117

(57.6)

55

(96.4)

0.49

(0.33 – 0.72)

<0,001

Antiplatelet

127

(75.1)

42

(10.9)

6.19

(4.17 – 9.19)

<0,001

EF < 40 %

SO

(46.0)

94

(19.3)

2.66

(1.85 – 3.80)

<0,001

EF 40–50 %

51

(29.3)

123

(23.1)

1.54

(1.05 – 2.27)

0.038

EF >50 %

43

(24.7)

131

(35.7)

0.27

(0.19 – 0.40)

<0,001

Euroscore > =6

138

(S2.6)

29

(9.9)

5.13

(3.31 – 7.93)

<0,001

IABP preop

25

(144)

149

(22.6)

12.25

(5.20 – 28.88)

<0,001

NYHA 111 + IV

116

(55.3)

59

(17.9)

2.12

(1.49 – 3.04)

<0,001

Emergent CABG

125

(71.4)

50

(11.2)

8.16

(5.55 – 11.99)

<0,001

Time between angiography and operation

<3d

100

(65.8)

52

(11.9)

6.61

(4.45 – 9.82)

<0,001

<24 h

92

(50.5)

52

(12.4)

8.77

(5.83 – 13.19)

<0,001

OP–time after 08.00 pm

35

(20.0)

60

(22.2)

4.22

(2.49 – 7.15)

<0,001

ICC

47

(28.0)

121

(23.9)

1.16

(0.79 – 1.72)

0.477

IWC

120

(71.4)

48

(27.1)

0.84

(0.57 – 1.23)

0.363

AoX < 80 min

164

(95.5)

5

(42.9)

0.43

(0.15 1.25)

0.122

AoX > 60 min

17

(10.0)

153

(25.0)

0.88

(0.50 – 1.56)

0.777

AoX > 45 min

53

(31.2)

117

(25.4)

0.90

(0.62 – 1.30)

0.574

CPB > 180 min

13

(7.5)

161

(23.8)

20.83

(4.65 – 93.29)

<0,001

CPB > 120 min

42

(24.1)

132

(21.3)

5.00

(3.03 – 8.26)

<0,001

OP–time > 180 min

111

(54 2)

62

(20.3)

1.75

(1.23 – 2.51)

0.002

Reperfusion time > 60 min

35

(20.5)

136

(21.2)

10.83

(5.47 – 21.43)

<0,001

Hemofiltration

59

(39.4)

106

(18.6)

5.49

(3.64 – 8.29)

<0,001

PDI (Corotrop)

81

(53.2)

92

(18.1)

3.64

(2.51 – 5.26)

<0,001

30–days mortiality

36

(20.6)

139

(21.4)

14.71

(6.92 – 31.25)

<0,001

ICU > 3d

118

(72.0)

46

(11.8)

5.27

(3.58 – 7.76)

<0,001

ICU > 5d

36

(52.4)

78

(15.6)

5.18

(3.54 – 7.59)

<0,001

ICU > 7d

72

(43.9)

92

(17.1)

5.30

(3.55 – 7.93)

<0,001

ICU > 10d

46

(32.0)

118

(19.9)

4.87

(3.03 – 7.83)

<0,001

Hospital stay > 15 d

55

(32.0)

117

(21.7)

2.11

(1.42 – 3.11)

<0,001

Ventilation time >48 h

72

(47 4)

80

(14.6)

14.49

(8.86 – 23.71)

<0,001

IABP perioperativ

83

(47.4)

92

(15.0)

  

<0,001

ECMO

18

(10.3)

157

(23.2)

  

<0,001

Blood transfusion

156

(97.6)

4

(7.5)

4.37

(1.55 – 12.30)

0.001

EK >5

84

(48.3)

90

(17.1)

5.04

(3.44 – 7.37)

<0,001

Total blood loss >11

91

(62.8)

52

(14.8)

2.83

(1.93 – 4.14)

<0,001

Total blood loss > 21

38

(26.2)

107

(18.8)

4.43

(2.69 – 7.29)

<0,001

Dialysis

27

(15.4)

148

(22.6)

7.12

(3.58 – 14.14)

<0,001

Inotropie support >48 h

113

(77.4)

33

(9.1)

6.69

(4.35 – 10.28)

<0,001

CardioAssist

105

(60.0)

70

(12.0)

109.93

(49.16 – 245.83)

<0,001

ACT > 150 sec.

26

(21.1)

97

(21.3)

1.69

(1.01 – 2.83)

0.048

Pneumonia

17

(9.8)

156

(23.4)

6.95

(2.94 – 16.41)

<0,001

Wound infection

15

(8.7)

158

(25.0)

1.02

(0.55 – 1.89)

1.000

Operative re–exploration

25

(14.5)

148

(23.1)

3.33

(1.86 – 5.97)

<0,001

Pre-,intra- and postoperative data in univariaten analysis. The nominal variables are shown in absolute and percentage figures, cerebro vascular accident (CVA), hypertension (HT), 3 vessel-coronary artery disease (3 V-CAD), left main stenosis (LMS), perimyocardial infarction (PMI), red blood cells (RBC)

In order to detect independent preoperative predictors for 30-day mortality and PMI binary logistic regression analysis was performed (Table 6 and 7) using only preoperative variables. Multivariate analysis revealed that EF < 40 % was the strongest independent predictor for 30-day mortality (OR 3.66; 95 %-CI 1.79-7.52; p < 0.001), followed by atrial fibrillation, PAD and anti-platelet drugs not suspended at least 5 days before surgery (Table 6). In contrast, three independent predictor variables showed a protective influence on 30-day mortality, namely 3-vessel-disease (OR 0.36; 95 %-CI 0.16-083; p = 0.016), preoperative statin therapy and dyslipidemia. The strongest independent predictor for PMI appeared to be preoperative anti-platelet drug therapy (OR 4.79; 95 %-CI 3.10-7.40; p < 0.001), followed by IABP, hemofiltration, EF < 40 %, atrial fibrillation and cerebrovascular disease (Table 7). Preoperative statin therapy tended to be a borderline predictor with a protective influence on PMI (OR 0.66; 95 %-CI 0.41-1.08; p = 0.101).
Table 6

Multivariate analysis, primary endpoint: 30-days mortality

Multivariate analysis, primary endpoint: 30-days mortality (n = 45)

Variable

O.R.

95 %-C.I.

p-value

HLP

0.39

(0.19 – 0.79)

0.009

AF

3.33

(1.49 – 7.47)

0.003

3 V–CAD

0.36

(0.16 – 0.83)

0.016

COPD

0.26

(1.05 – 6.21)

0.038

PAD

2.51

(1.13 – 5.55)

0.023

Statin

0.38

(0.18 – 0.80)

0.010

Antiplatelet.

1.99

(0.95 – 4.17)

0.070

EF <40 %

3.66

(1.79 – 7.52)

<0,001

Variable used in multivariable analysis:

Female

HT

pulm. HT

HLP

Diab. mellitus

AF

3 V–CAD

LMS

COPD

PAD

Smoker

Crea >2

Renal insuff. preop Crea <2

CVA

Beta-blocker

Statin

Antiplatelet.

EF <40 %

IABP preop

AF Atrial fibrillation, CVA cerebrovascular accident, HLP Hyperlipidemia, HT Hypertension, PAD peripherial artery disease, LMS left main stenosis

Table 7

Multivariate analysis, endpoint: PMI

Multivariate analysis, endpoint: PMI (n = 175)

Variable

O.R.

95 %-C.I.

p-value

AF

1.79

(0.98 – 3.27)

0.060

CVA

1.68

(0.98 – 2.89)

0.059

Statin

0.66

(0.41 – 1.08)

0.101

Antiplatelet

4.79

(3.10 – 7.40)

<0,001

EF < 40 %

2.04

(1.32 – 3.15)

0.001

IABP preap

3.68

(1.34 – 10.13)

0.012

Hemofiltration

3.61

(2.22 – 5.87)

<0,001

Variable used in multivariable analysis:

art. HT

pulm. HT

AF

LMS

HLP

PAD

Crea >2

Renal insuff. preop Crea <2

CVA

Beta–blocker

Statin

Antiplatelet

EF <40 %

IABP preop.

OP-time after 08:00 pm

Hemofiltration

AF Atrial fibrillation, CVA cerebro vascular accident, HLP Hyperlipidemia, HT Hypertension, PAD peripherial artery disease, LMS left main stenosis

Analysis of cause of death

In the IWC and ICC emergent CABG group 8 patients vs. 5 patients died after acute myocardial infarction with postcardiotomy ECMO, 2 of them had cerebrovascular events, 4 patients vs. 1 patient died due to severe sepsis with multiorgan failiure, 2 patients vs 0 patients with mesenterial ischemia and laparotomy, 1 patients vs. 0 patients with LV and LA thrombus in association with heparin induced thrombocytopenia and 6 patients vs. 3 patients died postoperatively after CPR due to electromechanical dissociation and low-output syndrome, respectively.

On the other hand, in the IWC and ICC elective CABG group 3 patients vs. 0 patients died after pericardial tamponade or pulmonary emboli with postcardiotomy ECMO, 3 patients vs. 0 patients died due to severe sepsis and multiorgan failiure, 1 patient vs 0 patients after mesenterial ischemia and laparotomy in association with sepsis and 3 patients vs. 0 patients postoperatively after CPR due to electromechanical dissociation and low-output syndrome, respectively.

Discussion

As several clinical studies have shown superior outcomes when using blood cardioplegia, this type of myocardial protection has been increasingly implemented in most centers including our department [6, 13]. So far, most prior research has been particularly focused on cold and warm blood cardioplegia in elective CABG patients [14, 15]. Also the differences between crystalloid and cold blood cardioplegia have been largely debated in previous research [16, 17]. In order to fill the gap in terms of analysis of differences in cold and warm blood cardioplegia in emergent setting, we conducted our study with particular attention to emergent CABG patients analysing the impact of different intermittent blood cardioplegia application. Previous research has indicated that there were no significant differences between antegrade and retrograde application of blood cardioplegia in terms of mortality and myocardial infarction [14, 18]. Due to easier technical aspects it has become the standard of care to administer antegrade blood cardioplegia for CABG procedures in our institution. In this study we analyzed different cardioplegia strategies in emergent compared to elective CABG patients. The intraoperative patient data showed similar results referring to CPB, operation, and reperfusion time, usage of IMA and the need for hemodialysis. However, it is interesting to note that even though the aortic cross clamp time was significantly longer in the IWC group there were no differences in PMI. In a recent study it was even suggested that cold blood cardioplegia seems to be associated with more harmful effects on the myocardium in CABG patients when compared to warm blood cardioplegia [19]. In contrast, another study by Liakopoulos et al. demonstrated that cold blood cardioplegia according to Buckberg provided superior myocardial protection in terms of 30-day mortality, cardiac death and PMI in patients requiring prolonged aortic cross clamp time during cardiac surgery [9]. However, it is very doubtful as to whether a meaningful comparison can be made between CABG and non-CABG surgery procedures precisely because severe coronary stenosis may impair cardioplegic delivery leading to a different delivery of each solution beyond the stenosis.

Another study with prospective randomized design which was published two decades ago showed strong evidence that warm blood cardioplegia was superior to cold blood cardioplegia in CABG patients in terms of PMI [20]. As it was a randomized study, there were several exclusion criteria, such as patients with renal failure, or emergent patients who were not able to sign informed consent. In order to present a real world experience, we did not intend to exclude any cases, analyzing consecutive patients including those requiring preoperative mechanical ventilation or patients with renal failure. Moreover, an emergent subgroup was created and matched with consecutive patients from the elective subgroup in order to provide the full analysis in patients with different risk profiles. Additionally, compared to the study by Warm Heart Investigators where cardioplegia was given antegradely and/or retrogradely depending on surgeon’s preference this potential bias is not present in our study as cardioplegia was always administered antegradely [20]. Similar to our report, another study by Calafiore et al. investigated 500 consecutive CABG patients who received IWC compared to ICC [5]. However, the blood cardioplegia in that study was given antegradely in all cases, the main difference to our study is that Calafiore et al. only included elective CABG patients. Interestingly, Calafiore et al. found that the outcome in the IWC group was superior to the ICC group in terms of requirement for circulatory assistance, IABP, and incidence of myocardial infarction and cerebrovascular accidents. In another prospective randomized trial Franke et al. also showed a significantly improved myocardial protection in the IWC group compared to ICC group in elective setting [15]. Surprisingly, there is only one experimental animal study which showed that IWC is superior to ICC in ischemic myocardium [21]. Despite the fact that the concept of myocardial protection in the beginning of cardiac surgery was recommended with introduction of hypothermic crystalloid cardioplegia it has been continuously adjusted and improved by pharmacological additives, blood cardioplegia and different application techniques [22]. Despite the fact that warm and cold cardioplegia resulted in similar 30-days and long-term mortality in our study, there has been a substantial amount of research showing that warm cardioplegia reduces several adverse post-operative events [7, 23]. However, totally different results were found in a meta-analysis with a total of 41 randomized controlled trials including 5879 patients comparing warm vs. cold cardioplegia. This study demonstrated no statistically significant differences in the incidences of clinical events [24]. Hence, our results seem to support this theory that there are no statistically significant differences in using cold vs. warm blood cardioplegia in emergent CABG patients particularly those with aortic cross clamp time less than 60 min according to the mean cross clamp time results of our study. Additionally, we performed a multivariate analysis which further showed that the type cardioplegia is not an independent predictor for PMI or 30-day mortality independent of the procedure urgency.

In terms of our additional findings suggesting preoperative risk factors for PMI the strongest independent predictor appeared to be preoperative use of anti-platelet drugs also supported by Micelli et al. demonstrated previously [25]. Our further findings on predictors of early mortality, such as decreased EF of less than 40 %, AF and PAD are also consistent with previous research [26, 27]. Whereas van Straten et al. found evidence that PAD is associated with an increased risk for long-term mortality, our findings suggested that PAD is also an independent predictor for short-term mortality [28]. Finally, our data support that preoperative statin treatment may have protective effects on mortality similarly to recent studies by Kulik et al. and Girerd et al. [29, 30] and prevents cardiovascular complications by pleiotropic effects [31]. Nevertheless, optimal mortality prediction should still be performed using established scoring systems [32, 33]. Our study is also in consistence with the fact that statins may reduce cytokine release and neutrophil adhesion via a nitric oxide-mediated mechanism and improve postoperative myocardial perfusion of bypassed areas [34, 35].

Conclusions

Summarizing, there are no clinically significant differences in using cold and warm blood cardioplegia in emergent CABG patients including long-term outcomes regardless of the urgency status. Decreased EF, AF and PAD remain main predictors for 30-day mortalitiy whereas preoperative use of statins is associated with protective effects. Warm blood cardioplegia and normothermic systemic perfusion offer safe myocardial protection strategies in emergent CABG patients and IWC is a cost-effective alternative. Therefore, we suggest to use warm blood cardioplegia antegradely in elective and emergent CABG procedures regardless of the emergent status.

Limitations

This is a retrospective study with consecutive elective and emergent patients. Even though we consecutively matched the emergent cohort 1:2 to a control elective cohort to avoid selection bias there is still a limitation in interpreting the results due to the use of cardioplegia depending on surgeons’ preferences. There were surgeons who routinely used cold blood cardioplegia and surgeons who routinely used warm blood cardioplegia which may have influenced cross clamp times in IWC and ICC groups.

Notes

Declarations

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
(2)
Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, Harefield, Middlesex, UK
(3)
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
(4)
Heart and Vascular Institute, Pennstate Hershey, Philadelphia, PA, USA

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