Keywords
cardiopulmonary bypass (CPB) - coronary artery bypass grafts surgery (CABG) - myocardial
protection/cardioplegia - perfusion
Introduction
Coronary artery bypass grafting (CABG) using extracorporeal circulation (ECC) is the
gold standard in the treatment of complex coronary artery disease.[1]
[2]
[3] The minimal extracorporeal circulation (MiECC) system, a minimized and closed form
of the ECC, maintains their advantages, but reduces the area of artificial surfaces
and avoids blood–air contact.[4] The use of MiECC in CABG surgery has been reported to be associated with excellent
mid- and long-term outcomes.[4]
[5]
[6]
[7]
[8]
[9] Moreover, regarding perioperative myocardial damage reflected by cardiac markers,
the use of MiECC was comparable to off-pump coronary artery bypass grafting (OPCABG),[10] and has now been implemented into the European Association for Cardio-Thoracic Surgery/European
Association of Cardiothoracic Anaesthesiology (EACTS/EACTA) guidelines.[11]
In our hospital MiECC is the standard perfusion strategy in isolated CABG surgery
if OPCABG is not performed. Until May 2017, Cardioplexol® (Bichsel, Interlaken, Switzerland) was used to induce cardiac arrest. Cardioplexol® is a single-shot cardioplegia (100 mL) which is directly applied via the aortic root.[5]
[9]
[11]
[12]
[13] However, there is literature showing significantly higher values of cardiac markers
in the subgroup of patients with isolated left main trunk (LMT) stenosis (> 50%) compared
with patients with severe three vessel disease (3-VD) or combined LMT and 3-VD when
Cardioplexol® was used as cardioplegia.[14]
To further ameliorate cardiac protection during surgery, we have introduced the Myocardial
Protection System (second-generation, MPS) as an additional tool to the MiECC to deliver
a refined microplegia (Basel Microplegia Protocol).[15] The use of microplegia was previously found to be beneficial in regard to adverse
events, length of stay on the intensive care unit (ICU), and in-hospital stay compared
with traditional cardioplegia, as well as with lower incidence of postoperative low
cardiac output syndrome in isolated CABG surgery.[16]
[17]
Our first experience showed that the use of the Basel Microplegia Protocol is safe
and reliable, and associated with low postoperative cardiac markers, indicating an
excellent myocardial protection during surgery.[15] This study aims to investigate whether the finding of low cardiac markers is indeed
a consequence of the application of the microplegia, instead of being due to mere
patient selection. This is why we conducted a propensity-matched cohort study with
a 3:1 matching to compare the two cardioplegic solutions: Basel Microplegia Protocol
versus Cardioplexol®.
Patients and Methods
Ethical Approval
The local ethical committee (EKNZ BASEC Req-2018–00926) approved the study protocol,
which is in accordance with the principles of the declaration of Helsinki. The ethical
committee has waived the need to obtain informed consent.
The trial was registered at ClinicalTrials.gov (ID NCT03612388). The authors designed
the study, gathered and analyzed the data, vouched for the data and analysis, wrote
the paper, and decided to publish.
Technical Aspects and Cardioplegia Protocol
Technical aspects and development of our microplegia solution were previously described
in detail.[15] In brief, the surgical technique remains unchanged to the use of MiECC with Cardioplexol® except for repeated microplegia administration at 20-minute intervals, as well as
the “hot-shot” application prior to declamping,. The microplegia (composed of patient's
blood with K, Mg, and Lidocaine, thus normovolemic) is applied under pressure and
flow control via the aortic root. The targeted flow is approximately 300 mL/min and
for safety reasons, the pressure is limited to 250 mm Hg (measured directly in the
MPS console). Microplegia protocol consists of 4 minutes induction time (with reduced
dosage of K after 2 minutes) and repetitive administration of 2 minutes in every 20
minutes. Before declamping, a hot shot is given for 1 minute[15] ([Table 1]).
Table 1
Composition of the microplegia applied via the MPS (Basel Microplegia Protocol)
|
Time
(min)
|
Potassium
(mmol/L)
|
Magnesium
(g/L)
|
Lidocaine (mg/L)
|
Flow
(mL/min)
|
|
Induction
|
2
|
20
|
1.6
|
40
|
300
|
|
2
|
13
|
1.6
|
40
|
300
|
|
Repetition dose
|
2
|
6
|
1.6
|
40
|
300
|
|
Hot shot
|
1
|
−
|
1.6
|
40
|
300
|
The technique of the application of Cardioplexol® was also described in detail before.[6]
[10]
[12]
[13]
[14]
[15]
[18] The Cardioplexol® is a single-shot cardioplegia (100 mL) based on procaine, magnesium (Mg), and potassium
(K). It is directly and manually applied via the aortic root. Cardioplexol® ensures a controlled cardiac arrest for approximately 45 minutes per 100 mL shot
and repetitive administration up to four times with a maximum dosage of 500 mL is
feasible ([Table 2]).[6]
[10]
[12]
[13]
[14]
[15]
[18]
Table 2
Composition of Cardioplexol®
|
Potassium
(mmol/100 mL)
|
Magnesium
(mmol/100 mL)
|
Procaine
(mmol/100 mL)
|
Xylitol
(mmol/100 mL)
|
|
Induction 100 mL
|
10
|
16.2
|
1.1
|
29.6
|
|
Repetition dose 100 mL
|
10
|
16.2
|
1.1
|
29.6
|
Source: Matt, Arbeleaz et al. Thorac Cardiovasc Surgeon 2012.
Patients and Study Design
MiECC-assisted surgery or OPCABG are the standard procedures for isolated CABG in
our institution. Conventional ECC is predominantly applied in emergency operations
or nonCABG surgeries.[15] Before the introduction of the second-generation MPS and the development of the
Basel Microplegia Protocol, Cardioplexol® was used standardly to induce cardiac arrest when using the MiECC. In May 2017, we
started to deliver our institutionally refined microplegia (Basel Microplegia Protocol)
using the MPS, as an adjunct to the MiECC.[15] Since it performed excellent results, this combination became routine in isolated
CABG with MiECC. To investigate the quality of the two cardioplegia strategies (Basel
Microplegia Protocol vs. Cardioplexol®) on the basis of our own observational data, we chose a propensity score-matched
cohort study design with a 3:1 matching to reduce a bias by indication (more details
in section “Statistical Analysis”). Patients with OPCABG surgery, nonstandard cardioplegic
strategy, concomitant ablation, or previous myocardial infarction within 7 days before
the operation were excluded ([Fig. 1]) from this analysis.
Fig. 1 Patient flow chart. CABG, coronary artery bypass grafting; OPCAB, off-pump coronary
artery bypass. Note: the matching procedure did not find three matched pairs for each patient who underwent
surgery with use of Basel Microplegia Protocol.
Using a prospectively maintained institutional registry (Intellect 1.7, Dendrite Clinical
Systems, Henley-on-Thames, United Kingdom), we identified all patients who underwent
isolated CABG in our institution after February 2010 when our laboratory introduced
high-sensitivity cardiac troponin (hs-cTn). The clinical data were exported from this
registry where data have been regularly controlled for completeness and accuracy.
Intraoperative data were collected prospectively in a standardized fashion.[15] Serological parameters were assessed according to the standard algorithm in our
hospital, starting on postoperative day (POD)-1 at 6:00 a.m. This was continued during
the following days until a normalization of the values was noticed. As a correlate
for perioperative myocardial damage, high-sensitivity cardiac troponin-T (hs-cTnT), creatine kinase (CK), and creatine kinase-myocardial
type (CK-MB) were analyzed (first postoperative as well as peak values). Furthermore,
we assessed major adverse cardiac and cerebrovascular events (MACCE) as a further
safety endpoint. Moreover, we recorded intra- and perioperative data, such as length
of stay on the intensive care unit (ICU), in-hospital mortality, postoperative atrial
fibrillation (AFIB), aortic cross-clamping time, and number of distal anastomoses.
Statistical Analysis
We conducted a propensity-matched analysis, and included age, body mass index (BMI),
ejection fraction, hypertension, and prior myocardial infarction (MI) into the propensity
model. We trimmed the tails of the propensity score distribution at the more centered
2.5th and 97.5th percentile of the two groups ([Supplementary Fig. S1]; available online only). We used nearest neighbor matching with caliper width one-quarter
of the standard deviation (SD) of propensity score. To account for matched pairs,
mixed models were used for continuous variables and conditional logistic regression
for binary variables, except if the model did not converge, in which case we used
Fisher's exact test. Differences between the treatment groups (Basel Microplegia Protocol
and Cardioplexol®) before and after matching were expressed as standardized differences, to assess
the difference independently of the number of observations. As a sensitivity analysis
of the main analysis, we used a generalized linear model of the Poisson family with
logarithmic link function and robust standard errors. As a second sensitivity analysis,
we used the Kruskal–Wallis rank test that ignores the matched-pairs structure. Continuous
data are reported as mean ± SD if normally distributed or as geometric mean with confidence
interval if skewed, and categorical data are reported as numbers with percentages.
Confidence intervals and p-values are two-sided, a p-value below 0.05 was considered significant. All analyses were performed by a biostatistician
(BG) using Stata 14 (Stata Corp, Texas).
Results
Preoperative Data
From February 2010 until March 2018, 2,256 consecutive patients underwent isolated
CABG surgery, 1,126 of which met the inclusion criteria and thus represented the cohort
of this study ([Fig. 1]). Patients receiving Cardioplexol® were younger (mean [SD] 65.6 [9.5] vs. 69.5 [8.6] years, p = 0.001). Ejection fraction (EF) was lower in the Cardioplexol® group than in the microplegia group (53.6 [10.4]% vs. 56.1 [10.8]%, p = 0.045; [Table 3]). After trimming, 67 patients remained in the intervention group and 981 in the
control group of whom 56 microplegia patients could be matched to 155 Cardioplexol® patients. More precisely, 44 microplegia patients could be matched with three Cardioplexol® patients (n = 132), 11 microplegia patients with two Cardioplexol® (n = 22), and one microplegia patient with only one Cardioplexol® patient.
Table 3
Patient characteristics
|
Before matching
|
After matching
|
|
Microplegia
n = 72
|
Cardioplexol®
n = 1054
|
Diff.
|
p-Value
|
Microplegia
n = 56
|
Cardioplexol®
n = 155
|
Diff.
|
p-Value
|
|
Age, m (SD)
|
69.5 (8.6)
|
65.6 (9.5)
|
0.434
|
0.001
|
69.3 (8.4)
|
68.7 (8.2)
|
0.069
|
0.629
|
|
Female, n (%)
|
15 (20.8)
|
162 (15.4)
|
−0.021
|
0.220
|
11 (19.6)
|
31 (20)
|
0.001
|
0.974
|
|
BMI in kg/m2, m (SD)
|
28.6 (5.1)
|
27.8 (4.3)
|
0.158
|
0.160
|
28.7 (5.2)
|
28.4 (4.5)
|
0.068
|
0.644
|
|
Diabetes mellitus, n (%)
|
30 (41.7)
|
403 (38.2)
|
−0.017
|
0.563
|
22 (39.3)
|
52 (33.5)
|
−0.028
|
0.386
|
|
Current smoker, n (%)
|
11 (15.3)
|
258 (24.5)
|
0.037
|
0.080
|
6 (10.7)
|
30 (19.4)
|
0.031
|
0.146
|
|
Peripheral artery disease, n (%)
|
10 (13.9)
|
141 (13.4)
|
−0.002
|
0.902
|
8 (14.3)
|
21 (13.5)
|
−0.003
|
0.887
|
|
Preoperative stroke, n (%)
|
2 (2.8)
|
68 (6.5)
|
0.008
|
0.226
|
2 (3.6)
|
7 (4.5)
|
0.002
|
0.754
|
|
Renal disease, n (%)
|
2 (2.8)
|
49 (4.6)
|
0.004
|
0.465
|
1 (1.8)
|
9 (5.8)
|
0.008
|
0.207
|
|
Dialysis[a], n (%)
|
0 (0.0)
|
9 (0.9)
|
0.001
|
1.000
|
0 (0)
|
0 (0)
|
0.000
|
1.000
|
|
COPD, n (%)
|
13 (18.1)
|
152 (14.4)
|
−0.013
|
0.400
|
9 (16.1)
|
18 (11.6)
|
−0.015
|
0.473
|
|
Hypertension, n (%)
|
60 (83.3)
|
964 (91.5)
|
0.027
|
0.023
|
50 (84.7)
|
137 (84.0)
|
0.003
|
0.872
|
|
Hypercholesteremia, n (%)
|
55 (76.4)
|
891 (84.5)
|
0.032
|
0.071
|
48 (85.7)
|
134 (87.1)
|
0.048
|
0.030
|
|
NYHA III or IV, n (%)
|
13 (18.1)
|
225 (21.3)
|
0.013
|
0.509
|
10 (17.9)
|
39 (25.2)
|
0.030
|
0.301
|
|
Atrial fibrillation, n (%)
|
4 (5.6)
|
24 (2.3)
|
−0.006
|
0.095
|
4 (7.1)
|
8 (5.2)
|
−0.005
|
0.483
|
|
Prior myocardial infarction, n (%)
|
22 (30.6)
|
514 (48.8)
|
0.091
|
0.003
|
15 (26.8)
|
39 (25.2)
|
−0.007
|
0.681
|
|
Emergency operation[a], n (%)
|
0 (0.0)
|
16 (1.5)
|
0.001
|
0.618
|
0 (0)
|
1 (0.6)
|
0.000
|
1.000
|
|
3-vessel coronary artery disease, n (%)
|
63 (87.5)
|
925 (87.8)
|
0.001
|
0.948
|
48 (85.7)
|
135 (87.1)
|
0.005
|
0.798
|
|
Left main trunk stenosis, n (%)
|
23 (31.9)
|
316 (30.0)
|
−0.009
|
0.725
|
18 (32.1)
|
53 (34.2)
|
0.010
|
0.646
|
|
Ejection fraction in %, m (SD)
|
56.1 (10.8)
|
53.6 (10.4)
|
0.240
|
0.045
|
55.7 (10.3)
|
57.3 (8.7)
|
−0.170
|
0.255
|
|
logistic EuroSCORE[b]
|
2.8 (2.4–3.3)
|
2.9 (2.7–3.0)
|
−0.019
|
0.880
|
2.8 (2.3–3.4)
|
2.9 (2.6–3.2)
|
−0.036
|
0.795
|
|
EuroSCORE II[b]
|
1.4 (1.3–1.7)
|
1.3 (1.3–1.4)
|
0.127
|
0.315
|
1.4 (1.2–1.7)
|
1.3 (1.2–1.5)
|
0.092
|
0.550
|
Abbreviations: COPD, chronic obstructive pulmonary disease; Diff., standardized differences
to express the difference independent of the number of observations; NYHA, New York
Heart Association; SD, standard deviation.
a For nonconvergence of the model no accounting for matched pairs.
b Geometric mean (confidence interval).
Note: Data are presented as mean and standard deviation or as numbers (%). Note that the
matching procedure did not find three matched pairs for each patient who underwent
surgery with use of microplegia.
After matching, there were no relevant differences between the study groups, as all
absolute standardized difference values were below 0.2. However, hypercholesteremia
did not occur equally frequently in either group (75.0 vs. 87.1%; p = 0.030).
Intraoperative Data
There was no difference regarding intraoperative data, such as number of distal anastomoses,
or the usage of left internal mammary artery (LIMA), right internal mammary artery
(RIMA), or both internal mammary arteries (BIMA), neither before nor after matching.
Aortic clamping time and perfusion time were comparable in both groups. Need for defibrillation
(related to the whole operation) was higher in the microplegia group, but did not
reach statistical significance (21.8 versus 11.1%; p = 0.066). Intraoperative data are provided in [Table 4]
.
Table 4
Intraoperative data
|
Before matching
|
After matching
|
|
Microplegia
n = 72
|
Cardioplexol®
n = 1,054
|
Diff.
|
p-Value
|
Microplegia
n = 56
|
Cardioplexol®
n = 155
|
Diff.
|
p-Value
|
|
Total arterial revascularisation, n (%)
|
14 (19.4)
|
170 (16.1)
|
−0.013
|
0.463
|
11 (19.6)
|
27 (17.4)
|
−0.009
|
0.714
|
|
Use of LIMA, n (%)
|
68 (94.4)
|
1009 (95.7)
|
0.003
|
0.606
|
52 (92.9)
|
148 (95.5)
|
0.006
|
0.360
|
|
Use of RIMA, n (%)
|
9 (12.5)
|
156 (14.8)
|
0.008
|
0.594
|
7 (12.5)
|
19 (12.3)
|
−0.001
|
0.871
|
|
Use of BIMA, n (%)
|
9 (12.5)
|
145 (13.8)
|
0.004
|
0.764
|
7 (12.5)
|
18 (11.6)
|
−0.003
|
0.774
|
|
Use of radial artery, n (%)
|
16 (22.2)
|
269 (25.5)
|
0.014
|
0.534
|
13 (23.2)
|
38 (24.5)
|
0.006
|
0.878
|
|
IV inotropes at the end of operation, n (%)
|
10 (14.3)
|
241 (22.9)
|
0.034
|
0.099
|
6 (11.1)
|
31 (20.1)
|
0.033
|
0.197
|
|
Number of distal anastomoses, m (SD)
|
3.7 (1.1)
|
3.8 (0.9)
|
−0.092
|
0.403
|
3.7 (1.2)
|
3.7 (1.0)
|
−0.035
|
0.817
|
|
Aortic clamping time in min, m (SD)
|
60.9 (17.4)
|
58.8 (19.2)
|
0.115
|
0.364
|
60.9 (16.3)
|
58.6 (17.5)
|
0.138
|
0.381
|
|
Perfusion time in min[a]
|
88.3
(83.1–93.9)
|
88.4
(86.9–89.9)
|
−0.004
|
0.977
|
88.2
(82.5–94.3)
|
87.0
(83.2–91.0)
|
0.049
|
0.756
|
|
Need for defibrillation, n (%)
|
13 (18.1)
|
116 (11.0%)
|
−0.025
|
0.076
|
12 (21.8)
|
17 (11.1)
|
−0.040
|
0.066
|
Abbreviations: BIMA, both internal mammary arteries; BMP, Basel Microplegia Protocol;
Diff., standardized differences to express the difference independent of the number
of observations. IV, intravenous; LIMA, left internal mammery artery; RIMA, right
internal mammary artery; SD, standard deviation.
a Geometric mean (confidence interval).
Note: Data are presented as mean and standard deviation or as numbers (%). Note that
the matching procedure did not find three matched pairs for each patient who underwent
surgery with use of microplegia.
Postoperative Data
In-hospital mortality was low in both groups (microplegia: 0% vs. Cardioplexol®: 1.3%; p = 1.0). Patients operated using microplegia stayed significantly shorter on the ICU
(geometric mean [confidence interval]: 1.5 days [1.2–1.8 days] vs. 1.9 days [1.7–2.1
days]; p = 0.011), whereas length of hospital stay was comparable in both groups. MACCE were
equally frequent in both groups (1.8 vs. 5.2%; p = 0.331). The proportion of postoperative renal failure (defined as a doubling of
the preoperative creatinine value and a postoperative creatinine value > 172 micromol/L,
or new onset of need for dialysis) was similar in both groups. The same was seen for
postoperative AFIB.
Endpoint Analysis
With respect to the cardiac markers, group differences were larger after matching
than before ([Table 6]). Furthermore, group differences were more emphasized in the peak measurements than
in first postoperative measurements. Geometric mean (confidence interval) hs-TnT on
the first POD (223 ng/L [184–269 ng/L] vs. 296 ng/L [262–336 ng/L]; p = 0.016) as well as peak hs-cTnT (233 ng/L [194–280 ng/L] vs. 362 ng/L [315–416 ng/L];
p = 0.001) were significantly lower in the microplegia group than in the Cardioplexol® group ([Fig. 2]). The same was observed for CK-MB on the first (13.2 µg/L [10.5–16.7 µg/L] vs. 17.9
µg/L [15.8–20.3] µg/L]; p = 0.025) and the peak of CK-MB (13.8 µg/L [9.6–19.9 µg/L] vs. 21.6 µg/L [18.9–24.6
µg/L]; p = 0.026). CK on the first POD (462 U/L [372–572 U/L] vs. 542 U/L [486–605 U/L]; p = 0.182) showed a trend toward lower values in the microplegia group but did not
reach statistical significance. Peak CK was significantly lower in the microplegia
group compared with the Cardioplexol® group (539 U/L [458–633 U/L] vs. 719 U/L [645–801 U/L]; p = 0.011; [Fig. 3]).
Table 5
Postoperative data
|
Before matching
|
After matching
|
|
Microplegia
n = 72
|
Cardioplexol®
n = 1054
|
Diff.
|
p-Value
|
Microplegia
n = 56
|
Cardioplexol®
n = 155
|
Diff.
|
p-Value
|
|
In-hospital mortality[a], n (%)
|
0 (0.0)
|
17 (1.6)
|
0.001
|
0.620
|
0 (0)
|
2 (1.3)
|
0.001
|
1.000
|
|
MACCE, n (%)
|
1 (1.4)
|
64 (6.1)
|
0.009
|
0.133
|
1 (1.8)
|
8 (5.2)
|
0.006
|
0.331
|
|
Reoperation for bleeding[a], n (%)
|
1 (1.4)
|
17 (1.6)
|
0.000
|
0.884
|
1 (1.8)
|
4 (2.6)
|
0.001
|
1.000
|
|
Atrial fibrillation at discharge, n (%)
|
22 (30.6)
|
236 (22.4)
|
−0.036
|
0.113
|
17 (30.4)
|
42 (27.1)
|
−0.015
|
0.721
|
|
Pulmonary infection, n (%)
|
2 (2.8)
|
63 (6.0)
|
0.007
|
0.272
|
2 (3.6)
|
5 (3.2)
|
−0.001
|
0.944
|
|
Postoperative MI[a], n (%)
|
0 (0.0)
|
33 (3.1)
|
0.004
|
0.264
|
0 (0)
|
5 (3.2)
|
0.004
|
0.328
|
|
Postoperativ stroke, n (%)
|
1 (1.4)
|
27 (2.6)
|
0.002
|
0.543
|
1 (1.8)
|
2 (1.3)
|
−0.001
|
0.741
|
|
Postoperative renal failure, n (%)[a]
|
1 (1.4)
|
65 (6.2)
|
0.009
|
0.129
|
1 (1.8)
|
9 (5.8)
|
0.008
|
0.296
|
|
Renal substitution therapy[a], n (%)
|
0 (0.0)
|
9 (0.9)
|
0.001
|
1.000
|
0 (0)
|
2 (1.3)
|
0.001
|
1.000
|
|
Intubation > 72 h[a], n (%)
|
0 (0.0)
|
25 (2.4)
|
0.003
|
0.399
|
0 (0)
|
4 (2.6)
|
0.003
|
0.575
|
|
Length of ICU stay in days[b]
|
1.4 (1.2–1.7)
|
1.9 (1.9–2.0)
|
−0.449
|
0.000
|
1.5 (1.2–1.8)
|
1.9 (1.7–2.1)
|
−0.386
|
0.011
|
|
Length of hospital stay in days, m (SD)
|
9.1 (3.5)
|
10.0 (8.5)
|
−0.142
|
0.359
|
9.2 (3.8)
|
9.5 (4.1)
|
−0.082
|
0.597
|
Abbreviations: Diff., standardized differences to express the difference independent
of the number of observations; ICU, intensive care unit; MACCE, major adverse cardiac
and cerebrovascular events; MI, myocardial infarction; SD, standard deviation.
a For nonconvergence of the model no accounting for matched pairs.
b Geometric mean (confidence interval).
Note: data are presented as mean and standard deviation or as numbers (%). Note that the
matching procedure did not find three matched pairs for each patient who underwent
surgery with use of microplegia.
Table 6
Cardiac markers
|
Before matching
|
After matching
|
|
Microplegia
n = 72
|
Cardioplexol®
n = 1054
|
Diff.
|
p-Value
|
Microplegia
n = 56
|
Cardioplexol®
n = 155
|
Diff.
|
p-Value
|
|
hs-cTnT, 1. POD, ng/L
|
220
(184–263)
|
278
(264–293)
|
−0.293
|
0.033
|
223
(184–269)
|
296
(262–336)
|
−0.380
|
0.016
|
|
Peak hs-cTnT, ng/L
|
230
(194–272)
|
328
(310–346)
|
−0.435
|
0.002
|
233
(194–280)
|
362
(315–416)
|
−0.557
|
0.001
|
|
CK-MB 1. POD, µg/L
|
13.2
(10.5–16.5)
|
16.7
(15.9–17.5)
|
−0.264
|
0.059
|
13.2
(10.5–16.7)
|
17.9
(15.8–20.3)
|
−0.363
|
0.025
|
|
Peak CK-MB, µg/L
|
13.7
(9.9–19.1)
|
19.2
(18.2–20.2)
|
−0.281
|
0.077
|
13.8
(9.6–19.9)
|
21.6
(18.9–24.6)
|
−0.389
|
0.026
|
|
CK 1. POD, U/L
|
457
(371–563)
|
534
(509–560)
|
−0.182
|
0.214
|
462
(372–572)
|
542
(486–605)
|
−0.213
|
0.182
|
|
Peak CK, U/L
|
539
(461–631)
|
737
(707–768)
|
−0.454
|
0.004
|
539
(458–633)
|
719
(645–801)
|
−0.445
|
0.011
|
Abbreviations: CK, creatine kinase; CK-MB, creatine kinase-myocardial type; Diff.,
standardized differences to express the difference independent of the number of observations;
hs-cTnT, high-sensitivity cardiac troponin T; POD, postoperative day.
Note: Data are presented as geometric mean (confidence interval). Note that the matching
procedure did not find three matched pairs for each patient who underwent surgery
with use of microplegia.
Fig. 2 Boxplots hs-cTnT.
Fig. 3 Boxplots CK. CK, creatine kinase.
Both sensitivity analyses indicated significantly reduced peak TnT values in the microplegia
group, as compared with the Cardioplexol® group. The generalized linear model yielded p = 0.001, Kruskal–Wallis-test resulted in p = 0.0003.
Discussion
This propensity score-matched cohort study with a 3:1 matching aimed to compare two
cardioplegia protocols, an institutionally refined microplegia applied with the MPS
(Basel Microplegia Protocol) and Cardioplexol® in patients undergoing isolated CABG surgery using the MiECC. We report five major findings.
First, the use of the Basel Microplegia Protocol is safe and feasible in isolated CABG
surgery. Second, MACCE was comparably low in both groups, which indicates the safety of the MiECC
system in CABG surgery. Third, there were no differences regarding postoperative AFIB between both groups. Fourth, patients operated by using microplegia were significantly shorter on the ICU compared
with patients operated using the Cardioplexol®. Fifth, and probably of most clinical significance, the use of microplegia was associated
with significantly lower postoperative values of hs-cTn, CK-MB, and CK, which is indicative
for less myocardial injury and optimal cardiac protection during surgery. This was
seen for peak values of hs-cTnT, CK, and CK-MB, as well as for the values on POD-1
for hs-cTnT and CK-MB ([Fig. 4]). CK values on POD-1 showed a trend toward lower values in the microplegia group,
but did not reach statistical significance.
Fig. 4 Boxplots CK-MB. CK-MB, creatine kinase-myocardial type.
These data corroborate our promising first experience of introducing our institutionally
refined dose/volume dependent microplegia applied with the MPS in isolated CABG surgery
using the MiECC.[15] There were no differences in intraoperative data, such as number of distal anastomoses,
aortic clamping time, or perfusion time, between the two cardioplegia concepts indicating
satisfactory conditions for the surgeons.
Because of the closed system of the MiECC and the possible risk of volume overload,
only few cardioplegic solutions qualify for the combined use with MiECC and high-volume
crystalloid cardioplegic solutions are not feasible.[4] This led to the development of Cardioplexol®. However, we believe that this technique has two major disadvantages compared with
the use of microplegia applied with the MPS: First, Cardioplexol® is a low volume cardioplegia which is given at a volume of 100 mL.[6]
[10]
[12]
[13]
[14]
[15]
[17] Though this avoids hemodilution, it may lead to running-off of the cardioplegic
solution to less stenotic vessels and could additionally pose the risk of a higher
loss of cardioplegic solution in the aortic root and tubes. In contrast, when using
microplegia applied with the MPS, the heart is supplied with high-volume blood cardioplegia
without any hemodilution due to the use of autologous blood.[15] Second, the application of microplegia with the MPS is provided in a flow- and pressure-controlled
fashion, with a constant dosage per volume and a controlled pressure.[15] In contrast, the application of Cardioplexol® is performed manually, without any control of pressure and flow. Therefore, we believe,
that the delivery of microplegia using the MPS in MiECC assisted surgery is beneficial,
especially in high grade stenoses.[15] Regarding differences between isolated LMT stenosis and 3-VD, subgroup analyses
were not possible due to the small number of patients with isolated LMT that were
operated using microplegia (n = 4).
Need for defibrillation (related to the entire procedure) was higher in the microplegia
group compared with the Cardioplexol® group, but did not reach statistical significance (21.8 vs. 11.1%; p = 0.066). However, the rate of defibrillation in the microplegia group was lower
compared with Buckberg cardioplegic solution in CABG surgery but was higher compared
with the results from our feasibility study and compared with Calafiore cardioplegia
in CABG surgery (Buckberg cardioplegic solution: 39.6%; MPS feasibility study: 11%;
Calafiore cardioplegic solution: 9.3%).[15]
[19] This needs further investigations.
There was only a trend toward lower rates of MACCE, in-hospital mortality, and postoperative
MI in the microplegia group in our study. However, there is literature showing an
association between high postoperative values of cTn and adverse outcomes after on-pump
cardiac surgery including CABG.[20]
[21]
[22] Moreover, the association between elevated values of cTn and adverse outcome in
high-risk patients with coronary artery disease or after noncardiac surgery has been
shown in various studies.[23]
[24]
[25]
[26] Therefore, we strongly believe that optimizing cardioplegic solutions, reflected
by low postoperative cardiac markers, is a crucial cornerstone in CABG surgery to
provide best possible outcomes. Additionally, these low values corroborate our primary
results when introducing this technique in our daily routine. It endows the surgeon
with the reliance for a good cardiac protection also during longer operations. Nonetheless,
the clinical significance of reduced postoperative cardiac markers especially for
long-term outcomes has to be further evaluated.
Patients operated using microplegia were significantly shorter on the ICU compared
with patients receiving Cardioplexol®. This is in line with a previous study using microplegia.[16] The use of microplegia was shown to be beneficial regarding postoperative low cardiac
output syndrome.[17] Therefore, a beneficial hemodynamic situation after the use of microplegia can be
assumed.
Though it is well known that the use of MiECC significantly reduces the incidence
of postoperative AFIB when compared with conventional ECC (class of recommendation
I, level of evidence A),[4] the incidence of postoperative AFIB was relatively high in both groups of our patient
cohort (microplegia: 30.4% vs. Cardioplexol®: 27.1%; p = 0.721). We believe that this is more because of a stringent definition of AFIB
in our clinic rather than the cardioplegia regime. Every postoperative AFIB > 48 hours
or > two episodes during the hospital stay is defined as postoperative AFIB, independently
of the existing rhythm at the moment of discharge.[15]
Some limitations warrant consideration when interpreting the findings of this study.
First, it was an observational single-center study, which may compromise the external
validity of our findings. Second, due to the matching method, the final study populations
are relatively small, and therefore, the generalizability of our results may be questioned.
Further studies with larger sample sizes will be more beneficial to enlighten the
topic. On the other hand, the standardized differences after propensity matching indicate
that the treatment groups are very similar with respect to patient characteristics,
so differences observed during postoperative course are likely to be related to the
treatment.
Third, due to the retrospective analysis of patients operated using the Cardioplexol®, we only can provide defibrillation rates related to the entire operation and not
specific after removal of the aortic clamp.
Forth, the as arrest agents used ingredients (K, Mg, and Lidocain) have the drug approval
and are licensed to use in humans. However, a possible off-label use is to consider.[15]
Conclusions
In conclusion, the use of the Basel Microplegia Protocol is beneficial regarding postoperative
biomarker values, and it is associated with a significantly shorter stay on the ICU
compared with the use of Cardioplexol® in isolated coronary artery bypass grafting using the MiECC.
