Custodiol (Histidine-Tryptophan-Ketoglutarate) versus Modified St. Thomas Cold Crystalloid Cardioplegia: Short-term Results

INTRODUCTION

The term "myocardial protection" refers to strategies used either to reduce or to prevent post-ischemic myocardial insult that occurs throughout, and after open-heart surgery.¹ A single dose method for myocardial protection is attractive in long operations, as the surgeon does not need to stop several times to re- administer cardioplegia.²

The mechanism of cold crystalloid cardioplegia is extracellular, it induces fast cardiac arrest through excessive potassium and magnesium concentrations, while the Histidine-Tryptophan-Ketoglutarate (HTK) cardioplegia is an intracellular type, it contains lower concentrations of sodium and calcium and induces cardiac arrest with the aid of deprivation of extracellular sodium for action potential.³

The major advantage of HTK cardioplegia is derived specially from histidine, which acts as a buffer, enhancing the efficiency of anaerobic glycolysis.

Kresh et al. discovered that a histidine protein-kind buffer solution was better than bicarbonate in stabilizing intracellular PH.⁴

The primary endpointaimed to evaluate whether the custodial or the crystalloid cardioplegia is better in myocardial protection in patients Undergoing Double Valve Replacement Surgery.Secondary endpoint aimed to show the effect of both cardioplegic solutions on myocardium regarding cardiac enzymes, postoperative ICU stay and ejection fraction (EF).

PATIENTSAND METHODS

Design and patients:

This studyis prospective, comparative, non-randomized, non-blinded, multicenter (not single) and small volume sample cohort. The study was conducted from 08/2017 -07/2019 on 50 patients who had double valve replacement surgery (DVR) attending the National Heart Institute and Alazhar University Hospital. We includedPatients with double valve disease who underwent Valve replacement through conventional Median Sternotomy with cardio-pulmonary bypass time more than 80 minutes. We excluded cases with concomitant surgical procedure, emergency, re-operative surgery, cases with end-organ dysfunction and cases with ejection fraction less than 40%.The median follow-up duration was 6 months.

Ethicalconsideration:

The local Ethical Committee accredited the work, and all the cases signed consentpervious to enrollment.

Method and information collection:

All cases had preoperative laboratory investigations, 12-lead ECG, trans-thoracic echocardiography, and cardiac catheterization.

All cases had surgical intervention under general anesthesia with endotracheal intubation. The surgical approach was through median sternotomy, then the pericardium is opened. All patients had aortic and venous cannulation. Antegrade cardioplegia was given in all patients.Left atrial unipolar radiofrequency ablation was done in cases withpermanent AF just after applying the cross clamp and administrating cardioplegia. Ablation was done using (Medtronic Inc.) probeencircling the orifices of the pulmonary veins and posterolateral part of mitral annulus. After ablation, the mitral and the aortic valves were replaced and caseswith tricuspid regurge underwent tricuspid repair using segmental DeVega technique.The heparin action was reversed with protamine sulfate with ratio of one mg for every 100 IU heparin. After achieving medical and surgical hemostasis, the sternum was closed, and the patient got transported automatically ventilated to the intensive care unit (ICU). We studied the cardiopulmonary bypass time, and the ischemic time, and the need for mechanical support.

Postoperative analysis covered the duration of mechanical ventilation, arrhythmias, and length of ICU stay. Postoperative echocardiography was routinely ordered prior to discharge.

Statistical analysis:

Data had been collected, revised, coded and entered to the Statistical Package for Social Science (IBM SPSS) version 23. The quantitative statistics had been demonstrated as mean, standard deviations and ranges when their distribution found. Also, qualitative variables had been demonstrated as number and percentages.

The comparison among the studied groups concerning the qualitative data was achieved by the Chi-square test. The comparisonbetween the two independent groups with quantitative information and parametric distribution had been achieved by the usage of Independent t-test while two groups with paired datawere compared by the usage of Paired t-test.

The confidence interval has been adjusted to 95% and the margin of error acceptedhas been adjusted to5%.So, the p-value was considered non-significant (P > 0.05); significant (P < 0.05) and highly significant (P < 0.01).

RESULTS

Fifty patients were collected among them,14 patients were males (56%) and 11 patients (44%) were females in Group A while in Group B 15 patients(60%) were males and 10 patients (40%) were females. 15 patients (60%) were diabetic in Group A, while 10 patients (40%) were diabetic in Group B.15 patients (60%) were hypertensive in Group A, and 18 (72%) patients in Group B (Table 1). In Group A, 4 patients (16.0%) had permanent AF, while in Group B 3 patients (12%) had permanent AF. Maze procedure was done to both groupsusing left atrial unipolar radiofrequency ablation. Patients were reviewed regularly at one, three, six and twelve months with ECG. The difference in freedom from AF was not statistically significant between the two groups with 75% (3/4) in Group A compared to 66% (2/3) in Group B.

Table 1: Risk factors distribution of the study groupshows that there was no statistically significant difference found between the two studied groups regarding risk factors with p-value > 0.05.

The mean cardiopulmonary bypass time was in custodial group was 99.4±8.46 while in cold crystalloid cardioplegia group was 95.6±12.27 minutes. (Table 2) .

Table 2: Cardiopulmonary bypass time and aortic cross-clamp time (minutes) presented as range and (mean and standard deviation):

The mean ICU stay in custodial group was 1.28±0.46 while in cold crystalloid cardioplegia group was 1.72±0.61.The mean duration of mechanical ventilation (MV) in custodial group was 4.64±0.86 while in cold crystalloid cardioplegia group was 7.04±0.84.The mean total hospital stay in custodial group was 6.48±0.59 while in cold crystalloid cardioplegia group was 7.96±1.27  (Table 3).

Table 3: Comparison between the two studied groups regarding postoperative data showing that there was statistically significant difference between them regarding ICU stay total hospital stay and duration of mechanical ventilation.

Troponin:Venous blood samples were collected immediately postoperative, 12 hours and 24 hours postoperative. The troponin elevation mean in the immediate post-operative: in custodiol group was 8.46±2.21 while in the cold crystalloid group was 10.08±2.18.While, in twelve hours post-operative: in custodiol group was 21.62±5.24, while in the cold crystalloid group was 24.86±5.33 (Table 4).Intwenty-four hours after CPB Troponin values decreased in both groups without statistically significant difference among them, with mean Troponin I in custodial group was 8.1±0.84in comparison to8.6±1.5 in crystalloid group.

Table 4: Comparison between the two studied groups regarding troponin showing significant elevation in the troponin level in the cold crystalloid group in the immediate and 12 hours post operative in comparison to the custodial group.

Echocardiography: A comparison of postoperative echo study revealed that the mean EF in Group A was 50.4 ± 4.29 while in Group B was 50.24 ± 6.79 (Table 5).

Table (5): Comparison between the two studied groups regarding Postoperative Echo

Reopening: there was no significant difference in the rate of re-exploration for bleeding between the two groups as 1 patients (4%) in the custodiol group was re-explored due to bleeding from sternal wire and 2 patients (8%) in the cold crystalloid group were re-explored due to bleeding from left atriotomy.

No valve complications were detectedtill the end of the study.

DISCUSSION

Our trial was conducted on 50 cases, which were categorized into two groups, Group A (n=25) with custodiol cardioplegia, and Group B (n=25) with intermittent antegrade cold cardioplegia.Clinical and laboratory investigations were ordered to assess the two methods regarding myocardial protection in double valve replacement surgery.

In our study 27 cases (54%) are diabetics, which is comparable to different studies.^{5, 6}Hypertension was diagnosed in 66% of our cases, in agreement to different studies.^{5, 6}

Echocardiography was routinely ordered preoperatively to evaluate left ventricle function, valves, and pulmonary artery systolic pressure. The mean EF in our study is [41.43±9.25] %. Inagreement to other studies.^7,8

In our results, the cardiopulmonary bypass time in Group A is 99.4±8.46, and in Group B is 95.6±12.27.The mean cross clamp time in Group A is 72.2±89.36, and in Group B was 68±12.58 showing no statistical difference compared to different studies.^{7, 9}

The mean ICU stay in our results in Group A is 1.28±0.46 and at the same time in Group B it is 1.72±0.61 with p-value 0.006. We found that the mean length of MV in custodial group is 4.64±0.86 and in crystalloid cardioplegia groupit is 7.04±0.84 with p-value 0.000 showing a remarkable statistical difference between the two groupssuggesting thesuperiority of HTK solution over the crystalloid cardioplegia which was similar to different studies.^{10, 11} (Table 3)

The mean elevation of troponin-T in 12 hours post-operative in group A is  21.62±5.24 in our results, whilst in Group B is 24.86±5.33 with p-value 0.035 Showing a remarkable statistical difference suggesting higher myocardial safety with HTK cardioplegia, which come in agreement with different studies.^{6, 12} (Table 4)

Postoperative echocardiography revealedthat the mean EF in Group A became 50.4 ± 4.29 while in Group B became 50.24 ± 6.79. 6 patients (24%) in Group A had pericardial effusion and 5 patients (20%) had pericardial effusion in Group B with no statistical difference, which is comparable to different studies.¹³ (Table 5)

Study limitations:

The main limitation of the study is the restrictednumber of patients and short period of study. We suggest the conduction of a multi-center study for a better evaluation of the effect of HTK VS cold crystalloid cardioplegia in myocardial protection.

CONCLUSION

The results suggest that Custodiol provides myocardial protection that is equivalent to that of cold crystalloid cardioplegia however;Custodiol cardioplegia is attractive for its potential to give long myocardial protectionand motionless operative field after single-dose application. The present studydemonstrated that HTK cardioplegia is associated with less ICU stay, mechanical ventilation, postoperative hospitalization, and troponin T release in low-risk patients undergoing double valve replacement.