Comparison of effect of antegrade with combined antegrade-retrograde cardioplegia on inflammatory response and left ventricular systolic function in coronary bypass surgery : A prospective randomized Study

Aim: Nonhomogeneous distribution of antegrade cardioplegia especially in cases with severe myocardial hypertrophy or proximal stenosis of coronary arteries may be a serious problem. This prospective randomized study was designed to determine whether combined antegrade–retrograde cardioplegia provides improved myocardial protection in the early period and is associated with better laboratory results compared with antegrade technique alone. Material and Methods: A total of 60 patients who underwent coronary artery bypass grafting surgery, 45 (75%) males and 15 (25%) females, were included in the study as 2 groups: In Group 1, 30 patients were given the combined cardioplegia solution antegrade via the aortic root and retrograde via the coronary sinus, in Group 2, 30 patients were given only antegrade cardioplegia solution via the aortic root. The CK-MB, TpI, TNFα, IL-1, IMA, ICAM-1, and BNP parameters were studied in the blood samples which were taken preoperatively, intraoperatively and postoperative sixth day. The patients were evaluated preoperatively and on the sixth postoperative day using transthoracic echocardiography. Results: The postoperative mean EF decrease was significantly lower in Group 1 compared to Group 2 (4.13 ± 9.09 vs 8.90 ± 10.76 in Group 1 vs. Group 2, respectively, p=0.046). When the change in TNF-α levels were compared between groups 1 and 2, the magnitude of increase in TNF-α was significantly higher in Group 2 (p=0.047). Conclusion: We concluded that co-administration of antegrade and retrograde cardioplegia may provide improved myocardial protection compared to antegrade cardioplegia method alone in the early postoperative period.


Introduction
Since the time when open heart surgery first began, intraoperative myocardial protection has been one of the most serious problems associated with cardiovascular surgery, and its topicality as a subject which has been studied throughout the world has continued to this day.Myocardial damage which has occurred as a result of inadequate or false protection generally manifests itself as myocardial contractile dysfunction which appears minutes or hours after a cardiopulmonary bypass (CPB).Sufficient myocardial protection during open heart surgery may be provided by the rapid infusion of cold potassium cardioplegia together with systemic and topical hypothermia resulting diastolic arrest.Sufficient myocardial protection using cardioplegic solutions might, however, be possible in case where cardioplegia has been distributed homogeneously on every side of the myocardium [1].Many studies hitherto have been carried out on the composition of these solutions and the manner in which they are given.While in a section of the literature concerned with the method of giving cardioplegic solutions, the better efficacy of antegrade cardioplegia on myocardial protection is defended, a portion of researchers advocate that cardioplegic solutions given using the retrograde method can better protect the myocardium.
On the other hand, some other researchers, who see the antegrade and retrograde cardioplegia techniques as methods which supplement each other, have carried out studies on the combined cardioplegia method, in the assumption that these two methods may be used in combination [2,3,4].
This study was designed to determine whether combined antegrade-retrograde cardioplegia provides improved myocardial protection in the early postoperative period and is associated with better laboratory results compared with antegrade technique alone.In our prospective, randomized study, the parameters of echocardiography, creatine kinase MB isoenzyme (CK-MB), troponin-I (TpI), brain natriuretic peptide (BNP), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), ischaemia modified albumin (IMA), and intercellular adhesion molecule -1 (ICAM-1) were compared, in patients who underwent coronary artery bypass graft surgery (CABG) with different cardioplegia application strategies.

Material and Methods
The study protocol was approved by Ethics Committee and written informed consent was obtained from all patients who participated to the study.

Surgical Technique and Protection of the Myocardium
All the patients underwent elective operation through a standard median sternotomy.The left internal mammarian artery (LIMA) and saphenous vein graft (SVG) were harvested.
The ascending aorta and right atrium were cannulated after administration of heparin.Antegrade and retrograde cardioplegia cannulae were placed in all the patients.The aim of the retrograde cardioplegia cannula placed in patients in Group 2 was to obtain blood samples from the coronary sinus for evaluation.The pump with a non-pulsatile flow was set so that the flow-rate would be between 1.8 and 2.4 L/min/m2.
Moderate hypothermia (28-32oC) was used.During the CPB, haematocrit was maintained at between 20-25% and mean artery pressure between 50-70 mmHg.Activated clotting time (ACT) was maintained at 480 seconds.After cross clamping the aorta, cold blood cardioplegia (4oC) was applied from 15-20 ml/kg at the beginning.In Group 2, the heart was stopped using cold blood cardioplegia given via the antegrade route.In Group 1, the heart was stopped using cold blood cardioplegia given, at intervals, first via the antegrade route (2/3 of the cardioplegia) then via the retrograde route (1/3 of the cardioplegia).During the cross-clamp time, for redosing, 10-15 ml/kg dose of cold blood cardioplegia was given every 20 minutes via the antegrade, retrograde routes and through the grafts to completed distal anastomosis in Group 1; while for the patients in Group 2 the cardioplegia was given via the aortic root and through the grafts to the completed distal anastomosis.After the distal anastomoses had been completed, a hot-shot (34-36oC) cardioplegia solution was given to both groups before the cross clamps were removed.
Rewarming was initiated during the last distal coronary anastomosis.Proximal anastomoses were constructed with side clamps after the cross-clamp release.
The cold blood cardioplegia (4oC) used in our clinic was prepared in a manner where there is a ¼ ratio between the blood and a crystalloid solution of 500 cc of 40 mEq of potassium within 0.9% NaCl, 5 cc of 10% calcium, 10 cc of magnesium, and 10 mEq of sodium bicarbonate.For the hot-shot (warm blood) cardioplegia, 1 ampule (1.5 grams) of MgSO4 and 2 ampules (1.68 grams totally) of NaHCO3 were added to 100 cc of 0.9% NaCl and prepared by mixing it with blood to a ratio of ¼ to a temperature of between 34-36oC.

Biochemical Measurements
Routine biochemical parameters and CK-MB, TpI, BNP, TNF-α, IL-1, IMA, and ICAM-1 were studied in the blood samples taken from the patients just before the induction of anesthesia.
The CK-MB, TpI, TNF-α, IL-1, IMA, and ICAM-1 parameters were studied in the coronary sinus blood samples that were taken before aorta cross-clamping and at the beginning of reperfusion.The BNP and IMA were looked in the blood samples at the sixth postoperative day.
The CK-MB, BNP, and TpI analyses were performed with chemiluminescent methods using original Beckman Coulter brand commercial kits in a Beckman Coulter Unicel DxI-800 brand immune analyzer.The IL-1, TNFα, and ICAM-1 were measured using an eBioscience brand kit worked using ELISA method.The IMA level was analyzed manually using the method specified by Bar-Or et al [5].

Echocardiographic Evaluation
The patients were evaluated preoperatively and on the 6th postoperative day using transthoracic echocardiography.The evaluation was carried out by the same cardiologist blinded to the study.Standard cardiac diameters and routine values were determined.

Statistical Analysis
The SPSS for Windows v20.0 software (SPSS Inc, Chicago, IL, USA) was used in the analysis of the statistical data.The Student-t test (those conforming to normal distribution) and the Mann-Whitney U Test (those not conforming to normal distribution) were used in the comparison between the two groups of numeric variables acquired by taking measurements from the patients on one occasion.All statistical hypothesis controls were applied at a significance level of α=0.05.Results which came out as p<0.05 were interpreted as being significant.

Results
A total of 60 patients who underwent coronary artery bypass grafting surgery, 45 (75%) males and 15 (25%) females, were included in the study.
The preoperative characteristics of the patients included in the study are presented in Table 1.There was no significant difference between 2 groups in terms of age, gender, comorbid conditions, additional procedures, coronary artery lesions, blood lipid parameters, and inflammatory status (p>0.05).
There was no statistically significant difference between the groups with respect to number of distal anastomosis per patient, aortic cross-clamping time, cardiopulmonary bypass time, volume of cardioplegia, spontaneous cardiac activity, need of inotropic agents, ventilation time, bleeding amount, postoperative arrhythmia, intensive care unit duration, and length of stay in hospital (Table 2).
When both groups were compared, the magnitude of the changes (difference between pre and post CPB) in the CK-MB, TpI, IL-1, IMA, and ICAM-1 values were not statistically significant (p=0.112,p=0.394, p=0.391, p=0.13, and p=0.182, respectively).The magnitude of increase in TNFα was significantly higher in Group 2 (p=0.047)(Table 3).The values from echocardiography revealed that mean EF decreased after operation in both groups.However, the magnitude of decrease in EF was significantly higher in Group 2 compared to Group 1 (p=0.046).The mean BNP values increased after operation in both groups.The magnitude of increase in BNP was significantly higher in Group 2 (p=0.032)(Table 4).

Discussion
Most favorable myocardial protection requires homogeneous delivery of cardioplegic solution throughout the heart.Despite developments in surgical techniques and progress in myocardial protection methods, there is no consensus on applying an ideal method for the protection of myocardium during open heart surgery.Reperfusion damage generally manifests itself as myocardial systolic and diastolic dysfunction which appears minutes or hours after CPB.
A number of authors who argue for the supremacy of antegrade cardioplegia have reported that the infusion of cardioplegic solution through the aortic root is a simple delivery method used by cardiac surgeons.Antegrade cardioplegia provides diastolic arrest more quickly than retrograde cardioplegia.However, when there is a critical stenosis in proximal parts of coronary arteries especially in proximal left anterior descending lesion accompanied by poor collaterals, this method can cause nonhomogeneous distribution of cardioplegic solution to the myocardium.On the other hand, the inability for cardioplegia given via the aortic root in patients who have coronary lesions accompanied by aortic insufficiency is an important restrictive factor in the usage of the antegrade cardioplegia method [6].Clinical trials regarding the risk of athero-embolisms and air embolisms by using different cardioplegia methods demonstrate that antegrade cardioplegia can cause more embolic complications compared to retrograde one [7].When there is a severe left ventricular hypertrophy (for any reason), the cardiac tissue will not be protected adequately due to disproportional increment of myocardial thickness relative to the myocardial vascular network.Consequently, this situation increases the possibility of myocardial ischemia resulting cardiac injury during aortic cross-clamping [8].On the other hand, because of reasons such as slow flow rate, heterogeneous distribution, and poor protection of the right ventricle wall, the use of the retrograde cardioplegia method on its own is also restricted.For this reason, the use of the antegrade and retrograde cardioplegia methods together can increase its efficacy [6,9].The aim in using antegrade and retrograde cardioplegia in combination is to supplement each other.It has been reported that, by the combined antegrade-retrograde cardioplegia method, myocardial functions are better preserved, that the production of myocardial lactate is lower, the ATP is better preserved, arrhythmias and hospitalization duration in the postoperative period are lower [10,11].
This prospective study examines the impact of different cardioplegic solution delivery systems to left ventricular systolic functions and the levels of some biochemical markers which increased in response to ischemic and inflammatory conditions in randomized patients undergoing first time one or more vessel CABG.
The TNF-α is released in the early stages of acute inflammation.This biochemical marker was also examined in the samples taken from the coronary sinus before and after the cardioplegia, while the TNF-α level increased much more significantly in antegrade cardioplegia group demonstrating that inflammation associated with ischemia and reperfusion damage appeared less in the hearts in which combined cardioplegia were applied.
Cardiac markers can be detected to be higher than normal levels if a complication occurs following open heart surgery [12,13].CK-MB and troponin I as surrogate cardiac markers of myocardial ischemia were increased in both groups compared to basal levels after the cardioplegia despite there was no perioperative MI observed in our patients.However, when the magnitude of the changes were compared there was no statistically significant difference between the groups (p=0.112 and p=0.394, respectively).Albeit troponin I and CK-MB are sensitive cardiac biomarkers demonstrating myocardial injury; some other factors such as myocardial manipulation, dissection of the myocardium to detect the coronary arteries, placement of purse-string sutures may also increase the markers, so the difference between the groups was non-significant.
Chello et al. [14] reported in preoperative patients that there was an inverse relationship between the levels of BNP values and left ventricular systolic and diastolic functions.In some studies, it has been also reported that pre-operative high BNP values may be an indicator of high risk for patients who are undergoing CABG [15][16][17][18][19].There was a statistically significant rise in BNP levels in both groups.If we compare the BNP changes in two groups, the increase in BNP levels was higher in Group 2. This situation was also supported by statistically significant difference between the groups in regarding the changes of EF values.
Lesser decrease in EF values in combined cardioplegia group was a substantial factor demonstrating that the superiority of combined cardioplegia compared to antegrade cardioplegia alone from the point of view of myocardial protection.
As a conclusion, according to results of our clinical trial, we demonstrate that co-administration of retrograde and antegrade cardioplegia is more advantageous compared to antegrade one in terms of myocardial protection.

Declaration of conflict of interest
There is no conflict of interest.

Volume 9
The study was conducted according to the principles of Helsinki declaration.This prospective study was carried out on 60 patients who underwent elective CABG with CPB between June 2011 and December 2011.The participants were block randomized into two groups: In Group 1, 30 patients were given the combined cardioplegia solution, antegrade via the aortic root and retrograde via 180 Number 3 p: 179-184

Table 1 :
Preoperative demographic, laboratory, and echocardiographic characteristics of the patients

Table 2 :
Comparison of surgical and postoperative variables between the 2 groups

Table 3 :
Comparison of the magnitude of the changes after CPB between 2 groups

Table 4 :
Comparison of the magnitude of the changes after operation between 2 groups