Abstract
Background:
We analyzed the adequacy of the myocardial protection achieved with a single dose of retrograde crystalloid Celsior®, compared with an accepted standard (microplegia), in on-pump coronary artery bypass grafting surgery (CABG).
Methods:
This was a retrospective comparative clinical study conducted in a single institution that included all the patients operated on who had elective isolated on-pump CABG, from March 2006 to June 2014. We evaluated maximum postoperative troponin T (TnT) as a marker of myocardial damage, adjusted for possible confounders using propensity score matching. We also analyzed markers of recovery of myocardial function, and the safety of the intravenous use of Celsior®.
Results:
During the study period, 261 patients were included, divided in two groups: (a) continuous retrograde blood-based microplegia (114 patients); (b) retrograde single-dose crystalloid Celsior® (147 patients). The propensity score adjusted maximum TnT was significantly lower in the Celsior group [average treatment effect = −0.55 ng/dl; 95% confidence interval (CI) −1.10 to −0.1 ng/dl; p = 0.048]. There were no differences in the postoperative use of intra-aortic balloon of counterpulsation or in the requirements of high-dose inotropic medications. In-hospital mortality was equivalent in both study groups (p = 0.73); surgical re-exploration because of bleeding was equivalent (p = 0.37). There were no differences in prolonged mechanical ventilation (p = 0.65) and intensive care unit length of stay (p = 0.87).
Conclusion:
An isolated single dose of retrograde Celsior® may be an effective and safe myocardial protection strategy in on-pump CABG.
Keywords
Introduction
Cardioplegia was first introduced in the 1960s, and there have been many improvements in its composition since then. Despite the advances in its formulation, there is still an open debate over which one is the ideal cardioplegic solution. The two preferred alternatives are either repeated doses of blood-based cardioplegic solutions, or a single dose of crystalloid cardioplegia. 1 Although evidence-based medicine guidelines are currently scarce, nowadays, there is a worldwide preference in favor of the use of intermittent cold-blood cardioplegia, 2 although crystalloid cardioplegia is a simpler method of myocardial protection, as they are administered in a single shot, allowing long periods of ischemia.
Celsior® (Genzyme Corp., Boston, MA) is an organ preservation crystalloid solution, developed for organ protection and transportation in the context of heart transplantation. It has demonstrated its cardioprotective effectiveness, with an optimal functional recovery of transplanted hearts even after prolonged times of ischemia. 3 Recently, Celsior® has been tested as a cardioplegic solution in different institutions.4,5 We have previously published our experience with the use of Celsior® for myocardial protection in isolated aortic valve replacement, 6 and our results showed an optimal postoperative myocardial recovery achieved with the use of this crystalloid solution.
In addition, an important characteristic of ischemic coronary artery disease is that the pathway employed for myocardial protection delivery is of paramount importance, as the distribution of the cardioplegic solution to the viable myocardium could be burdened in the patients with known coronary artery disease, due to the existence of obstructive lesions in the coronary circulation. Because of this potential risk, cardioplegia delivery in a retrograde fashion could improve the distribution of the cardioplegia to all the myocardial regions, 7 although a combined delivery of antegrade and retrograde cardioplegia is generally preferred to optimize the protection of the right ventricle.
In this report, we analyzed the effectiveness of the myocardial protection achieved with a single-dose crystalloid Celsior®, administered in a solely retrograde pathway, compared with a continuous retrograde blood-based cardioplegia (microplegia), in the context of on-pump coronary artery bypass (CABG) surgery.
Material and methods
Study design
This was a retrospective comparative clinical study conducted in a single institution. We assessed the effectiveness of the myocardial protection achieved with the use of a single dose of retrograde crystalloid Celsior®, compared with a currently accepted standard in myocardial protection, such as microplegia. 8
All the study variables were prospectively recorded at the time of the admission for the surgical procedure and were digitally recorded in the database of the Heart Department. A database query was conducted to extract all the desired variables for this analysis.
Study population
The study included all the patients with ischemic heart disease, who were operated on, receiving elective isolated on-pump CABG in our institution, from March 2006 to June 2014. The standard protocol for myocardial protection in our institution for CABG was microplegia until 2008. In 2008, we started using Celsior® in this setting, and we progressively expanded its use in the following years. Nowadays, Celsior® has become the routine myocardial protection in any cardiac surgical procedure in our institution. Therefore, the patients included in this analysis are the ones that were operated during this transition period. Due to the fact of the observational nature of the present report, no randomized distribution of both treatment arms was implemented.
The study population was divided into two groups, depending on the myocardial protection strategy that was employed during the surgical procedure: (a) myocardial protection with continuous retrograde microplegia; and (b) myocardial protection with a single dose of retrograde crystalloid Celsior®.
The exclusion criteria for this study were:
(1) emergency surgery
(2) nonisolated CABG
(3) off-pump CABG
(4) myocardial protection with a different strategy than microplegia or isolated retrograde crystalloid Celsior®. To achieve two homogeneous study groups, all the patients in whom Celsior® was administered in an antegrade pathway or a combination of both (antegrade and retrograde) were excluded from the analysis, as a major bias could be introduced if combined delivery of Celsior® was included.
Protocol of myocardial protection
We have previously described in detail our protocol for microplegia. 6 Microplegia is one of the accepted standards for comparative studies on myocardial protection. 1 In brief, microplegia consists of a retrograde continuous infusion of warm blood through the coronary sinus, supplemented with potassium and magnesium.
The protocol of our institution for myocardial protection with isolated retrograde crystalloid Celsior® is:
(1) after the aorta is cross-clamped, the cold crystalloid Celsior® infusion is started with a temperature of less than 4°C, in a retrograde fashion, through the coronary sinus, with a targeted coronary sinus pressure of 20–40 mmHg;
(2) the volume of Celsior® depends on the patient’s weight, with a calculated dose of 10–15 ml/kg. To avoid volume overload, we advocate the use of routine hemofiltration during cardiopulmonary bypass (CPB);
(3) before the removal of the aortic clamp, we recommend 2–5 min of warm-blood reperfusion administered through the cannula of retroplegia to avoid abrupt rewarming of the heart.
Study objectives
The primary endpoint was the analysis of the quality of the myocardial protection achieved with Celsior®, through the analysis of markers of myocardial damage and recovery of myocardial function:
(1) We evaluated maximum postoperative troponin T (TnT) as a marker of myocardial damage.9,10
(2) We analyzed as markers of recovery of myocardial function: spontaneous recovery of heart rhythm, need of electrical cardioversion after the release of the aortic cross-clamp, use of high doses of postoperative inotropes, and use of intra-aortic balloon of counterpulsation (IABP). The dose of inotropic support was considered as a high dose if, at any time in the postoperative period, the vasoactive inotropic score was over 15. 11 The use of IABP was considered as prolonged if the device was needed for more than 24 h in the postoperative period.
The secondary endpoint was the analysis of the safety of the intravenous use of Celsior®:
(1) in-hospital mortality;
(2) allergic reactions;
(3) hematologic disturbances;
(4) renal insufficiency. Postoperative acute renal failure was considered as a creatinine increase above 50% of the preoperative levels, or if the use of renal replacement therapy was required.
Statistical analysis
The statistical analysis was processed using Stata/IC 14.1 Software (StataCorp LP, College Station, TX). Continuous variables were expressed as mean and standard deviation (SD). Normal distribution of continuous variables was assessed with the Shapiro–Wilk normality test. Categorical variables were expressed as counts and percentages.
The student’s t test was used to compare continuous variables. Categorical variables were compared using the chi-square test, or Fisher’s exact test where appropriate.
Pearson’s linear correlation coefficient was used to estimate the correlation of two continuous variables and was expressed as the coefficient with its 95% confidence interval (CI). The power of the study was 80.6% to find bilateral differences in the mean maximum TnT between both study groups, higher than 0.5 ng/dl, with the current study sample size and an alpha risk of 0.05.
A statistical adjustment for possible confounding factors was performed using propensity score (PS) matching. Previous studies have addressed the preoperative factors that influence TnT release after CABG. 9 The preoperative variables that are known to influence TnT release are: 9 age (years), body mass index (kg/m2), number of diseased vessels, number of grafts performed, cardiopulmonary bypass time (min), cross-clamp time (min), estimated glomerular filtration rate (ml). PS matching was performed, and it was used to evaluate the average effect of the treatment (type of cardioplegia) on the treatment-dependent outcome (maximum postoperative TnT), adjusted by all the previously mentioned covariates (included in the model as independent covariates). A one-to-one number of matches per observation was requested.
Simple logistic regression was used to analyze the relationship between several binary outcomes (use of IABP, use of high doses of inotropic medication, postoperative mortality) and maximum TnT levels, and was expressed as odds ratios (ORs) with their 95% CI.
A p value of less than 0.05 was considered statistically significant.
Ethical considerations
The Clinical Research Ethics Board (Comité Ético de Investigación del Principado de Asturias) approved the implementation of this study (protocol number 57/16). This work was a retrospective observational clinical study, with no intervention made by the investigator team.
Authorization was granted to waive informed consent, because patients had been treated according to standard procedures in our institution.
The identification of the patients is encoded, complying with the requirements of the Organic Law on Data Protection 15/1999.
Results
Patient population
During the study period, 261 patients were included for the analysis. The study population was divided into two groups depending on the myocardial protection strategy employed:
(1) continuous retrograde microplegia (114 patients);
(2) isolated ‘single shot’ retrograde crystalloid Celsior® (147 patients).
Table 1 shows the preoperative characteristics of both groups. There were no significant differences in most of the analyzed preoperative variables, although patients in the microplegia group had a significantly higher average number of affected coronary vessels.
Patient characteristics.
GFR, glomerular filtration rate; SD, standard deviation, calculated using the Cockcroft-Gault formula. Bold text represents the variables were a significant difference was observed between both study groups.
Surgical procedure
All the CABG procedures were performed under general anesthesia through a full median sternotomy, with central cannulation for CPB. CPB circuits were primed with Plasma-lyte (Baxter Health-care, Deerfield, IL), and cardiopulmonary bypass was instituted under full systemic heparinization, with an activated clotting time of more than 480 sec. The distal anastomoses were performed first, under cardioplegic arrest of the heart. The proximal anastomoses of the remaining free grafts were connected to the aorta with a side-biting clamp, after the release of the aortic cross clamp.
The characteristics of the surgical revascularization are shown in Table 2. The quality of the revascularization was equivalent in both groups. There were no differences in the absolute percentage of patients in whom complete revascularization was achieved, with a similar number of grafts constructed in each group. Moreover, the percentage of myocardial territories with a severe obstructive lesion that was indeed grafted was similar between both groups.
Characteristics of the surgical revascularization.
CPB, cardiopulmonary bypass; CX, circumflex artery; LAD, left anterior descending artery; RC, right coronary artery; SD, standard deviation. Bold text represents the variables were a significant difference was observed between both study groups.
Table 2 also shows that clamp time and CPB time were significantly longer in the Celsior group.
Moreover, Table 2 shows the final volume balance at the end of the surgical procedure. Mean volume of Celsior® per patient was 1029 ml (SD = 412 ml). Hemofiltration was established in 95% of the patients in the Celsior group, as per protocol recommendation, while in microplegia group only 25% of the patients were hemofiltered during CPB.
Although microplegia is considered as the myocardial protection strategy that adds the minimal amount of volume of cardioplegia, 8 final volume balance was significantly less positive in the Celsior group because the mean extracted volume was larger than the infused cardioplegia volume (mean extracted volume of 1334 ml, SD = 555 ml). Additionally, urine output during the operation was higher in the Celsior group (mean urine output was 135 ml more in the Celsior® group; 95% CI 74–214 ml more in Celsior group; p < 0.001).
Markers of myocardial damage and myocardial function recovery
Table 3 shows the surrogates of myocardial protection stratified by the type of cardioplegia. We analyzed TnT as a marker of postoperative myocardial damage; mean maximum TnT of the overall cohort was 1.02 ng/dl (SD = 1.43 ng/dl; range 0.02–12.4 ng/dl). This postoperative peak of TnT after a CABG procedure is consistent with other previously published data. 10 Figure 1 shows the boxplot of TnT release with each myocardial protection strategy. Mean maximum unadjusted postoperative TnT was significantly higher in the microplegia group (1.27 ng/dl versus 0.82 ng/dl; p = 0.017). PS matching was employed to adjust the effect of the type of cardioplegia on maximum TnT release, adjusted by several covariates that are known to potentially influence TnT release after a CABG surgery. 9 A total of 237 observations with data in all the covariates were paired in a one-to-one PS matching, and 122 valid pairs were generated using nearest neighbor PS matching. The estimated average treatment effect (ATE) on the population of the type of cardioplegia on maximum TnT was significantly lower in the Celsior group (ATE = −0.55 ng/dl; 95% CI −1.10 to −0.1 ng/dl; p = 0.048).
Markers of myocardial damage and myocardial function recovery.
CABG, coronary artery bypass graft; IABP, intra-aortic balloon counterpulsation; VIS, vasoactive inotropic score; SD, standard deviation; TnT, troponin T. Bold text represents the variables were a significant difference was observed between both study groups.
Boxplot of maximum postoperative troponin T in both study groups.
Additionally, we analyzed markers of recovery of myocardial function. Regarding the recovery of electrical activity of the heart, Table 3 shows that the spontaneous recovery of heart rhythm was significantly higher in microplegia group, and that patients in Celsior group significantly required more electrical cardioversion attempts to obtain a stable heart rhythm after the release of the aortic cross clamp.
There were no significant differences in the postoperative percentage of patients who required the use of an intra-aortic balloon of counter pulsation (IABP) or high-dose inotropic medications.
Moreover, maximum TnT was not associated with an increased postoperative mortality, but it was significantly associated with an increased use of postoperative IABP (OR 1.54; 95% CI 1.23–1.93; p < 0.001), and with a close to significant trend of increased requirements of high doses of inotropic medications (OR 1.21; 95% CI 1.00–1.46; p = 0.051).
Secondary endpoints: safety of Celsior®
As shown in Table 4, in-hospital mortality was equivalent in both study groups (p = 0.73).
Postoperative outcomes.
ICU, intensive care unit; SD, standard deviation. Bold text represents the variables were a significant difference was observed between both study groups.
Table 4 also shows that although 24 h chest tube drainage was statistically significantly higher in the Celsior group (102 ml more, 95% CI 5–200 ml; p = 0.040), the percentage of patients who required surgical re-exploration because of bleeding was equivalent (p = 0.37).
In addition, the Celsior group had a significantly higher postoperative transfusion of packed red cells (Table 4). The mean transfused packed red cells was 0.97 units higher in the Celsior group. There were no differences in plasma or platelet transfusions.
There were no differences in the percentages of prolonged mechanical ventilation (p = 0.65) and intensive care unit length of stay (p = 0.87).
We found a significantly increased postoperative acute renal failure in the microplegia group (Fisher’s exact test p = 0.023), but only two patients required postoperative renal replacement therapy.
We found no allergic reaction attributed to Celsior® administration in any patient.
Discussion
In this report, we analyzed the effectiveness of the myocardial protection achieved with the use of a retrograde single-dose administration of Celsior® in on-pump CABG. The study included all the patients who received a single dose of retrograde Celsior® and were compared with a group of patients who received an accepted myocardial protection standard (continuous retrograde microplegia). The main finding of our study is that a single dose of retrograde crystalloid Celsior®, which is a very simple technique of cardioprotection in the setting of on-pump heart surgery, could be as effective as more complex currently accepted methods, such as continuous microplegia, in terms of postoperative elevation of markers of myocardial damage (TnT) and myocardial recovery of function.
Most of the surgical procedures performed on the heart require variable periods of myocardial ischemia, and an adequate protection against ischemia is mandatory to recover an optimal cardiac function afterwards. Nowadays, cardioplegic solutions are the most effective myocardial protection strategies because they can reduce the metabolic activity of the myocardium, and they enhance the potential of the heart to withstand a prolonged duration of ischemia. Owing to this fact, cardioplegia has become one of the main pillars in modern cardiac surgery.
Blood-based solutions are generally considered a more effective protection strategy, 12 but, on the other hand, single-dose crystalloid solutions could simplify the surgical procedure, as no interruptions are needed for the administration of repeated doses of cardioplegia. Over the years, several studies have been conducted comparing crystalloid and blood-based cardioplegic solutions, and most of the observational studies published up to date showed no significant differences in the clinical outcomes obtained with each alternative, 1 despite the fact that most of these studies did not include modern advanced-formulation crystalloid solutions, such as Custodiol®, Celsior® or Del Nido cardioplegia. 13
Although there is a general preference in the surgical community for blood-based cardioplegic solutions, 2 there are several studies that have supported the use of crystalloid solutions for myocardial protection in CABG. Ovrum and colleagues 14 conducted a randomized prospective study, including 1440 CABG patients, finding no differences between crystalloid and blood-based solutions. Two recent meta-analyses have been conducted, studying the clinical advantages of each alternative, and they concluded that although blood cardioplegia is better than crystalloid solutions in terms of release of enzymatic markers of myocardial injury, there was not a clear clinical correlation, in terms of recovery of myocardial function or mortality.13,15 Moreover, none of these meta-analyses included any of the new advanced formulation crystalloid solutions, such as Celsior®, Custodiol® or Del Nido cardioplegia, which could have improved the results of this myocardial protection alternative.
Crystalloid cardioplegia has the potential advantage that it avoids the inconvenience resulting from a repeated or a continuous infusion of a blood-based cardioplegia, which can complicate the correct visualization of the coronary arteries while being on-pump CABG. Therefore, its use could help the surgeon to obtain better anastomosis. Moreover, most of the crystalloid cardioplegic solutions are used as a ‘single shot’ delivery. Due to this fact, no interruptions are needed during the surgical procedure, in contrast with blood-based cardioplegia that needs a continuous infusion (such as microplegia), or repeated doses every 20–30 min of clamp time.
The myocardial protection that we employed in the control group of our study, the infusion of continuous retrograde microplegia, 16 is one of the accepted alternatives of a blood-based solution for comparative studies when analyzing myocardial protection, 1 and there are several clinical studies endorsing its use.8,17–20 Moreover, it is considered as the myocardial protection strategy that adds less volume, and therefore, minimizes the risk of hemodilution during an on-pump procedure. 8
In recent years, using both Custodiol®1,21–23 or Del Nido1,24 cardioplegia have provided excellent results, and their use has increased worldwide. Also, there are some reports dealing with the use of Celsior® as a crystalloid cardioplegia.4–6 Nowadays, Celsior® is considered as an organ protection solution, with a proven cardioprotective effect in the field of heart transplantation,3,25–28 although its use as a cardioplegic solution has not been deeply studied. One of the possible advantages with the use of crystalloid Celsior® is that it is a simple and effective alternative, using an easily available product, and it has some potential advantages over Custodiol® or Del Nido cardioplegia. On the one hand, Custodiol® has the disadvantage that much more volume of crystalloid solution is needed to obtain an optimal myocardial protection. On the other hand, Del Nido cardioplegia is a published formulation, not readily available for commercial distribution, that has to be prepared in exact and sterile conditions wherever it is going to be used, and the maintenance of optimal preparation standards could not be warranted by every institution.
In our institution, myocardial protection until 2006 in on-pump CABG was achieved with the continuous infusion of retrograde microplegia. In 2006, we started to employ isolated crystalloid Celsior® for myocardial protection in nontransplant heart surgery. Owing to the optimal results of this new strategy, we expanded its use during the following years. Nowadays, it has become our standard myocardial protection strategy. 6
In this report, we analyzed the effectiveness of the myocardial protective effect of Celsior®, when used as a single-dose retrograde crystalloid cardioplegia. Our findings show that the postoperative elevation of markers of myocardial damage (TnT) is even lower when compared with microplegia, after the statistical adjustment for several possible confounding factors using PS matching. We also found that myocardial function recovery with Celsior® was as effective as with microplegia, with similar postoperative inotropic or IABP requirements.
We also consider that the intravenous use of Celsior® was safe, with no unexpected toxicity or side effects. Moreover, although microplegia is considered to be the alternative of myocardial protection that produces less hemodilution, the final balance in the operating room was lower in the Celsior group, produced by an increased hemofiltration during the surgical procedure, and also an increased urine output, that could be related to the mannitol content of Celsior®. Despite the use of hemofiltration, the Celsior group was transfused a mean of one more bag of packed red cells. This finding could be related to the great potential of microplegia to avoid hemodilution, the main strength favoring its use.
Furthermore, the myocardial protection with Celsior® could be even further enhanced if Celsior® is administered in a combined antegrade and retrograde pathway, as the cardioprotective solution distribution to all the viable myocardium could be improved. In a different analysis, we found a statistically significant better recovery of spontaneous heart rhythm with the combined strategy of Celsior® administration (76.7% versus 46.2%; p < 0.001), and a lower percentage of patients who required electric cardioversion (35.1% versus 73.9%; p < 0.001). Moreover, there was a nonsignificant trend to lower high-dose inotropic medication requirements (13.9% versus 20.4%) and lower IABP use (8.1% versus 13.6%). These data suggest that although isolated retrograde Celsior® may be at least equivalent to microplegia, myocardial protection with Celsior® may even be improved if it is administered in combination with both antegrade and retrograde pathways, to enhance cardioplegia delivery to all the viable myocardium.
Study limitations
The main limitation of this work is that it is a retrospective study, performed in a single institution. Multicenter randomized studies must be conducted to obtain higher evidence-based results.
Despite the theoretical advantage of a crystalloid solution that its use could simplify the procedure, in our study, aortic cross-clamp time and CPB time were significantly longer in the Celsior group. This difference could be correlated to a nonsignificant slightly higher number of mean grafts in the Celsior group because, as expected, the number of grafts performed had a significant linear correlation with the duration of CPB time (Pearson’s correlation coefficient = 0.54; 95% CI 0.44–0.62; p < 0.001).
Most of the patients in the microplegia group were operated on from 2006 to 2010, while most of the patients in the Celsior group were operated on from 2008 to 2014. Despite there being no other major changes in the surgical protocol during the transition period, a possible bias for different time frames could not be ruled out.
Although there are several markers of myocardial injury, the only marker that is routinely measured and registered in the database in our institution is maximum TnT after the procedure. Single and highest measurement of troponin concentration does not allow conclusion on total myocardial injury attributable to mode of protection due to several confounders, such as the preoperative values, individual metabolism, and the exact time frame of postoperative measurement. Although there is published evidence that Troponin I measured 24 h after heart surgery is an independent predictor of operative mortality, perioperative myocardial infarction, and length of stay in the hospital, only postoperative dynamic change in TnT may be taken as a surrogate for the quantitative assessment of myocardial injury, but owing to the retrospective nature of the present report, these data were not available for analysis. This biological marker alone may not be a sufficient marker of myocardial injury, but combined with other physiological aspects, such as inotropic drug requirements, could indicate how adequate myocardial protection was achieved.
Although the administration of Celsior® in combination with both antegrade and retrograde pathways seemed even more effective than isolated retrograde Celsior®, there was a heterogeneous distribution of the amount of total Celsior® volume that was administered in each way, so no clear recommendation could be made on how much percentage of the total volume of cardioplegia should be delivered in an antegrade or retrograde pathway.
Conclusion
An isolated single dose of retrograde Celsior® may be an effective and safe myocardial protection strategy in on-pump CABG.
Footnotes
Author contributions
Javier Miguelena contributed to conception/design; contributed to analysis/interpretation, and critically revised the manuscript.
Carlos Morales contributed to conception/design.
Francisco Callejo contributed to data acquisition.
Jacobo Silva critically revised the manuscript and gave final approval.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of interest.
