Patients and methods: The retrospective study included 150 patients (123 males, 27 females; mean age: 59.8±9.7 years; range, 38 to 84 years) who underwent isolated coronary bypass operation between January 2020 and May 2022. The DN solution was applied differently from the practice in the literature. Seventy-five percent of the dose calculated according to the body weight of the patients was administered at the first moment. The remaining amount was continued to be given through the saphenous veins as distal anastomoses were made. When the cross-clamp was lifted, all grafts were tied to the aorta cannula, and the coronary vascular bed was cleared. Follow-up of patients was done routinely.

Results: The mean preoperative ejection fraction was 49.9±5.6, and the mean postoperative ejection fraction value was 50.3±5.0 (p=0.079). A statistically significant difference was found between the preoperative troponin level and the postoperative troponin level at 6 h (p<0.001). However, there was no significant difference between the postoperative 6 h and the postoperative 24 h. Spontaneous rhythm occurred at the termination of cardiopulmonary bypass in most of the patients (97%). No permanent pacing was required in any patient. An intra-aortic balloon pump was used in nine patients, and extracorporeal membrane oxygenation was used in two patients. Two patients died in the early period.

Conclusion: The use of DN with this method seems to be a reliable alternative to eliminate hesitations in isolated coronary bypass surgery.

The contents of DN cardioplegia solution are presented in Table 1. This solution differs from classic cardioplegia in that it contains lidocaine, which limits calcium entry into the cell and prolongs the duration of action.[5] It reduces the intracellular accumulation of harmful calcium ions, decreases the energy consumption rate, enables free radical clearance, and causes a major reduction in myocardial edema.[6] It is administered as a single dose. According to a study, the most important benefits include postoperative spontaneous rhythm, less need for defibrillation and inotropic support, and rapid improvement in troponin values.[7]

Table 1: Contents of the del Nido cardioplegia solution

Studies showing positive results of DN use in adults have increased. However, it is still not widely used in adults. Based on previous studies, we aimed to share the early results of surgeries in which we used the DN solution.

Surgical procedure and method of cardioplegia delivery
All patients were operated with a median sternotomy. A left anterior thoracic artery (LITA) graft was used in all patients, except for two in whom LITA was dissected. The Trillium Affinity NT (Medtronic, Minneapolis, MN, USA) was used as the oxygenator, and the Terumo Advanced Perfusion System 1 (Terumo Cardiovascular, Ann Arbor, MI, USA) was used as the perfusion system. Standard cannulation was performed from the atrium and aorta in all patients, and the cardioplegia was delivered from the aortic root. In the first stage, 75% of the cardioplegia solution, calculated according to weight, was administered all at once. The remaining amount was continued to be applied at half the rate of the first application from the graft after each distal anastomosis. At the end of the distal anastomoses, the cardioplegia solution was set to run out. After the cross-clamp was lifted, the cardioplegia cannula was connected to the aortic cannula, and the cardioplegia solution was removed from the myocardium by continuously washing it with hot blood. The patient’s body temperature was held at 32-34°C. After the cross-clamp was placed, a topical cold application was administered to the myocardium. The cardioplegia solution was delivered as described here: For a 70-kilogram adult patient, a 70×20=1,400 mL solution was prepared as the first dose. Of this amount, 75% (1,050 mL) was initially delivered. The remaining 350 mL was continuously applied from the grafts with a lower flow rate after each of the distal anastomoses was finished. The properties of the cardioplegia solution are presented in Table 1. Proximal anastomoses were performed with a side clamp. Neutralization with protamine was performed after decannulation.

Postoperative follow-up
In our clinic, hemodynamic or neurological follow-ups were performed in accordance with the routine procedure. Vital signs and laboratory values were recorded. Along with routine laboratory followups, troponin I values were monitored in the first 24 h (at postoperative 6 and 24 h). The hemograms and electrolytes of all patients were monitored four times a day during the intensive care follow-up. Blood transfusions and electrolyte replacements were performed based on these results. The drains in the patients were removed if they collected less than 100 mL in the previous 12 h. Patients with stable hemodynamics were discharged from the intensive care unit. Patients who did not have any problems during follow-up were discharged.

Statistical analysis
The Number Cruncher Statistical System 2007 (NCSS LLC., Kaysville, UT, USA) was used for the statistical analysis. When evaluating the study data, descriptive statistical methods were used (mean, standard deviation, median, frequency, ratio, minimum, and maximum), and the distribution of the data was calculated using the Shapiro-Wilk test. The Friedman test was used for quantitative comparisons of three or more periods that did not show normal distributions, and the Wilcoxon test was used for two-term comparisons. Significance was evaluated at p<0.01 and p<0.05.

Table 2: Demographic data and preoperative data

Table 3: Intraoperative and postoperative data

The mean preoperative ejection fraction of the patients was 49.9±5.6, while the postoperative early-period values were 50.3±5.0. The pre- and postoperative values of troponin I, creatine kinase, creatine phosphokinase, and lactate dehydrogenase are given in Table 4. There were no significant changes from preoperative to postoperative creatine kinase, creatine phosphokinase, or lactate dehydrogenase values. Although troponin I values increased at postoperative 6 h relative to preoperative values, there was no significant difference between the values at the 6 and 24 h.

Table 4: Preoperative and postoperative laboratory data

The mean duration of extubation was 6.1±1.5 h, hospital stay was 5.9±1.2 days, and intensive care follow-up time was 48.6±10.3 h. Important complications (such as renal failure, cerebrovascular accident, severe bleeding, and revision) encountered in postoperative follow-up are given in Table 5.

Table 5: Postoperative complications

There are significant concerns about the use of DN cardioplegia in coronary artery disease, particularly in patients with multiple vessels.[9] Although an effective solution has been provided by administering retrograde cardioplegia to patients who are given conventional blood cardioplegia, there may be confusion in this regard since DN cardioplegia is applied all at once and antegrade. Another important benefit of not requiring retrograde cardioplegia is preventing complications, such as coronary sinus injury or bleeding from the entrance in the atrium. As suggested by our study, appropriate cardiac arrest can be induced with adequate myocardial protection without the need for retrograde cardioplegia. In the application of DN cardioplegia to multivessel patients in our clinic, after the first dose antegrade, one-fourth of the next dose was given from the anastomotic grafts (Figure 1). Thus, the distribution of cardioplegia solution to the whole heart was facilitated. We believe that this contributed to myocardial protection. There is convincing evidence that the DN cardioplegia solution provides strong myocardial protection.[7,10] In a study by Zeng et al.,[11] intermittent washing of metabolites and reoxygenation of blood were demonstrated as an advantage of cold blood cardioplegia. Regarding our method, we believe that the continuous low dose of cardioplegia solution from the saphenous veins and, ultimately, the cleaning of the entire coronary vascular bed with warm blood from the aorta contributes to the removal of all metabolites, ensuring better protection of the myocardium (Figure 2).

Figure 1: Intraoperative view of the cardioplegia solution being administered from saphenous vein grafts.

Figure 2: Image demonstrates the connecting of the cardioplegia cannulas to the aortic cannula after the cross-clamp is lifted.

The DN solution was developed to protect immature myocardium against reperfusion injury. However, it has been shown that it also provides functional improvements in elderly hearts.[12] Inspired by these studies, we have used the DN cardioplegia solution in our clinic for the last two years. Although no significant difference was observed in postoperative ejection fraction data in our study, the changes in troponin I values in postoperative follow-up are in accordance with most of the literature. Despite partial elevations, troponin I remained at acceptable levels after coronary artery bypass surgery. It would not be wrong to characterize the preservation of cardiac functions in terms of ejection fraction and troponin I levels. In contrast with this view, some studies have found that troponin I values were not low in groups given DN cardioplegia.[13] Although the main goal of our study was to properly protect cardiac functions through a new application of DN cardioplegia, the need for ventricular defibrillation and temporary pacemakers to address intraoperative arrhythmias was found to be reduced. The rate of spontaneous rhythm was noted to be higher. Since there was no control group in our study, the observational data were compared with the literature.[14] Considering that there were no differences in the intraoperative body temperatures, blood gas data, or electrolyte data of the patients, we believe this finding was an effect of the cardioplegic solution being strengthened. We think that delivering the blood from the aorta to the myocardium through saphenous vein grafts and completely cleaning the cardioplegia solution also contributed to this effect. Many studies have reported a significant decrease in ventricular fibrillation rates after DN use.[8,15] With less need for defibrillation, the possibility of subepicardial necrosis, which may occur through direct contact with the epicardium, is also reduced-contributing, in turn, to a reduction in myocardial damage.[16] Moreover, the components of DN are known to contribute to protection. Due to its hyperosmotic properties, mannitol is effective in clearing out free radicals and reducing edema.[17] Lidocaine acts as a depolarizing agent by inhibiting sodium channels and reducing calcium and sodium entry into cells.[18] Another important component in DN cardioplegia is magnesium. When used as an electrolyte, magnesium has been proven to increase myocardial recovery by blocking calcium channels.[19]

One of the challenges in cardiac surgery is the low cardiac output state. Mechanical support devices (IABP or ECMO) may be needed in patients who have difficulty weaning from a cardiopulmonary bypass and who develop low cardiac output state. The need for IABP ranges from 7 to 17% in different studies.[20,21] The fact that this rate was 6% in our study is seen as a positive outcome. In our study, the need for ECMO support in only two patients (patients with a 35% ejection fraction) was also interpreted positively.

When analyzing arrhythmias in our study, positive effects of the ingredients of the DN (mannitol, lidocaine, and magnesium) were observed. The main benefits were the formation of spontaneous rhythms and reduction in the duration and frequency of arrhythmias, such as atrial fibrillation and ventricular tachycardia. In our study, it was not possible to analyze all the etiological factors that may have caused these rhythm disorders one by one. However, the fact that the frequency of atrial fibrillation in the literature is 45 to 65% suggests that cardioplegia solution is effective at a lower frequency.[20,22] Of course, the findings on this subject will become stronger as studies are conducted with larger prospective patient populations. Another positive finding was that no significant ventricular arrhythmia was experienced in the early postoperative period by any of the patients treated with DN. As in many studies, no differences were observed in the postoperative follow-up parameters (intubation time, major complications, or discharge time).[23,24] It was observed that observational intensive care followup times were shorter compared to our other patients who underwent conventional cardioplegia. We believe that the decreased postoperative arrhythmia contributed to this outcome. Waiting for patients to recover from arrhythmia before being removed from the ICU prolongs this period. No significant difference was observed in terms of the amount of drainage, the number of blood transfusions, the number of patients using inotropic support, or the laboratory data in the postoperative period, which reflects and supports findings that this cardioplegia solution can be used safely in isolated coronary artery bypass grafting.

One of the features of the content of the DN is a lack of glucose, which decreases the need for intraoperative insulin administration. Mick et al.[6] found that glucose levels were lower following the use of DN, and therefore, less insulin was required. In our study, we observed that intraoperative glucose control was easier with low glucose levels.

Although the use of DN cardioplegia for isolated coronary artery bypass grafting was not recommended in a study conducted at the Cleveland Clinic in 2014,[3] more reassuring findings have been reached in other studies.[15,25] Due to the lack of studies with prospective large patient numbers, concerns about this issue cannot be eliminated completely. However, as shown in many studies, DN cardioplegia has become increasingly preferred due to the shortened clamping and operation time and the possibility of performing cardioplegia all at once. In a large-scale study, Guajardo Salinas et al.[15] showed that DN cardioplegia application provides a significant economic advantage as well as other clinical benefits. We found that DN could be used safely in all patients undergoing isolated coronary bypass by following the method presented in our study.

The main limitation of this study is that since a novel application of DN cardioplegia was employed in the study, it could not be compared with the classical DN application. The data were compared instead with the literature. Additionally, only the ejection fraction and troponin I levels were taken as markers of myocardial protection. This restriction prevented a strong assessment from being made for analysis.

In conclusion, although DN cardioplegia solution is more common in pediatric cardiac surgery, it is increasingly used in adult cardiac surgery. However, there are still concerns about its use in isolated coronary bypass surgery. We believe that the method we followed together with a single-dose application will help address these reservations. Studies with more patients are needed for stronger interpretations.

Ethics Committee Approval: The study protocol was approved by the Atatürk University Faculty of Medicine Clinical Research Ethics Committee (date: 04.15.2021, no: 3/48). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept, design, literature review, writing the article: F.B.; Data collection and/or processing: Y.K.; Control/supervision, analysis and/or interpretation, final approval of the manuscript: B.E.; Analysis and/or interpretation, final approval of the manuscript: M.Ü., K.T.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

1) Yamamoto H, Yamamoto F. Myocardial protection in cardiac surgery: A historical review from the beginning to the current topics. Gen Thorac Cardiovasc Surg 2013;61:485-96. doi: 10.1007/s11748-013-0279-4.

2) Beyersdorf F. Intraoperative myocardial protection: still the cornerstone of cardiac surgery. Eur J Cardiothorac Surg 2022;61:1133-4. doi: 10.1093/ejcts/ezab510.

3) Kim K, Ball C, Grady P, Mick S. Use of del Nido cardioplegia for adult cardiac surgery at the Cleveland Clinic: Perfusion implications. J Extra Corpor Technol 2014;46:317-23.

4) An KR, Rahman IA, Tam DY, Ad N, Verma S, Fremes SE, et al. A systematic review and meta-analysis of del Nido versus conventional cardioplegia in adult cardiac surgery. Innovations (Phila) 2019;14:385-93. doi:10.1177/1556984519863718.

5) Dobson GP, Jones MW. Adenosine and lidocaine: A new concept in nondepolarizing surgical myocardial arrest, protection, and preservation. J Thorac Cardiovasc Surg 2004;127:794-805. doi: 10.1016/s0022-5223(03)01192-9.

6) Mick SL, Robich MP, Houghtaling PL, Gillinov AM, Soltesz EG, Johnston DR, et al. del Nido versus Buckberg cardioplegia in adult isolated valve surgery. J Thorac Cardiovasc Surg 2015;149:626-36. doi: 10.1016/j.jtcvs.2014.10.085.

7) Ad N, Holmes SD, Massimiano PS, Rongione AJ, Fornaresio LM, Fitzgerald D. The use of del Nido cardioplegia in adult cardiac surgery: A prospective randomized trial. J Thorac Cardiovasc Surg 2018;155:1011-8. doi: 10.1016/j. jtcvs.2017.09.146.

8) O’Donnell C, Wang H, Tran P, Miller S, Shuttleworth P, Boyd JH. Utilization of del Nido cardioplegia in adult coronary artery bypass grafting - a retrospective analysis. Circ J 2019;83:342-6. doi: 10.1253/circj.CJ-18-0780.

9) Kim K, Ball C, Grady P, Mick S. Use of del Nido cardioplegia for adult cardiac surgery at the Cleveland clinic: Perfusion implications. J Extra Corpor Technol 2014;46:317-23.

10) Timek T, Willekes C, Hulme O, Himelhoch B, Nadeau D, Borgman A, et al. Propensity matched analysis of del Nido cardioplegia in adult coronary artery bypass grafting: Initial experience with 100 consecutive patients. Ann Thorac Surg 2016;101:2237-41. doi: 10.1016/j.athoracsur.2015.12.058.

11) Zeng J, He W, Qu Z, Tang Y, Zhou Q, Zhang B. Cold blood versus crystalloid cardioplegia for myocardial protection in adult cardiac surgery: A meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth 2014;28:674-81. doi: 10.1053/j.jvca.2013.06.005.

12) Mishra P, Jadhav RB, Mohapatra CK, Khandekar J, Raut C, Ammannaya GK, et al. Comparison of del Nido cardioplegia and St. Thomas Hospital solution - two types of cardioplegia in adult cardiac surgery. Kardiochir Torakochirurgia Pol 2016;13:295-9. doi: 10.5114/kitp.2016.64867.

13) Ziazadeh D, Mater R, Himelhoch B, Borgman A, Parker JL, Willekes CL, et al. Single-dose del Nido cardioplegia in minimally invasive aortic valve surgery. Semin Thorac Cardiovasc Surg 2017:S1043-0679(17)30287-3. doi: 10.1053/j. semtcvs.2017.10.001.

14) Karaarslan K, Abud B. Effects of del Nido and terminal warm blood cardioplegia on myocardial protection and rhythm in isolated CABG patients. Heart Surg Forum 2021;24:E808-13. doi: 10.1532/hsf.4103.

15) Guajardo Salinas GE, Nutt R, Rodriguez-Araujo G. Del Nido cardioplegia in low risk adults undergoing first time coronary artery bypass surgery. Perfusion 2017;32:68-73. doi: 10.1177/0267659116661051.

16) Kerber RE, Carter J, Klein S, Grayzel J, Kennedy J. Open chest defibrillation during cardiac surgery: Energy and current requirement. Am J Cardiol 1980;46:393-6. doi:10.1016/0002-9149(80)90006-5.

17) Matte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston Children's Hospital. J Extra Corpor Technol 2012;44:98-103.

18) Pulaş M. Yetişkin kalp cerrahisinde del Nido kardiyoplejisinin hücre membran stabilizasyonunda etkisi ve kullanımı. Cardiovasc Perf Nurs 2022;1:44-51. doi:10.5606/e-cvpn.2022.195.

19) Brown PS Jr, Holland FW, Parenteau GL, Clark RE. Magnesium ion is beneficial in hypothermic crystalloid cardioplegia. Ann Thorac Surg 1991;51:359-66. doi:10.1016/0003-4975(91)90845-h.

20) Jannati M, Attar A. Intra-aortic balloon pump postcardiac surgery: A literature review. J Res Med Sci 2019;24:6. doi:10.4103/jrms.JRMS_199_18.

21) Shah SMA, Awan NI, Jan A, Rehman MU. Characteristics, morbidity and mortality factors associated with Intra- Aortic Balloon Pump in Coronary Artery Bypass Graft Surgery patients. Pak J Med Sci 2020;36:1318-24. doi:10.12669/pjms.36.6.2649.

22) Öztürk S, Öztürk İ. Atrial fibrillation after cardiac surgery and preoperative vitamin D levels: A systematic review and meta-analysis. Turk Gogus Kalp Dama 2020;28:101-7. doi:10.5606/tgkdc.dergisi.2020.18387.

23) Lahtinen J, Biancari F, Salmela E, Mosorin M, Satta J, Rainio P, et al. Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77:1241-4. doi: 10.1016/j. athoracsur.2003.09.077.

24) Tran DT, Perry JJ, Dupuis JY, Elmestekawy E, Wells GA. Predicting new-onset postoperative atrial fibrillation in cardiac surgery patients. J Cardiothorac Vasc Anesth 2015;29:1117-26. doi: 10.1053/j.jvca.2014.12.012.

25) Cayir MC, Yuksel A. The use of del Nido cardioplegia for myocardial protection in isolated coronary artery bypass surgery. Heart Lung Circ 2020;29:301-7. doi: 10.1016/j. hlc.2018.12.006.