Results of a study of the effectiveness of direct coronary oxygen persufflation as a donor heart conditioning method

Objective: to evaluate the technical feasibility as well as functional, metabolic and structural integrity of donor heart myocardium after 4 hours of direct intracoronary oxygen persufflation in an experiment. Materials and methods. Mini-pig siblings aged 3 months with a body weight of 23–36 kg were used as the experimental model. In the control group (n = 8), donor hearts were cold preserved by injecting 2 liters of Bretschneider cardioplegic solution (Custodiol®, Germany, HTK) into the aortic root. In the experimental group (n = 8), modified HTK solution (with 40 mg/L hyaluronidase added) was used to initiate cardioplegia, then moistened carbogen (95% O₂, 5% CO₂) was injected into the ascending aorta, maintaining 40–45 mm Hg aortic root pressure. The hearts were stored in an mHTK solution at 0–4 °С. After 3 hours of donor heart preservation, orthotopic heart transplantation (OHTx) was performed. In the post-transplant period, we studied central hemodynamic parameters, myocardial oxygen consumption, level of myocardial ischemia markers (troponin I, TnI; creatine phosphokinase-MB, CPKMB; lactate dehydrogenase, LDH), and histological signs of structural cellular injury. Results. Sixteen OHTx surgeries were performed during the study. At 120 minutes after restoration of spontaneous cardiac activity, cardiac output was 2.99 [4.85; 3.17] L/min and 2.48 [2.04; 2.92] L/min (p > 0.05) in the control and experimental groups, respectively. Changes in LDH, TnI and lactate levels in the blood flowing from the coronary sinus were significantly higher in the early reperfusion period. However, there was no statistically significant difference between the groups (p > 0.05). Myocardial oxygen consumption in the control and experimental groups was 8.2 [7.35; 9.35] ml-O2/min/100 g and 7.7 [6.75; 10.12] ml-O₂/min/100 g, respectively (p > 0.05). Morphological examinations also showed no significant myocardial ischemia injury in the persufflation group compared to the control group. Conclusion. The experiment showed the technical feasibility and safety of direct intracoronary oxygen persufflation for 4 hours at the ex vivo donor heart conditioning stage. At the same time, experimental data showed no significant advantages of coronary persufflation over the standard protocol of cold preservation of donor heart with Bretschneider cardioplegic solution.

1. Сostanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. The Journal of heart and lung transplantation, 2010; 29 (8): 914–956.

2. Fomichev AV, Khvan DS, Agaeva HA, Zhulkov MO, Doronin DV, Chernyavsky AM. Experience of heart transplantation with an extended cold ischemic time of donor heart. Russian Journal of Cardiology. 2020; 25 (8): 4011. [In Russ, English abstract]. https://doi.org/10.15829/1560-4071-2020-4011.

3. Banner NR, Thomas HL, Curnow E, Hussey JC, Rogers CA, Bonser RS et al. The importance of cold and warm cardiac ischemia for survival after heart transplantation. Transplantation. 2008; 86 (4): 542–547. https://doi.org/10.1097/TP.0b013e31818149b9.

4. Russo MJ, Iribarne A, Hong KN, Ramlawi B, Chen JM, Takayama H et al. Factors associated with primary graft failure after heart transplantation. Transplantation. 2010 Aug 27; 90 (4): 444–450. doi: 10.1097/TP.0b013e3181e6f1eb. PMID: 20622755.

5. Schnitzler MA, Hauptman P, Takemoto S, Burroughs TE, Salvalagio P, Lentine KL et al. The impact of cold ischemia time on the life-year benefit of heart transplant. Transplantation. 2006; 82 (1): 382.

6. Zhulkov MO, Fomichev AV, Alsov SA, Cleaver EN, Chernyavsky AM. Current state of the problem and results of ex vivo perfusion of donor hearts. Russian Journal of Transplantology and Artificial Organs. 2019; 21 (4): 143–146. [In Russ, English abstract]. https://doi.org/10.15825/1995-1191-2019-4-143-146.

7. Khoronenko VE, Mandryka EA, Baskakov DS, Suvorin PA. Adjuvant cardioprotection in thoracic oncosurgery. Russian Journal of Anaesthesiology and Reanimatology = Anesteziologiya I Reanimatologiya. 2019; 1: 35–43. [In Russ, English abstract]. https://doi.org/10.17116/anaesthesiology201901135.

8. Messer S, Ardehali A, Tsui S. Normothermic donor heart perfusion: current clinical experience and the future. Transpl Int. 2015 Jun; 28 (6): 634–642. doi: 10.1111/tri.12361. Epub 2014 Jul 7. PMID: 24853906.

9. Imber CJ, St Peter SD, Lopez de Cenarruzabeitia I, Pigott D, James T, Taylor R et al. Advantages of normothermic perfusion over cold storage in liver preservation. Transplantation. 2002 Mar 15; 73 (5): 701–709. doi: 10.1097/00007890-200203150-00008. PMID: 11907414.

10. Bagul A, Hosgood SA, Kaushik M, Kay MD, Waller HL, Nicholson ML. Experimental renal preservation by normothermic resuscitation perfusion with autologous blood. Br J Surg. 2008 Jan; 95 (1): 111–118. doi: 10.1002/bjs.5909. PMID: 17696214.

11. Osaki S, Ishino K, Kotani Y, Honjo O, Suezawa T, Kanki K, Sano S. Resuscitation of non-beating donor hearts using continuous myocardial perfusion: the importance of controlled initial reperfusion. Ann Thorac Surg. 2006 Jun; 81 (6): 2167–2171. doi: 10.1016/j.athoracsur.2006.01.066. PMID: 16731148.

12. Collins MJ, Moainie SL, Griffith BP, Poston RS. Preserving and evaluating hearts with ex vivo machine perfusion: an avenue to improve early graft performance and expand the donor pool. Eur J Cardiothorac Surg. 2008 Aug; 34 (2): 318–325. doi: 10.1016/j.ejcts.2008.03.043. Epub 2008 Jun 6. PMID: 18539041; PMCID: PMC2649718.

13. Magnus R. Die Thatigkeit des uberlebenden Saugethierherzens bei Durchstromung mit Gasen. Archiv fur experimentelle Pathologie und Pharmakologie. 1902; 47: 200–208. https://doi.org/10.1007/BF01929646.

14. Denecke H, Isselhard W, Stelter W, Berger M, Sachweh D. Recovery of the kidney from aerobic and anaerobic ischemia in deep hypothermia. Eur Soc Exp Surgery. 1971: 182.

15. Suszynski TM, Rizzari MD, Scott WE 3rd, Tempelman LA, Taylor MJ, Papas KK. Persufflation (or gaseous oxygen perfusion) as a method of organ preservation. Cryobiology. 2012 Jun; 64 (3): 125–143. doi: 10.1016/j.cryobiol.2012.01.007. Epub 2012 Jan 26. PMID: 22301419; PMCID: PMC3519283.

16. Reddy MS, Carter N, Cunningham A, Shaw J, Talbot D. Portal Venous Oxygen Persufflation of the Donation after Cardiac Death pancreas in a rat model is superior to static cold storage and hypothermic machine perfusion. Transpl Int. 2014 Jun; 27 (6): 634–639. doi: 10.1111/tri.12313. Epub 2014 Apr 12. PMID: 24628941.

17. Arata K, Iguro Y, Yotsumoto G, Ueno T, Terai H, Sakata R. Use of continuous retrograde gaseous oxygen persufflation for myocardial protection during open heart surgery. Surg Today. 2010 Jun; 40 (6): 549–554. doi: 10.1007/s00595-008-4093-z. Epub 2010 May 23. PMID: 20496137.

18. Kuhn-Regnier F, Bloch W, Tsimpoulis I, Reismann M, Dagktekin O, Jeschkeit-Schubbert S et al. Coronary oxygen persufflation for heart preservation in pigs: analyses of endothelium and myocytes. Transplantation. 2004 Jan 15; 77 (1): 28–35. doi: 10.1097/01.TP.0000090162.96787.D0. PMID: 14724431.

19. Fischer JH. Methods of Cardiac Oxygen Persufflation. Organ Preserv Reengineering. 2011: 105–126.

20. Reichenspurner H, Russ C, Uberfuhr P, Nollert G, Schlüter A, Reichart B et al. Myocardial preservation using HTK solution for heart transplantation. A multicenter study. Eur J Cardiothorac Surg. 1993; 7 (8): 414–419. doi: 10.1016/1010-7940(93)90005-v. PMID: 8398188.

21. Steinberg JB, Doherty NE, Munfakh NA, Geffin GA, Titus JS, Hoaglin DC et al. Oxygenated cardioplegia: the metabolic and functional effects of glucose and insulin. Ann Thorac Surg. 1991 Apr; 51 (4): 620–629. doi: 10.1016/0003-4975(91)90322-h. PMID: 2012422.

22. Effect of oxygenation and consequent pH changes on the efficacy of St. Thomas’ Hospital cardioplegic solution – PubMed [Electronic resource]. URL: https://pubmed.ncbi.nlm.nih.gov/1908927/ (accessed: 12.05.2022).

23. Retrograde perfusion of the coronary arteries with gaseous oxygen cardiopulmonary bypass – PubMed [Electronic resource]. URL: https://pubmed.ncbi.nlm.nih.gov/5901448/ (accessed: 12.05.2022).

24. Sabiston Jr DC, Talbert JL, Riley Jr LH, Blalock A. Maintenance of the heart beat by perfusion of the coronary circulation with gaseous oxygen. Annals of Surgery. 1959; 150 (3): 361.

25. Retrograde perfusion of the coronary sinus with gaseous oxygen – PubMed [Electronic resource]. URL: https://pubmed.ncbi.nlm.nih.gov/13836716/ (accessed: 16.05.2022).

26. Retrograde perfusion of the coronary sinus for direct vision aortic surgery – PubMed [Electronic resource]. URL: https://pubmed.ncbi.nlm.nih.gov/13422152/ (accessed: 16.05.2022).

27. Sinusal standstill with ventricular automatism during retrograde perfusion of the coronary sinus under hypothermia for direct surgical approach to the aortic valves: an experimental study – PubMed [Electronic resource]. URL: https://pubmed.ncbi.nlm.nih.gov/13576547/ (accessed: 16.05.2022).

28. Kuhn-Régnier F, Fischer JH, Jeschkeit S. Coronary oxygen persufflation for long-term myocardial protection. Thorac Cardiovasc Surg. 1998 Sep; 46 Suppl 2: 308– 312. doi: 10.1055/s-2007-1013091. PMID: 9822185.

29. Fischer JH, Kuhn-Régnier F, Jeschkeit S, Switkowski R, Bardakcioglu O, Sobottke R, Rainer de Vivie E. Excellent recovery after prolonged heart storage by preservation with coronary oxygen persufflation: orthotopic pig heart transplantations after 14-hr storage. Transplantation. 1998 Dec 15; 66 (11): 1450–1459. doi: 10.1097/00007890-199812150-00007. PMID: 9869085.

30. Laine GA, Allen SJ. Left ventricular myocardial edema. Lymph flow, interstitial fibrosis, and cardiac function. Circ Res. 1991 Jun; 68 (6): 1713–1721. doi: 10.1161/01.res.68.6.1713. PMID: 2036720.