1. Antonio Maria CALAFIORE Choices and possibilities to optimise myocardial protection during ischemic periods

2. Technical success and avoidance of intraoperative damage are both the main targets of any cardiac operation. The early and late success of a cardiac procedure is related to how well the surgeon corrected the mechanical problem, and how carefully myocardial protection avoided secondary dysfunctional effects of aortic clamping for technical repair.

3. Myocardial ischemia is characterized by rapid accumulation of protons, cessation of electron transport and initiation of the inefficient process of anaerobic metabolism. Reperfusion injury is a major complication characterized by restoration of flow to a previously ischemic heart.

4. Significant evidence now exists that the primary mediators of reversible and irreversible myocardial ischemia/reperfusion injury include intracellular Ca++ overload during ischemia/reperfusion and oxidative stress induced by reactive oxygen species generated at the onset of reperfusion. Ischemia/reperfusion injury

5. Intracellular Ca++ overload at the onset of reperfusion is due to restoration of intracellular pH via Na+/H+ exchange with consequent reversed Na+/Ca++ exchange. Reduction of free energy for ATP hydrolysis causes reduced efficiency of pumps to maintain intracellular Ca++ homeostasis. Ischemia/reperfusion injury

6. Reactive oxygen species (ROS), including superoxyde anion (O 2 ¯ ), hydrogen peroxide (H 2 O 2 ) and the hydroxil radical (OH), are derivatives of many biological systems and in high concentration are associated with oxidative stress and consequent cardiovascular tissue injury. Ischemia/reperfusion injury

7. Neutrophils activation and nitroxide (NO) are involved in ROS production. Neutrophils, activated by inflammatory mediators, respond by rolling, adhering and transmigrating rolling, adhering and transmigrating across the endothelial layer to reach the extravascular interstitium. extravascular interstitium. Ischemia/reperfusion injury

8. Neutrophils contain a potent arsenal of proteolitic and cytotoxic substances. Activated neutrophils release hystotoxic enzymes such as elastase, myeloperoxidase, collagenase and others. They also release cytokines and oxygen free radicals. Ischemia/reperfusion injury

9. NO can also interact with ROS to generate various reactive nitrogen species and appears capable of both contributing and reducing injury. In the absence of normal levels of its cofactors, nitric oxide sinthase itself can generate superoxide anion. Ischemia/reperfusion injury

10. Regardless of which stage is being addressed, current cardioprotection strategies are designed to reduce cellular and subcelluar ROS formation and oxidative stress, and to prevent intracellular Ca++ overload. Ischemia/reperfusion injury

11. Cardiac arrest during cardiac surgery in a flaccid diastolic state (with reduction in myocardial oxygen consumption as important consequence) can be achieved by targeting various points in the excitation-contraction coupling pathway. Cardioplegia

12. The agents used for this purpose induce either a depolarized arrest (the membrane potential is higher than –80mV) or a polarized or hyperpolarized arrest (the membrane potential is maintained at –80mV or at lower levels). Cardioplegia

14. The most commonly used method for inducing rapid diastolic arrest is moderate elevation of the extracellular [K+] (15 to 40 mmol/L). As [K+] increases, the resting Em becomes progressively more depolarized. Depolarized cardiac arrest

15. As Em depolarizes to around –65 mV ([K+] around 10 mmol/L), the voltage-dependent fast Na+ channel is inactivated, preventing the rapid Na+-induced spike of the action potential and arresting the heart in diastole. Depolarized cardiac arrest

16. With further increase of [K+] (around 30 mmol/L), resting Em becomes –40 mV with consequent activation of the slow Ca++ channel and Ca++ overload. The beneficial effects of increasing [K+] is then limited to a narrow window. Depolarized cardiac arrest

17. The increase of intracellular [Ca++] will cause contracture even in the arrested conditions and will contribute to Ca++ overload and reperfusion injury. Energy- dependent transmembrane pumps remain active in an attempt to correct this abnormal ionic gradient, further depleting critical energy supplies. Depolarized cardiac arrest

18. High concentration of extracellular Mg++ can arrest alone the heart, possibly by displacing Ca++ from the rapid exchangeable sarcolemmal binding sites involved in the excitation- contraction coupling. As concentrations required are too high, it is used normally as an effective additive protective agent. Depolarized cardiac arrest

19. An alternative to depolarization is to maintain polarization of the Em close to the resting Em. Polarized cardiac arrest

20. It can be obtained through different mechanisms. @ blockage of Na+ channels (procaine, lidocaine), preventing the rapid, Na+ induced depolarization of the action potential @ opening of ATP-sensitive K+ channels, causing Em to be shifted towards the K+ equilibrium potential (nicorandil, pinacidil, diazoxide) Polarized cardiac arrest

21. Even if adverse side effects can be anticipated, K+ CPL is today the only reliable tool we have to arrest the heart. Different agents can be used as additive, but we are far from clinical utilization of polarizing or hyperpolarizing solutions.

22. There are two types of crystalloid cardioplegic solutions: the intracellular (absent or low concentration of Na+ and Ca++) and the extracellular (high concentration of Na+, Ca++ and Mg++) one. [K+] is between 10 and 40 mEq/L, and both contains bicarbonate for buffering. Hypothermia is a fundamental component of the cardioplegic strategy. Cardioplegic solutions

23. Blood cardioplegia can be used with a variety of different dilutions, temperature, components and delivered, as the crystalloid one, with different routes. In the last decade, with the introduction of warm blood cardioplegia, many publications suggested the following trends. Cardioplegic solutions

24. The assumption that continuous oxygenated perfusion of the normothermically arrested heart enables the perfect matching of energy demand and supply so that ischemia is eliminated is probably an oversemplification. Some metabolic damage can occur, probably due to loss of contraction and consequent interruption of lymphatic flow and edema. Cardioplegic solutions

25. The assumption that hyopothermia gives superior protection is discussed. Randomized trial showed lower TnI release (lower myocardial damage) in intermittent lukewarm or warm blood cardioplegia (CPL) if compared with cold blood CPL. Cardioplegic solutions

26. Myocardial oxygen uptake mL/ 100 mg/ min

27. The initially attractive concept of aerobic arrest inherent in continuous oxygenated perfusion has been somewhat diverted in an intermittent pattern of CPL delivery. Cardioplegic solutions

28. A 31 P-nuclear magnetic resonance study of intermittent warm blood Cardioplegia. Tian e coll. J Thorac Cardiovasc Surg 1995;109:1155-63.

29. This is not an homogeneous entity, as ischemic intervals are still not clearly stated. It is very likely that 13-15 min of ischemia in such conditions are well tolerated, but temperature of the perfusate, duration of the reperfusion phases are part of the equation. Cardioplegic solutions

30. Retrograde CPL administration is very popular among the cardiac surgeons. However, there are evidences that retroperfusion of the heart is less effective than the antegrade. The particular anatomy of the coronary veins is the main reason, as its unpredictibility avoids an uniform CPL distribution. This was demonstrated in the animals and in the humans. Route of administration

31. Tian et al. Retrograde cardioplegia. J Thorac Cardiovasc Surg 2003;125:872-880 J Thorac Cardiovasc Surg 2003;125:872-880

32. Nevertheless, clinical results are globally satisfying, but retrograde CPL delivery has to be used in conjunction with the antegrade route to obtain an effective cardioprotection. Route of administration

33. From what previously described, the best way to avoid ischemia/reperfusion injury is to avoid ischemia. This is unrealistic, as: 1) it is not possible to reproduce the same conditions of working heart while operating on the heart, except in some sporadic cases 2) a compromise is needed between the necessity of protecting the heart and the quality of the surgical treatment. Cardioplegic strategy

34. Since 1991 we heve been using a protocol for intermittent antegrade warm blood cardioplegia in all the patients we are operated on. Cardioplegic strategy

35. The cardioplegia temperature is the same of the perfusate (isothermic cardioplegia). Today there is no conceptual evidence against the use of a temperature between 32° and 37°C. But, according to the surgeon’s preference, the perfusate temperature can be lowered as much as necessary, as in case of DHCA. Cardioplegic strategy

36. Blood is taken directly from the oxygenator and, by means of a 1/4 inch tubing and a roller pump, is injected into the aortic root or coronary ostia. The tubing is connected to a syringe pump that delivers K + (1 ml=2mEq). A bubble trap is positioned before the aortic root. Intermittent Antegrade Intermittent Antegrade Warm Blood Cardioplegia

37. Flow rate DoseDuration Roller pump Syringe pump [K + ] (min) (ml/min) (ml/h) (mEq/l) 1st 2 300 push 2 ml than 150 18-20 2nd 2 200 60 10 3th 2 200 60 10 4th 2 200 60 10 5th 2 200 40 6.7 6th 2 200 40 6.7 Infusion protocol Intermittent Antegrade Intermittent Antegrade Warm Blood Cardioplegia

38. Doses following the first one are administered after each anastomoses during coronary surgery and after 15 minutes during non coronary surgery. Intermittent Antegrade Intermittent Antegrade Warm Blood Cardioplegia

39. To prevent the opening of the Ca++ channels, we added to the previous protocol the injection of 1 g of Mg++ sulphate at the end of the 1st dose. If necessary, Mg++ sulphate can be further administered at lower dose (200 mg). Intermittent Antegrade Intermittent Antegrade Warm Blood Cardioplegia

40. In presence of waveform contraction K+ administration has not to be increased, but reduced, and Mg++ injected (Em is higher than –40 mV with subsequent opening of the slow Ca++-channels). In presence of well organized contractions a dose of CPL with higher [K+] has to be repeated. Intermittent Antegrade Warm Blood Cardioplegia

41. This protocol is used everytime the ascending aorta is not opened: coronary artery bypass grafting, mitral valve surgery, surgery for LV scars, and so on. According to the surgeon’s preference, ischemic interval can be shortened and/or reperfusion time can be lengthened. This because of the flexibility of the technique. Intermittent Antegrade Warm Blood Cardioplegia

42. In particular conditions, as when the ascending aorta is opened, when there is a mild aortic regurgitation or in selected patients with low ejection fraction and/or dilated cardiomyopathy, the retrograde route can be added. Cardioplegic strategy

43. Cardioplegia is always blood and K+, supplemented, when necessary, with Mg++. CPL is administered antegrade and retrograde, antegrade (following the usual protocol) at least every 30 minutes, retrograde as long as possible at a fixed rate (150 ml/min), in relationship with the surgical necessities. Cardioplegic strategy

44. In the last part of the procedure, retrograde administration can deliver only blood without K+ to facilitate intracellular K+ washout and to re-establish energy stores. Cardioplegic strategy

45. Purpose of any strategy we use is to minimize TnI release, even if with long cross clamping times. Cardioplegic strategy

46. We must be aware that also minor damages to the heart can produce, in the midterm, unsatisfying results, compromising what was done in the surgical theatre. Cardioplegic strategy

47. cold blood CPL 266 (9.2%) IAWBC 2171 (74.8%) cold cristalloid CPL 464 (16.0%) January 1982 – December 2001 CABG n = 2901

48. CKMB  19 UI/L CKMB 20- 38 UI/L CKMB 39- 57 UI/L CKMB  58 UI/L 88.0  1.1  90.1  1.5  84.8  1.6  p 0.0012 91.4  1.3 

49. CKMB  19 UI/L CKMB 20- 38 UI/L CKMB 39- 57 UI/L CKMB  58 UI/L 85.9  1.1  86.4  1.6  79.6  1.9  p < 0.0001 88.7  1.5 

50. MB  19 MB 20-38 MB 39-57 MB  58 %

51. @ simple. If not always “the simpler the better” is true, surely “the more complicated the better” is never true. @ inexpensive. The circuit is represented by a ¼ inch tubing and a connector with a conventional syringe pump. The additives are only K+ and Mg++. Advantages

52. @ flexible. This protocol can be modified during surgery, as duration of ischemic intervals and of reperfusion can be lengthened, and [K+] can be lowered. @ efficient. Clinical studies, from our group and from different teams, have demonstrated that contractile function is preserved, especially in patients with low EF and in long lasting procedures. Advantages

53. Mycardial protection is a global stratgey that has the goal to reduce the ischemia/perfusion injury. This target can be reached in different ways, but it is as important as the surgical procedure itself. The choice of the proper strategy is today crucial, as the quality of the patients is rapidly worsening. Conclusion