Normothermic retrograde blood cardioplegia with or without preceding ischemic preconditioning

doi:10.1016/S0003-4975(97)00100-8

The Annals of Thoracic Surgery

Volume 63, Issue 5, May 1997, Pages 1268-1274

https://doi.org/10.1016/S0003-4975(97)00100-8 Get rights and content

Background.

Preconditioning has been suggested as the most powerful mechanism of myocardial protection against prolonged ischemia. However, whether preconditioning offers additional benefits over cardioplegia during coronary artery bypass grafting is not known.

Methods.

Thirty patients undergoing coronary artery bypass grafting were randomized into two groups. After aortic cross-clamping, group 1 received antegrade blood and blood cardioplegia followed by normothermic retrograde blood cardioplegia (controls), whereas group 2 patients were subjected to 5 minutes of global ischemia followed by reperfusion with antegrade and retrograde blood cardioplegia (preconditioned). The transcardiac differences in oxygen saturation, pH, and lactate were measured during cardiopulmonary bypass. Myocardial biopsy specimens were taken from half of the patients for adenosine triphosphate determination. The extent of myocardial injury was estimated by monitoring the postoperative leakage of creatine kinase-MB and troponin T. Immediate hemodynamic recovery and postoperative complications were also observed.

Results.

The 5-minute preconditioning induced marked lactate and acid production, and myocardial adenosine triphosphate levels tended to decrease. The hearts continued to produce lactate and acid during retrograde cardioplegia, but the transcardiac pH and lactate differences were similar in both groups. Adenosine triphosphate level measured at the end of the cross-clamp period was decreased to a half and one third of the preclamp values in the control and preconditioned groups, respectively. The postoperative creatine kinase-MB and troponin T effluxes tended to be more elevated in the preconditioned group, yet hemodynamic recovery and the number of postoperative complications were similar in both groups.

Conclusions.

The results show that a 5-minute preconditioning ischemia does not offer any additional benefits over normothermic retrograde blood cardioplegia during coronary artery bypass grafting.

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Myocardial reperfusion injury has been identified as a key determinant of myocardial infarct size in patients undergoing percutaneous or surgical interventions. Although the molecular mechanisms underpinning reperfusion injury have been elucidated, attempts at translating this understanding into clinical benefit for patients undergoing cardiac interventions have produced mixed results. Ischemic conditioning has been applied before, during, or after an ischemic insult to the myocardium and has taken the form of local induction of ischemia or ischemia of distant tissues. Clinical studies have confirmed the safety of differing conditioning techniques, but the benefit of such techniques in reducing hard clinical event rates has produced mixed results. The aim of this article is to review the role of ischemic conditioning in patients undergoing percutaneous and surgical coronary revascularization.
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We assessed whether aortic cross-clamping or limb remote ischemic preconditioning improved postoperative outcomes, reduced myocardial injury and incidences of postoperative complications in patients undergoing on-pump coronary artery bypass grafting (CABG).
PubMed, EMBASE, the Cochrane Library, and ClinicalTrials databases were searched for studies comparing the effects of ischemic preconditioning with no preconditioning in adult patients undergoing on-pump CABG. The primary end points were mechanical ventilation time, the length of stay in intensive care unit and hospital, whereas the secondary end points were peak values of myocardial biomarkers and postoperative complications. Mean differences were estimated for the primary end points, as well as standard mean differences and odds ratios for the secondary end points.
A total of 29 randomized controlled trials with 1791 patients were included. Compared with control group, aortic cross-clamping preconditioning reduced mechanical ventilation time (mean difference [95% confidence interval {CI}]) (−5.59 h [−9.21 to −1.96]), whereas limb remote ischemic preconditioning was not associated with improvement of postoperative outcomes. For myocardial biomarkers, both aortic cross-clamping and limb remote ischemic preconditioning reduced peak values of myocardial biomarkers (standard mean difference [95% CI]) (−0.48 [−0.81 to −0.14]; −0.19 [−0.36 to −0.02], respectively). Subgroup analysis showed that aortic cross-clamping preconditioning protocols with ischemia episodes <5 min did reduce the release of biomarkers (−0.69 [−1.04 to −0.34]) but those with 5 min ischemia episodes elevated them (0.40 [0.04–0.75]). Cardiovascular, cerebrovascular, renal, and intestinal complications were reported, and aortic cross-clamping preconditioning seemed to reduce the incidences of cardiac arrhythmia (odds ratio [95% CI]) (0.46 [0.27–0.80], P = 0.006).
Cardiac surgeons could consider aortic cross-clamping or limb remote ischemic preconditioning to reduce myocardial injury during CABG. Moreover, aortic cross-clamping preconditioning is associated with a decreased risk of postoperative respiratory failure and cardiac arrhythmia.
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Myocardial infarct size is a major determinant of prognosis. Ischaemic preconditioning with brief coronary occlusion and reperfusion before a sustained period of coronary occlusion with reperfusion delays infarct development. Ischaemic postconditioning uses repetitive brief coronary occlusion during early reperfusion of myocardial infarction and reduces infarct size. Remote ischaemic preconditioning uses brief ischaemia and reperfusion of a distant organ to protect the myocardium. These conditioning protocols recruit a complex signal cascade of sarcolemmal receptor activation, intracellular enzyme activation, and ultimately mitochondrial stabilisation and inhibition of death signalling. Conditioning protocols have been successfully used in patients undergoing elective coronary revascularisation and reperfusion after acute myocardial infarction. Pharmacological recruitment of cardioprotective signalling has also been used to reduce infarct size, but so far without prognostic benefit. Outcomes of cardioprotection are affected by age, sex, comorbidities, and drugs, but also by technical issues related to determination of infarct size and revascularisation procedure.
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Coronary heart disease (CHD) is the leading cause of death world-wide. Its major pathophysiological manifestation is acute myocardial ischaemia–reperfusion injury. Innovative treatment strategies for protecting the myocardium against the detrimental effects of this form of injury are required in order to improve clinical outcomes in patients with CHD. In this regard, harnessing the endogenous protection elicited by the heart's ability to ‘condition’ itself, has recently emerged as a powerful new strategy for limiting myocardial injury, preserving left ventricular systolic function and potentially improving morbidity and mortality in patients with CHD.
‘Conditioning’ the heart to tolerate the effects of acute ischaemia–reperfusion injury can be initiated through the application of several different mechanical and pharmacological strategies. Inducing brief non-lethal episodes of ischaemia and reperfusion to the heart either prior to, during, or even after an episode of sustained lethal myocardial ischaemia has the capacity to dramatically reduce myocardial injury—a phenomenon termed ischaemic preconditioning (IPC), perconditioning or postconditioning, respectively. Intriguingly, similar levels of cardioprotection can be achieved by applying the brief episodes of non-lethal ischaemia and reperfusion to an organ or tissue remote from the heart, thereby obviating the need to ‘condition’ the heart directly. This phenomenon has been termed remote ischaemic ‘conditioning’, and it can offer widespread systemic protection to other organs which are susceptible to acute ischaemia–reperfusion injury such as the brain, liver, intestine or kidney. Furthermore, the identification of the signalling pathways which underlie the effects of ‘conditioning’, has provided novel targets for pharmacological agents allowing one to recapitulate the benefits of these cardioprotective phenomena—so-termed pharmacological preconditioning and postconditioning.
Initial clinical studies, reporting beneficial effects of ‘conditioning’ the heart to tolerate acute ischaemia–reperfusion injury, have been encouraging. Larger multi-centred randomised studies are now required to determine whether these ‘conditioning’ strategies are able to impact on clinical outcomes. In this article, we provide an overview of ‘conditioning’ in all its various forms, describe the underlying mechanisms and review the recent clinical application of this emerging cardioprotective strategy.
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It was firstly described by Murray [4] in the heart muscle, and further advanced in subsequent studies which reported in non-cardiac tissue and in a wide spectrum of animals [5–7], as well as in human [8]. Under the basic researches, IPC alone has been used in clinical trials, such as liver resection [9,10], coronary artery bypass grafting (CABG) [11–16, liver transplantation [17–21] to limit the ischemia reperfusion injury. Here, I want to ask one question: “can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation?”
Organ transplantation is the only choice for treatment of end-stage disease. The ischemia reperfusion injury (I/RI) occurring after cold ischemia is an unavoidable injury during transplantation, which is also one of the main causes of graft failure. Multiple mechanisms have been postulated to explain tissue injury that occurs after I/RI. It is well-known that ischemic preconditioning (IPC), a short period of ischemia followed by reperfusion, arouses the endogenous mechanism of protection against a sustained ischemic insult. Can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation?
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Normothermic retrograde blood cardioplegia with or without preceding ischemic preconditioning

Background.

Methods.

Results.

Conclusions.

Ann Thorac Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Ann Thorac Surg

Lancet

Ann Thorac Surg

Ann Thorac Surg

J Cardiothorac Vasc Surg

J Am Coll Cardiol