Prospective, Randomized Clinical Study of Ischemic Preconditioning as an Adjunct to Intermittent Cold Blood Cardioplegia

doi:10.1016/S0003-4975(97)01346-5

The Annals of Thoracic Surgery

Volume 65, Issue 3, March 1998, Pages 748-752

https://doi.org/10.1016/S0003-4975(97)01346-5 Get rights and content

Abstract

Background. Ischemic preconditioning has been shown to be beneficial to myocardial preservation in a variety of models. This study was performed to determine whether ischemic preconditioning can ameliorate the postischemic myocardial dysfunction often seen in patients undergoing open heart operations.

Methods. Seventy patients were prospectively randomized to receive or not receive ischemic preconditioning before intermittent cold blood cardioplegic arrest. Ischemic preconditioning was induced by 1 minute of aortic cross-clamping followed by 5 minutes of reperfusion during normothermic cardiopulmonary bypass, immediately before cardioplegic arrest. Control patients had an extra 6 minutes of normothermic cardiopulmonary bypass before cardioplegic arrest. Hemodynamic parameters were obtained before bypass, and at 1, 6, and 12 hours after weaning from bypass. All patients were monitored for the development of postoperative complications and need for inotropic agents or intraaortic balloon pumping.

Results. Preconditioned patients showed marked improvement in cardiac index from a preoperative value of 2.2 ± 0.1 L · min⁻¹ · m⁻² to 2.5 ± 0.1 L · min⁻¹ · m⁻² at 1 hour after bypass (p < 0.01), 2.8 ± 0.1 L · min⁻¹ · m⁻² at 6 hours after bypass (p < 0.0001), and 2.9 ± 0.1 L · min⁻¹ · m⁻² at 12 hours after bypass (p < 0.0001). In the control group the cardiac index deteriorated significantly from 2.5 ± 0.1 to 2.2 ± 0.1 L · min⁻¹ · m⁻² at 1 hour after bypass (p < 0.05), and then only returned to baseline at 6 and 12 hours after bypass. Thirteen control patients required inotropic agents; however, none of the ischemic preconditioning group required inotropic agents (p < 0.001). There was no significant difference between the groups with respect to postoperative morbidity and mortality.

Conclusions. Ischemic preconditioning significantly improves heart function in clinical cardiac operations, decreases the need for inotropic support, and could be an important adjunct to myoprotective strategies.

Section snippets

Material and Methods

Seventy patients undergoing cardiac surgical procedures were prospectively entered into the study, which was approved by our institutional review committee on July 11, 1995. All patients who were primary cardiac surgical patients and who could give informed consent were entered into the study. Reoperative cases were not considered because of the risk of embolization from old vein grafts, or the aorta, with the increased manipulation required with IP. Study participants had preoperative morphine

Preoperative and Intraoperative Data

The major preoperative and intraoperative variables were similar in the two groups (Table 1). There were no significant differences between the mean values of age, ejection fraction, cross-clamp time, or CPB time between the two groups. In the −IP group there were 30 patients with CABG procedures, 2 with single-valve procedures, 2 with double-valve procedures, 1 with a valve and CABG procedure, and 1 with a triple-valve procedure. In the +IP group there were 27 patients with CABG procedures, 4

Comment

These data indicate that IP is a safe and effective adjunct to clinical myocardial preservation with cold intermittent blood cardioplegia. The significant increase in CI exhibited by the +IP patients is particularly striking, because the 13 patients in the −IP group who required inotropic agents had continuation of these drugs for the duration of the study and did not display any significant increase in CI. These differences cannot be explained by variations in preload as measured by pulmonary

References (16)

RW Illes et al.
Ischemic preconditioning improves preservation with crystalloid cardioplegia
Ann Thorac Surg
(1994)
LP Perrault et al.
Ischemic preconditioning in cardiac surgerya word of caution
J Thorac Cardiovasc Surg
(1996)
DM Yellon et al.
Stress proteins and myocardial protection
J Mol Cell Cardiol
(1992)
RJ Schott et al.
Ischemic preconditioning reduces infarct size in swine myocardium
Circ Res
(1990)
GC Li et al.
Myocardial protection with preconditioning
Circulation
(1990)
CE Murry et al.
Preconditioning with ischemiaa delay of lethal cell injury in ischemic myocardium
Circulation
(1986)
DM Walker et al.
Ischemic preconditioningfrom mechanisms to exploitation
Cardiovasc Res
(1992)
E Deutsch et al.
Adaption to ischemia during percutaneous transluminal angioplastyclinical, hemodynamic, and metabolic features
Circulation
(1990)

There are more references available in the full text version of this article.

Cited by (87)

Prevention of Ischemic Injury in Cardiac Surgery
2021, Perioperative Medicine: Managing for Outcome, Second Edition
Prevention of myocardial ischemic injury is essential for the successful execution of cardiac surgery. Myocardial protection strategies continue to be refined, and depend on many pre-, intra-, and postoperative factors. Many of the essential components are well established and date back to the origins of cardiac surgery, and others are novel and yet to be fully realized. The following will review the critical components of prevention of ischemic injury.
Brief pressure overload of the left ventricle reduces myocardial infarct size via activation of protein kinase C
2015, Journal of the Chinese Medical Association
Citation Excerpt :
The phenomenon of ischemic preconditioning also suppresses postischemic arrhythmia and improves myocardial recovery from stunning.2,3 These laboratory findings have been used to inform and enhance strategies to protect human myocardium in cardiac surgery.4–7 To avoid ischemic insult, several nonischemic maneuvers, including rapid cardiac pacing,8 heat stress,9 pharmacological administration,10 and volume overload,11,12 have been developed to mimic ischemic preconditioning and to protect myocardium.
We have previously reported that brief pressure overload of the left ventricle reduced myocardial infarct (MI) size. However, the role of protein kinase C (PKC) remains uncertain. In this study, we investigated whether pressure overload reduces MI size by activating PKC.
MI was induced by a 40-minute occlusion of the left anterior descending coronary artery and a 3-hour reperfusion in anesthetized Sprague-Dawley rats. MI size was determined using triphenyl tetrazolium chloride staining. Brief pressure overload was achieved by two 10-minute partial snarings of the ascending aorta, raising the systolic left ventricular pressure 50% above the baseline value. Ischemic preconditioning was elicited by two 10-minute coronary artery occlusions and 10-minute reperfusions. Dimethyl sulfoxide (vehicle) or calphostin C (0.1 mg/kg, a specific inhibitor of PKC) was administered intravenously as pretreatment.
The MI size, expressed as the percentage of the area at risk, was significantly reduced in the pressure overload group and the ischemic preconditioning group (19.0 ± 2.9% and 18.7 ± 3.0% vs. 26.1 ± 2.6% in the control group, where p < 0.001). Pretreatment with calphostin C significantly limited the protection by pressure overload and ischemic preconditioning (25.2 ± 2.4% and 25.0 ± 2.3%, where p < 0.001). Calphostin C itself did not significantly affect MI size (25.5 ± 2.4%). Additionally, the hemodynamics, area at risk, and mortality were not significantly different.
Brief pressure overload of the left ventricle reduced MI size. Since calphostin C significantly limited the decrease of MI size, our results suggested that brief pressure overload reduces MI size via activation of PKC.
The role of adenosine in preconditioning by brief pressure overload in rats
2015, Journal of the Formosan Medical Association
Brief pressure overload of the left ventricle reduced myocardial infarct (MI) size in rabbits has been previously reported. Its effects in other species are not known. This study investigates effects of pressure overload and the role of adenosine in rats in this study.
MI was induced by 40-minute occlusion of the left anterior descending coronary artery followed by 3-hour reperfusion. MI size was determined by triphenyl tetrazolium chloride staining. Brief pressure overload was induced by two 10-minute episodes of partial snaring of the ascending aorta. Systolic left ventricular pressure was raised 50% above the baseline value. Ischemic preconditioning was elicited by two 10-minute coronary artery occlusions.
The MI size (mean ± standard deviation), expressed as percentage of area at risk, was significantly reduced in the pressure overload group as well as in the ischemic preconditioning group (17.4 ± 3.0% and 18.2 ± 1.5% vs. 26.6 ± 2.4% in the control group, p < 0.001). Pretreatment with 8-(p-sulfophenyl)-theophylline (SPT), an inhibitor of adenosine receptors, did not significantly limit the protection by pressure overload and ischemic preconditioning (18.3 ± 1.5% and 18.2 ± 2.0%, respectively, p < 0.001). SPT itself did not affect the extent of infarct (25.4 ± 2.0%). The hemodynamics, area at risk and mortality were not significantly different among all groups of animals.
Brief pressure overload of the left ventricle preconditioned rat myocardium against infarction. Because SPT did not significantly alter MI size reduction, our results did not support a role of adenosine in preconditioning by pressure overload in rats.
Ischemic preconditioning-an unfulfilled promise
2015, Cardiovascular Revascularization Medicine
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.
Cardioprotection: Chances and challenges of its translation to the clinic
2013, The Lancet
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.
Delayed Protective Effects of Hyperoxia Against Cardiac Arrhythmias and Infarction in Anesthetized Rats
2009, Journal of Surgical Research
Previous studies have shown that pretreatment with normobaric hyperoxia has cardioprotective effect in isolated rat heart. The present study was designed to test the hypothesis that pretreatment normobaric hyperoxia could induce delayed cardioprotection effect in an in vivo regional heart ischemia.
Experiment 1: Rats were exposed to normobaric normoxia or to normobaric hyperoxia (O₂ > 95%) for 15, 30, 60, 120, and 180 min (H15, H30, H60, H120, and H180 groups, respectively). After 24 h, they were subjected to 30 min regional ischemia and 90 min reperfusion. Then, the hearts were harvested for measurement of infarct size. Lead II of electrocardiogram was continuously recorded for analysis of ischemic arrhythmias. Experiment 2: Different oxygen concentrations were tested in the same model of heart ischemia.
Compared with normoxia group, infarct size significantly reduced in H120 and H180 groups (from 48.1 ± 4 to 31.4 ± 3.3 and 30 ± 2.4, respectively); 120 and 180 min of >95% hyperoxia significantly reduced the number of ventricular beats (from 314 ± 34.9 to 173 ± 20.3 and 178 ± 15.7, respectively) and incidence of ventricular fibrillation (from 66.8% to 30% and 22.2%, respectively). When the oxygen concentration decreased to 80%, its effect on infarct size was abolished; however, its antiarrhythmic effect persisted. Further reduction of oxygen concentration eliminated both the effects.
These results show that hyperoxia pretreatment may induce delayed anti-infarct and antiarrhythmic effects in anesthetized rats. These effects are dependent on the exposure time and oxygen concentration.

View all citing articles on Scopus

View full text

Original ArticlesProspective, Randomized Clinical Study of Ischemic Preconditioning as an Adjunct to Intermittent Cold Blood Cardioplegia

Abstract

Section snippets

Material and Methods

Preoperative and Intraoperative Data

Comment

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Mol Cell Cardiol

Ischemic preconditioning reduces infarct size in swine myocardium

Circ Res

Myocardial protection with preconditioning

Circulation

Preconditioning with ischemiaa delay of lethal cell injury in ischemic myocardium

Circulation

Ischemic preconditioningfrom mechanisms to exploitation

Cardiovasc Res

Adaption to ischemia during percutaneous transluminal angioplastyclinical, hemodynamic, and metabolic features

Circulation

Original Articles
Prospective, Randomized Clinical Study of Ischemic Preconditioning as an Adjunct to Intermittent Cold Blood Cardioplegia