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Ann Thorac Surg 1998;65:748-752
© 1998 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

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

Richard W. Illes, MD, Katharine D. Swoyer, CCP

Susquehanna Health System, The Williamsport Hospital, Williamsport, Pennsylvania, USA

Accepted for publication September 30, 1997.

Dr Illes, Susquehanna Health System, The Williamsport Hospital Campus, 777 Rural Ave, Williamsport, PA 17701-3198.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Ischemic preconditioning (IP) has been documented to have beneficial effects on the recovery of myocardium exposed to subsequent periods of prolonged ischemia [1][2][3]. Various studies have shown that ischemic preconditioning limits infarct size, improves postischemic ventricular function, and can even improve hypothermic multidose cold cardioplegia in the experimental setting [3][4][5]. The beneficial effects of IP in humans has been demonstrated clinically during repeated episodes of ischemia induced with percutaneous transluminal coronary angioplasty [6]. Low cardiac output after cardiac operations, assumed to be secondary to stunning, continues to be problematic in certain patients and results in increased costs and morbidity. This study was designed to determine whether IP could improve myocardial function in clinical cardiac surgical patients and to determine its safety in humans.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
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 sulfate, scopolamine, and diazepam before general anesthesia using fentanyl, isoflurane, midazolam, and pancuronium bromide. Anesthesia was administered by the same group of 3 anesthesiologists. All patients were operated on by a single surgeon and had preoperative placement of Swan-Ganz and arterial catheters for hemodynamic monitoring throughout the study. Each patient had a median sternotomy performed and was heparinized and placed on cardiopulmonary bypass (CPB) with cannulation appropriate for their type of cardiac operation. Once the patient was on CPB, the procedure was carried out in the exact same fashion up to the point of aortic cross-clamping and cardioplegic arrest. Then the patients randomized to the experimental group (+IP) underwent IP on normothermic CPB by cross-clamping the aorta for a period of 1 minute, with the aortic root vented, followed by 5 minutes of normothermic reperfusion before the institution of cold multidose blood cardioplegic arrest. The control group (-IP) underwent an extra 6 minutes of normothermic CPB before the institution of cardioplegic arrest. Every patient was maintained at 37°C until their heart was arrested and they were then cooled to 32°C for coronary artery bypass graft patients and to 28°C for any patient with a valve operation as part of their procedure. All patients had cardioplegic arrest maintained by intermittent cold (10°C) blood cardioplegia that was reinfused after each graft was completed, or every 15 minutes during cases involving valve procedures. The initial dose of cardioplegia was 10 mL/kg of body weight and each subsequent dose was 5 mL/kg of body weight. The cardioplegia consisted of 1 L of normal saline solution to which was added 50 g glucose, 60 mEq potassium chloride, 250 mg lidocaine, 12.5 g mannitol, and 35 mL citrate–phosphate–dextrose. This solution was mixed in a 4:1 ratio with pump blood for delivery. Every patient who had only coronary artery bypass graft (CABG) operation received only antegrade cardioplegia, whereas all patients who had valves, or combined procedures, had both antegrade and retrograde cardioplegia. Proximal grafts were performed first in all patients who had CABG procedures. All patients received a nitroglycerin drip at 0.5 µg · kg-1 · min-1 and were dual chamber paced at a rate of 90 beats/min as they were weaned from CPB and for the duration of the study. Each patient received 2 g calcium chloride intravenously after separation from CPB. If a patient had a cardiac index (CI) less than 2 L · min-1 · m-2 that did not respond to optimizing preload and afterload, or if the patient could not be weaned from CPB, administration of inotropic agents appropriate for the clinical parameters was started. If administration of inotropic agents was started during the study, it was continued for the duration of the study. If a patient continued to have a CI of less than 2 L · min-1 · m-2 with 10 µg · kg-1 · min-1 of two of either dopamine, dobutamine, or amrinone (Inocor), or one of these agents at 10 µg · kg-1 · min-1 and 0.5 µg · kg-1 · min-1 of epinephrine, then an intraaortic balloon pump was placed. All patients had recordings of CI, central venous pressure, pulmonary capillary wedge pressure, mean arterial pressure, and heart rate before bypass (PRE) and 1 hour (PST 1), 6 hours (PST 6), and 12 hours (PST 12) after discontinuing CPB. Creatinine kinase MB levels were monitored every 8 hours after discontinuation of CPB until they peaked and electrocardiograms were monitored for the development of Q-wave myocardial infarctions. All patients were evaluated for complications for 30 days after their procedure. Lengths of stay in the intensive care unit and the hospital were tabulated. Postoperative care was managed by the operating surgeon and strict adherence to the study protocol was observed in all cases.

All results are expressed as mean ± the standard error of the mean. Analysis of variance was used to compare multiple measurements within groups and Fisher’s exact test was used to compare differences in complications and baseline characteristics between the groups. A p value of less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
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 with single-valve procedures, 1 with a valve and CABG procedure, 1 with a double-valve and CABG procedure, and 1 with a triple-valve procedure. Ejection fractions in the +IP patients ranged from 0.25 to 0.65 and in the -IP patients, from 0.35 to 0.60. Cross-clamp times in the +IP patients ranged from 11 minutes to 124 minutes and from 17 minutes to 120 minutes in the -IP group. Times on CPB ranged from 40 minutes to 150 minutes in the -IP group and from 27 minutes to 181 minutes in the +IP group. The distribution of triple-vessel disease, left main disease, unstable angina, and average number of grafts is tabulated in Table 1. There were no significant differences in any of these variables.


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  		Preoperative and Intraoperative Data1

 
Postoperative Data
The need for myocardial support with inotropic agents and IABP and measurements of postoperative morbidity and lengths of stay are presented in Table 2. The number of patients who needed inotropic support was significantly greater in the -IP group with 13 (36%) requiring inotropic support versus 0 for the +IP patients (p < 0.001).


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  		Postoperative Data

 
In the -IP group 1 patient required an intraaortic balloon pump, had a Q-wave myocardial infarction, and died as a result of low cardiac output syndrome. This patient was an 80-year-old man who had critical left main stenosis, a preoperative myocardial infarction, and diffuse calcified coronary artery disease. He had a postoperative myocardial infarction 48 hours after surgery and died because of pump failure. In the +IP group 1 patient had a reversible neurologic deficit, no patient required an intraaortic balloon pump, and there were no Q-wave infarctions or deaths. There were no significant differences in these values.

The peak creatine kinase MB levels for the -IP group was 53 ± 10 versus 62 ± 11 ng/mL for the +IP group, which was not significantly different.

The CI in the +IP group significantly and continuously improved after CPB from a PRE value of 2.2 ± 0.1 L · min-1 · m-2 to 2.5 ± 0.1 L · min-1 · m-2 at PST 1, a PST 6 value of 2.8 ± 0.5 L · min-1 · m-2, and a PST 12 value of 2.9 ± 0.1 L · min-1 · m-2 (p < 0.01 to p < 0.0001). The CI for the -IP patients significantly deteriorated from a PRE value of 2.5 ± 0.1 L · min-1 · m-2 to 2.2 ± 0.1 L · min-1 · m-2 at PST 1 (p < 0.05). At PST 6, the CI returned to the baseline value of 2.5 ± 0.1 L · min-1 · m-2 and then slightly increased to 2.7 ± 0.2 L · min-1 · m-2 at PST 12, which was not significantly different from PRE (Fig 1).



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  		Cardiac index in patients receiving ischemic preconditioning (+IP) (A) and patients not receiving ischemic preconditioning (-IP) (B). (PRE = before bypass; PST 1 = 1 hour after bypass; PST 6 = 6 hours after bypass; PST 12 = 12 hours after bypass; *p < 0.05 versus PRE; {dagger}p < 0.01 versus PRE; {dagger}{dagger}p < 0.0001 versus PRE.)

 
The heart rates in both groups were significantly increased at all times after bypass compared with the PRE heart rates secondary to pacing each patient after CPB. In the +IP group, the heart rate increased an average of 27% whereas the heart rate in the -IP group increased an average of 36%. The mean arterial blood pressure in both groups was significantly depressed by 10% at PST 12 compared with the PRE value. There were no other differences between the before and after bypass hemodynamic measurements in either group (Table 3).


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  		Hemodynamics

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
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 capillary wedge pressure or afterload as measured by mean arterial pressure. Even though volume administration was not examined in these patients, the fact that the pulmonary capillary wedge pressure and central venous pressure for the two groups were the same indicates their volume status was equivalent. These parameters remained the same throughout the study period except for an equal decrease in mean arterial pressure of 10% in both groups at PST 12, which was probably related to decreasing sympathetic tone in all patients at this time after the operation. The heart rates in both groups were significantly increased after bypass secondary to each patient in the study being paced after the operation. The -IP group had an average increase in heart rate of 36% after bypass compared with the PRE value, with an average increase in the +IP group of only 27%. This slight difference is most likely related to a lower PRE heart rate in the -IP group compared with the +IP group. This should have resulted in a relatively higher CI for the -IP group, because heart rate is intimately related to CI, with CI equaling heart rate times stroke volume divided by body surface area. The beneficial effects of IP on CI overshadowed this influence. The baseline characteristics and intraoperative variables were not significantly different between the groups, and therefore cannot be used to explain the differences in inotropic agent use and CI observed in this study. These data suggest that IP exerts its beneficial effect by preventing stunning. However, with the development of clinical testing for troponin levels, and other, as yet undiscovered, more sensitive indicators of myocardial cellular death, perhaps it will be determined that stunning is actually minimal myocardial necrosis. This mechanism would be consistent with prior studies that indicate that IP prevents myocardial cellular death [1][3].

Ischemic preconditioning seems to be cost-effective even though a thorough analysis of patient charges was not done in this study. If the 1 patient in the +IP group who had a reversible neurologic deficit is excluded, the average hospital length of stay for the +IP group drops to 3.9 ± 0.2 days, which is significantly different from the -IP group hospital length of stay of 4.7 ± 0.2 days (p < 0.001). To discuss these data without this patient’s length of stay of 20 days is a valid way to analyze these data, because this patient’s length of stay was more than 5 standard deviations greater than the mean and is clearly an outlier. The cost savings from not using inotropic agents is more obvious, but probably less significant, than potential length of stay savings. Definitive determination of potential savings from IP must await a complete analysis of a larger group of patients, but certainly appear to be real.

There is a paucity of other studies in the literature dealing with IP in clinical cardiac operations and the results are quite disparate. In one limited study, IP was induced by two 3-minute cycles of aortic cross-clamping, followed by 2 minutes of reperfusion before a 10-minute period of normothermic ventricular fibrillation [7]. This study demonstrated improved ventricular adenosine triphosphate levels in the IP patients, suggesting better myocardial preservation. Another recent study warns of possible deleterious effects of IP during human cardiac operations [8]. In one group of 10 patients, IP was induced with 3 minutes of aortic cross-clamping followed by 2 minutes of reperfusion before continuous retrograde warm cardioplegic arrest. Compared with a similar control group of 10 patients, IP was found to cause a greater release of creatine kinase MB than in controls and a higher level of lactate production across the myocardium, possibly indicating less effective protection in the IP patients. Both of these studies are hindered by lack of any myocardial functional data and by terminating the study at the end of CPB. The different conclusions reached could be attributable to the different methods of inducing IP and methods of myocardial preservation used. The method of inducing IP in our study was based on previous work in rabbit hearts [5], which have many characteristics similar to human hearts, such as prominent postextrasystolic potentiation [9][10], a positive force–frequency relation [11], and a positive response to an increase in extracellular calcium concentration [12]. The 1-minute ischemic time was also chosen to limit any potential deleterious effects in this initial human study.

The mechanism of the myoprotective properties of IP cannot be determined in this clinical study. Peak creatine kinase MB levels were somewhat higher in the +IP group, but not significantly higher. The low incidence of Q-wave myocardial infarction in this study prevents us from concluding that IP exerts its protection by preventing gross myocardial necrosis, even though this is widely accepted as a benefit of IP. Because we did not measure troponin levels, it is possible that this more sensitive indicator of myocardial necrosis would yield different results, perhaps even indicating that minute amounts of necrosis were prevented by IP. Potential mechanisms of improving myocardial preservation are multiple and include activation of A1 adenosine receptors [13], activation of adenosine triphosphate–sensitive potassium channels [14], induction of heat-shock proteins [15], and preservation of cellular adenosine triphosphate levels [16]. Further discussion of these various possible mechanisms of the effects of IP is beyond the scope of this clinical paper and the exact delineation of the biochemical basis of the protective effects of IP must await more basic research. Regardless of mechanism, IP seems to be independently beneficial to myocardial preservation in human cardiac operation patients based on the findings of this study.

The results of this study must be viewed in the context of certain limitations. Because a single surgeon did all the cases and managed the postoperative course, there could be no blinding, thus potentially adding bias to the results. The two groups were not case matched and there was no measurement of cardiac function other than CI. The number of cases in each group was limited and the mix of CABG and valve cases could be criticized as having two different basic pathologic conditions. However, prospective randomization and strict adherence to the study protocol minimized, if not eliminated, most of those limitations. Even though the number of patients studied is limited, this is still the largest reported human surgical IP series and the statistical significance of these data are quite compelling.

In summary, IP has been shown in this initial prospective, randomized, clinical study of cardiac surgical patients to improve postoperative myocardial function, decrease the need for inotropic support, and possibly decrease hospital length of stay. That these effects were observed in the context of multidose, hypothermic blood cardioplegia indicates that IP exerts a powerful influence on myocardial preservation in humans. Although the search for the basic mechanism of IP must continue, it would be difficult to imagine a safer, more cost-effective method of inducing these beneficial effects than the simple protocol used in this study. Questions regarding the optimal periods of ischemia and reperfusion for IP in humans remain, as does the categorization of patients most likely to benefit from IP. We have incorporated IP in our myoprotective strategies for patients with anticipated extended cross-clamp times and those with significantly depressed left ventricular function.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Schott RJ, Rohmann ER, Braun ER, Scharper W Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res 1990;66:1133-1142.[Abstract/Free Full Text]
  2. Li GC, Vasquez JA, Gallagher KP, Lucchesi BR Myocardial protection with preconditioning. Circulation 1990;82:609-619.[Abstract/Free Full Text]
  3. Murry CE, Jennings RB, Reimer KA Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-1136.[Abstract/Free Full Text]
  4. Walker DM, Yellon DM Ischemic preconditioning: from mechanisms to exploitation. Cardiovasc Res 1992;26:734-739.[Free Full Text]
  5. Illes RW, Wright JK, Inners-McBride K, Yang C-J, Tristan A Ischemic preconditioning improves preservation with crystalloid cardioplegia. Ann Thorac Surg 1994;58:1481-1485.[Abstract]
  6. Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW, Jr, Herrmann HC, Laskey WK Adaption to ischemia during percutaneous transluminal angioplasty: clinical, hemodynamic, and metabolic features. Circulation 1990;82:2044-2051.[Abstract/Free Full Text]
  7. Alkhulaifi AM, Yellon MD, Pugsley WB Preconditioning the human heart during aorto-coronary bypass surgery. Eur J Cardiothorac Surg 1994;8:270-276.[Abstract]
  8. Perrault LP, Menasché P, Bel A, et al. Ischemic preconditioning in cardiac surgery: a word of caution. J Thorac Cardiovasc Surg 1996;112:1378-1386.[Abstract/Free Full Text]
  9. Anderson PAW, Manring A, Johnson EA Force–frequency relationship. A basis for a new index of cardiac contractility?. Circ Res 1973;33:665-671.[Abstract/Free Full Text]
  10. Anderson PAW, Manring A, Serwer GA, et al. The force–interval relationship of the left ventricle. Circulation 1979;60:334-338.[Abstract/Free Full Text]
  11. Edman KAP, Johannson M The contractile state of rabbit papillary muscle in relation to stimulation frequency. J Physiol (Lond) 1976;254:565-581.[Abstract/Free Full Text]
  12. Nassar R, Reedy MC, Anderson PAW Developmental changes in the ultrastructure and sarcomere shortening of the isolated rabbit ventricular myocyte. Circ Res 1987;61:465-483.[Abstract/Free Full Text]
  13. Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey J Protection against infarction afforded by preconditioning is mediated by A1-adenosine receptors in rabbit heart. Circulation 1991;84:350-356.[Abstract/Free Full Text]
  14. Gross GJ, Auchampach JA Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992;70:223-233.[Abstract/Free Full Text]
  15. Yellon DM, Latchman DS Stress proteins and myocardial protection. J Mol Cell Cardiol 1992;24:113-124.[Medline]
  16. Murry C, Jennings R, Reimer K Preconditioning with ischemia: a delay in lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-1136.



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Asian Cardiovasc Thorac Ann, September 1, 1999; 7(3): 173 - 176.
[Abstract] [Full Text] [PDF]

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 SEMIN CARDIOTHORAC VASC ANESTHHome page
H.-S. V. Chen, S. C. Body, and S. K. Shernan
Myocardial Preconditioning: Characteristics, Mechanisms, and Clinical Applications
Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 1999; 3(2): 85 - 97.
[Abstract] [PDF]

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 Eur. J. Cardiothorac. Surg.Home page
G. Li, S. Chen, E. Lu, and Y. Li
Ischemic preconditioning improves preservation with cold blood cardioplegia in valve replacement patients
Eur. J. Cardiothorac. Surg., May 1, 1999; 15(5): 653 - 657.
[Abstract] [Full Text] [PDF]

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 Ann. Thorac. Surg.Home page
K. Peuhkurinen
Reply
Ann. Thorac. Surg., December 1, 1998; 66(6): 2164 - 2164.
[Full Text] [PDF]

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