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Ann Thorac Surg 2001;72:S2235-S2243
© 2001 The Society of Thoracic Surgeons
a Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA
b Department of Surgery, VA Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
c Boston Biostatistics Research Foundation, Newton, Massachusetts, USA
* Address reprint requests to Dr Khuri, Surgical Service (112), VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132, USA
e-mail: shukri.khuri{at}med.va.gov
Presented at Monitoring and Improving Patient Safety During and Following Cardiac Surgery, San Diego, CA, May 5, 2001.
Abstract
Inadequate myocardial protection continues to be encountered despite improved methods of cardioplegia delivery. Although myocardial temperature is commonly monitored to assess the adequacy of cardioplegia delivery, its relationship to the metabolic status of the myocardium has not been investigated. We prospectively reviewed patients who underwent valvular heart surgery with blood (n = 47) or crystalloid (n = 48) cardioplegia and continuous measurement of intraoperative myocardial tissue pH and temperature. We previously demonstrated a high correlation (r = 0.99) between extracellular myocardial pH, levels of intracellular hydrogen ion concentration, and a lowering of tissue ATP during coronary occlusion. Clinically, optimal metabolic protection was defined as the absence of myocardial tissue acidosis during the period of aortic occlusion as quantified by a temperature-corrected integrated mean pH of 6.8 or greater, which has been shown to be predictive of a favorable postoperative outcome. Age, bypass time, myocardial temperature, myocardial tissue pH at the onset of aortic occlusion, cross-clamp time, and volume of cardioplegia were not significantly different between blood and crystalloid groups. Linear regression analysis demonstrated no significant correlation between mean myocardial tissue pH and the corresponding mean myocardial temperature in either group during aortic occlusion. There was also no correlation between the mean myocardial tissue pH and volume of cardioplegia delivered in both groups. These data demonstrate wide intercardiac and intracardiac variability in the degree of regional tissue acidosis encountered during of hypothermic cardioplegia. Cardioplegia delivery guided by measurement of myocardial temperature or by standardized protocol did not prevent the occurrence of tissue acidosis and thus, did not ensure optimal metabolic protection of the heart. In 95 patients undergoing valvular heart surgery with cold blood or crystalloid cardioplegia, there was no correlation between myocardial tissue pH and mycardial temperature or between myocardial tissue pH and volume of cardioplegia administered. Temperature is a poor indicator of the metabolic state of the myocardium.
Cardioplegia administration is either monitored by myocardial septal temperature measurements, or is not monitored and is determined by a well-defined protocol (ie, an initial dose of a set volume of cardioplegia followed by the repeated administration of a set volume at a set time interval throughout the period of aortic occlusion). The optimal myocardial temperature or volume of cardioplegia that would achieve adequate myocardial protection remain elusive. The relationships of myocardial temperature and cardioplegia volume to the underlying metabolic status of the myocardium have not been systematically investigated in a clinical setting.
Numerous experimental studies conducted in our laboratory over the past 25 years have demonstrated the validity of the measurement of myocardial tissue pH in quantifying regional myocardial ischemia. Significant correlations have been demonstrated between myocardial tissue pH and myocardial tissue PCO2, intramyocardial ST segment changes, myocardial ultrastructural morphometry, regional myocardial blood flow, and tissue ATP content [1–6]. In vivo NMR spectroscopy studies performed in our laboratory during a 3-hour period of coronary occlusion have demonstrated a high correlation between extracellular tissue pH, as measured by our pH electrode, and intracellular myocardial pH measured simultaneously using phosphate NMR spectroscopy (r = 0.89 to 0.98, p = 0.0001) [1]. In these studies, myocardial tissue pH during coronary occlusion also correlated significantly with the degree of fall in tissue ATP (r = 0.91, p = 0.0001). Clinical studies performed in patients undergoing cardiac surgery in whom myocardial tissue pH was measured continuously during the operation also demonstrated that myocardial tissue pH levels during the period of aortic occlusion were reflective of the clinical outcome and of the adequacy of myocardial preservation [7–10]. Thus, the basic assumptions underlying this study are that during the period of aortic occlusion, a fall in myocardial tissue pH is reflective of tissue acidosis and inadequate metabolic protection of the heart.
This study examines the respective roles of myocardial temperature measurement and the volume of cardioplegia delivered in reflecting and achieving adequate myocardial protection, as indicated by myocardial tissue pH measurements obtained online in patients undergoing valvular heart surgery.
Material and methods
This report is based on data collected prospectively from 95 patients who underwent valve replacement, either with or without coronary revascularization, and in whom myocardial tissue pH and myocardial temperature were measured online as part of a clinical practice that did not require a special patient consent form. The Research and Development Committee and the Human Studies Committee at our institution approved this study.
Intraoperative management and techniques
After a standard median sternotomy, cardiopulmonary bypass was instituted through standard aortic and right atrial or bicaval cannulation with systemic cooling to 28°C. The left ventricle was vented in all patients through the right superior pulmonary vein. Half of the patients received cold potassium blood cardioplegia, and half received cold potassium crystalloid cardioplegia in the amount necessary to maintain the myocardial temperature at 10° to 15°C. Each liter of crystalloid cardioplegia contained 2.5% dextrose, 0.45% sodium chloride, 4.5 mEq of sodium bicarbonate, and 20 mEq of potassium chloride; the temperature was 4°C, pH 7.8 at 25°C, and osmolarity 305 mOsm. After the initial liter, the concentration of potassium was reduced to 5 mEq/L. Blood for the sanguineous cardioplegia was collected from the arterial filter of the cardiopulmonary bypass circuit. The hematocrit value of the blood cardioplegia was maintained at less than 20 volume percent by the addition of lactated Ringer’s solution. Each liter contained 20 mEq of potassium chloride (which was reduced to 5 mEq after the administration of the first liter) and 4.5 mEq of sodium bicarbonate; the temperature was between 8° and 10°C and the pH 7.6 to 7.8 at 25°C.
In patients requiring coronary artery bypass grafting, revascularization was performed before valve replacement. The distal anastomoses of the free grafts were performed initially and their proximal ends were then connected to tubing through which additional cardioplegia was infused. The distal internal thoracic artery grafts were performed last. Valve replacement was then performed. After closure of the aorta or left atrium or both, the aortic clamp was released and rewarming begun. The proximal anastomoses were then performed and the heart was defibrillated during the rewarming period. In patients requiring mitral valve replacement, cardioplegia was administered antegrade through the aortic root. In patients undergoing aortic or double valve replacement without coronary revascularization, the initial dose of cardioplegia was administered through the aortic root and subsequent doses were administered directly through the coronary ostia. In patients undergoing aortic or double valve replacement with revascularization, the cardioplegia was initially administered through the aortic root, whereas subsequent doses were administered simultaneously through the coronary ostia and the proximal ends of the newly constructed grafts as described above. Cold cardioplegia was administered in an initial bolus of 500 to 1000 mL to obtain a myocardial temperature of approximately 12°C. Throughout the period of aortic occlusion, cardioplegia was administered intermittently or continuously in all patients to maintain the myocardial temperature at less than 15°C. Topical hypothermia with ice-cold saline was also used. There were no interventions or adjustments of cardioplegia made based on the myocardial tissue pH data obtained. The cardioplegia was administered through a calibrated perfusion pump that allowed the perfusionist to maintain an accurate measurement of the volume of cardioplegia, its rate of administration, and its hematocrit.
Measurement of myocardial tissue pH
The system used for the continuous monitoring of myocardial tissue pH has been described in more detail in previous publications [7, 8]. After institution of cardiopulmonary bypass, a pointed, right-angled, silver/silver-chloride pH glass electrode (10 mm in length, 1 mm in diameter) was inserted into the anterior left ventricular wall in 95 patients and into both the anterior and the posterior left ventricular wall in 40 patients. The myocardial temperature, at the same depth within the left ventricular wall, was measured with a thermistor probe connected to a meter (Yellow Springs Instrument Corporation, Yellow Springs, OH) and inserted within 5 mm of the pH electrode. The reference electrode was placed in a beaker (at room temperature) containing potassium chloride 3 mEq/L. The circuit was completed with a potassium chloride–agar bridge inserted subcutaneously in the patient’s forearm. The system was calibrated in two buffers at two temperatures before and after each case. The outputs from the electrode (in millivolts) and thermistor (in degrees celsius) were captured at 20-second intervals by the Khuri Tissue pH Monitor (Vascular Technology Inc, Lowell, MA), which printed out continuous plots of myocardial tissue pH and myocardial temperature [7, 8].
Calculations and data analysis
Myocardial tissue pH measurements were corrected for temperature in two ways. The physical effect of temperature on the slope of the pH electrode was corrected by the use of the Nernst equation in the course of the calibration of the pH electrode [7, 8]. To account for the physiologic change in pH with temperature, a correction factor of 0.015 pH units/°C was used to generate plots of pH corrected to 37°C, thus allowing for a comparative assessment of the acid/base state of the myocardium independent of the effect of changes in myocardial temperature [9, 11]. Integrated mean myocardial tissue pH and myocardial temperature values were calculated for the period of aortic occlusion by planimetry of the myocardial tissue pH and myocardial temperature plots during that period, as described previously [8]. All variables are expressed as mean ± standard deviation. Simple linear regression was used to perform correlation analysis. The Student’s t test was used for comparisons between the two cardioplegic groups. Significance was determined at the level of p less than 0.05 for all analyses.
Results
The characteristics of the patient cohort are shown in Table 1. There were no significant differences at base line between the blood and crystalloid cardioplegia groups. The variables measured during cardiopulmonary bypass are shown in Table 2. The patients who received blood cardioplegia during aortic occlusion had a significantly lower myocardial temperature and a significantly higher myocardial tissue pH in the blood cardioplegia group. A subgroup of patients (n = 40) had myocardial tissue pH and myocardial temperature monitored in both the anterior and posterior left ventricular walls (blood, n = 25; crystalloid, n = 15) (Table 3). The mean myocardial tissue pH was significantly higher and the mean myocardial temperature significantly lower in the anterior wall compared with the posterior wall throughout the period of aortic occlusion. These findings were similar in both the blood and crystalloid cardioplegia groups.
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In the majority of cardiac surgical procedures today, the aorta is occluded, allowing a bloodless operative field with a still, relaxed heart that enables the procedure to be performed in a timely, efficient manner. Because the coronary circulation is interrupted during the period of aortic occlusion, time-dependent ischemic and reperfusion damage is bound to occur. The objective of the various myocardial protective techniques that have been developed over the years is to avoid this damage and to extend as much as possible the "safe" period during which an operative procedure can be performed [12]. Because hypothermic cardioplegic arrest has been one of the earliest and most common myocardial protection techniques, measurement of myocardial septal temperature has been used as a monitor of the delivery of the hypothermic cardioplegic solution. Myocardial temperature measurement, in the context of hypothermic preservation techniques, is the only commercially available intraoperative online method that has been used as a monitor of the "adequacy" of myocardial protection, although there have been no studies that have investigated systematically the efficacy of myocardial temperature measurement in assessing the adequacy of myocardial protection. The use, by some, of warm (normothermic) cardioplegia [13–16], has precluded the use of myocardial temperature measurement as a monitor of cardioplegia delivery under these conditions, and has generated ongoing debates about the protective role of hypothermia and the optimal myocardial temperature for hypothermic protection. It is clear that myocardial hypothermia has both beneficial and detrimental effects. Favorable effects have included a reduction in the rate of myocardial metabolism and oxygen consumption, reduction in the rate and force of the process leading to myocardial cell death, and promotion of electromechanical quiescence [17]. Detrimental effects have been noted on the coronary endothelium and vascular resistance, ventricular wall characteristics, myocardial energy charge, and rate of recovery of ischemically damaged myocardium [17].
By relating regional myocardial temperature changes in the course of hypothermic cardioplegia to corresponding changes in myocardial tissue pH, this study addressed (1) the ability of the hypothermic state to achieve myocardial protection from tissue acidosis and ischemia, and (2) the validity of myocardial temperature monitoring as an online tool for the assessment of the adequacy of myocardial protection.
The lack of correlation demonstrated in this study between myocardial tissue temperature and myocardial tissue pH measured at the same site indicates that hypothermia fails to protect the myocardium from tissue acidosis and, hence, does not consistently achieve metabolic protection. The ischemic injury to the myocardium that occurs during aortic occlusion is related to an imbalance between energy supply and demand. Normothermic arrest (37°C) reduces oxygen demands by approximately 90%; hypothermic arrest at 22°C reduces oxygen demands to 97% below the requirements of the normal beating working heart [18]. Further reduction of myocardial temperature to less than 15°C has an immeasurably small effect on myocardial oxygen requirements. In addition, myocardial temperatures of less than 10° to 15°C may cause myocardial energy depletion, intracellular damage [19], and delayed metabolic and functional recovery [20]. Hence it is not surprising that, in this study, myocardial temperature of less than 15°C did not correlate with a marker of tissue acidosis, and hence metabolic protection.
The technique for optimal delivery of cardioplegia, and the method with which to reliably assess the efficacy of this technique, remain elusive. To guide cardioplegia delivery, surgeons have used the production of asystole [21, 22], the measurement of myocardial temperature in hypothermic conditions [23–30], or a variety of specific protocols related to the volume and time of cardioplegia delivery [14–16, 31–34]. Production of asystole as an indicator of cardioplegia delivery is limited to the initial few minutes after aortic clamping, as asystole is also an endpoint of ischemic myopathy, which can occur later in the course of aortic clamping. The septal temperature at which cardioplegia infusion has been discontinued has varied from 8° to 20°C [23, 35] and has usually ranged between 11° and 15°C. It is well recognized, however, that myocardial temperature may not be uniform, particularly in the presence of coronary artery disease [36, 37]. This has prompted the use of retrograde cardioplegia and the use of topical hypothermia in addition to the infusion of the hypothermic cardioplegia [21, 23, 28, 35, 38, 39]. By failing to show a correlation between regional myocardial temperature and myocardial tissue pH, this study underscored the limitations of using myocardial temperature as a surrogate monitor of adequacy of protection, particularly during prolonged periods of aortic clamping. Myocardial temperature changes at the onset of aortic occlusion may be useful in monitoring the adequacy of the initial delivery of the cold cardioplegia. Throughout the period of aortic clamping, there was no direct relationship between tissue temperature and pH irrespective of the topography of the heart or the type of cardioplegia used. As shown in Figure 1, for example, at a myocardial temperature of 12°C, the myocardial tissue pH ranged widely from normal (7.4) to severe acidosis (5.7), and a myocardial tissue pH of 7.0 was achieved with temperatures ranging from 5° to 35°C. In addition, as exemplified by the patient tracings in Figure 6, a marked regional variability in myocardial tissue pH could be observed during prolonged cross-clamping with no concomitant variation in myocardial temperature. Myocardial tissue pH in the anterior left ventricular wall was markedly different from that in the posterior wall throughout the period of aortic occlusion, with the posterior wall exhibiting marked ischemic changes, which were better appreciated when the myocardial tissue pH was expressed at a uniform temperature (Fig 6B). In contrast, myocardial temperature, which ranged between 8° and 15°C, was identical in both walls. A surgeon monitoring only the myocardial temperature would have assumed that the protection of both walls was adequate when, in fact, the protection in the posterior wall was inadequate.
The regional variation in myocardial tissue pH that was observed in this study reflects, in part, the variation in the tissue washout of the hydrogen ion by the cardioplegic solution, and it underscores the utility of myocardial tissue pH monitoring in depicting the regional distribution of the cardioplegic solution. This regional variation in myocardial tissue pH, which we observed relatively frequently during prolonged aortic clamping, also underscores the limitations of current techniques of myocardial protection in achieving, consistently and reliably, total metabolic protection of the heart.
Another guideline used in the delivery of cardioplegia has been the volume of cardioplegia and method of administration. Various techniques seeking to deliver an optimal volume of cardioplegia have been advocated. These have included the delivery of high-volume cardioplegic doses, calculated doses based on left ventricular mass, multiple versus single doses, retrograde coronary sinus perfusion, and delivery of a specific volume per given duration of infusion [13–16, 31–34]. In the present study, a relatively high volume of cardioplegia was administered because the guiding principle was the maintenance of myocardial temperature at less than 15°C. To assess the impact of the volume of cardioplegia on the adequacy of myocardial protection, the total volume of cardioplegia delivered per hour of aortic occlusion was compared, in each patient, to the integrated mean myocardial tissue pH achieved during the course of aortic occlusion. The integrated mean myocardial tissue pH during this period has been shown to correlate well with clinical criteria of adequate protection [8]. There was no predictable relationship demonstrated between the volume of cardioplegia administered and the ensuing levels of myocardial tissue pH (Fig 2). Hence, it is most unlikely that the periodic delivery of set volumes of cardioplegia would result consistently and predictably in adequate myocardial protection. A system of cardioplegia delivery that is guided by the administration of set volumes of a cardioplegia is just as limited in its ability to ensure optimal metabolic protection as a system guided by the online measurement of regional myocardial temperature.
This study was not designed to compare the efficacy of blood versus crystalloid cardioplegia in achieving adequate myocardial protection. Nevertheless, these data confirm previous studies from our laboratory that have demonstrated the superiority of blood over crystalloid cardioplegia in achieving satisfactory metabolic protection [9, 40]. The myocardial temperature during aortic occlusion was slightly lower in the blood cardioplegia group. However, even after correcting for the difference in temperature between the two cardioplegia groups, the myocardial tissue pH levels achieved with blood cardioplegia were significantly higher than those achieved with crystalloid cardioplegia.
Limitations of this study include the sole use of antegrade cardioplegia. The majority of these data were collected before our routine use of retrograde cardioplegia, which we have since recognized as having particular advantages in patients with ischemic and valvular heart disease. This review was done with the purpose of trying to understand what the importance and relationship of temperature and myocardial pH were in a clinical setting in patients with more prolonged periods of aortic occlusion. Consequently, no interventions were made based on the data that were obtained, despite the low pH in various regions of the heart noted during the course of some operations. Our current and future research efforts are concentrating on the acquisition of similar data regarding routes of cardioplegic administration, optimal cardioplegia temperature, as well as the benefits of various cardioplegic ingredients such as aspartate and glutamate. In addition, we are also investigating various intraoperative maneuvers to help correct myocardial tissue acidosis when it is identified during the course of operation.
In conclusion, myocardial tissue pH varies over a wide range and exhibits significant regional variation. Under hypothermic cardioplegic conditions, it does not correlate with myocardial temperature or with the volume of cardioplegia administered. Regional metabolic ischemic changes, manifested by regional tissue acidosis, can occur in the left ventricle in the face of low myocardial temperatures despite the delivery of high volumes of crystalloid or blood cardioplegia. These data emphasize the limitations of our current myocardial management techniques in achieving adequate homogenous metabolic protection of the heart, and underscore the limitation of using myocardial temperature measurement as an intraoperative online monitor of the "adequacy" of myocardial protection.
Acknowledgments
This work was supported by a Department of Veterans Affairs Merit Review Grant and by the Richard Warren Surgical Research and Educational Fund, Westwood, MA.
Footnotes
Doctor Khuri discloses that he has a financial relationship with Terumo Cardiovascular Systems, Inc.
References
This article has been cited by other articles:
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  E. Gongora and T. M. Sundt III Myocardial Revascularization with Cardiopulmonary Bypass Card. Surg. Adult, January 1, 2008; 3(2008): 599 - 632. [Full Text]
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 S. F. Khuri, N. A. Healey, M. Hossain, V. Birjiniuk, M. D. Crittenden, M. Josa, P. R. Treanor, S. F. Najjar, D. J. Kumbhani, and W. G. Henderson Intraoperative regional myocardial acidosis and reduction in long-term survival after cardiac surgery J. Thorac. Cardiovasc. Surg., February 1, 2005; 129(2): 372 - 381. [Abstract] [Full Text] [PDF]
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Y. J. Woo and T. J. Gardner Myocardial Revascularization with Cardiopulmonary Bypass Card. Surg. Adult, January 1, 2003; 2(2003): 581 - 607. [Full Text]
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