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Ann Thorac Surg 2001;72:S2227-S2233
© 2001 The Society of Thoracic Surgeons

Supplement: Monitoring and improving patient safety during and following cardiac surgery

Intraoperative metabolic monitoring of the heart: II. Online measurement of myocardial tissue pH

Kamal R. Khabbaz, MD*a, Fuad Zankoul, MDa, Kenneth G. Warner, MDa

a Department of Cardiothoracic Surgery, New England Medical Center, and Tufts University School of Medicine, Boston, Massachusetts, USA

* Address reprint requests to Dr Khabbaz, New England Medical Center Cardiothoracic Surgery, Box 266, 750 Washington Street, Boston, MA 02111, USA
e-mail: kkhabbaz{at}lifespan.org

Presented at Monitoring and Improving Patient Safety During and Following Cardiac Surgery, San Diego, CA, May 5, 2001.

Abstract

Under conditions of ischemia, the hydrogen ion [H+] accumulates in the myocardial tissue in proportion to the magnitude of the ischemic insult. The accumulation of [H+] is the result of both increased anaerobic production of [H+] secondary to decreased substrate and decreased washout of [H+] secondary to decreased coronary perfusion. The Khuri tissue pH electrode/monitoring system has been developed and validated over the past two decades. Its scientific basis and correlates have been established, and it is the only system that has been approved for use in humans. Myocardial tissue pH has been monitored in the anterior and posterior walls of the left ventricle in more than 700 patients undergoing major cardiac surgery. An understanding of the relationship between pH and temperature and between the pH and [H+] in tissues is important for the proper interpretation of the myocardial pH data generated in the course of an operation. Intraoperative monitoring of myocardial pH is the only modality available to the cardiac surgeon for online assessment and improvement of the adequacy of myocardial protection. By defining myocardial protection in terms of protection from myocardial tissue acidosis, this technology provides a new tool with which the comparative efficacy of the various myocardial protection techniques can be assessed. It also provides an online tool for assessing the adequacy of coronary revascularization, and has the potential of improving procedures and outcomes for off-pump coronary artery bypass grafting.

It is well established that regional and global alterations in the metabolic status of the myocardium occur throughout the period of aortic clamping and reperfusion in the course of cardiac surgical procedures. The functional recovery of the myocardium is highly dependent on the metabolic status of the heart during these intervals. Myocardial protection techniques, including the administration of cardioplegia, have been geared toward minimizing the metabolic derangements that might occur in the myocardium during these vulnerable periods. However, cardiac surgeons have not routinely used a metabolic marker to quantify the adequacy of the preservation of the metabolic status of the heart. One of the most sensitive markers of inadequate preservation of the myocardium and of the onset of myocardial ischemia is the development of myocardial tissue acidosis.

Myocardial tissue acidosis in ischemia and reperfusion

The myocardium has the highest fractional oxygen extraction capability of any organ in the body, at a rate of nearly 70% [1]. Myocardial metabolism is almost entirely aerobic. Under conditions of normal metabolism and adequate myocardial perfusion, the production and washout of hydrogen ions are in equilibrium, resulting in a normal tissue acid–base balance. Glycolysis, glycogenolysis, hydrolysis of adenosine triphosphate (ATP), hydrolysis of triglycerides, and the synthesis of triglycerides from palmitate are all sources of hydrogen ion production in the myocardial cell [2]. Under global ischemic conditions, when the myocardium is almost totally deprived of its oxygen supply, the major source of ATP is anaerobic glycolysis. In this state, there is an intracellular decrease in high-energy phosphates and an increase in inorganic phosphate. With increasing duration of ischemia, glycolysis is inhibited by increasing levels of lactate and hydrogen ions. Anaerobic glycolysis thus ceases after a period of 90 minutes [3]. The accumulation of hydrogen ions in this situation is due to an increased production from anaerobic glycolysis, glycogenolysis, and ATP hydrolysis, combined with decreased washout due to either diminution or cessation of blood flow. During regional ischemia, oxygen is available to the myocyte in reduced concentrations. When the supply for oxygen fails to meet the tissue demand, the intracellular production of hydrogen ions increases. The hydrogen ion then accumulates in the myocardial tissue if its rate of production exceeds the rate of its washout by the regional myocardial blood flow [4]. It is important to underscore that the accumulation of the hydrogen ion, under conditions of both global and regional myocardial ischemia, is dependent on both its rate of production and its rate of washout.

Interruption of the coronary flow to a segment of the myocardium results in a rapid accumulation of both tissue hydrogen ion and CO2 in that segment. Tissue acidosis results in increased CO2 production through the carbonic anhydrase reaction. A peak concentration of these metabolites is reached 30 to 45 minutes after the interruption of flow. The maximal rate of accumulation of these metabolites and the peak tissue concentration reached are proportional to the magnitude of the ischemic insult inflicted by the interruption of the blood flow [4]. After reaching a peak, the concentrations of both hydrogen ion and CO2 gradually decline. This decline is indicative of progressive ischemic cellular dysfunction, and indicates that the ability of the cell to produce hydrogen ion and CO2 is an index of its viability. Metabolically dysfunctional and dead myocardial tissues do not exhibit a rise in hydrogen ion and CO2 in response to an interruption of blood supply to these tissues [4–7].

Depression of myocardial contractility and function is known to occur in the setting of acidosis [8–11]. Hydrogen ion accumulation depresses myocardial contractility through direct actions on the myocyte and through interactions with intracellular calcium. Myocardial PCO2 has been shown to decrease contractility as well [12]. The relative contribution of the hydrogen ion versus CO2 to the diminution in contractility is unclear. Under conditions of global ischemia, the magnitude of tissue acidosis incurred throughout the period of aortic clamping, and the rate of rise in tissue [H+] throughout the first 10 minutes of reperfusion are important predictors of postischemic cardiac dysfunction [13]. Reducing the magnitude of tissue acidosis during the periods of global ischemia and reperfusion reduces postischemic cardiac dysfunction.

Myocardial cell culture studies have recently demonstrated that acidosis is a primary trigger of apoptosis [14–16]. These studies have shown that hypoxia alone is not enough to trigger apoptosis; it needs to be accompanied by acidosis or reperfusion to elicit such an effect. If confirmed in the intact human, these observations will have major implications on the monitoring and management of myocardial tissue acidosis in the course of open heart surgery.

Measurement of myocardial tissue acidosis

Myocardial tissue acidosis can be quantified by the measurement of tissue PCO2 or hydrogen ion [H+] concentration. Mass spectrometry has been adapted to the online measurement of myocardial tissue PCO2 [17]. Although reliable data could be obtained in the experimental laboratory with this technique [18, 19], it could not be brought to the operating room because of inherent limitations such as relatively long stabilization and response times.

Multiple methods have been suggested for the measurement of myocardial tissue [H+] or pH [3]. Epicardial (surface) electrodes were used in the early 1970s [20, 21] but were abandoned because of a lack of reproducibility and failure to measure pH in the deeper, more vulnerable layers of the myocardium. Plunge electrodes with glass or polymeric tips as well as fiberoptic probes have been used with variable results [22, 23]. Except for the electrode developed by Khuri [24, 25] and described below, these myocardial pH electrodes and probes did not stand the test of time and were never used clinically in humans to monitor myocardial metabolism.

Phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy [26] and fluorescent imaging techniques [27] allow the measurement of intracellular myocardial pH, and are commonly used in a variety of experimental cell, organ, and animal preparations. These techniques, however, are still not applicable to the operating room setting.

Since its initial description almost 17 years ago, the myocardial pH measuring technology developed by Khuri [24] and formerly manufactured by Vascular Technology Inc (Lowell, MA) has been extensively evaluated and validated in multiple animal and human studies. It is the only technology approved by the United States Food and Drug Administration for quantifying myocardial acidosis in humans, and has been consistently used in more than 700 patients undergoing cardiac surgery at the West Roxbury VA Medical Center in Boston. The system is comprised of a sensing electrode, a reference electrode, and a monitor that provides continuous online outputs with recording capabilities [24] (Fig 1). The electrode is a plunge-type probe that is approximately 10 mm in length and 1 mm in diameter, with a lead glass, silver/silver-chloride sensing surface. The electrode also contains a thermistor for the simultaneous measurement of myocardial temperature. The reference electrode is kept at room temperature and connected to the subcutaneous tissues with a salt bridge. The computerized monitoring system, after calibration of the electrodes, records and displays in real-time the myocardial temperature, pH, and [H+]. Myocardial pH and [H+] readings are corrected for the effect of temperature (as discussed below) and have been reported corrected to 37°C. The pH electrode has a 95% response time of 15 seconds. It is stable, with a drift of less than 0.1 pH unit over a 6-hour period.



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  		Fig 1. (A) Khuri tissue pH electrode as previously manufactured by Vascular Technology Inc (Lowell, MA). (B) The electrode being inserted perpendicularly into the anterior wall of the left ventricle. Once fully inserted, the sensing tip of the electrode would be 10 mm deep.

 
Under ischemic conditions, myocardial pH measurements have been shown to correlate with other established markers of ischemia including myocardial tissue PCO2, local intramural ST-segment changes, regional myocardial blood flow, contractile function, and intracellular high-energy phosphate stores [4–6, 18, 19, 28–35].

The electrode has been demonstrated to be sensitive in depicting regional ischemic events in the conscious chronic canine model [7] and in measuring global ischemic changes in canine subjects placed on cardiopulmonary bypass [30]. Simultaneous measurements made with the electrode and with nuclear magnetic resonance (NMR) spectroscopy in canine hearts subjected to regional ischemia showed an excellent correlation between electrode-derived pH and NMR-derived pH [36]. Electrode-derived pH in these studies also correlated very well with changes in myocardial tissue ATP [35], as shown in Figure 2.



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  		Fig 2. The relationship between tissue pH measured with the Khuri electrode and nuclear magnetic resonance (NMR)–derived pH (A) and adenosine triphosphate (ATP) (B) measured with nuclear magnetic resonance spectroscopy, during regional coronary artery occlusion. (Reproduced from Ref. 35 with permission.)

 
Relationship between pH and temperature
There is a direct relationship between the temperature of blood or tissues and the pH, which is independent of the production and washout of acid [37–39]. Hypothermia alone results in a rise in tissue pH. It has been demonstrated in a variety of animal species that for every degree celsius of change in tissue temperature, there is a corresponding change of 0.017 units in pH. Failure of the pH to rise in the presence of hypothermia is thus indicative of relative acidosis. This correction factor is built into the Khuri pH monitor. In the face of wide fluxes in myocardial temperature (such as one encounters during the delivery of cold cardioplegia), the pH monitor displays the pH or the [H+] continuously corrected for 37°C. This allows the surgeon to control for the effects of temperature on pH and to determine the changes that are due solely to acid–base metabolism (Fig 3).



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  		Fig 3. Anterior left ventricular wall pH and temperature recorded in the course of an aortic valve replacement. Broken line shows myocardial temperature, which fell to 13°C with administration of cold cardioplegia delivered immediately after aortic clamping. Thin solid line shows actual myocardial pH, whereas thick solid line shows pH corrected to 37°C. XC = cross-clamp.

 
Relationship between pH and hydrogen ion
The relationship of pH to hydrogen ion is logarithmic: pH = -log [H+]. Therefore, changes of equal magnitude along the pH scale do not reflect equal corresponding changes in hydrogen ion concentrations. As shown in Figure 4, a drop in pH from 7.0 to 6.9 reflects an increase of 30 nmol/L in [H+]. The same drop of 0.1 pH units from 6.1 to 6.0 reflects an increase of 206 nmol/L in [H+]. When evaluating changes in myocardial pH during ischemia, one should keep in mind that a progressive fall in myocardial pH is reflective of exponentially higher amounts of acid being produced. Another implication of this relationship is that when comparative analyses are undertaken to compare pH changes at different levels on the pH scale, the analyses will be more accurate if performed on the basis of changes in [H+] instead of pH. Likewise, if linear statistical analyses are performed in these comparisons, the data would be more accurate if expressed in terms of [H+].



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  		Fig 4. Relationship between pH (in units) and corresponding [H+] (in nanomoles). (See text for explanation.)

 
Clinical applications of the measurement of myocardial tissue pH

Assessment of the adequacy of myocardial protection during and after aortic cross-clamping and subsequent reperfusion
Myocardial pH was first measured in humans, continuously and online, by implanting a pH electrode in the myocardium of patients undergoing open heart surgery [24, 25]. A study comprising the first 44 patients in whom myocardial pH measurements were obtained in the course of aortic clamping and reperfusion [24, 25] underscored the importance of the integrated mean pH during the period of aortic clamping as a determinant of the adequacy of myocardial protection. Low integrated mean pH levels during this period were directly related to poor myocardial protection. Myocardial protection was assessed by a clinical score, which was devised on the basis of the intraoperative and postoperative need for inotropic support, creatine kinase isoenzyme levels, electrocardiographic changes, and results of radionuclide ventriculography. Deleterious clinical effects of acidosis associated with prolonged ischemia were documented despite recorded low myocardial temperatures [24, 25].

Since the publication of the first report, myocardial pH monitoring was further developed and refined in more than 700 patients who underwent operation at the West Roxbury VA Medical Center. The use of the Khuri tissue pH electrode/monitoring system at this center has proved to be reliable, reproducible, and safe. Figure 5 shows the myocardial pH tracings, corrected for 37°C, obtained online in the course of an aortic valve replacement and CABG to the LAD in a 51-year-old man. The figure provides a record of the blood cardioplegia delivery technique by showing the site, duration, and rate of delivery of the blood cardioplegia solution. The figure also provides an example of adequate myocardial protection in both the anterior and the posterior walls (see figure legend for details). In contrast, Figure 6 exemplifies a clinical situation in which the anterior wall was adequately protected but the posterior wall was not. The clinical experience in more than 700 patients has shown that patients in whom the integrated mean pH in both the anterior and posterior walls was kept at 6.8 or greater (uncorrected) were most likely to wean from cardiopulmonary bypass without significant inotropic support, even when the period of aortic clamping exceeded 3 hours [40]



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  		Fig 5. Myocardial pH recordings from anterior and posterior LV walls in a 52-year-old man who underwent coronary artery bypass grafting to the left anterior descending coronary artery (LAD) and aortic valve replacement. The cross-clamp period (shown between two broken vertical lines) was 2 hours 20 minutes, during which myocardial temperature was kept at approximately 20°C. Temperature-corrected myocardial pH is labeled on ordinate as 37°C pH (ie, pH is expressed as if myocardial temperature had remained constant at 37°C throughout duration of operation). Sites of cardioplegia delivery are indicated by symbols plotted according to the duration of delivery (shown on abscissa) and rate of cardioplegia delivery (shown on ordinate). Except for period during which the distal saphenous vein graft was being sutured to LAD, blood cardioplegia was continuously delivered, initially through the graft to LAD and subsequently retrograde through the coronary sinus. Mean integrated pH during total period of aortic clamping was 7.05 in anterior wall and 6.97 in posterior wall, indicating adequate myocardial protection achieved mainly with retrograde delivery. Adequate metabolic protection is commensurate with mean pH of 6.8 or greater during aortic clamping. After release of clamp, pH fell in posterior wall but was reversed with institution of blood flow through graft after completion of proximal anastomosis. This patient experienced defibrillation spontaneously after nearly 2.5 hours of aortic clamping and did not require inotropic support either at weaning or any other time postoperatively. (Ant = anterior wall; CP = cardioplegia; Est’d = established through the graft; LAD = cardioplegia delivery through proximal end of LAD graft; LM Ostium = cardioplegia delivery through ostium of left main coronary artery; Post = posterior wall; Root = cardioplegia delivery through aortic root; Retro = retrograde delivery of cardioplegia through coronary sinus; XC = cross-clamp.)

 


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  		Fig 6. Temperature corrected myocardial pH recordings in a 67 year-old-man undergoing complex aortic valve replacement. The pH was measured from three sites: anterior left ventricular (LV) wall (thick solid line); posterior LV wall (thick broken line); and anterior right ventricular (RV) wall (thin solid line). Temperature-corrected pH reached low of 6.0 in posterior LV wall and 5.8 in RV wall. This marked discrepancy between anterior and posterior wall pH occurred in face of continuous delivery of blood cardioplegia at high rates, mostly through coronary sinus. Delivering cardioplegic solutions through ostium of left main alone, through coronary sinus alone, or simultaneously through left main and coronary sinus failed to reverse fall in pH in posterior LV and anterior RV walls. Integrated mean pH during period of aortic clamping was 7.30 in anterior LV wall, 6.25 in posterior LV wall, and 6.05 in anterior RV wall, indicating poor protection of posterior LV wall and anterior RV wall. The patient had to be defibrillated three times and required significant inotropic support to wean from cardiopulmonary bypass; he continued to require inotropic support for 24 hours postoperatively. {blacktriangleup} = coronary ostium cardioplegia; {square} = retrograde cardioplegia; • = antegrade and retrograde cardioplegia (Abbreviations as in Fig 5.).

 
Over the past two decades, new strategies for myocardial protection have been developed. These strategies have revolved around the composition, temperature, and route of administration of cardioplegia to the myocardium. Myocardial pH monitoring has provided a new tool for the clinical evaluation of the efficacy of these various modalities. In studies comparing crystalloid with blood cardioplegic solutions, lower levels of tissue acidosis were recorded during the periods of aortic clamping and reperfusion with continuous cold blood cardioplegia [41, 42]. This correlated with lower inotropic and mechanical support postoperatively, and established the superiority of continuous cold blood over crystalloid cardioplegia in the prevention of intraoperative myocardial acidosis. Another study examined the determinants of regional acidosis in 140 myocardial segments in the course of complex cardiac surgery. It underscored the lack of delivery of the cardioplegic solution to a specific myocardial segment as the only significant determinant of the onset of myocardial acidosis in that segment. Neither the volume of the cardioplegic solution administered, nor its method of administration, nor its temperature influenced the onset of myocardial acidosis [43].



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  		Fig 7. Response of anterior and posterolateral wall pH to rapid atrial pacing (see text for clinical details). Bars on top show pacing rate. Pacing for 5 minutes at 120 beats/min resulted in fall in anterior wall pH. pH in posterolateral wall remained unchanged. Downward spike at beginning of posterolateral wall tracing is an artifact.

 
Assessment of the physiologic significance of coronary stenosis
The pH electrode has also been used to assess the physiologic significance of a critical coronary artery stenosis [19]. Although coronary angiography provides an adequate assessment of the anatomic extent of coronary artery disease in general, there are situations in which the physiologic significance of questionable angiographic lesions needs to be ascertained. Situations are also encountered intraoperatively in which angiography may not be available or feasible. Under these conditions, Khuri and colleagues [19] demonstrated that subjecting the heart to increased demand through atrial pacing, while continuously measuring myocardial pH, creates a "stress test" in which myocardial pH will fall if the lesion is physiologically significant (Fig 7). A pacing-induced fall in myocardial pH of 0.02 U or more, which is reversed after adequate revascularization, is indicative of a physiologically significant stenosis, even if this stenosis is not readily confirmed by angiography. This modality assists the surgeon in identifying, in the context of the operation, physiologically significant lesions that should be bypassed; it also provides a tool for detecting instances in which inadequate revascularization has occurred. Figure 7 shows the pH in the anterior and posterolateral walls of the left ventricle in a man who presented with malignant ventricular arrhythmias. The cause of the arrhythmias was thought to be ischemia of the posterolateral wall secondary to a totally occluded obtuse marginal branch of the circumflex. Rapid atrial pacing for 5 minutes localized the ischemia to the anterior and not the posterior wall, prompting the surgeon to abandon the plan to revascularize the occluded obtuse marginal branch. That also helped to uncover unsuspected ischemia in the anterior wall.

Assessment of the adequacy of coronary revascularization
The pH response to the administration of blood cardioplegia through a newly constructed graft, and to the restoration of blood flow through the pedicle of a newly anastomosed left internal mammary artery, is a good indicator of the efficacy of the newly constructed grafts. The restoration of tissue pH to normal levels in the anterior and posterior walls of the left ventricle, before weaning from cardiopulmonary bypass, is another indication of adequate revascularization. These concepts have been further elucidated in the article by Wolfe [44] in this supplement.

Potential uses for myocardial pH measurement in beating heart coronary revascularization
Off-pump coronary artery bypass surgery has emerged over the past few years as a viable alternative to standard techniques using cardiopulmonary bypass and cardioplegic arrest. Multiple stabilization platforms are available to the surgeon, and numerous techniques that aid in the exposure of the coronaries have been described. Some platforms are based on the use of intracoronary shunting during the construction of the distal anastomoses, whereas others use the technique of coronary occlusion either with or without preconditioning. Selective distal perfusion techniques have been described to bail out the acutely ischemic myocardium. Standard hemodynamic and electrocardiographic monitoring, in addition to the use of continuous cardiac output and mixed venous monitoring, are the only tools currently available to detect the onset of regional and global ischemia that may occur with gross manipulation and positioning of the heart. The characteristics of the Khuri myocardial pH monitoring system make this technology a potentially useful adjunct to the surgeon performing beating heart surgery. The probe size renders it unobtrusive to the surgical field. The ability to move it and to reinsert it in different myocardial segments allows regional determinations of pH along specific vessel distributions. The ability to quantify regional ischemic changes with a rapid response time enables the surgeon to monitor the evolution of an ischemic episode and to modify the operative procedure so as to avoid the consequences of major ischemic insults. Modifications of the operative procedure could include the placement of an intracoronary shunt or perfusion of the vein grafts through an arterial inflow source before proceeding with the proximal anastomoses or, alternately, performing the proximal anastomoses first. The ability to detect ischemia with temporary coronary occlusion may influence the sequence of performing the distal anastomoses. When global ischemia is encountered, assessed by progressive acidotic changes in both the anterior and posterior LV walls, the surgeon may decide to abort an "off-pump" procedure well before untoward consequences ensue.

Ensuring the technical adequacy of the distal anastomoses is one of the most challenging and uncertain aspects of off-pump coronary artery bypass surgery surgery, because of the complexity of having to sew the grafts while the heart is beating. As reported by Wolfe [44] elsewhere in this supplement, the adequacy of a newly constructed anastomosis can be determined by the magnitude of the tissue washout of H+ after reperfusion through the anastomosis. Failure of reperfusion to reverse tissue acidosis in the segment subtended by the grafted coronary artery is an indication of inadequate revascularization, most likely due to a technically disadvantaged anastomosis.

Conclusion

Online monitoring of myocardial tissue pH in the anterior and posterior walls of the left ventricle, using the Khuri tissue pH electrode/monitoring system, provides a validated clinical tool for the real-time metabolic assessment of the magnitude of myocardial ischemia sustained in the course of a cardiac operation. This tool also allows the comparative assessment of the efficacy of current and new myocardial protective techniques, and is promising in its potential for enhancing the safety and efficacy of off-pump coronary artery bypass operations.

Acknowledgments

The authors acknowledge the help of Dr Shukri Khuri, who provided the clinical material for this review, and Mrs Nancy Healey and Thomas McGary who provided editorial assistance.

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