Ann Thorac Surg 2001;72:S2267-S2270
© 2001 The Society of Thoracic Surgeons
Presented at Monitoring and Improving Patient Safety During and Following Cardiac Surgery, San Diego, CA, May 5, 2001.
Moderators: L. Henry Edmunds, Jr, MD, and Robert M. Mentzer, Jr, MD
Panelists: Shukri F. Khuri, MD, Sidney Levitsky, MD, Dennis T. Mangano, MD, PhD, Philippe Menasché, MD, Frank W. Sellke, MD, and Richard D. Weisel, MD
Outcomes in the assessment of myocardial injury
DR L. HENRY EDMUNDS, JR (Philadelphia, PA):
Doctor Manganos discussion of the presentation on outcomes left us with a lot of questions. We really dont have good definitions of variables and outcomes. We do have a pretty good definition of death. We certainly dont have a good definition of perioperative infarction, and variables like emergency surgery have different interpretations by different groups. In some hospitals it is "next day surgery," in other hospitals it is "any operating room now," and in others it is everything in between!
DR DENNIS MANGANO (San Francisco, CA):
Should we even be measuring nonfatal perioperative events in comparative studies, or should we be measuring more definitive end points at 6 months, such as death, the use of an intraaortic balloon pump, renal failure requiring dialysis, or hospitalization with stroke?
DR SIDNEY LEVITSKY (Boston, MA):
I think there is more or less universal agreement that operative mortality per se is not a good measure because, in good institutions, it is very low. A more meaningful measure is patient outcome at 1 year. This can be examined in Medicare patients using the federal computers in Washington, which give us a variety of important information. First, these computers allow us to assess the frequency of rehospitalization after discharge. For example, using these computers, we found at the Beth Israel Deaconess Hospital in Boston that 28% of our coronary artery bypass patients who had been discharged early had to be rehospitalized, mostly in different institutions. Rehospitalization within 1 year of surgery is easy to obtain on Medicare patients and, with the added benefits of the ICD-9 codes, one can have a good idea about the 1-year outcomes of these patients. Second, these computers provide an assessment of the 1-year mortality rate of these patients. Third, and more important, outcome information of this nature, particularly information about 1-year rehospitalizations and complications, allows us to calculate the true cost of a patients treatment and also to examine the cost-efficiency of the various aspects of our practice of cardiac surgery, such as the practice of discharging our patients early after surgery, or the efficacy of using cardioplegia. One-year outcomes are more reliable measures than 30-day mortality, particularly since the latter can be gamed by the ability to prolong the life of a terminal patient artificially beyond 30 days. Also, databases such as those of the Health Care Financing Administration are more reliable than voluntary databases.
You are telling us that the endpoint should be at 1 year, not at 30 days postop, is that so?
Well I think thats admirable. But as far as voluntary databases, one needs to recognize that every large database has a bias. In the absence of perfect data, it is better to have some imperfect data than no data at all. We clearly have a long way to go in improving these databases.
Acidosis, apoptosis, and myocardial injury
I would like to switch to the subject of pH monitoring and say one thing that I think is really important, although I have very little data to support it. Acidosis stimulates apoptosis. A patient who has had an acidotic exposure to his heart secondary to ischemia sustained in the course of a heart operation may sustain adverse myocardial apoptotic changes even if he weans normally from cardiopulmonary bypass and has an uneventful hospital course. A 15-, 20-, or 30-minute exposure to acidosis of the posterior wall of the left ventricle may begin a process of apoptosis which may not be detected clinically until a year, or even 5 years, postoperatively, at which time the patients heart would be weaker than it was at 30 days postoperatively. Maybe I can get Dr Khuri to respond to this.
DR SHUKRI F. KHURI (Boston, MA):
I agree with you fully and, in fact, we do have preliminary data that we have generated from our patients, which suggest this to be the case. It has been repeatedly shown in various cell culture studies that acidosis is a primary trigger of apoptosis. In a recent study published in the Journal of Clinical Investigation, hypoxia alone failed to trigger apoptosis. Only when hypoxia was accompanied with either acidosis or with reperfusion did it trigger an acceleration of the apoptotic process. Obviously we were very much interested in this at our own institution because of our long-term interest in myocardial acidosis. Doctor Hemant Thatte, using multiphoton imaging in our laboratory, has succeeded in developing a method with which myocardial apoptosis can be quantified in fresh right atrial tissues obtained from patients in the operating room. At the Surgical Forum next October, he will be presenting the results of a study in which he subjected human atrial tissue to various degrees of acidosis and convincingly demonstrated a direct relationship between the degree of tissue acidosis and the percentage of cells exhibiting apoptotic changes in these tissues. We are currently verifying this relationship in vivo by obtaining biopsies from the left ventricle in patients undergoing relatively long periods of aortic clamping, and comparing the magnitude of apoptosis observed during postclamp reperfusion to the level of myocardial tissue acidosis observed during and following aortic clamping, measured with our pH probe. We dont have the results of this study yet, but we do expect them to confirm a recent study that we performed in the pig, which revealed a marked increase in apoptosis during reperfusion following a period of aortic clamping and acidosis. Considering that our clinical studies with the pH electrode have revealed that more than 50% of patients undergoing complex cardiac surgery may be subjected, during the period of aortic clamping, to regional myocardial acidosis of more than 30 minutes, one needs to question the efficacy of our current intraoperative myocardial protection techniques, even though a large majority of these patients are weaned successfully from cardiopulmonary bypass and have a satisfactory postoperative course. Are we really protecting these patients if we are frequently subjecting them to severe acidosis and, possibly apoptosis? It is quite possible that we may not be achieving adequate long term protection in these patients, and that the future of myocardial protection should be directed first and foremost towards the prevention of intraoperative acidosis and apoptosis.
DR ROBERT M. MENTZER, JR (Lexington, KY):
I would like to ask Dr Khuri a question related to myocardial acidosis as an etiology of myocardial injury. Do you have information about the relationship between myocardial enzymes, such as CK-MB, over the course of 24 to 48 hours postoperatively and the degree of acidosis observed intraoperatively? You talk about critical levels of acidosis that result in myocardial necrosis. If the degree of acidosis correlates with myocardial necrosis, the latter could be reflected in the magnitude of CK released. Do you have any information on that?
We have not correlated intraoperative myocardial acidosis to postoperative enzymes alone, although these data are contained in our database and the relationship is certainly worth exploring. Using a statistical methodology called Automatic Interaction Detection Analysis, we have been able to identify critical levels of intraoperative myocardial acidosis below which a significant increase in the incidence of postoperative myocardial infarction was observed in our patient. Evidence of myocardial infarction in this study included, but was not limited to, postoperative myocardial enzymes. This study was presented at the meetings of the American Heart Association and will be submitted for publication soon. What is also clear from our experience to date, which includes more than 700 patients in whom we have monitored myocardial pH intraoperatively, is that patients who are diagnosed with a new postoperative myocardial infarction are more likely to have sustained, in retrospect, significant myocardial acidosis intraoperatively, either during the period of aortic clamping or during the period of reperfusion. Patients who do not develop acidosis intraoperatively are unlikely to sustain a perioperative myocardial infarction. So, in answer to your question, yes we do have clinical evidence linking intraoperative myocardial acidosis to necrosis, if you consider postoperative myocardial infarction a reflection of this necrotic process.
Relationship of myocardial pH to patient outcomes
QUESTION FROM THE AUDIENCE:
Doctor Khuri, in one of your slides you showed that pH levels during the period of aortic clamping were lower in the earlier group of patients in whom you measured pH compared to the more recent group of patients. What do you attribute this to, and was there a correlation between the intraoperative pH levels and the outcomes of these patients?
In the first tercile of patients in whom we monitored myocardial pH intraoperatively, we were simply trying to learn what the measurement of myocardial pH meant, and how it related to clinical events. As such, we did not attempt to intervene to alter the pH level observed, despite the fact that myocardial acidosis was encountered fairly frequently. In the second tercile of patients, we attempted to intervene to reverse regional acidosis but were only partially successful because we had not yet learned all the maneuvers that could improve myocardial pH levels in these patients. In the third tercile, we had learned most of the maneuvers that constituted what I referred to earlier today as "pH-guided myocardial management." The application of these maneuvers effected a significant reduction in the magnitude of intraoperative regional myocardial acidosis and accounted for the changes in the magnitude of intraoperative acidosis over the duration of the study. In terms of the relationship of intraoperative acidosis to outcome, in the study I alluded to previously, we used automatic interaction detection analysis to examine the relationship between intraoperative myocardial acidosis and 30-day outcomes in general. Specific myocardial acidosis levels were identified, both during aortic clamping and after 30 minutes of reperfusion, below which a significant increase in adverse outcome was observed. Adverse outcome was defined as a complication and/or death within 30 days postop. In a more recent study in which we obtained complete follow-up on more than 400 patients in whom myocardial pH was monitored between 1983 and 1997, we showed a direct relationship between certain intraoperative myocardial pH parameters and long-term patient survival. Since both of these studies are currently being prepared for publication, I cannot provide you with more information so as not to jeopardize their chances of being published in a good journal. Suffice to say we have generated over the years convincing data establishing a direct relationship between intraoperative myocardial acidosis and both short and long term patient outcomes.
A mitochondrial marker of injury
I think Dr Khuri is on to something very important because we need metabolic or biological markers to better assess the adequacy of our myocardial protection techniques. I want to share with you our work, which addressed another possible biological marker of myocardial injury. As some of you know, we have been looking in our laboratory at the molecular and biological effects of stunning, which sometimes leads to apoptosis and necrosis. Accompanying intracellular necrosis in these studies, we observed an increase in calcium in the nucleus and cytosol. With the enzymes associated with that, we found that we had DNA nicking or DNA fragmentation. Over the last couple of years, we carried this further in a few clinical studies and began to look at the mitochondria as our ultimate biological marker. Obviously we cant do this online. But one can look at mitochondrial DNA fragmentation and the genes that are affected during their reparative process or during the reperfusion process. It seems that its the genes associated with oxidative phosphorylation that are down regulated or slowed down so that the heart can undergo the reparative process to overcome stunning, perhaps reverse the precursors of apoptosis, and allow these patients to ultimately survive and get a good result. We have some clinical studies wherein investigators, blinded to the clinical course of the patients, predicted whether or not a patient required inotropic support, or intraaortic balloon counterpulsation, mainly on the basis of DNA fragmentation in biopsies obtained in the course of the operation. Therefore, this pH probe may be the beginning of a whole series of future molecular probes that will allow us to predict which patients might get in trouble, and will also help us reverse some of the adverse intraoperative events that may occur in these patients.
Intraoperative monitoring of myocardial pH
Let me ask Dr Weisel a follow-up question. What are your thoughts about using myocardial pH as an end point for outcome in clinical trials assessing the protective efficacy of drugs? Also what are your thoughts about ones ability to actually intervene during the operation, based on myocardial pH monitoring?
DR RICHARD D. WEISEL (Toronto, ON, Canada):
Obviously I dont have the experience that Dr Khuri has, but we have already heard that there is a wide variability among patients in their myocardial pH levels. We have certainly found this to be true in our metabolic monitoring of coronary sinus blood. Because of this wide variability, it was difficult in our studies to know at what level of acidosis one should intervene in a specific patient, particularly since it was difficult to predict what would happen with the intervention. However, a pH falling below 6.3 is definitely a problem and, if identified in the course of the operation, it should prompt an intervention because it indicates inadequate perfusion, such as inadequate perfusion through a newly constructed graft. On the other hand, mild levels of acidosis may, in fact, be beneficial. Several studies suggest that an acidotic environment may be protective, and that what we may need to do is to induce in our patients mild acidosis in order to protect them from ischemic injury. Of course we have to avoid severe acidotic episodes.
What level of acidosis do you consider to be "mild"?
I dont think we know that because no one has measured it except for you.
I agree that mild acidosis may be beneficial to the heart. Considering that normal myocardial tissue pH is in the range of 7.1 to 7.3, pH of 6.8 is considered to represent mild acidosis. Interestingly, this pH level is that which is considered to be optimal for intracellular enzymatic function. I agree that several studies have shown this level of acidosis to be salutary to the myocardium. Clinically, we have found the integrated mean pH during the period of aortic clamping to be an important indicator of the adequacy of myocardia protection, and have advocated maintaining this pH at or above 6.8. However, we still dont have data to show whether maintaining the integrated mean pH during this period at this level is better than maintaining it at or above 7.1 or 7.2
DR FRANK W. SELLKE (Boston, MA):
I would like to ask Dr Khuri whether the fall in pH is indicative of insufficient administration of cardioplegia, and if so, is low pH accompanied with increased heart movement or fibrillation?
A few years ago, we conducted a study which we presented at the Scientific Sessions of the American Heart Association in which we investigated the determinants of myocardial tissue acidosis during a relatively prolonged period of aortic clamping. The variables and interactions that we investigated included the volume and temperature of the cardioplegic solution (warm vs cold), its mode of delivery (antegrade, retrograde, or antegrade plus retrograde) and the regional topography of the left ventricle (anterior vs posterior walls). In the multivariate model, a single determinant of the magnitude of regional acidosis was identified. It was not the volume of the cardioplegic solution per se, nor its temperature or mode of delivery; it was the interaction between the volume of the cardioplegia delivered and the regional topography of the left ventricle. This means that the onset of acidosis in a specific segment of the left ventricular wall is determined primarily by whether or not cardioplegia is delivered to that specific segment of the left ventricular wall. Simple as it may seem, the best way to avoid acidosis in a specific segment of the left ventricular wall is simply to ensure the delivery to that specific segment of an adequate volume of the cardioplegic solution. This study, along with our clinical experience, has also shown that there is no specific cardioplegia temperature or mode of delivery that predictably and consistently prevents the onset of myocardial acidosis in all segments of the left ventricular wall. So in answer to your question, yes, the fall in pH during the period of aortic clamping is indicative of insufficient administration of cardioplegia. However, to ensure the adequate delivery of cardioplegia to specific myocardial segments, one needs to customize the volume, temperature, and mode of delivery of the cardioplegic solution based on real time knowledge of the myocardial pH of that segment. As to whether inadequate cardioplegia per se causes increased heart movement or fibrillation, we have found these events to relate more to the temperature of the cardioplegic solution than to the failure of cardioplegia in preventing acidosis. Adequate delivery of warm and tepid cardioplegia can result in ventricular fibrillation without the occurrence of tissue acidosis. It is an issue of supply and demand; acidosis occurs only when there is a metabolic imbalance between supply and demand.
I want to go back to the notion that "a little acidosis is good," because I think that is an important concept. Do you think that inflicting mild acidosis is really a preconditioning phenomenon? With intermittent cross clamping, we have short periods of ischemia, which probably lead to mild acidosis. So the question is have you measured the heat shock or any of the other enfolding proteins to determine whether all were doing with mild acidosis is eliciting preconditioning?
We have not measured heat shock proteins, but your idea is a very sound one. Before we knew anything about preconditioning, Dr Kenneth Warner, working then in our laboratory, published a study in Circulation Research in which he examined the effect of repeated 3-, 5-, and 15-minute regional coronary artery occlusions on myocardial pH and contractility. He showed a consistent reduction in acid production following the second occlusion. Doctor Robert Kloner, who shared with us the authorship of this paper, and who is now an authority in the field of preconditioning, believes that, in retrospect, the pH profile in the Warner experiments was indicative of a preconditioning phenomenon. This confirms your hypothesis that mild acidosis in our patients might be protective through a preconditioning phenomenon.
Thats what we found with adenosine as well. Infusion of adenosine in our patients, before applying the aortic clamp, induced a mild acidosis. Maybe that was the reason it was protective.
Myocardial pH and TEE in beating heart surgery
Doctor Menasché, from what youve heard today in terms of the value of monitoring intraoperative myocardial pH, how might we apply this technology in the off-pump group of CABG patients? We really dont have good information about whats happening to the heart off-pump in terms of regional ischemia. Do you see any role for pH monitoring in this group of patients?
DR PHILIPPE MENASCHÉ (Paris, France):
Well, I dont know. I must confess that the application of the pH probe to off-pump surgery is something new that I had not heard about before. In my own practice until now, TEE remains probably the best tool to determine whether or not you are inducing some stunning when you occlude a major vessel on the beating heart. Whether this surveillance could be made as effective, and probably simpler, by monitoring the pH in the occluded area, is really something that deserves to be investigated. As we all know, the transient coronary occlusion that is necessary for doing a bypass is usually and surprisingly well tolerated, except when the vessel is a big right coronary artery. It would be interesting to determine whether this is supported or not by some metabolic changes which are measurable in the myocardium. For example, it has been shown that even in patients who are doing very well after OPCAB, if one measures lactic efflux from the coronary sinus, lactic acid production can be observed when a shunt is not used. So, yes, I think pH monitoring can be an appropriate tool, for example, to determine whether a shunt is necessary or not. I discovered this today, and I think it is promising.
Let me ask Dr Mangano about the use of intraoperative transesophogeal echocardiography (TEE) for the detection of regional wall motion abnormalities in the OPCAB patients. I think you and others have reported that TEE may actually be more sensitive than ECG in detecting ischemia. Should we be thinking about using pH monitoring and TEE simultaneously in OPCAB?
Well, given what myocardial pH monitoring does, it should definitely be evaluated in this context because it is promising. Its clear that TEE, in experienced hands, is much more sensitive than ECG, and certainly more sensitive than any change in filling pressures or other global hemodynamic measurements. More than ten years ago, we proposed a study to correlate regional wall motion changes as observed by TEE with myocardial pH changes. This study was not funded, but I still think that it would be worthwhile. You asked a previous question about whether one could use myocardial pH as an endpoint in clinical trials. To get this accepted as an end point in a trial, one needs to show a very close association between intraoperative myocardial pH changes and hard outcomes. One also needs to demonstrate that manipulating and changing myocardial pH changes the outcome. This is a long process that is worthwhile; it might take years, but it will be great to have a device like that, which can depict early findings of ischemia.
Thank you all very much; this concludes our panel discussion.
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