Reperfusion of an Ischemic Myocardium

Surgical interventions requiring interruption of blood flow to the heart must, out of necessity, be followed by restoration of perfusion. Numerous experimental studies have provided compelling evidence that reperfusion, although essential for tissue or organ survival, or both, is not without risk because of the extension of cell damage as a result of reperfusion itself. Myocardial ischemia of limited duration (< 20 minutes), followed by reperfusion, are accompanied by functional recovery without evidence of structural injury or biochemical evidence of tissue injury.^8,9

Paradoxically, reperfusion of cardiac tissue, which has been subjected to an extended period of ischemia, results in a phenomenon known as myocardial reperfusion injury.^10–12 Thus, a paradox exists in that tissue viability can be maintained only if reperfusion is instituted within a reasonable time period, but only at the risk for extending the injury beyond that caused by the ischemic insult itself. This is supported by the observation that ventricular fibrillation was prominent when the regionally ischemic canine heart was subjected to reperfusion.¹³ Jennings et al¹⁴ reported adverse structural and electrophysiologic changes associated with reperfusion of the ischemic canine heart, and Hearse¹⁵ introduced the concept of an oxygen paradox in noting cardiac muscle enzyme release and alterations in ultrastructure when isolated hearts were reoxygenated after a period of hypoxic perfusion.

Myocardial reperfusion injury is defined as the death of myocytes, alive at the time of reperfusion, as a direct result of one or more events initiated by reperfusion. Myocardial cell damage results from the restoration of blood flow to the previously ischemic heart, thereby extending the region of irreversible injury beyond that caused by the ischemic insult alone. The cellular damage that results from reperfusion can be reversible or irreversible, depending on the length of the ischemic insult. If reperfusion is initiated within 20 minutes after the onset of ischemia, the resulting myocardial injury is reversible and is characterized functionally by depressed myocardial contractility, which eventually recovers completely. Myocardial tissue necrosis is not detectable in the previously ischemic region, although functional impairment of contractility may persist for a variable period, a phenomenon known as myocardial stunning. Initiating reperfusion after a duration of ischemia of longer than 20 minutes, however, results in irreversible myocardial injury or cellular necrosis. The extent of tissue necrosis that develops during reperfusion is directly related to the duration of the ischemic event. Tissue necrosis originates in the subendocardial regions of the ischemic myocardium and extends to the subepicardial regions of the area at risk, often referred to as the wavefront phenomenon. The cell death that occurs during reperfusion can be characterized microscopically by explosive swelling, which includes disruption of the tissue lattice, contraction bands, mitochondrial swelling, and calcium phosphate deposits within mitochondria.¹³

The magnitude of reperfusion injury is directly related to the magnitude of the ischemic injury that precedes it. In its most severe form, it manifests in a “no-reflow” phenomenon. In cardiac surgery, prevention of myocardial injury after the release of the AXC, including the prevention of no reflow, is directly dependent on the adequacy of myocardial protection during the period of aortic clamping. The combination of ischemic and reperfusion injury is probably the most frequent and serious type of injury that leads to poor outcomes in cardiac surgery today (see Chapters 2, 3, 6, 12 to 14, 18, and 28).

Basic science investigations (in mouse, human, and porcine hearts) have implicated acidosis as a primary trigger of apoptosis. Acidosis, reoxygenation, and reperfusion, but not hypoxia (or ischemia) alone, are strong stimuli for programmed cell death, as well as the demonstration that cardiac apoptosis can lead to heart failure.^16,17 This suggests that apoptotic changes might be triggered in the course of a cardiac operation, thus effecting an injurious cascade of adverse clinical events that manifest late in the postoperative course.

Based on the previous discussion, it is clear that a significant portion of perioperative cardiac morbidity is related primarily to intraoperative factors. However, preoperative risk factors may influence ischemia/reperfusion injury.

Adverse Systemic Effects of Cardiopulmonary Bypass

In addition to the effects of disruption and restoration of myocardial blood flow, cardiac morbidity may result from many of the components used to perform cardiovascular operations, which lead to systemic insults that result from CPB circuit-induced contact activation. Inflammation in cardiac surgical patients is produced by complex humoral and cellular interactions, including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, mast cells, and multiple inflammatory mediators.¹⁸ Because of the redundancy of the inflammatory cascades, profound amplification occurs to produce multiorgan system dysfunction that can manifest as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects. Coagulation and inflammation also are linked closely through networks of both humoral and cellular components, including proteases of the clotting and fibrinolytic cascades, as well as tissue factor. Vascular endothelial cells mediate inflammation and the cross-talk between coagulation and inflammation. Surgery alone activates specific hemostatic responses, activation of immune mechanisms, and inflammatory responses mediated by the release of various cytokines and chemokines (see Chapters 8 and 28 to 31). This complex inflammatory reaction can lead to death from nonischemic causes and suggests that preoperative risk factors may not predict morbidity. The ability to risk-adjust populations is critical to study interventions that may influence these responses to CPB.

Assessment of Cardiac Function

Cardiac contractile dysfunction is the most prominent feature of myocardial injury, despite the fact that there are virtually no perfect measures of postoperative cardiac function.

The need for inotropic support, thermodilution cardiac output (CO) measurements, and transesophageal echocardiography (TEE) may represent practical intraoperative options for cardiac contractility evaluation. The need for inotropic support and CO measurements are not reliable measures because they depend on loading conditions and practitioner variability. Failure to wean from CPB, in the absence of systemic factors such as hyperkalemia and acidosis, is the best evidence of intraoperative myocardial injury or cardiac dysfunction; but it also may be multifactorial and, therefore, a less robust outcome measure.

RWMAs follow the onset of ischemia in 10 to 15 seconds. Echocardiography can, therefore, be a sensitive and rapid monitor for cardiac ischemia/injury.²¹ If the RWMA is irreversible, this indicates irreversible myocardial necrosis (see Chapters 11 through 14). The importance of TEE assessment of cardiac function is further enhanced by its value as a predictor of long-term survival.²² In patients undergoing CABG, a postoperative decrease in left ventricular ejection fraction (LVEF) compared with preoperative baseline predicts decreased long-term survival.²³

The use of TEE is complicated because myocardial stunning (postischemic transient ventricular dysfunction) is a common cause of new postoperative RWMAs, which are transient. However, the appearance of a new ventricular RWMA in the postoperative period, whether caused by irreversible AMI or by reversible myocardial stunning, is an indication of some form of inadequate myocardial protection during the intraoperative period and, therefore, of interest for the assessment of new interventions. Echocardiographic and Doppler systems also have the limitation of being sensitive to alterations in loading conditions, similar to the need for inotropic support and CO determinations.²⁴ The interpretation of TEE images is also operator dependent.²⁵ In addition, there are nonischemic causes of RWMAs, such as conduction abnormalities, ventricular pacing, and myocarditis, which confound the use of this outcome measure for the assessment of ischemic morbidity.

Electrocardiography Monitoring

The presence of new persistent Q waves of at least 0.03-second duration, broadening of preexisting Q waves, or new QS deflections on the postoperative ECG have been considered evidence of perioperative AMI.²⁶ However, new Q waves also may be caused by unmasking of an old MI and therefore not indicative of a new AMI. Crescenzi et al²⁷ demonstrated that the association of a new Q wave and high levels of biomarkers was strongly associated with postoperative cardiac events, whereas the isolated appearance of a new Q wave had no impact on the postoperative cardiac outcome. In addition, new Q waves may actually disappear over time.²⁸ Signs of non–Q-wave MI, such as ST-T wave changes, are even less reliable signs of AMI after cardiac surgery in the absence of biochemical evidence. ST-segment changes are even less specific for perioperative MI because they can be caused by changes in body position, hypothermia, transient conduction abnormalities, and electrolyte imbalances (see Chapter 15).

Serum Biochemical Markers to Detect Myocardial Injury

Serum biomarkers have become the primary means of assessing the presence and extent of AMI after cardiac surgery. Serum biomarkers that are indicative of myocardial damage include the following (with post-insult peak time given in parentheses): myoglobin (4 hours), total CK (16 hours), CK-MB isoenzyme (24 hours), troponins I and T (24 hours), and lactate dehydrogenase (LDH) (76 hours). The CK-MB isoenzyme has been used most widely, but studies have suggested that troponin I is the most sensitive and specific in depicting myocardial ischemia and infarction.^29–34

With respect to CK-MB, the definition of an optimal cutoff has been defined best by the correlation of multiples of the upper limit of normal (ULN) for the laboratory and medium- and long-term outcomes. For example, Klatte et al³⁵ reported on the implications of CK-MB in 2918 high-risk CABG patients enrolled in a clinical trial of an anti-ischemic agent. The unadjusted 6-month mortality rates were 3.4%, 5.8%, 7.8%, and 20.2% for patients with a postoperative peak CK-MB ratio (peak CK-MB value/ULN for laboratory test) of less than 5, ≥5 to <10, ≥10 to < 20, and ≥20 ULN, respectively.³⁵ The relation remained statistically significant after adjustment for ejection fraction (EF), congestive heart failure (CHF), cerebrovascular disease, peripheral vascular disease, cardiac arrhythmias, and the method of cardioplegia delivery. In the Arterial Revascularization Therapies Study (ARTS), 496 patients with multivessel CAD undergoing CABG were evaluated by CK-MB testing and followed after surgery at 30 days and 1 year.³⁶ Patients with increased cardiac enzyme levels after CABG were at increased risk for both death and repeat AMI within the first 30 days. CK-MB increase also was independently related to late adverse outcome.

Studies suggest that postcardiac surgery monitoring of troponins can be used to assess myocardial injury and risk stratification. Increased cardiac-specific troponin I or T in patients after CABG has been associated with a cardiac cause of death and with major postoperative complications within 2 years after CABG.^37,38 The ACC/ESC definition includes biomarkers but does not include specific criteria for diagnosing post-CABG AMI using cardiac biomarkers.¹⁹

There are a few new biomarkers of perioperative cardiac injury or ischemia under development. Brain natriuretic peptide (BNP) could be detected in the early stages of ischemia and decreases shortly after ischemic insult, allowing better detection of reinjury.³⁹ BNP concentrations after CABG in the patients who had cardiac events within 2 years were significantly greater than those in the patients free of cardiac events.⁴⁰ Soluble CD40 ligand (sCD40L) is another early biomarker of myocardial ischemia,⁴¹ and CPB causes an increase in the concentration of plasma sCD40L. A corresponding decrease in platelet CD40L suggests that this prothrombotic and proinflammatory protein was derived primarily from platelets and may contribute to the thrombotic and inflammatory complications associated with CPB.⁴² Future research will be required to determine how these biomarkers will be used to assess outcome after cardiac surgery.

Variability in Diagnosis of Perioperative Myocardial Infarction

The variability in diagnosing perioperative AMI has been studied by Jain and colleagues,⁴³ who evaluated data from 566 patients at 20 clinical sites, collected as part of a clinical trial. The occurrence of AMI by Q-wave, CK-MB, or autopsy criteria was determined. Of the 25% of patients who met the Q-wave, CK-MB, or autopsy criteria for AMI, 19% had increased CK-MB concentrations, as well as ECG changes. Q-wave and CK-MB or autopsy criteria for AMI were met by 4% of patients. Multicenter data collection showed a substantial variation in the incidence of AMI and an overall incidence rate of up to 25%. The definition of perioperative AMI was highly variable depending on the definitions used.

Clinicians are still in search for a “gold standard” approach to diagnose perioperative AMI. Perioperative myocardial necrosis/injury ranges from mild to severe and can have ischemic and nonischemic origin in patients undergoing cardiac surgery. Perioperative ECG changes, including Q-waves, and new RWMAs on ECGs are less reliable than in the nonperioperative arena. Currently, troponin I or T is the best indicator of myocardial damage after cardiac surgery. The level of enzymes correlates with the extension of the injury, but there is no universal cutoff point defining perioperative MI.

Predictors of Postoperative Morbidity and Mortality

Clinical and angiographic predictors of operative mortality were initially defined from the Coronary Artery Surgery Study (CASS).^47,48 A total of 6630 patients underwent isolated CABG between 1975 and 1978. Women had a significantly greater mortality rate than men; mortality increased with advancing age in men, but this was not a significant factor in women. Increasing severity of angina, manifestations of heart failure, and number and extent of coronary artery stenoses all correlated with greater mortality, whereas EF was not a predictor. Urgency of surgery was a strong predictor of outcome, with those patients requiring emergency surgery in the presence of a 90% left main coronary artery stenosis sustaining a 40% mortality rate.

A risk-scoring scheme for cardiac surgery (CABG and valve) was introduced by Paiement et al³ at the Montreal Heart Institute in 1983. Eight risk factors were identified: (1) poor left ventricular (LV) function, (2) CHF, (3) unstable angina or recent (within 6 weeks) MI, (4) age greater than 65 years, (5) severe obesity (body mass index > 30 kg/m²), (6) reoperation, (7) emergency surgery, and (8) other significant or uncontrolled systemic disturbances. Three classifications were identified: patients with none of these factors (normal), those presenting with one risk factor (increased risk), and those with more than one factor (high risk). In a study of 500 consecutive cardiac surgical patients, it was found that operative mortality increased with increasing risk (confirming their scoring system).

One of the most commonly used scoring systems for CABG was developed by Parsonnet and colleagues (Table 1-1).⁴⁹ Fourteen risk factors were identified for in-hospital or 30-day mortality after univariate regression analysis of 3500 consecutive operations. An additive model was constructed and prospectively evaluated in 1332 cardiac procedures. Five categories of risk were identified with increasing mortality rates, complication rates, and length of stay at the Newark Beth Israel Medical Center. The Parsonnet Index frequently is used as a benchmark for comparison among institutions. However, the Parsonnet model was created earlier than the other models and may not be representative of the current practice of CABG. During the period after publication of the Parsonnet model, numerous technical advances now in routine use have diminished CABG mortality rates.

TABLE 1-1 Components of the Additive Model

* On the actual worksheet, these risk factors require justification.

† Values were predictive of increased risk for operative mortality in univariate analysis.

Bernstein and Parsonnet⁵⁰ simplified the risk-adjusted scoring system in 2000 to provide a handy tool in preoperative discussions with patients and their families, and for preoperative risk stratification calculation. The authors developed a logistic regression model in which 47 potential risk factors were considered, and a method requiring only simple addition and graphic interpretation was designed for relatively easily approximating the estimated risk. The final estimates provided by the simplified model correlated well with the observed mortality (Figure 1-2).

Figure 1-2 Preoperative Risk-Estimation Worksheet.

(From Bernstein AD, Parsonnet V: Bedside estimation of risk as an aid for decision-making in cardiac surgery. Ann Thorac Surg 69:823, 2000, by permission from the Society of Thoracic Surgeons.)

O’Connor et al⁵¹ used data collected from 3055 patients undergoing isolated CABG at five clinical centers between 1987 and 1989 to develop a multivariate numerical score. A regression model was developed in a training set and subsequently validated in a test set. Independent predictors of in-hospital mortality included patient age, body surface area, comorbidity score, prior CABG, EF, LV end-diastolic pressure, and priority of surgery. The validated multivariate prediction rule was robust in predicting the in-hospital mortality for an individual patient, and the authors proposed that it could be used to contrast observed and expected mortality rates for an institution or a particular clinician.

Higgins et al⁵² developed a Clinical Severity Score for CABG at The Cleveland Clinic. A multivariate logistic regression model to predict perioperative risk was developed in 5051 patients undergoing CABG between 1986 and 1988, and subsequently validated in a cohort of 4069 patients. Independent predictors of in-hospital and 30-day mortality were emergency procedure, preoperative serum creatinine level of greater than 168 μmol/L, severe LV dysfunction, preoperative hematocrit of less than 34%, increasing age, chronic pulmonary disease, prior vascular surgery, reoperation, and mitral valve insufficiency. Predictors of morbidity (AMI and use of the intra-aortic balloon pump [IABP], mechanical ventilation for ≥3 days, neurologic deficit, oliguric or anuric renal failure, or serious infection) included diabetes mellitus, body weight of 65 kg or less, aortic stenosis, and cerebrovascular disease. Each independent predictor was assigned a weight or score, with increasing mortality and morbidity associated with an increasing total score.

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