An anesthesiologist-in-training posed the question, “Why is my presence necessary during cardiopulmonary bypass [CPB]? The perfusionist has direct control of the patient’s blood pressure and respiration. The inhalation anesthetic is attached to the bypass circuit. Drugs are administered into the venous reservoir. What is my role?”¹ The resident’s own answer was incomplete but more robust than that argued by many clinicians, who suggest that the presence of a member of the anesthesia care team (e.g., anesthesiologist, nurse anesthetist, credentialed anesthesia assistant) during CPB is not essential. The American Society of Anesthesiologists (ASA) states that the absence of anesthesia personnel during the conduct of a general anesthetic violates the first of the ASA Standards for Basic Anesthesia Monitoring.² The absence of a member of the anesthesia care team during CPB is below the accepted standard of care. Moreover, to bill for anesthesia care when an anesthesia provider is not physically present in the patient’s operating room constitutes fraud.³ At a minimum, the anesthesiologist’s role during CPB is to maintain the anesthetic state—a more challenging task than the usual case when the patient’s blood pressure, heart rate, and movement provide information regarding the depth of anesthesia. The complexities of CPB and the necessary integration of risk factors with the nuances of cardiac surgery warrant the constant thinking and rethinking of how the conduct of CPB and surgery modulates the risk and what protective strategies need implementation. This chapter outlines the tasks, challenges, and responsibilities of the cardiovascular anesthesiologist that extend beyond the maintenance of the anesthetic state, focusing on overall organ protection.

Historic perspective on cardiopulmonary bypass

On May 6, 1953, John Gibbon, Jr., surgically treated a young woman using CPB, and the long-elusive goal of extracorporeal circulation (ECC) was achieved (Figure 28-1). This accomplishment was preceded by 15 years of work by Gibbon and colleagues to develop a device that would provide ECC and support respiration. The 50th anniversary of the first successful use of CPB was celebrated in 2003. A number of insightful perspectives on this important medical landmark accompanied the anniversary of this achievement.⁴^–⁷

Figure 28-1 Dr. John Gibbon, Jr., before the first successful application of total extracorporeal circulation for cardiac surgery in humans.

(Courtesy of Mütter Museum of the College of Physicians of Philadelphia.)

Reviewing the history of CPB and cardiac surgery shows that the development of this lifesaving technology occurred in three distinct phases. In the 1950s, cardiac surgeons adopted ECC to care for patients suffering from previously untreatable congenital heart disease. At the conclusion of the decade, the backlog of patients with surgically correctable congenital heart disease had diminished, and a new frontier emerged: valvular heart disease. Through the early 1960s, Starr and others described their success with prosthetic valves. Previously untreatable anatomic maladies of the heart could be corrected. As the population aged more, the importance of coronary artery bypass grafting (CABG) with extracorporeal support increased. This third phase includes more than 1 million CABG patients annually. As Pierre Galletti observed, during none of these phases was the next step in perfusion quantitatively anticipated. It is difficult to predict how CPB will be used in this millennium.

This chapter briefly describes modern bypass circuits and highlights the many current controversies regarding the management of patients during CPB. It also deals with perfusion accidents that can be life-threatening events. It is critical that all members of the cardiac surgery team anticipate and respond appropriately to mishaps during CPB (see Chapter 29). More common than the rare catastrophe that can occur are the injurious end-organ effects that can result from the inherently physiologic nature of CPB. The multiple pathophysiologic perturbations precipitated by the process of ECC and the putative effects of these phenomena on end-organ function are discussed in detail.

Goals and mechanics of cardiopulmonary bypass

The CPB circuit is designed to perform four major functions: oxygenation and carbon dioxide elimination, circulation of blood, systemic cooling and rewarming, and diversion of blood from the heart to provide a bloodless surgical field. Typically, venous blood is drained by gravity from the right side of the heart into a reservoir that serves as a large mixing chamber for all blood return, additional fluids, and drugs. Because (in most instances) negative pressure is not used, the amount of venous drainage is determined by the central venous pressure (CVP), the column height between the patient and reservoir, and resistance to flow in the venous circuitry. Negative pressure will enhance venous drainage and is used in some bypass approaches.

Venous return may be decreased deliberately (as is done when restoring the patient’s blood volume before coming off bypass) by application of a venous clamp. From the reservoir, blood is pumped to an oxygenator and heat exchanger unit before passing through an arterial filter and returning to the patient. Additional components of the circuit generally include pumps and tubing for cardiotomy suction, venting, and cardioplegia delivery and recirculation, as well as in-line blood gas monitors, bubble detectors, pressure monitors, and blood sampling ports. A schematic representation of a typical bypass circuit is depicted in Figure 28-2 (see Chapter 29).

Figure 28-2 Components of the extracorporeal circuit: (1) integral cardiotomy reservoir; (2) membrane oxygenator bundle; (3) venous blood line; (4) arterial blood line; (5) arterial filter purge line; (6) arterial line filter; (7) venous blood pump (also called the arterial pump head; this pump forces venous blood through the membrane oxygenator and arterialized blood to the patient’s aortic root); (8) cardiotomy suction pump; (9) ventricular vent pump; (10) cardioplegia pump; (11) crystalloid cardioplegia; (12) water inlet line; (13) water outlet line; and (14) gas inlet line.

(From Davis RB, Kauffman JN, Cobbs TL, Mick SL: Cardiopulmonary Bypass. New York, Springer-Verlag, 1995, p 239.)

The cannulation sites and type of CPB circuit used are dependent on the type of operation planned.⁸ Most cardiac procedures use full CPB, in which the blood is drained from the right side of the heart and returned to the systemic circulation through the aorta. The CPB circuit performs the function of the heart and lungs. Aorto-atriocaval cannulation is the preferred method of cannulation for CPB, although femoral arteriovenous cannulation may be the technique of choice for emergency access, “redo” sternotomy, and other clinical settings in which aortic or atrial cannulation is not feasible. Procedures involving the thoracic aorta often are performed using partial bypass in which a portion of oxygenated blood is removed from the left side of the heart and returned to the femoral artery. Perfusion of the head and upper extremity vessels is performed by the beating heart, and distal perfusion is provided below the level of the cross-clamp by retrograde flow by the femoral artery. All blood passes through the pulmonary circulation, eliminating the need for an oxygenator.

Physiologic parameters of cardiopulmonary bypass

The primary objective of CPB is maintenance of systemic perfusion and respiration. Controversy arises whether systemic oxygenation and perfusion should be “optimal or maximal” or “adequate or sufficient.” Remarkably, after more than a half century of CPB, there is continued disagreement regarding the fundamental management of ECC. Clinicians and investigators disagree on what are the best strategies for arterial blood pressure goals, pump flow, hematocrit, temperature, blood gas management, or mode of perfusion (pulsatile vs. nonpulsatile). Whereas each of these physiologic parameters has to be taken into account individually, the application of each has organ-specific effects. As a result, the ensuing discussion deals with these parameters on an organ-specific basis.

End-organ effects of cardiopulmonary bypass

Modern cardiac surgery continues to be challenged by the risk for organ dysfunction and the morbidity and mortality that accompany it. Catastrophic organ system failure was common in the early days of CPB, but advances in perfusion, surgical techniques, and anesthesia have allowed most patients to undergo surgery without major morbidity or mortality. However, organ dysfunction, ranging in severity from the most subtle to the most severe, still occurs, manifesting most frequently in patients with decreased functional reserves or extensive comorbidities. With more than 1,000,000 patients worldwide undergoing various cardiac operations annually, understanding organ dysfunction and developing perioperative organ protection strategies are of paramount importance.

A number of injurious common pathways may account for the organ dysfunction typically associated with cardiac surgery. CPB itself initiates a whole-body inflammatory response with the release of various injurious inflammatory mediators. Add to this the various preexisting patient comorbidities and the potential for organ ischemic injury because of embolization and hypoperfusion, and it becomes clear why organ injury can occur. Most cardiac surgery, because of its very nature, causes some degree of myocardial injury. Other body systems can be affected by the perioperative insults associated with cardiac surgery (particularly CPB), including the kidneys, lungs, gastrointestinal (GI) tract, and central nervous system (CNS).

Understanding the fundamentals of organ dysfunction, including the incidence, significance, associated risk factors, etiology, and pathophysiology, provides a framework for discussing various organ-specific protective strategies. The following section describes the various organ dysfunction syndromes that can occur in the cardiac surgical patient, with particular emphasis directed at strategies for reducing these injuries.

Central nervous system injury

Incidence and Significance of Injury

CNS dysfunction after CPB represents deficits ranging from neurocognitive deficits, occurring in approximately 25% to 80% of patients, to overt stroke, occurring in 1% to 5% of patients.⁹^–¹² The significant disparity between studies in the incidence of these adverse cerebral outcomes relates, in part, to their definition and to numerous methodologic differences in the determination of neurologic and neurocognitive outcome. Retrospective versus prospective assessments of neurologic deficits account for a significant portion of this inconsistency, as do the experience and expertise of the examiner. The timing of postoperative testing also affects determinations of outcome. For example, the rate of cognitive deficits can be as high as 80% for patients at discharge, between 10% and 35% at approximately 6 weeks after CABG, and 10% to 15% more than a year after surgery. Greater rates of cognitive deficits have been reported 5 years after surgery, when up to 43% of patients have documented deficits.¹⁰ The issue of whether cardiac surgery causes cognitive loss has been greatly debated. Although some have questioned whether long-term deficits result as a consequence of surgery,¹³ even if only present in the short term, they are meaningful to patients and families¹⁴ (see Chapter 36).

Although the incidence of these deficits varies greatly, the significance of these injuries cannot be overemphasized. Cerebral injury is a most disturbing outcome of cardiac surgery. To have a patient’s heart successfully treated by the planned operation but discover that the patient no longer functions as well cognitively or is immobilized from a stroke can be devastating. There are enormous personal, family, and financial consequences of extending a patient’s life with surgery, only to have the quality of the life significantly diminished.^12,¹⁵ Mortality after CABG, although having reached relatively low levels in recent years (generally < 1% overall), increasingly is attributable to cerebral injury.¹²

Risk Factors for Central Nervous System Injury

Successful strategies for perioperative cerebral and other organ protection begin with a thorough understanding of the risk factors, causative factors, and pathophysiology involved. Risk factors for CNS injury can be considered from several different perspectives. Most studies outlining risk factors take into account only stroke. Few describe risk factors for neurocognitive dysfunction. Although it often is assumed that their respective risk factors are similar, few studies consistently have reported the preoperative risks for cognitive loss after cardiac surgery. Factors such as a poor baseline (preoperative) cognitive state, years of education (i.e., more advanced education is protective), age, diabetes, and CPB time frequently are described.^16,¹⁷

Stroke is better characterized with respect to risk factors. Although studies differ somewhat as to all the risk factors, certain patient characteristics consistently correlate with an increased risk for cardiac surgery–associated neurologic injury. In a study of 2108 patients from 24 centers conducted by the Multicenter Study of Perioperative Ischemia, incidence of adverse cerebral outcome after CABG surgery was determined and the risk factors analyzed. Two types of adverse cerebral outcomes were defined. Type I included nonfatal stroke, transient ischemic attack, stupor or coma at time of discharge, and death caused by stroke or hypoxic encephalopathy. Type II included new deterioration in intellectual function, confusion, agitation, disorientation, and memory deficit without evidence of focal injury. A total of 129 (6.1%) of the 2108 patients had an adverse cerebral outcome in the perioperative period. Type I outcomes occurred in 66 (3.1%) of 2108 patients, with type II outcomes occurring in 63 (3.0%) of 2108 patients. Stepwise logistic regression analysis identified eight independent predictors of type I outcomes and seven independent predictors of type II outcomes (Table 28-1).

TABLE 28-1 Risk Factors for Adverse Cerebral Outcomes after Cardiac Surgery

Risk Factor	Type I Outcomes*	Type II Outcomes*
Proximal aortic atherosclerosis	4.52 (2.52–8.09)
History of neurologic disease	3.19 (1.65–6.15)
Use of IABP	2.60 (1.21–5.58)
Diabetes mellitus	2.59 (1.46–4.60)
History of hypertension	2.31 (1.20–4.47)
History of pulmonary disease	2.09 (1.14–3.85)	2.37 (1.34–4.18)
History of unstable angina	1.83 (1.03–3.27)
Age (per additional decade)	1.75 (1.27–2.43)	2.20 (1.60–3.02)
Admission systolic BP > 180 mm Hg		3.47 (1.41–8.55)
History of excessive alcohol intake		2.64 (1.27–5.47)
History of CABG		2.18 (1.14–4.17)
Arrhythmia on day of surgery		1.97 (1.12–3.46)
Antihypertensive therapy		1.78 (1.02–3.10)

BP, blood pressure; CABG, coronary artery bypass graft surgery; IABP, intra-aortic balloon pump.

* Adjusted odds ratio (95% confidence intervals) for type I and II cerebral outcomes associated with selected risk factors from the Multicenter Study of Perioperative Ischemia.

From Arrowsmith JE, Grocott HP, Reves JG, et al: Central nervous system complications of cardiac surgery. Br J Anaesth 84:378, 2000.

In a subsequent analysis of the same study database, a stroke risk index using preoperative factors was developed (Figure 28-3). This risk index allowed for the preoperative calculation of the stroke risk based on the weighted combination of the preoperative factors, including age, unstable angina, diabetes mellitus, neurologic disease, prior coronary artery or other cardiac surgery, vascular disease, and pulmonary disease.¹⁸ Of all the factors in the Multicenter Study of Perioperative Ischemia analysis and in multiple other analyses,^12,¹⁹^–²² age appeared to be the most overwhelmingly robust predictor of stroke and of neurocognitive dysfunction after cardiac surgery.^9,¹⁰ Tuman et al²² demonstrated that age has a greater impact on neurologic outcome than it does on perioperative myocardial infarction or low cardiac output states after cardiac surgery (Figure 28-4).

Figure 28-3 Preoperative stroke risk for patients undergoing coronary artery bypass graft surgery. The individual patient’s stroke risk can be determined from the corresponding cumulative risk index score in the nomogram. CNS, central nervous system.

(From Arrowsmith JE, Grocott HP, Reves JG, et al: Central nervous system complications of cardiac surgery. Br J Anaesth 84:378, 2000.)

Figure 28-4 Relative effect of age on the predicted probability of neurologic and cardiac morbidity after cardiac surgery.

(From Tuman KJ, McCarthy RJ, Najafi H, et al: Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 104:1510, 1992.)

The influence of sex on adverse perioperative cerebral outcomes after cardiac surgery has been evaluated. Women appear to be at greater risk for stroke after cardiac surgery than men.²³ Hogue et al²⁴ found that women appear more likely to suffer deficits in the visuospatial cognitive domain after cardiac surgery, although the frequency of cognitive dysfunction after cardiac surgery is similar for women and men.

Other consistent risk factors for stroke after cardiac surgery are the presence of cerebrovascular disease and atheromatous disease of the aorta. With respect to cerebrovascular disease, patients who have had a prior stroke or transient ischemic attack are more likely to suffer a perioperative stroke.^23,²⁵^–²⁷ Even in the absence of symptomatic cerebrovascular disease, such as the presence of a carotid bruit, the risk for stroke increases with the severity of the carotid artery disease. Breslau et al²⁸ reported that Doppler-detected carotid disease increased the risk for stroke after cardiac surgery by threefold. Similarly, Brener et al²⁹ found that a carotid stenosis greater than 50% increased the risk for stroke from 1.9% to 6.3%.

Although the presence of cerebrovascular disease is a risk factor for perioperative stroke, it does not always correlate well with the presence of significant aortic atherosclerosis.³⁰ Atheromatous disease of the ascending, arch, and descending thoracic aorta has been consistently implicated as a risk factor for stroke in cardiac surgical patients.³¹^–³⁴ The increased use of transesophageal echocardiography (TEE) and epiaortic ultrasonography has added new dimensions to the detection of aortic atheromatous disease and the understanding of its relation to stroke risk. These imaging modalities have allowed the diagnosis of atheromatous disease to be made in a more sensitive and detailed manner, contributing greatly to the information regarding potential stroke risk. The risk for cerebral embolism from aortic atheroma was described early in the history of cardiac surgery,³⁵ and has been described repeatedly in detail since then.^12,³⁶^–³⁸ For example, Katz et al³⁹ found that the incidence rate of stroke was 25% in patients with a mobile atheromatous plaque in the aortic arch, compared with a stroke rate of 2% in those with limited atheromatous disease. Studies consistently have reported greater stroke rates for patients with increasing atheromatous aortic involvement (particularly the ascending and arch segments).⁴⁰ This relation is outlined in Figure 28-5.

Figure 28-5 Stroke rate 1 week after cardiac surgery as a function of atheroma severity.

Atheroma was graded by transesophageal echocardiography as follows: I, normal; II, intimal thickening; III, plaque < 5 mm thick; IV, plaque > 5 mm thick; V, any plaque with a mobile segment.

(From Hartman GS, Yao FS, Bruefach M 3rd, et al: Severity of aortic atheromatous disease diagnosed by transesophageal echocardiography predicts stroke and other outcomes associated with coronary artery surgery: A prospective study. Anesth Analg 83:701, 1996.)

Cause of Perioperative Central Nervous System Injury

Because CNS dysfunction represents a wide range of injuries, differentiating the individual causes of these various types of injuries becomes somewhat difficult (Box 28-1). They frequently are grouped together and superficially discussed as representing different severities on a continuum of brain injury. This likely misrepresents the different causes of these injuries. The following section addresses stroke and cognitive injury (Table 28-2), and their respective causes are differentiated where appropriate.

BOX 28-1. Causes of Central Nervous System Complications After Cardiopulmonary Bypass

• Cerebral emboli

• Global hypoperfusion

• Inflammation

• Cerebral hyperthermia

• Cerebral edema

• Blood-brain barrier dysfunction

• Genetics

TABLE 28-2 Causes of Cognitive Dysfunction after Cardiac Surgery

Cause	Possible Settings
Cerebral microemboli	Generated during cardiopulmonary bypass (CPB); mobilization of atheromatous material or entrainment of air from the operative field; gas injections into the venous reservoir of the CPB apparatus
Global cerebral hypoperfusion	Hypotension, occlusion by an atheromatous embolus leading to stroke
Inflammation (systemic and cerebral)	Injurious effects of CPB, such as blood interacting with the foreign surfaces of pump-oxygenator; upregulation of proinflammatory mediators
Cerebral hyperthermia	Hyperthermia during and after cardiac surgery, such as aggressive rewarming, from hypothermic CPB
Cerebral edema	Edema from global cerebral hypoperfusion or from hyponatremia; increased cerebral venous pressure from cannula misplacement
Blood-brain barrier dysfunction	Diffuse cerebral inflammation; ischemia from cerebral microembolization or increased intracranial pressure
Pharmacologic influences	Anesthetic-related cognitive damage; apoptosis of neonatal brains; proteomic changes
Genetic influences	Effects of single nucleotide polymorphisms on risk for Alzheimer disease or for acute coronary syndromes and other inflammatory disorders

Cerebral Embolization

Macroemboli (e.g., atheromatous plaque) and microemboli (e.g., gaseous and particulate) are generated during CPB, and many emboli find their way to the cerebral vasculature.⁴¹ Macroemboli are responsible for stroke, with microemboli being implicated in the development of less severe encephalopathies. Sources for the microemboli are numerous and include those generated de novo from the interactions of blood within the CPB apparatus (e.g., platelet-fibrin aggregates) and those generated within the body by the production and mobilization of atheromatous material or entrainment of air from the operative field. Other sources for emboli include lipid-laden debris that can be added by cardiotomy suction.⁴² Other gaseous emboli may be generated through injections into the venous reservoir of the CPB apparatus itself.^43,⁴⁴

Numerous studies outline the relation between emboli and cognitive decline after cardiac surgery.⁴⁵^–⁴⁷ However, one of the major limitations in understanding this relation has been the relative inability to discern between gaseous and particulate microemboli.⁴⁸ Typically, Doppler ultrasonography has been used to measure cerebral embolic signals, but Doppler cannot reliably distinguish between gaseous and particulate emboli.⁴⁹ In addition to using Doppler evidence, Moody et al⁴¹ performed histologic analyses on brains from cardiac surgical patients and described the presence of millions of cerebral emboli represented as small capillary arteriolar dilations.

The impact of aortic atheroma on cognitive decline is incompletely understood. It is widely known from nonsurgical and cardiac surgical studies that there is a clear relation between aortic atheroma and stroke,^31,⁵⁰^–⁵² but the relation between cognitive outcome and cerebral atheroma is uncertain. Several studies describe different results.^53,⁵⁴ Whereas some data suggest that cerebral emboli are more likely with a greater degree of atheroma in the ascending aorta,⁵⁵ there is a relative failure to demonstrate that these atheroma correspond to cognitive decline.⁵³ Part of the discordance between these two findings may reflect the limitation of Doppler technology to discriminate between gaseous and particulate emboli, thereby possibly misrepresenting the true cerebral embolic load.⁵⁶

Global Cerebral Hypoperfusion

The concept that global cerebral hypoperfusion during CPB may lead to neurologic and neurocognitive complications originates from the earliest days of cardiac surgery, when significant (in degree and duration) systemic hypotension was a relatively common event. Although making intuitive sense (i.e., that hypotension would lead to global cerebral hypoperfusion), studies that have examined the relation between mean arterial pressure (MAP) and cognitive decline after cardiac surgery generally have failed to show any significant relation.^17,^57,⁵⁸

This is not the case for stroke, for which Hartman et al ³⁸ and Gold et al⁵⁹ demonstrated a link between hypotension and the presence of a significantly atheromatous aorta with an increased risk for stroke (see Figure 28-5). This is not a clear relation, however, and likely represents an interaction between macroembolism and global cerebral hypoperfusion. It is likely, for example, that if an area of the brain that is being perfused by a cerebral vessel becomes occluded by an atheromatous embolus, it may be more susceptible to hypoperfusion if collateral perfusion is compromised by concomitant systemic hypotension.⁶⁰ Other evidence for global cerebral hypoperfusion comes from Mutch et al,⁶¹ who examined magnetic resonance imaging assessments of cerebral blood flow (CBF) showing progressive decreases in CBF during the course of experimental CPB in pigs. However, clinical demonstrations of a reduction in CBF during lengthy CPB have not been seen.⁶²

Temperature-Related Factors

The impact of CPB temperature (i.e., hypothermia) on outcome is addressed further in this section. However, with the various trials of hypothermia during CPB and with detailed temperature monitoring, the observation has been made that hyperthermia can occur during certain periods during and after cardiac surgery. During rewarming from hypothermic CPB, there can be an overshoot in cerebral temperature because of aggressive rewarming generally aimed at decreasing time on CPB and overall operating room time. This cerebral hyperthermia may well be responsible for some of the injury that occurs in the brain.⁶³

The postoperative period is also a critical time in which hyperthermia can contribute to brain injury.^64,⁶⁵ Grocott et al⁶⁴ demonstrated that the peak temperature in the postoperative period (24 hours after surgery) was related to cognitive decline 6 weeks after cardiac surgery. It is not clear whether this hyperthermia causes de novo injury or whether it exacerbates injury that already has occurred (e.g., injury that might be induced by cerebral microembolization or global cerebral hypoperfusion). It is necessary to be cautious in concluding whether these relations are temporal or causal. However, it is assumed that the brain is injured during CPB, and because experimental brain injury is known to cause hyperthermia (resulting from hypothalamic injury⁶⁶), the hyperthermia that is demonstrated in the postoperative period may be caused by the occurrence or extent of brain injury. However, if hyperthermia results from the inflammatory response to CPB, the hyperthermia itself may induce or exacerbate cerebral injury.

Inflammation

Although it is well-known that blood interacts with the foreign surfaces of the pump-oxygenator to stimulate a profound inflammatory response,⁶⁷ the systemic end-organ effects of this inflammatory response are less clearly defined. Much of the data relating organ dysfunction in the CNS to the inflammatory response in the cardiac surgical patient have focused on indirect experimental and clinical evidence. It is not clear whether a cerebral inflammatory response occurs as a result of CPB in humans. Hindman et al⁶⁸ reported that cyclooxygenase mRNA was upregulated after CPB, suggesting that on the molecular biologic level, CPB induces overexpression of this proinflammatory gene in the brain. What is not clear was whether this was a primary event (i.e., as a direct result of the proinflammatory effects of CPB) or a secondary event as a result of other injurious effects of CPB (e.g., microembolization). In settings other than cardiac surgery, inflammation has been demonstrated to directly injure the brain (e.g., sepsis-mediated encephalopathy),⁶⁹ but it also is known to result as a response to various cerebral injuries (e.g., ischemic stroke).⁷⁰

There is no direct evidence that inflammation causes cardiac surgery–associated adverse cerebral outcome; however, there is some supportive indirect evidence. For example, Mathew et al ⁷¹ demonstrated a relation between poor cognitive outcome and an impaired immune response to circulating endotoxin, which inevitably translocates from the gut into the bloodstream because of alterations in splanchnic blood flow during CPB. Having a low antibody response to circulating endotoxin is paradoxically associated with an overstimulated inflammatory response,⁷² thus demonstrating that the relation between low endotoxin antibodies and poor cognitive outcome may be mediated by an augmented inflammatory response. Increasingly, there is genetic evidence linking inflammation to adverse cerebral outcomes, both stroke and cognitive loss (see Genetic Influences section later in this chapter).

Cerebral Edema

Cerebral edema after CPB has been reported in several studies.^73,⁷⁴ The explanation for why cerebral edema may occur early in the postbypass period is not clear. It may be caused by cytotoxic edema resulting from global cerebral hypoperfusion or possibly by hyponatremia-induced cerebral edema. Generalized cerebral edema caused by increases in cerebral venous pressure caused by cannula misplacement, which frequently occurs during CPB, is another reason.⁷⁵ Specifically, use of a dual-stage venous cannula often can lead to cerebral venous congestion during the vertical displacement of the heart during access to the lateral and posterior epicardial coronary arteries. It is not clear from these studies whether the edema results because of injury that occurs during CPB, leading to cognitive decline, or whether the edema itself directly causes the injury by consequent increases in intracranial pressure with global or regional decreases in CBF and resulting ischemia.

Blood-Brain Barrier Dysfunction

The function of the blood-brain barrier (BBB) is to aid in maintaining the homeostasis of the extracellular cerebral milieu protecting the brain against fluctuations in various ion concentrations, neurotransmitters, and growth factors that are present in the serum.⁷⁶ The impact of CPB on the function and integrity of the BBB is not clearly known. Gillinov et al⁷⁷ were unable to show any changes in BBB dysfunction 2 hours after CPB in piglets as assessed using carbon 14-aminoisobutyric acid tracer techniques in postbypass brain homogenates. However, Cavaglia et al,⁷⁸ measuring the leakage of fluorescent albumin from blood vessels in brain slices after CPB, were able to demonstrate significant breaches in the BBB. Both studies looked at a single time point (i.e., immediately after CPB), and it is not known whether there are temporal changes in the BBB integrity.

It is difficult to determine whether the changes in BBB integrity, if present at all, are a primary cause of brain dysfunction or simply a result of other initiating events such as ischemia (i.e., from cerebral microembolization) or a diffuse cerebral inflammatory event. Changes in the BBB could cause some of the cerebral edema that has been demonstrated, or it could result from cerebral edema if the edema resulted in ischemic injury (from increases in intracranial pressure).⁷⁴

Possible Pharmacologic Influences

Anesthetics have been demonstrated to affect cognitive loss after surgery. Experimental studies of cognitive outcome in young rats exposed to anesthetics have demonstrated that relatively brief (several hours) exposure to isoflurane can lead to long-term cognitive changes in the animals.^79,⁸⁰ Coupled with the demonstration in other experimental models of apoptosis in neonatal brains exposed to certain anesthetic agents (e.g., isoflurane, midazolam, nitrous oxide),⁸¹ this added to the data suggesting that corresponding proteomic changes can occur in the brain after exposure to anesthetics⁸² and highlighted this as a potential area for further research.

Genetic Influences

Genetics may play a role in modifying the degree of CNS injury or in the ability of the brain to recover after an injury has occurred. Several investigations have assessed the genetic influences on cerebral outcome after CPB. The most commonly explored gene variant, or single nucleotide polymorphism (SNP), has been the ε4 allele of the apolipoprotein gene. This gene has been reported to be responsible for increasing the risk for sporadic and late-onset Alzheimer disease (as well as complicating outcome after a variety of other head injuries).⁸³ Although early reports suggest that this may be an important influence,⁸⁴ later reports shed some doubt on how robust this effect is.⁸⁵ A second SNP examined relates to the platelet surface receptor glycoprotein IIb/IIIa P1^A2 (P1^A2) receptor polymorphism. This platelet integrin receptor polymorphism is important in the cause of acute coronary syndromes and other thrombotic disorders.^86,⁸⁷ A small study in cardiac surgery patients demonstrated worse impairments in the Mini-Mental Status Examination in the P1^A2-positive patients compared with P1^A2-negative patients.⁸⁸

With the multitude of genes that may play a role in injury, it is important to go beyond examining the impact of single SNPs and explore the impact of multiple SNPs, alone or in combination. In a study of 2140 patients examining 26 different SNPs, the presence of the minor alleles of C-reactive protein (CRP), interleukin-6 (IL-6) had a threefold increase in the risk for stroke after cardiac surgery.⁸⁹ Of note, no single (or combination of) prothrombotic genes were associated with stroke, suggesting that inflammatory, as opposed to thrombotic, mechanisms may be more important to the risk for a stroke.

With respect to cognitive dysfunction after cardiac surgery, a recent study outlined the impact of genetics on outcome after cardiac surgery. In a study of 513 patients who were extensively genotyped (30 SNPs) and had cognitive testing after cardiac surgery, a link between SNPs of CRP and P-selectin (CRP1059G4/C and SELP1087G/A), and a reduction in cognitive deficit were found.⁹⁰ The incidence rate of cognitive deficit was 16.7% in carriers of the minor alleles of both these genes compared with 42.9% of the patients possessing these major alleles. Unique in this study was the mechanism-based genetic effect in which these polymorphisms also were associated with reductions in both CRP and platelet activation, suggesting that an attenuation of perioperative inflammatory and prothrombotic states may be beneficial with respect to reducing the cognitive deficits after cardiac surgery.⁹¹

Neuroprotective Strategies

Emboli Reduction

There are multiple sources of particulate and gaseous emboli during cardiac surgery. Within the CPB circuit itself, particulate emboli in the form of platelet-fibrin aggregates and other debris are generated. Gaseous emboli can be created in the circuit or augmented, if already present, by factors such as turbulence-related cavitation and, potentially, even by vacuum-assisted venous drainage.⁹² Air in the venous return tubing is variably handled by the bypass circuit (i.e., reservoir, oxygenator, and arterial filters). The ability of the circuit to prevent the transit of gaseous emboli through the oxygenator varies considerably between manufacturers and remains a significant source of emboli. The impact of perfusionist interventions on cerebral embolic load also has been studied. Borger et al⁴⁴ found that after drug injections into the venous reservoir, gaseous emboli can make a rapid passage through to the arterial outflow. Reducing these perfusionist interventions reduced emboli generation and neurocognitive impairment.

Significant quantities of air can be entrained from the surgical field into the heart itself; flooding the field with carbon dioxide has been proposed as being effective in reducing this embolic source.⁹³ Its ability to specifically reduce cerebral injury has not been rigorously evaluated, although it has been demonstrated to significantly reduce the number of TEE-detectable bubbles in the heart after cardiac surgery.⁹⁴ Even with the use of carbon dioxide in the surgical field, significant amounts of entrained air can be present. Although the oxygenator-venous reservoir design attempts to purge this air before reaching the inflow cannula, the arterial line filter handles a great deal of what is left. The capacity of the arterial filter to remove all sources of emboli (gaseous or particulate) has significant limitations, and despite its use, emboli can pass easily through and on into the aortic root.

The aortic cannula may be very important to reduce cerebral emboli production. Placement of the cannula into an area of the aorta with a large atheroma burden may cause the direct generation of emboli from the “sandblasting” of atherosclerotic material in the aorta.⁹⁵ The use of a long aortic cannula, where the tip of the cannula lies beyond the origin of the cerebral vessels, also has been found to reduce emboli load.⁹⁶ The type of cannula itself may be an important factor. Various designs have allowed the reduction of sandblasting-type jets emanating from the aortic cannula. Baffled cannulae and cannulae that allow the incorporation of regional brain hypothermia and diversion of emboli away from the cerebral vessels have been investigated.⁹⁷ A cannula that has a basket-like extension that can be inserted just before cross-clamp removal also has been studied.⁹⁸ In a large (N = 1289) study, this Embol-X cannula was unable to reduce the incidence of CNS dysfunction.⁹⁹ A smaller (N = 24) study paradoxically showed an increase in embolic signals with its deployment in the aorta.¹⁰⁰ This has been because of air bubbles trapped within the basket or abrasion of the atheromatous aortic wall. Few other emboli-reducing strategies, besides arterial line filtration and reducing perfusion interventions itself,^44,⁴⁷ have been studied sufficiently to determine their impact on cognitive loss after cardiac surgery. The safety of introducing new techniques also has not been thoroughly studied; the additional risk assumed when significantly altering a standard of practice to use a new device must be considered (see Chapters 3, 29, and 39).

Blood that is returned from the surgical field through the use of the cardiotomy suction may significantly contribute to the particulate load in the CPB circuit and, subsequently, in the brain. The use of cell-salvage devices to process shed blood before returning it to the venous reservoir may minimize the amount of particulate- or lipid-laden material that contributes to embolization.^42,⁴³ Most of this material is small enough or so significantly deformable (due to its high lipid content) that it can pass through standard 40-μm arterial filters. There are several issues with the cell saver, however. One is the cost that is incurred with its use, and the other is its side effects of reducing platelet and coagulation factors through its intrinsic washing processes. Modest use of cell salvage up to a certain, although as yet undefined, volume of blood likely is prudent. Despite this rationale, the results from studies examining neurologic outcome have shown variable effects of cell-saver use on cognitive outcome. A study by Djaiani et al¹⁰² demonstrated a benefit, whereas one by Rubens et al¹⁰¹ did not. This may have been caused by differences in cell savers used that likely varied in their ability to remove lipid emboli (see Chapter 29).

Management of Aortic Atherosclerosis

Although the previous section dealt with issues related to reduction of emboli, many of which likely are spawned from atheromatous plaque in the aorta, further specific management of the atheromatous aorta, particularly as it relates to stroke risk, requires special attention. The widespread use of TEE and complementary (and preferably routine) epiaortic scanning has had a tremendous impact on the understanding of the risks involved in the patient with a severely atheromatous aorta. There is indisputable evidence linking stroke to atheroma.^31,⁵⁰^–⁵² However, the strength of association between atheroma and cognitive decline seen after cardiac surgery is less clear.

A small study used a combination of epiaortic scanning and atheroma avoidance techniques (with respect to cannulation, clamping, and vein graft anastomosis placement) to attempt to reduce neurocognitive deficits.⁵⁴ In that study, the incidence of cognitive decline was lower in patients who had an avoidance technique guided by epiaortic scanning compared with no epiaortic scanning. It was limited by its small size, but it identified an area that requires more investigation. Others have examined this issue and found the relation between cognitive decline and atheroma to be doubtful.¹⁰³ Regardless of whether atheroma cause cognitive dysfunction, their contribution to cardiac surgery–associated stroke is enough to warrant specific strategies for their management.

One of the difficulties in interpreting studies that have evaluated atheroma avoidance strategies is the absence of any form of blinding of the investigators. For the most part, a strategy is chosen based on the presence of known atheroma, and the results of these patients are compared with historic controls. What constitutes the best strategy is unclear. Multiple techniques can be used to minimize atheromatous material liberated from the aortic wall from getting into the cerebral circulation. These range from optimizing placement of the aortic cannula in the aorta up to an area relatively devoid of plaque to the use of specialized cannulae that reduce the sandblasting of the aortic wall. Alternative aortic cannulae and using different locations possess the ability to decrease embolization of atheromatous plaque. The avoidance of partial occlusion clamping for proximal vein graft placement by performing all of the anastomoses made in a single application of an aortic cross-clamp has been demonstrated to have benefit.¹⁰⁴ Specialized cannulae that contain filtering technologies⁹⁸ and other means to deflect emboli to more distal sites have been developed and are being studied.¹⁰⁵ Technology is advancing rapidly, and proximal (and distal) coronary artery anastomotic devices are becoming increasingly available and focus on minimizing manipulation of the ascending aorta. None of these aortic manipulations has yet yielded significant neuroprotective results in large, prospective, randomized trials, but the potential holds promise.

Pulsatile Perfusion

A large volume of literature has accumulated comparing the physiology of pulsatile with nonpulsatile perfusion.^106,¹⁰⁷ Nevertheless, it remains uncertain whether pulsatile CPB has shown substantive clinical improvement in any outcome measure compared with standard, nonpulsatile CPB. Table 28-3, although by no means complete, represents this highly contradictory body of literature.¹⁰⁸^–¹³⁷ Claims of advantages to pulsatile flow are effectively offset by conflicting studies of similar design (see Chapter 29).

TABLE 28-3 Comparison of Studies Investigating Pulsatile Flow during Cardiopulmonary Bypass

	References
Proposed Beneficial Effect of Pulsatile Flow	Yes	No
Reduced systemic vascular resistance	108–114	115–123
Changes in systemic blood flow distribution	108, 124	110, 115, 116, 121
Improved microcirculatory flow/aerobic metabolism	108, 109, 111, 123, 125, 126	110, 115, 116, 121–123
Attenuation of hormonal responses
Catecholamines	127	109, 119
Renin/angiotensin	114, 119, 122	115, 116, 127, 128
Antidiuretic hormone	113, 127	117
Cortisol		117, 128
Thromboxane/prostacyclin	120
Improved renal blood flow or urine output	111, 113, 115, 124, 126	110, 116–118, 123, 129, 136
Improved pancreatic blood flow	124, 129
Improved cerebral blood flow, metabolism, or outcome	112, 125, 130–132, 140	137–139

Nonpulsatile CPB is the most commonly practiced form of artificial perfusion. As intuitive as it may seem that this type of nonphysiologic, nonpulsatile pump flow could be injurious, there is an overall lack of data to suggest that using pulsatile flow during clinical CPB has a neurologic benefit. In a large (N = 316), double-blind, randomized investigation by Murkin et al,¹³⁸ examining the effect of pulsatile versus nonpulsatile CPB on neurologic and neuropsychologic outcome, no significant benefit was demonstrated. One study of balloon pump–induced pulsatile perfusion during CPB failed to show any improvements in jugular venous oxygen saturation of regional brain oxygenation.¹³⁹ A significant limitation to most pulsatility studies is that, because of technical limitations, true “physiologic” pulsatility is almost never accomplished. Instead, variations of sinusoidal pulse waveforms are produced that do not replicate the kinetics and hydrodynamics of normal physiologic pulsation. A review by Hickey et al,¹⁰⁷ published in 1983, offered important criticism and insight into this controversy and remains germane to recent reports. A fundamental difference between pulsatile and nonpulsatile flow is that additional hydraulic energy is required and applied to move blood when pulsatile flow is used. This extra kinetic energy is known to improve red blood cell (RBC) transit, increase capillary perfusion, and aid lymphatic function.¹³³ The hydraulic power of pulsatile flow is the sum over time of the product of instantaneous pressure and instantaneous flow. CPB may influence many of the properties of the blood (viscosity) and the vasculature itself (arterial tone, size, and geometry) as a result of hemodilution, hypothermia, alteration of RBC deformability, and redistribution of flow. As a result of these changes, generation of what appears to be a normal pulsatile pressure waveform may not result in a normal pulsatile flow waveform. Simply reproducing pulsatile pressure is not sufficient to assure reproduction of pulsatile flow, nor does it allow quantification of energetics.

Virtually no study has quantified the energetics of the pulsatile or nonpulsatile perfusion used. Few studies report representative pressure waveforms.¹⁰⁸^–¹¹³ Even fewer give flow waveforms.^134,¹³⁵ When pulsatile flow is not quantified, critical features such as vascular impedance and the hydraulic power delivered cannot be evaluated (i.e., whether the pulsatile perfusion used in a particular study was really delivering more hydraulic power than the nonpulsatile perfusion with which it was compared). Grossi et al¹³⁵ developed two indices of pulsatility: the pulsatility index, which quantitates the relative sharpness of a given waveform with respect to its mean flow; and the pulse power index, which quantifies the power of a pulsatile waveform compared with nonpulsatile equal flow. They found that despite use of a computer-controlled pulsatile pump, in every case, pulsatility index or pulse power index was considerably less than control (nonbypass pulsatility). Only with specific combinations of pulse rate and pulsatile flow contours, which had high pulsatility index or pulse power index, was lactate production lower than the nonpulsatile perfusion at the same minute flow during pulsatile CPB. This study indicates that not all pulsatile perfusion is the same and that pulsatile modes are not necessarily capable of improved perfusion relative to nonpulsatile systems.

It is, therefore, not surprising that such a wide disparity of results should occur. The authors are unaware of any human study in which pulsatility has been quantitated in terms other than pulse pressures. Consequently, whether the generated pressure waveform is a sine wave or some other pattern cannot be ascertained.^113,^114,^117,^119–123,¹²⁶^–¹²⁸ The comparatively small size of the arterial inflow cannula effectively can filter out a large component of the pulsatile kinetic energy. Consequently, as achieved clinically, pulsatile flow may actually be quite similar energetically to nonpulsatile flow.

Newer pulsatile technologies may better reproduce the normal biologic state of cardiac pulsatility. Computer technologies that allow creating a more physiologic pulsatile perfusion pattern have, at least experimentally, demonstrated preservation of cerebral oxygenation. This approach showed some promise in a pig model of CPB in which pulsatile flow controlled by a computer to replicate the normal biologic variability in pulsatility was associated with significantly lower jugular venous oxygen desaturation during rewarming after hypothermic CPB.¹⁴⁰ However, most studies do not present convincing evidence to suggest that routine pulsatile flow during CPB, as can be achieved by widely available technology, is warranted.

Acid-Base Management: Alpha-Stat versus pH-Stat

Optimal acid-base management during CPB has long been debated. Theoretically, alpha-stat management maintains normal CBF autoregulation with the coupling of cerebral metabolism (CMRO₂) to CBF, allowing adequate oxygen delivery while minimizing the potential for emboli. Although early studies ¹³⁸ were unable to document a difference in neurologic or neuropsychologic outcome between the two techniques, later studies showed reductions in cognitive performance when pH-stat management was used, particularly in cases with prolonged CPB times.¹⁴¹ pH-stat management (i.e., CO₂ is added to the fresh oxygenator gas flow) results in a greater CBF than is necessary for the brain’s metabolic requirements. This luxury perfusion risks excessive delivery of emboli to the brain. Except for congenital heart surgery, for which most outcome data support the use of pH-stat management^142,¹⁴³ because of its improvement in homogenous brain cooling before circulatory arrest, adult outcome data support the use of alpha-stat management.

Temperature and Rewarming Strategies

The use of hypothermia remains a mainstay of perioperative management in the cardiac surgical patient. Its widespread use relates to its putative, although not definitively proved, global organ-protective effects. Although hypothermia has a measurable effect on suppressing cerebral metabolism (approximately 6% to 7% decline per 1° C),¹⁴⁴ it is likely that its other neuroprotective effects may be mediated by nonmetabolic actions. In the ischemic brain, for example, moderate hypothermia has multimodal effects, including blocking the release of glutamate,¹⁴⁵ reducing calcium influx,¹⁴⁶ hastening recovery of protein synthesis,¹⁴⁷ diminishing membrane-bound protein kinase C activity,¹⁴⁸ slowing of the time to onset of depolarization,¹⁴⁹ reducing formation of reactive oxygen species,¹⁵⁰ and suppressing nitric oxide (NO) synthase activity.¹⁵¹ Some or all of these effects in combination may convey some of the neuroprotective effects of hypothermia. Although experimental demonstrations of this are abundant, clinical examples of hypothermia neuroprotection have been elusive until recently.¹⁵²^–¹⁵⁵

Some of the most meaningful data on CPB temperature and cerebral outcome came from work that had its origins in the late 1980s and early 1990s. It was at that time that warm CPB was used because of its putative myocardial salvaging effects when used with continuous warm cardioplegia.¹⁵⁶^–¹⁵⁹ However, because CPB was being conducted at higher temperatures than what were considered conventional, the implications for the brain were also studied. Several large studies have been undertaken to elucidate the effects of temperature management on cerebral outcome after cardiac surgery. The Warm Heart Investigators trial,¹⁵⁶ a trial performed at Emory University,¹⁶⁰ and a later trial at Duke University,¹⁶¹ although having several methodologic differences, had similar results with respect to neurocognitive outcome,^162,¹⁶³ but some divergent results with respect to stroke. None of the studies, or ones performed since, demonstrated any neuroprotective effect of hypothermia on neurocognitive outcome after cardiac surgery. However, the Emory trial did demonstrate an apparent injurious effect (as manifest by a worse stroke outcome) of what were most likely mild degrees of hyperthermia during CPB. Neither the Warm Heart Investigators trial nor the Duke trial showed any effect of temperature on stroke per se. These data suggest that active warming to maintain temperatures at (or greater) than 37° C may pose an unnecessary risk for stroke.

Just as hypothermia has some likely protective effects on the brain, hyperthermia, in an opposite and disproportionate fashion, has some injurious effects. Although the studies referred to previously ^156,^160,¹⁶¹ demonstrated no neuroprotective effect, there is emerging evidence that if some degree of neuroprotection is afforded by hypothermia, it may be negated by the obligatory rewarming period that must ensue.⁶³ Grigore et al⁶³ demonstrated in a prospective trial that compared with conventional “fast” rewarming, slower rewarming resulted in a lower incidence of neurocognitive dysfunction 6 weeks after cardiac surgery. These lower rewarming rates led to lower peak cerebral temperatures during rewarming, consistent with past observations that rapid rewarming can lead to an overshoot in cerebral temperature resulting in inadvertent cerebral hyperthermia.¹⁶⁴ By reducing this rewarming rate, it reduces the overshoot in temperature and prevents the negative effects of cerebral hyperthermia. Consistent with the concept that preventing some of the rewarming may be protective was a study by Nathan et al¹⁶⁵ that demonstrated an intermediate-term (3 months) neurocognitive benefit for patients who were maintained between 34° C and 36° C for a prolonged (12 hours) period after surgery. That trial may have had its beneficial effect by the avoidance of cerebral hyperthermia during rewarming rather than the prolonged hypothermia.¹⁶⁵ However, the 5-year follow-up rate did not show a sustained benefit.¹⁶⁶

Although there are numerous sites for monitoring temperature during cardiac surgery, several warrant special consideration. One of the lessons learned from the three warm versus cold trials, as well as from other information regarding temperature gradients between the CPB circuit, nasopharynx, and brain,¹⁶⁴ is that it is important to monitor (and use as a target) a temperature site relevant to the organ of interest. If it is the body, a core temperature measured in the bladder, rectum, pulmonary artery, or esophagus is appropriate. However, if the temperature of the brain is desired, barring implantation of a thermistor directly into the brain (which actually has been done),¹⁶⁷ it is important to look at surrogates of brain temperature. These include nasopharyngeal temperature and tympanic membrane temperature. More invasive surrogates of brain temperature have been obtained using a jugular bulb thermistor.^164,¹⁶⁸ Testing these different temperature sites has demonstrated that vast temperature gradients appear across the body and across the brain. It is likely that during periods of rapid flux (e.g., during rewarming), these temperature gradients are maximal.

Mean Arterial Pressure Management during Cardiopulmonary Bypass

The relation between blood pressure during CPB and CBF is pertinent to understanding whether MAP can be optimized to reduce neurologic injury. Tables 28-4 and 28-5 outline some of the pertinent studies regarding the relation (or lack thereof) between blood pressure and neurologic outcome. Plochl et al¹⁶⁹ examined the lower threshold of the autoregulatory curve in dogs whereby further decreasing blood pressure would result in inadequate CBF and oxygen delivery during CPB. In that study, the brain became perfusion pressure dependent below 50 mm Hg. The investigators also demonstrated that hypothermia did not shift this threshold leftward. Clinically, the available data suggest that in an otherwise normal patient, CBF during nonpulsatile hypothermic CPB using alpha-stat blood gas management is largely independent of MAP as long as that MAP is within or near the autoregulatory range for the patient (i.e., 50 to 100 mm Hg).¹⁷⁰ Although the autoregulatory curve traditionally is considered a horizontal plateau, this plateau has a slightly positive slope, but this slight upward slope is unlikely to have a significant clinically meaningful effect. For example, Newman et al¹⁷ demonstrated that under hypothermic conditions, CBF changed only 0.86 mL/100 g/min for every 10-mm Hg change in MAP. Although this change (1.78 mL/100 g/min) was greater with normothermia,¹⁷¹ these changes represented a relatively small fraction of the normal CBF of approximately 50 mL/100 g/min. Underlying essential hypertension as a comorbidity, however, likely is the effect of a rightward shift in the autoregulatory curve. The degree to which this rightward shift occurs is not clear, but it would be reasonable to expect that it is at least 10 mm Hg, suggesting that the lower range of autoregulatory blood flow is more likely to be 60 than 50 mm Hg.¹⁷² In addition, diabetes may lead to autoregulatory disturbances that make CBF more pressure passive than in individuals without diabetes.^173,¹⁷⁴

TABLE 28-4 Studies Supporting Relation between Intraoperative Hypotension and Postoperative Neurologic Dysfunction

First Author	Year	Patients
Gilman⁷⁴⁶	1965	35
Javid⁷⁴⁷	1969	100
Tufo⁷⁴⁸	1970	100
Lee⁷⁴⁹	1971	71
Stockard⁷⁵⁰	1973	25
Stockard⁷⁵¹	1974	75
Branthwaite⁷⁵²	1975	538
Savageau⁷⁵³	1982	227
Gardner⁷⁵⁴	1985	168
Gold⁵⁹	1995	248

TABLE 28-5 Studies Not Supporting Relation between Intraoperative Hypotension and Postoperative Neurologic Dysfunction

First Author	Year	Patients
Kolkka⁷⁵⁵	1980	204
Ellis⁷⁵⁶	1980	30
Sotaniemi⁷⁵⁷	1981	49
Slogoff⁷⁵⁸	1982	204
Govier¹⁷⁰	1984	67
Nussmeier⁵⁷	1986	182
Fish⁷⁵⁹	1987	100
Townes⁷⁶⁰	1989	90
Slogoff⁶⁴⁴	1990	504
Bashein⁷⁶¹	1990	86
Stanley⁷⁶²	1990	19
Kramer⁷⁶³	1994	230
McKhann⁷⁶⁴	1997	456

Although the data relating MAP to neurologic and neurocognitive outcome after CABG surgery are inconclusive, most data suggest that MAP during CPB is not the primary predictor of cognitive decline or stroke after cardiac surgery. However, with increasing age, MAP during CPB may play a role in improving cerebral collateral perfusion to regions embolized, improving neurologic and cognitive outcome.¹⁷

Gold et al ⁵⁹ added significantly to the understanding of the influence of perfusion pressure on outcome after cardiac surgery in a study of 248 patients randomized to low (50 to 60 mm Hg) or high (80 to 100 mm Hg) MAP during CPB. Although a difference was demonstrated in their composite end point of combined adverse cardiac and neurologic outcome (4.8% high vs. 12.9% low; P = 0.026), when the individual outcomes were compared, there were similar trends but no statistical differences. A secondary analysis of the same data performed by Hartman et al³⁸ found interesting interactions among pressure, aortic atheroma, and stroke; patients who were at risk for cerebral embolic stroke (from having severely atheromatous aortas) were more likely to manifest a stroke if MAP was maintained in the lower range than in the higher range. Intuitively, this is logical. Some experimental data in the noncardiac surgical setting suggest that collateral perfusion to penumbral areas of brain suffering from ischemic injury are relatively protected by higher perfusion pressure.⁶⁰ Overall, it appears that MAP (in the normal range) has little effect on cognitive outcome; but in those with significant aortic atheroma, it may be prudent to modestly increase blood pressure.

Glucose Management

Hyperglycemia is a common occurrence during the course of cardiac surgery. Administration of cardioplegia containing glucose and stress response–induced alterations in insulin secretion and resistance increase the potential for significant hyperglycemia.¹⁷⁵ Hyperglycemia has been repeatedly demonstrated to impair neurologic outcome after experimental focal and global cerebral ischemia.¹⁷⁶^–¹⁷⁸ The explanation for this adverse effect likely relates to the effects that hyperglycemia have on anaerobic conversion of glucose to lactate, which ultimately cause intracellular acidosis and impair intracellular homeostasis and metabolism.¹⁷⁹ A second injurious mechanism relates to an increase in the release of excitotoxic amino acids in response to hyperglycemia in the setting of cerebral ischemia.¹⁷⁷ If hyperglycemia is injurious to the brain, the threshold for making injuries worse appears to be 180 to 200 mg/dL.^180,¹⁸¹

Despite much experimental data, the role of glucose management on cerebral outcome after clinical CPB is not clear. Although Hindman et al ¹⁸² cautioned about the use of glucose-containing prime for CPB, Metz and Keats¹⁸³ did not find a difference in neurologic outcome in patients undergoing CPB with a glucose prime (blood glucose during CPB of 600 to 800 mg/dL) versus no glucose prime (blood glucose level of 200 to 300 mg/dL). This finding was supported by Nussmeier et al,¹⁸⁴ who reported that use of a glucose-containing prime was not a risk factor for cerebral injury in nondiabetic or diabetic patients having CABG procedures. In the largest retrospective review, outcome data from 2862 CABG patients showed no association between the intraoperative maximum glucose concentration and major adverse neurologic outcome or in-hospital mortality.^185,¹⁸⁶

The appropriate type of perioperative serum glucose management and whether it adversely affects neurologic outcome in patients undergoing CPB remain unclear. The major difficulty in hyperglycemia treatment is the relative ineffectiveness of insulin therapy. Using excessive amounts of insulin during hypothermic periods may lead to rebound hypoglycemia after CPB. Chaney et al ¹⁸⁷ attempted to maintain normoglycemia during cardiac surgery with the use of an insulin protocol and came to the conclusion that even with aggressive insulin treatment, hyperglycemia often is resistant and may actually predispose to postoperative hypoglycemia. This concern over potentially increasing adverse effects by exerting tight glycemic controls reportedly has been demonstrated.^188,¹⁸⁹ Attempting to mediate injury may actually predispose to additional injury.

Off-Pump Cardiac Surgery

Off-pump coronary artery bypass (OPCAB) surgery frequently is used for the operative treatment of coronary artery disease (CAD). Although its ability to optimally treat CAD (through the demonstration of long-term graft patency) has not yet been shown in a long-term, prospective, randomized, controlled fashion, it is clear that OPCAB and similar operations will continue to be mainstays of cardiac surgery, although in an evolving fashion. Their impact on adverse cerebral outcomes after cardiac surgery has been variably reported.¹⁹⁰

Although early data suggested less cognitive decline after OPCAB procedures, most studies have not seen it eliminated altogether. The reasons for this are unclear but likely reflect the complex pathophysiology involved. For example, if inflammatory processes play a role in initiating or propagating cerebral injury, OPCAB, with its continued use of sternotomy, heparin administration, and wide hemodynamic swings, all of which may contribute to a stress and inflammatory response, may be a significant reason why cognitive dysfunction is still seen. Ascending aortic manipulation, with its ensuing particulate embolization, is also still commonly used (see Chapter 18).

The results of the largest OPCAB study by Van Dijk et al ¹⁹¹ to examine cognitive dysfunction showed that, although there was a reduction in cognitive decline in the early months after surgery, at 1 year,¹⁹² and even at 5 years,¹⁶⁶ there were no differences between groups. In a subset of patients from this study, jugular bulb saturation was examined. More desaturation (indicative of ischemia risk to the brain) was seen in the OPCAB group. This may have been caused by the low cardiac output that can be seen during manipulation of the heart, as well as jugular venous hypertension.¹⁹³ The effects of OPCAB on stroke risk have not been sufficiently analyzed, but one meta-analysis showed no beneficial effect on the incidence of stroke.¹⁹⁴

Pharmacologic Neuroprotection

Buy Membership for Anesthesiology Category to continue reading. Learn more here

Kaplans Cardiac Anesthesia Expert Consult Premium 6e

Recent Posts

Meta

Categories

Search Engine

Cardiopulmonary Bypass Management and Organ Protection