Cerebral Embolization

Macroemboli (eg, atheromatous plaque) and microemboli (ie, gaseous and particulate) are generated during CPB, and many emboli find their way to the cerebral vasculature. 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 (eg, 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. Other gaseous emboli may be generated through injections into the venous reservoir of the CPB apparatus itself.

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 this concept (ie, that hypotension would lead to global cerebral hypoperfusion) makes intuitive sense, studies that have examined the relationship between mean arterial pressure (MAP) and cognitive decline after cardiac surgery have generally failed to show any significant relationship.

This is not the case for stroke, for which a link between hypotension and the presence of a significantly atheromatous aorta with an increased risk of stroke has been demonstrated. This is not a clear relationship, 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.

Temperature-Related Factors

During rewarming from hypothermic CPB, there can be an overshoot in cerebral temperature due to 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. The postoperative period is also a critical time in which hyperthermia can contribute to brain injury. It is not clear whether this hyperthermia causes de novo injury or exacerbates injury that has already occurred (eg, injury that might be induced by cerebral microembolization or global cerebral hypoperfusion). It is assumed that the brain is injured during CPB, and because experimental brain injury is known to cause hyperthermia (resulting from hypothalamic injury), 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, the systemic end-organ effects of this inflammatory response are less clearly defined. In settings other than cardiac surgery, inflammation has been demonstrated to injure the brain directly (eg, sepsis-mediated encephalopathy), but it is also known to result as a response to various cerebral injuries (eg, ischemic stroke). There is no direct evidence that inflammation causes cardiac surgery–associated adverse cerebral outcome; however, there is some supportive indirect evidence. There is increasing genetic evidence linking inflammation to adverse cerebral outcomes, both stroke and cognitive loss.

Cerebral Edema

Cerebral edema after CPB has been reported in several studies. The explanation for why cerebral edema may occur early in the period after bypass 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 due to increases in cerebral venous pressure caused by cannula misplacement, which frequently occurs during CPB, is another reason. Specifically, use of a dual-stage venous cannula can often 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 cerebral blood flow (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. The impact of CPB on the function and integrity of the BBB is not clearly known.

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 (ie, 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 could result from cerebral edema if the edema resulted in ischemic injury (from increases in intracranial pressure).

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. Air in the venous return tubing is variably handled by the bypass circuit (ie, 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 has also been confirmed.

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. Its ability to specifically reduce cerebral injury has not been rigorously evaluated, although it has been demonstrated to reduce the amount of TEE-detectable bubbles in the heart after cardiac surgery significantly. 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 easily pass 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. The use of a long aortic cannula, where the tip of the cannula lies beyond the origin of the cerebral vessels, has been found to reduce emboli load. The type of cannula itself may be an important factor. Various designs have allowed the reduction of various sandblasting-type jets emanating from the aortic cannula. Blood that is returned from the surgical field though 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. Most of this material is small enough or so significantly deformable (because of its high lipid content) that it can pass through standard 20- to 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 is likely prudent. Despite this rationale, the results from studies examining neurologic outcome have shown variable effects of cell-saver use on cognitive outcome.

Management of Aortic Atherosclerosis

The widespread use of TEE and complementary (and preferably routine) epiaortic scanning has contributed greatly to the understanding of the risks involved in managing patients with a severely atheromatous aorta. There is indisputable evidence linking stroke to atheroma. However, the strength of association between atheroma and cognitive decline seen after cardiac surgery is less clear. Regardless of whether atheroma causes cognitive dysfunction, its contribution to cardiac surgery–associated stroke is enough to warrant specific strategies for 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 to an area relatively devoid of plaque to the use of specialized cannulas that reduce the sandblasting of the aortic wall. The avoidance of partial occlusion clamping for proximal vein graft placement by performing all of the anastomoses in a single application of an aortic cross-clamp has demonstrated a benefit. Specialized cannulas that contain filtering technologies and other means to deflect emboli to more distal sites have been developed and studied. 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 their potential holds promise.

Pulsatile Perfusion

A large body of literature has accumulated comparing the physiology of pulsatile with nonpulsatile perfusion. Nevertheless, it remains uncertain whether pulsatile CPB has shown substantive clinical improvement in any outcome measure compared with standard, nonpulsatile CPB. Claims of advantages to pulsatile flow are effectively offset by conflicting studies of similar design.

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. 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 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 transit, capillary perfusion, and lymphatic function. 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 red blood cell 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 ensure reproduction of pulsatile flow, nor does it allow quantification of energetics.

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 demonstrated, at least experimentally, preservation of cerebral oxygenation. 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 (CMRO ₂ ) to CBF, allowing adequate oxygen delivery while minimizing the potential for emboli. Although early studies 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. pH-Stat management (ie, CO ₂ is added to the oxygenator fresh gas flow) results in a higher CBF than is needed 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 because of its improvement in homogenous brain cooling before circulatory arrest, adult outcome data support the use of only alpha-stat management.

Temperature and Rewarming Strategies

The use of some 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), 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. Although experimental demonstrations of this are abundant, clinical examples of hypothermia neuroprotection have been elusive.

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 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. 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, 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, it is important to look at surrogates of brain temperature. These include nasopharyngeal temperature and tympanic membrane temperature. 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 (eg, during rewarming), these temperature gradients are maximal.

Mean Arterial Pressure Management During Cardiopulmonary Bypass

The relationship between blood pressure during CPB and CBF is pertinent to understanding whether MAP can be optimized to reduce neurologic injury. 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 (ie, 50–100 mm Hg). Underlying essential hypertension as a comorbidity, however, likely includes 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 60-70 than 50 mm Hg. In addition, diabetes may lead to autoregulatory disturbances that make CBF more pressure passive than in patients without diabetes.

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. 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. 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 increase blood pressure modestly.

Rather than choosing a specific or fixed (and arguably arbitrary) blood pressure threshold based on the conflicting preceding data, a more prudent approach may be to individualize the blood pressure targets based on the emerging concept of cerebral oximetry–based real-time physiologic feedback. Technologies such as near-infrared spectroscopy-based cerebral oximetry have played an important role in guiding this approach. This may allow for the determination of individual autoregulatory-driven blood pressure targets.

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. Hyperglycemia has been repeatedly demonstrated to impair neurologic outcome after experimental focal and global cerebral ischemia. The explanation for this adverse effect likely relates to the effects that hyperglycemia has on anaerobic conversion of glucose to lactate, which ultimately causes intracellular acidosis and impairs intracellular homeostasis and metabolism. 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. If hyperglycemia is injurious to the brain, the threshold for making injuries worse appears to be 180 to 200 mg/dL.

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. Studies that have attempted to maintain normoglycemia during cardiac surgery with the use of an insulin protocol have shown that, even with aggressive insulin treatment, hyperglycemia is often resistant and may actually predispose patients to postoperative hypoglycemia. This concern over potentially increasing adverse effects by exerting tight glycemic controls has reportedly been supported. Attempting to mediate injury may predispose patients to additional injury.

Off-Pump Cardiac Surgery

Off-pump coronary artery bypass (OPCAB) surgery is frequently used for the operative treatment of coronary artery disease. The impact on adverse cerebral outcomes after cardiac surgery has been variably reported. 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.

Pharmacologic Neuroprotection

No pharmacologic therapies have been approved by the US Food and Drug Administration or foreign regulatory agencies for the prevention or treatment of cardiac surgery–associated cerebral injury, despite numerous previous investigations of specific pharmacologic agents in this setting ( Table 25.3 ). The failure to discern any single compound that might protect the brain is not unique to cardiac surgery. With the exception of thrombolysis, there are no other therapies in the general medical field either.

Early Acute Kidney Injury Biomarkers

Beyond serum creatinine, the race is on to identify one or more “early biomarkers” for AKI. As a condition whose treatment paradigm demands prompt intervention, AKI currently has no equivalents to CK-MB, troponin, and the ST segment for the heart.

While only a few new early biomarker candidates involve a substitute “ideal” creatinine, most involve one of three other early consequences of AKI: tubular cell damage, tubular cell dysfunction, and the adaptive stress response of the kidney. For example, damaged renal cells leak contents directly into urine; this strategy underpins tubular enzymuria AKI biomarkers, including β- N -acetyl-β- d -glucosaminidase and at least eight other candidates. Monitoring markers of the kidney’s stress response provides another strategy for AKI recognition, including some frontrunners; these include neutrophil gelatinase-associated lipocalcin, urinary IL-18, and at least three other candidates. Simple urinary partial pressure of oxygen (P o ₂ ) monitoring correlates with changes in renal medullary oxygen levels and predicts subsequent AKI in cardiac surgery patients.

Several large prospective observational studies are currently under way that may help identify the winner(s) of the early AKI biomarker race. It will be important for surgical and anesthesia advocates to highlight AKI biomarker issues unique to cardiac surgery lest these be overlooked in the broader pursuit of consensus AKI definitions.

Cardiopulmonary Bypass Management and the Kidney

Basic issues in the management of CPB that relate to the kidney involve the balance between oxygen supply and oxygen demand, particularly to the renal medulla. Perfusion pressure (ie, MAP during CPB) and oxygen-carrying capacity (as related to hemodilution and transfusion) address the supply issues, with the use of hypothermia being directed at modulating renal oxygen demand.

Profound hypothermia is a highly effective component of the protective strategy used during renal transplantation. Mild hypothermia during CPB would, therefore, seem to be a logical component of a perioperative renal protective strategy. However, threeseparate studies have not found any protective benefit of mild hypothermia duringCPB.

Low CPB blood pressure is typically not associated with the hypoperfusion characteristic of hypovolemic shock and LCOS, conditions that are highly associated with AKI. Studies addressing the role of perfusion pressure have not shown an association with AKI. Interestingly, some data are emerging on the interrelationship between cerebral autoregulatory limits (ie, defining individual blood pressure targets) and AKI after cardiac surgery.

Moderate hemodilution is thought to reduce the risk of kidney injury during cardiac surgery through blood viscosity–related improvement in regional blood flow. However, the practice of extreme hemodilution (hematocrit <20%) during CPB has been linked to adverse renal outcome after cardiac surgery. Studies suggest that profound hematocrit change (eg, >50% drop) may be even less well tolerated, highlighting the importance of a clinical strategy including transfusion only after all measures of hemodilution avoidance have been taken.

Glycemic control during CPB has been identified as a potential opportunity to attenuate AKI. Despite widespread adoption of intensive insulin protocols, numerous subsequent studies have failed to reproduce Van den Berghe’s findings of benefit. In a study combining Van den Berghe–like postoperative management of 400 cardiac surgery patients randomized to intensive intraoperative insulin therapy (target 80–100 mg/dL) versus usual management, Gandhi and associates found no benefit and similar dialysis rates (6/199 vs 4/201; P = .54), even noting an unexpected increase in 30-day mortality and stroke with tight control.

Pharmacologic Intervention

There is very little in terms of interventions available to the clinician to prevent or treat established perioperative AKI pharmacologically. Proposed changes to improve the likelihood of success in finding renoprotective strategies have included increasing the size of studies designed to see benefit should it be present and, as outlined earlier, improving timely AKI detection to allow earlier intervention.

Unfortunately, because of the limitations of current research tools, most potential renoprotective therapies have not been subjected to the rigor of a large randomized trial or even meta-analysis, and none has been given the opportunity to be used immediately after the onset of AKI. Additional data, including rationale and existing studies for a number of these therapies, is outlined next.