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 al³⁸ 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 al⁷¹ 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

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

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 studies¹³⁸ 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

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

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 al⁵⁹ 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 al¹⁸² 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 al¹⁸⁷ 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 al¹⁹¹ 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

In addition to the improvements in CPB technology, knowledge of the molecular workings of the brain has improved significantly, revealing potential pharmacologic neuroprotective targets. The oversimplified concept that depletion of high-energy phosphates and destruction of brain tissue rapidly follow ischemia has been replaced by a considerably more complex temporal, topographic, and biochemical picture. Advanced imaging techniques have discovered spatial gradations of residual CBF in the downstream territory of an occluded cerebral vessel, producing an ischemic penumbra, in which CBF is critically reduced but still sufficient to prevent immediate cell death. There is a marked difference in the temporal association between the ischemic insult and eventual cell death, resulting in a therapeutic window in which intervention (particularly pharmacologic) may attenuate infarct size. This window differs between the profoundly ischemic core and the penumbra. In the ischemic core, restoration of oxygen and glucose supplies is essential where high-energy phosphates have been severely depleted. In contrast, in the penumbra, the decreases in oxygen and glucose delivery are insufficient to kill cells directly. In these regions, pharmacologic agents with little or no ability to modify CBF have been shown experimentally to effectively reduce cerebral infarct volume, even if administered after the onset of permanent focal ischemia.

The CNS ischemic cascade (Figure 28-6) is triggered by reductions in CBF, globally or regionally, to the point at which the demands of cerebral metabolism can no longer be met.¹⁹⁵ This depletion in cerebral energy stores leads to membrane ionic pump failure, resulting in a number of injurious events mediated by the influx of sodium, the opening of voltage-dependent calcium gates, a release of stored intracellular calcium, and overall membrane depolarization. Membrane depolarization results in the release of excitatory amino acids (e.g., glutamate, aspartate), with subsequent dramatic increases in intra-cellular calcium. This increase in cytoplasmic calcium propagates the cascade through the activation of a number of calcium-dependent enzymes, including endonucleases, NO synthase, various proteases, protein kinases, and phospholipases. If left unabated, these enzymes will result in neuronal death.

Figure 28-6 Cerebral ischemic cascade.

A simplified overview of central nervous system events that occur after energy failure in the ischemic brain. NO, nitric oxide.

(From Dirnagl U, Iadecola C, Moskowitz M: Pathobiology of ischemic stroke: An integrated review. Trends Neurosci 22:391, 1999.)

Although some of these events are potentially reversible if reperfusion is quickly reestablished, reperfusion itself initiates a number of other destructive pathways. The reestablishment of oxygen delivery provides substrate for the production of reactive oxygen species, so-called free radicals. Reperfusion initiates a number of other damaging extracellular events, including BBB breakdown, endothelial swelling, and localized thrombosis that together may culminate in microvascular occlusion and further ischemia. Each of these pathways in the ischemic cascade represents discrete groups of potential targets for neuroprotection. The ischemic cascade has formed the basis for the initiation of pharmacologic neuroprotective strategies in the setting of overt stroke and of cardiac surgery-related cerebral injury.

No pharmacologic therapies have been approved by the U.S. 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 28-6). This has not stopped progress, however, with multiple clinical trials ongoing. The most relevant cardiac surgery pharmacologic neuroprotection strategies, past and present, are reviewed here.

TABLE 28-6 Agents Studied as Pharmacologic Neuroprotectants during Cardiac Surgery

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.

The search for better early AKI biomarkers currently involves several contenders involving numerous physiologic mechanisms (Table 28-7). Markers such as creatinine and cystatin C that accumulate to diagnostic levels because of decreased clearance are further challenged during the perioperative period because of “signal-to-noise” confounders, such as hemodilution, which complicate early AKI recognition by disrupting steady-state assumptions. Although 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 lipocalin, urinary IL-18, and at least three other candidates. Simple urinary Po₂ monitoring correlates with changes in renal medullary oxygen levels and predicts subsequent AKI in cardiac surgery patients.

TABLE 28-7 Early Acute Kidney Injury Biomarkers

Composition of Cardioplegia Solutions

The composition of the various cardioplegia solutions used during cardiac surgery varies as much between institutions as it does between individual surgeons. In general terms, cardioplegia can be classified into blood-containing and nonblood-containing (i.e., crystalloid) solutions. Crystalloid cardioplegia has fallen out of favor, with blood cardioplegia in various combinations of temperatures and routes of delivery being the most used solution. However, even within the category of blood cardioplegia, the individual chemical constituents of the solution vary considerably with respect to the addition of numerous additives. Table 28-9 outlines the various additives to cardioplegia solutions together with their corresponding rationale for use. Although all cardioplegia solutions contain greater than physiologic levels of potassium, solutions used for the induction of diastolic arrest contain the greatest concentrations of potassium as opposed to solutions used for the maintenance of cardioplegia. In addition to adjustment of electrolytes, manipulation of buffers (e.g., bicarbonate, tromethamine), osmotic agents (e.g., glucose, mannitol, potassium), and metabolic substrates (e.g., glucose, glutamate, and aspartate) constitute the most common variations in cardioplegia content. Oxygenation of crystalloid cardioplegia before infusion is aimed at increasing aerobic metabolism, but the limited oxygen-carrying capacity of crystalloid makes a rapid decline in metabolic rate through immediate and sustained diastolic arrest critical to effective cardioprotection with this technique.

TABLE 28-9 Strategies for the Reduction of Ischemic Injury with Cardioplegia

From Vinten-Johansen J, Thourani VH: Myocardial protection: An overview. J Extra Corpor Technol 32:38, 2000.

Blood cardioplegia has the potential advantage of delivering sufficient oxygen to ischemic myocardium to sustain basal metabolism or even augment high-energy phosphate stores, as well as possessing free radical scavenging properties.⁴⁸⁵ The introduction of blood cardioplegia in the late 1970s followed recognition of the clinical utility of this technique.⁴⁸⁶ Although low-risk cardiac surgical patients appear to do equally well with crystalloid or blood cardioplegic protection, evidence is compelling that more critically ill patients, including those with “energy-depleted” hearts (e.g., cardiogenic shock, AMI before CPB), have improved outcomes using blood cardioplegia.^487,488 Patients at high risk also appear to have better recovery using a combination of antegrade and retrograde blood cardioplegia delivery, when compared with antegrade administration alone.⁴⁸⁸

Because an infusion of oxygenated blood cardioplegia is in many ways similar to myocardial reperfusion, it is not surprising that the composition of blood cardioplegia is based on reperfusate parameters known to minimize myocardial stunning.^489,490 These parameters include maintenance of Ca²⁺ at 1.0 mEq/L (by chelating Ca²⁺ from perfusate blood) to diminish myocyte Ca²⁺ uptake; pH between 7.6 and 7.8 (the pH of water in the hypothermic temperature range used); osmolality between 340 and 360 mOsm to minimize edema-related myocardial dysfunction after reperfusion; and hyperkalemia between 10 and 25 mEq/L to safely sustain electromechanical arrest. Blood is mixed in a ratio of 4:1 with a prepared crystalloid solution to create blood cardioplegia with these characteristics.

Infusion of a single, warm (37° C) reperfusion dose of cardioplegia (so-called hot shot) containing metabolic substrates (i.e., glucose, glutamate, and aspartate) just before aortic cross-clamp removal is preferred by some clinicians. The rationale for this is evidence that normothermia maximally enhances myocardial aerobic metabolism and recovery after an ischemic period. Although some have advocated continuous infusion of hyperkalemic warm cardioplegia throughout the period of aortic cross-clamping,⁴⁹¹ this technique has not gained wide popularity for CABG because of the technical challenges of grafting vessels perfused in this way and the threat of ischemia to nonperfused (warm) myocardium during grafting.

Numerous other cardioplegia additives continue to be assessed involving various buffers, osmotic agents, metabolites, ATP and precursors, enzymes controlling ATP synthesis and catabolism, oxygen radical scavengers and antioxidants. Protection of myocardial β-adrenergic receptor function using intracoronary administration of esmolol appears to hold promise as an alternate cardioprotective method.⁴⁹² Alternative cardioplegia strategies potentially extending safe ischemic periods for heart transplantation to up to 24 hours also are being evaluated.^493–495

Cardioplegia Temperature

The composition of cardioplegia solutions varies considerably; in contrast, myocardial temperature during cardioplegia is almost uniformly reduced to between 8° C and 10° C or less by the infusion of refrigerated cardioplegia and external topical cooling with ice slush. However, the introduction of warm cardioplegia has challenged the once universally accepted necessity of hypothermia for successful myocardial protection.¹⁵⁶ Although hypothermic cardioplegia is the most commonly used, numerous investigations have examined tepid (27° C to 30° C) and warm (37° C to 38° C) temperature ranges for the administration of cardioplegia. Much of the work aimed at determining the optimum temperature of the cardioplegia solution centered on the fact that, although hypothermia clearly offered some advantages to the myocardium in suppressing metabolism (particularly when intermittent cardioplegia was delivered), it may have some detrimental effects.

The deleterious effects of hypothermia include the increased risk for myocardial edema (through ion pump activity inhibition) and the impaired function of various membrane receptors on which some pharmacologic therapy depends (such as the various additives to the cardioplegia solutions). The other disadvantages of hypothermic cardioplegia, in addition to the production of the metabolic inhibition in the myocardium, are an increase in plasma viscosity and a decrease in RBC deformability.^157,482,496 As a result, investigations aimed at using warmer cardioplegia temperatures have been conducted.^156,497 During the initial phase of cardioplegia delivery, hypothermic temperatures, in addition to inhibiting some of the needed drug-receptor interactions, fail to optimize the metabolic rate in the myocardium. Hypothermia results in a leftward shift in the oxygen hemoglobin dissociation curve, inhibiting the release of oxygen into tissues. The myocardium is relatively ischemic during this initial induction phase of cardioplegia, with the uptake of the oxygen to this tissue being low and, as a result, significant oxygen debt occurs.

The adverse effects of hypothermia spawned interest in using warm cardioplegia. With the warm induction of cardiac arrest, metabolic activity is maintained, ion exchanges through cellular membranes are maintained, intracellular acidosis occurring with hypothermia is eliminated, oxygen delivery is optimized by maintaining a near-normal hemoglobin-oxygen dissociation curve, hypothermia-induced changes in viscosity and blood rheology are avoided, and RBC deformability and resulting flow through the myocardial microvasculature are maintained. The principal differences in cold versus warm cardioplegia result from the timing and route of delivery. If the myocardium is maintained at normothermic temperature, continuous cardioplegia must be delivered to adequately supply substrate to the metabolically active myocardium. In most cases, this is done using continuous retrograde cardioplegia (discussed later).

A compromise temperature (tepid, 27° C to 30° C) also has been proposed.⁴⁹⁷ Ikonomidis et al⁴⁹⁷ compared outcomes for patients receiving warm, tepid, or cold cardioplegia. Although numerous differences were found among the various groups, the recovery of LV stroke work at 1 and 4 hours after surgery was optimal in the tepid group. The researchers concluded that tepid cardioplegia provided better overall protection with superior functional recovery.⁴⁹⁸ Hayashida et al⁴⁹⁸ conducted a randomized trial comparing the effects of cold (9° C), tepid (29° C), and warm (37° C) cardioplegia in 42 patients undergoing CABG surgery. Overall, the investigators found that Mvo₂ and lactate production were greatest in the warm group, intermediate in the tepid group, and least in the cold cardioplegia group. However, early postoperative LV function was optimized in the tepid cardioplegia group.⁴⁹⁸

Cardioplegia Delivery Routes

If using tepid or warm cardioplegia administration, the continuous administration of this cardioplegia needs to be ensured. Retrograde cardioplegia, in which a cardioplegia catheter is introduced into the coronary sinus, allows for almost continuous cardioplegia administration. Retrograde delivery is also useful in settings in which antegrade cardioplegia is problematic, such as with severe aortic insufficiency or during aortic root or aortic valve (and, frequently, mitral) surgery. It also allows the distribution of cardioplegia to areas of myocardium supplied by significantly stenosed coronary vessels. Retrograde cardioplegia has proved safe and effective for cardioplegia in patients with CAD and in those undergoing valve surgery.^499,500 With the administration of retrograde cardioplegia, certain provisos should be considered. The acceptable perfusion pressure to limit perivascular edema and hemorrhage needs to be limited to less than 40 mm Hg.⁵⁰¹

Two trials added information about cardioplegia routes of delivery. The CABG patch trial⁵⁰² enrolled high-risk CAD patients with impaired LV function and demonstrated the superiority of the combined antegrade and retrograde delivery of blood cardioplegia compared with antegrade cardioplegia alone. The limitation of this trial was that the antegrade group received crystalloid cardioplegia (as opposed to blood cardioplegia in the antegrade-retrograde group), raising questions about whether the differences in the groups were seen because of the route of administration or the constituents of the cardioplegia itself. A second trial failed to demonstrate any differences when the administration of intermittent antegrade cold blood cardioplegia was compared with a group receiving antegrade cold blood cardioplegia induction followed by retrograde cold blood maintenance for valve surgery.⁵⁰³ They did find that the antegrade-retrograde approach was technically more convenient, allowing for shorter aortic cross-clamp times.

Retrograde cardioplegia does have some limitations. Although the retrograde approach has been shown to effectively deliver cardioplegia adequately to the left ventricle, because of shunting and blood flowing into the atrium and ventricles by the thebesian veins and various arteriosinusoidal connections, the right ventricle and septum frequently receive inadequate delivery of cardioplegia. Difficulties with retrograde delivery also can occur if the coronary sinus catheter is placed beyond the great cardiac vein, or if anatomic variants occur that communicate with systemic veins, such as a persistent left superior vena cava (SVC).^501,504,505 Because retrograde cardioplegia is inefficient in producing arrest of the beating heart, induction of arrest with this technique must be achieved by a single antegrade infusion of cardioplegia before its institution (Box 28-3; see Chapter 29).

Ischemic Preconditioning

Myocardial stunning during cardiac surgery is affected by several parameters. The preischemic state of the myocardium can influence the degree of stunning that follows an ischemic event. Ischemic preconditioning (IPC) is endogenous myocardial protection triggered by exposure to brief (5 to 15 minutes) periods of ischemia. IPC is a natural defense mechanism that permits the heart to better tolerate myocardial ischemia. Although brief ischemic episodes in themselves result in stunning, they also build up a temporary resistance to the adverse effects of subsequent more prolonged ischemia.^506,507 IPC has been well described experimentally.^508–510 Several proposed mechanisms are responsible for IPC, including the activation of several myocardial G protein–coupled receptors, most notably A₁ adenosine and α₁-adrenergic receptors.⁵¹¹ Protein kinase C appears to be a key cellular mediator of IPC, in part through activation of ATP-sensitive potassium channels.⁵¹²

Myocardial protection strategies continue to be an active area of investigation, including assessment of IPC. Attempts to induce IPC by brief ischemia or pharmacologic means before CPB have been assessed in human cardiac surgical patients. Sevoflurane, a frequently used volatile anesthetic, has been demonstrated to pharmacologically replicate IPC.⁵¹³ Administration of adenosine, before bypass or in cardioplegic solutions, has been studied as a pharmacologic means to induce IPC. It has been associated with reduced postoperative myocardial injury, reduced inotropic requirements, and improved myocardial recovery.^514,515 The potential for myocardial stunning after beating heart OPCAB has not been fully assessed. Intermittent coronary occlusion before OPCAB to induce IPC, although unclear as to its effect, has also undergone clinical assessment.⁵¹⁶ (See Chapter 9.)

Cardiopulmonary Bypass Management

Because CPB itself has been shown to impair splanchnic blood flow, modifications in how it is conducted may have some salutary effects on GI tract integrity. Several studies have focused on the issue of the relative importance of pressure versus flow during CPB, demonstrating that it is likely more beneficial to maintain an adequate bypass flow rate than only maintaining pressure during bypass.^545–547 The addition of significant vasoconstrictors to artificially maintain an adequate MAP in the presence of inadequate flow on CPB may lead to further compromise of splanchnic blood flow. Few definitive data offer guidance about pulsatility. Some studies have shown improvements with pulsatility by indirect measurements (i.e., gastric mucosal intracellular pH), but no studies have found definitive differences in clinical outcomes. Similarly, the optimal bypass temperature to protect the gut also is unknown. Just as aggressive rewarming can be injurious to the brain,⁶³ there is some evidence that rewarming can cause increases in visceral metabolism, making any overshoot in temperature suspect by adversely altering the balance of gut oxygen consumption and delivery.⁵⁴⁸

Emboli Reduction

Whereas microembolization and macroembolization to the splanchnic bed clearly occur during CPB and possibly even during the postbypass period, there are few data to determine whether emboli reduction strategies can alter GI outcome. Mythen et al⁵⁴⁹ found a relation between transcranial Doppler–detected emboli (used as a surrogate for overall microembolic load within the body) and adverse changes in gastric mucosal intracellular pH. However, with respect to microembolization, a trial that used an intra-aortic filter to reduce atheroemboli failed to have any influence on the rate of GI complications.⁹⁹ It remains prudent to avoid maneuvers (i.e., aortic cannulation and cross-clamping) in areas of high atheroma burden, which is an overall tenet of cardiac surgery for the prevention of all other complications.

Drugs

A range of vasoactive drugs has been used to enhance splanchnic blood flow during CPB. It is likely that most of these drugs, such as the phosphodiesterase III inhibitors, dobutamine, and other inotropic agents, maintain or enhance splanchnic blood flow not because of a direct effect on the vasculature but by the inherent enhancement in cardiac output. Dobutamine and dopamine have had a paradoxic detrimental effect on the splanchnic vasculature, with some evidence that they cause further mucosal ischemia.^550,551 Dopexamine also has been studied in a small group that did show an improvement in mucosal blood flow (using laser–Doppler flowmetry), but there was no beneficial effect on gastric mucosal intracellular pH.⁵⁵² An increasingly common drug in the setting of cardiac surgery is vasopressin. Although vasopressin clearly can augment systemic MAP, it does so at the cost of severe impairments to splanchnic blood flow.⁵⁵³ Although there are always trade-offs when choosing which vasoactive agent to use, if having a very low MAP is going to be detrimental to other organ systems, the choice to use vasopressin should at least be made with the knowledge that it can have an adverse effect on splanchnic blood flow.

Selective Gastrointestinal Decontamination

Addressing the concept that gut translocation of endotoxin plays a role in inflammation and other organ injuries, one interesting therapy that has been tried in the setting of cardiac surgery involves the administration of oral antibiotics to selectively decontaminate the GI tract before surgery.⁵⁵⁴ Although examined in a small (N = 100) study, a combination of oral polymyxin, tobramycin, and amphotericin before surgery for 3 days reduced the degree of endotoxemia, it was not associated with a beneficial effect on patient outcomes. One possible explanation is that there is such an overwhelmingly large depot of gram-negative organisms in the GI tract that the elimination of even a large population of these by oral antibiotics still leaves significant repositories of endotoxin in the gut. Killing these bacteria may in itself cause the release of the endotoxin, which can then be absorbed into the systemic circulation by impairment of mucosal blood flow inherent in the unphysiologic flow during CPB.

Off-Pump Cardiac Surgery

There is little evidence that the use of off-pump cardiac surgery is in any way beneficial to the GI tract. Three retrospective studies^525,533,555 have shown no differences in GI complications. One reason for this lack of apparent difference between on-pump and off-pump cardiac surgery may again be related to the common denominator of splanchnic perfusion. OPCAB surgery is fraught with hemodynamic compromise that may lead to prolonged periods of splanchnic hypoperfusion by itself or as a result of the concurrent administration of vasopressors to maintain normal hemodynamics during the frequent manipulations of the heart.

Anti-inflammatory Therapies

Although the inflammatory response to CPB has been implicated as a causative factor in GI complications after cardiac surgery, few data are available to assess the ability of various anti-inflammatory therapies (e.g., corticosteroids, aprotinin, complement inhibitors) to reduce these types of complications.

Ventilatory Strategies

Several studies have examined the use of continuous positive airway pressure during CPB as a means to minimize the decrement in the A-a Do₂ gradient that can occur after surgery. In a small study by Gilbert et al,⁵⁹⁶ the effect of continuous positive airway pressure was examined in a randomized trial of 18 patients undergoing CABG surgery with CPB. Continuous positive airway pressure did not appear to make any difference with respect to changes in measured lung resistance and elastance. In a larger (N = 61) study by Berry et al,⁵⁹⁷ continuous positive airway pressure did appear to have some transient beneficial effects on A-a Do₂; however, these minor differences dissipated 4 hours after bypass. Overall, it is unlikely that continuous positive airway pressure plays any major role in preventing or treating the pulmonary dysfunction that occurs in the setting of cardiac surgery.

The inspired oxygen content of the gases that the lungs see during the period of apnea during CPB may have an effect on the A-a Do₂ gradient, probably because of the enhanced effect of greater Fio₂ on the atelectasis (so-called absorption atelectasis). With these findings in mind, it would be prudent to reduce the Fio₂ to room air levels during CPB. Several simple therapies can be introduced before separation from CPB, including adequate tracheobronchial toilet and the delivery of several vital capacity breaths that may reduce the amount of atelectasis that has occurred during CPB⁵⁶⁸ (Box 28-5; see Chapter 35).

Ventilatory support of patients with acute lung injury (including ARDS) has undergone changes.^598,599 Although not studied specifically in the setting of cardiac surgery, a study authored by the Acute Respiratory Distress Syndrome network highlighted the avoidance of ventilator-associated pulmonary mechanotrauma.⁵⁹⁹ Delivery of repeated large tidal volumes may damage the alveoli and other small lung structures, and these mechanical stresses may activate a pulmonary inflammatory response with a local release of cytokines, further enhancing injury to the lungs. As a result, these groups of investigators randomized patients to small (approximately 6 mL/kg) or traditional tidal volumes (12 mL/kg). They demonstrated that the low tidal volume ventilation strategy could reduce mortality in patients with ARDS by up to 25%. It would be prudent to use this beneficial ventilator strategy in the cardiac surgical patient presenting with significant acute lung injury.

Pharmacologic Pulmonary Protection

Arterial Cannulation

Arterial cannulation generally is established before venous cannulation to allow volume resuscitation of the patient, should it be necessary. The ascending aorta is the preferred site for aortic cannulation because it is easily accessible, does not require an additional incision, accommodates a larger cannula to provide greater flow at a reduced pressure, and carries a lower risk for aortic dissection compared with other arterial cannulation sites (femoral or iliac arteries). Because hypertension increases the risk for aortic dissection during cannulation, the aortic pressure may be temporarily reduced (MAP < 70 mm Hg) during aortotomy and cannula insertion. Several potential complications are associated with aortic cannulation including embolization of air or atheromatous debris, inadvertent cannulation of aortic arch vessels, aortic dissection, and other vessel wall injury.^615–620

Reviews and clinical reports emphasize the importance of embolization as the major mechanism of focal cerebral injury in cardiac surgery patients. Barzilai et al⁶²¹ and Wareing et al⁶¹⁶ reported intraoperative use of two-dimensional epiaortic ultrasound imaging as a guide to selection of cross-clamping and cannulation sites. In 24% and 33% of the patients in these studies, respectively, ultrasonic findings led to selection of alternate cannulation sites. A femoral or axillary artery, rather than the ascending aorta, can be cannulated for systemic perfusion. These alternate sites can be used when ascending aortic cannulation is considered relatively contraindicated, as in severe aortic atherosclerosis, aortic aneurysm or dissection, or known cystic medial necrosis.^{8,118,622,623} The anesthesiologist can look for evidence of cannula malposition by checking for unilateral blanching of the face, gently palpating carotid artery pulses for new unilateral diminution, and by measuring blood pressure in both arms to check for new asymmetries. However, robust assessments of CBFs can be made more reliably with the use of near-infrared spectroscopy cerebral oximetry (see Chapter 16).

Venous Cannulation

Venous cannulation can be achieved using a single atrial cannula that is inserted into the right atrium and directed inferiorly (Figure 28-11). Drainage holes in this multistage cannula are located in the inferior vena cava (IVC) and right atrium to drain blood returning from the lower extremities and the SVC and coronary sinus, respectively. This technique has the advantage of being simpler, faster, and requiring only one incision; however, the quality of drainage can be compromised easily when the heart is lifted for surgical exposure.⁶²⁴ The bicaval cannulation technique, required in cases in which right atrial access is necessary, involves cannulating the SVC and IVC (Figure 28-12). Loops placed around the vessels can be tightened to divert all caval blood flow away from the heart. Blood returning to the right atrium from the coronary sinus will not be drained using this technique, so an additional vent or atriotomy is necessary.

Figure 28-11 Aortic (Ao) and single, double-staged, right atrial (RA) cannulation.

Notice the drainage holes of venous cannula in right atrium and inferior vena cava.

(From Connolly MW: Cardiopulmonary Bypass. New York, Springer-Verlag, 1995, p 59.)

Figure 28-12 Position of two-vessel cannulation of right atrium (RA) with placement of drainage holes into superior vena cava (SVC) and inferior vena cava (IVC). The aortic cannula is not shown.

(From Connolly MW: Cardiopulmonary Bypass. New York, Springer-Verlag, 1995, p 59.)

During CPB, blood will continue to return to the left ventricle from a variety of sources, including the bronchial and thebesian veins, as well as blood that traverses the pulmonary circulation. Abnormal sources of venous blood include a persistent left SVC, systemic-to-pulmonary shunts, and aortic regurgitation. It is important to avoid LV filling and distention during CPB to prevent myocardial rewarming, minimize LV wall tension, and limit myocardial oxygen demand.⁶²⁵ This can be accomplished with the use of a vent placed in the left ventricle via the left superior pulmonary vein. Alternate sites include the pulmonary artery, the aortic root, or directly into the left ventricle via the ventricular apex.

Venous cannulae, using a multistage or bicaval cannula, are large and can impair venous return from the IVC or SVC. Superior vena caval obstruction is detected by venous engorgement of the head and neck, conjunctival edema, and increased SVC pressure. IVC obstruction is far more insidious, presenting only as decreased filling pressures and lowered venous return to the bypass circuit.

Femoral venous cannulation is sometimes used for CPB without, or before, sternotomy or right atrial cannulation (e.g., redos, ascending aortic aneurysms). Because of their comparatively small size and long length, venous return can be impaired but is optimized when the tip of the cannula is advanced (under TEE guidance) until it is placed at the level of the vena cava-right atrium junction. Kinetic or vacuum-assisted negative pressure can be applied to further enhance drainage.

Uncomplicated Initiation

Once all preparatory steps have been taken, the perfusionist progressively increases delivery of oxygenated blood to the patient’s arterial system, as systemic venous blood is diverted from the patient’s right side of the heart, maintaining the pump’s venous reservoir volume. After full flow is achieved, all systemic venous blood is (ideally) drained from the patient to the pump reservoir. An on-CPB checklist of issues to address shortly after initiation of bypass can serve as a valuable safety tool (Table 28-13). The central venous pressure (CVP) and pulmonary arterial pressure should decrease to near zero (2 to 5 mm Hg), whereas systemic flow, arterial pressure, and oxygenation are maintained at desired values.

TABLE 28-13 Checklist for Bypass Procedure