Stroke is better characterized with respect to risk factors. Although studies differ somewhat as to all the risk factors, certain patient characteristics consistently correlate with an increased risk for cardiac surgery–associated neurologic injury. In a study of 2108 patients from 24 centers in a study conducted by the Multicenter Study of Perioperative Ischemia, incidence of adverse cerebral outcome after CABG surgery was determined and the risk factors analyzed.² Two types of adverse cerebral outcomes were defined. Type I included nonfatal stroke, transient ischemic attack (TIA), stupor or coma at time of discharge, and death caused by stroke or hypoxic encephalopathy. Type II included new deterioration in intellectual function, confusion, agitation, disorientation, and memory deficit without evidence of focal injury. A total of 129 (6.1%) of the 2108 patients had an adverse cerebral outcome in the perioperative period. Type I outcomes occurred in 66 (3.1%) of 2108 patients, with type II outcomes occurring in 63 (3.0%) of 2108 patients. Stepwise logistic regression analysis identified eight independent predictors of type I outcomes and seven independent predictors of type II outcomes (Table 23-1).

Table 23-1 Risk Factors for Adverse Cerebral Outcomes after Cardiac Surgery

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

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

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

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

Of all the factors in the Multicenter Study of Perioperative Ischemia analysis, age appears to be the most overwhelmingly robust predictor of stroke and of neurocognitive dysfunction after cardiac surgery. Age has a greater impact on neurologic outcome than it does on perioperative myocardial infarction or low cardiac output states after cardiac surgery (Fig. 23-1).

Figure 23-1 The relative effect of age on the predicted probability of neurologic and cardiac morbidity after cardiac surgery.

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

Atheromatous disease of the ascending, arch, and descending thoracic aorta has been consistently implicated as a risk factor for stroke in cardiac surgical patients. The increased use of transesophageal echocardiography (TEE) and epiaortic ultrasonography has added new dimensions to the detection of aortic atheromatous disease and the understanding of its relation to stroke risk. These imaging modalities have allowed the diagnosis of atheromatous disease to be made in a more sensitive and detailed manner, contributing greatly to the information regarding potential stroke risk. Studies have consistently reported higher stroke rates for patients with increasing atheromatous aortic involvement (particularly the ascending and arch segments). This relationship is outlined in Figure 23-2.

Figure 23-2 Stroke rate 1 week after cardiac surgery as a function of atheroma severity. Atheroma was graded by transesophageal echocardiography as follows: I, normal; II, intimal thickening; III, plaque < 5 mm thick; IV, plaque > 5 mm thick; V, any plaque with a mobile segment.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

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

Cause of Perioperative Central Nervous System Injury

Because central nervous system dysfunction represents a wide range of injuries, differentiating the individual causes of these different types of injuries becomes somewhat difficult (Box 23-1). They are frequently grouped together and superficially discussed as representing different severities on a continuum of similar injury. This likely misrepresents the different causes of these injuries. The following section addresses stroke and cognitive injury (Table 23-2).

BOX 23-1 Causes of Central Nervous System Complications after Cardiopulmonary Bypass

• Cerebral emboli

• Global hypoperfusion

• Inflammation

• Cerebral edema

• Cerebral hyperthermia

Table 23-2 Causes of Cognitive Dysfunction after Cardiac Surgery

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

Neuroprotective Strategies

Emboli Reduction

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 distal aortic cannula, where the tip of the cannula lies beyond the origin of the cerebral vessels has also been found to reduce emboli load.

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.

Management of Aortic Atherosclerosis

A combination of epiaortic scanning and atheroma avoidance techniques (with respect to cannulation, clamping, and vein graft anastomosis placement) have been used to attempt to reduce neurocognitive deficits.⁴ The incidence of cognitive decline may be lower in patients who had an avoidance technique guided by epiaortic scanning compared with no epiaortic scanning. It is an area that requires more investigation. 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 historical controls. 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. Alternative aortic cannulas and using different locations possess the ability to decrease embolization of atheromatous plaque. The avoidance of partial occlusion clamping for proximal vein graft anastomosis using a single-step automated anastomotic device and the use of alternatives to cross-clamping all possess the ability to mitigate injury due to embolization.

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

Optimal acid-base management during CPB has long been debated. Theoretically, α-stat management maintains normal CBF autoregulation with the coupling of cerebral metabolism (CMRO₂) to CBF, allowing adequate oxygen delivery while minimizing the potential for emboli. Although early studies 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 (i.e., CO₂ is added to the fresh oxygenator 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 due to its improvement in homogenous brain cooling before circulatory arrest, adult outcome data support the use of α-stat management.⁵

Mean Arterial Pressure Management during Cardiopulmonary Bypass

Although the data associating MAP with neurologic and neurocognitive outcome after CABG surgery are inconclusive, most data suggest that MAP during CPB is not a 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.

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 have on anaerobic conversion of glucose to lactate, which ultimately cause intracellular acidosis and impair 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. Chaney and associates ⁶ 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 is often resistant and may actually predispose to postoperative hypoglycemia. Attempting to mediate injury may actually predispose to additional injury.

Off-Pump Cardiac Surgery

Off-pump coronary artery bypass grafting (OPCAB) is frequently used for the operative treatment of coronary artery disease. Some preliminary data suggest less cognitive decline after OPCAB procedures, but most studies have not seen it eliminated altogether. The reasons for this are unclear but likely reflect on 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.

ACUTE RENAL INJURY

Despite the recognition, made more than 40 years ago, of acute renal injury as a serious complication of cardiac surgery, postoperative renal dysfunction persists today as an independent predictor of postoperative mortality. Even during procedures where there is no evidence of acute renal injury as reflected by a rise in serum creatinine, more subtle markers have demonstrated renal tubular injury. Patients with increasing degrees of acute renal injury after cardiac surgery require disproportionately more short- and long-term resources and have increasingly poorer outcome and greater costs.⁷ The association of acute renal dysfunction with mortality and major morbidity may reflect its role as a marker of, rather than as a contributor to, the insult of cardiac surgery; however, there is compelling evidence that acute renal injury itself also contributes directly to adverse outcome. Accumulation of “uremic toxins” and release of inflammatory mediators from the injured kidney also appear to contribute significantly to remote organ dysfunction.

Incidence and Significance

Definitions and the incidence of renal injury vary, with approximately 8% to 15% of cardiac surgery patients sustaining a moderate renal injury (defined by a peak rise in the serum creatinine level of more than 1.0 mg/dL) and 1% to 5% requiring dialysis. Each type of cardiac surgical procedure has its own specific pattern of renal injury. As a result, surgical procedure type is an important variable when examining the incidence and severity of postoperative acute renal injury. For example, elevation of the serum creatinine level, a common marker of acute renal injury, typically peaks on the second day after CABG with CPB and, in most cases, returns to baseline by postoperative day 4 or 5.⁸

In-hospital mortality rates for CABG range from less than 1% for patients with subclinical renal injury to 20% for those with moderate renal injury, and rates exceed 60% when dialysis is required. Survivors of significant postoperative renal injury have higher in-hospital resource use. In addition to the direct relationship with renal injury of morbidity, mortality, and perioperative cost, intensive care unit stays are up to five to six times longer and overall hospital length of stay increases approximately three times. Patients with renal dysfunction are also more likely to be discharged to an extended-care facility, with its own associated costs. Accelerated long-term decline of renal function after cardiac surgery may lead to later end-stage renal disease.

Risk Factors for Surgery-Related Acute Renal Injury

Numerous studies have characterized risk factors for nephropathy after cardiac surgery (Table 23-3). Preoperative variables are most useful for renal risk stratification with intraoperative and postoperative issues contributing to overall clinical management decisions. Equivalent renal injury for a patient with preoperative renal dysfunction does result in a greater rise in serum creatinine due to the nonlinear relationship between reductions in glomerular filtration rate (GFR) and creatinine rise. Even small amounts of additional renal impairment may lead to dialysis for a surgical patient with severe renal disease at baseline.

Table 23-3 Risk Factors for Renal Injury

Important Factors	Probably Not Important
Preoperative Factors
Advanced age	Gender
Obesity	Renal artery stenosis
Preexisting renal insufficiency
Diabetes
Hyperglycemia
Hypertension
Ascending aortic atherosclerosis
Peripheral vascular disease
IABP
COPD
Loop diuretic therapy
Corticosteroid therapy
Nephrotoxins (radiocontrast dye, cyclosporin, aminoglycosides, cephalosporins, NSAIDs)
Genetic variants
Intraoperative Factors
Aprotinin	Lysine analogs
Loop diuretic (increased risk)	Low-dose dopamine
Transfusion	Mannitol
Hyperglycemia
Procedure type (CABG < valve < HCA)
Emergency procedure
Reoperation
IABP
CPB management	CPB management
Extended CPB duration	Hypothermia
Hemodilution	Blood pressure management
Postoperative Factors
Low cardiac output
Excessive inotrope use
Prolonged ventilation
Transfusion
Sepsis
CMV infection

CABG = coronary artery bypass graft surgery; CPB = cardiopulmonary bypass; CMV = controlled mechanical ventilation; COPD = chronic obstructive pulmonary disease; HCA = hypothermic circulatory arrest; IABP = intra-aortic balloon pump; NSAIDs = nonsteroidal anti-inflammatory drugs.

Causes and Pathophysiology of Renal Injury

Ischemia-Reperfusion Injury

A long-standing assumption regarding the causes and pathophysiology of renal dysfunction after cardiac surgery is that hypoperfusion with resulting renal ischemia plays a central role (Box 23-2). This assumption is supported by an understanding of the precarious oxygen supply and demand physiology of the renal medulla, particularly during CPB, as well as the responsiveness of experimental acute renal injury to improved renal perfusion. However, clinically applied techniques directed at improving perfusion (e.g., including low-dose dopamine) and reducing oxygen consumption (e.g., loop diuretics) have been uniformly unsuccessful in cardiac surgical patients and in most other settings. Other risk factors supporting the ischemia-reperfusion hypothesis of acute renal injury and nephropathy after cardiac surgery include episodes of circulatory arrest and perioperative low cardiac output states and prolonged bypass duration.⁹

BOX 23-2 Causes of Renal Injury during Cardiopulmonary Bypass

• Emboli

• Renal ischemia

• Reperfusion injury

• Pigments, radiocontrast agents, aprotinin

Drug-Related Nephropathy

Several agent-specific nephrotoxicities are relevant to cardiac surgery. Cephalosporin-related renal injury to the proximal renal tubule has been reported. Aminoglycoside antibiotics also have a potent nephrotoxic effect. Nonsteroidal anti-inflammatory drug nephrotoxicity is thought to be related to renal vasoconstriction from inhibition of locally synthesized endogenous renal vasodilator prostaglandins. Radiocontrast agents have also been shown to adversely effect renal function.

Concern continues regarding the use of antifibrinolytic agents during cardiac surgery. Benign proximal tubule effects of lysine analog agents cause “tubular proteinuria” in cardiac surgery patients; however, no change in the incidence of acute renal injury has been documented in longitudinal studies examining institutional rates of renal injury before and after periods of ε-aminocaproic acid use.¹⁰ Aprotinin also interacts with the proximal renal tubule and is thought to saturate tubular transport mechanisms, resulting in tubular proteinuria. Aprotinin has been implicated in postoperative renal dysfunction after cardiac surgery.¹¹

Pigment Nephropathy: Hemoglobinuria and Myoglobinuria

Severe intravascular hemolysis leading to release of hemoglobin in amounts sufficient to exceed the absorptive capacity of circulating haptoglobin and the normal renal metabolic reserve can lead to hemoglobinuria and acute renal injury. The deterioration in kidney function appears to be the result of a combination of renal vasoconstriction, direct cytotoxicity, and tubular obstruction by casts.

Although free hemoglobin is often seen in the urine during and after cardiac surgery, particularly after prolonged CPB, the significance of hemoglobinuria as a contributor to nephropathy after cardiac surgery is unknown. Myoglobinuria can occur after femoral artery cannulation for CPB or IABP insertion if ipsilateral leg ischemia develops. Myoglobinuric acute renal failure has been reported after cardiac surgery with femoral artery cannulation, particularly in children. However, it is not clear that femoral artery cannulation is a concern for most patients.

Strategies for Renal Protection

Cardiopulmonary Bypass Management

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 (i.e., 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.

Pharmacologic Intervention

dopamine

Mesenteric dopamine-1 (D₁) receptor agonists increase renal blood flow, decrease renal vascular resistance, and enhance natriuresis and diuresis. Despite the absence of clinical evidence of renoprotection, this rationale has been used to justify the use of low-dose (“renal-dose”) dopamine (<5 μg/kg/min) for decades. Despite the lack of benefit and accumulating concerns regarding the use of low-dose dopamine, continued use of this agent for renoprotection is prevalent.¹²

fenoldopam

Fenoldopam mesylate, a benzazepine derivative, is a selective D₁-receptor agonist. Although first approved as an antihypertensive agent, fenoldopam has shown promise in the prevention of contrast-induced nephropathy. A recent meta-analysis by Landoni et al provides evidence that fenoldopam may confer significant benefits in preventing renal replacement therapy and reducing mortality in patients undergoing cardiovascular surgery.¹³

diuretic agents

Diuretics increase urine generation by reducing reuptake of tubular contents. This can be achieved by numerous mechanisms, including inhibiting active mechanisms that lead to solute reuptake (e.g., loop diuretics), altering the osmotic gradient in the tubular contents to favor solute remaining in the tubule (e.g., mannitol), or hormonal influences that affect the balance of activities of the tubule to increase urine generation (e.g., atrial natriuretic peptide). The general renoprotective principle of diuretic agents is that increasing tubular solute flow through injured renal tubules will maintain tubular patency, avoiding some of the adverse consequences of tubular obstruction, including oliguria or anuria and possibly the need for dialysis.

MYOCARDIAL INJURY

From the earliest days of modern cardiac surgery, perioperative myocardial dysfunction, with its associated morbidity and mortality, has been reported. Evidence, including substantial subendocardial cellular necrosis, led to the conclusion that this injury resulted from an inadequate substrate supply to the metabolically active myocardium. Optimizing myocardial protection during cardiac surgery involves several compromises inherent in allowing surgery to be performed in a relatively immobile, bloodless field while preserving postoperative myocardial function. The fundamental tenets of this protection center on the judicious use of hypothermia along with the induction and maintenance of chemically induced electromechanical diastolic cardiac arrest. Despite continued efforts directed at myocardial protection, it is clear that myocardial injury, although reduced, still remains a problem, and with it, the representative phenotype of myocardial dysfunction.

Incidence and Significance of Myocardial Dysfunction after Cardiopulmonary Bypass

Unlike other organs at risk of damage during cardiac surgery, it is assumed, owing to the very nature of the target of the operation being performed, that all patients having cardiac surgery suffer some degree of myocardial injury. Although the injury can be subclinical, represented only by otherwise asymptomatic elevations in cardiac enzymes, it frequently manifests more overtly. The degree to which these enzymes are released by injured myocardium, frequently to levels sufficiently high to satisfy criteria for myocardial infarction, has been related to perioperative outcome after cardiac surgery. CK-MB values more than 10 times the upper limit of normal during the initial 48 hours after CABG were significantly associated with 6-month mortality (P < .001).¹⁴

Risk Factors for Myocardial Injury

With an increasingly sicker cohort of patients presenting for cardiac surgery,¹⁵ many with acute ischemic syndromes (e.g., often with evolving myocardial infarction) or significant left ventricular dysfunction, the need has never been greater for optimizing myocardial protection to minimize the myocardial dysfunction consequent to aortic cross-clamping and cardioplegia. The continued increase in cardiac transplantation and other complex surgeries in the heart failure patient has served to fuel the search for better myocardial protection strategies.

Pathophysiology of Myocardial Injury

The metabolic consequences of oxygen deprivation become apparent within seconds of coronary artery occlusion. With the rapid depletion of high-energy phosphates, accumulation of lactate and intracellular acidosis in the myocytes soon follows, with the subsequent development of contractile dysfunction. When myocyte adenosine triphosphate levels decline to a critical level, the subsequent inability to maintain electrolyte gradients requiring active transport (e.g., Na⁺, K⁺, Ca²⁺) leads to cellular edema, intracellular Ca²⁺ overload, and loss of membrane integrity.

Predictably with the release of the aortic cross-clamp and the restoration of blood flow, myocardial reperfusion occurs. With reperfusion the paradox, represented by the balance of substrate delivery restoration needed for normal metabolism that also can serve as the substrate for injurious free radical production, becomes a significant issue for consideration. Reperfusion causes a rapid increase in free radical production within minutes, and it plays a major role initiating myocardial stunning.

A potential additional mechanism for myocardial dysfunction specific to the setting of CPB relates to proposed acute alterations in β-adrenergic signal transduction. Acute desensitization and downregulation of myocardial β-adrenergic receptors during CPB have been demonstrated after cardiac surgery. Although the role of the large elevations in circulating catecholamines seen with CPB on β-adrenergic malfunction is unclear, it has been proposed that an increased incidence of post-CPB low cardiac output states and reduced responsiveness to inotropic agents may, in part, be attributed to this effect.

Myocardial Protection during Cardiac Surgery: Cardioplegia

Optimizing the metabolic state of the myocardium is fundamental to preserving its integrity. The major effects of temperature and functional activity (i.e., contractile and electrical work) on the metabolic rate of myocardium have been extensively described.¹⁶ With the institution of CPB, the emptying of the heart significantly reduces contractile work and myocardial oxygen consumption . Nullifying this cardiac work reduces the by 30% to 60%. With subsequent reductions in temperature, the further decreases, and with induction of cardiac arrest and hypothermia, 90% of the metabolic requirements of the heart can be reduced. Temperature reductions diminish metabolic rate for all electromechanical states (i.e., beating or fibrillating) of the myocardium.

Although cardiac surgery on the empty beating heart or under conditions of hypothermic fibrillation (both with the support of CPB) is sometimes performed, aortic cross-clamping with cardioplegic arrest remains the most prevalent method of myocardial preservation. Based on the principle of reducing metabolic requirements, the introduction of selective myocardial hypothermia and cardioplegia (i.e., diastolic arrest) marked a major clinical advance in myocardial protection. With the various additives in cardioplegia solutions (designed to optimize the myocardium during arrest and attenuate reperfusion injury) and the use of warm cardioplegia, the idea of delivering metabolic substrates (as opposed to solely reducing metabolic requirements) is also commonplace. Several effective approaches to chemical cardioplegia are employed. The clinical success of a cardioplegia strategy may be judged by its ability to achieve and maintain prompt continuous arrest in all regions of the myocardium, early return of function after cross-clamp removal, and minimal inotropic requirements for successful separation from CPB. Composition, temperature, and route of delivery constitute the fundamentals of cardioplegia-derived myocardial protection.

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 very general terms, cardioplegia can be classified into blood-containing and non–blood-containing (i.e., crystalloid) solutions. Table 23-4 outlines the various additives to cardioplegia solutions along with their corresponding rationale for use. Although all cardioplegia solutions contain higher than physiologic levels of potassium, solutions used for the induction of diastolic arrest contain the highest 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) constitutes the most common variations in cardioplegia content.

Table 23-4 Strategies for the Reduction of Ischemic Injury with Cardioplegia

Principle	Mechanism	Component
Reduce O₂ demand	Hypothermia	Blood, crystalloid, ice slush, lavage
	Perfusion
	Topical/lavage
	Asystole	KCl, adenosine(?), hyperpolarizing agents
Substrate supply and use	Oxygen	Blood, perfluorocarbons, crystalloid(?)
	Glucose	Blood, glucose, citrate-phosphate-dextrose
	Amino acids	Glutamate, aspartate
	Buffer acidosis	Hypothermia (Rosenthal factor), intermittent infusions
	Buffers	Blood, tromethamine, histidine, bicarbonate, phosphate
	Optimize metabolism	Warm induction (37°C), warm reperfusion
Reduce Ca²⁺ overload	Hypocalcemia	Citrate, Ca²⁺ channel blockers, K channel openers(?)
Reduce edema	Hyperosmolarity	Glucose, KCl, mannitol
	Moderate infusion pressure	50 mmHg

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. The introduction of blood cardioplegia in the late 1970s followed recognition of the clinical utility of this technique.

Cardioplegia Temperature

The composition of cardioplegia solutions varies considerably; in contrast, myocardial temperature during cardioplegia is almost uniformly reduced to between 10°C and 15°C or less by the infusion of refrigerated cardioplegia and external topical cooling with ice slush. However, the introduction of warm cardioplegia has challenged this once universally considered necessity of hypothermia for successful myocardial protection. Although hypothermic cardioplegia is the most commonly used temperature, 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 of 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 red blood cell deformability. As a result, investigations aimed at using warmer cardioplegia temperatures have been explored.

Cardioplegia Delivery Routes

Retrograde cardioplegia, where a cardioplegia catheter is introduced into the coronary sinus, allows for almost continuous cardioplegia administration. Retrograde delivery is useful in settings where antegrade cardioplegia is problematic, such as with severe aortic insufficiency or during aortic root or aortic valve surgery (Box 23-3). 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 coronary artery disease and in those undergoing valve surgery. 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 mmHg.¹⁷

BOX 23-3 Uses for Retrograde Cardioplegia

• Along with anterograde cardioplegia

• In the presence of aortic insufficiency

• For aortic valve surgery

• To perfuse severely diseased coronary arteries

GASTROINTESTINAL COMPLICATIONS

Incidence and Significance

Gastrointestinal complications after cardiac surgery, although occurring relatively infrequently (0.5% to 5.5%), portend a significantly increased incidence of overall adverse patient outcome. The variability in the reported incidence of gastrointestinal complications is partly a reflection of how they are defined and the variable patient and operative risk factors in the studied cohorts. Although the most commonly considered gastrointestinal complications include pancreatitis, gastrointestinal bleeding, cholecystitis, and bowel perforation or infarction, hyperbilirubinemia (total bilirubinemia > 3.0 mL/dL) has also been described as an important complication after cardiac surgery. In one of the largest prospective studies examining these complications after CPB, McSweeney and associates studied 2417 patients undergoing CABG (with or without concurrent intracardiac procedures) in a multicenter study in the United States. The overall incidence of gastrointestinal complications in this study was 5.5%, ranging from 3.7% for hyperbilirubinemia to 0.1% for major bowel perforation or infarction.¹⁸

In addition to their association with other morbid events, adverse gastrointestinal complications are significantly associated with increased mortality after cardiac surgery. The average mortality among subtypes of gastrointestinal complications in the study by McSweeney and associates was 19.6%, and in other reports the mortality rate ranges from 13% to 87%, with an overall average mortality of 33%. Even the seemingly insignificant complication of having an increased laboratory measurement of total bilirubin was associated with an odds ratio of death of 6.6 in the study of McSweeney and associates, compared with a death odds ratio of 8.4 for all adverse gastrointestinal outcomes combined. Apart from the significant effect on mortality, the occurrence of an adverse gastrointestinal outcome also significantly increases the incidence of perioperative myocardial infarction, renal failure, and stroke, as well as significantly prolonging intensive care unit and hospital length of stay.

Risk Factors

A long list of preoperative, intraoperative, and postoperative risk factors for gastrointestinal complications have been identified in a number of studies.¹⁹ As many factors are associated with one another, it is only when these risk factors are examined in multivariable analyses that a more accurate understanding of what the most significant risk factors for visceral complications after cardiac surgery are. Preoperatively, age (>75 years), history of congestive heart failure, presence of hyperbilirubinemia (>1.2 mg/dL), combined cardiac procedures (e.g., CABG plus valve), repeat cardiac operation, preoperative ejection fraction less than 40%, preoperative elevations in partial thromboplastin time, emergency operations; intraoperatively, prolonged CPB, use of TEE, and blood transfusion; and postoperatively, requirements for prolonged inotropic vasopressor support, IABP use for the treatment of low cardiac output; and prolonged ventilatory support are all risk factors. These factors identify patients at high risk, and they lend some credence to the overall pathophysiology and suspected causes of these adverse events. If there is a common link between all these risks, it is that many of these factors would be associated with impairment in oxygen delivery to the splanchnic bed.

Pathophysiology and Etiology

Impairments in splanchnic perfusion commonly occur during even the normal conduct of cardiac surgery. When this is superimposed on an already depressed preoperative cardiac output or is associated with prolonged postoperative low cardiac output, the impairment in splanchnic blood flow is further perpetuated. The systemic inflammatory response to CPB itself can be initiated by splanchnic hypoperfusion by means of translocation of endotoxin from the gut into the circulation. De novo splanchnic hypoperfusion can be a result of the humoral vasoactive substances that are released by inflammation remote from the gut. Another etiologic factor for gastrointestinal complications directly related to splanchnic hypoperfusion is atheroembolism. Prolonged ventilator support is another etiologic factor for gastrointestinal complications. Several lines of investigation have described a relationship between prolonged ventilation and gastrointestinal adverse events; this likely results from a direct effect of positive-pressure ventilation impairing cardiac output and subsequently splanchnic perfusion.

Protecting the Gastrointestinal Tract during Cardiac Surgery

As with other aspects of organ protection, critical etiologic factors need to be addressed with specific targeted therapies (Box 23-4). Unfortunately, as with most other organ-protective strategies, the major limitation in making definitive recommendations is an overall lack of large, well-controlled, prospectively randomized studies to provide supportive data for any one particular technique.

BOX 23-4 Protecting the Gastrointestinal Tract during Cardiopulmonary Bypass

• Avoiding use of profound vasopressors

• Maintaining a high perfusion flow

• Reducing emboli-producing maneuvers

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 gastrointestinal 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. 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. The optimal bypass temperature to protect the gut is also unknown. Just as aggressive rewarming can be injurious to the brain, 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.

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. An increasingly common drug in the setting of cardiac surgery is vasopressin. Although vasopressin can clearly augment systemic MAP, it does so at the cost of severe impairments to splanchnic blood flow. 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.

Off-Pump Cardiac Surgery

There is little evidence that the use of off-pump cardiac surgery is in any way beneficial to the gastrointestinal tract. Three retrospective studies ²⁰ have shown no differences in gastrointestinal 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 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.

LUNG INJURY DURING CARDIAC SURGERY

Incidence and Significance

Pulmonary dysfunction was one of the earliest recognized complications of cardiac surgery employing CPB.²¹ However, as improvements in operative technique and CPB perfusion technologies occurred, the overall frequency and severity of this complication decreased. Juxtaposed to the improvements in cardiac surgery, which led to an overall reduction in complications, is an evolving patient population that now comprises a higher-risk group with a higher degree of pulmonary comorbidities, increasing their risks of postoperative pulmonary dysfunction. With the advent of fast-track techniques, even minor degrees of pulmonary dysfunction have reemerged as significant contributors to patient morbidity and the potential need for extended postoperative ventilation. As with most postoperative organ dysfunction, there is a range of dysfunction severity. Arguably, some degree of pulmonary dysfunction occurs in most patients after cardiac surgery; however, it manifests clinically only when the degree of dysfunction is particularly severe or the pulmonary reserve is significantly impaired. As a result, even minor CPB-related pulmonary dysfunction can cause significant problems in some patients.

The full range of reported pulmonary complications includes simple atelectasis, pleural effusions, pneumonia, cardiogenic pulmonary edema, pulmonary embolism, and various degrees of acute lung injury ranging from the mild to the most severe (i.e., acute respiratory distress syndrome [ARDS]). Although the final common pathway in all these forms of pulmonary dysfunction complications is the occurrence of hypoxemia, these complications vary widely in their incidence, cause, and clinical significance.