Anxiolysis, Amnesia, and Analgesia

The purposes of premedication are to pharmacologically reduce apprehension and fear, to provide analgesia for potentially painful events before induction (e.g., vascular cannulation), and to produce some degree of amnesia. In patients with CAD, premedication may help prevent preoperative anginal episodes that are relatively commonly observed and may be elicited by tachycardia caused by anxiety or painful stimuli, or both. Regardless of the drugs used, the clinician should be prepared to give intravenous drugs (e.g., short-acting benzodiazepines) when the patient arrives in the preoperative area. All patients should receive supplemental oxygen after premedication and be monitored with pulse oximetry, ECG, and noninvasive blood pressure.

The sedative and anesthetic-sparing actions of α₂-adrenergic agonists (e.g., clonidine, dexmedetomidine) have been evaluated for their efficacy in several studies of CABG patients alone or in combination with a benzodiazepine.^123–125 The use of α₂-adrenergic agonists reduced stress response and anesthetic requirements compared with conventional regimens. A meta-analysis reported reductions in mortality and postoperative myocardial infarction with their use in cardiac surgery (started before surgery and often continuing until CPB).¹²⁶ Nevertheless, some of the hemodynamic side effects of α₂-agonists warrant caution in certain patient populations. Decreased HR, MAP, cardiac output (CO), contractility, and transiently increased systemic vascular resistance (SVR) seen with the less-selective α₂-blocker clonidine, as well as an increased risk for hypotension during anesthesia induction, have been reported in general and cardiac surgery patients who were premedicated with α₂-agonists.^127,128 Consequently, α₂-agonists should be used with caution in patients with preexisting severe bradycardia, conduction problems such as second- or third-degree heart block, hypovolemia, or hypotension.

Management of Antianginal and Antihypertensive Medications

The use of β-blocking agents in patients with poor ventricular function has been evaluated. Contrary to earlier reports,¹²⁹ Kaplan et al^130,131 reported in the mid-1970s and long before the ongoing discussion of perioperative β-blockade in noncardiac surgical patients that it was safe to continue β-blockade in patients presenting for cardiac and noncardiac surgery. Slogoff et al¹³² performed a randomized trial evaluating the safety of administration of propranolol within 12 hours of surgery. Based on a significantly greater increase in the incidence of pre-CPB ischemia in patients withdrawn from propranolol (within 24 to 72 hours), they also recommended continuation of therapy up until the time of surgery. Further work by these and other investigators in the 1980s documented the efficacy of β-blocker continuation through CABG surgery with regard to reducing pre-CPB ischemia and their superior efficacy over the increasingly popular calcium channel blockers^133,134 (Box 18-2).

The earlier mentioned studies were instrumental in laying the groundwork for the subsequent noncardiac surgery studies in the late 1980s.^135–137 They led to the contemporary randomized trials of Poldermans et al¹³⁸ and Mangano et al,¹³⁹ which rallied support for routine perioperative β-blocker use; and the most recent conclusions drawn from the POISE trial¹⁴⁰ that questioned parts of this practice. These trials resulted in the latest recommendations of β-blockade in patients undergoing noncardiac surgery.¹⁴¹ There is little doubt that β-blockers are beneficial for most CABG patients, particularly if HR is increased. When acutely administered in adequate dose, they significantly reduce myocardial oxygen demand and the incidence of atrial and ventricular arrhythmias. Several observational studies have documented associations of β-blocker therapy with reduction in perioperative mortality in CABG patients.^142,143 The largest of these by Ferguson et al¹⁴⁴ considered 629,877 patients in the STS database (1996 to 1999) in which a modest but statistically significant reduction in 30-day risk-adjusted mortality was reported. This treatment effect was observed in many high-risk subgroups, although a trend toward increased mortality was seen in patients with EF less than 30%. In a meta-analysis, Wiesbauer et al¹⁴⁵ found that perioperative β-blockers reduced perioperative arrhythmias after cardiac surgery, but they had no effect on myocardial infarction or mortality. Considerable efforts are being expended by major organizations (STS, American College of Cardiology) in increasing compliance with existing guidelines for use of β-blockers at the time of hospital discharge (together with use of aspirin, statins, and angiotensin-converting enzyme [ACE] inhibitors).^146,147

An increasing number of patients are presenting for CABG surgery while being treated with platelet inhibitors. Aspirin is a well-recognized component of primary and secondary prevention strategies for all patients with ischemic heart disease.^148,149 Treatment with clopidogrel is required for coronary artery stent placement, has been shown to improve outcome, and is now recommended in combination with aspirin after acute coronary syndrome.^150,151 Antiplatelet therapy is also used after CABG to reduce ischemic complications. Aspirin (and other platelet inhibitors such as dipyridamole) have long been recognized to have strong efficacy in the prevention of early graft thrombosis after CABG.¹⁵² Mangano et al,¹⁵³ in a large observational analysis, reported substantial reduction in overall mortality rate (1.3% vs. 4.0%) and ischemic complications of the heart, brain, kidneys, and gastrointestinal tract in 5065 patients at 70 hospitals when aspirin was administered within 48 hours after surgery.

The combination of aspirin and clopidogrel after CABG may be even more effective.¹⁵⁴ However, great controversy exists in regard to preoperative antiplatelet therapy. The risk for hemorrhagic complications needs to be weighed against the potential benefits of antiplatelet therapy. In a recent meta-analysis, patients receiving aspirin immediately before surgery had more mediastinal bleeding and received more blood products.¹⁵⁵ Several retrospective studies have reported that CABG surgery in patients receiving clopidogrel is associated with increased bleeding and transfusion requirements.¹⁵⁶ Filsoufi et al¹⁵⁷ also reported longer ICU and hospital length of stay (LOS) and increased all-cause morbidity and mortality in clopidogrel-treated patients. In a multicenter, retrospective study, Berger et al¹⁵⁸ reported that clopidogrel-treated patients were at increased risk for reoperation, major bleeding, and increased LOS.

Recent guidelines from the American College of Chest Physicians on antithrombotic and thrombolytic therapies recommend institution of aspirin within 6 hours after CABG surgery over continuation of preoperative therapy (level of evidence IIa).¹⁵⁹ In those with ongoing bleeding, it should be administered as soon as possible thereafter. In those allergic to aspirin, clopidogrel should be used instead. Low-dose aspirin should be continued indefinitely. They further recommend the use of clopidogrel in addition to aspirin for 9 to 12 months after CABG after a non–ST-elevation acute coronary syndrome. The STS has released formal practice guidelines on this topic. In high-risk patients (those with unstable angina or recent myocardial infarction) requiring urgent or emergent CABG, aspirin should be continued until the time of surgery (Class IIa recommendation) unless they are in an “aspirin-sensitive high-risk subgroup” (i.e., those on other antiplatelets or anticoagulants, or those who have platelet abnormalities). For elective patients in whom active platelet aggregation is less likely to be a critical factor in precipitating ischemia, they recommend discontinuation of aspirin for 3 to 5 days before surgery to reduce transfusion requirements (Class IIa), with reinstitution in the early postoperative period (Class I).¹⁶⁰ The American College of Chest Physicians practice guidelines, as well as the American Heart Association/American College of Cardiology guidelines, also suggest discontinuing clopidogrel 5 days before CABG surgery in patients who received clopidogrel for acute coronary syndrome if clinical circumstances allow.^159,161

The efficacy of calcium channel antagonists with regard to their anti-ischemic properties in patients undergoing CABG is a controversial topic. Early observational studies suggest they were ineffective, particularly relative to β-blockers.^162,163 Subsequently, there was even less enthusiasm for their use given concerns in the mid-1990s of excess mortality with shorter-acting preparations (in particular, nifedipine, which was thought to cause reflex adrenergic activation because of abrupt vasodilation with each dose).¹⁶⁴ Two meta-analyses evaluating their efficacy in noncardiac surgery produced conflicting information.^165,166 However, one meta-analysis and a large observational cohort study with propensity matching adjustment suggest they are effective in reducing mortality in CABG patients.^167,168 For patients taking them chronically, it appears prudent to continue them perioperatively. Caution is advised with concurrent administration of nondihydropyridine drugs (diltiazem) and β-blockers, although the risk (purported to be possible precipitation of advanced degrees of atrioventricular block) appears to be minor, based on a lack of problems in a reported large cohort of thoracotomy patients in whom this was done frequently.¹⁶⁹ A new issue recently has been raised as well, which will require further investigation. A recent observational study concluded that calcium channel blockers decrease clopidogrel-mediated platelet inhibition, the latter playing a crucial role in the management of CAD.¹⁷⁰

ACE inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) currently are receiving special attention as agents because of a variety of important “pleiotropic” effects (e.g., effects independent of their primary antihypertensive or lipid-lowering actions, respectively).^171–173 Potent anti-inflammatory and antithrombotic effects and beneficial effects on endothelial function have been reported for both agents, as well as less clear effects on angiogenesis.^174,175 Both agents commonly are administered acutely during PCI,^176–178 and have direct effects on platelet aggregation and plasminogen activator inhibitors.^173,179 Statins have been reported to reduce circulating levels of adhesion molecules, which have been implicated in endothelial dysfunction after CPB (Figure 18-12).^180–182 Statins also have been shown to attenuate myocardial reperfusion injury after cardiac surgery.¹⁸³ ACE inhibitors are widely considered to be vasculoprotective, particularly with regard to ventricular remodeling after acute myocardial infarction, and they appear to reduce damage after ischemic reperfusion (likely related to reduction in ischemia-induced vasoconstriction and reduction in leukocyte adhesion).¹⁸⁴ Several investigators have published retrospective studies with similar reports of the efficacy of statins to reduce the short-and long-term mortality of CABG patients.^185–189 In a large meta-analysis evaluating the impact of preoperative statin use on adverse clinical outcomes after cardiac surgery, Liakopoulos et al¹⁹⁰ reported that preoperative statin use significantly reduced all-cause mortality after surgery. Statins also have been found in retrospective studies to decrease the need for postoperative renal replacement therapy,¹⁹¹ possibly a reflection of their anti-inflammatory properties, with conflicting results regarding a reduction in acute renal dysfunction.^192,193 In addition, statins have been shown to decrease the incidence of atrial fibrillation after cardiac surgery.¹⁹⁴ The current American College of Cardiology/American Heart Association guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery patients recommend the continuation of statins in patients currently on them and the consideration of starting statins in patients with clinical risk factors.¹⁹⁵ Most clinicians continue them routinely (albeit orally only, so there is usually a short withdrawal period after surgery). Postoperative withdrawal of statin treatment is independently associated with increased hospital mortality after CABG.¹⁹⁶

Figure 18-12 Bar graph of the mean values of circulating intercellular adhesion molecule-1 (ICAM-1), a glycoprotein circulating adhesion molecule expressed by endothelial cells in response to inflammation. Levels in response to cardiopulmonary bypass are shown for 15 control subjects, 15 patients on simvastatin with good control of cholesterol (i.e., responsive), and 15 patients on the drug but with poor control (i.e., not responsive) of cholesterol. Statin patients had lower ICAM-1 levels at 24 and 48 hours after surgery (***, statistically significant), suggesting possible anti-inflammatory properties. Base, baseline; ccr, cross-clamp release; end, end of cardiopulmonary bypass; po, postoperative period.

(From Chello M, Carassiti M, Agro F, et al: Simvastatin blunts the increase of circulating adhesion molecules after coronary artery bypass surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 18:605, 2004.)

Fewer studies have been performed on ACE inhibitors. The QUO VADIS (QUinapril on Vascular Ace and Determinants of Ischemia) study¹⁹⁷ showed a significant reduction in ischemic events in patients on ACE inhibitors before CABG. ACE inhibitor therapy before CABG has also been associated with a reduced risk for acute kidney injury¹⁹⁸ and may be effective in the prevention of new-onset atrial fibrillation.¹⁹⁹ ACE inhibitors, however, also have been associated with greater degrees of hypotension during induction or even profound degrees of vasodilation (vasoplegic syndrome) during CPB and weaning because of their vasodilatory effects.^200–208 In a large, retrospective, observational study on more than 10,000 patients undergoing CABG surgery, preoperative ACE inhibitor therapy was associated with an increased incidence of perioperative hypotension and ACE inhibitor therapy was found to be an independent predictor of mortality, need for inotropic support, postoperative renal dysfunction, and new-onset postoperative atrial fibrillation.²⁰⁹ Another concern expressed by Lazar²¹⁰ was in relation to potential antagonism between ACE inhibitors and aspirin because ACE inhibitors increase prostaglandin levels, whereas aspirin inhibits them. Despite strongly promoting their perioperative use, he advised they be withheld for 24 to 48 hours before surgery if possible and restarted after surgery after reinstitution of β-blockade (assuming systolic blood pressure > 100 mm Hg). They are otherwise contraindicated with renal insufficiency, and their adverse effect of cough can be detrimental to sternal stability in the early postoperative period. At this point, further studies are needed to make recommendations about the perioperative use and/or continuation of ACE inhibitors and their effect on outcome parameters in patients undergoing CABG surgery.

Electrocardiogram

On arrival in the operating room, the patient undergoing CABG should have routine monitors placed, including pulse oximetry, noninvasive blood pressure (BP), and the ECG. A five-lead system is standard in patients undergoing cardiac surgery. Monitoring leads V₅ and II allows for the detection of 90% of ischemic episodes, as well as monitoring the rhythm to diagnose various atrial and ventricular arrhythmias. The ECG detection of myocardial ischemia is reviewed in Chapter 15 (Box 18-3).

Arterial Pressure Monitoring

The radial artery usually is cannulated for BP monitoring during CABG. Choosing the best site for radial artery cannulation depends on surgery-specific considerations, as well as institutional and practitioner preferences. Surgical technique such as radial artery harvesting or axillary CPB cannulation may influence the site chosen for invasive arterial pressure monitoring. With modern sternal retractors, blunting of the arterial pressure tracing on the ipsilateral side of internal mammary artery (IMA) dissection is not typically seen. Some practitioners use bilateral arterial cannulation or choose a more central artery such as the axillary or femoral artery to ensure accurate pressure readings after CPB. Radial arterial pressures have been shown to be inaccurate immediately after hypothermic CPB. Substantial reductions in radial arterial versus aortic pressure have been reported in several clinical investigations, often requiring 20 to 60 minutes after CPB to resolve.^211–215 Alterations in forearm vascular resistance (decrease) are believed to be responsible for this common phenomenon. This problem can be overcome by temporarily transducing the arterial pressure directly from the aorta (by a needle or a cardioplegia cannula).

Central Venous Cannulation

The placement of a central venous pressure (CVP) catheter routinely is performed in cardiac anesthesia both for pressure measurement and for infusing vasoactive drugs. Some centers routinely place two catheters (a large introducer and a smaller CVP catheter) in the central circulation to facilitate volume infusion and vasoactive or inotropic drug administration. Increasingly, ultrasound guidance is used for placement, although there remains controversy in the literature regarding whether it is a standard of care^216–218 (see Chapter 14).

Pulmonary Artery Catheterization

The use of PAC in medical and surgical settings has declined steadily, mostly because of the increasing amount of data from large randomized studies showing that major clinical outcomes (particularly mortality) are not changed by PAC use and that adverse effects of PAC monitoring have to be considered. This includes surgery for myocardial revascularization and in the ICU setting, suggesting that despite the substantial amount of physiologic information obtained, patient outcome is independent of PAC use. Tuman et al,²¹⁹ in a prospective observational study, examined the effect of the PAC on outcome in 1094 patients undergoing CABG surgery. Although no direct data on LV function were provided, there was no difference in the incidence of LV dysfunction between the group treated with a CVP versus the group treated with a PAC. In this study, the investigators could not demonstrate that a PAC had any effect on outcome; however, 7% of the patients initially assigned to CVP monitoring subsequently required a PAC for management.

Several other reports have focused exclusively on PAC use in CABG surgery. Stewart et al²²⁰ reported a retrospective analysis of 312 patients undergoing CABG (in 1996) who were believed to be low risk and suitable for CVP monitoring alone. Of these, 32% had a PAC placed and received greater volumes of fluid, gained more weight, and had longer times to extubation. Ramsey et al²²¹ retrospectively analyzed a commercial health care outcomes benchmarking database with 13,907 patients undergoing nonemergent CABG in 56 hospitals (Figure 18-13). Patients who had a PAC placed for perioperative monitoring (58% of the patients) were found to have a greater risk for mortality after risk adjustment (relative risk = 2.1), longer lengths of stay, and higher total costs, particularly in the hospitals with low rates of PAC use. Schwann et al²²² retrospectively analyzed 2685 consecutive CABG patients at a single private center (1994 to 1998) in which PAC use was “highly selective” (i.e., used in only 9% based on consideration of multiple cardiac risk factors). Of these PACs, 6.6% were planned, with the remainder placed after surgery in response to adverse intraoperative events. Multivariate analysis revealed EF, STS risk score, use of IABP, congestive heart failure, redo operation, and New York Heart Association Class IV to be independent predictors of PAC use. Based on their reported overall mortality rate (2.3%), it appears as if this highly selective approach was safe, although these data cannot necessarily be generalizable outside this particular center given multiple other process variables involved in providing care for these patients. London et al²²³ documented the high rate of PAC use based on analysis of 3256 CABG patients included in a larger multicenter, observational study in patients undergoing cardiac surgery in the Department of Veterans Affairs (1994 to 1996). More than 95% of all cases were monitored with a PAC, and 49% of these used the more expensive mixed venous oxygen saturation catheter. Use of this catheter was clearly center specific, and with the exception of a small reduction in number of postoperative arterial blood gas and thermodilution CO measurements, it was not associated with improvement in outcome over the routine PAC.

Figure 18-13 Variation in the use of pulmonary artery catheter (PAC) for elective coronary artery bypass grafting (CABG) in 13,907 patients at 56 community-based hospitals in 26 states in 1997, with data obtained from an administrative health outcomes benchmarking database. PAC was used in 58% and was associated with greater risk of in-hospital mortality, particularly in hospitals with the lowest use of PAC, hospital length of stay, and costs. Purple bars indicate the total number of CABG cases; gray bars indicate the number of patients with PAC.

(From Ramsay SD, Saint S, Sullivan SD, et al: Clinical and economic effects of pulmonary artery catheterization in nonemergent coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 14:113, 2000.)

Based on the existing literature, it is not possible to give precise criteria for PAC use in CABG surgery (see Chapter 14). The greater the patient risk (based primarily on established preoperative clinical predictors), the more favorable is the risk/benefit ratio. Risk factors include significant impairment of ventricular function (EF < 30%), and patients with known pulmonary hypertension and/or right-heart failure. Some authors have advocated a wait-and-see approach. In a prospective observational study, Djaiani et al²²⁴ showed the safety and usefulness of delaying the insertion of a PAC until the clinical need arises in the operating room or in the ICU after CABG surgery.

Although most of the recent clinical reports of patients undergoing OPCAB have used and many recommend the use of a PAC, it is not possible to give firm recommendations on this because of the lack of evidence-based data. In a retrospective study, Resano et al²²⁵ did not find significant differences in mortality, conversion to on-pump procedure, or inotropic drug use between the group treated with a CVP versus the group treated with a PAC.

Many of the complications reported with PAC use are related to large-bore catheter central vein cannulation. With the increasing use of intraoperative TEE monitoring, PAC use may decrease even more. For a more detailed review of PAC use, see Chapter 14.

Transesophageal Echocardiography

The ASA, together with the Society of Cardiovascular Anesthesiologists, developed practice guidelines in 1996 to provide recommendations for the perioperative use of TEE.²²⁶ These guidelines were updated recently,²²⁷ and the routine use of TEE is now recommended for all cardiac or thoracic aortic surgery, which includes most patients undergoing CABG or OPCAB surgery, or both. The ASA Task Force thereby acknowledged the increasing evidence that TEE can provide important information that may impact perioperative anesthetic and surgical management and, possibly, patient outcome.

TEE is highly sensitive but not specific for myocardial ischemia.^228,229 It is appreciated that the earliest signs of myocardial ischemia include diastolic dysfunction followed by systolic regional wall motion abnormalities (RWMAs), which occur within seconds of acute coronary occlusion. New RWMAs detected in the intraoperative period, however, frequently may occur because of nonischemic causes such as changes in loading conditions, alteration in electrical conduction in the heart, post-CPB pacing, myocardial stunning caused by ischemia before or during weaning from CPB, or poor myocardial preservation. Worsening of RWMAs after CABG surgery is associated with an increased risk for long-term adverse cardiac morbidity and has been suggested as a prognostic indicator of adverse cardiovascular outcome.²³⁰ The transgastric short-axis midpapillary muscle view, commonly used because of its inclusion of myocardium supplied by the three major coronary arteries, may entirely miss RWMAs occurring in the basal or apical portions of the heart. A comprehensive TEE examination recommended by the American Society of Echocardiography/Society of Cardiovascular Anesthesiologists Task Force before and after CPB or after completion of revascularization in OPCAB is, therefore, recommended.²³¹ TEE is not perfect for ischemia monitoring because all wall segments would have to be monitored continuously in real-time and compared with preoperative findings.

A wide variety of uses aside from detection of ischemia are well documented for TEE. TEE can assist in the pre-CPB evaluation of cardiac function, associated valvular lesions including functional mitral regurgitation, evaluation of atheromatous plaques in the aorta (site of cannulation and aortic cross-clamping, possible no-touch technique), detection of a patent foramen ovale, and persistent left superior vena cava (retrograde cardioplegia problematic). CPB cannulation including retrograde cardioplegia cannula positioning, aortic cannula positioning and associated complications such as iatrogenic aortic dissection and positioning in the left subclavian artery, verification of PAC location, volume status, ventricular function and response to inotropic agents, and de-airing after release of the aortic cross-clamp can also be evaluated by TEE.

A new and exciting application of perioperative TEE is now emerging. The conventional method for analyzing regional myocardial function is by visual assessment of inward radial motion and wall thickening from two-dimensional (2D) echocardiographic images. Precise and reproducible quantitative assessment is much more appealing. Early attempts at using Doppler-based techniques for this purpose have been limited by angle-dependency and artifacts.^232,233 A novel quantitative approach is speckle tracking. It uses 2D images and analyzes the movement of stable acoustic markers (speckles) between frames.²³⁴ Kukucka et al²³⁵ demonstrated the feasibility of intraoperative determination of speckle tracking–derived strain from TEE images and correlated it with visual assessment of RWMA. They showed that it had better interobserver agreement than visually obtained data, allowed for determination of radial and longitudinal RWMAs, and that strain analysis and not visually obtained semiquantitative assessment of wall motion detected differences between normally perfused and ischemic segments (see Chapter 12).

The use of perioperative TEE in patients undergoing cardiac surgery is increasing, and it will be interesting to see how this trend develops with the newly adopted ASA guidelines on the perioperative use of TEE in patients undergoing cardiac surgery. Morewood et al²³⁶ obtained more than 1800 survey responses from members of the Society of Cardiovascular Anesthesiologists in 2000. Of approximately 1500 clinicians involved in CABG, only 11% reported never using TEE, but more than 30% used it frequently or always. This number is probably greater today because of the growth of OPCAB and ongoing popularity of the technology. A variety of observational studies since 1990 have supported the efficacy of this technique, although in the absence of a true randomized, controlled trial, it is impossible to conclusively prove the efficacy of intraoperative TEE on patient outcome parameters such as perioperative morbidity and mortality.^237–239 Proper education and certification are critical, and guidelines about training requirements and certification have been published^240,241 (see Chapter 41). The clinician must realize that there are serious complications that can and do occur (albeit rarely) with the intraoperative use of TEE and that a strong association between esophageal dysmotility and aspiration, particularly in elderly patients, has been suggested in several observational reports.^242–247

Cerebral Oximetry

Cerebral oximetry monitoring, a continuous, noninvasive monitor of regional cerebral oxygen saturation, is being used increasingly during cardiac surgery. The technologic background of near-infrared spectroscopy technology has been reviewed in detail elsewhere (see Chapter 16).²⁴⁸ The main principles on which near-infrared spectroscopy devices rely are the facts that most biologic tissues, other than hemoglobin and cytochrome oxidase, are relatively transparent to infrared light in the range closest to the visual spectrum (700 to 1000 nm) and that the absorbance spectrum of hemoglobin depends on its oxygenation status (deoxygenated hemoglobin absorbs more red light and less infrared light than oxygenated hemoglobin). Regardless of the manufacturer, all devices emit light at wavelengths within the earlier mentioned spectrum and analyze photons returning to the transducer. The source of the light signal(s) (laser vs. diode), number of wavelengths used, and distance of the emitting light source to the receiving sensors vary among the manufacturers. Because the change in intensity of the reflected light is dependent on the oxyhemoglobin/deoxyhemoglobin ratio, oxyhemoglobin saturation can be derived.²⁴⁹ Because the greatest contribution to a tissue’s absorption spectrum is from blood contained within venules and veins (approximately 3:1 ratio of venous to arterial blood), these devices provide a venous weighted value.²⁵⁰ In comparison, pulse oximetry provides measurement of an arterial oxygen saturation reflecting oxygen supply to tissue. Therefore, near-infrared spectroscopy technology is considered complementary to pulse oximetry. Unlike pulse oximetry that requires pulsatile flow, tissue oximetry does not and is, therefore, ideal in low-flow conditions such as LCOS and/or nonpulsatile CPB or cardiocirculatory assist devices.

The use of cerebral oximetry has been suggested for cardiac surgical patients for several reasons. It is unique in its ability to continuously monitor regional tissue oxygenation even in the LCOS and nonpulsatile flow, the latter commonly seen during CPB. Multiple case reports have demonstrated that cerebral oximetry can provide early warning signs for detecting catastrophic events otherwise not detected by other monitoring devices such as pulse oximetry.²⁵¹ In addition, the cerebral cortex can be seen as an index organ. Although autoregulatory mechanisms have to be considered, low cerebral tissue oxygenation correlates with measures of systemic oxygen delivery and consumption.²⁵² Postoperative cognitive dysfunction is still one of the most frequently reported complications after cardiac surgery. It is likely multifactorial in origin, but embolization and hypoperfusion of the brain are two of the most frequently cited causative factors.²⁵³ Although cerebral oximetry, because of its localized area of interrogation, may not detect even massive particulate emboli to the brain resulting in catastrophic neurologic adverse outcomes such as stroke, these events fortunately are rare, with rates of 1% to 3% reported in the literature (see Chapter 36).²⁵⁴

Many studies have estimated the incidence of neurocognitive dysfunction after cardiac surgery to be greater than 50%.²⁵⁵ There are emerging data that a correlation exists between cerebral oxygen desaturations (measured with cerebral oximetry) and cognitive dysfunction in CABG patients.^256,257 There has been an ongoing debate, however, about the clinical value of near-infrared spectroscopy monitoring as a trend monitor only or as a noninvasive tool that allows clinical decision making based on adequate correlation with absolute measurements. There still need to be data from large, randomized, controlled studies with clearly defined treatment protocols and outcome measures to demonstrate that interventions based on cerebral oximetry readings can improve neurologic outcome in CABG patients.²⁵⁸ Two prospective trials in CABG patients that fit those criteria have been published to date. Slater et al²⁵⁷ randomized 265 CABG patients to a blinded control group or an unblinded intervention group. There were no statistically significant differences in cognitive decline and major postoperative complications (cerebrovascular accident, myocardial infarction, renal insufficiency, reoperation for bleeding) between the two study groups, a result the authors attributed to poor compliance with the treatment protocol. In the multivariate analysis, however, prolonged rSo₂ desaturation was an independent risk factor for postoperative cognitive decline regardless of the assigned study group. Murkin et al,²⁵⁹ in a similar study, demonstrated that treatment of cerebral oxygen desaturations improved outcome in patients undergoing CABG surgery. They randomized 200 patients undergoing CABG surgery to either an intervention group in which cerebral tissue desaturation was linked to a treatment intervention protocol attempting to correct those readings back to baseline values or a control group in which cerebral oximetry readings were blinded to the practitioner. The hypothesis was that most of the interventions to optimize cerebral oxygen saturation would influence systemic perfusion as well. There was no difference in the overall incidence of adverse complications; however, significantly more patients in the control group had major organ morbidity or mortality such as death, ventilation longer than 48 hours, stroke, myocardial infarction, and return for re-exploration. The results of both studies clearly demonstrated that further studies are needed to determine whether postoperative cognitive dysfunction can be reduced by treatment of intraoperative cerebral oxygen desaturations, as well as to define a clear threshold below which the risk for postoperative cognitive dysfunction is increased.

Anesthetic Agents

Considerations for choice of induction agent in the patient undergoing CABG are based on theoretic and practical clinical considerations. Hypertension and tachycardia are most commonly seen in patients with normal ventricular function, a history of arterial hypertension, and left ventricular hypertrophy. They should be avoided, as well as hypotension and excessive myocardial depression, in a patient with depressed ventricular function or with severe flow-dependent stenoses (e.g., left main or proximal LAD disease, coexisting severe valvular stenosis). The cardiac effects of each of the commonly used induction agents have been investigated over many years, sometimes with conflicting results. Increasing sophistication of experimental preparations and measurements is providing new information. Unraveling the direct versus indirect effects of a particular drug on the heart and circulation is complex because overall effects are based on contractility, vascular tone, and response of the autonomic nervous system and baroreceptors. Closely related to this are the details of the animal preparation (e.g., species, acute vs. chronic preparation, open vs. closed chest) or the clinical setting (e.g., type and speed of induction, use of concurrent β-blockers, or other antihypertensives, sophistication of cardiac monitoring) in which the drug is being investigated. Rarely is one drug used exclusively (particularly in this setting in which opioids, volatile agents, and benzodiazepines are often used simultaneously). All of the drugs usually are titrated to effect.

Thiopental had been used for decades for induction in this setting; however, it is rarely used nowadays. Its predominant hemodynamic effects include reductions in MAP and CO accompanied by a modest increase in HR. These are believed to result from a combination of direct myocardial depression, venodilation, and a decrease in central sympathetic outflow. In isolated muscle, whole-animal,²⁶⁰ and clinical studies (including use of load-independent measures of contractility),^261,262 it generally is reported to have greater negative inotropic effects than propofol. A greater degree of vasodilation with propofol also may account for less depression of CO.^263,264 A study of isolated human atrial muscle from CABG patients reported no effect of propofol, midazolam, and etomidate on contractility in contrast with strong effects for thiopental and, paradoxically, slight negative effects for ketamine.²⁶⁵ However, a sheep preparation, in which “site-directed” coronary arterial injection was used to isolate direct cardiac effects using doses small enough to preclude indirect effects from recirculated drug in the central nervous system, reported similar direct cardiac depressant effects for thiopental and propofol (including the thiopental enantiomer and racemate).²⁶⁶ Despite these findings and its use in epidemiologic studies of anesthetic techniques for CABG,²⁶⁷ the use of thiopental in most centers has declined substantially in favor of propofol. Adverse effects on airway resistance, a greater propensity to elicit bronchospasm, and a greater association with postoperative nausea and vomiting are other potential factors (see Chapter 9).

Administration of ketamine generally is associated with increases in HR and MAP through indirect central and peripheral sympathetic stimulation (e.g., inhibition of neuronal reuptake of catecholamines). In states associated with depletion of catecholamines and in isolated preparations, ketamine appears to have direct negative inotropic and vasodilating effects,^265,268 and it may have a negative lusitropic effect decreasing diastolic compliance.²⁶⁹ In a double-blind, randomized, controlled trial, Zilberstein et al²⁷⁰ documented a potent anti-inflammatory effect (i.e., suppression of increases in superoxide anion production after CPB) with a very small dose of ketamine (0.25 mg/kg) that persisted for several days after surgery. Ketamine is used relatively infrequently in CABG patients and is reserved primarily for induction in those with severe reduction of EF.

Etomidate appears to have minimal or no direct negative inotropic effects or sympathomimetic effects.^271,272 In an isolated rabbit heart preparation, Komai et al²⁷³ demonstrated that at very high concentrations, etomidate inhibited the influx of extracellular calcium but had no effect on availability of intracellular calcium required for excitation-contraction coupling. It is known to inhibit adrenal mitochondrial hydroxylase activity, resulting in reduced steroidogenesis even after a single bolus dose, although the studies are conflicting.^274,275 Its use for induction in cardiac patients with impaired ventricular function is common. Myoclonic jerking can be observed in the absence of muscle relaxation. The use in patients with normal ventricular function should be carefully considered because blunting of the adrenergic response to intubation is poor and may result in hypertension and tachycardia, particularly with the low-dose opioid techniques used today. Greater associations with postoperative nausea and vomiting are other potential adverse effects seen with etomidate administration.

The clinical effects of propofol are, in general, similar to those of thiopental. However, it has numerous advantages over thiopental based on its predictable pharmacokinetics and dynamics.^276,277 It often is used for sedation after CABG surgery,²⁷⁸ although with the recent approval of dexmedetomidine for this indication,²⁷⁹ its use may decline. Its isolated effects on contractility are controversial, with conflicting findings depending on the model used. A sophisticated analysis of its effects in CABG patients using TEE assessment of preload-adjusted maximal power, a load-independent measure of contractility, at four different plasma concentrations (0.6 to 2.6 mg/mL) found no direct effect on contractility, although it lowered preload and afterload.²⁸⁰ It previously was evaluated in numerous clinical studies for induction and maintenance with an opioid (most commonly sufentanil) compared with a volatile-opioid combination for CABG in patients with normal and depressed EF. These studies reported minimal differences in hemodynamics or in the incidence of myocardial ischemia.^281–286 However, more sophisticated and larger contemporary studies closely evaluating ventricular function on weaning from CPB and perioperative release of biomarkers of ischemia consistently reported better myocardial protective properties with the use of volatile agents over a total intravenous anesthetic technique with propofol. This is apparently related to anesthetic preconditioning and postconditioning effects of volatile agents (see Chapter 9). Propofol has been reported to have strong free radical scavenging properties that in one CABG study appeared to have attenuated myocardial lipid peroxidation in atrial tissue biopsies.²⁸⁷ In addition, propofol may have cardioprotective properties. The PRO-TECT II (PROpofol cardioproTECTion for type II diabetics) study is investigating whether high-dose propofol can confer cardioprotection to diabetics, a population that may not benefit as much from inhalation anesthetics.²⁸⁸

Benzodiazepines commonly are used in combination with a narcotic to induce anesthesia for CABG. In most settings, midazolam has replaced diazepam, given its numerous advantages (particularly water solubility, a shorter half-life, and absence of metabolites capable of accumulation, prolonging the sedative effects).²⁸⁹ Stanley et al^290,291 and Liu et al²⁹² were among the first to report on the addition of diazepam to high-dose morphine and, shortly thereafter, fentanyl anesthesia for CABG. They reported a mild-to-moderate reduction in CO (approximately 20% relative to opioid alone, with the greatest decrease in the fentanyl group). These studies suggested that diazepam should not be used, particularly in patients with impaired ventricular function. However, with the realization that breakthrough adrenergic responses, as well as a substantial incidence of anesthetic recall with fentanyl alone, can occur, supplementation with diazepam or midazolam quickly grew in popularity together with high-dose opioids in the early to mid-1980s.

Numerous clinical series of widely different sizes and designs, reporting on the efficacy of diazepam or, more commonly, midazolam used with high-dose opioids, were subsequently published.^293–304 Moderate degrees of hypotension were reported in most studies, primarily attributed to a reduction in SVR (or from the effects of the high-dose opioid itself given the potent bradycardic effects of high-dose sufentanil). With rare exception, most investigators considered it safe and effective.³⁰⁵

There has been relatively little research on the direct cardiac effects of midazolam. Messina et al³⁰⁶ reported a clinical study of 40 CABG patients in whom 0.1 mg/kg midazolam was administered after induction and intubation with thiopental, fentanyl, and pancuronium. Contractility was depressed by midazolam, although afterload was reduced simultaneously, resulting in no net change in cardiac index. Patients with depressed baseline EF had lower indices of contractility at baseline but a similar magnitude of change. This study provided clinical confirmation of the safety of midazolam in clinical practice, particularly given its experimental design. Most clinicians have reduced dosing of midazolam to the range used in the latter study. Midazolam is used widely because of clinicians concerns regarding recall. However, with the use of continuous volatile anesthesia and availability of convenient neuromonitoring techniques, it should no longer be considered a necessity, particularly with use of small amounts as a component of the premedication.

High-dose opioid anesthesia was introduced into cardiac surgery by Lowenstein et al³⁰⁷ in 1969, in an attempt to provide safe anesthesia without myocardial depression in patients with severe valvular heart disease and compromised cardiac function. Although this revolutionized anesthesia for patients with cardiac dysfunction, it was apparent that morphine had several disadvantages: vasodilation from histamine release, increased requirements for fluids and vasoconstrictors, and prolonged respiratory depression. When morphine was given to patients with normal LV function, with most patients undergoing CABG particularly in the previous decades, dramatic hemodynamic responses occurred with surgical stress and amnesia could not be guaranteed; the anesthesia often was inadequate. Despite these well-known adverse effects, morphine has regained attention because of its possibly unique cardioprotective and anti-inflammatory properties.^308,309

In the late 1970s, Stanley and collaborators first reported on the use of high doses of the synthetic opioid fentanyl for CABG, with and without supplemental benzodiazepines.^310–312 Clinicians worldwide who perceived the lack of histamine release to be a favorable property rapidly adopted it into their clinical practice.^313–319 However, it was recognized early on that recall still could be a problem.³²⁰ Reports on the use of the more potent sufentanil appeared at the same time as fentanyl, although most studies were not reported until the late 1980s.^321–330 It, too, was widely adopted, although there was concern over its potent bradycardic effects at high dosages, particularly when administered with nonvagolytic muscle relaxants.^331,332

In the mid-1990s, remifentanil was introduced. Fueled by intense interest in fast-tracking (being promoted in the same time frame), it has been intensively investigated.^333–342 Careful planning with regard to when it is terminated and adequate continuation of pain control is required. The combination with neuraxial anesthetics also has been advocated.³⁴³ There have been reports of greater degrees of hypotension compared with fentanyl or sufentanil.^344,345 Remifentanil infusion was found to attenuate the perioperative endocrine stress response as compared with fentanyl boluses as an adjunct to inhalation anesthesia.³⁴⁶

Based on computer modeling and clinical data, sufentanil appears to have the most favorable characteristics for continuous infusion with very predictable termination of effect.^347,348 This characteristic was believed to be particularly important in the early 1990s when early postoperative suppression of ischemia by “intensive analgesia” was proposed as an important treatment goal just before the widespread interest in fast-tracking.³⁴⁹ The substantially greater costs of sufentanil (than fentanyl) and the apparent aversion of many cardiac anesthesiologists to use continuous anesthetic infusions have limited its use. Most evidence suggests that despite documented associations of sufentanil use with shorter times to extubation, overall costs and hospital lengths of stay are unaffected relative to fentanyl.^350–352 Nonetheless, it remains popular with many clinicians, many of whom infuse it continuously during surgery.

These drugs are pure opioid agonists, and none provides complete anesthesia as defined by predictable dose–response relations for suppression of the stress response and release of endogenous catecholamines (particularly norepinephrine), even with high serum concentrations.^353–355 Hypertension and tachycardia commonly have been reported in response to induction/intubation and surgical stimuli (particularly with sternotomy) in older studies of high-dose opioid anesthesia with fentanyl or sufentanil.^356,357Figures 18-14 and 18-15 demonstrate this lack of association of serum levels with hemodynamic responses. The seminal study of Philbin et al³⁵⁸ (see Figure 18-15) investigated the relation between opioid dose and hemodynamic effect with fentanyl or sufentanil in a randomized study of CABG patients. Forty premedicated patients were allocated to receive fentanyl (50 or 100 μg/kg) or sufentanil (10, 20, or 30 μg/kg) in bolus dosing with 100% oxygen and the relaxant metocurine, with an additional 40 patients randomized to sufentanil bolus dosing (10, 20, or 40 μg/kg, followed by continuous infusions). Plasma opioid (only for sufentanil in the bolus/continuous infusion groups) and catecholamine concentrations were obtained after intubation and after sternotomy. A hemodynamic response was defined as a 15% or greater increase in systolic blood pressure (HRs were not reported), and a hormonal response was a 50% or greater increase from control. For both opioids, the frequency of hemodynamic responders (33% to 60%) was similar between all fentanyl and sufentanil bolus groups. In the sufentanil infusion groups, the plasma concentrations were consistent and dose related, with wide spreads between the groups. Twenty-four of the 40 patients were hemodynamic responders (with 18 occurring with sternotomy), and the frequency of response was unrelated to plasma sufentanil levels. Although this study had design flaws (e.g., small sample sizes and lack of power analyses, lack of reporting of actual hemodynamics), it is widely quoted to support the contention that even high-dose opioids alone provide incomplete anesthesia. Despite this, “narcotic anesthesia” was for many years considered synonymous with a “cardiac anesthetic” that should be used in all patients with CAD. It is only recently that this erroneous association is being laid to rest as volatile-based fast-tracking techniques have become standard of care in most patients undergoing myocardial revascularization.

Figure 18-14 The plasma fentanyl concentration and number of patients with a hypertensive response at each event studied. Purple circles indicate hypertensive status; green circles indicate normotensive status.

(From Wynands JE, Townsend GE, Wong P, et al: Blood pressure response and plasma fentanyl concentrations during high and very high-dose fentanyl anesthesia for coronary artery surgery. Anesth Analg 62:661, 1983.)

Figure 18-15 The graph plots patients with a hemodynamic response and the plasma sufentanil concentration at that time, as well as the sufentanil concentrations for the nonresponders. Therapy was initiated at the time of the initial response, and no further data points were included for those patients.

(From Philbin DM, Rosow CE, Schneider RC, et al: Fentanyl and sufentanil anesthesia revisited: How much is enough? Anesthesiology 73:5, 1990.)

The usual practice to provide complete anesthesia is to supplement opioids with inhaled or other intravenous agents. This permits a reduction in the total dose of opioid and, particularly with volatile agents, more rapid return of respiratory drive, facilitating early extubation. Thomson et al³⁵⁹ have incorporated this approach and extended the concepts investigated by Philbin and Roscow³⁶⁰ in a small but sophisticated study of CABG patients whereby specific effect site concentrations of fentanyl or sufentanil were targeted by using a computer-assisted infusion pump. Three targeted concentrations for each opioid were evaluated: sufentanil 0.4, 0.8, and 1.2 ng/mL and fentanyl 5, 10, and 15 ng/mL and the end-tidal concentration of isoflurane required to control MAP and HR in the prebypass period by predetermined criteria were monitored. The sufentanil subgroups required approximately 1.9, 3.1, and 4.9 μg/kg, and fentanyl subgroups received 18.8, 33.9, and 50.4 μg/kg in this period. The average end-tidal concentration of isoflurane was significantly greater between the low and medium/high groups, with no difference between medium and high groups. Most of the responses were increases in MAP (incidentally, the prime focus of Philbin and Roscow’s³⁶⁰ study). Regression analysis revealed significant correlations between serum opioid concentrations and isoflurane concentrations at most of the time points sampled in the pre-CPB period. By inspecting plots of the data pairs, they were able to ascertain the inflection point at which the isoflurane concentration began to increase rapidly, indicating poor control of hemodynamics by the respective opioid. For sufentanil, this was 0.71 ± 0.13 ng/mL, and for fentanyl, it was 7.3 ± 1.1 ng/mL. Given the use for fast-tracking with approximate ranges of 20 μg/kg for fentanyl and 3 μg/kg for sufentanil for the entire case, it is unlikely these concentrations will be obtained. However, reliance on volatile anesthesia, benzodiazepines, propofol, or dexmedetomidine infusion can provide hemodynamic control. The level of preexisting β-blockade and/or calcium channel-blockade and the type of muscle relaxant used influence each patient’s response.

Neuromuscular Blocking Agents

All of the available neuromuscular blocking agents have been used to produce adequate intubating conditions and relaxation during CABG surgery (Table 18-3). Murphy et al³⁶¹ conducted a national survey of more than 400 active members of the Society of Cardiovascular Anesthesiologists evaluating their neuromuscular blocking drug of choice in the cardiac surgical setting. Despite availability of newer short-acting neuromuscular blocking agents, pancuronium was still used in most patients undergoing on-pump and off-pump cardiac surgical procedures 10 years ago. Traditionally, pancuronium had been advocated for use with high-dose narcotic techniques, because it offset opioid-induced bradycardia. However, it has long been recognized that clinically significant tachycardia resulting in myocardial ischemia could occur during induction of anesthesia with high-dose fentanyl and pancuronium.³⁶² With the increasing popularity of fast-track cardiac surgery, early extubation is now most desirable, and the longer duration of action of pancuronium is a potential disadvantage. Several studies have compared the durations of action of pancuronium and rocuronium in patients undergoing cardiac surgery. Irrespective of a single intubating dose or a continuous infusion, patients receiving rocuronium had significantly less residual neuromuscular blockade³⁶³ and shorter time to extubation.^364,365

When continuous infusions of rocuronium and cisatracurium were compared in prolonged surgical procedures, recovery to 75% of the train of four was faster in patients receiving cisatracurium.³⁶⁶ Reich et al³⁶⁷ compared neuromuscular transmission recovery times in pediatric cardiac patients receiving cisatracurium or vecuronium infusions in the ICU setting. Cisatracurium was associated with significantly faster spontaneous recovery of neuromuscular function. Especially in fast-track cardiac surgery, shorter-acting neuromuscular blocking agents such as cisatracurium or rocuronium are recommended to avoid residual paralysis and to allow for early extubation and ICU discharge. Neuromuscular transmission monitoring to assess for residual blockade and use of pharmacologic reversal is advisable, especially if a fast-track anesthesia technique is used.^368,369 In patients with a potentially difficult airway or emergency patients who are not NPO, succinylcholine is still the agent of choice.

Additional considerations are warranted in patients with underlying comorbidities such as chronic renal failure, which may alter pharmacokinetics. When magnesium is administered to cardiac surgical patients for prophylaxis of perioperative arrhythmias, blockade from nondepolarizing neuromuscular blocking agents may be significantly prolonged.³⁷⁰ There remains the question whether continuous neuromuscular blockade for cardiac surgery really is necessary. Gueret et al³⁷¹ showed that a single intubating dose of atracurium or cisatracurium provided adequate paralysis and surgical conditions leading to quicker neuromuscular blockade recovery in cardiac surgical patients. Advocates of this technique also point to potential advantages with regard to prevention of recall (as indicated by patient movement). However, potential disadvantages include the possibility of greater oxygen demand and consumption, or movement during surgery.

α₂-Agonists: Dexmedetomidine

The intraoperative use of α₂-agonists can be a useful adjunct, given their sedative, analgesic, and hemodynamic-stabilizing properties. α₂-Agonists prevent hypertension and tachycardia during intubation, surgical stimulation, and emergence from anesthesia, and decrease plasma catecholamine levels.^372–375 Jalonen et al,³⁷⁶ in a randomized, double-blind study, administered dexmedetomidine or placebo to CABG patients starting before induction (50 ng/kg/min for 30 minutes) and continued until the end of surgery (7 ng/kg/min). Patients receiving dexmedetomidine had significantly lower plasma norepinephrine levels and more stable hemodynamics (less increase in MAP and HR during induction, less intraoperative variability of systolic arterial pressure). Dexmedetomidine administration was associated with decreased incidences of intraoperative (5% vs. 32%) and postoperative (4% vs. 40%) tachycardia when compared with placebo. Patients who received dexmedetomidine also were less likely to receive β-blocker therapy for tachycardia. Despite the findings before and after CPB, a greater incidence of hypotension (MAP < 30 mm Hg) was seen during CPB (22% vs. 0% patients, dexmedetomidine vs. placebo). These data demonstrate that dexmedetomidine is effective in attenuating sympathetic responses, although this effect may predispose patients toward hypotension.

Because of the decreased oxygen demand and HR seen with dexmedetomidine administration, it may be beneficial during OPCAB. Nevertheless, in a small series of OPCAB patients, hypotension (12 mm Hg below baseline) occurred shortly after its administration during rewarming in the ICU, prompting the study authors to recommend volume loading and normothermia before its use.³⁷⁷ Experimental data demonstrated a decrease in the inflammatory response to endotoxin-induced shock in a rat model.³⁷⁸

Inhalation Anesthetics and Myocardial Protection

There is steadily increasing evidence from laboratory and clinical studies that inhalation anesthetic agents have favorable properties in patients undergoing CABG surgery, particularly in comparison with total intravenous anesthetic approaches. Concurrent with the now routine use of fast-track anesthesia techniques, there has been a major resurgence in their use as the primary anesthetic in patients undergoing cardiac surgery. Inhalation anesthetics are thought to protect the myocardium against ischemia by their ability to elicit protective cellular responses that are seen with ischemic preconditioning. The latter has been shown to reduce myocardial infarction size after periods of ischemia,³⁷⁹ protect the heart against postischemic LV dysfunction,³⁸⁰ and reduce the incidence of arrhythmias after cardiac surgery.³⁸¹

Murry et al³⁸² first showed that brief periods of ischemia before 40 minutes of coronary artery occlusion significantly reduced infarction size after myocardial reperfusion. Exposing the myocardium to short periods of ischemia followed by reperfusion is called ischemic preconditioning. These brief periods of ischemia initiate signaling pathways that render the myocardium resistant to subsequent prolonged periods of ischemia (i.e., memory effect).³⁸³ After a short ischemic period (i.e., preconditioning signal), the myocardium is rendered more resistant to prolonged ischemia when the subsequent ischemic event occurs within a certain time window. This may occur in two distinct phases as early preconditioning (about 2 hours) and delayed or late preconditioning (24 to 72 hours), although not all stimuli elicit both responses. Even though multiple approaches are used to protect the heart during CPB (e.g., blood cardioplegia, topical hypothermia, pharmacologic additives), aortic cross-clamping defines a period of myocardial ischemia that often results in transient or prolonged dysfunction after reperfusion.^384,385 Brief periods of aortic cross-clamping with consequent reperfusion intervals before a period of ventricular fibrillation have been shown to preserve adenosine triphosphate (ATP) content, decrease markers of ischemia such as troponin I, and improve cardiac function in patients undergoing CABG.^386–389 However, this approach is controversial and cumbersome because an ischemic episode may reduce cardiac reserves and exacerbate symptoms.³⁹⁰ In addition, the accomplishment of brief periods of ischemia by short cross-clamping of an atherosclerotic aorta may result in embolism formation and endothelial damage, thereby increasing mortality.³⁹¹ Interestingly, this protection is now believed to be conferred even when the brief period of ischemia is applied to organs or tissues remote from the heart (remote preconditioning), thus improving its applicability.^392–396

Pharmacologic interventions have been sought that mimic ischemic preconditioning. There is increasing evidence that aside from potent volatile anesthetics, opioids and, in particular, morphine trigger preconditioning.^397,398 Other intravenous anesthetics such as etomidate and ketamine do not appear to have the same cardioprotective properties.^399,400 Pharmacologic preconditioning and ischemic preconditioning initiate similar pathways that protect the myocardial cell against ischemic damage.

The pathways associated with myocardial preconditioning involve a variety of triggering stimuli, mediators, receptors, and effectors.⁴⁰¹ It is thought that activation of sarcolemmal and mitochondrial K_ATP channels play a pivotal role in the preconditioning process.⁴⁰² Opening of these channels protects the myocardium by preventing cytosolic and mitochondrial Ca²⁺ overload. The exact mechanisms of preconditioning are still actively under investigation. After the administration of a preconditioning signal such as ischemia, inhalation anesthetics including the noble gases, morphine, bradykinin, or nitroglycerin (NTG), membrane-bound receptors (adenosine A₁, adrenergic, bradykinin, muscarinic, delta-1 opioid) coupled to inhibitory G proteins are activated.^403–408 Consequently, products of intracellular transduction pathways (e.g., protein kinase C [PKC], tyrosine kinases, MAP kinases) mediate the opening and stabilization of ATP-sensitive mitochondrial K_ATP channels, the effectors thought to be mainly responsible for the preconditioning phenomenon.^409,410 Increased formation of nitric oxide (NO),^411,412 free oxygen radicals,⁴¹³ and enzymes such as cyclooxygenase-2⁴¹⁴ are also involved in the preconditioning process. The role of NO recently was confirmed by Smul et al using a rabbit model.⁴¹⁵ The delayed phase of myocardial protection, which may last well beyond the documented 24 to 72 hours, probably is based on transcriptional changes of protective proteins,^416,417 which may explain the gap of time between early and late preconditioning.⁴¹⁸ Inhalation anesthetics also preserve cardiac function after reperfusion and decrease ischemia-induced intracoronary adhesion of polymorphonuclear neutrophils and platelets.^419–423

Initially, most data were based on in vitro studies or from data obtained during PCIs. Whether these results could be generalized to cardiac surgery remained questionable. Multiple studies now have investigated anesthetic preconditioning in the cardiac surgery setting and its impact on outcome parameters. Belhomme et al⁴²⁴ exposed patients to 5 minutes of preconditioning with a 2.5 minimum alveolar concentration of isoflurane after the onset of CPB but before aortic cross-clamping. Troponin I and creatine kinase (CK)-MB levels were not significantly different from those of the control group. Nevertheless, patients who were exposed to isoflurane had increased activity of 5-nucleotidase, a marker for protein kinase C activation, which is early evidence of preconditioning pathway activation similar to the in vitro findings. Penta de Peppo et al⁴²⁵ reported on myocardial function and the preconditioning effects of enflurane in patients undergoing CABG surgery. Myocardial function was assessed using the end-systolic pressure-area relation, a relatively load-independent index of myocardial contractility. Although the number of patients studied was small, myocardial function was better preserved in patients who were exposed to enflurane before cardioplegic arrest.

Julier et al,⁴²⁶ in a double-blinded, placebo-controlled, multicenter study, reported on the effect of sevoflurane preconditioning on biochemical markers for myocardial and renal dysfunction in patients undergoing CABG surgery. Patients who had sevoflurane preconditioning during the first 10 minutes of CPB had lower levels of biochemical markers of myocardial and renal impairment. Brain natriuretic peptide level as an indicator of myocardial dysfunction was significantly decreased in the sevoflurane group. Conzen et al⁴²⁷ studied randomized patients undergoing OPCAB surgery with a propofol infusion versus a continuous inhalation-based anesthetic technique with sevoflurane. Patients in the sevoflurane group had significantly lower troponin I levels, as well as better LV function. Nader et al⁴²⁸ added vaporized sevoflurane (2%) versus oxygen alone to a cold blood cardioplegia solution in a small randomized trial of patients undergoing CABG surgery. Markers of the inflammatory response (i.e., neutrophil β-integrins, tumor necrosis factor-α, and interleukin-6) were lower, and cardiac function (i.e., stroke work index and wall motion analysis) was better preserved in the sevoflurane group (Figure 18-16). Table 18-4 summarizes the results of the randomized, prospective clinical studies.^429–440

Figure 18-16 Blunting of increase of interleukin-6 (IL-6) levels in response to cardiopulmonary bypass (CPB) in patients receiving 2% sevoflurane (SEVO) added to the cardioplegia solution (1.4 ± 1.2 to 38.2 ± 21.6 pg/mL vs. 4.1 ± 1.4 to 118.2 ± 23.5 pg/mL; P < 0.05). Levels were similar by 6 hours after CPB. CS, coronary sinus; T1, baseline; T2, after separation from CPB; T3, 6 hours after separation from CPB. *†, statistically significant.

(From Nader ND, Li CM, Khadra WZ, et al: Anesthetic myocardial protection with sevoflurane. J Cardiothorac Vasc Anesth 18:269, 2004.)

Whether these biochemical markers of improved cardiac outcome actually translate into reduced mortality or improved long-term outcome remains a matter of debate.⁴⁴¹ Garcia et al⁴³⁵ reported on the results of a prospective, randomized study of the effect of sevoflurane preconditioning (10 minutes before aortic cross-clamping) on late cardiac events. Coronary artery reocclusion, congestive heart failure, and cardiac death were assessed at 6 and 12 months after surgery. Preconditioning with sevoflurane significantly reduced the incidence of late cardiac events. In a prospective, randomized, nonblinded study, De Hert et al⁴⁴² compared the inhalation anesthetics desflurane and sevoflurane with an intravenous anesthetic technique with a continuous propofol infusion in high-risk patients undergoing CABG surgery. In the volatile anesthetic group, myocardial function was better preserved, troponin I levels were lower, and ICU and hospital LOS were shorter compared with propofol or midazolam-based anesthetic regimens in this setting.⁴⁴³ Guarrancino et al⁴⁴⁴ showed that a desflurane-based anesthetic resulted in reduced troponin I release, inotropic drug use, and number of patients requiring prolonged hospitalization compared with a propofol-based technique in off-pump CABG.

Three recent meta-analyses examined preconditioning and mortality or long-term outcome in patients undergoing cardiac surgery. In a meta-analysis that included only studies with sevoflurane and desflurane, Landoni et al⁴⁴⁵ showed a reduction in mortality and the incidence of myocardial infarction after cardiac surgery. In two other meta-analyses that also included isoflurane, no such benefit was seen.^446,447 Data from a retrospective Danish database multicenter analysis including 10,535 patients did not show any difference in overall postoperative mortality or myocardial infarction between propofol and sevoflurane-based anesthesia.⁴⁴⁸ To further investigate these controversial findings, Bignami et al⁴⁴⁹ conducted a longitudinal survey among 64 Italian cardiac surgical centers to study the correlation between the use of volatile anesthetics and 30-day mortality in CABG surgery. The results showed that risk-adjusted 30-day mortality was significantly reduced when volatile agents were used during cardiac surgery, especially when there was prolonged use of these agents. Interestingly, the most consistent results were found when isoflurane was used. In a recent multicenter trial comparing desflurane or sevoflurane with propofol-based anesthesia, De Hert et al⁴⁵⁰ were unable to find a difference in troponin release but did show that the use of inhalation anesthetics reduced hospital LOS and patients in the inhalation anesthetic group had a lower 1-year mortality.

The optimal timing and duration of inhalation anesthetic administration are still under investigation.^451–454 Whereas some of the studies use brief periods of anesthetic preconditioning before aortic cross-clamping, others have reported on use of volatile anesthetics throughout the operative period. The older studies using brief periods of preconditioning showed improved cardiac function, although markers of myocardial injury such as CK-MB or troponin I often were not significantly different from the control group. De Hert et al⁴⁵⁵ showed that the best results for myocardial protection were achieved when sevoflurane was administered throughout the intraoperative period and not just immediately before the planned myocardial ischemic event. Most similarly designed studies have confirmed those findings. Bein et al,⁴⁵⁶ however, found that myocardial cell damage and dysfunction were lower in patients who received sevoflurane in an interrupted manner. Frassdorf et al⁴⁵⁷ also demonstrated that preconditioning-related myocardial protection was superior with multiple periods of sevoflurane administration applied rather than one short period. When sevoflurane was added to the anesthesia regimen after the coronary anastomoses were completed, myocardial recovery was faster compared with a propofol-based anesthetic technique. Nevertheless, patients who received sevoflurane during the entire procedure had the lowest troponin I levels, and the stroke volume changed the least compared with baseline levels.⁴⁵⁵ Most data available to date suggest not limiting the use of inhalation anesthetics to brief periods, but rather to use prolonged administration.

Research on pharmacologic preconditioning is not restricted only to inhalation anesthetics. There is increasing evidence that a variety of drugs that are administered perioperatively have cardioprotective properties involving preconditioning pathways. Besides inhalation anesthetics, opioids (delta-opioid receptor), adenosine (adenosine A₁ receptor), and bradykinin have been investigated for their preconditioning effects, with variable results.^458–461

During cardiac surgery, several of the known preconditioning triggering agents may be used and appear to be additive or synergistic in effect. Toller et al⁴⁶² reported that the administration of sevoflurane and mechanical ischemic preconditioning reduced infarction size significantly compared with either stimulus alone. Ludwig et al⁴⁶³ demonstrated the additive effect of isoflurane and morphine on the reduction of infarction size. There are still insufficient data on how the potential beneficial effect of potent inhalation anesthetics differs between OPCAB and on-pump CABG patients, with some preliminary data that OPCAB patients may benefit more.⁴⁶⁴

Several clinical factors appear to impair the protective effects of preconditioning. Two groups of patients, diabetic and female patients, appear to have attenuated responses to mechanical preconditioning signals (during PCI).⁴⁶⁵ Intraoperative hyperglycemia blocks the preconditioning effect, although this effect may be reversed by N-acetylcysteine, an oxygen radical scavenger.^466–470

The role of postconditioning is now also starting to be elucidated. Prompt treatment of myocardial ischemia is essential for limiting myocardial damage. However, the damage to the myocardium is not only a result of the ischemic time but of the reperfusion itself. Brief episodes of ischemia/reperfusion applied during the first few minutes of reperfusion after a prolonged ischemia have been shown to decrease myocardial infarct size to the same extent as that induced by ischemic preconditioning.^471,472 It is thought that mitochondrial K_ATP channels, NO, and protein kinase C play important roles in postconditioning as well.⁴⁷³ Protein kinase C is one of a larger group of kinases labeled “reperfusion injury salvage kinases” that play a role in postconditioning.^474–476 The beneficial effects of ischemic postconditioning also have been shown in humans during coronary angioplasty for acute myocardial infarction.^477,478 As in preconditioning, postconditioning also has been found to work when applied remotely.⁴⁷⁹ Inhalation anesthetics also may be effective in blunting the deleterious effects of postischemic reperfusion injury and the inflammatory response syndrome after cardiac surgery.^480,481 Thus far, most data about anesthetic postconditioning have been gathered from studies in animals and in vitro isolated human myocardium. Postconditioning has been shown to improve contractile function⁴⁸² and attenuate postischemic arrhythmias.⁴⁸³ Recent data further suggest that the protective properties of potent inhalation anesthetics may not be restricted only to the myocardium but extend to other organ systems.^484–487

In summary, there is increasing evidence suggesting that potent inhalation anesthetics should be part of the anesthetic regimen in patients undergoing cardiac surgery, particularly in patients undergoing CABG, OPCAB, and/or patients at high risk for ischemic events.⁴⁸⁸

Intraoperative Awareness and Recall

Intraoperative awareness (i.e., recall), usually defined as postoperative memory for intraoperative events, is an infrequent but well-recognized phenomenon during general anesthesia. Awareness, a conscious subjective experience (i.e., implicit memory), may be much more frequent than conscious recall (i.e., explicit memory) of intraoperative events.⁴⁸⁹ In a prospective, nonrandomized, descriptive cohort study of more than 19,000 patients undergoing surgery with general anesthesia at seven academic medical centers in the United States, awareness with explicit recall occurred in 0.13% of the cases.⁴⁹⁰ Patients undergoing cardiac surgery always have been considered to be at increased risk because of anesthetic regimens intentionally devoid of cardiodepressant inhalation anesthetics (before the era of improved myocardial preservation and fast-tracking) and because of frequent periods of light anesthesia in the presence of hemodynamic instability resulting from surgical manipulation of the heart and great vessels, depressed contractility after CPB, or bleeding. The published incidence rate of awareness in patients undergoing cardiac surgery is significantly greater than that reported for general surgery, with older reports of up to 23%.⁴⁹¹ However, the introduction of fast-track anesthesia techniques and the more frequent use of inhalation agents have helped to reduce the risk for intraoperative awareness for this type of surgery. Ranta et al⁴⁹² found definite intraoperative awareness with recall in 0.5% of patients undergoing cardiac surgery under general anesthesia, with various anesthesia regimens using inhalation or total intravenous anesthetic techniques. Greater doses of benzodiazepines, such as midazolam, resulted in a lower incidence of awareness. Phillips et al⁴⁹³ interviewed 700 patients after cardiac surgery with CPB and found that 8 patients (1.8%) reported intraoperative recall regardless of whether benzodiazepines or inhalation agents were used. Fast-track anesthesia techniques typically combine low-dose narcotics with short-acting anesthetics such as inhalation agents or propofol infusions. Dowd et al⁴⁹⁴ reported a low incidence rate (0.3%) of intraoperative awareness with this technique, attributing it to the continuous administration of volatile anesthetics or propofol.

Measures to prevent intraoperative awareness typically are based on anesthetic regimens that interfere with memory processing, such as the use of inhalation anesthetics and benzodiazepines. However, the anesthesia technique does not always correlate with the incidence of intraoperative awareness. In a large series of more than 11,000 patients undergoing general anesthesia, 18 cases of recall occurred (0.18%), but the analysis suggested that this number could not have been reduced with monitoring of end-tidal anesthetic gas concentrations or more frequent use of preoperatively administered benzodiazepines.⁴⁹⁵ Efforts to determine time periods that are prone to awareness or recall usually are based on physiologic or hemodynamic parameters that indicate light anesthesia, such as tachycardia, arterial hypertension, or patient movement. Nevertheless, Kerssens et al⁴⁹⁶ showed that hemodynamic variables were poor predictors of intraoperative awareness, although these parameters were able to differentiate between patients with or without conscious recall. In contrast, electroencephalogram-derived parameters were highly significant predictors of intraoperative awareness but were not able to detect patients with conscious recall.

Consequently, if hemodynamic parameters or measures of anesthetic concentrations are insufficient in preventing intraoperative awareness, the question arises whether monitoring neurophysiologic parameters such as processed electroencephalographic data decreases the incidence of intraoperative awareness or recall (see Chapter 16). Neurophysiologic monitoring is usually based on fast Fourier transformation and bispectral analysis of one-channel electroencephalographic data obtained from electrodes on the patient’s forehead. Several devices have been approved by the U.S. Food and Drug Administration (FDA).^497–500 Two large studies showed a significant reduction in awareness under general anesthesia when the Bispectral Index (BIS) was monitored. Myles et al⁵⁰¹ studied 2463 patients considered to be at high risk for awareness in a prospective, randomized, double-blinded, multicenter trial with 45% undergoing high-risk cardiac surgery or OPCAB. Patients were randomized to BIS-guided or routine anesthesia care. BIS monitoring reduced the risk rate for awareness by 82%, although the absolute number of confirmed events was small (2 vs. 11). In patients undergoing cardiac surgery, three events occurred (two routine, one BIS). “Possible” awareness events (not confirmed by the end-point committee) occurred irrespective of the use of BIS monitoring. Ekman et al,⁵⁰² in a large, nonrandomized, historically controlled study, also showed a significantly reduced incidence rate of intraoperative awareness (0.04% vs. 0.18%) in the BIS monitored patients. However, in a small series of patients, Barr et al⁵⁰³ found no correlation between bispectral electroencephalographic analysis of anesthesia depth and conscious recall in patients undergoing cardiac surgery. This was attributed to exclusive use of midazolam and fentanyl.

Besides monitoring anesthetic depth, neurophysiologic monitoring also may help to decrease the incidence of hemodynamic disturbances, may guide titration of anesthetic agents to their effective dose, and may be associated with improved patient satisfaction.^504,505 In clinical experience, the use of BIS monitoring has been helpful in more accurately gauging the need for reinstitution of volatile anesthesia after weaning from CPB. In this potentially unstable period with a depressed myocardium or untoward responses to protamine, this can be an important factor. Often the BIS remains in the low range for the first 15 to 30 minutes after weaning, especially in older patients with longer pump times. It also is helpful to ensure adequacy of burst suppression for hypothermic circulatory arrest.

In summary, published data appear to indicate that despite a substantial reduction in awareness resulting from a shift to greater use of volatile anesthetics, patients undergoing cardiac surgery are still at risk for intraoperative awareness or recall. Neurophysiologic monitoring decreases the incidence of these events, but given the low incidence, a large number of patients have to be monitored to prevent one case of intraoperative awareness. The implications of intraoperative awareness or conscious recall are not yet fully understood. These events may be unrecognized or not necessarily experienced as unpleasant,⁵⁰⁶ but they also may lead to severe post-traumatic stress disorders with chronic health impairment.⁵⁰⁷

Incidence

In addition to providing anesthesia, a major concern of the anesthesiologist is the prevention and treatment of myocardial ischemia. Numerous laboratory and clinical studies have examined the incidence of myocardial ischemia in the perioperative period, as it relates to the administration of anesthetic drugs. Although the incidence rate of prebypass ischemia in patients appears to be between 10% and 50%, it is not at all clear that the anesthetic drug combination per se is a determinant of this incidence. Several studies have addressed whether the anesthetic technique (e.g., fast-track or early extubation, high thoracic epidural) is related to perioperative morbidity and myocardial ischemic events. An extensive meta-analysis of more than 30 randomized, controlled trials of patients undergoing cardiac surgery showed no difference in the relative risk of postoperative myocardial ischemia when early extubation protocols were compared with conventional extubation management.⁵⁰⁸

Hemodynamic Changes Related to Myocardial Ischemia

Besides ECG abnormalities, some hemodynamic changes should alert the anesthesiologist to the possibility of intraoperative myocardial ischemia. The association of tachycardia with hypotension or increased LV filling pressure, both of which reduce coronary perfusion pressure [CPP], is a particularly undesirable combination, jeopardizing the oxygen supply-demand relation. Figure 18-17 demonstrates how hypertension in the absence of tachycardia, in response to surgical stress (skin incision), can be associated with pulmonary hypertension, increased PCWP, and prominent A and V waves on the PCWP waveform.⁵⁰⁹ Although ECG changes occurred later, the early hemodynamic abnormalities almost certainly were the result of ischemic LV dysfunction. Treatment included deepening anesthesia and administering an NTG infusion.

Figure 18-17 Nitroglycerin (NTG) relieved postintubation intraoperative myocardial ischemia, as evidenced by large V waves in the pulmonary capillary wedge pressure (PCWP) tracing and then by ST-segment depression. BP, blood pressure.

(From Kaplan JA, Wells PH: Early diagnosis of myocardial ischemia using the pulmonary arterial catheter. Anesth Analg 60:789, 1981.)

LV diastolic dysfunction detected with TEE is one of the earliest changes identified after coronary artery occlusion, and it often precedes the development of abnormal systolic function. RWMAs also have been described as early signs of ischemia. They occur within seconds of inadequate blood flow or oxygen supply. RWMAs detected by TEE have been shown to be a more sensitive method of detecting myocardial ischemia in patients undergoing CABG, compared with ST-segment changes.⁵¹⁰ Myocardial ischemia or repositioning the heart during OPCAB can be the cause of a sudden onset of mitral regurgitation or worsening of preexisting mitral regurgitation, both of which can be detected with TEE monitoring (see Chapter 12).

Intraoperative Treatment of Myocardial Ischemia

Close attention to hemodynamic control and rapid treatment of abnormalities are fundamental principles of the intraoperative management of the patient with CAD. If there is a hemodynamic abnormality that is temporally related to the onset of ischemia, it should be treated accordingly. Hemodynamic treatment to ensure an adequate CPP (diastolic blood pressure minus left ventricular end-diastolic pressure [LVEDP]) should be a priority, as should control of HR, the single most important treatable determinant of myocardial oxygen consumption. Table 18-5 summarizes the treatment of acute perioperative myocardial ischemia. The earliest objective evidence of successful treatment of ischemia may be the return to normal of the PAP and the PCWP waveforms. In the following section, some of the routinely used pharmacologic interventions for intraoperative myocardial ischemia are discussed.

TABLE 18-5 Acute Treatments for Suspected Intraoperative Myocardial Ischemia

Ensure adequacy of oxygenation, ventilation, and intravascular volume status, and consider surgical factors, such as manipulation of heart or coronary grafts.

IV, intravenous; PRN, as needed.

* Tachyarrhythmias (e.g., paroxysmal atrial tachycardia, atrial fibrillation) should be treated directly with synchronized cardioversion or specific pharmacologic agents.

† Bolus doses (25–50 μg) and high infusion rate may be required initially.

Intravenous Nitroglycerin

Since the introduction in 1976 by Kaplan et al⁵¹¹ of the V₅ lead to diagnose myocardial ischemia, and intravenous NTG to treat it,⁵¹² NTG has been one of the mainstays in the treatment of perioperative myocardial ischemia. Intravenous NTG acts immediately to reduce LV preload and wall tension, primarily by decreasing venous tone in lower doses. In larger doses, it also may decrease arterial resistance and epicardial coronary arterial resistance.^513,514 NTG has been shown to consistently decrease LV filling pressures, systemic BP, and myocardial oxygen consumption and to improve LV performance in patients with severe dysfunction.⁵¹⁵ It is most effective in treating acute myocardial ischemia with ventricular dysfunction accompanied by sudden increases in LVEDV, LVEDP, and PAP. These increases in LV preload and wall tension further exacerbate perfusion deficits to the ischemic subendocardium and usually respond immediately to NTG (Figure 18-18).

Figure 18-18 The effects of nitrates on the circulation include prominent venodilation and reduction of preload. Afterload is decreased because of mild arteriolar dilatation. Coronary dilation also occurs to benefit the ischemic myocardium.

(From Opie LH: Drugs and the heart. II. Nitrates. Lancet 1:750, 1980.)

Before surgery, NTG often is used to treat patients with unstable angina or ischemic mitral regurgitation and limit the size of an evolving myocardial infarction, reduce associated complications, and reverse RWMAs.^516,517 In the pre-CPB period and during OPCAB, NTG is used to treat signs of ischemia such as ST-segment depression, hypertension uncontrolled by the anesthetic technique, ventricular dysfunction, or coronary artery spasm (Box 18-5). During CPB, NTG can be used to control the MAP with a time to onset of effect ranging from 4.1 ± 0.8 to 7.8 ± 2.8 minutes at doses of 1.7 ± 0.3 to 2.9 ± 0.7 μg/kg/min.⁵¹⁸ However, NTG is not always effective in controlling MAP during CPB (approximately 60% of patients respond) because of alterations of the pharmacokinetics and pharmacodynamics of the drug with CPB. Factors contributing to the reduction of its effectiveness include adsorption to the plastic in the CPB system, alterations in regional blood flow, hemodilution, and hypothermia. Booth et al⁵¹⁹ have shown that different oxygenators and filters sequester up to 90% of circulating NTG during CPB. After revascularization, NTG is used to treat residual ischemia or coronary artery spasm and reduce preload and afterload. It may be combined with vasopressors (e.g., phenylephrine) to increase the CPP when treating coronary air embolism (Box 18-6).

BOX 18-5. Intraoperative Use of Intravenous Nitroglycerin

Hypertension > 20% above control values

Pulmonary capillary wedge pressure > 18 to 20 mm Hg

AC and V waves > 20 mm Hg

ST changes > 1 mm

New regional wall motion abnormalities on transesophageal echocardiography

Acute right ventricular or left ventricular dysfunction

Coronary artery spasm

BOX 18-6. Uses of Intravenous Nitroglycerin on Termination of Cardiopulmonary Bypass

• Increased pulmonary capillary wedge pressure

• Increased systemic vascular resistance or pulmonary vascular resistance

• Incomplete revascularization

• Ischemia

• Intraoperative myocardial infarction

• Coronary artery spasm

• Infusion of oxygenator reservoir volume

Studies of the prophylactic role of NTG in preventing perioperative myocardial ischemia have shown mixed results, with most studies showing no effects of NTG infusions on the incidence of perioperative myocardial ischemic events.^520–522 In a prospective, double-blinded, placebo-controlled study, Zvara et al⁵²³ randomized patients undergoing CABG surgery using a fast-track anesthesia technique to 2 μg/kg/min NTG or placebo starting before induction and continuing until 6 hours after extubation in the ICU. They found a similar incidence, severity of symptoms, and duration of myocardial ischemia, regardless of whether the patients received NTG or placebo (37% vs. 35%, respectively). Even though there were more patients in the placebo group with positive enzymes and ECG signs of myocardial infarction, these findings were not statistically significant. Similarly, in a prospective, randomized, controlled study, 0.5 to 1 μg/kg/min NTG administered after aortic cross-clamp release in patients undergoing CABG surgery did not decrease the incidence of postoperative myocardial ischemia.⁵²⁴

Intravenous NTG has been compared with other vasodilators such as nitroprusside and the calcium channel blockers during CABG and in other clinical situations. Kaplan and Jones⁵²⁵ demonstrated that NTG was preferable to nitroprusside during CABG. Both drugs were shown to control intraoperative hypertension and to decrease myocardial oxygen consumption; however, NTG improved ischemic changes on the ECG, but nitroprusside did not. The lack of improvement in the ischemic ST segments with nitroprusside was thought to result from a decrease in CPP or the production of an intracoronary steal. When NTG was compared with calcium channel blockers in patients undergoing CABG surgery, the results depended on the class of calcium channel blocker, the usage of arterial conduits, and the administered doses.

Sedation

Patients usually are sedated to facilitate transport to the ICU and in the immediate postoperative period until extubation criteria are fulfilled. α₂-Adrenergic receptor agonists such as dexmedetomidine, as well as propofol, are intravenously administered agents with favorable properties in this setting.

α₂-Adrenergic receptor agonists have unique properties (Box 18-7) that explain their increasing use in cardiac surgical patients. Although the FDA approved clonidine in 1974, it was available only as an oral formulation in the United States, limiting its widespread use. In 1999, the FDA approved dexmedetomidine for continuous (up to 24 hours) intravenous sedation in the ICU setting. It is seeing increasing use in the operating room and ICU settings. Dexmedetomidine is a more selective α₂-adrenoceptor agonist than clonidine (approximately eight times greater). It exhibits both central sympatholytic and peripheral vasoconstrictive effects. Intravenous infusion of dexmedetomidine (0.2 to 0.7 μg/kg/hr) causes transient increases of MAP and SVR because of stimulation of α- and β₂-adrenergic receptors in vascular smooth muscle. This is followed by decreases in MAP, HR, SV, CO, and plasma catecholamine levels.^556,557 Greater doses of dexmedetomidine result in more profound sedation and analgesia with a persistent increase in MAP, SVR, and PAP.⁵⁵⁸

There are limited data from animal studies demonstrating potential coronary vasoconstrictive and cardiodepressant effects.^559–562 However, coronary vasoconstriction was seen mainly with bolus doses of 10 μg/kg and greater. At the recommended loading doses (0.5 to 2 μg/kg) and maintenance (0.2 to 0.7 μg/kg/hr), dexmedetomidine most likely has a favorable effect on myocardial perfusion.⁵⁶³ Roekaerts et al^564,565 showed an increase in endocardial-to-epicardial blood flow ratio in the postischemic myocardium, with an overall reduction of myocardial oxygen demand after experimentally induced myocardial ischemia in dogs. As expected, the greatest reduction in oxygen demand is seen when baseline HR and arterial BP are increased. Intravenous dexmedetomidine exhibits a rapid distribution phase with a distribution half-life of about 6 minutes. Dexmedetomidine shows high protein binding (94%) and undergoes extensive biotransformation in the liver with direct glucuronidation and cytochrome P450–mediated metabolism. Although dexmedetomidine mainly is excreted renally (95%), no dose adjustments are necessary in patients with renal insufficiency, although slightly prolonged sedation should be expected.⁵⁶⁶ Severe hepatic impairment may necessitate a dose reduction.

Dexmedetomidine may be a useful agent in the early postoperative period because its sedative properties are associated with minimal respiratory depression and, in this regard, appear to mimic natural sleep patterns.⁵⁶⁷ When administered continuously in postsurgical patients, it caused no statistical differences in respiratory rate, oxygen saturation, arterial pH, and arterial carbon dioxide tension when compared with placebo.⁵⁶⁸ These patients usually were effectively sedated but still arousable and cooperative to verbal stimulation.⁵⁶⁹ Because of its analgesic properties, it significantly reduced additional opioid analgesia requirements in mechanically ventilated patients in the ICU.^570–572 The α₂-agonists have been used successfully in patients with postoperative delirium and withdrawal symptoms in alcohol or drug addicts, and they are associated with a low rate of shivering.^573,574

Propofol has been used extensively intraoperatively, as well as for sedation in the ICU. Several studies compared propofol and dexmedetomidine in the postoperative period after surgery. Venn et al⁵⁷⁵ randomized a small number of patients to propofol versus dexmedetomidine sedation in the immediate postoperative period. Dexmedetomidine reduced the requirement for opioid analgesia, but importantly for patients after myocardial revascularization, it reduced HR more than propofol, whereas the arterial blood pressure did not differ between the two groups. In a multicenter, randomized study, Herr et al⁵⁷⁶ compared a dexmedetomidine-based sedation regimen with propofol sedation after CABG in the ICU. Although there were no differences in time to extubation, the investigators found a significantly reduced need for additional analgesics (i.e., propofol-sedated patients required four times the mean dose of morphine), antiemetics and diuretics and had fewer episodes of tachyarrhythmias requiring β-blockade (ventricular tachycardia in 5% of the propofol-sedated group vs. none in the dexmedetomidine group). In this study, however, hypotension was more common in the dexmedetomidine group compared with the propofol-sedated patients (24% vs. 16%; Figure 18-19). Approximately 25% of the dexmedetomidine-associated hypotension occurred in the first hour of the study (starting at sternal closure), particularly during or within 10 minutes after the loading infusion of 1 μg/kg. The combination of reduction of preload during sternal closure and the loading dose would seem to indicate this was not the optimal manner in which to use this agent. Loading doses are infrequently administered in today’s clinical practice to avoid hypotension seen with a large loading dose of dexmedetomidine, but a continuous maintenance dose started earlier to achieve appropriate plasma levels at the time of patient transfer from the operating room.

Figure 18-19 Changes from baseline in systolic blood pressure (SBP) between coronary artery bypass grafting (CABG) patients sedated with dexmedetomidine or propofol. The baseline is mean systolic pressure for each treatment group just before sternal closure. Numbers of patients receiving each drug (x-axis) declines progressively as they are extubated after surgery.

(From Herr DL, Sum-Ping ST, England M: ICU sedation after coronary artery bypass graft surgery: Dexmedetomidine-based versus propofol-based sedation regimens. J Cardiothorac Vasc Anesth 17:576, 2003.)

With regard to patient satisfaction, insufficient data are available to clearly favor one of the two agents. Corbett et al⁵⁷⁷ randomized 89 adult patients after CABG surgery to either dexmedetomidine or propofol. Patients were interviewed regarding awareness, recall, generalized comfort, level of pain, ability to interact with healthcare providers and family, feelings of agitation and anxiety, ability to sleep and rest, and overall satisfaction with ICU stay. The level of awareness and additional morphine and midazolam requirements did not differ between the groups. Patients favored propofol to sleep and rest, there were more patient discomfort and pain in the dexmedetomidine group, and the authors concluded that dexmedetomidine did not offer any advantages over propofol for short-term sedation after CABG surgery. The increased incidence of pain in the dexmedetomidine group is surprising, and most studies show reduced opioid requirements with α₂-adrenoceptor agonists. Barletta et al⁵⁷⁸ compared propofol and dexmedetomidine after CABG and/or valve surgery in a fast-track recovery room setting. Patients (n = 100) were matched according to surgery type and left ventricular function. Dexmedetomidine resulted in lower opioid requirements, but this did not result in shorter duration of mechanical ventilation, improved quality of sedation, or rate of adverse events.

In summary, even though there are theoretic advantages to using dexmedetomidine for sedation after CABG surgery, no clear benefits have been documented for either drug, and sedation-related costs are greater with dexmedetomidine administration.

Coronary Artery and Arterial Conduit Spasm

Since 1981, when Buxton et al⁵⁷⁹ first reported coronary artery spasm immediately after CABG, there have been numerous descriptions of this problem. Spasm usually has been associated with profound ST-segment elevation on the ECG, hypotension, severe dysfunction of the ventricles, and myocardial irritability. Many hypotheses have been put forward to explain the origin of coronary artery spasm; some of the mechanisms that may play a role are demonstrated in Figure 18-20.⁵⁸⁰ The mechanism of postoperative spasm may or may not be the same as that underlying Prinzmetal’s variant angina, but the same stimuli seem to be present and therapy is usually effective with a wide range of vasodilators such as NTG, calcium channel blockers, milrinone, or combinations of NTG and calcium channel blockers in both situations. Arterial grafts such as the LIMA, and particularly radial artery grafts, are prone to spasm after revascularization, and its prevention and recognition are crucial to prevent serious complications.⁵⁸¹ He et al⁵⁸² tested the reactivity of ring segments of human IMAs in organ baths to various constrictor and dilator agents. It was found that thromboxane was the most potent IMA constrictor, followed by norepinephrine, serotonin, phenylephrine, and potassium chloride. NTG, NO, papaverine, and the calcium channel blockers nifedipine, verapamil, and diltiazem, as well as milrinone, all produced relaxation. In a similar study, Mussa et al⁵⁸³ observed the vasodilating properties of topically applied phenoxybenzamine. It prevented vasoconstriction with a long-lasting effect (>5 hours) in response to various vasoconstrictors, followed by verapamil/NTG (5 hours) and papaverine (1 hour). In vivo, for prophylaxis of IMA spasm, the calcium antagonists, especially diltiazem, were thought to be as useful as NTG.^584–586

Figure 18-20 Schematic representation of the pathogenesis of coronary artery spasm.

Nevertheless, prevention and treatment of arterial conduit spasm with diltiazem may cause serious adverse effects such as low CO or conduction abnormalities. Diltiazem is a more expensive drug compared with NTG. Shapira et al⁵⁸⁷ showed in vitro (radial artery, IMA, saphenous vein) and in vivo (radial artery) that NTG was a superior vasodilator compared with diltiazem. The same investigators monitored patients undergoing CABG surgery using radial artery grafts who were randomized to receive NTG or diltiazem intravenously after induction of anesthesia followed by an NTG patch or oral diltiazem after surgery for 6 months. There was no significant difference in outcome (morbidity, myocardial infarction, CK-MB) between the two groups. Nevertheless, the 6-month diltiazem treatment was associated with 16-fold greater costs and significantly more patients requiring cardiac pacing compared with NTG (28% vs. 13%, respectively).⁵⁸⁸ In a double-blind, randomized study, Mollhoff et al⁵⁸⁹ compared milrinone (0.375 μg/kg/min) with nifedipine (0.2 μg/kg/min) in patients with impaired LV function undergoing CABG surgery. ST changes after revascularization (including the use of the IMA graft) indicative of myocardial ischemia occurred in 33.3% of the milrinone group compared with 86.6% in the nifedipine group. Biochemical markers of myocardial damage (CK-MB and troponin I) after 24 hours were significantly greater in the nifedipine group.

Fast-Track Management for Coronary Artery Bypass Grafting Surgery

Efforts to reduce resource consumption for patients undergoing CABG have received considerable attention by a variety of interested payers since the 1990s. With the changing pattern of reimbursement based on the ever-escalating costs of health care, payers have drastically reduced incentives to expend unnecessary resources, with hospitals and clinicians attempting to minimize consumption yet maintain patient safety. The financial pressures are illustrated by the observation that Medicare costs for CABG increased from $2.8 billion in 1990 to $7.3 billion in 1997, whereas case volume increased only 40% during that period. In 1990, Krohn et al⁵⁹⁰ reported a study of 240 patients undergoing CABG at a private southern California hospital between 1984 and 1986, describing a clinical pathway emphasizing early extubation, rapid mobilization, intraoperative fluid restriction, and steroid administration. This program was associated with a median postoperative LOS of 4 days and in-hospital mortality rate of only 2%. This program itself was forged out of intense economic competition with the first major incursion of managed care into this area’s competitive market. This particular pathway is widely recognized as the first formal report of what is now called fast-tracking for cardiac surgery. In a similar time frame, reports from the financially constrained U.K. health care system, in which formal ICU care was “bypassed” based primarily on rapid early extubation (with apparent success), appeared.^591,592 The publicity associated with these reports contributed to Medicare’s interest in cost reduction, leading to the Medicare Participating Heart Bypass Center Demonstration conducted between 1991 and 1996, in which seven participating hospitals agreed to a single sharply discounted rate for CABG (in return for preferential market share, a concept that ultimately has not materialized).⁵⁹³ Over the 5-year period, it is estimated that $50.3 million dollars were saved. In their summary report, reduction of cost and LOS by retooling processes of care is emphasized (and reducing time to extubation was considered a key factor). In the participating centers, LOS, together with mortality, declined annually despite increased severity of case mix. Observational data by Engelman et al,^594,595 from the Baystate Medical Center of a large case series of fast-track patients, generated additional widespread publicity in the surgical community (particularly among members of the influential Society of Thoracic Surgery).

Although the fast-track clinical pathway encompasses a variety of perioperative (and after-hospital discharge) management strategies, early extubation is the one that has received perhaps the greatest attention (Box 18-8) (see Chapter 33). Because it is a simple, continuous variable (e.g., hours to extubation), it is one that many observational reports, a smaller number of randomized, controlled trials, and meta-analyses have reported to be safe and effective.^596,597 Early extubation is acknowledged as a key component of the fast-track clinical pathway and one that was considered perhaps the most radical change in practice during the peak of scrutiny of the fast-track pathway (middle to late 1990s; Box 18-9). Reports of prolonged ventilatory management after cardiac surgery first appeared in the late 1950s (for valve surgery as CABG was not yet performed), and those from the 1960s (including the first reports of CABG patients) strongly advocated its routine use.⁵⁹⁸ This was further emphasized with the adoption of high-dose morphine and, subsequently, fentanyl and sufentanil, at the end of that decade.^599,600