Anesthesia for Cardiac Surgical Procedures PDF

50. Anesthesia for Cardiac Surgical Procedures BOOK CHAPTER Anesthesia for Cardiac Surgical Procedures Muhammad F. Sarwar (chapter://search/Sarwar%20Muhammad F./%7B%22type%22:%22author%22%7D), Cesar Rodriguez-Diaz (chapter://search/Rodriguez-Diaz%20Cesar/%7B%22type%22:%22author%22%7D), Matthew Dabski (chapter://search/Dabski%20Matthew/%7B%22type%22:%22author%22%7D), Bruce E. Searles (chapter://search/Searles%20Bruce E./%7B%22type%22:%22author%22%7D) and Linda Shore-Lesserson (chapter://search/Shore-Lesserson%20Linda/%7B%22type%22:%22author%22%7D) Miller's Anesthesia (chapter://browse/book/3-s2.0-C20211026104), 50, 1577-1682.e14 KEY POINTS ▪ Cardiac surgical procedures include coronary revascularization with or without the use of cardiopulmonary bypass (CPB). These procedures can be performed in combination with valvular repair or replacement, depending upon the patient’s disease process. Additional cardiac procedures can range from valve repairs and replacements, surgical management of heart failure, e.g. placement of ventricular assist devices, transcatheter aortic valve replacement (TAVR), intervention for structural heart disease, pericardiocentesis, occlusion of left atrial appendage, ablation procedures for arrhythmias, surgical correction of congenital heart defects and heart transplant. In addition, traumatic cardiac and major vascular injuries present another aspect of cardiac surgical patients that cardiac anesthesiologists routinely take care of. ▪ Choice of anesthetic induction agents and of the maintenance agents will depend upon the patient’s disease process and the comorbidities with which the patient presents. Additionally, choice of anesthetic agents will also be determined by the fact if the surgical procedure is elective or emergent. Management of anesthesia includes close control of hemodynamics in the prebypass period. ▪ Effects of CPB on coagulation pathway, especially platelet function, are mediated through hemodilution, hypothermia and contact activation by bypass circuit materials. ▪ Issues in the postoperative period can range from relatively minor to major issues. Arrhythmias, low output cardiac failure, hypovolemia and electrolyte abnormalities are a few of the problems of a long list of problems that need to be addressed when present or anticipated. ▪ Guidelines for management of specific issues are periodically published by various associations, including, The Society of Thoracic Surgeons (STS), Society of Cardiovascular Anesthesiologists, American Society of ExtraCorporeal Technology, European Association of Cardio-Thoracic Surgery and European Association of Cardiothoracic Anesthesiology. ▪ In recent years there has been a decrease in the incidence of stroke after cardiac surgery. Major factors responsible for postoperative stroke include particulate or micro gaseous emboli, cerebral hypoperfusion and inflammatory response. ▪ STS guidelines recommend blood glucose control of less than 180 mg/dl. Although many institutions practice an even tighter control of glucose. Hypoglycemia is a risk if a tighter control is pursued, especially as the CPB run is winding down. ▪ Enhanced sympathetic tone secondary to poor pain control can result in myocardial stress and inability of the patient to effectively clear pulmonary secretions. Therefore, for both cardiac and pulmonary recovery of a patient good postoperative pain control is necessary. Cardiovascular Disease in the 21st Century Age, Gender, and Race An estimated 82,600,000 US adults ( LVEDP Positive-pressure ventilation PEEP Increased intrathoracic pressure Non–West lung zone III PAC placement Chronic obstructive pulmonary disease Increased pulmonary vascular resistance Left atrial myxoma Mitral valve disease (e.g., stenosis, regurgitation) PCWP < LVEDP Noncompliant left ventricle (e.g., ischemia, hypertrophy) Aortic regurgitation (premature closure of the mitral valve) LVEDP >25 mm Hg Some PA catheters are designed with a thermistor to register blood temperature changes, which are used to calculate right-sided heart cardiac output (CO) or ejection fraction (EF) by thermodilution. PA catheters may also have oximetric capabilities to measure mixed venous oxygen saturation ( Sv̄ 𝑆𝑣¯ O 2 ). Thus, a PA catheter can be used to assess intravascular volume status, measure CO, measure Sv̄ 𝑆𝑣¯ O 2 , and derive hemodynamic parameters. 26 The CO, the amount of blood delivered to the tissues by the heart, is of particular interest to cardiac anesthesiologists. The product of stroke volume and heart rate, CO is affected by preload, afterload, heart rate, and contractility. PA catheters capable of measuring CO continuously were introduced into clinical practice in the 1990s. 26 The correlation of continuous CO measurements with those measurements obtained by using the intermittent thermodilution method is good in physiologically and thermally stable pre-bypass and post-bypass periods. Continuous monitoring of Sv̄ 𝑆𝑣¯ O 2 provides a means to estimate the adequacy of oxygen delivery relative to oxygen consumption. 26 Decreases in Sv̄ 𝑆𝑣¯ O 2 may indicate decreased CO, increased oxygen consumption, decreased arterial oxygen saturation, or decreased hemoglobin concentration. If it is assumed that oxygen consumption and arterial oxygen content are constant, changes in Sv̄ 𝑆𝑣¯ O 2 should reflect changes in CO. 26 However, London and colleagues found that continuous Sv̄ 𝑆𝑣¯ O 2 monitoring did not lead to better outcomes than standard PA catheter monitoring. 27 Pacing PA catheters are also commercially available. Electrode PA catheters include five electrodes for atrial, ventricular, or atrioventricular (AV) sequential pacing. Paceport PA catheters (Edwards Lifesciences, Irvine, CA) have a port for the insertion of a ventricular wire or of both atrial and ventricular wires for temporary pacing. The risk-to-benefit ratio involved in using PA catheters has been a subject of controversy since the 1990s. Complications of PA catheter placement include those mentioned in the section on CVP placement, as well as transient arrhythmias, complete heart block, pulmonary infarction, endobronchial hemorrhage, thrombus formation, catheter knotting and entrapment, valvular damage, and thrombocytopenia. 26 In addition, a common complication is incorrect interpretation of the data obtained from the PA catheter, with resultant incorrect treatment of the patient. 28 Schwann and colleagues published a large, international, prospective observational study showing that using a PA catheter was associated with a more frequent risk of a composite mortality and morbidity outcome than using a CVP alone in patients undergoing CABG surgery. 24 Smaller observational trials have also associated the PA catheter with increased morbidity and decreased survival in cardiac surgical patients. 29 , 30 Currently, the trend in the United States is to be selective in deciding which patients may benefit from a PA catheter, especially with the widespread use of transesophageal echocardiography (TEE). Absolute contraindications to PA catheter placement include tricuspid or pulmonic valvular stenosis, right atrial (RA) or right ventricular (RV) masses, and tetralogy of Fallot. 26 Relative contraindications include severe arrhythmias and newly inserted pacemaker wires (which may be dislodged by the catheter during insertion). Clearly, patients undergoing low-risk cardiac surgical procedures can be managed safely without PA catheter placement. 26 However, many cardiac surgeons and anesthesiologists still use the device in high-risk cardiac operations and in patients with right-sided heart failure (HF) or pulmonary hypertension, particularly to assist in postoperative management ( Box 50.3 (b0020) ). BOX 50.3 Possible Clinical Indications for Pulmonary Artery Catheter Monitoring Modified from Kaplan JA, Reich DL, Savino JS, eds. Kaplan’s Cardiac Anesthesia: The Echo Era, 6th ed. St. Louis: Saunders; 2011:435. Major procedures involving large fluid shifts or blood loss in patients with: Right-sided heart failure, pulmonary hypertension Severe left-sided heart failure not responsive to therapy Cardiogenic or septic shock or multiple organ failure Hemodynamic instability requiring inotropes or intraaortic balloon counterpulsation Surgery of the aorta requiring suprarenal cross-clamping Hepatic transplantation Orthotopic heart transplantation Transesophageal and Epiaortic Echocardiography Cerebral embolization of atheromatous plaque can occur during manipulation of the ascending aorta, particularly during aortic cannulation. 31 Palpation by the surgeon as well as TEE can be utilized to detect major atherosclerosis. TEE allows direct visualization of the first segment of the ascending aorta, the middle distal segment of the aortic arch, and a good portion of the descending thoracic aorta. The distal segment of the ascending aorta and the proximal midportion of the aortic arch cannot be visualized well because of the interposition of the trachea and bronchi between the TEE probe and these aortic structures. Instead, epiaortic scanning (EAS) with a handheld, high-frequency probe placed over the ascending aorta or aortic arch can be used to visualize aortic segments that are in the TEE probe’s “blind spot.” EAS is the preferred method of screening. A large retrospective study showed that the use of perioperative EAS significantly improved neurologic outcomes because the cannulas were relocated and the operative course was changed in 4% of the patients due to the finding of aortic disease. 32 A trial comparing EAS versus manual aortic palpation found that the use of EAS led to modifications in the intraoperative surgical approach in 29% of patients undergoing CABG. 33 However, there were no differences in the incidence of neurologic complications between the groups. TEE is used in most cardiac surgical procedures. See Chapter 33 (chapter://content/3-s2.0-B978032393592000033X) for detailed discussion of echocardiography. Central Nervous System The incidence of perioperative stroke after cardiac surgery is estimated around 1% and is associated with about a 10-fold increased mortality compared to the non-stroke patients. 34 Neurocognitive dysfunction is another perioperative complication with an incidence ranging from 10% to 40%, depending on the definition and the timeframe. 35 Risk factors for central nervous system (CNS) injury or dysfunction after cardiac surgery are listed in the figure below. 36 The most common cause is thought to be particulate or microgaseous emboli. 37 , 38 Other factors include cerebral hypoperfusion, particularly in patients with cerebrovascular disease, and 39 , the inflammatory response to surgery and CPB. 40 Multimodal monitoring has been advocated in an attempt to reduce perioperative CNS injury. 41 , 42 Cerebral Oximetry Cerebral oximetry uses near-infrared spectroscopy (NIRS) technology similar to that used in pulse oximeters, with the main difference being the signal is mostly registering venous blood in the cerebral cortex. Light-emitting electrodes and receptors are placed on the patient’s forehead, lateral to the midline, and over both frontal cortices. The light that bounces back to the receptor in a banana-shaped pathway through the skull is used to calculate the regional cerebral oxygen saturation, based on the light absorption characteristics of oxygenated and deoxygenated blood when exposed to light of at least two different wavelengths. The cerebral oximetry number represents a balance between oxygen delivery and consumption. Once the electrodes are applied, a baseline reading is obtained with the patient awake, breathing room air, and any deviation below 20% of baseline during the procedure is considered a significant desaturation event. 43 A low baseline cerebral oximetry reading even though the patient is breathing supplemental oxygen (absolute value ≤50%) has been identified as an independent risk factor for 30-day and 1-year mortality. 44 The data supporting improved outcomes for cerebral oximetry monitoring and intervention during cardiac surgery are contradictory, however instinctive they might be. A study found the duration and magnitude of the desaturation events were associated with early neurocognitive dysfunction and hospitalization length. 45 Another study found the utilization of an algorithm to treat desaturation events was associated with fewer incidences of major organ dysfunction. 46 Other studies have found improved neurocognitive function on the cerebral oximetry treatment 47 , 48 group. On the contrary, two studies found no difference in outcomes when a cerebral oximetry optimization algorithm was used. 49 , 50 Two recent systematic reviews have not found support for cerebral oximetry monitoring improving outcomes during cardiac surgery. 51 , 52 Transcranial Doppler Transcranial Doppler (TCD) monitoring during cardiac surgery involves the ultrasonic interrogation of blood flow velocity through the middle cerebral artery as an indirect measure of cerebral blood flow. 53 The technology has been used extensively as a research tool. For example, in conjunction with cerebral oximetry, TCD has been used to delineate the limits of cerebral autoregulation during CPB. 54 TCD can also detect cerebral emboli. However, the association between TCD-detected emboli and postoperative cognitive dysfunction (POCD) is questionable. 55 , 56 A primary limitation of TCD technology has been its inability to discern gaseous from solid emboli. It has been suggested that properties such as size and composition instead of the number of microemboli determine the risk of adverse cerebral outcomes. 57 , 58 Gaseous microemboli during CPB may dissolve within seconds and could have minimal effects on brain function. 55 Other general limitations of TCD technology include the following: (1) the quality of information is heavily user dependent; (2) accuracy requires stable and precise probe placement, which can be quite cumbersome; and (3) information is affected by patient-related characteristics, such as skin thickness. These difficulties have limited use of this technology in the perioperative setting. 53 To date, there is no evidence that the routine use of TCD can improve clinical outcomes after cardiac surgery, and its use remains largely experimental. 59 Electroencephalography and Bispectral Index Monitoring The electroencephalogram (EEG), recorded from multiple adhesive or screw-in scalp electrodes, represents surface cerebral cortical activity. Awake patients produce a pattern of EEG readings that differs from the pattern produced by patients who are under anesthesia. Establishing a baseline and monitoring the changes from that baseline form the premise of EEG monitoring. Changes in the frequency of EEG signals (slower brain waves) and the reduction of wave amplitude may indicate changes in cortical neuronal function that warrant concern. Multichannel raw EEG monitoring is not routinely used in cardiac surgery. However, a resurgence of interest in processed EEG monitoring, such as the bispectral index (BIS) or SedLine, has occurred. 53 , 60 , 61 BIS has been the most studied processed EEG monitor for the prevention of intraoperative awareness, to facilitate fast tracking and to provide information on cerebral perfusion. Three randomized trials showed BIS helps prevent awareness in high-risk population, but it is not better than an end-tidal anesthetic gas protocol 62 63 64 ; however, they failed to show a specific benefit in cardiac surgery population. The effectiveness of BIS monitoring in contributing to the success of fast tracking of cardiac surgery patients has not been demonstrated by randomized clinical trials in cardiac surgical patients. 65 BIS and raw EEG may be useful for detecting brain ischemia, especially when anesthesia is stable, if the insult is sudden, extended, or located in the frontal area, and if the preoperative EEG was normal. 66 Sudden EEG changes during cardiac surgery and CPB can be attributable to correctable problems such as superior vena cava obstruction or severe decrease in cardiac output. 67 However, many variables may confuse EEG interpretation during cardiac surgery. These include hypothermia, the pharmacologic suppression of EEG signals, and interference produced by pump mechanics. In addition, the EEG measures only cortical activity, so ischemic or embolic injury that occurs below the level of the cortex may go undetected. Therefore, the EEG and derived indices are neither sensitive nor specific in detecting cerebral ischemia. 68 Summary Currently, evidence-based recommendations cannot be made regarding the efficacy of treatment for abnormal values. Although not yet recognized as a clinical standard of care, neuromonitoring will likely continue to be the subject of significant research effort. Renal System Acute kidney injury (AKI) after cardiac surgery remains a significant cause of postoperative morbidity, increased cost of care, later development of chronic kidney disease, and short-term as well as long-term mortality. 69 Although the pathogenesis of AKI is multifactorial, control of some specific factors may limit its incidence in cardiac surgical patients. Bellomo and associates identified six major injury pathways of cardiac surgery–associated AKI: toxins (both exogenous and endogenous), metabolic factors, ischemia–reperfusion injury, neurohormonal activation, inflammation, and oxidative stress. 70 Randomized trials of specific potential preventive measures for AKI after cardiac surgery are few. Certainly, all potentially nephrotoxic drugs should be avoided in the perioperative period ( Box 50.4 (b0025) ). 69 BOX 50.4 Drugs That Contribute to Kidney Injury Modified from Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380:756– 766. Radiocontrast agents Aminoglycosides Amphotericin Nonsteroidal anti-inflammatory drugs β-Lactam antibiotics (specifically contribute to interstitial nephropathy) Sulfonamides Acyclovir Methotrexate Cisplatin Cyclosporine Tacrolimus Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers Hydration is, of course, a universally accepted component of strategies to prevent contrast nephropathy. 71 Unfortunately, no pharmacologic strategy has definitive efficacy in preventing early AKI. 70 Atherosclerosis of the ascending aorta appears to be an independent risk factor for AKI. 70 Intraoperative TEE should be used to identify patients at increased risk for thromboembolic phenomena. 70 , 71 Although observational studies have suggested a possible benefit of off-pump procedures and avoidance of aortic manipulation, definitive evidence is lacking. 70 , 71 For cardiac surgical cases that require CPB, the duration of aortic cross-clamping should be limited if possible, especially in patients who are at a higher-than-normal risk for renal complications, such as patients with preexisting renal insufficiency. 70 Hemodynamic instability should be addressed 70 , 71 quickly, and intravascular volume should be maintained or rapidly restored. Finally, perioperative hyperglycemia should be avoided. 70 , 71 Clearly, definition of measures that may prevent AKI after cardiac surgery is needed. 70 , 71 The cost of this complication to the patient and to society is probably higher than previously thought. 69 Endocrine System Glucose Control Hyperglycemia in surgical patients is a consequence of the inflammatory or stress response to the trauma of surgery. Components of this response include an endocrine response (i.e., increased production of counterregulatory hormones such as cortisol, growth hormone, glucagon, and catecholamines) ( Fig. 50.3 (f0020) ), 72 an immune response resulting in increased cytokine production, an autonomic response resulting in increased sympathetic stimulation, and altered insulin signaling. These changes increase glucose production, decrease glucose elimination during CPB, and induce insulin resistance, thereby causing hyperglycemia. 73 Fig. 50.3 (A) Plasma levels of epinephrine (Epi) during cardiac surgery. Bars indicate standard error of the mean. X- clamp, cross-clamp. (B,C) Levels of cortisol during cardiac surgery. ECC, extracorporeal circulation; Midop, intraoperatively; N.S., not significant; op, operatively; PCV, packed cell volume; Postop, postoperatively; Preop, preoperatively. A, Redrawn from Reves JG, Karp RB, Buttner EE, et al. Neuronal and adrenomedullary catecholamine release in response to cardiopulmonary bypass in man. Circulation. 1982;66:49–55; B,C, From Taylor KM, Jones JV, Walker MS, et al. The cortisol response during heart-lung bypass. Circulation. 1976;54:20–25. All patients are at risk for developing hyperglycemia during cardiac surgery. Older patients, diabetic patients, and patients with CAD are particularly prone to perioperative hyperglycemia. Although cardiac surgery without CPB initiates a stress response, CPB increases this response many-fold. 73 The degree of hyperglycemia depends on several variables associated with the use of CPB, such as the pump prime fluid selected, and the degree of hypothermia induced. Epinephrine and other inotropic drugs may contribute to hyperglycemia after CPB by stimulating hepatic glycogenolysis and gluconeogenesis. Impaired fasting glucose blood levels before cardiac surgery and persistently increased glucose levels during and immediately after surgical procedures are predictive of longer hospital stay and , 75 increased perioperative morbidity and mortality in both diabetic and nondiabetic patients. 74 However, in diabetic patients undergoing cardiac operations, hyperglycemia may only partly explain the increased risk for adverse outcomes. 75 Immunologic abnormalities common to diabetic patients, such as decreased chemotaxis, phagocytosis, opsonization, bacterial killing, and antioxidant defense, also promote adverse outcomes by increasing diabetic patients’ risk of infection. 76 Glucose blood levels should be controlled, beginning in the preoperative period and continuing until discharge. 77 However, in a classic study, patients were randomly assigned to intensive intraoperative insulin treatment (to maintain glucose levels at 80 to 100 mg/dL) or to standard insulin treatment (to keep glucose levels 7.0 50 >65 ≤60 Isovolumic relaxation time (ms) 60–80 25–40 >80 Notably, hypothyroidism is more common in female than in male patients undergoing CABG. 84 Zindrou and associates noted a 17% higher mortality rate in women who underwent CABG while receiving thyroxine replacement therapy for hypothyroidism. 85 A review of the literature by Edwards and colleagues concluded that ensuring a perioperative euthyroid state in women with hypothyroidism who were undergoing CABG could be helpful in reducing the perioperative mortality of these patients. 86 Hematologic System Bleeding is the primary complication of cardiac operations requiring CPB. In fact, 10% to 15% of blood product use in the United States is associated with cardiac surgery. This percentage is increasing, largely because of the increasing complexity of cardiac surgical procedures. Real- world data obtained from a large sample of patients and entered into the STS Adult Cardiac Surgery Database suggest that 50% of patients who undergo cardiac surgical procedures receive a blood transfusion. 87 Complex cardiac operations such as “redo” procedures, aortic operations, and the implantation of ventricular assist devices (VADs) require blood transfusion much more often than do simpler operations. Donor blood is viewed as a scarce resource associated with increased health care costs and significant risk to patients. Perioperative blood transfusion is associated with worse short-term and long-term outcomes. 88 , 89 Hence, reducing bleeding and blood transfusions has become a major focus of quality improvement efforts in cardiac surgery. See Chapters 45 (chapter://content/3-s2.0-B9780323935920000456) and 46 (chapter://content/3-s2.0- B9780323935920000468) for a comprehensive review of transfusion therapy and coagulation management. Heparin as an Anticoagulant Since its discovery by Jay McLean, MD, in 1915, heparin remains the primary anticoagulant used in cardiac operations that require CPB. The mechanism underlying heparin’s anticoagulant effect centers on the heparin molecule’s ability to bind simultaneously to antithrombin III and thrombin. Modern nomenclature refers to antithrombin III as antithrombin (AT). The binding process is mediated by a unique pentasaccharide sequence that binds to AT. The proximity of AT and thrombin, mediated by the heparin molecule, allows AT to inhibit the procoagulant effect of thrombin by binding to the active-site serine residue of the thrombin molecule. 90 The inhibitory effect of AT is increased 1000-fold in the presence of heparin. The heparin–AT complex can affect several coagulation factors, but factor Xa and thrombin are the most sensitive to inhibition by heparin, and thrombin is 10 times more sensitive to the inhibitory effects of unfractionated heparin than is factor Xa. 91 Only approximately one-third of the heparin molecules in a dose of heparin contain the critical pentasaccharide segment that is needed for high-affinity binding to AT. Thus, relatively large doses are required to produce the anticoagulant effect necessary for CPB. In fact, dosing of heparin for CPB is somewhat empiric. After a baseline activated clotting time (ACT) is measured (the normal range is 80–120 seconds), a dose of 300–400 units/kg of heparin is given as an intravenous bolus. Commercially available assays are used for calculating the patient’s dose- responsiveness to heparin in vitro. Subsequent heparin dosing for extracorporeal circulation (ECC) is targeted at maintaining ACT values longer than 400 to 480 seconds. Also available is a heparin concentration monitor that uses protamine titration analysis for ex vivo calculation of the whole blood heparin concentration. This result is often used as an adjunct to the ACT value in confirming an adequate heparin concentration for CPB. Unfortunately, ACT test results vary substantially with clinical conditions and the particular platform used for measurement. Thus, the evidence supporting the use of a threshold of 400 or 480 seconds is almost entirely anecdotal. 92 The dose of heparin used in patients on CPB is based on early landmark work published by Bull and coauthors in 1975. 93 A small study that sought evidence of thrombin activity during CPB in nonhuman primates and pediatric patients found results supporting a safe lower limit for ACT of 400 seconds. 94 In 1979, Doty and colleagues proposed a simplified dosing regimen guided by ACT values without dose–response curves. 95 The data and recommendations from these few studies constitute the primary basis for current heparin dosing protocols. Despite heparin’s historic and continued role in anticoagulation for patients maintained on CPB, it is not a perfect anticoagulant. Intrinsic and extrinsic pathway coagulation occurs despite heparin administration, and platelets can still be activated by contact with bypass circuitry and by heparin directly. 96 Alternative anticoagulants are discussed briefly in the section on heparin- induced thrombocytopenia (HIT). Monitoring of Anticoagulation Using ACT to monitor the effectiveness of heparin is not an exact science. Tremendous variability is observed in patients’ anticoagulation responses to a given dose of heparin; reasons for this variability include variations in levels of heparin-binding proteins and AT. Hence, ACT values correlate poorly with actual heparin concentrations. Nevertheless, since the publication of Bull and colleagues’ early work, 93 ACT has been the mainstay of anticoagulation monitoring in cardiac operations that require CPB. Many different ACT measurement devices are commercially available, each using a different platform for clot detection and end-point signaling. However, they all involve the addition of whole blood to a tube or channel containing a contact-phase activator. The activator can be celite, kaolin, glass, or any combination thereof. The sample is warmed to 37°C before the measurement technique is performed. Clot formation occurs, and the measurement ends when a change in velocity, pressure, oscillation, electromagnetic forces, or even color is observed, depending on the specific platform of measurement. Several clinical variables can affect the ACT ( Table 50.2 (t0015) ). In addition to physiologic variations, the design of ACT measurement devices (which varies across their many manufacturers) also affects ACT normal and therapeutic values. ACTs also correlate poorly with whole blood and plasma heparin levels, and responses to heparin differ somewhat between adult and pediatric patients. 97 Some authors argue that, because of its poor correlation with heparin concentration, ACT alone is not an adequate monitor of heparin efficacy, and that simultaneous or adjunct monitoring of heparin concentration should also be used during CPB. Prolongation of ACT by non-heparin-related clinical factors, such as hypothermia, hemodilution, or quantitative or qualitative platelet abnormalities, is a well-documented phenomenon, and the anesthesiologist must understand these factors to determine whether it is safe to reduce the heparin dose when the ACT is prolonged. The poor correlation between ACT and measured heparin concentration also makes it possible that a dose reduction will render the heparin concentration inadequate, even when the ACT remains within an acceptable range. Table 50.2 Clinical Variables That Can Affect the Activated Clotting Time Hemodilution Prolongs ACT in heparinized patients Hypothermia Prolongs ACT Thrombocytopenia Prolongs ACT Platelet inhibitors Prolongs ACT Platelet lysis Shortens ACT Aprotinin Prolongs only celite ACT Surgical stress Shortens ACT ACT, activated clotting time. Some point-of-care (POC) monitors, such as the Hepcon HMS system (Medtronic Perfusion Systems, Minneapolis, MN), use a protamine titration assay to calculate the heparin concentration. Despotis et al. suggest that monitoring and maintaining heparin concentration – and thus giving larger doses of heparin – actually protect the hemostatic system and may decrease transfusion requirements. 98 However, other investigators have not been able to confirm that higher doses of heparin confer better hemostatic protection; markers of ongoing coagulation are essentially the same whether traditional ACT monitoring or heparin concentration monitoring is used. 99 The 2018 STS, Society of Cardiovascular Anesthesiologists (SCA), and the American Society of ExtraCorporeal Technology (AmSECT) Guidelines state: “Use of heparin concentration monitoring in addition to ACT might be considered, for the maintenance of CPB, as this strategy has been associated with a significant reduction in thrombin generation, fibrinolysis, and neutrophil activation. However, its effects on postoperative bleeding and blood transfusion are inconsistent (class IIb, Level of Evidence B).” 92 An additional recommendation includes: “During CPB, routine administration of heparin at fixed intervals, with ACT monitoring, might be considered and offers a safe alternative to heparin concentration monitoring (class IIb, Level of Evidence C).” 92 The high-dose thrombin time (HiTT) is a modification of the thrombin time that is designed to measure the high levels of heparin that are used during CPB. 96 Unlike ACT, the HiTT correlates well with heparin concentration, both before and during CPB, and it is not affected by hemodilution and hypothermia. As a measure of thrombin inhibition, the HiTT is a more specific test of heparin’s effect on thrombin than ACT, and it appears to possess less artifactual variability. Preoperative heparin infusions do not affect HiTT values. 100 Protamine and Reversal of Anticoagulation Protamine, which has been in clinical use for as long as heparin has, remains the heparin reversal drug of choice in cardiac surgery. The protamine dose required to reverse heparin is somewhat controversial. In the first published study to examine this question, Bull and associates chose a dose of 1.3 mg protamine for every 100 units of heparin to provide a slight excess of protamine from a projected needed amount of 1.2 mg for every 100 units of heparin. 101 Protamine is usually administered according to the total amount of heparin given (i.e., 1–1.3 mg protamine per 100 units of heparin). This method may result in luxuriant protamine doses, which reduce any theoretic or real risks of heparin rebound but may put the patient at higher risk for bleeding events because of the anticoagulant effect of protamine. Guidelines for the practice of anticoagulation in CPB recommend the following: 1. “It is reasonable to limit the ratio of protamine/heparin to less than 2.6 mg protamine/100 Units of heparin, since total doses above this ratio inhibit platelet function, prolong ACT, and increase the risk of bleeding (class IIa, Level of Evidence C).” 92 2. Because of the risk of heparin rebound in patients requiring high doses of heparin and with prolonged CPB times, low-dose protamine infusion (25 mg/h) for up to 6 hours after the end of CPB may be considered as part of a multimodality blood conservation program (class IIb, Level of Evidence C). 92 Protamine can also be administered at a dose calculated from the heparin concentration, which is measured by a protamine titration assay. Guidelines 92 do support this practice stating that “it can be beneficial to calculate the protamine reversal dose based upon a titration to existing heparin in the blood, since this technique has been associated with reduced bleeding 98 and blood transfusion” (class IIa, Level of Evidence B). 98 If the heparin concentration is not measured, the protamine dose can be graphically derived by plotting ACT values throughout the case and creating heparin dose–response curves. The amount of protamine used in this method is based on the circulating concentration of heparin in the patient at the time of reversal. Because, theoretically, no excess protamine exists, these patients may be at risk for heparin rebound and therefore may require additional protamine. In a small study conducted in patients undergoing valve surgery, administering protamine in two divided doses by titration resulted in a larger dose but reduced bleeding, presumably by treating heparin rebound. 102 Unique Hematologic Considerations in Cardiac Surgery Hematologic Effects of Cardiopulmonary Bypass The hematologic effects of CPB are complex. Exposure of blood to the surfaces of the extracorporeal circuit is a profound stimulus for inflammatory system upregulation, and activation of the hemostatic system is a component of the normal inflammatory response. According to traditional models of hemostasis, ECC activates both the intrinsic and extrinsic coagulation pathways and directly impairs platelet function. Intrinsic pathway activation can occur by contact activation and the conversion of factor XII to factor XIIa on the various surfaces of the CPB circuit. The tissue factor generated from the wound and the circulating tissue thromboplastin combine to cause the extrinsic activation of coagulation by cell-mediated hemostasis, which involves tissue factor–bearing leukocytes and activated endothelial cells. Tissue factor pathway generation of thrombin has a primary role in CPB-associated hemostasis abnormalities ( Fig. 50.5 (f0030) ). 103 Fig. 50.5 Coagulation can be activated during cardiopulmonary bypass (CPB) by the intrinsic pathway, with surface adsorption and activation of factor XII, high-molecular-weight kininogen (HMWK), and prekallikrein (PK). Activation of the extrinsic pathway during CPB occurs with tissue injury, as well as with systemic inflammation, and it leads to monocyte and endothelial expression of tissue factor (TF). TF, in combination with factor VIIa, starts the common pathway with the activation of factor X to factor Xa. Assembly of the prothrombinase complex on phospholipid surfaces leads to the production of thrombin and conversion of fibrinogen to fibrin. Tissue factor pathway inhibitor (TFPI) inhibits TF/VIIa. Thrombin can overcome this TFPI blockade by activating factors XI, VIII, and V and initiating activation of factor X by the tenase complex. K , kallikrein. From Kottke-Marchant K, Sapatnekar S. Hemostatic abnormalities in cardiopulmonary bypass: pathophysiologic and transfusion considerations. Semin Cardiothorac Vasc Anesth. 2001;5:187–206. In addition to activating both extrinsic and intrinsic coagulation pathways, CPB directly impairs platelet function through a variety of mechanisms. Platelets express on their surface numerous glycoproteins that serve as receptors for several circulating ligands, such as fibrinogen, thrombin, and collagen ( Fig. 50.6 (f0035) ). Fig. 50.6 Platelet activation by cardiopulmonary bypass materials is facilitated by rapid adhesion and conformational alteration of plasma proteins, including von Willebrand factor (vWF) and fibrinogen (Fib). Platelets adhere to vWF through the glycoprotein (Gp) Ib/IX/V surface glycoprotein and to fibrinogen through the Gp IIb/IIIa receptor. Platelet adhesion stimulates intracellular signaling, which leads to degranulation of α granules (platelet factor 4 [PF4] and β-thromboglobulin [βTG]) and phospholipid reorganization with the formation of coagulation complexes and fibrin formation. Release of adenosine diphosphate (ADP) from dense granules and activation of the Gp IIb/IIIa receptor also occur and lead to the aggregation of platelets to the adherent layer. Because of shear forces, adherent and aggregated platelets can detach from the membrane and circulate in a degranulated state or form small microaggregates that lodge in the distal vasculature. From Kottke-Marchant K, Sapatnekar S. Hemostatic abnormalities in cardiopulmonary bypass: pathophysiologic and transfusion considerations. Semin Cardiothorac Vasc Anesth. 2001;5:187–206. The components of the bypass circuit adsorb circulating proteins that can serve as foci for platelet attraction and adherence. These surface-bound platelets activate and release the contents of their cytoplasmic granules, which can then serve as localized sources of thrombin generation, or they may embolize to initiate microvascular thrombosis. Fibrinolytic activity is also increased by CPB. Contact activation leads to the activation of factor XII, prekallikrein, and high-molecular-weight kininogen, which causes endothelial cells to produce tissue plasmin activator, and lysis of fibrin and fibrinogen ensues ( Fig. 50.7 (f0040) ). Fig. 50.7 The fibrinolytic system results in the degradation of fibrin by plasmin. The intrinsic factors participate in the fibrinolytic system. Adsorption and activation of factor XII, high-molecular-weight kininogen (HMWK), and prekallikrein (PK) occur on the cardiopulmonary bypass material surfaces. Kallikrein ( K ) and factor XIIa participate in the conversion of plasminogen to plasmin. Plasminogen is also activated by tissue plasminogen activator (t-PA), which is released from endothelial cells, along with its inhibitor, plasminogen activator inhibitor-1 (PAI-1). Plasmin degrades not only fibrin but also coagulation factors V and VIII (fV and fVIII) and platelet surface glycoproteins (PLT GP). Kallikrein plays additional roles in the activation of complement and the angiotensin system, and HMWK accelerates fibrinolysis by stimulating endothelial production of t-PA. FDP , fibrin degradation product; α2PI , α 2 plasmin inhibitor. From Kottke-Marchant K, Sapatnekar S. Hemostatic abnormalities in cardiopulmonary bypass: pathophysiologic and transfusion considerations. Semin Cardiothorac Vasc Anesth. 2001;5:187–206. The vascular endothelium is itself an active substrate that is sensitive to circulating mediators, and it expresses and releases anticoagulant and procoagulant factors. When exposed to hypoxia or inflammatory mediators during CPB, the endothelium responds and can induce a relatively prothrombotic state marked by tissue factor upregulation, accelerated platelet adhesion, and increased expression of leukocyte adhesion molecules ( Fig. 50.8 (f0045) ). 104 Fig. 50.8 Procoagulant endothelial cell activation. When endothelial cells are activated, they express tissue factor, which converts prothrombin to thrombin. Thrombin has multiple biologic actions: (1) stimulation of the release of von Willebrand factor and P-selectin, which cause platelet clumping and platelet, neutrophil, and endothelial cell adhesion; (2) conversion of fibrinogen to fibrin, the solid component of clot; (3) downregulation of the thrombomodulin/protein C and S systems; (4) release of tissue plasminogen activator (t-PA), which catalyzes the formation of plasmin; and (5) release of thrombospondin, which binds to t-PA, prevents its breakdown by plasminogen activator inhibitor-1 (PAI-1), and accelerates the formation of plasmin. LPS , lipopolysaccharide. From Boyle EM Jr, Verrier ED, Spiess BD. Endothelial cell injury in cardiovascular surgery: the procoagulant response. Ann Thorac Surg. 1996;62:1549–1557. Heparin Resistance, Altered Heparin Responsiveness, and Antithrombin Heparin resistance is marked by the inability to raise the ACT to therapeutic levels after administration of the recommended doses of unfractionated heparin. Some investigators have defined heparin resistance as an ACT of less than the target (400–480 seconds) after 600 to 800 units/kg of intravenous heparin are administered. 105 Others have defined heparin resistance as an ACT of less than 400 seconds at any time during the course of CPB and heparin administration. 106 Heparin resistance can result from a congenital deficiency or abnormality of AT, which requires treatment with AT to restore heparin’s anticoagulant properties. 107 More often, however, heparin resistance is the result of an acquired condition caused by the patient’s disease status and physiologic state. Giving these patients larger doses of heparin may augment the ACT value; therefore, a more accurate term for describing these clinical findings is altered heparin responsiveness. This alteration can result from an acquired AT deficiency, increased levels of heparin-binding proteins, activated platelets, sepsis, or other conditions. In a small study of cardiac surgical patients stratified by their history of preoperative heparin use, altered heparin responsiveness was found in approximately 40% of the patients who had received preoperative heparin therapy. 107 Reported risk factors for altered heparin responsiveness include AT levels less than 60% of normal, preoperative heparin therapy, and a platelet count greater than 300,000/μL. Ranucci and associates also found that low postoperative AT levels were predictive of a longer length of stay in the ICU, 108 and others have associated low AT levels with adverse myocardial outcomes. 109 Not all heparin resistance is AT mediated; thus, it is critical to understand the physiologic factors that contribute to the altered heparin responsiveness so that appropriate treatment can be instituted. 110 111 112 The most common treatment for altered heparin responsiveness is supplemental heparin. In refractory cases, treatment with AT concentrate, or recombinant AT, in doses that are calculated to produce 80% to 100% AT activity, restores heparin responsiveness. AT supplementation is a class I indication for heparin resistance that is due to AT deficiency. 113 Thus the practice of replacing AT using this specific factor replacement is preferred over the use of plasma transfusion, which is no longer recommended due to the morbidity of allogeneic transfusion. When AT is used for this purpose, careful neutralization with protamine and attention to hemostasis are essential because AT augments the effect of heparin and thereby slightly increases postoperative bleeding. 113 Heparin Rebound Heparin rebound is clinical bleeding that occurs within approximately 1 hour of protamine neutralization. It is accompanied by coagulation test results indicating residual heparinization, such as a prolonged partial thromboplastin time (PTT) or thrombin time and increased anti– factor Xa activity. Mechanisms of heparin rebound include slow dissociation of protein-bound heparin after protamine clearance, more rapid clearance of protamine than of heparin, lymphatic return of extracellular sequestered heparin, and the clearance of an unknown heparin antagonist. Heparin rebound is rare, yet it is more likely to occur when the protamine dose is based on the residual heparin concentration at the end of CPB than when protamine is given as a ratio to the total heparin administered, because using this ratio usually results in a slight “overdose.” With coagulation monitoring, heparin rebound is easily prevented or treated with supplemental protamine. A protamine infusion has also been successful in preventing heparin rebound in patients in whom heparin rebound is a risk. 114 These include cases in which high doses of heparin were administered or in whom CPB time was prolonged. Perfusion management guidelines suggest that a low-dose protamine infusion (25 mg/h) for up to 6 hours after the end of CPB may be considered as part of a multimodality blood conservation program (class IIb, Level of Evidence C). 93 Heparin-Induced Thrombocytopenia HIT is an immune-mediated prothrombotic disorder that occurs in patients exposed to heparin. Antibodies form against the protein platelet factor 4 (PF4) when PF4 has formed a complex with heparin. Although PF4 is found in only trace amounts in human plasma and is stored in platelet α granules, the presence of heparin increases plasma PF4 concentrations 15- to 30-fold by displacing bound PF4 on endothelial cell surfaces. PF4 is also expressed on the surface membrane of activated platelets by membrane fusion with the α-granule membrane; thus, PF4 is exposed and available to bind with heparin. The resulting PF4–heparin complex on the platelet surface is recognized by a specific immunoglobulin G (IgG), which binds to the complex and leads to immunologically mediated platelet activation. Hyperaggregability of these activated platelets is the hallmark of HIT and is responsible for its prothrombotic complications. 115 , 116 Often a clinical score, such as the 4 Ts score, can be used to determine whether a heparin- platelet antibody test should be performed to diagnose HIT (class IIa, Level of Evidence B). 93 Diagnosis can be difficult in the post–cardiac surgery patient and often the 4 Ts score is unreliable. A common presentation in patients with HIT is a reduction in the platelet count to less than 100,000/μL or to less than 50% of the baseline count. The incidence of seroconversion after CPB and heparin exposure is quite frequent (20%–50%). 117 However, the reported prevalence of clinical HIT after CPB is only 1% to 3%. 118 Thus, the risk of HIT in cardiac surgical patients with postoperative seroconversion is less than 10%. The strength of the immunologic response, not the mere presence of PF4 or heparin antibodies, may determine which patients are prone to HIT and are at risk for thromboembolic complications. 118 The presence of preoperative antibody, in addition to postoperative antibody, has been associated with increased morbidity after cardiac surgery. 119 This morbidity takes the form of gut ischemia, renal dysfunction, limb ischemia, and other prothrombotic events. Management of the cardiac surgical patient with HIT includes a careful risk-to-benefit analysis. The likelihood that a patient has true disease and is at increased risk for a thrombotic event must be weighed against the risks posed by using an alternative anticoagulant to heparin. The urgency of the surgical procedure is also an important factor. It is preferable, if possible, to defer the operation until antibody titers have become undetectable 93 or only weakly positive, which may occur after 90 days (class IIa, Level of Evidence C). 118 If surgical postponement is not practical, then other therapeutic options must be considered ( Boxes 50.5 (b0030) and 50.6 (b0035) ). BOX 50.5 Therapeutic Options for Anticoagulation for Cardiopulmonary Bypass in Patients with Heparin-Induced Thrombocytopenia Modified from Kaplan JA, Reich DL, Savino JS, eds. Kaplan’s Cardiac Anesthesia: The Echo Era, 6th ed. St. Louis: Saunders; 2011:966. RGD, receptor glycoprotein–derived. 1. Ancrod 2. Low-molecular-weight heparin or heparinoid (test first) 3. Alternative thrombin inhibitor (hirudin, bivalirudin, argatroban) 4. Using a single dose of heparin, promptly neutralizing it with protamine, and a. Delaying surgery so antibodies can regress or b. Using plasmapheresis to decrease antibody levels or c. Inhibiting platelets with iloprost, aspirin and dipyridamole (Persantine), abciximab, or RGD blockers In all cases: 1. No heparin in flush solutions 2. No heparin-bonded catheters 3. No heparin lock intravenous ports No agent is currently indicated for anticoagulation in cardiopulmonary bypass. BOX 50.6 Potential Alternative Anticoagulants for Cardiopulmonary Bypass From Kaplan JA, Reich DL, Savino JS, eds. Kaplan’s Cardiac Anesthesia: The Echo Era, 6th ed. St. Louis: Saunders; 2011:967. Low-molecular-weight heparins Factor Xa inhibitors Bivalirudin or other direct thrombin inhibitors (hirudin, argatroban) Currently, the direct thrombin inhibitors are used as the anticoagulants of choice. Hirudin and argatroban are approved by the US Food and Drug Administration (FDA) for use in patients with HIT-related thrombosis. 120 The use of these drugs as anticoagulants for CPB is fraught with hemorrhagic complications. Bivalirudin has been approved by the FDA for use in percutaneous interventions and, because of its short half-life, has been favored as an anticoagulant for CPB in patients with HIT. 121 122 123 Guidelines suggest that in patients with a diagnosis of HIT and in need of an urgent operation requiring CPB, bivalirudin is a reasonable option (class IIa, Level of Evidence B). 93 However, no drug other than heparin has FDA approval for specific use as an anticoagulant in patients undergoing CPB. Bivalirudin undergoes renal elimination. Therefore, in seropositive HIT patients who have significant renal dysfunction, anticoagulation for urgent operations requiring CPB can be accomplished with argatroban, plasmapheresis prior to heparin to remove antibodies, or heparin with concomitant antiplatelet agents to prevent platelet activation (tirofiban, iloprost) (class IIb, Level of Evidence C). 93 These latter two techniques have risk because they include heparin and have been fraught with increased risks of bleeding. Boxes 50.5 (b0030) and 50.6 (b0035) ) summarize therapeutic options and alternative anticoagulant strategies for the patient with HIT whose operation cannot be deferred until seronegativity is documented. Fig. 50.9 (f0050) delineates how each alternative drug inhibits factor Xa, thrombin, or fibrinogen. Fig. 50.9 Alternatives to heparin. Newer anticoagulants are shown in the boxes on the right side of the figure; these drugs inhibit factor Xa, thrombin, or fibrinogen. LMWH , low-molecular-weight heparin; TF , tissue factor. From Kaplan JA, Reich DL, Savino JS, eds. Kaplan’s Cardiac Anesthesia: The Echo Era , 6th ed. St. Louis: Saunders; 2011:968. Protamine Reactions Protamine is associated with several hemodynamic effects that can be categorized by their presentation and mechanism. Adverse reactions to protamine range from moderate hypotension to profound and hemodynamically significant reactions that can increase in-hospital mortality risk. 124 , 125 The clinical presentation of these reactions serves as a starting point for understanding their mechanistic relationships. Commonly, these reactions are classified as type I, type II, or type III. A type I protamine reaction involves isolated hypotension, with normal to low filling pressures and normal airway pressures. This reaction is usually mild and responds to volume infusion, slowing of protamine infusion, and the gentle titration of vasoactive medications. Type II reactions include moderate to severe hypotension and features of anaphylactoid reactions, such as bronchoconstriction. Anaphylactoid reactions include protamine sensitivity reactions that are classically immunologic or allergic in that they are immunoglobulin E (IgE) antibody mediated. Nonimmunologic mechanisms may involve IgG antibodies or complement activation. Type III reactions are thought to be caused by large heparin–protamine complexes that lodge in the pulmonary circulation, cause the release of mediators, and result in severe hypotension and elevated PA pressures that may lead to acute RV failure. This is obviously a profound response, resulting in global cardiovascular collapse or necessitating the reinstitution of CPB because of intractable RV failure. Fortunately, catastrophic hypotension and intractable RV failure are relatively rare events on the spectrum of protamine reactions. 124 Mechanistic explanations for protamine reactions include endothelial nitric oxide release, mast cell degranulation, and histamine release associated with rapid infusion. A study by Kimmel and colleagues found that neutral protamine Hagedorn insulin use, documented fish allergy, and a history of nonprotamine medical allergies were independent risk factors for protamine hypersensitivity reactions. 126 In this study, 39% of patients who presented for cardiac surgery had one or more of these risk factors. Other possible but unconfirmed risk factors include prior exposure to protamine, a history of vasectomy, decreased LV function, and hemodynamic instability. 126 The site of injection does not influence the incidence of protamine reactions. 127 Pretreatment with histamine blockade is not preventive. The following principles summarize treatment options for patients at risk for protamine reactions: 1. Protamine should be administered slowly (i.e., over ≥5 minutes). Limit protamine dose to less than 2.6 mg protamine/100 units of heparin, since total doses above this ratio inhibit platelet function, prolong ACT, and increase the risk of bleeding (class IIa, Level of Evidence C). 93 2. In patients with documented adverse events related to protamine, consideration should be given to not readminister protamine to the patient. Pharmacologic alternatives to protamine can be considered, or a decision can be made not to reverse heparin. Consideration may be given to using non-heparin-based CPB, performing off-pump coronary artery bypass (OPCAB) with an alternative to heparin, or, if heparin is used, administering nonprotamine heparin reversal drugs such heparinase, or simply waiting for heparin’s effects to dissipate. 3. Hypotension associated with protamine reversal of heparin often is ameliorated by simply slowing or pausing protamine infusion while volume is infused through intravenous lines or the aortic cannula. Vasoactive medications, such as phenylephrine or ephedrine, use of calcium chloride, or increased inotropic support may be necessary. 4. Severe or intractable hypotension, with or without evidence of pulmonary circulatory involvement, bronchospasm, or overt RV failure, demands immediate aggressive attention, intervention, and planning for a potential return to CPB. Steps to consider include the following: a. Reheparinization to prepare the patient for a return to CPB and to reduce heparin– protamine complex size. If hemodynamics permit, a low dose of heparin (70 units/kg) may be tried first while supportive treatment continues, followed by a full CPB dose of heparin (300 units/kg) if it becomes necessary to return the patient to CPB (class I, Level of Evidence C). 93 b. Inotropic support, either by infusion or by intermittent bolus administration, is warranted. Epinephrine and norepinephrine are acceptable options, and milrinone may be considered if the patient’s hemodynamic status permits. c. If the patient’s hemodynamic status allows, nebulized albuterol is helpful in the management of bronchospasm and elevated airway pressures. Antifibrinolytic Therapy: Prophylaxis for Bleeding Prophylactic use of antifibrinolytic drugs before CPB reduces bleeding and transfusion requirements in cardiac surgical patients in randomized trials and in multiple meta-analyses. 128 , 129 The most well-known antifibrinolytic drugs include the synthetic lysine analogues ε- aminocaproic acid (EACA) and tranexamic acid (TA) and the serine protease inhibitor aprotinin. Presumably, the blood-sparing effects of the synthetic drugs result from the inhibition of fibrinolysis by their binding to the lysine-binding sites on plasmin. This also has platelet protective properties because plasmin’s antiplatelet effects are also inhibited by antagonist binding. Aprotinin is a direct enzymatic inhibitor of plasmin and has other protease-inhibiting properties that confer its anti-inflammatory and antikallikrein effects. However, aprotinin was notably associated with increases in post-CPB creatinine values and other adverse organ system outcomes in large-scale observational trials. 130 When a randomized prospective trial showed an increase in mortality in the aprotinin group, despite a reduction in bleeding, the drug was removed from the global market. 131 Although the causes of death in the aprotinin-treated patients were not found to be related to thrombosis or other drug-related effects, aprotinin was rendered unavailable for commercial use for years after publication of this study. The decision to remove aprotinin from clinical use was revisited on reevaluation of these study data, and aprotinin has been reintroduced in Canada and other countries specifically for use as labeled in CABG surgery. Hypercoagulable States The use of antifibrinolytics has become common in cardiac operations that require CPB. The use of antifibrinolytic drugs and prohemostatic drugs and blood products to treat bleeding has brought to light the risk of thrombosis in CPB, during which feedback mechanisms are critical and homeostasis is perturbed. All patients incur this risk of thrombosis as consumptive coagulopathy increases, but the risk is greatly increased in patients with congenital or acquired thrombophilic states. 132 These states may be important in view of current practices that involve pharmacologically inhibiting fibrinolytic pathways in cardiac surgical patients. The factor V Leiden (FVL) mutation is the most common inherited thrombophilic disorder; its prevalence is 3% to 7% in White populations. 133 , 134 Mechanistically and clinically, FVL has been implicated in thrombotic complications in cardiac operations, most often those involving a period of circulatory arrest and the use of antifibrinolytics. 135 In a review of FVL mutation, Donahue gave the following summation and recommendations 132 : ▪ Cardiac surgical patients who are heterozygous for the FVL mutation bleed less than do noncarriers. ▪ The risk of early graft thrombosis may be increased in patients with FVL deficiency. ▪ The use of antifibrinolytic drugs may increase thrombotic risk in patients with FVL. ▪ Anecdotal evidence suggests that in patients with FVL mutation who are exposed to deep hypothermic circulatory arrest, antifibrinolytics increase thrombotic risk. Cardiac Surgical Patients Taking Anticoagulant or Antithrombotic Drugs Antithrombotic therapy in cardiac surgical patients has many roles and applications. Patients with ischemic heart disease can be managed short or long term with pharmacologic drugs that may include aspirin, AT inhibitors (heparins), direct thrombin inhibitors, or an array of platelet inhibitors (adenosine diphosphate [ADP] receptor inhibitors and glycoprotein IIb/IIIa [Gp IIb/IIIa] receptor inhibitors). Patients with a history of peripheral vascular disease, valvular heart disease, or low ventricular ejection states can similarly be managed with some form of antithrombotic therapy that may also include warfarin. Frequently, patients arrive for surgery while receiving multiple antithrombotic medications. Thus, postoperative bleeding is a common but challenging complication of cardiac surgery, especially when the bleeding risk posed by CPB itself is considered. The use of percutaneous coronary interventions (PCIs) such as angioplasty and intracoronary stent deployment for ischemic heart disease has led to the use of antithrombotic medications to maintain stent patency and to prevent stent thrombosis. The American College of Cardiology and AHA (ACC/AHA) initial guidelines for percutaneous coronary intervention recommended (on the basis of class I evidence) the use of both aspirin and clopidogrel for at least 1 year after drug- eluting stent placement. 136 However, percutaneous coronary intervention data with the second- generation drug-eluting stents indicate that shorter periods of dual antiplatelet therapy are equally effective in preventing in-stent thrombosis, and thus allow for earlier cessation of a single antiplatelet agent after 6 months. 137 This opens the door for interventions and surgical procedures to be performed sooner and with less risk of bleeding. The administration of thienopyridine antiplatelet drugs in addition to aspirin increases the risk of bleeding after cardiac surgery 138 ; however, it is unclear whether aspirin alone increases this risk. Abundant evidence (mostly level B Evidence from small, retrospective, nonrandomized studies) suggests that the ADP receptor antagonist clopidogrel (Plavix) has been associated with excessive perioperative bleeding in patients who undergo CABG. 139 This trend has even been reported in the OPCAB population, although not consistently. 140 Earlier recommendations included a 5- to 7-day delay after discontinuation of clopidogrel in patients who require CABG. However, guidelines 88 suggest that a 3-day delay may be sufficient to lessen bleeding risk and provide safe outcomes. 141 It is likely that a 5- to 7-day delay is not necessary, but some interval between the discontinuation of clopidogrel and CABG is supported by the available evidence. Patients with a history of Gp IIb/IIIa receptor blockade as a part of their acute coronary syndrome management are at risk of increased bleeding and blood component use when they are given abciximab, especially within 12 hours of cardiac surgery. 142 , 143 Shorter-acting Gp IIb/IIIa receptor antagonists do not seem to increase bleeding or adverse outcomes and in fact may improve myocardial outcomes when Gp IIb/IIIa blockers are in use. 144 The interval between the discontinuation of antiplatelet therapy and cardiac or noncardiac surgery is critical to preventing thrombotic events without increasing the risk of bleeding. These decisions regarding the cessation of therapy can be guided by knowledge of drug pharmacology and testing of antiplatelet drug efficacy. Enoxaparin, a low-molecular-weight heparin, increases transfusion rates and the risk of surgical re-exploration when it is used in association with CPB. 145 Low-molecular-weight heparin may also decrease heparin responsiveness. 146 Patients who present for cardiac surgery with residual warfarin effects may benefit by having enhanced anticoagulation during CPB. Postoperatively, if excessive bleeding is noted and is confirmed by hemostasis testing, factor replacement can be performed with blood products or pharmacologic prothrombin complex concentrates (PCCs). Patients with atrial fibrillation may be maintained on new antithrombotic therapeutic drugs, direct oral anticoagulants (DOACs) that include thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). These drugs are potent and long acting, and they have no antidote, so one would expect that treating cardiac surgical patients with these drugs would increase their bleeding risk. When compared to vitamin K antagonists, the DOACs have similar thromboprophylaxis efficacy yet fewer bleeding complications. 147 An additional benefit is that DOACs have a predictable pharmacodynamic profile and routine monitoring is often unnecessary. Routine monitoring tests such as the international normalized ratio (INR) and activated partial thromboplastin time (aPTT) do not even accurately assess anticoagulant activity of the DOACs and thus a thrombin time or a direct measure of anti-Xa activity would be considered more accurate. 148 , 149 In summary, patients who present for cardiac surgery with preexisting, pharmacologically induced inhibition of the hemostatic system may have undesirable post-CPB bleeding. The diagnosis and treatment of this complication should be the same whether the derangement is a function of CPB itself, coexisting pharmacologic inhibition, or both. The management and treatment of persistent postoperative bleeding are discussed in the section on problems in the postoperative period. Premedication The anesthesiologist should ensure that appropriate premedications are administered with a sip of water on the morning of surgery. With a few exceptions, patients should receive their usual long-term medications, particularly β-adrenergic blocking drugs, on the day of surgery. The clinician should be aware that ACE inhibitors (ACEIs), if administered on the day of surgery, may increase the patient’s propensity for hypotension. 150 With respect to aspirin, it is recognized that aspirin administration in the early postoperative period may reduce the risk of ischemic complications after CABG surgery. 151 However, patients who receive aspirin immediately preoperatively may have more mediastinal bleeding and greater transfusion requirements. A consensus statement published by the STS recommends that low-intensity antiplatelet drugs (e.g., aspirin) be discontinued before cardiac surgery to reduce patients’ blood transfusion requirements, but this should be done only in purely elective cases in patients without acute coronary syndromes. 152 However, drugs that inhibit the platelet P2Y12 receptor should be discontinued before operative coronary revascularization (either on-pump or off-pump), if possible. 152 The interval between drug discontinuation and operation is determined from the drug’s pharmacodynamics but may be as short as 3 days for irreversible inhibitors of the P2Y12 platelet receptor. POC tests are available to measure platelet ADP responsiveness. POC tests that show normal platelet ADP responsiveness after administration of an initial dose of clopidogrel indicate P2Y12 resistance with as much as 85% specificity. 153 , 154 This is called “high on-treatment platelet reactivity.” Flow cytometry may be more specific in diagnosing the degree of platelet inhibition, but it cannot be measured at the point of care. 153 , 155 The prospect of undergoing cardiac surgery provokes anxiety in most patients. Furthermore, the insertion of intravenous and arterial catheters is painful and must be done before anesthesia is induced. The resultant anxiety and pain can lead to undesirable sympathetic stimulation, with consequent tachycardia and hypertension. The first step in preventing this cycle is thoroughly explaining the anticipated anesthetic techniques and procedures to the patient. Premedication with a narcotic or anxiolytic drug, or both, to mitigate pain and anxiety is usually indicated before the patient is transported to the operating suite. Supplemental intravenous drugs – commonly midazolam and possibly fentanyl – are usually necessary during radial artery cannulation before anesthesia is induced. However, in patients with low CO secondary to congestive HF (CHF), sedation should be performed judiciously to avoid myocardial depression and resultant hypotension. Moreover, in patients with significant pulmonary hypertension, oversedation and respiratory depression leading to hypercapnia or hypoxia must be avoided. Induction of Anesthesia In preparing for induction, the clinician should have the following drugs immediately available: vasopressors (e.g., phenylephrine, ephedrine, calcium chloride, readily available vasopressin), one or more inotropes (e.g., ephedrine; epinephrine; readily available norepinephrine, dopamine, or dobutamine), one or more vasodilators (e.g., nitroglycerin, nitroprusside, nicardipine), an anticholinergic drug (atropine), antiarrhythmic drugs (e.g., lidocaine, esmolol, magnesium, amiodarone, adenosine), and heparin. 156 Commonly administered drugs should be drawn up and ready for administration by bolus or infusion, as appropriate; agents that are used less commonly should be readily available in the operating room. Protamine should be readily available, but many institutions require that protamine be stored in unique packaging or at a separate, nearby location to prevent inadvertent premature administration. Furthermore, the selected antibiotic should be ready to administer. The STS recommends a cephalosporin as the primary prophylactic antibiotic for cardiac surgery; the drug should be administered within 1 hour before incision. 157 In patients who are allergic to penicillin, vancomycin is administered within 2 hours of incision. Finally, antifibrinolytic drugs are commonly used to minimize bleeding and the need for transfusion during cardiac surgery. The most commonly used antifibrinolytic drugs are the synthetic lysine analogues TA and EACA; both reduce total blood loss and decrease the number of patients who require blood transfusion during cardiac procedures. 158 Anesthetic drugs and techniques for inducing anesthesia should be selected with consideration of the patient’s cardiac pathophysiology and other comorbid conditions. No single “recipe” can guarantee hemodynamic stability during anesthetic induction. Hypotension may result in a patient who is relatively hypovolemic and receives a vasodilator or whose sympathetic tone is reduced by anesthesia. Hypotension is particularly common in patients with poor LV function. Conversely, in patients with good myocardial function, hypertension may occur during induction because of pre-induction anxiety or sympathetic stimulation caused by laryngoscopy and endotracheal intubation. The radial artery or an alternative site should be cannulated before induction of anesthesia to monitor arterial pressure on a beat-to-beat basis. If the radial artery is being harvested as a vascular conduit, the contralateral radial or brachial artery or a femoral artery can be cannulated. Basic monitors, including the ECG and pulse oximeter, should also be used during the induction of anesthesia. During any cardiac surgical procedure, central venous access is necessary to secure so that volume infusion, transfusion therapy, and vasoactive drug administration can be easily delivered directly to the central circulation. A central venous catheter or a PA catheter can be placed either before or after anesthesia is induced. Placement before anesthesia induction is ideal so that the CVPs can be monitored during the induction of anesthesia. However, the placement of these lines in the awake patient can take more time and create discomfort, thus causing unwanted hypertension and tachycardia. The risk–benefit analysis usually dictates that the central venous line be placed after anesthesia induction. The urinary bladder catheter, nasogastric tube, TEE probe, and any additional temperature monitors (e.g., a nasopharyngeal probe) are positioned after induction of anesthesia. When choosing anesthetic drugs and doses during induction and maintenance, one should consider any pharmacodynamic properties that could affect arterial blood pressure, heart rate, or CO, as well as the desirability of “early” extubation of the trachea (i.e., within a few hours after the operation is completed). Anesthesia is most commonly induced with an opioid and a sedative–hypnotic (etomidate, propofol, or midazolam). All anesthetics decrease arterial blood pressure by decreasing sympathetic tone, decreasing systemic vascular resistance (SVR), inducing bradycardia, or directly depressing myocardial function. The only exception is ketamine, which has sympathomimetic effects; however, in patients with catecholamine depletion, ketamine’s sympathomimetic effects may not counterbalance its direct negative inotropic effects. Because of their pharmacologic complexities, all anesthetic agents should be administered judiciously in patients who are critically ill or who have poor LV function. Muscle relaxants are usually given early in the sequence of anesthetic induction, particularly if relatively large doses of opioids are administered, to minimize chest wall rigidity. With the routine use of fast-track anesthesia techniques, including a trend toward earlier extubation, volatile anesthetics are often chosen as the primary maintenance anesthetic. The predominant effect of isoflurane, desflurane, and sevoflurane is dose-dependent vasodilation with resultant decreases in SVR and arterial blood pressure. These volatile anesthetics may have an advantage in inducing preconditioning, which is particularly important in patients undergoing either CABG with CPB or OPCAB, in which myocardial ischemic insults are likely. The volatile anesthetic agents have several cardioprotective effects, including triggering the preconditioning cascade and mitigating reperfusion injury. 159 However, nitrous oxide probably should be avoided because it can increase gaseous bubble size and adversely affect pulmonary vascular resistance (PVR). The Pre–Cardiopulmonary Bypass Period See detailed discussion of CPB later in this chapter. After anesthesia is induced, several important details must be remembered, especially positioning. Methods of positioning the arms vary according to institutional practice, but one must avoid causing brachial plexus injury by hyperextending the arms, ulnar nerve injury by improperly padding the olecranon, radial nerve injury by compressing the upper part of the arm against the sternal retractor support posts, or finger injury by entrapping the finger against the metal edge of the surgical table. Proper positioning also ensures that arterial catheters previously placed in the radial, ulnar, or brachial arteries are not “dampened.” The head should be padded and occasionally repositioned during the procedure to prevent occipital alopecia, which can occur several days postoperatively. The eyes should be taped, possibly lubricated, and definitely free from pressure. Pressure-related injury to any soft tissue will potentially be exacerbated by hypothermia and decreased perfusion during CPB. All monitors and tubing should be checked after final positioning to ensure that none are kinked, entrapped, tangled, or inaccessible. Additionally, antibiotics must be administered (with documentation) within 1 hour of incision (vancomycin within 2 hours). Arterial blood gases and blood chemistry (electrolytes, glucose, and calcium), as well as baseline ACT, should be measured shortly after anesthesia is induced. If a continuous mixed venous PA catheter has been inserted, mixed venous hemoglobin oxygen saturation should be measured to calibrate the device. During the pre-bypass period, the anesthesiologist’s main goal is to maintain the hemodynamic and metabolic stability of the patient while preparing for CPB. The degree of surgical stimulation varies markedly during this period. Positioning the patient, inserting additional monitors, preparing the skin, and harvesting the saphenous vein or veins cause only minimal sympathetic stimulation. Therefore, hypovolemic patients and those with poor ventricular function may be susceptible to hypotension during these periods. In contrast, chest incision, sternal splitting, and harvesting of the IMA involve more intense surgical stimulation. These events may cause hypertension, tachycardia, and dysrhythmias, even in previously hypotensive patients. However, just before CPB is initiated, during the cannulation of the great vessels, surgical stimulation is again minimal, and manipulation of the heart and great vessels may transiently decrease venous return and cause a precipitous decline in blood pressure. The anesthesiologist must be ready to treat all hemodynamic aberrations with the vasopressor, inotropic, vasodilator, antiarrhythmic, and anticholinergic drugs mentioned earlier. In preparation for CPB, anticoagulation must be achieved. Heparin is still the standard drug used and is administered through a central venous catheter at an initial dose of 300 to 400 units/kg. The onset of anticoagulation is almost immediate, but generally, the drug is allowed to circulate for 3 to 5 minutes before its effect is measured. The ACT must increase to at least 300 seconds before CPB is initiated, although most institutions use at least 400 seconds as their standard. Additional heparin is administered, if necessary, to increase the ACT to the desired level. Subsequently, it is common to administer an antifibrinolytic drug (EACA or TA) in an attempt to minimize bleeding and the need for transfusion during cardiac surgery. After heparinization, the next major step in the pre-bypass phase is vascular cannulation. One or more large veins or the right atrium is cannulated so that all systemic venous blood is diverted to the pump oxygenator. Additionally, a large artery, usually the ascending aorta, is cannulated so that oxygenated blood is delivered back to the arterial circulation. Heparin is always administered before cannulation. Usually, arterial cannulation is established before venous cannulation to allow rapid intravascular volume or blood resuscitation if necessary. Complications of aortic cannulation include arterial dissection, hemorrhage and resultant hypotension, inadvertent cannulation of the aortic arch vessels, and embolic phenomena caused by dislodged atherosclerotic plaque or by air introduced into or entrained around the aortic cannula. Complications of venous cannulation include hypotension from blood loss, dysrhythmias, and surgical mechanical compression of the heart or great vessels. When arterial cannulation is successful and the cannula has been inspected to ensure that no air is present, volume can be administered in 100-mL increments to treat bleeding and hypovolemia. If necessary, dysrhythmias are treated by cardioversion, medications, or rapid initiation of CPB. Patients undergoing redo cardiac surgery (i.e., those who have previously had a median sternotomy) warrant special concern about the possibility of sudden, massive hemorrhage. At least 2 units of blood should be immediately available for all redo cases. Frequently, the surgeon will elect to use an oscillating saw in these patients, but mediastinal structures adherent to the underside of the sternum may nevertheless be injured. If the right atrium, right ventricle, great vessels, or an existing coronary graft is cut, the surgeon may elect to initiate CPB on an emergency basis. Therefore, the anesthesiologist should have a systemic dose of heparin prepared. As soon as the patient is heparinized, the femoral or aortic arterial cannula is inserted, and the cardiotomy suckers can be used to create venous return (so-called sucker bypass). Onset of Cardiopulmonary Bypass Preparing for the onset of CPB brings about a new set of challenges for a cardiac anesthesiologist. As a preparation for CPB, the surgeon would start by placing purse-string sutures in the ascending aorta for the eventual placement of aortic cannula. It is imperative that at this point the anesthesiologist keeps the patient’s blood pressure in a range that would not jeopardize the integrity of the aorta while the cannula is placed. A systolic blood pressure of 90 to 110 mm Hg is traditionally accepted for this stage of the procedure. Around this time heparin will also be administered. Usually 300 units/kg patient weight is administered for a target ACT of 450 to 500 seconds, to safely start the CPB. After the safe placement of aortic cannula, remaining cannulas will be placed by the surgeon, followed by start of the CPB. During the above-mentioned process, a cardiac anesthesiologist monitors the patient’s hemodynamics and rhythm for any undesired changes. With the onset of CPB, to guard against malposition of the aortic or venous cannula, the perfusionist checks the aortic inflow line pressure and for signs of inadequate venous return while the anesthesiologist checks for persistently low arterial pressure, unilateral blanching of the face, or any swelling in the neck veins, face, or conjunctiva. Once full bypass is established and aortic ejection by the heart has ceased, ventilation and inhaled drugs can be discontinued. If a PA catheter is present, it is pulled back 3 to 5 cm to minimize the risk of pulmonary perforation as the pulmonary arteries collapse. Pre-bypass urine output is recorded and emptied so that urine output during CPB can be monitored separately. The TEE probe may be used to watch for LV distention with the onset of CPB, which may indicate aortic valve regurgitation or other hemodynamic problems. Once CPB is established, the probe is left in the unlocked (neutral) position until the cardiac chambers are de-aired and the patient is weaned from CPB. To ensure adequate anesthetic depth, supplemental intravenous sedative–hypnotics are administered, or a volatile agent is administered through a vaporizer connected to the oxygenator gas inlet of the CPB circuit. Administration of muscle relaxant is continued to prevent spontaneous ventilation, movement, or shivering during hypothermia and rewarming. Weaning from Cardiopulmonary Bypass After the completion of surgery on CPB, the patient is prepared for coming off of the CPB and the resumption of the patient’s own physiology. As part of a cardiac anesthesiologist’s responsibilities, it is of paramount importance to make a plan beforehand for this part of cardiac surgery. The plan should consider the nature of surgery, the length of bypass run, length of the aortic cross-clamp and patient’s presurgical cardiac status and comorbidities. In preparation of weaning the patient off of the CPB, several issues need to be addressed before a successful weaning process is started. Issues that need to be addressed include temperature, electrolytes (specifically potassium), rhythm, systemic blood pressure, contractility, and any air in the left ventricle (LV). After addressing the above-mentioned issues, the perfusionist gradually allows more and more blood to be pumped by the heart instead of the bypass machine. During this time the cardiac anesthesiologist ensures that any inotropic and/or volume requirements of the patient are met to successfully bring the CPB run to its conclusion. The “Cvp” Mnemonic Fortunately, for most patients, separation from CPB is a relatively uneventful process. A review by Licker and colleagues emphasized that the key to successful weaning from bypass is clear communication among members of the operating room team. 160 In a study conducted at the Mayo Clinic in Rochester, Minnesota, 161 a strong correlation was noted between the frequency of technical errors and poor communication or coordination among the surgeon, anesthesiologist, and perfusionist. Regarding clinical issues, several criteria should be met in all cardiac surgical cases before weaning from CPB is attempted. Morris and colleagues suggest a mnemonic, “CVP,” to help the clinician remember the main tasks necessary for the successful termination of CPB ( Table 50.3 (t0020) ). 162 Each letter of CVP represents several tasks or important points to remember that begin with that letter. Table 50.3 Elements of Morris, Romanoff, and Royster’s “Central Venous Pressure” Mnemonic for Weaning Patients from Cardiopulmonary Bypass From Morris BN, Romanoff ME, Royster RL. The postcardiopulmonary bypass period: weaning to ICU transport. In: Hensley FA, Martin DE, Gravlee GP, eds. A Practical Approach to Cardiac Anesthesia. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:230–260. C V P Cold Ventilation Predictors C V P Conduction Visualization Pressure Cardiac output Vaporizer Pressors Cells Volume expanders Pacer Calcium Potassium Coagulation Protamine The first “C” stands for cold, which refers to the patient’s temperature at the time of weaning from CPB, which should be 36°C to 37°C. Neither the temperature of the venous blood returning to the CPB circuit, nor the nasopharyngeal temperature should ever exceed 37°C because hyperthermia may increase the risk of postoperative neurologic complications (see the later section on “Temperature”). The second “C” stands for conduction, which refers to cardiac rate and rhythm. A heart rate of 80 to 100 beats/min is usually desirable. Bradycardia is treated with epicardial pacing wires and/or with β-adrenergic drugs that have chronotropic and dromotropic, as well as inotropic, properties. Tachycardia (i.e., heart rate >120 beats/min) is also undesirable. Sinus tachycardia may result from anemia, hypovolemia, “light” anesthesia, or the administration of chronotropic drugs; treatment is tailored to the presumed cause. Rhythm is also an important factor in optimizing CO. Third-degree AV block requires pacing, ideally AV pacing. Sinus rhythm is preferable, particularly in patients with poor LV compliance, who are especially dependent on an “atrial kick” to achieve adequate filling. If supraventricular tachycardia is present, direct synchronized cardioversion is often warranted. In addition, pharmacologic therapy with amiodarone, esmolol, verapamil, or adenosine may be used in the initial treatment of or to prevent the recurrence of supraventricular tachycardia. The third “C” stands for CO or contractility. Contractility may be estimated from TEE or PA catheter data, if available. The fourth “C” refers to cells (i.e., red blood cells [RBCs]). The patient’s hemoglobin concentration should be 7 to 8 g/dL, or slightly higher, before weaning from CPB. If the hemoglobin concentration is less than 6.5 g/dL when rewarming commences, the perfusionist and anesthesiologist can consider hemoconcentration or transfusion of a unit of packed RBCs (PRBCs). The fifth “C” refers to calcium, which should be immediately available for possible administration to treat hypocalcemia and hyperkalemia. Ionized calcium levels should be measured after rewarming to help direct therapy. Although calcium is not administered routinely, if ionized calcium levels are in the low–normal range, SVR can be beneficially increased by calcium administration. The sixth “C” stands for coagulation. After protamine is administered, ACT is measured. In patients at risk for coagulation abnormalities, prothrombin time (PT), PTT, and platelet count should also be measured a few minutes later. If POC coagulation monitoring such as the viscoelastic tests are available, these should be measured at this time. Examples of patients at risk for coagulation abnormalities include the following: those with long CPB times; those with extreme hypothermia, elective circulatory arrest, or both, during CPB; and those with chronic renal failure. Platelet function tests may be useful in patients taking platelet inhibitors (e.g., clopidogrel or aspirin). (For further discussion of patients having emergency surgery who are taking warfarin or who have been exposed to thrombolytic drugs, antiplatelet Gp IIb / IIIa agents, or direct thrombin inhibitors see the sections on the Hematologic System and on Bleeding and Coagulopathy.) The first “V” stands for ventilation of the lungs. As CPB is discontinued, the venous outflow line is gradually occluded, and PA blood flow is gradually restored. Pulmonary ventilation and oxygenation must be reestablished, thus allowing the lungs to become the site of gas exchange again. Ideally, the lungs are initially re-inflated manually, with a few sustained inflations to a peak pressure of approximately 30 cmH 2 O. If an IMA has been grafted to a coronary artery, the anesthesiologist must examine the surgical field during these inflations to ensure that the grafted artery is not overstretched, which could disrupt the distal anastomosis. Additionally, the compliance of the lungs is judged by these initial inflations, and bronchodilators can be administered if necessary. The surgeon should remove any fluid or blood from the pleural spaces and ensure that any pneumothorax is treated with a chest tube. The second “V” refers to visualization of the heart, both directly in the surgical field (where the right-sided chambers are visible) and on the TEE, to estimate global and regional contractility. Furthermore, the degree of chamber filling (hypovolemic, euvolemic, or distended) can be estimated. In addition, one can do a final check for air within the cardiac chambers with TEE examination. The third “V” stands for vaporizer, meaning that if volatile agents were used to ensure lack of awareness or to control blood pressure during CPB, the clinician usually reinstitutes a low dose immediately after weaning. However, because all the volatile agents decrease contractility and blood pressure, these effects can confuse the differential diagnosis of hypotension and myocardial dysfunction during weaning. The final “V” refers to volume expanders. When all products from the pump have been exhausted and if blood transfusion is not indicated, crystalloid and albumin or hetastarch should be readily available to increase preload rapidly if necessary. As for the letter “P” in the CVP mnemonic, Morris et al. explained that the first task “P” represents the need to be aware of predictors of adverse cardiovascular outcome. 162 For example, preoperative low EF and prolonged CPB often predict difficulty in weaning the patient from CPB and the need for inotropic support. In addition, emergency surgery in patients with acute coronary syndrome may lead to myocardial stunning. Furthermore, inadequate surgical repair (e.g., incomplete coronary revascularization) may result in ongoing ischemia. The second “P” stands for pressure. Calibration and rezeroing are accomplished shortly before the patient begins being weaned from CPB. Any discrepancy between the distal (usually radial) arterial pressure and the central aortic pressure should be recognized. Occasionally, the surgeon may need to insert a temporary aortic root cannula or a longer-lasting femoral arterial cannula to monitor systemic blood pressure accurately during and after the termination of CPB. The third “P” refers to pressors, meaning vasopressors and inotropic agents that should be immediately available. A vasodilator, such as nitroglycerin, nicardipine, or nitroprusside, also should be immediately available. The fourth “P” represents pacer because an external pacemaker should be readily available for all patients. Pacing is often needed to treat bradycardia. In patients with heart block, ideally, an AV sequential pacemaker is used to maintain the atrial kick. The fifth “P” stands for potassium because hypokalemia may contribute to dysrhythmias, and hyperkalemia may result in conduction abnormalities. In addition, the patient’s ionized calcium level is usually checked; most clinicians have a low threshold for administering additional calcium chloride. Furthermore, magnesium (2–4 g) is usually administered before CPB is terminated. Although magnesium’s efficacy in preventing postoperative atrial or ventricular dysrhythmias has not been clearly demonstrated, hypomagnesemia is common after CPB. The risk-to-benefit ratio for administering a 2- to 4-g dose is low. The final “P” refers to protamine. Many institutions require that protamine be uniquely packaged or kept in a nearby but separate area to ensure that the drug is not prematurely administered. (Administration during ongoing CPB is a disastrous error.) Nevertheless, it should take but a few moments to retrieve protamine when the surgeon, anesthesiologist, and perfusionist agree that it is time to reverse anticoagulation. Termination of Cardiopulmonary Bypass After all the preparations described previously have been made and the patient’s ventilation has been reestablished, the venous return to the pump is reduced by gradually clamping the venous line. The patient’s intravascular volume is carefully increased by continued inflow through the aortic or other arterial cannula. Ventricular distention should be avoided because it increases wall tension and myocardial oxygen consumption. The pump flow into the aorta is lowered, in effect moving into a “partial bypass” phase, in which some of the venous blood still goes into the pump and some passes through the right ventricle and lungs to be ejected into the aorta by the LV. Some clinicians reduce the pump flow to half flow rather than gradually reducing venous return to the pump. Once loading conditions are optimal and contractility appears adequate, the aortic inflow line may be clamped to separate the patient from CPB. If CPB has been successfully terminated but cardiac performance is not optimal, preload can be increased by infusing additional blood from the pump into the aortic cannula, usually in 100-mL increments in adult patients. Monitoring the left intraventricular volume in a qualitative fashion by TEE, observing the right ventricle directly, and monitoring the filling pressures give a good estimate of the adequacy of preload. At this point, the anesthesiologist and surgeon jointly determine whether myocardial filling and performance are adequate. This determination can best be accomplished by using TEE to observe the global and regional function of both ventricles. Supplemental information can be obtained by measuring CO, if possible. Afterload can also be optimized at this point. Usually, 95 to 125 mm Hg is a desirable systolic pressure in adult patients in the immediate post-bypass period, whereas increased systolic blood pressure should be avoided to prevent excessive stress on suture lines in the heart and aorta. If the patient is hemodynamically unstable and additional time is needed to administer initial or additional inotropes or vasoconstrictors, CPB can be reinstituted by unclamping the venous outflow line and directing all flow to the oxygenator again ( Fig. 50.10 (f0055) ). 163 Fig. 50.10 Algorithm for weaning from cardiopulmonary bypass (CPB). ACT , activated clotting time; CI , cardiac index; Hct , hematocrit; HR , heart rate; IV , intravenous; K + , potassium; LV , left ventricular; MAP , mean arterial pressure; Mg 2+ , magnesium; NO , nitric oxide; NPS , sodium nitroprusside; NTG , nitroglycerin; PGI 2 , prostacyclin; PH , pulmonary hypertension; RV , right ventricular; Sv̄ 𝑆𝑣¯ O 2 , mixed venous oxygen saturation; TEE , transesophageal echocardiography. From Licker M, Diaper J, Cartier V, et al. Clinical review: management of weaning from cardiopulmonary bypass. Ann Card Anaesth. 2012;15:206–223. Once protamine is administered, the reinstitution of CPB becomes a more complicated process because the patient must first be re-heparinized and antithrombin levels may be inadequate. Therefore, final checks of cardiac function, heart rate and rhythm, preload, afterload, and perfusion should be made jointly by the anesthesiologist and the surgeon. The venous cannula or cannulas are usually removed after the initial test dose of protamine is given. Many surgeons remove the aortic cannula only after at least half of the protamine dose has been administered. The rate and mode of protamine administration (incremental small boluses vs. continuous infusion) vary according to institutional and individual clinicians’ practices, but a large dose of protamine should never be administered as a rapid bolus. Table 50.4 (t0025) shows the characteristics and treatment modalities of specific TEE-diagnosed difficulties that may be encountered during weaning and termination from CPB. 163 Table 50.4 Characteristics and Treatment M

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