A Practical Approach to Cardiac Anesthesia (Practical Approach Series) 5th Ed.

8 Anesthetic Management during Cardiopulmonary Bypass

Neville M. Gibbs and David R. Larach

KEY POINTS

 1. Prior to cannulation for cardiopulmonary bypass (CPB), the anesthesiologist must assure that adequate heparin-induced anticoagulation has been achieved, which is typically diagnosed as an activated clotting time (ACT) >400 s.

 2. At commencement of CPB, the anesthesiologist should confirm full bypass (typically by loss of pulsatile arterial waveform), discontinue mechanical ventilation, and assess adequacy of perfusion pressure and flow. Other tasks include assessment of adequacy of anesthesia and neuromuscular blockade, emptying of urine, withdrawing the pulmonary artery (PA) catheter to the proximal PA, and assessment of adequacy of other monitors such as central venous pressure (CVP), electrocardiogram (ECG), and temperature measurement devices.

 3. During cardioplegic arrest, the anesthesiologist monitors the adequacy of left ventricular emptying via direct observation of the heart, by ensuring of low cardiac filling pressures, and by the presence of electrical silence on the ECG.

 4. Anesthesia during CPB can be maintained with various combinations of volatile agents, opioids, and hypnotic agents (e.g., propofol, midazolam). Especially during hypothermia, maintaining neuromuscular blockade is important in order to avoid spontaneous breathing and visible or subclinical shivering. Anesthetic requirements are reduced during hypothermia.

 5. Appropriate perfusion flows and pressures during CPB are controversial, but for most patients a normothermic perfusion index of 2.4 L/min/M2 and mean arterial pressures (MAPs) of 50 to 70 mm Hg suffice. Continuous monitoring of mixed venous oxygen saturation is useful to assess global perfusion adequacy, as are intermittent arterial blood gas measurements.

 6. Moderate hemodilution is useful during CPB, as aided by clear CPB circuit priming solutions. Minimum safe hemoglobin (Hb) concentrations during CPB are controversial, but for most patients Hb 6.5 g/dL (hematocrit [Hct]  20%) is safe in the absence of evidence for inadequate oxygen delivery (e.g., metabolic acidosis, low SVO2).

 7. Hypothermia is commonly used during CPB to reduce oxygen consumption and metabolism and to confer organ protection. Often temperatures of 32 to 34°C are used in combination with alpha-stat arterial blood gas management. Rewarming should be accomplished slowly and should not proceed beyond a core temperature of 37°C.

 8. Cardioplegic solutions have a variety of “recipes,” but most contain a hyperkalemic solution at a low temperature as well as a combination of crystalloid and blood. Cardioplegia can be administered in an antegrade (via coronary arteries) or retrograde (via coronary sinus) direction.

 9. CPB can produce catastrophic events such as aortic dissection, cerebral ischemia from aortic cannula malposition, regional venous congestion from venous cannula malposition, venous obstruction from air lock, massive air embolism, pump or oxygenator failure, and blood clots in the extracorporeal circuit.

10. A variety of unusual conditions such as sickle cell disease, cold agglutinin disease, malignant hyperthermia (MH), and angioedema may present during or influence the management of CPB.

I. Preparations for CPB

    This requires close communication and coordination between surgeon, perfusionist, and anesthesiologist.

   A. Assembling and checking the CPB circuit

       The perfusionist assembles the CPB circuit (Fig. 8.1) before commencement of surgery, so that CPB can be instituted rapidly if necessary. The circuit components [e.g., pump (roller or centrifugal), tubing (e.g., standard or heparin-bonded), reservoir (venous and possibly arterial), oxygenator, filters, and safety monitors] are usually decided by institutional preference, but should comply with guidelines of professional organizations. Similarly, the type and volume of CPB prime are decided by the perfusionist in consultation with surgeon and anesthesiologist. The perfusionist checks all components using an approved checklist. See Chapter 21 for details on CPB circuit design and use.

   B. Anesthesiologist pre-CPB checklist (Table 8.1)

Figure 8.1 CPB circuit (example). Blood drains by gravity (or with vacuum assistance) (A) from venae cavae (1) through venous cannula (2) into venous reservoir (3). Blood from surgical field suction and from vent is pumped (B, C) into cardiotomy reservoir (not shown) and then drains into venous reservoir (3). Venous blood is oxygenated (4), temperature adjusted (5), raised to arterial pressure (6), filtered (7, 8), and injected into either aorta (10B) or femoral artery (10A). Arterial line pressure is monitored (9). Note that items 3, 4, and 5 often are single integral units. (Modified from Nose Y. The Oxygenator. St. Louis, MO: Mosby; 1973: 53.)

1

       A separate pre-CPB checklist is undertaken by the anesthesiologist (Table 8.1). This includes ensuring that anticoagulation is sufficient for cannulation and CPB (e.g., ACT >400 s), adequate anesthesia will be provided during CPB, fluid infusions are ceased, and monitors are withdrawn to safe positions for CPB (e.g., Swan Ganz catheter, if present, is withdrawn into the proximal PA and a transesophageal echocardiography [TEE] probe, if present, is returned to a neutral position within the esophagus). This is also an appropriate time to empty the urinary catheter drainage bag, and to check the patient’s face and pupils so that any changes occurring as a result of CPB can be recognized.

Table 8.1 Prebypass checklist

   C. Management of arterial and venous cannulation

       In most cases, the arterial cannulation site will be the distal ascending aorta. Prior to cannulation, adequate anticoagulation must be confirmed, and nitrous oxide, if used, must be ceased (to avoid the expansion of any air bubbles inadvertently introduced during cannulation). The anesthesiologist typically reduces the systemic systolic blood pressure to about 80 to 100 mm Hg to reduce the risk of arterial dissection while the cannula is placed. The perfusionist then can check that the pressure trace through the arterial cannula matches the systemic blood pressure trace, which ensures that the arterial cannula has been placed within the aortic lumen. If a two-stage venous cannula is selected, the surgeon then inserts the venous cannula into the right atrium and guides the distal stage of the cannula into the inferior vena cava. A separate smaller cannula is guided via the right atrium into the coronary sinus if retrograde cardioplegia is planned. Femoral arterial cannulation may be used if access to the distal ascending aorta is limited, but axillary artery cannulation has become popular in this situation, because this avoids retrograde flow in the often-atherosclerotic thoracic and abdominal aorta. The venous cannula can also be inserted through a femoral vein if necessary, but must be advanced to the right atrium for adequate drainage. In these cases, TEE is required to confirm satisfactory venous cannula position.

II. Commencement of CPB

   A. Establishing “full” flow

       Once the cannulas are in place and all other checks and observations are satisfactory, the surgeon indicates that CPB should commence. The perfusionist gradually increases the flow of oxygenated blood through the arterial cannula into the systemic circulation. If an arterial cannula clamp is present, this must first be released. At the same time, the venous clamp is gradually released, allowing an increasing proportion of systemic venous blood to drain into the CPB reservoir. Care is taken to match the arterial flow to the venous drainage. Typically, the arterial inflow is increased to equate to a normal cardiac output (CO) for the patient over about 30 to 60 s. The “normal” CO is usually based on a cardiac index of about 2.4 L/min/M2. This is known as “full flow.” At this stage the left ventricle (LV) will have ceased to eject, and the CVP will be close to zero.

2

   B. Initial bypass checklist (Table 8.2)

Table 8.2 Initial Cardiopulmonary bypass checklist

       As CPB commences, the anesthesiologist should check the patient’s face for asymmetry of color and the patient’s pupils for asymmetry of size. Satisfactory oxygenator function should be confirmed by checking the color of the arterial blood and, if available, the in-line PaO2 or oxygen saturation monitor. Adequate venous drainage is confirmed by the absence of pulsatility in the arterial waveform and low CVP (typically <5 mm Hg).

   C. Cessation of ventilation

       If the observations of the initial CPB checklist are satisfactory and full flow is established, ventilation of the lungs is ceased, and the airway pressure release valve is opened fully to avoid inflation of the lungs. It is not necessary to disconnect the anesthesia circuit from the anesthesia machine.

3

   D. Monitoring. Patient monitoring during CPB includes continuous ECG, MAP, CVP, core temperature (e.g., nasopharyngeal, tympanic membrane, bladder), blood temperature, and urine output. Continuous monitoring of arterial and venous oxygen saturations and in-line monitoring of arterial blood gases, pH, electrolytes, and Hct are also recommended. Measurement errors may lead to inappropriate management with potentially disastrous consequences, so frequent checks confirming accuracy are advised. Intermittent monitoring of coagulation (e.g., ACT), laboratory arterial blood gases, electrolytes (including calcium, potassium, blood glucose, and possibly lactate), and Hb are also appropriate. Estimates of Hb and blood glucose can be obtained rapidly using point-of-care devices.

III. Typical CPB sequence

   A. Typical coronary artery bypass graft (CABG) operation. A typical CABG operation proceeds as follows. Total CPB is initiated and mild-to-moderate hypothermia is either actively induced (30 to 34°C) or permitted to occur passively (sometimes called “drifting”). The aorta is cross-clamped and cardioplegic solution is infused antegrade through the aortic root and/or retrograde via the coronary sinus to arrest the heart. The distal saphenous vein grafts are placed on the most severely diseased coronary arteries first, to facilitate administration of additional cardioplegic solution (via the vein graft) distal to the stenoses. The internal mammary artery anastomosis (if used) is often constructed last because of its fragility and shorter length. Rewarming typically begins when the final distal anastomosis is started. The aorta is unclamped and either an aortic side clamp is applied or an internal occlusive device is used to permit construction of proximal vein graft anastomoses while cardioplegic solution is being washed out of the heart. When it is sufficiently warm, the heart is defibrillated if necessary. Alternatively, the proximal anastomoses are completed with the aortic clamp in place, in order to reduce instrumentation of the aorta (with the risk of dislodging of atheroma). Total CPB continues until the heart is reperfused from its new blood supply. Finally, when the patient is adequately rewarmed and the coronary artery grafts are completed, epicardial pacing wires are placed, and CPB is then terminated.

   B. Typical aortic valve replacement or repair operation. After initiation of CPB and application of the aortic cross-clamp, the aortic root is opened, and cardioplegic solution is infused into each coronary ostium under direct vision (to prevent retrograde filling of the LV with cardioplegic solution through an incompetent aortic valve). Commonly, cardioplegia is administered retrograde via the coronary sinus either instead of or in addition to antegrade cardioplegia. The valve is repaired or replaced. Rewarming commences toward the end of valve replacement. The heart is irrigated to remove air or tissue debris, and the aortotomy is closed except for a vent. The aortic cross-clamp is removed (often with the patient in a head-down position) and the heart is defibrillated if necessary. Final de-airing occurs as venous drainage to the pump is retarded, the heart fills and begins to eject (partial CPB), and air is aspirated through the aortic vent, an LV vent, or a needle placed in the apex of the heart. During de-airing, the lungs are inflated to help flush bubbles out of pulmonary veins and the heart chambers, and TEE is viewed to monitor air evacuation.

   C. Typical mitral valve replacement or repair operation. This operation is similar to aortic valve surgery (see Section 2 above), except that the left atrium (or right atrium for a trans-atrial septal approach) is opened instead of the aorta and the cardioplegia infusion can take place through the aortic root and the coronary sinus. The valve is replaced or repaired, and a large vent tube is passed through the mitral valve into the LV to prevent ejection of blood into the aorta until de-airing is completed. After thorough irrigation of the field and closure of the atriotomy except for the LV vent, the aortic cross-clamp is removed, often with the patient in a head-down position. The heart is defibrillated if necessary, and de-airing occurs as described above. Finally, the LV vent is removed, and de-airing is completed.

   D. Typical combined valve–CABG operation. Usually the distal vein–graft anastomoses are created first, to permit cardioplegia of the myocardium distal to severe coronary stenoses. Also, lifting the heart to access the posterior wall vessels can disrupt myocardium if an artificial valve has been inserted, especially in the case of mitral valve replacement. Next, the valve is operated on, and the operation proceeds as described above.

IV. Maintenance of CPB

   A. Anesthesia

     1. Choice of agent and technique. Just as in the pre-CPB period, anesthesia is typically provided by a potent volatile agent or an infusion of intravenous anesthetic (e.g., propofol) on a background of opiates(e.g., fentanyl, sufentanil) and other sedative drugs (e.g., benzodiazepines). Volatile agents have a more defined role in myocardial protection than other anesthetics through ischemic preconditioning and reduction of reperfusion injury [1].

     2. Potent volatile agent via pump oxygenator. This requires a vaporizer mount in the gas inlet line to the oxygenator. A flow- and temperature-compensated vaporizer, often containing isoflurane, is then attached to the mount. The concentration of agent is typically 0.5 to 1.0 MAC at normothermia, depending on the amount of supplementary opiates and sedatives, and is reduced with hypothermia. With most oxygenators, uptake and elimination of the volatile agent are more rapid than that observed via an anesthesia machine, breathing circuit, and normal lungs and heart. Volatile agent administration can be confirmed by disconnecting the gas analysis line from the airway circuit and reconnecting it to the oxygenator outlet [2]. If volatile agents are used, appropriate scavenging of the oxygenator outlet should be ensured. Nitrous oxide is never used, because of its propensity to enlarge gas-filled spaces, including micro- and macro-gas emboli.

4

     3. Total intravenous anesthesia. Total intravenous anesthesia (TIVA) can be provided during CPB using a combination of opiates and sedatives, either by intermittent bolus or by infusion. For propofol, the typical infusion rates are 3 to 6 mg/kg/h or a target plasma concentration of 2 to 4 μg/mL, depending on the use of other IV agents and the patient’s temperature. The advantages of TIVA are simplicity, less myocardial depression, and the absence of a need for oxygenator scavenging. However, as with all forms of TIVA, ensuring adequate depth is more difficult, providing greater justification for anesthesia depth monitoring (e.g., bispectral index, entropy) [3,4].

     4. Muscle relaxation. Movement of the patient during CPB risks cannula dislodgement and should be avoided. If additional muscle relaxants are not used, adequate anesthesia to prevent movement must be ensured. As in the pre-CPB period, train-of-four monitoring can be titrated to a level of approximately one twitch. Similarly, spontaneous breathing must be avoided, as this risks the development of negative vascular pressures and potential air entrainment.

     5. Effect of temperature. Anesthetic requirements fall as temperature drops. However, due to its relatively high blood supply, brain temperature changes faster than core temperature. For this reason, particular care should be taken to ensure adequate anesthesia as soon as rewarming commences, and additional opiates or sedatives may be required. When the patient is normothermic, anesthetic requirements are the same as the pre-CPB phase, although the context-sensitive half-time for most anesthetic drugs increases substantially during and after CPB.

     6. Monitoring anesthetic depth. Awareness may be difficult to exclude clinically due to the use of high-dose opiates, cardiovascular drugs (e.g., β-adrenergic blockers), and muscle relaxants. Moreover, hemodynamic cues cannot be used during CPB. The patient should be checked for pupillary dilation and sweating, but these signs may be affected by opiate medication and rewarming. Therefore, emphasis should be placed on ensuring delivery of adequate anesthesia, or the use of depth-of-anesthesia monitors [3,4].

     7. Altered pharmacokinetics and pharmacodynamics. The onset of CPB increases the circulating blood volume by the amount of the priming solution for the extracorporeal circuit, but the percentage change in the total volume of distribution of most anesthetic agents is minimal. Neuromuscular blockers constitute an exception to this; hence, they may require supplementation at the onset of CPB. Hemodilution reduces the concentration of plasma proteins, increasing the unbound active proportion of many drugs (e.g., propofol) to offset the reduced total plasma concentration induced by the increased circulating blood volume [5]. A small proportion of some agents (e.g., fentanyl, nitroglycerin) may be absorbed onto the foreign surfaces of the CPB circuit. Hypothermia reduces the rate of drug metabolism and elimination, as does reduction in blood flow to the liver and kidneys. Bypassing the lungs reduces pulmonary metabolism and sequestration of certain drugs and hormones. Reduced blood supply to vessel-poor tissues such as muscle and fat may result in sequestration of drugs given pre-CPB. The response to drugs may also be altered by hypothermia and hemodynamic alterations associated with CPB. The combined effect of these pharmacological changes may be difficult to predict, so the principle of titrating drugs to achieve a certain endpoint is particularly important during CPB.

   B. Hemodynamic management. See also Chapter 19.

     1. Systemic perfusion flow rate. The most fundamental hemodynamic change during CPB is the generation of the CO by the CPB pump rather than the patient’s heart. The perfusionist regulates the CPB pump to deliver the desired perfusion flow rate for the patient. This is usually based on a nomogram taking into consideration the patient’s height and weight and the core temperature. Typically the perfusion flow rate is set to deliver an effective perfusion flow rate of 2.4 L/min/M2 at 37∞C and about 1.5 L/min/M2 at 28∞C. The amount delivered by the CPB pump is usually set slightly higher than the target flow rate to account for any recirculation within the CPB circuit. For example, a continuous flow of about 200 mL/min from the arterial line filter may be returned to the reservoir through a purge line to provide a mechanism for purging trapped microbubbles. An inadequate perfusion flow rate will result in a low venous Hb oxygen saturation (continuously monitored in the CPB venous return), and the development of a metabolic acidosis due to anaerobic metabolism and the accumulation of lactic acid. If other causes for a low venous Hb oxygen saturation can be excluded (e.g., excessive hemodilution, inadequate anesthesia, over-rewarming to increase metabolism), the perfusion flow rate should be increased accordingly. Unfortunately, a normal venous oxygen saturation does not confirm adequate perfusion of all tissues. Shunting may occur leaving some tissue beds underperfused. An increased metabolic rate due to shivering, which may be subclinical during hypothermia, or to much more unlikely causes such as thyrotoxicosis or MH, may also reduce venous HbO2 saturations despite normal flow rates.

5

     2. MAP. The optimum MAP during CPB is not known. Systolic and diastolic pressures are generally of no concern, because the vast majority of CPB is conducted using nonpulsatile flow. If an adequate perfusion flow rate is delivered, the MAP may be irrelevant, so long as the limits of autoregulation have not been exceeded, and also there is no critical stenosis in the arterial supply to individual organs. A higher MAP than necessary should be avoided to reduce noncoronary collateral blood flow (which may wash out cardioplegia). In adults, a conservative approach is usually taken, maintaining the MAP between 50 and 70 mm Hg. Higher levels may be required in patients with pre-existing hypertension or known cerebrovascular disease. Lower levels may be tolerated in children. This range of MAP assumes a CVP <5 mm Hg. The possibility of measurement error due to inappropriate position of the pressure transducers or zero drift should be checked frequently.

     3. Hypotension. The most important consideration in the management of hypotension is to ensure that an adequate perfusion flow rate is being delivered. While a transient reduction of perfusion flow rate (such as may be requested by the surgeon at particular stages of the procedure) is of little consequence, sustained reductions must be avoided. Once adequate perfusion flow rate is confirmed, the MAP may be corrected by increasing the systemic vascular resistance (SVR) with the use of vasoconstrictors such as phenylephrine (0.5 to 10 μg/kg/min, or noradrenaline 0.03 to 0.3 μg/kg/min), on the basis of the following relationship:

SVR = (MAP - CVP)/effective perfusion flow rate (L/min)

        where MAP is expressed in mm Hg, CVP in mm Hg, and SVR in mm Hg/L/min (to convert to dyne.s.cm-5, multiply by 80).

          As there is substantial individual variability in response to vasoconstrictors, especially during CPB, the dose should be titrated, commencing with less potent agents (e.g., phenylephrine) or smaller doses, and progressing to higher doses of more potent agents (e.g., noradrenaline) if required. Occasionally vasopressin (e.g., 0.01 to 0.05 units/min) is required. The perfusion flow rate can be increased above normal to correct hypotension temporarily (e.g., while vasoconstrictors take effect), but this is not an appropriate strategy to correct persistent hypotension. The onset of CPB is typically associated with sudden hemodilution, which decreases SVR. Cardioplegia solution entering the circulation also reduces SVR and is a common cause of hypotension. Reperfusion of the myocardium after release of the aortic cross-clamp is another common cause of transient hypotension. For these reasons, the use of vasoconstrictors during CPB is common. (Reduced SVR constitutes an oft-underutilized opportunity for communication between the perfusionist and the anesthesia team. Perfusionists can at times create a “roller coaster” with frequent intermittent boluses of phenylephrine at times when MAP management would be smoother if the anesthesiologist would initiate a continuous phenylephrine infusion.)

     4. Hypertension. Hypertension is usually the result of an increase in SVR, which may be due to endogenous sympathetic stimulation or hypothermia. Before treating hypertension with direct vasodilators (e.g., nitroglycerin 0.1 to 10 μg/kg/min, sodium nitroprusside 0.1 to 2 μg/kg/min, nicardipine 2 to 5 mg/h), adequate anesthesia should be ensured. Artifactual hypertension due to aortic cannula malposition should also be excluded (see I.C and VII.A). The perfusion flow rate can be decreased below normal to correct hypertension temporarily (e.g., while vasodilators take effect), but not to correct persistent hypertension. Hypertension should be avoided during all aortic cross-clamp manipulations, including the application and release of side-biting clamps.

     5. Central venous pressure. With appropriate venous drainage, the CVP should be low (0 to 5 mm Hg). A persistently high CVP indicates poor venous drainage, which may require adjustment of the venous cannula or cannulas by the surgeon. Venous drainage can also be improved slightly by raising the operating table height, thereby increasing the hydrostatic gradient between the heart and the venous reservoir. Increasingly in recent years, suction (vacuum-assisted venous drainage) is applied to the venous reservoir, especially for miniaturized circuits (see Chapter 21), during which one should suspect excessive suction if the CVP reading should fall to levels below 5 mm Hg. As the CVP is a low-range pressure, it is very sensitive to measurement errors (e.g., hydrostatic gradient between transducer and right atrium). Care should also be taken to ensure that the catheter measuring the CVP is in a large central vein and is not snared by surgical tapes.

   C. Fluid management and hemodilution

     1. CPB Prime. The CPB circuit is “primed” with a balanced isotonic crystalloid solution, to which colloids, mannitol, or buffers may be added, depending on perfusionist, anesthesiologist, and surgical preference (see Chapter 21). CPB prime also contains a small dose of heparin (e.g., 5,000 to 10,000 units) and a dose of the antifibrinolytic agent being used (e.g., aminocaproic acid 5 g). The volume of the prime depends on the circuit components, but is typically about 800 to 1,200 mL for adults, and can be even lower when a miniaturized system is used (see Chapter 21).

     2. Hemodilution. The use of a non-sanguineous prime inevitably results in hemodilution. The degree of hemodilution on commencement of CPB can be estimated prior to CPB by multiplying the Hb concentration (or Hct) prior to CPB by the ratio of the patient’s estimated blood volume to the patient’s estimated blood volume plus the CPB prime volume. Moderate hemodilution is usually well tolerated, because oxygen delivery remains adequate and oxygen requirements are often reduced during CPB, especially if hypothermia is used. Moderate hemodilution may also be beneficial, because it reduces blood viscosity, which counters the increase in blood viscosity induced by hypothermia.

6

     3. Limits of hemodilution. While the safe limit of hemodilution during CPB in individual patients is not known, a conservative approach is to avoid Hb levels <6.5 g/dL (approximately an Hct of 20%). If the estimated degree of hemodilution on commencement of CPB is too low, allogeneic red blood cells (RBCs) can be added to the CPB prime. This is particularly important for smaller patients (due to their lower estimated blood volumes) (e.g., pediatric patients), and anemic patients. If venous oxygen saturations are low during CPB despite normal effective perfusion flow rates, excessive hemodilution as a cause should be considered, and additional RBCs added if necessary. Similarly, inadequate oxygen delivery will result in anaerobic metabolism and the development of acidosis. Patients with known stenosesof cerebral or renal arteries may be less tolerant of hemodilution.

     4. Time course of hemodilution. During the course of CPB, crystalloid fluid will diffuse from the vascular to the extracellular space and also will be filtered by the kidney, gradually reducing the extent of hemodilution. However, crystalloid cardioplegia returning to the circulation will increase hemodilution, as will the addition of other crystalloids or colloids used to replace blood loss or redistribution of fluid into nonvascular compartments.

     5. Monitoring hemodilution. The Hb (or Hct) should be measured frequently (e.g., every 30 to 60 min) (if possible, it should be monitored continuously), especially if there is ongoing blood loss, or low mixed venous oxygen saturations.

     6. Acute normovolemic hemodilution. In adult patients with average (or greater) body size and normal preoperative Hb, acute normovolemic hemodilution prior to, or at the time of commencement of, CPB should be considered. Typically, 1 to 2 units of anticoagulated blood are collected, and replaced with colloids or a combination of crystalloids and colloids. This blood, containing pre-CPB Hb, platelet, and clotting factor levels can be re-infused post-CPB.

     7. Allogeneic blood transfusion. The trigger for allogeneic RBC transfusion varies between institutions, and will depend also on patient and surgical factors. Conservative triggers are an Hb <6.5 g/dL during the maintenance phase of CPB, and <8.0 g/dL at the time of separation, although lower levels may be tolerated in selected patients.

     8. Cardiotomy suction. Shed blood may be returned to the CPB circuit using cardiotomy suction. However, shed blood often contains activated coagulation and fibrinolytic factors, especially if exposed to the pericardium. Excessive cardiotomy suction may also be associated with hemolysis, especially if there is co-aspiration of air. For this reason, some choose to return only brisk blood loss to the CPB circuit. An alternative is separate cell salvage with washing of RBCs before returning them to the CPB circuit.

     9. Fluid replacement. Fluid may be lost from the circuit through blood loss, redistribution to other compartments, and filtration by the kidney. A reduction in the circulating blood volume will manifest as a fall in the CPB reservoir fluid level. A falling CPB reservoir fluid level is dangerous, as it reduces the margin of safety for air embolism. In many circuits an alarm will be activated if the reservoir volume falls to unsafe levels. The replacement fluid is typically crystalloid with colloid added depending on perfusionist, surgeon, and anesthesiologist preference.

     10. Diuresis and ultrafiltration. Occasionally the return of cardioplegia solution to the CPB circuit, or contraction of the vascular space by vasoconstrictors or hypothermia, will cause reservoir level to increase. If high levels persist, diuresis can be encouraged by the use of diuretic agents such as furosemide or mannitol. Alternatively, an ultrafiltration device can be added to the circuit to remove water and electrolytes (see Chapter 21).

     11. Urine production should be identified and quantified as a sign of adequate renal perfusion and to assist in appropriate fluid management. Very high urine flow rates (e.g., >300 mL/h) may be seen during hemodilution (due to low plasma oncotic pressure), especially if mannitol is also present in the priming solution. Oliguria (less than 1 mL/kg/h) should prompt an investigation, because it may indicate inadequate renal perfusion. However, some hypothermic patients demonstrate oliguria without an apparent cause. Kinking of urinary drainage catheters should be excluded.

   D. Management of anticoagulation (see also Chapter 19)

     1. Monitoring anticoagulation. The ACT or a similar rapid test of anticoagulation must periodically confirm adequate anticoagulation (e.g., ACT > 400 s; see also Chapter 19). The ACT should optimally be checked after initiating CPB and every 30 min thereafter. The ACT can be checked within 2 min of administering heparin [6]. As the ACT falls over time, often a higher target is chosen (e.g., >500 s), so that the lowest ACT remains >400 s. During periods of normothermia, heparin elimination is faster, so a requirement for heparin supplementation is more likely.

     2. Additional heparin is usually given in 5,000 to 10,000 unit increments, and the ACT is repeated to confirm an adequate response. Use of fully heparin-coated circuits does not eliminate the need for heparin; an ACT of 400 s or greater is often recommended [7].

     3. Heparin resistance is a term used to describe the inability to achieve adequate heparinization despite conventional doses of heparin. It may be due to a variety of causes, but it is most common in patients who have received heparin therapy for several days preoperatively. Most cases will respond to increased doses of heparin. However, if an ACT > 400 s cannot be achieved despite heparin > 600 units/kg, consideration should be given to administering supplemental antithrombin III (AT-III). A dose of 1,000 units of AT-III concentrate will increase the AT-III level in an adult by about 30%. Fresh frozen plasma, 2 to 4 units, is a less expensive alternative, but it is less specific and carries the risk of infective and other complications. For a detailed discussion of heparin resistance and AT-III deficiency, see Chapter 19.

   E. Temperature management

     1. Benefits of hypothermia. Hypothermia during CPB reduces metabolic rate and oxygen requirements and provides organ protection against ischemia.

     2. Disadvantages of hypothermia. Hypothermia may promote coagulation abnormalities, and may increase the risk of microbubble formation during rewarming. Hypothermia shifts the Hb oxygen saturation curve to the left, reducing peripheral oxygen delivery, but this is countered by the reduced oxygen requirements.

7

     3. Choice of maintenance temperature. The optimal temperature during the maintenance phase of CPB is not known. Typically the patient’s core temperature at the onset of CPB is 35 to 36°C. Core temperature is usually measured in the nasopharynx or tympanic membrane, but the bladder or esophagus may also be used. The target temperature is chosen on the basis of the type and length of surgical procedure, patient factors, and surgical preference. Often the temperature is allowed to drift lower without active cooling. Alternatively, the heat exchanger is used to provide moderate hypothermia, which may be as low as 28°C, but is more often 32°C or above. If there is a concern about the adequacy of myocardial protection, lower temperatures may be used (see also Chapter 23).

     4. Slow cooling. Lack of response of the nasopharyngeal or tympanic temperature during the cooling phase may indicate inadequate brain cooling, and should prompt investigation of the cause (e.g., ineffective heat, exchanger, inadequate cerebral perfusion). The position and function of the temperature monitor should also be checked to exclude artifactual causes.

     5. Deep hypothermic circulatory arrest (DHCA). For certain surgical procedures in which circulatory arrest is required (e.g., repairs of the aortic arch), deep hypothermia is used as part of a strategy to prevent cerebral injury. The typical target temperature prior to circulatory arrest is about 15 to 17°C. Other strategies to minimize injury include limiting the period of circulatory arrest to as short a time as possible, anterograde or retrograde cerebral perfusion during the period of DHCA, and pharmacological protection using barbiturates (e.g., thiopental 10 mg/kg), corticosteroids (e.g., methylprednisolone 30 mg/kg), and mannitol (0.25 to 0.5 g/kg). These must be given before DHCA is commenced (see also Chapter 25). Achieving deep neuromuscular blockade (0–1 twitches on train-of-four) prior to DHCA is advisable.

     6. Rewarming. Rewarming commences early enough to ensure that the patient’s core temperature has returned to 37°C by the time the surgical procedure is completed, so that separation from CPB is not delayed. The surgeon will usually advise the perfusionist when rewarming should commence, taking into account the patient’s core temperature at the time, how long the patient has been at this temperature, and the patient’s body size. The rate of rewarming is limited by the maximum safe temperature gradient between the water temperature in the heat exchanger and the blood (<10°C, some centers use a maximum of 6 to 8°C). Higher gradients risk the formation of microbubbles. Typically, patients’ core temperature rises no faster than 0.3°C/min. Vasodilators may facilitate rewarming by improving distribution of blood and permitting higher pump flow rates.

     7. Hypothermia and arterial blood gas analysis. Hypothermia increases the solubility of oxygen and carbon dioxide, thereby reducing their partial pressures. However, arterial blood gas measurement is performed at 37°C, so the values have to be “temperature corrected” to the patient’s blood temperature if the values at the patient’s blood temperature are required. The reduced PaO2 is of limited clinical significance, so long as increased fractions of oxygen are administered (FiO2 > 0.5). However, the reduced PaCO2 produces an apparent respiratory alkalosis when temperature-corrected values are used. To keep the pH normal (pH stat) it would be necessary to add CO2 to the oxygenator. The alternative is to avoid temperature correction of arterial blood gases and accept that the degree of dissociation of H+ also varies with temperature (alpha stat). With this strategy there is no requirement to add CO2 to maintain neutrality. These complex biochemical considerations are avoided by using non–temperature-corrected values, and making decisions based on the values measured at 37°C, irrespective of the patient’s blood temperature. See Chapter 24 for detailed discussion of arterial blood gas management.

     8. Shivering. Shivering should not occur if adequate anesthesia is provided, especially if a muscle relaxant is administered.

   F. ECG management. Isolated atrial and ventricular ectopic beats are common during cardiac manipulation and require no specific intervention. If ventricular fibrillation occurs before aortic cross-clamp placement, defibrillation may be required. Ventricular fibrillation once the aortic cross-clamp has been placed is likely to be short-lived because the delivery of cardioplegia will achieve cardiac standstill. Persistent ventricular fibrillation indicates ineffective cardioplegia. Return of electrical activity after cardioplegic arrest suggests washout of cardioplegia solution. The surgeon should be notified as additional cardioplegia may be required. Ventricular fibrillation may occur during the rewarming phase after the release of the aortic cross-clamp. This often resolves spontaneously, but may require defibrillation, especially if the patient remains hypothermic.

   G. Myocardial protection (see also Chapter 23)

     1. Cardioplegia. When the myocardial blood supply is interrupted by the placement of an aortic cross-clamp, cardioplegic arrest of the myocardium is required. The antegrade technique is achieved by administering cardioplegia solution into the aortic root between the aortic valve and aortic clamp. The interval between the placement of the cross-clamp and the administration of the cardioplegia is kept to a minimum (no more than a few seconds) to prevent any warm ischemia. The cardioplegia solution is typically high in potassium, arresting the heart in diastole. The solution is typically cold (8 to 12°C) to provide further protection, although warm continuous cardioplegic techniques are used in some institutions. Cardioplegic solutions may be entirely crystalloid or may be mixed with blood (blood cardioplegia). Cardioplegia may also be administered retrograde through a catheter in the coronary sinus. In patients with aortic regurgitation, administration of cardioplegia directly into the left and right coronary ostia may be required. Cardioplegia is typically given intermittently every 20 to 30 min, but may be given continuously.

8

     2. Cold. Most myocardial protection techniques involve cold cardioplegia, and ice may be placed around the heart to provide further protection. Systemic hypothermia, if used, contributes to keeping the myocardium cold.

     3. Venting. During cross-clamping, vents are typically placed in the aortic root to ensure that the heart does not distend. For open-chamber procedures vents are placed also in the left atrium or LV to remove both blood and air. Inadequate venting may result in the development of tension in the LV, causing potential ischemia and subendocardial necrosis. The coronary perfusion pressure for cardioplegia is also reduced.

     4. Avoiding electrical activity. See Section IV.F above.

   H. Arterial blood gas and acid–base management

     1. Alpha stat or pH stat strategy? (see Section IV.E.7 and Chapter 24)

      2. The arterial PO2 is maintained between 150 and 300 mm Hg by adjusting the percentage oxygen in the sweep (analogous to inspired) gas delivered to the oxygenator. Arterial hypoxemia may indicate inadequate oxygenator sweep gas flow (or leak) or inadequate oxygen percentage in the oxygenator sweep gas. Alternatively, it may indicate oxygenator dysfunction.

      3. The arterial Pco2 is maintained at approximately 40 mm Hg by adjusting the sweep gas flow rate through the oxygenator. There is an inverse relationship between the sweep gas flow rate and the arterial PCO2Hypercapnea (PCO2 > 45 mm Hg) should be avoided as it is associated with sympathetic stimulation and respiratory acidosis. Hypercapnea may be caused by an inadequate sweep gas flow rate, absorption of CO2 used to flood the wound during open chamber procedures [8], or increased CO2 production. The administration of bicarbonate also increases the PCO2Hypocapnea (PCO2 < 35 mm Hg) should also be avoided as it is associated with respiratory alkalosis and left shift of the HbO2 dissociation curve (further reducing oxygen delivery), and cerebral vasoconstriction.

     4. Metabolic acidosis (e.g., lactic acidosis) is prevented where possible by ensuring adequate oxygen delivery and tissue perfusion. Severe metabolic acidosis should be corrected cautiously with the use of sodium bicarbonate. If unexplained acidosis occurs with signs of an increased metabolic rate (e.g., low mixed venous oxygen saturations, elevated PCO2), malignant hyperthermia (MH) should be considered.

   I. Management of serum potassium and sodium

     1. Hyperkalemia may occur when cardioplegia solution (which contains high potassium concentrations) enters the circulation. This is usually mild or transient unless large amounts of cardioplegia are used, or the patient has renal dysfunction. Hyperkalemia more often follows the first dose of hyperkalemia than later ones, because both the volume and potassium concentration are typically higher for the initial cardioplegia solution. Hyperkalemia can cause heart block, negative inotropy, and arrhythmias. Hyperkalemia can be treated by promoting potassium elimination by loop diuretics (e.g., furosemide) or by ultrafiltration. Potassium can also be shifted into cells by the administration of insulin and glucose, or by creating an alkalosis. In rare cases, hemodialysis is required. If the patient has severe renal dysfunction or the serum potassium remains above the normal range, the cardioplegia delivery technique should be modified to ensure that cardioplegia is vented separately and not returned to the circulation.

     2. Hypokalemia. If a patient is hypokalemic, initiating K+ replacement during CPB is much safer than waiting until after bypass, thus avoiding hypokalemic dysrhythmias during CPB weaning or potential cardiac arrest during rapid K+ replacement post-CPB.

     3. Sodium. Serum sodium should be maintained within the normal range where possible. Rapid corrections should be avoided due to the risk of acute changes in intracranial pressure as a result of the changes in plasma osmolality.

   J. Management of blood glucose

     1. Hyperglycemia. Glucose tolerance is often impaired during CPB due to the stress response associated with CPB, as well as from insulin resistance induced by hypothermia. Hyperglycemia may exacerbate neuronal injury and increase the risk of wound infection. Blood glucose should be measured frequently, especially in patients with diabetes mellitus. Glucose containing fluids should be avoided. Blood glucose should optimally be maintained below 180 mg/dL, which may require the infusion of insulin.

     2. Hypoglycemia. Hypoglycemia should be avoided at all costs during CPB, because severe hypoglycemia is associated with neurological injury within a short period, and the signs of hypoglycemia are masked by both the anesthesia and the hemodynamic changes during CPB. Blood glucose should be measured more frequently if patients are receiving insulin or have received hypoglycemic agents preoperatively on the day of surgery.

V. Rewarming, aortic cross-clamp release, and preparation for weaning

   A. Rewarming. On commencement of rewarming, additional anesthetics may be required, because the brain rewarms faster then the body core. Additional heparin may be required, because the rate of metabolism of heparin returns to normal at normothermia. The extent of hemodilution should be re-assessed because oxygen requirements increase during rewarming (see also Section IV.E.6 above).

   B. Release of aortic cross-clamp

     1. De-airing. Air may collect in the pulmonary veins, left atrium, or LV, particularly during open chamber procedures. This is aspirated through the aortic root vent prior to cross-clamp release or other vents. Temporarily raising the CVP and inflating the lungs will fill the LV and permit easier surgical aspiration of intracavity air. Residual air can be detected using TEE [9]. Flushing the surgical field with CO2 prior to cardiac chamber closure [8] may reduce residual air, as CO2 is reabsorbed much faster than air.

     2. Blood pressure. Hypertension should be avoided at the time of aortic cross-clamp release. Transient hypotension may occur after the release of the cross-clamp due to residual cardioplegia or metabolites returning to the circulation as the myocardium is reperfused.

   C. Preparation for weaning from CPB. In preparation for weaning from CPB, cardiac pacing equipment is attached and checked, electrolytes and acid–base disturbances are corrected if necessary, an adequate Hb is ensured, and additional inotropic drug infusions (e.g., epinephrine, dobutamine) required for the weaning process are prepared and attached to the patient. If loading doses of inodilators (e.g., milrinone) or calcium sensitizers (e.g., levosimendan) are required, these should be given before completion of CPB. If the negative inotropic effects of volatile agents are a concern, they should be ceased before weaning commences, and other agents used to maintain adequate anesthesia. Anesthetic management of weaning from CPB is covered in Chapter 9.

VI. Organ protection during CPB

   A. Renal protection. The most important renal protective strategy is to ensure adequate renal perfusion during CPB by optimal fluid loading, appropriate pump flow rates, close attention to the renal perfusion pressure, and avoidance of intravascular hemolysis and hemoglobinuria. It may be possible to reduce the risk of development of acute renal failure through the use of drugs to increase renal blood flow and urine production, although there is no definitive evidence to support their routine use. Mannitol, low-dose dopamine, furosemide, prostaglandin E, and fenoldopam (a selective dopamine-1 receptor agonist) have been advocated for use in high-risk patients during CPB, particularly if oliguria is present. Of these, fenoldopam 0.05 to 0.10 μg/kg/min shows the most promise [10]. N-acetylcysteine (a free-radical scavenger) and urinary alkalinization have also been used. Hemolysis and hemoglobinuria are managed by correcting the cause where possible, and by promoting a diuresis.

   B. Brain protection during CPB involves ensuring adequate cerebral perfusion pressure (MAP-CVP) and oxygen delivery, and measures to prevent increases in intracranial pressure (which will reduce cerebral perfusion pressure). Mild or moderate hypothermia is often used to provide additional protection, and deep hypothermia if circulatory arrest is required (see also Section IV.E.5 above). Care is taken to avoid emboli, both particulate (e.g., atheroma) and gaseous, by meticulous surgical and perfusion technique. Brain protection is covered in detail in Chapter 24.

   C. Myocardial protection. See Section IV.G above.

   D. Inflammatory response to CPB. CPB is one of the main factors contributing to the inflammatory response associated with cardiac surgery. Reactions are usually mild or subclinical, but may be severe in some cases and contribute to brain, lung, renal, or myocardial injury. For a detailed discussion of this inflammatory response to CPB and cardiac surgery, see Chapter 21.

     1. Etiology

        a. Exposure of blood to circuit components. The extensive contact between circulating blood and the extracorporeal circuit results in variable amounts of thrombin generation, activation of complement, release of cytokines, and expression of immune mediators, all of which may contribute to the inflammatory response.

        b. Return of shed blood to the CPB circuit. Shed blood is in contact with mediastinal tissues (e.g., pericardium) and air, and is exposed to shear stress when suction is used. It is a potent source of activated coagulation factors and inflammatory mediators and may cause hypotension when returned to the bypass circuit. Unless bleeding is brisk or stasis is minimal, shed blood should not be returned directly to the CPB circuit. A cell saver can be used to conserve red blood cells.

        c. Ischemia due to inadequate tissue perfusion or organ protection

        d. Endotoxemia due to splanchnic hypoperfusion

     2. Prevention

          Severe reactions are difficult to predict or prevent. Adequate anticoagulation, organ perfusion, and myocardial protection are fundamental. Biocompatible surface coated circuits may be beneficial. The use of miniature bypass circuits, steroids, and leuco-depletion filters are controversial. Fibrinolysis can be reduced by the use of aminocaproic or tranexamic acid. Novel anti-inflammatory agents (e.g., pexelizumab) [11] remain investigational, but as yet have no proven benefit.

     3. Management

          Low SVR and evidence of capillary leak may be observed during CPB, but most reactions manifest post-CPB. No specific therapy is available and management is supportive.

VII. Prevention and management of CPB catastrophes (see also Chapter 21)

       The safe conduct of perfusion requires vigilance on the parts of the perfusionist, anesthesiologist, and cardiac surgeon to ensure that perfusion-related problems are prevented where possible, and diagnosed early and managed quickly if they occur. Appropriate training, expertise, and accreditation of all personnel are required, and adherence to protocols and checklists is encouraged. The following complications must be actively sought during initiation of CPB. They may, however, occur at any time during CPB [12]. Prevention is paramount.

9

   A. Malposition of arterial cannula

     1. Aortic dissection. If the cannula orifice is situated within the arterial wall, not in the true lumen, there is a risk of aortic dissection upon commencement of CPB. Therefore, either arterial cannula pressure or pressure in the arterial tubing proximal to it should always be monitored, and pressure and pulsatility checked before starting CPB. If the pressure in the aortic cannula does not match the systemic pressure, CPB must not commence until the cannula position has been corrected. If the pressure is instead monitored in the arterial tubing, a pressure gradient should be expected across the aortic cannula. If this gradient exceeds the recommended range for the flow/cannula combination, either cannula malposition or aortic dissection should be strongly considered. If CPB has commenced and a dissection has occurred or is suspected, CPB must cease, the aortic cannula be repositioned, and the dissection repaired if necessary.

     2. Carotid or innominate artery hyperperfusion (Fig. 8.2) can occur if the aortic cannula outflow is too close to the innominate artery or the left carotid artery. Deleterious effects include cerebral edema or possibly even arterial rupture from the high flows and pressures. Prevention is surgical; use of a short aortic cannula with a flange may help prevent this complication. Diagnosis is suggested by facial flushing, pupillary dilation, and conjunctival chemosis (edema). There is likely to be low blood pressure measured by a left radial or femoral arterial catheter. A right radial arterial catheter may show hypertension due to innominate artery hyperperfusion. The surgeon must reposition the arterial cannula, and measures to reduce cerebral edema (e.g., mannitol, head-up position) may be required.

Figure 8.2 Potential aortic cannulation problems. A: Cannula extends into carotid owing to excessive length, causing excessive carotid flow. B: Angle of cannula insertion is improper, which also causes carotid hypoperfusion. C: Correct placement. D: Cannula diameter is too small; high-velocity jet of blood may damage intima and occlude a vessel. (Redrawn from Moores WY. Cardiopulmonary bypass strategies in patients with severe aortic disease. In: Utley JR, ed. Pathophysiology and Techniques of Cardiopulmonary Bypass. Vol. 2. Baltimore, MD: Williams & Wilkins; 1983:190, with permission.)

   B. Reversed cannulation. Venous drainage connected to the arterial cannula with arterial inflow into the right atrium or vena cava is very unlikely in adults, due to different size tubing for arterial and venous drainage. This complication is avoided also by ensuring that arterial pressures are observed in the arterial outflow line before commencing CPB. Reversed cannulation will result in very low systemic pressures and high venous pressures. More importantly, negative pressure in the aortic cannula risks the entrainment of air, which must be avoided at all costs. Reverse rotation of roller pumps must also be avoided. Management requires cessation of CPB, placing the patient in a steep head-down position, de-airing the cannulas and executing a massive gas embolism protocol if necessary (Table 8.3).

Table 8.3 Massive gas embolism emergency protocola

   C. Obstruction to venous return. Sudden reduced venous drainage from the patient during CPB will lower the reservoir level, increasing the risk of air embolism. At the same time the venous pressures in the patient will rise, reducing perfusion pressure to organs. To avoid emptying the venous reservoir further, the perfusionist must reduce the perfusion flow rate, further reducing organ perfusion. Alternatively, large fluid volumes must be added to the reservoir. For this reason, the cause must be determined immediately and the venous drainage restored as quickly as possible. Most centers use electronic monitors for low reservoir volume (see VII.E.1.a).

     1. Air lock. A sudden reduction in venous blood draining into the venous reservoir may be caused by the presence of large air bubbles within the venous drainage cannula. This creates an “air lock” due to the lower pressure gradient and the surface tension in the air–blood interface. The air lock is overcome by sequentially elevating the venous tubing allowing the air bubble to rise (float to the surface), followed by dropping the tubing to allow the column of blood to force the bubble distally toward the reservoir.

     2. Mechanical. Lifting of the heart within the chest by the surgeon often impedes venous drainage. The venous cannula may be malpositioned or kinked inadvertently during surgical manipulations. If reduced venous drainage is observed, the surgeon must be notified immediately, and appropriate venous drainage restored urgently.

   D. High pressure in arterial pump line. Normally, arterial inflow line pressure proximal to the aortic cannula is up to three times the patient’s arterial pressure, due to high resistance in the tubing and arterial cannula. However, kinking of the inflow line during pump operation will further increase the pressure, risking disruption of the tubing or connections, especially if the line is inadvertently clamped. For this reason, a high-pressure alarm is used, often with automatic feedback to stop roller pump operation.

   E. Massive gas embolism. Most massive (macroscopic) gas emboli [12] consist of air, although oxygen emboli can be generated by a defective or clotted oxygenator. (For further discussion of this and CPB safety devices, see Chapter 21.) Use of a vented arterial line filter is an important safety device that can help prevent gas emboli reaching the patient; its routine use is strongly recommended. Because of the high risk of stroke, myocardial infarction, or death after massive gas embolism, prevention is of utmost importance.

     1. Etiology

        a. Empty or low oxygenator reservoir level. Air may be pumped from an empty reservoir. Avoiding this scenario is one of the key tasks of the perfusionist. There are also alarms to alert staff when the oxygenator reservoir level is reaching an unsafe level. Many such alarms are linked to an automatic cessation of the arterial roller pump. Vortexing can permit air entrainment and embolism when the reservoir blood level is very low but not empty. This is the most important cause of bypass catastrophes when utilizing a closed reservoir system. A high-risk period for air embolism or entrainment is at the time of separation from CPB, when the oxygenator reservoir level is often low.

        b. Leaks in the negative pressure part of the CPB circuit (between the oxygenator reservoir and the arterial pump) may result in air entrainment, e.g., clotted or defective oxygenator, disruption of tubing connections.

        c. Entrainment of air around the aortic cannula. This may occur during cannula insertion. Entrainment can also occur via this route if negative pressure in the arterial cannula is allowed to develop during periods of no flow (e.g., before or after the onset of CPB). To prevent negative pressure and draining blood from the patient, the aortic cannula must be clamped during all periods when the arterial pump is inactive.

        d. Inadequate de-airing prior to aortic cross-clamp release. This is particularly important for open-chamber procedures.

        e. Reversed roller pump flow in vent line or arterial cannula.

        f. Pressurized cardiotomy reservoir (causing retrograde flow of air through a non-occlusive vent line roller head into heart or aorta)

        g. Runaway pump head (switch inoperative; must unplug pump and crank by hand)

        h. Other causes not related specifically to CPB include an improper flushing technique for arterial or left atrial pressure monitoring lines, paradoxical embolism of venous air across atrial or ventricular septal defects. Occasionally, a persistent left superior vena cava (SVC) communicates with the left atrium (IV air from a left-sided IV may enter the systemic circulation through this SVC).

     2. Prevention. Vigilance is required. Safety devices and alarms must be activated.

     3. Diagnosis. Gas embolism is diagnosed mostly by visual inspection. The extent of gas embolism can be gauged by signs of myocardial or other organ ischemia.

     4. Management. A massive gas embolus emergency protocol should be available and followed by all staff [13]. See Table 8.3Figures 8.3 and 8.4.

   F. Failure of oxygen supply. Inadequate oxygenator gas flow or a hypoxic mixture will result in arterial hypoxemia. The blood in the arterial line will appear dark, and the lower PO2 will register on in-line PO2 or Hb oxygen saturation monitors. An oxygen analyzer can be incorporated in the oxygenator gas inflow line as an early alert for hypoxic mixtures. The O2 supply should be restored immediately, connecting a portable O2cylinder to the oxygenator if necessary. If a delay is anticipated, either separate from CPB (if still plausible) or cool the patient maximally until O2 supply is restored. Ventilation with room air is preferable to no ventilation at all, if immediate restoration of O2 supply is not possible.

Figure 8.3 Retrograde perfusion in the treatment of massive air embolism. A: Massive arterial gas embolism has occurred. B: Bubbles in the arterial tree are flushed out by performing retrograde body perfusion into the SVC by connecting the deaired arterial pump line to the SVC cannula (and tightening caval tapes). Blood and bubbles exit the aorta from the cannulation wound. (Redrawn from Mills NL, Ochsner JL. Massive air embolism during cardiopulmonary bypass: Causes, prevention, and management. J Thorac Cardiovasc Surg.1980;80:713, with permission.)

Figure 8.4 Carotid (A) and vertebral (B) artery de-airing during retrograde perfusion. In the management of massive arterial gas embolism, steep head-down position helps to flush bubbles out of the carotid arteries. Application of intermittent pressure to the carotid arteries increases retrograde vertebral artery flow, which helps to evacuate bubbles.

(Redrawn from Mills NL, Ochsner JL. Massive air embolism during cardiopulmonary bypass: Causes, prevention, and management. J Thorac Cardiovasc Surg. 1980;80:713, with permission.)

   G. Pump or oxygenator failure

     1. Pump failure may be due to electrical or mechanical failure, tubing rupture or disconnection, or automatic shutoff by a bubble or low reservoir detector. A runaway pump head may raise the pump flow to its maximum inappropriately, and the pump control switch will be inoperative. For systems designed to be used with an electromagnetic or ultrasonic transducer, failure of the sensor can prevent one from knowing the actual pump flow rate. If the occlusion of a roller pump is improperly set, excessive regurgitation occurs (causing hemolysis) and the forward flow is reduced. In the event of electrical failure, CPB pumps can be hand cranked until current is restored. Mechanical failure requires replacement of the pump. In case of a runaway pump head, the CPB machine must be unplugged and the tubing switched to a different roller head.

     2. Oxygenator failure may be due to a manufacturing defect, mechanical obstruction from clot, disruption of the oxygenator shell (trauma, spill of volatile liquid anesthetic), or leakage of water from heat exchanger into blood. The diagnosis is based on arterial blood gas abnormalities, acidosis, blood leak, excessive hemolysis, or high premembrane pressures. For severe failure, the oxygenator must be replaced. A protocol should be in place for rapid oxygenator replacement. If body perfusion will be low or absent for more than 1 or 2 min and if the patient cannot be immediately weaned from CPB, then hypothermia to 18 to 20°C should be induced if possible and consideration given to brain, myocardial, and renal protection during the oxygenator replacement. Open cardiac massage may be necessary, depending on the stage of the operation.

   H. Clotted oxygenator or circuit. This serious event can interfere with gas exchange, prevent CPB flow, or cause massive gas embolus. The main cause is inadequate anticoagulation, which may result from inadequate dose, heparin resistance, or the inadvertent administration of protamine during CPB. This potentially lethal catastrophe should not occur if adequate anticoagulation is confirmed before initiating CPB and at frequent intervals thereafter. It can be diagnosed by visual observation of clot in the oxygenator, or high arterial line pressure (evidence of partially clotted arterial line filter). There may also be clues to inadequate heparinization by the presence of clot in the surgical field. Management involves cessation of CPB, and replacement of the oxygenator and tubing if necessary. If the patient is not cold, open cardiopulmonary resuscitation and topical hypothermia may be required. The patient should then be reheparinized using a different lot of heparin if possible, and satisfactory anticoagulation confirmed before re-instituting CPB.

VIII. Less-invasive surgical techniques

   A. Port access CPB is similar to conventional CPB but requires additional instrumentation and monitoring [14,15]. Arterial and venous CPB cannulas are inserted peripherally (e.g., femoral artery and vein). An aortic occlusion catheter is placed in the ascending aorta under fluoroscopic or TEE guidance. An endocoronary sinus catheter is inserted for delivery of retrograde cardioplegia, and a PA vent catheter is inserted to decompress the heart through the left atrium. Correct position of the inflated aortic occlusion catheter balloon should be checked regularly using TEE. Loss of the right radial arterial pressure trace may indicate cephalad migration of the balloon. Frequent interaction among surgeon, perfusionist, and anesthesiologist is required for a successful outcome (see Chapter 13).

   B. Mitral valve surgery through a right minithoracotomy. In this procedure arterial and venous cannulas are inserted peripherally and CPB is instituted prior to a right minithoracotomy [15]. TEE guidance is used to ensure that the venous cannula enters or crosses the right atrium to drain the SVC as well as the IVC. Due to the increased length and decreased diameter of the venous cannula, suction is typically required to maintain adequate venous drainage. If the right atrium is opened (e.g., for tricuspid valve surgery), a separate SVC cannula (often inserted percutaneously) may be required. With the onset of CPB, ventilation of the lungs is no longer required. Collapse of the right lung on opening of the chest provides surgical access to the heart and great vessels. An aortic root cannula for the administration of cardioplegia can then be placed, followed by an aortic cross-clamp. Access to the mitral valve is obtained through the left atrium. CPB management is otherwise unchanged, although before final separation from CPB, a trial separation is undertaken to ensure satisfactory mitral valve function (as assessed by TEE). For further details see Chapter 13.

IX. Management of unusual or rare conditions affecting bypass

   A. Sickle cell trait and disease [1619]. The congenital presence of abnormal Hb S as the trait (heterozygote, Hb-AS) but especially as the disease (homozygote, Hb-SS) allows RBCs to undergo sickle transformation and occlude the microvasculature or lyse. RBC sickling may be induced by exposure to hypoxemia, vascular stasis, hyperosmolarity, or acidosis. Hypothermia produces sickling only by causing vasoconstriction and stasis. Although anesthesia for noncardiac surgery is well tolerated in sickle trait patients, the risks are higher for operations requiring CPB. CPB may induce sickling by redistributing blood flow, causing stasis, and reducing venous O2 tensions. Sickle cell trait (heterozygous Hb-AS) patients are at low risk for RBC sickling unless the O2 saturation is below 40%. Djaiani et al. reported a series of 10 sickle cell trait patients who successfully underwent fast-track coronary revascularization using normothermic CPB, although one very high-risk patient died of multiorgan failure after a protracted postoperative course [19]. In contrast, sickle cell disease (homozygous Hb-SS or Hb-SC) patients develop RBC sickling at O2 saturations less than 85% and are at risk for developing potentially fatal thromboses during CPB unless appropriate measures are taken. CPB should be avoided if alternative treatment options are available (e.g., off-pump surgery). If CPB is required, hypothermia should ideally be avoided.

10

     1. Diagnosis. In the United States, high-risk newborns have been routinely screened for sickle cell disease and trait for over 20 yrs, so most African-American patients will know if they have sickle cell trait or disease. If not, the rapid “sickle-dex” test or “sickle-prep” is appropriate for screening, whereas Hb electrophoresis yields important quantitative information if the result of a screening test is positive. Expert preoperative hematologic consultation is advised for sickle cell disease patients before CPB.

     2. Management. Hypoxia, acidosis, and conditions leading to vascular stasis (e.g., hypovolemia, dehydration) should be avoided or minimized in all patients with sickle cell trait or disease.

     3. Preoperative transfusion to achieve a total Hb concentration of 10 g/dL or higher is appropriate for sickle cell disease patients, and possibly higher if the patient will tolerate the intravascular volume. Increasing the Hct improves O2 carriage, dilutes Hb-SS, and suppresses erythropoiesis, but also increases the risk of alloimmunization [18]. Preoperative Hb concentration for sickle cell patients should optimally exceed 10 g/dL, which may require transfusion.

     4. Preoperative transfusion with Hb-A donor RBCs is the conservative approach to the management of sickle cell disease patients requiring hypothermic CPB. Heiner and colleagues [16] recommended that, prior to CPB with deep hypothermia, patients with sickle trait or sickle disease be transfused with donor cells (containing no Hb-S) until the proportion of native RBCs containing any Hb-S (RBCs) be reduced from 100% to less than 33%.

          If used, intraoperative exchange transfusion has an advantage because invasive monitoring may be used to guide transfusion and volume replacement. CPB per se provides an opportunity for limited exchange transfusion because of the necessary priming volume, which most often should contain allogeneic blood in patients with sickle cell disease. For patients with sickle cell disease, it seems sensible to maintain total Hb concentration at 8 g/dL or higher during CPB, and to achieve a total Hb concentration of 10 g/dL or higher at separation from CPB or soon thereafter. Donor Hb-A RBCs can be used to prime the CPB circuit. If additional exchange is desired, upon initiation of CPB, the patient’s venous blood can be diverted into a separate reservoir. The diverted blood can then be replaced by further donor HbA transfusion and volume replacement.

     5. CPB management. Avoid arterial or venous hypoxemia, acidosis, dehydration, hyperosmolarity, and hypothermia if possible. Higher-than-usual pump flow rates theoretically may raise venous oxygen saturations and reduce sickling. Shivering or other factors that increase O2 consumption and reduce venous oxygen saturation should be avoided. If cold cardioplegia is required, crystalloid cardioplegia can be used to flush out Hb-S from the coronary circulation. If blood cardioplegia is used, it should be normothermic and have less than 5% Hb-S.

   B. Cold agglutinin disease [2022]

     1. Pathophysiology

        a. Autoantibodies against RBCs in patients with cold agglutinin disease are activated by even transient cold exposure. At temperatures below the critical temperature for an individual patient, hemagglutination will occur, resulting in vascular occlusion with organ ischemia or infarction. Hemagglutination also can fix complement, leading to hemolysis on RBC rewarming. The antibodies are typically immunoglobulin M (IgM).

        b. Symptoms usually are of vascular occlusion, manifesting as acrocyanosis on exposure to cold. Signs of hemolytic anemia may be present.

        c. Low titers of antibodies with a low critical temperature (e.g., <28°C) are common, but of little clinical relevance. In contrast, patients who have high titers of antibodies with a high critical temperatureare at risk of hemagglutination perioperatively, especially during hypothermic CPB.

        d. The organ at greatest risk of damage is the myocardium, because RBCs are exposed to extreme hypothermia (4 to 8°C) during the preparation of blood cardioplegia solution. Aggregates thus formed may be infused into the coronary vasculature, causing severe microcirculatory occlusion and preventing distribution of cardioplegia.

        e. The idiopathic form of cold agglutinin disease is seen most frequently in older patients and probably represents a subclinical form of a lymphoproliferative or immunoproliferative disorder, either of which can induce cold agglutinins. The disease also occurs after mycoplasmal pneumonia, mononucleosis, and other infections.

     2. Diagnosis

        a. Routine blood cross-matching using the direct Coombs’ test may identify patients with critical temperatures (thermal amplitude) at or above room temperature. However, autoantibodies responding to such warm temperatures are seen rarely (less than 1% of cardiac surgical patients). Direct Coombs’ tests run at varying temperatures will characterize the critical temperature of a cold agglutinin.

        b. An RBC precipitate (hemagglutination) may form when blood is mixed with a cold high-K+ solution (e.g., cold blood cardioplegia). A rapid diagnostic test has been proposed in which approximately 5 mL of the patient’s blood is added to the chilled cardioplegia solution during setup. Routine use of this test has been advocated.

        c. Unexplained high aortic root pressure during cold blood cardioplegia infusion may indicate cold agglutinin disease.

        d. The sudden appearance of hemolysis with hemoglobinuria during hypothermic CPB or use of blood cardioplegia may be diagnostic.

     3. Management

        a. If cold agglutinins are suspected preoperatively, careful assessment by a hematologist is warranted, including characterizing the type of antibody, its titer, and its critical temperature.

        b. The thermal design of the operation should be reviewed and revised if possible. CPB should be avoided if alternative strategies (e.g., off-pump surgery) are feasible. If CPB is required, systemic temperatures (including arterial and venous blood values) should be maintained above the critical temperature. Systemic temperatures of 28°C or higher are generally safe in asymptomatic patients. DHCA is feasible, provided the coldest blood temperature is several degrees warmer than the critical temperature.

        c. Cardioplegia management includes avoidance of cold blood cardioplegia. Induction of cardiac arrest is achieved with warm crystalloid cardioplegia to wash all RBCs out of the myocardium. Subsequently, cold crystalloid cardioplegia can be used to maintain arrest. Alternatives include warm blood cardioplegia or warm ischemic arrest with intermittent reperfusion.

        d. Plasmapheresis. If a reduction of the patient’s core temperature below their critical temperature for hemagglutinin formation is unavoidable, preoperative plasmapheresis may be required, particularly if the patient has high antibody titers. Plasmapheresis removes the majority of IgM antibodies, which are large and mainly intravascular. However, not all IgM antibodies are removed, so limiting cold exposure as much as possible is still required.

   C. Cold urticaria [23,24]. Patients with this disorder develop systemic histamine release and generalized urticaria in response to cold exposure. Cold CPB should be avoided if possible, because marked histamine release occurs during CPB rewarming and can cause hemodynamic instability. If cold CPB is unavoidable, the cardiovascular responses to histamine can be prevented by pretreatment with H1- and H2-receptor blockade; concomitant steroid administration may be useful.

   D. Malignant Hyperthermia (MH) [2527]

       An acute MH crisis may occur in susceptible patients exposed to triggering agents, and in rare cases, may manifest for the first time during CPB.

     1. Prevention. Management of known susceptibility requires the avoidance of triggering agents. During CPB it may be prudent to rewarm the patient gradually, avoid calcium administration unless Ca2+concentration is low, and possibly avoid a-adrenergic agonists.

     2. Diagnosis of an MH crisis. During CPB the usual early signs of signs of an MH crisis of hyperthermia, rigidity, and tachycardia may be absent due to the use of hypothermia and cardioplegia. However, the increased skeletal muscle metabolism associated with the disorder may cause a mixed metabolic and respiratory acidosis, hyperkalemia, rhabdomyolysis with myoglobinuria (and late renal failure) even during CPB. Recognition of MH crisis can be difficult, particularly during the rewarming phase when temperature is expected to increase. A high index of suspicion is required for patients with known MH susceptibility. Monitoring the rate of CO2 elimination (by monitoring oxygenator exhaust gas) or O2 uptake (by arteriovenous O2 measurements and pump flow rate) may permit early diagnosis of MH.

     3. Management involves ceasing triggering agents, cooling to reduce hyperthermia, correction of acid–base and electrolyte changes, and the early administration of dantrolene (1 to 2 mg/kg IV initially, with further doses as required titrated to effect). Active cooling and treatment of other MH complications may be necessary in the post-CPB period.

   E. Hereditary angioedema [28,29]. A deficiency or abnormality in function of an endogenous inhibitor of the C1 esterase complement protein leads to exaggerated complement pathway activation. Edema involving the airway, face, gastrointestinal tract, and extremities may follow even minor stresses. CPB can cause fatal complement activation in patients with hereditary angioedema; peak activation follows protamine administration. In the past, management of acute episodes has been mainly supportive, because epinephrine, steroids, and histamine antagonists are of little benefit, and fresh frozen plasma may exacerbate the reaction by providing additional complement substrates. Subacute and chronic therapies include androgens (stanozolol) and antifibrinolytics. A purified human C1 esterase inhibitor replacement protein (C1-INHRP) concentrate (Cinryze, ViroPharma, Exton, PA) is now available for prophylaxis against and treatment of acute episodes, and another purified C1-INH concentrate (Berinert, CSL Behring, King of Prussia, PA) is available for treatment [29]. Other drugs have been introduced recently to block bradykinin B2 receptors or inhibitor plasma kallikrein and reduce the severity of reactions [29].

   F. Pregnancy [30,31]. Cardiac surgery with CPB during pregnancy involves a high risk of fetal demise or morbidity (10% to 50%), although maternal mortality appears to be no greater than in the nonpregnant patient. Longer duration of CPB appears to increase the risk to the fetus.

     1. Physiology. Placental ischemia may be caused by microembolization, elevated inferior vena cava pressure due to obstructed drainage, or low pump flow rates (pregnant patients have a larger resting CO and require higher than usual flows during CPB). In addition, uterine blood flow is not autoregulated, so hypotension of any origin is likely to cause placental hypoperfusion. Uterine contractions may be induced by CPB, possibly related to rewarming or to dilution of progesterone.

     2. Management

        a. Additional monitoring. Fetal heart rate monitoring is mandatory, although in the first trimester this may not be possible. Uterine contractile activity should be monitored using a tocodynamometer applied to the maternal abdomen.

        b. Blood pressure and flow. Maintaining an increased perfusion pressure (e.g., >70 mm Hg) is advocated. Using increases in pump flow to elevate the blood pressure may be preferable to using pressor drugs, due to the risk of uterine artery vasoconstriction with α-adrenergic stimulation. Toward term, left uterine displacement is appropriate. Fetal bradycardia not related to hypothermia may indicate placental hypoperfusion and should be treated promptly by increasing the pump flow and perfusion pressure.

        c. Metabolic state. Maintain normal blood gases (including avoiding very high PaO2 values, ideally keep in 100 to 200 range) and ensure adequate oxygen delivery (Hct > 28%), and maintain normothermia if possible. The duration of CPB should be minimized and pulsatile perfusion should be considered. An adequate blood glucose level must be maintained.

        d. Tocolytic drugs such as magnesium sulfate, ritodrine, or terbutaline may be necessary.

        e. Inotropic drugs ideally should not have unbalanced α-vasoconstrictor and uterine-contracting activity. Milrinone, or low-to-moderate doses of epinephrine or dopamine, have theoretical advantages.

   G. Jehovah’s Witnesses rarely accept retransfusion of their own blood if it has left their circulation. Therefore, it is important to ensure continuous circulation of blood from commencement of CPB until full separation.

REFERENCES

 1. Frahdorf J, De hert S, Schlack W. Anaesthesia and myocardial ischaemia/reperfusion injury. Br J Anaesth. 2009;103:89–98.

 2. Graham J, Gibbs NM, Weightman WM. Relationship between temperature corrected oxygenator exhaust PCO2 and arterial PCO2 during hypothermic cardiopulmonary bypass. Anaesth Intensive Care.2005;33:457–461.

 3. Sebel PS. Central nervous system monitoring during open heart surgery: An update. J Cardiothorac Vasc Anesth. 1998; 12:3–8.

 4. Baulig W, Seifert B, Schmid ER, et al. Comparison of spectral entropy and bispectral index electroencephalography in coronary artery bypass surgery. J Cardiothor Vasc Anesth. 2010;24:544–549.

 5. Dawson PJ, Bjorksten AR, Blake DW, et al. The effects of cardiopulmonary bypass on total and unbound plasma concentrations of propofol and midazolam. J Cardiothorac Vasc Anesth. 1997;11:556–561.

 6. Gravlee GR, Angert KC, Tucker WY, et al. Early anticoagulation peak and rapid distribution after intravenous heparin. Anesthesiology. 1988;68:126–129.

 7. Aldea GS, O’Gara P, Shapira OM, et al. Effect of anticoagulation protocol on outcome in patients undergoing CABG with heparin-bonded cardiopulmonary bypass circuits. Ann Thorac Surg.1998;65:425–433.

 8. Nadolney EM, Svennson LG. Carbon dioxide field flooding techniques for open heart surgery: Monitoring and minimizing potential adverse effects. Perfusion. 2000;15:151–153.

 9. Oka Y, Inoue T, Hong Y, et al. Retained intracardiac air. Transesophageal echocardiography for definition of incidence and monitoring removal by improved techniques. J Thorac Cardiovasc Surg.1986;63:329–338.

10. Rannucci M, De Benedetti D, Biachini C, et al. Effects of fenoldapam infusion on in complex cardiac operations: A prospective, double-blind, placebo-controlled study. Minerva Anesthesiol.2010;76:249–259.

11. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg. 2003;75:S715–S720.

12. von Segesser LK. Unusual problems in cardiopulmonary bypass. In: Gravlee GR, Davis RF, Stammers AH, Ungerleider RM, eds. Cardiopulmonary Bypass: Principles and Practice. 3rd ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2008:608–613.

13. Mills NL, Ochsner JL. Massive air embolism during cardiopulmonary bypass: Causes, prevention, and management. J Thorac Cardiovasc Surg. 1980;80:713.

14. Schwartz DS, Ribakove GH, Grossi EA, et al. Single and multivessel port access coronary artery bypass grafting with cardioplegic arrest: Technique and reproducibility. J Thorac Cardiovasc Surg.1997;114:46–52.

15. Walther T, Falk V, Mohr FW. Minimally invasive mitral valve surgery. J Cardiovasc Surg. 2004;45:487–495.

16. Heiner M, Teasdale SJ, David T, et al. Aorto-coronary bypass in a patient with sickle cell trait. Can Anaesth Soc J. 1979;26:428–434.

17. Koshy M, Weiner SJ, Miller ST, et al. Surgery and anesthesia in sickle cell disease. Cooperative study of sickle cell diseases. Blood. 1995;86:3676–3684.

18. Firth PG, Head CA. Sickle cell disease and anesthesia. Anesthesiology. 2004;101:766–785.

19. Djaiani GN, Cheng DCH, Carroll JA, et al. Fast-track cardiac anesthesia in patients with sickle cell abnormalities. Anesth Analg. 1999;89:598–603.

20. Agarwal SK, Ghosh PK, Gupta D. Cardiac surgery and cold-reactive proteins. Ann Thorac Surg. 1995;60:1143–1150.

21. Bratkovic K, Fahy C. Anesthesia for off-pump coronary artery surgery in a patient with cold agglutinin disease. J Cardiothorac Vasc Anesth. 2008;22:449–452.

22. Atkinson VP, Soeding P, Horne G, et al. Cold agglutinins in cardiac surgery: Management of myocardial protection and cardiopulmonary bypass. Ann Thorac Surg. 2008;85:310–311.

23. Johnston WE, Moss J, Philbin DM, et al. Management of cold urticaria during hypothermic cardiopulmonary bypass. N Engl J Med. 1982;306:219–221.

24. Lancey RA, Schaefer OP, McCormick MJ. Coronary artery bypass grafting and aortic valve replacement with cold cardioplegia in a patient with cold-induced urticaria. Ann Allergy Asthma Immunol.2004;92:273–275.

25. Byrick RJ, Rose DK, Ranganathan N. Management of a malignant hyperthermia patient during cardiopulmonary bypass. Can Anaesth Soc J. 1982;29:50–54.

26. Larach DR, High KM, Larach MG, et al. Cardiopulmonary bypass interference with dantrolene prophylaxis of malignant hyperthermia. J Cardiothorac Anesth. 1987;1:448–453.

27. Metterlein T, Zink W, Haneya A, et al. Cardiopulmonary bypass in malignant hyperthermia susceptible patients: A systematic review of published cases. J Thorac Cardiovasc Surg. 2010;141:1488–1495.

28. Jaering JM, Comunale ME. Cardiopulmonary bypass in hereditary angioedema. Anesthesiology. 1993;79:1429–1433.

29. Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: Current and emerging option. Anesth Analg. 2010;110:1271–1280.

30. Strickland RA, Oliver WC, Chamtigian RC. Anesthesia, cardiopulmonary bypass, and the pregnant patient. Mayo Clin Proc. 1991;66:411–429.

31. Chandrasekhar S, Cook CR, Collard CD. Cardiac surgery in the parturient. Anesth Analg. 2009;108:777–785.