Chapter 12. Extracorporeal Circulation

Cardiopulmonary bypass for support during cardiac surgery is unique because blood exposed to foreign, nonendothelial cell surfaces is collected and continuously recirculated throughout the body. This contact with synthetic surfaces within the perfusion circuit, as well as open tissue surfaces within the wound triggers a defense reaction that involves at least five plasma protein systems and five types of circulating blood cells. This inflammatory response to cardiopulmonary bypass initiates a powerful thrombotic stimulus and the production, release, and circulation of vasoactive and cytotoxic substances that affect every organ and tissue within the body. Because of this, open- heart surgery using cardiopulmonary bypass is essentially not possible without anticoagulation, usually with heparin; thus the inflammatory response to cardiopulmonary bypass involves the consequences of exposing heparinized blood to foreign surfaces, not lined with endothelial cells.

Although the inflammatory response has been well characterized, the development of a nonthrombogenic artificial surface that would allow heparin-free circulatory support has not yet occurred. This chapter summarizes the application of extracorporeal circulation in adult cardiac surgery, and is divided into three sections. The first section describes the components and operation of perfusion systems and related special topics. The issues of thrombosis and bleeding are addressed in the second section, whereas the humoral response to cardiopulmonary bypass, including the reaction of blood elements and the inflammatory response are presented later in this chapter. The final section, deals with organ damage as a consequences of extracorporeal perfusion.

Perfusion Systems

Components

During cardiopulmonary bypass (CPB) for cardiac surgery, blood is typically drained by gravity into the venous reservoir of the heart-lung machine via cannulas placed in the superior and inferior vena cavae or a single cannula placed in the right atrium. Specialized cannulas can also be placed into the lower IVC through a femoral approach. Blood from the reservoir is then pumped through a hollow fiber oxygenator, and after appropriate gas exchange takes place, into the systemic arterial system through a cannula placed in the distal ascending aorta, the femoral artery, or the axillary artery (Fig. 12-1). This basic extracorporeal perfusion system can be adapted to provide partial or total circulatory and respiratory support or partial support for the left or right heart or for the lungs separately.

The complete heart-lung machine includes many additional components (Fig. 12-2).1 Most manufacturers consolidate a hollow-fiber oxygenator, venous reservoir, and heat exchanger into a single unit. A microfilter-bubble trap is added to the arterial outflow. Depending on the operation, various suction systems can be used to return blood from the surgical field, cardiac chambers, and/or the aorta, directly back into the cardiotomy reservoir, through a microfilter and then into the venous reservoir. Increasing evidence of the potential harmful effects of returning fat and lipid particles from the field into directly into the circulation, have increasingly led surgeons to preferentially use a cell saver system to collect and wash shed blood within the surgical field, and return the blood to the patient or circuit as packed red cells. In addition to adjusting pump flow, partially occluding clamps on venous and arterial lines allow additional regulation of venous drainage and flow. Access ports for sampling and sensors for monitoring pressures, temperatures, oxygen saturation, blood gases, and pH are included within most CPB systems. A separate pump and circuit for the administration of cardioplegic solutions at controlled composition, rate, and temperature is usually included in the system. An untrafilter can be easily added within the circuit for the removal of excess fluid, electrolytes, and some inflamatory mediators, or simply for hemoconcentration.

Venous Cannulation and Drainage

Principles of Venous Drainage

Venous blood usually enters the circuit by gravity or siphonage into a venous reservoir placed 40 to 70 cm below the level of the heart. The amount of drainage is determined by central venous pressure, the height differential and any resistance within the system (cannulas, tubing, and connectors). Successful drainage is dependent on a continuous column of blood or fluid and the absence of air within the system. Central venous pressure is determined by intravascular volume and venous compliance, which is influenced by medications, sympathetic tone, and anesthesia. Inadequate blood volume or excessive siphon pressure may cause compliant venous or atrial walls to collapse against cannular intake openings to produce "chattering" or "fluttering." This phenomenon is corrected by adding volume to the system (circuit and/or patient), or partially occludding the venous line near the inlet to decrease the negative pressure.

Venous Cannulas and Cannulation

Most venous cannulas are made out of flexible plastic, which may be stiffened with wire reinforcement to prevent kinking. Cannula tips may be straight or angled and often are constructed of thin, rigid plastic or metal. Cannula sizes are selected based on patient size and weight, anticipated flow rate, and an index of catheter flow characteristics and resistance (provided by the manufacturer), as well as size of the vessel to be cannulated. For an average adult with 60-cm negative siphon pressure, a 30-French cannula in the superior vena cava (SVC), and 34 French in the IVC or a single 42-French cavoatrial catheter almost always provides excellent venous drainage. Thin metal tipped right angle cannulas allow placement of smaller diameter cannulas with equal flow characterisitcs, and assist with insertion directly into the vena cavae. Catheters are typically inserted through pursestring guarded incisions in the right atrial appendage, lateral atrial wall, or directly in the SVC and IVC.

Three basic approaches for central venous cannulation are used: bicaval, single atrial, or cavoatrial ("two-stage") (Fig. 12-3). Bicaval cannulation and caval tourniquets are necessary to prevent bleeding into the field, and air entry into the system when the right heart is entered during CPB. Because of coronary sinus return, caval tourniquets should not be tightened without decompressing the right atrium if the heart is not still ejecting. Bicaval cannulation without caval snares is sometimes preferred to facilitate venous return during exposure of the left atrium and mitral valve.

Single venous cannulation is adequate for most aortic valve and coronary artery surgery; however, usually a cavo-atrial cannula ("two-stage") is employed (Fig. 12-3B). Introduced via the right atrial appendage, the narrowed distal end is guided into the IVC, leaving the wider proximal portion with multiple side holes to rest within the mid-right atrium. This tends to provide better venous drainage than a single cannula; however, proper positioning is critical.2 Care must be taken with both a single and two-stage cannula as elevation of the heart may kink the superior cavoatrial junction, decreasing venous return, and potentially, and more importantly, impeding venous outflow from the cerebral circulation.

Venous cannulation can also be accomplished via the femoral or iliac veins through an open or percutaneous technique. This technique is frequently employed in emergency situations, where central venous cannulation may be difficult (as in complex redo sternotomies3) or for cardiopulmonary support when a thoracotomy is the approach of choice, as in descending aortic procedures, or redo mitral valve operations. It is also valuable in the support of critically ill or unstable patients prior to the induction of anesthesia, and for applications of CPB that do not require a chest incision. Adequate venous drainage requires the use of larger cannulas (up to 28 French), with the drainage ports either within the intrahepatic IVC or in the right atrium. Transesophageal echocardiography (TEE) can be particularly helpful in assuring proper placement of these cannulas. Specially designed commercially manufactured long, ultrathin, wire-reinforced catheters are available for this purpose.

Persistent Left Superior Vena Cava

A persistent left superior vena cava (PLSVC) is present in 0.3 to 0.5% of the general population and usually drains into the coronary sinus; however, in about 10% of cases it drains into the left atrium.4 Although more common in association with other congenital defects, it can be seen as an isolated anomaly, and should be suspected when the (left) innominate vein is small or absent, or when a large coronary sinus (or the PLSVC itself) is seen on baseline TEE.5

A PLSVC may complicate the delivery of retrograde cardioplegia or entry into the right heart.6 If an adequate-sized innominate vein is present (30% of patients), the PLSVC can simply be occluded during CPB, assuming the ostium of the coronary sinus is present, and the coronary venous drainage is not dependent on the PLSVC.7 If the right SVC is absent (approximately 20% of patients with PLSVC), the left cava cannot be occluded and should be drained. With a normal RSVC, but an innominate vein that is absent (40% of patients) or small (about 33%), occlusion of the PLSVC may cause venous hypertension and possible cerebral injury. Although division of the innominate vein during redo-sternotomy or complex surgery such as transplantation has been shown to be safe, occlussion of the PLSVC during CPB relies on drainage of the cerebral venous return by the contralateral system, and so special attention must be paid to assure adequate RSVC cannula size, and prevent any kinking of the RSVC. In circumstances in which retrograde cardioplegia is required (severe aortic insufficiency) in the presence of a PLSVC, the retrograde cardioplegia cannula can be directly inserted into the coronary sinus and secured with a pursestring around the orifice of the coronary sinus, and with temporary snaring of the PLSVC, successful retrograde cardioplegia can be delivered.

Augmented or Assisted Venous Return

Negative pressure can be applied to the venous line to provide assisted venous drainage using either a roller or a centrifugal pump system,8 or by applying a regulated vacuum to a closed hard-shell venous reservoir (vacuum-assisted venous drainage, VAVD).9 This may permit use of smaller diameter catheters10 and may be helpful when long, peripheral catheters are used. However augmented negative pressure in the venous line increases the risk of aspirating gross or microscopic air and causing cerebral injury,11,12 hemolysis, or aspiration of air into the blood phase of hollow fiber oxygenators. Conversely, positive pressure in the venous reservoir can cause air to enter the venous lines and the right heart.13 These potential complications require special safety monitors and devices and adherence to detailed protocols when using assisted venous drainage techniques.13,14

Complications Associated with Venous Cannulation and Drainage

Atrial arrhythmias, bleeding from atrial or vena caval tears, air embolization, venous injury, or obstruction owing to catheter malposition, reversing arterial and venous lines, and unexpected decannulation can all occur during the conduct of cannulation for CPB. Encircling the vena cavae for snaring may lacerate branches or nearby vessels (eg, right pulmonary artery), or injure the vena cava itself. All of these injuries are more likely in the presence of previous surgey, and need to be recognized and corrected early to assure the proper conduct of CPB and minimize additional complications.

Either before or after CPB, cannulas still in place may compromise venous return to the right atrium. The venous cannulas in the SVC, or the superior caval tape may displace or compromise central venous or pulmonary arterial monitoring catheters. Conversely, monitoring catheters may compromise the function of caval tapes, allowing air to enter the venous lines between the cannulas and the catheters or sheaths.

During the conduct of the operation itself, any intracardiac catheter may be trapped by sutures, which may impede removal before or after the wound is closed. Any connection between the atmosphere and cannula intake ports may entrain air to produce an air lock or gaseous microembolism. Assisted venous drainage (AVD) increases the risk of air entrainment.15 Finally, improperly placed pursestring sutures may obstruct a cava when tied, particularly in the SVC.16

Causes of Low Venous Return

Low venous pressure, hypovolemia, drug- or anesthetic-induced venous dilatation, inadequate differential height between the heart and the reservoir, inadequate cannula size, cannula obstruction or kinking, "air-lock," and excessive flow resistance in the drainage system are all possible causes of impaired or inadequate venous return. These can usually be prevented or quickly corrected through close attention to detail, keeping the venous lines visible within the field when possible, and perhaps most importantly, frequent and detailed communication between surgeon and perfusionist. In addition to contributing to inadequate antegrade flow from the pump, partial obstruction of the venous line may lead to right ventricular distention and impair contractility off CPB.

Arterial Cannulation

Arterial Cannulas

The tip of the arterial cannula is usually the narrowest part of the perfusion system and may produce high pressure differentials, jets, turbulence, and cavitation at the required flows for CPB, particularly if the arterial catheters are small. Most arterial catheters are rated by a performance index, which relates external diameter, flow, and pressure differential.17 High-velocity jets may damage the aortic wall, dislodge atheroemboli, produce dissections, disturb flow to nearby vessels, and cause cavitation and hemolysis. Pressure differences that exceed 100 mm Hg cause excessive hemolysis and protein denaturation.18 Weinstein19 attributed a predominance of left-sided stroke after cardiac surgery to the "sand-blasting" effect of end-hole aortic cannulas directing debris into the left carotid artery. Available aortic catheters with only side ports20 are designed to minimize jet effects and better distribute arch vessel perfusion and pressure21 and may be associated with fewer strokes.19

Recently a dual-stream aortic perfusion catheter has been developed that features an inflatable horizontal streaming baffle that is designed to protect the arch vessels from atherosclerotic and other emboli and permits selective cerebral hypothermia.22 Another novel aortic cannula features a side port that deploys a 120-μm mesh filter to remove particulate emboli beyond the ascending aorta.23 Although this catheter may increase the pressure gradient by 50%,24 it has been shown to remove an average of eight emboli in 99% of 243 patients studied, and reduce the incidence of cerebral injuries below an expected rate.25

Connection to the Patient

Anatomical sites available for arterial inflow include the proximal aorta, innominate artery and distal arch, femoral, external iliac, axillary, and subclavian arteries. Cannulation can be direct by arterial puncture within a pursestring, through a side graft anastomosed to an arterial vessel, or percutaneous, although usually only in emergency situations. The choice is influenced by the planned operation26 and distribution of atherosclerotic disease.27

Atherosclerosis of the Ascending Aorta

Dislodgement of atheromatous debris from the aortic wall from manipulation,28 cross-clamping, or the sand-blasting effect of the cannula jet is a major cause of perioperative stroke29 as well as a risk factor for aortic dissection30 and postoperative renal dysfunction.31 Simple palpation has been shown to be sensitive and accurate for detecting severe atherosclerosis than epiaortic ultrasonic scanning.28,32 Although some have advocated for its use, even transesophageal echocardiolgraphy (TEE) views of the middle and distal ascending aorta are often inadequate.32,33 Epiaortic scanning is now the preferred method of screening in all patients with a history of transient ischemic attack, stroke, severe peripheral vascular disease, palpable calcification in the ascending aorta, calcified aortic knob on chest radiograph, age older than 50 to 60 years, or TEE findings of moderate aortic atherosclerosis.28 A calcified aorta ("porcelain aorta"), which occurs in 1.2 to 4.3% of patients,34 is another indication for relocation of the aortic cannula.35 Alternative sites include the distal aortic arch34 along with the innominate, axillary-subclavian, or femoral arteries.

Ascending Aortic Cannulation

The distal ascending aorta is the the most common cannulation site because of easy access, and few complications. The cannula is usually placed through a small stab wound within one or two concentric pursestring sutures, that are then snared to secure the cannula and provide hemostasis. Risk of dissection may be reduced by avoiding cannulation into the hypertensive aorta, and many surgeons choose to transiently reduce the systemic pressure below 100 mm Hg. The observation of pulsatile back bleeding into the cannula confirms that the tip is within the lumen of the aorta, and then the cannula should be positioned to direct flow to the mid-transverse aorta. The use of a long catheter with the tip placed beyond the left subclavian artery has also been reported.36 Proper cannula placement is critical21 and is confirmed by noting pulsatile pressure in the aortic line monitor and equivalent pressure in the radial artery. The cannula must be properly secured in place to prevent inadvertant dislodgement during the conduct of the operation.

Complications include difficult insertion; bleeding; tearing of the aortic wall; intramural or malposition of the cannula tip (in or against the aortic wall, toward the valve, or in an arch vessel)37; atheromatous emboli; failure to remove all air from the arterial line after connection; injury to the aortic back wall; high line pressure, indicating obstruction to flow; inadequate or excessive cerebral perfusion38; inadvertent decannulation; and aortic dissection.39 It is essential to monitor aortic line and radial artery pressures and carefully observe the aorta for possible cannula-related complications particularly during the initiation of CPB as well as during the placement of aortic clamps. Asymmetric cooling of the face or neck may suggest a problem with cerebral perfusion. Late bleeding and infected or noninfected false aneurysms are delayed complications of aortic cannulation.

Aortic dissection occurs in 0.01 to 0.09% of aortic cannulations30,40 and is more common in patients with aortic root disease. Early signs of aortic dissection include discoloration beneath the adventia near the cannulation site, an increase in arterial line pressure, or a sharp reduction in return to the venous reservoir. TEE may be helpful in confirming the diagnosis,41 but prompt action is necessary to limit the dissection and maintain perfusion. The cannula must be promptly transferred to a peripheral artery or uninvolved distal aorta. Blood pressure should be controlled pharmacologically and perfusion cooling to temperatures less than 20°C initiated. During hypothermic circulatory arrest, the aorta is opened at the original site of cannulation and repaired by direct suture, patch, or circumferential graft.40 When recognized early, survival rates range from 66 to 85%, but when undiscovered until late during of after the operation, survival is approximately 50%.

Cannulation of the Femoral or Iliac Artery

These vessels are usually the first alternative to aortic cannulation, but may be the primary choice for rapid initiation of cardiopulmonary bypass for severe bleeding, cardiac arrest, acute intraoperative dissection, or severe shock. It is also a common first choice for limited access cardiac surgery, as well as in selected reoperative patients.3 Femoral or iliac cannulation limits cannula size but the retrograde distribution of blood flow is similar to antegrade flow.42 Percutaneous cannulation kits are available for emergency femoral access, and many surgeons also use these long wire reinforced peripheral arterial cannulas with an open Seldinger technique, inserting the cannula through a pursestring in the femoral or iliac vessel by direct cutdown. This may reduce some of the complications of open insertion of large short cannluas, and simplifies cannula removal and arterial repair. Femoral cannulation may be associated with many complications,3 including tears, dissection, late stenosis or thrombosis, bleeding, lymphatic collection or drainage, groin infection, and cerebral and coronary atheroembolism. In patients with prior aortic dissections, retrograde femoral perfusion may create a malperfusion situation; thus, some surgeons recommend alternative cannulation sites for these patients.43 Ischemic complications of the distal leg may occur during prolonged (3- to 6-hour) retrograde perfusions,44,45 unless perfusion is provided to the distal vessel. This may be provided by a small Y catheter in the distal vessel45 or a side graft sutured to the artery.46

Retrograde arterial dissection is the most serious complication of femoral or iliac arterial cannulation and may extend to the aortic root or cause retroperitoneal hemorrhage with an incidence of around 1% or less,47 and is associated with a mortality of about 50%. This complication is more common in patients greater than 40 years, and in those with significantly diseased arteries. The diagnosis is similar to an aortic cannula dissection and may be confirmed by TEE of the descending thoracic aorta.41 Antegrade perfusion in the true lumen must be immediately resumed by either the heart itself or cannulation in the distal aorta or axillary-subclavian artery. It is not always necessary to repair the dissected ascending aorta unless it progresses proximally to involve the aortic root.47

Other Sites for Arterial Cannulation

The axillary-subclavian artery has been increasingly used for cannulation.48,49 Advantages include freedom from atherosclerosis, antegrade flow into the arch vessels, and protection of the arm and hand by collateral flow. Because of these advantages and the dangers of retrograde perfusion in patients with aortic dissection, some surgeons prefer this cannulation site over femoral access for these patients.49 Brachial plexus injury and axillary artery thrombosis are reported complications.48 The axillary artery is approached through a subclavicular incision, whereas the intrathoracic subclavian artery may be cannulated through a thoracotomy.50

Occasionally the innominate artery may be cannulated through a pursestring suture without obstructing flow to the right carotid artery by using a 7- or 8-French cannula.26 The ascending aorta can also be cannulated by passing a cannula through the aortic valve from the left ventricular apex.51 Coselli and Crawford52 also describe retrograde perfusion through a graft sewn to the abdominal aorta.

Venous Reservoir

The venous reservoir serves as volume reservoir during cardiopulmonary bypass and particularly with the body exsanguination of deep hypothermic circulatory arrest. It is placed immediately before the arterial pump when a membrane oxygenator is used (see Fig. 12-1). This reservoir serves as a high-capacitance (ie, low-pressure) receiving chamber for venous return, facilitates gravity drainage, is a venous bubble trap, provides access for drugs, fluids, or blood, and increases the storage capacity for the perfusion system. As much as 1 to 3 L of blood may be translocated from patient to circuit when full CPB is initiated. The venous reservoir also provides several seconds of reaction time if venous return is suddenly decreased or interrupted.

Reservoirs may be rigid (hard) plastic canisters ("open" types) or soft, collapsible plastic bags ("closed" types). The rigid canisters facilitate volume measurements and management of venous air, often have larger capacity, are easier to prime, permit suction for vacuum-assisted venous drainage, and may be less expensive. Some hard-shell venous reservoirs incorporate macrofilters and microfilters and can serve as cardiotomy reservoirs to receive vented blood.

Disadvantages include the use of silicon antifoam compounds, which may produce microemboli,53 and increased activation of blood elements.54 Soft bag reservoirs eliminate the blood-gas interface and by collapsing reduce the risk of pumping massive air emboli if venous return is suddenly interrupted.

Oxygenators

Membrane oxygenators imitate the natural lung by interspersing a thin membrane of microporous polypropylene or polymethylpentene (0.3- to 0.8-μm pores), or silicone rubber between the gas and blood phases. Compared with previously used bubble oxygenators, membrane oxygenators are safer, produce less particulate and gaseous microemboli,55 are less reactive to blood elements, and allow superior control of blood gases.56 With microporous membranes, plasma-filled pores prevent gas entering blood, but facilitate transfer of both oxygen and CO2. Because oxygen is poorly diffusible in plasma, blood must be spread as a thin film (approximately 100 μm) over a large area with high differential gas pressures between compartments to achieve oxygenation. Areas of turbulence and secondary flow enhance diffusion of oxygen within blood and thereby improve oxyhemoglobin saturation.57 Carbon dioxide is highly diffusible in plasma and easily exits the blood compartment despite small differential pressures across the membrane.

The most popular design uses sheaves of hollow fibers (120 to 200 μm) connected to inlet and outlet manifolds within a hard-shell jacket (Fig. 12-4). The most efficient configuration creates turbulence by passing blood between fibers and oxygen within fibers. Arterial PCO2 is controlled by gas flow rate, and PO2 is controlled by the fraction of inspired oxygen (FIO2) produced by an air-oxygen blender. Modern membrane oxygenators add up to 470 mL of O2 and remove up to 350 mL CO2 per minute at 1 to 7 L of flow with priming volumes of 220 to 560 mL and resistances of 12 to 15 mm Hg per liter blood flow. Most units combine a venous reservoir, heat exchanger, and hollow fiber membrane oxygenator into one compact unit.

Oxygen and CO2 diffuse across thin silicone membranes, which are made into envelopes and wound around a spool to produce a spiral coil oxygenator. Gas passes through the envelope and blood passes between the coil windings. Because of protein leakage that frequently ccurs with hollow fiber membranes after 8 to 12 hours of use, these spiral coil silicone membranes have been preferred for the prolonged perfusions (days) used in long-term respiratory and cardiac support of extracorporeal membrane oxygenation or "ECMO" systems. More recently, however, the development of polymethylpentene oxygenators have combined the benefit of efficient small surface area hollow fiber oxygenators without the detrimental plasma leakage seen with polypropylene, and have allowed these membranes to be used with both CPB and ECMO.

Other membranes feature a very thin (0.05 μm), solid membrane on the blood side of a highly porous support matrix. This membrane reduces the risk of gas emboli and plasma leakage during prolonged CPB, but may impair transfer of volatile anesthetics.58

Flow regulators, flow meters, gas blender, oxygen analyzer, gas filter, and moisture trap are parts of the oxygenator gas supply system used to control the ventilating gases within membrane oxygenators. Often an anesthetic vaporizer is added, but care must be taken to prevent volatile anesthetic liquids from destroying plastic components of the perfusion circuit.

Bubble oxygenators are obsolete in the United States, but may still be used elsewhere for short-term CPB because of low cost and efficiency. Because each bubble presents a new foreign surface to which blood elements react, bubble oxygenators cause progressive injury to blood elements and entrain more gaseous microemboli.59 In bubble oxygenators, venous blood drains directly into a chamber into which oxygen is infused through a diffusion plate (sparger). The sparger produces thousands of small (approximately 36-μm) oxygen bubbles within blood. Gas exchange occurs across a thin film at the blood-gas interface around each bubble. Carbon dioxide diffuses into the bubble and oxygen diffuses outward into blood. Small bubbles improve oxygen exchange by effectively increasing the surface area of the gas-blood interface,60 but are difficult to remove. Large bubbles facilitate CO2 removal. Bubbles and blood are separated by settling, filtration, and defoaming surfactants in a reservoir. Bubble oxygenators add 350 to 400 mL oxygen to blood and remove 300 to 330 mL CO2 per minute at flow rates from 1 to 7 L/min.56 Priming volumes are less than 500 mL. Commercial bubble oxygenators incorporate a reservoir and heat exchanger within the same unit and are placed upstream to the arterial pump.

Oxygenator malfunction requiring change during CPB occurs in 0.02 to 0.26% of cases,61–63 but the incidence varies between membrane oxygenator designs.64 Development of abnormal resistant areas in the blood path is the most common cause,63 but other problems include leaks, loss of gas supply, rupture of connections, failure of the blender, and deteriorating gas exchange. Blood gases need to be monitored to ensure adequate CO2 removal and oxygenation. Heparin coating may reduce development of abnormally high resistance areas.62

Heat Exchangers

Heat exchangers control body temperature by heating or cooling blood passing through the perfusion circuit. Hypothermia is frequently used during cardiac surgery to reduce oxygen demand or facilitate operative exposure with brief periods of circulatory arrest. Because gases are more soluble in cold than in warm blood, rapid rewarming of cold blood within the circuit or the body may cause formation of bubble emboli.65 Most membrane oxygenator units incorporate a heat exchanger upstream to the oxygenator to minimize this potential problem. Blood should not be heated above 40°C to prevent denaturation of plasma proteins, and the temperature gradient between the body and the perfusion circuit remain within 10°C to prevent bubble emboli. The heat exchanger may be supplied by hot and cold tap water, but separate heater/cooler units with convenient temperature-regulating controls are preferred. Leakage of water into the blood path can cause hemolysis and malfunction of heater/cooler units may occur.61

Separate heat exchangers are needed for cardioplegia. The simplest system uses bags of precooled cardioplegia solution; however, commonly cardioplegia fluid is circulated through through a dedicated heat exchanger or tubing coils placed in an ice or warm water bath.

Pumps

Most heart-lung machines use two types of pumps, although roller pumps can be used exclusively (Table 12-1). Centrifugal pumps are usually used for the primary perfusion circuit for safety reasons and for a possible reduction in injury to blood elements, although this remains controversial and unproved.66

Centrifugal pumps (Fig. 12-5) consist of a vaned impeller or nested, smooth plastic cones, which when rotated rapidly, propel blood by centrifugal force.67 An arterial flowmeter is required to determine forward blood flow, which varies with the speed of rotation and the afterload of the arterial line. Unless a check valve is used,68 the arterial line must be clamped to prevent backward flow when the pump is off. Centrifugal blood pumps generate up to 900 mm Hg of forward pressure, but only 400 to 500 mm Hg of negative pressure and, therefore, less cavitation and fewer gaseous microemboli. They can pump small amounts of air, but become "deprimed" if more than 30 to 50 mL of air enters the blood chamber. Centrifugal pumps are probably superior for temporary extracorporeal cardiac assist devices and left heart bypass, and for generating pump-augmented venous return.

Roller pumps consist of a length of 1/4- to 5/8-inch (internal diameter) polyvinyl, silicone, or latex tubing, which is compressed by two rollers 180 degrees apart, inside a circular raceway. Forward flow is generated by roller compression and flow rate depends upon the diameter of the tubing, rate of rotation (RPM), the length of the compression raceway, and completeness of compression or "occlusion." Compression is adjusted before use to be barely nonocclusive against a standing column of fluid that produces 45 to 75 mm Hg back pressure.69 Hemolysis and tubing wear are minimal at this degree of compression.69 Flow rate is determined from calibration curves for each pump for different tubing sizes and rates of rotation. Roller pumps are inexpensive, reliable, safe, insensitive to afterload, and have small priming volumes, but can produce high negative pressures and microparticles shed from compressed tubing (spallation).70 Roller pumps are vulnerable to careless operation that results in: propelling air; inaccurate flow calibration; backflow when not in use if rollers are not sufficiently occlusive; excessive pressure with rupture of connections if arterial inflow is obstructed; tears in tubing; and changing roller compression settings during operation. In general roller pumps rather than centrifugal pumps are used for sucker systems and for delivering cardioplegic solutions.

Centrifugal pumps produce pulseless blood flow and standard roller pumps produce a sine wave pulse around 5 mm Hg. The arterial cannula dampens the pulse of pulsatile pumps, and it is difficult to generate pulse pressures above 20 mm Hg within the body during full CPB.71 To date no one has conclusively demonstrated the need for pulsatile perfusion during short- or long-term CPB or circulatory assistance.72

Complications that may occur during operation of either type of pump include loss of electricity; loss of the ability to control pump speed, which produces "runaway pump" or "pump creep" when turned off; loss of the flow meter or RPM indicator; rupture of tubing in the roller pump raceway; and reversal of flow by improper tubing in the raceway. A means to manually provide pumping in case of electrical failure should always be available.

Filters and Bubble Traps

Microemboli

During clinical cardiac surgery with CPB the wound and the perfusion circuit generate gaseous and biologic and nonbiologic particulate microemboli (<500 μM diameter).23,73,74 Microemboli produce much of the morbidity associated with cardiac operations using CPB (see section 'Organ Damage' later in this chapter). Gaseous emboli contain oxygen or nitrogen and may enter the perfusate from multiple sources and pass through other components of the system.12,15 Potential sources of gas entry include stopcocks, sampling and injection sites,74 priming solutions, priming procedures, intravenous fluids, vents, the cardiotomy reservoir, tears or breaks in the perfusion circuit, loose pursestring sutures (especially during augmented venous return),12 rapid warming of cold blood,65 cavitation, oxygenators, venous reservoirs with low perfusate levels,15 and the heart and great vessels. Bubble oxygenators produce many gaseous emboli; membrane oxygenators produce very few.55,56 Aside from technical errors (open stopcocks, empty venous reservoir, air in the heart) the cardiotomy reservoir is the largest source of gaseous emboli in membrane oxygenator perfusion systems.

Blood produces a large number of particulate emboli related to thrombus formation (clots), fibrin, platelet and platelet-leukocyte aggregation, hemolyzed red cells, cellular debris, and generation of chylomicrons, fat particles, and denatured proteins.75 Stored donor blood is also an important source of blood-generated particles.76 Other biologic emboli include atherosclerotic debris and cholesterol crystals and calcium particles dislodged by cannulation, manipulation for exposure, or the surgery itself. Both biologic and nonbiologic particulate emboli are aspirated from the wound. Bits of muscle, bone, and fat are mixed with suture material, talc, glue, and dust and aspirated into the cardiotomy reservoir.76,77 Materials used in manufacture, spallated material, and dust may also enter the perfusate from the perfusion circuit76 if it is not first rinsed by recirculating saline through a prebypass microfilter, which is discarded.

In vivo microemboli larger than 100 microns are detected by transcranial Doppler ultrasound,78 fluorescein angiography,55 TEE, and retinal inspection. In the circuit, microemboli are monitored by arterial line ultrasound79 or monitoring screen filtration pressure. Microfilter weights and examination, histology of autopsy tissues, and electron particle size counters of blood samples76 verify microemboli beyond the circuit.

Prevention and Control of Microemboli

Table 12-2 outlines sources of microemboli. Major methods include using a membrane oxygenator and cardiotomy reservoir filter; minimizing and washing blood aspirated from the field80; and preventing air entry into the circuit and using left ventricular vents when the heart is opened.81,82

The brain receives 14% of the cardiac output and is the most sensitive organ for microembolic injury.83 Strategies to selectively reduce microembolism to the brain include reducing PaCO2 to cause cerebral vasoconstriction84; hypothermia85; placing aortic cannulas downstream to the cerebral vessel36,74; and using special aortic cannulas with22,23,30 or without19 special baffles or screens designed to prevent cannula-produced cerebral atherosclerotic emboli.

Two types of blood microfilters are available for use within the perfusion circuit: depth and screen.86,87 Depth filters consist of packed fibers or porous foam, have no defined pore size, present a large, tortuous, wetted surface, and remove microemboli by impaction and absorption. Screen filters are usually made of woven polyester or nylon thread, have a defined pore size, and filter by interception. Screen filters vary in pore size and configuration and block most air emboli; however, as pore size decreases, resistance increases. As compared with no filter, studies indicate that all commercial filters effectively remove gaseous and particulate emboli.88,89 Most investigations find that the Dacron wool depth filter is most effective, particularly in removing microscopic and macroscopic air. Pressure differences across filters vary between 24 and 36 mm Hg at 5 L/min flow. Filters cause slight hemolysis and tend to trap some platelets; nylon filters may also activate complement.86

The need for microfilters in the cardiotomy suction reservoir is universally accepted,77 and most commercial units contain an integrated micropore filter. The need for a filter in the cardioplegia delivery system, however, remains debatable,90 and although almost always used, the requirement of an arterial line filter is unsettled.87 In vitro studies demonstrate that an arterial filter reduces circulating microemboli89 and clinical studies are confirmatory.89 However, these filters do not remove all microemboli generated by the extracorporeal circuit.12,74,77 When bubble oxygenators are used, studies show equivocal or modest reductions in microemboli55,91 and neurologic outcome markers.91 In contrast, membrane oxygenators produce far fewer microemboli and when used without an arterial filter, the numbers of microemboli are similar to those found with bubble oxygenators plus arterial line filters.87

Although the efficacy of arterial line microfilters remains unsettled, their use is almost universal;92 and although they are effective bubble traps, they do increase cost, occasionally obstruct during use, are difficult to de-air during priming, and require a small bypass line and valved purge line to remove any air.

Other sources of biologic microemboli may be more important. Cerebral microemboli are most numerous during aortic cannulation,93,94 application and release of aortic clamps,94 and at the beginning of cardiac ejection after open heart procedures.95 Furthermore, as compared with perfusion microemboli, surgically induced emboli are more likely to cause postoperative neurologic deficits.96

Leukocyte-Depleting Filters

Leukocyte-depleting filters are discussed later in this chapter and have been recently reviewed.97 These filters reduce circulating leukocyte counts in most studies,98 but fail to produce convincing evidence of clinical benefit.99

Tubing and Connectors

The various components of the heart-lung machine are connected by polyvinyl tubing and fluted polycarbonate connectors. Medical grade polyvinyl chloride (PVC) tubing is universally used because it is flexible, compatible with blood, inert, nontoxic, smooth, nonwettable, tough, transparent, resistant to kinking and collapse, and can be heat sterilized. To reduce priming volume, tubing connections should be short. To reduce turbulence, cavitation, and stagnant areas, the flow path should be smooth and uniform without areas of constriction or expansion. Wide tubing improves rheology, but also increases priming volume. In practice 1/2- to 5/8-inch (internal diameter) tubing is used for most adults, but until a compact, integrated, complete heart-lung machine can be designed and produced as a unit, the flow path will produce some turbulence. Loose tubing connections can be sources of air intake or blood leakage and so all connections must be secure. For convenience and safety, most tubing and connectors are prepackaged and disposable.

Heparin-Coated Circuits

Heparin can be bound to blood surfaces of all components of the extracorporeal circuit by ionic or covalent bonds. The Duraflo II heparin coating ionically attaches heparin to a quaternary ammonium carrier (alkylbenzyl dimethyl-ammonium chloride), which binds to plastic surfaces (Edwards Lifesciences, Irvine, CA). Covalent attachment is produced by first depositing a polyethylenimine polymer spacer onto the plastic surface, to which heparin fragments bind (Carmeda Bioactive Surface, Medtronic, Inc., Minneapolis, MN). Ionic-bound heparin slowly leaches, but this is irrelevant in clinical cardiac surgery. The use of heparin-coated circuits during CPB has spawned an enormous literature100–102 and remains controversial largely because studies are contaminated by patient selection, reduced doses of systemic heparin, and washing or discarding field-aspirated blood.102 There is no credible evidence that heparin-coated perfusion circuits reduce the need for systemic heparin or reduce bleeding or thrombotic problems associated with CPB. Although the majority of studies indicate that heparin coatings reduce concentrations of C3a and C5b-9,103 the inflammatory response to CPB is not reduced and the evidence for clinical benefit is not convincing.104

Other surface modifications and coatings in development101 include a phosphorylcholine coating,105 surface-modifying additives,107 and a trillium biopassive surface.106

Cardiotomy Reservoir and Field Suction

Blood aspirated from the surgical wound may be directed to the cardiotomy reservoir for defoaming, filtration, and storage before it is added directly to the perfusate. A sponge impregnated with a surfactant removes bubbles by reducing surface tension at the blood interface and macro, micro, or combined filters remove particulate emboli. Negative pressure is generated by either a roller pump or vacuum applied to the rigid outer shell of the reservoir. The degree of negative pressure and blood level must be monitored to avoid excessive suction or introducing air into the perfusate.

The cardiotomy suction and reservoir are major sources of hemolysis, particulate and gaseous microemboli, fat globules, cellular aggregates, platelet injury and loss, thrombin generation, and fibrinolysis.73,77,108 Air aspirated with wound blood contributes to blood activation and destruction and is difficult to remove because of the high proportion of nitrogen, which is poorly soluble in blood. High suction volumes and admixture of air are particularly destructive of platelets and red cells.108 Commercial reservoirs are designed to minimize air entrainment and excessive injury to blood elements. Air and microemboli removal are also facilitated by allowing aspirated blood to settle within the reservoir before it is added to the perfusate.

An alternative method for recovering field-aspirated blood is to dilute the blood with saline and then remove the saline to return only packed red cells to the perfusate. Two types of centrifugal cell washers automate the process. Intermittant centrifugation (eg, Haemonetics Cell Saver, Meomonetics Corp., Braintree, MA) removes air, thrombin, and many biologic and nonbiologic microemboli from the aspirate at the cost of discarding plasma. Continuous centrifugation (eg, Fresenius/Terumo CATS, Elkton, MD) in addition removes fat and activated leukocytes.109 A third alternative is to discard all field-aspirated blood, although most surgeons would find this practice unacceptible if it increased allogeneic blood transfusion. Increasingly, field-aspirated blood is recognized as a major contributor to the thrombotic, bleeding, and inflammatory complications of CPB.

Venting the Heart

If the heart is unable to contract, distention of either ventricle is detrimental to subsequent contractility.110 Right ventricular distention during cardiac arrest or ventricular fibrillation is rarely a problem, but left ventricular distention can be insidious in that blood can enter the flaccid, thick-walled chamber from multiple sources during this period. During CPB, blood escaping atrial or venous cannulas and from the coronary sinus and thebesian veins may pass through the unopened right heart into the pulmonary circulation. This blood plus bronchial arterial and venous blood, blood regurgitating through the aortic valve, and blood from undiagnosed abnormal sources (patent foramen ovale, patent ductus, etc.) may distend the left ventricle unless a vent catheter is used (Fig. 12-6). During CPB bronchial blood and noncoronary collateral flow average approximately 140 ± 182 and 48 ± 74 mL/min, respectively.111

There are several methods for venting the left heart during cardiac arrest. Although it was used commonly in the past, few surgeons in the modern era vent the left ventricular apex directly because of inconvenience and myocardial injury. Most often a multihole, soft-tip catheter (8 to 10 French) is inserted into the junction of the right superior pulmonary vein and left atrium (see Fig. 12-6) or left atrial appendage and may or may not be passed into the left ventricle. Others prefer to place a small suction catheter into the pulmonary artery.112 The ventricle can also be vented by passing a catheter retrograde across the aortic valve when working on the mitral valve. Vent catheters are drained to the cardiotomy reservoir by a roller pump, vacuum source, or gravity drainage,113 but must be carefully monitored for malfunction. If connected to a roller pump, the system should be carefully tested before use to ensure proper operation. Although inspection and palpation may detect ventricular distention, TEE monitoring or direct measurements of left atrial or pulmonary arterial pressures are more reliable. The heart is no longer vented for most myocardial revascularization operations, but the ventricle must be protected from distention.114 If the heart cannot remain decompressed during distal anastomoses, a vent should be inserted. Often the cardioplegia line inserted into the aortic root is used for venting when not used for cardioplegia.115

The most common and serious complication of left heart venting is residual air when the heart is filled and begins to contract. De-airing maneuvers and TEE are important methods for ensuring removal of all residual air. In addition, many surgeons aspirate the ascending aorta via a small metal or plastic cannula to detect and remove any escaping air as the heart begins to eject.116 Bleeding, atrial perforation, mitral valve injury, and direct injury to the myocardium are other complications associated with left ventricular vents.

Cardioplegia Delivery Systems

Cardioplegic solutions contain 8 to 20 mEq/L potassium, magnesium, and often other components that are infused into the aortic root proximal to the aortic cross clamp, or retrograde into the coronary sinus to arrest the heart in diastole. The carrier may be crystalloid or blood and is infused at temperatures around 4 or 37°C, depending upon surgeon's preference. Normothermic cardioplegia must be delivered almost continuously to keep the heart arrested while cold cardioplegia may be infused intermittently. Cardioplegic solutions are delivered through a separate perfusion system that includes a reservoir, heat exchanger, roller pump, bubble trap, and perhaps microfilter (see Fig. 12-2). Temperature and infusion pressure are monitored. The system may be completely independent of the main perfusion circuit or it may branch from the arterial line. The system also may be configured to vent the aortic root when not delivering cardioplegia.

Antegrade cardioplegia is delivered through a small cannula in the aortic root or via cannulas directly into the coronary ostia when the aortic valve is exposed. Retrograde cardioplegia is delivered through a cuffed catheter inserted into the coronary sinus.117 Proper placement of the retrograde catheter is critical, but not difficult, and is verified by palpation, TEE, color of the aspirated blood, or pressure waveform of a catheter pressure sensor.118 Complications of retrograde cardioplegia include rupture or perforation of the sinus, hematoma, and rupture of the catheter cuff.119

Hemoconcentrators (Hemofiltration/Ultrafiltration)

Hemoconcentrators, like oxygenators, contain one of several available semipermeable membranes (typically hollow fibers) that transfer water, electrolytes (eg, potassium), and molecules up to 20 kDa out of the blood compartment.120 Hemoconcentrators may be connected to either venous or arterial lines or a reservoir in the main perfusion circuit, but require high pressure in the blood compartment to effect fluid removal. Thus a roller pump is needed unless connected to the arterial line. Suction may or may not be applied to the air side of the membrane to facilitate filtration. Up to 180 mL/min of fluid can be removed at flows of 500 mL/min.121 Hemoconcentrators conserve platelets and most plasma proteins as compared with centrifugal cell washers, and may allow greater control of potassium concentrations than diuretics.122 Aside from cost, disadvantages are few and adverse effects are rare.121

Perfusion Monitors and Safety Devices

Table 12-3 lists monitors and safety devices that are commonly used during CPB. Pressure in the arterial line between pump and arterial line filter is monitored continuously to instantly detect any increased resistance to arterial inflow into the patient. This pressure should be higher than radial arterial pressure because of resistance of the filter (if used) and cannula. The arterial pressure monitor may be connected to an audible alarm or the pump switch to alert the perfusionist to dangerous increases in the arterial line pressure.

An arterial line flowmeter is essential for centrifugal pumps and may be desirable to confirm flow calculations with roller pumps as well.

In-line devices are available to continuously measure blood gases, hemoglobin/hematocrit, and some electrolytes.123 Placed within the venous line, these devices permit continuous assessment of oxygen supply and demand.124 In the arterial line the devices offer better control of blood gases.125 The need for these devices is unproved and because reliability is still uncertain, use may distract operative personnel and spawn unnecessary laboratory measurements.126 The use of automated analyzers by the perfusion team in the operating room is an alternative if frequent measurement of blood gases, hematocrit, and electrolytes is desirable.123

The flow and concentration of oxygen entering the oxygenator should be monitored.127 Some teams also monitor exit gases to indirectly estimate metabolic activity and depth of anesthesia.127 Some manufacturers recommend monitoring the pressure gradient across membrane oxygenators, which may be an early indication of oxygenator failure, although it is a rare event.62–64

Temperatures of the water entering heat exchangers must be monitored and carefully controlled to prevent blood protein denaturation and gaseous microemboli.65 During operations using deep hypothermia, changes in venous line temperatures reflect rates of temperature change in the patient, and monitoring arterial inflow temperature helps prevent brain hyperthermia during rewarming.

A low-level sensor with alarms on the venous reservoir and a bubble detector on the arterial line are additional safety devices sometimes used. A one-way valve is recommended in the purge line between an arterial filter/bubble trap and cardiotomy reservoir to prevent air embolism. Ultrasound transducers imbedded in the arterial perfusion tubing distal to the filter are now available to monitor low-level air entry into the circulation. Valves in the venous and vent lines protect against retrograde air entry into the circulation or in the arterial line to prevent inadvertent exsanguination.68

Automatic data collection systems are available for preoperative calculations and to process and store data during CPB.128 Computer systems for operating CPB are in development.129

Conduct of Cardiopulmonary Bypass

The Perfusion Team

Although the surgeon is directly responsible for the outcome of the operation, he or she needs a close working relationship with both the anesthesiologist and the perfusionist. These three principals must communicate freely, often, and candidly. Their overlapping and independent responsibilities relevant to CPB are best defined by written policies that include protocols for various types of operations and emergencies and by periodic multidisciplinary conferences. This teamwork is not unlike the communication advocated for the cockpit crew of commercial and military aircraft.

The surgeon determines the planned operation, target perfusion temperatures, methods of cardioplegia, cannulations, and anticipated special procedures. During operation the surgeon communicates the procedural steps involved in connecting and disconnecting the patient to CPB and interacts with the other principals to coordinate perfusion management with surgical exposure and working conditions. The perfusionist is responsible for setting up and priming the heart-lung machine, performing safety checks, operating the heart-lung machine, monitoring the conduct of bypass, monitoring anticoagulation, adding prescribed drugs, and maintaining a written perfusion record.

The anesthesiologist monitors the operative field, anesthetic state and ventilation of the patient, the patient's physiology, and conduct of perfusion. A vigilant anesthesiologist is the safety officer and often "troubleshooter" of these complex procedures and along with the surgeon is in the best position to anticipate, detect, and correct deviations from desired conditions. In addition the anesthesiologist provides TEE observations before, during, and immediately after bypass.

Assembly of Heart-Lung Machine

The perfusionist is responsible for setting up and preparing the heart-lung machine and all associated components necessary for the proposed operation. Most perfusionists use commercial, sterile, pre-prepared customized tubing packs that are connected to the various components that constitute the heart-lung machine. This dry assembly takes about 10 to 15 minutes, and a dry system can be kept in standby for up to 7 days. Once the system is primed with fluid, which takes about 15 minutes, it should be used within 8 hours to prevent malfunction of the oxygenator. After assembly, the perfusionist conducts a safety inspection and completes a written pre-bypass checklist.

Priming

Traditional adult extracorporeal perfusion circuits require 1.5 to 2.0 L of balanced electrolyte solution such as lactated Ringer's solution, Normosol-A, or Plasma-Lyte. Before connections are made to the patient, the prime is recirculated through a micropore filter to remove any residual particulate matter or air. In the average-sized adult, the priming volume represents approximately 30 to 35% of the patient's blood volume and reduces the hematocrit to about two-thirds of the preoperative value. In smaller patients or in the presence of peroperative anemia, banked blood may be added to the prime volume to raise the hematocrit to a predetermined minimum (eg, 25% or more), to achieve an acceptable resultant hemotocrit once CPB has been initiated. There is no consensus regarding the optimal hematocrit during CPB; most perfusates have hematocrits between 20 and 25% when used with moderate hypothermia (25 to 32°C). Dilution reduces perfusate viscosity, which is not a problem during clinical CPB, but also reduces oxygen-carrying capacity; mixed venous oxygen saturations less than 60% usually prompt either transfusion or increased pump flow.124 Sometimes 12.5 to 50 g of mannitol is added to stimulate diuresis and possibly minimize postoperative renal dysfunction.

Efforts to avoid the use of autologous blood include reducing the priming requirement of the machine by using smaller-diameter and shorter tubing lengths and operating the machine with minimal perfusate in the venous and cardiotomy reservoirs. This latter practice increases the risk of air embolism, the risk of which can be reduced by using collapsible reservoirs and reservoir level sensors that stop the pump. In recent years, smaller, more compact circuits have been designed to reduce the prime volume and subsequent hemodilution, reducing transfusion requirements and platelet consumption.130 Many of these circuits have totally removed the venous reservoir and used a variety of coated surfaces in an attempt to reduce hemodilution, avoid points of stasis and minimize activation of inflammation and coagulation cascades. A typical such mini-circuit is pictured in Fig. 12-7.

Autologous blood prime is another technique to minimize hemodilution, which displaces and then removes crystalloid prime by draining blood volume from the patient into the circuit just before beginning CPB.131 This method reduces perfusate volume, but phenylephrine may be required to maintain stable hemodynamics.131 The method reduces transfusions and does not affect clinical outcome.

The use of colloids (albumin, gelatins, dextrans, and hetastarches) in the priming volume is controversial.132 Although their use clearly minimizes the decrease in colloid osmotic pressure133 and may reduce the amount of fluid entering the extracellular space, any impact on clinical outcome remains unproved. Prospective clinical studies have failed to document significant clinical benefits with albumin,133 which is expensive and may have adverse effects.134 Hetastarch may contribute to postoperative bleeding.135 McKnight et al. found no influence of prime composition on postoperative nitrogen balance.136 Because of possible adverse effects, including neurologic deficits, the addition of glucose and/or lactate to the prime is generally avoided.137,138

Anticoagulation and Reversal

Porcine heparin (300 to 400 units/kg IV) is administered before arterial or venous cannulas are inserted, and CPB is not started until anticoagulation is confirmed by either an activated clotting time (ACT) or the Hepcon test. Although widely used, bovine heparin is more antigenic in inducing antiplatelet IgG antibodies than is porcine heparin.139 Although the distribution of intravenously administered heparin has been shown to be extremely rapid,140 in general, the anticoagulation effect is measured about 3 minutes after heparin administration. However, groups differ in the minimum ACT that is considered safe for CPB. The generally accepted minimum for ACT before initiation of CPB is greater than or equal to 400 seconds; however, many groups recommend 480 seconds141 because heparin only partially inhibits thrombin formation during CPB. More recently, in an attempt to reduce surgical bleeding, some centers have advocated accepting lower ACTs in the 300 range. Although early unpublished results may suggest that this can be done safely, it is still not generally accepted. Outside the United States, where aprotinin is still available, it is important to measure ACT with kaolin as opposed to celite, because celite may artifactually and erroneously increases the ACT. Failure to achieve a satisfactory ACT may result from either inadequate heparin dosage or low concentrations of antithrombin. If a total of 500 units/kg of heparin fails to adequately prolong ACT, antithrombin III should be administered to the patient either as fresh-frozen plasma or as recombinant antithrombin III when available142 to increase antithrombin concentrations to overcome "heparin resistance." Antithrombin III is a necessary cofactor that binds circulating thrombin; heparin accelerates this reaction a thousandfold. See Thrombosis and Bleeding for mangagement of patients with suspected or proved heparin-induced antiplatelet IgG antibodies and alternative anticoagulants to heparin.

During CPB, ACT or the Hepcon test is measured every 30 minutes. If ACT goes below the target level, more heparin is given. As a general rule, one-third of the initial total heparin bolus required for adequate anticoagulation is given every hour even when the ACT is within the normal range. The Hepcon test titrates the heparin concentration and is more reproducible than ACT, but ACT provides satisfactory monitoring of anticoagulation. Although excessively high concentrations of heparin (ACT >1000 s) may cause remote bleeding away from operative sites, low concentrations increase circulating thrombin concentrations and risk clotting within the extracorporeal perfusion circuit.

After the patient has successfully weaned from CPB and remains stable, 1 mg of protamine is given for each 100 units of heparin given in the initial bolus dose, but not to exceed 3 mg/kg. The heparin–protamine complex activates complement and may causes acute hypotension, which may be attenuated by the administration of calcium (2 mg/1 mg protamine). Once the administration of protamine has begun, it is generally recommended that the use of cardiotomy suction into the reservoir is discontinued because of the risk of generating clot within the circuit and losing the potential for emergency support should the patient become unstable. Rarely, protamine may cause an anaphylactic reaction in patients with antibodies to protamine insulin.143 This severe reaction may require urgently placing the patient back on CPB, although it may also be treating with resuscitation using epinephrine and immediate discontinuation of the protamine infusion. Neutralization of heparin is usually confirmed by an ACT or Hepcon test and more protamine (50 mg) is given if either test remains prolonged and bleeding is a problem. Heparin rebound is a term used to describe a delayed heparin effect because of release of tissue heparin after protamine is cleared from the circulation, particularly from heparin deposited in adipose tissues, and seen more often in obese patients. Although protamine is a mild anticoagulant at higher doses, one or two supplemental 25- to 50-mg doses can be given empirically if heparin rebound is suspected, or if the ACT remains elevated. It is also noted that the ACT can be elevated in the presence of significant thrombocytopenia, despite the full reversal of heparin. As a rule, the heart-lung machine should be available for unexpected decompensation and the need for urgent return to CPB until the wound is closed, the drapes are removed, and at many centers until the patient leaves the operating room.

Initiation of Cardiopulmonary Bypass

Once the appropriate cannulation has occurred and adequate anticoagulation has been confirmed, CPB is initiated at the surgeon's request with concurrence of the anesthesiologist and perfusionist. As the venous return enters the machine, the perfusionist progressively increases arterial flow while monitoring the patient's blood pressure and volume levels in all reservoirs. Six observations are critical:

1. Is venous drainage adequate for the desired flow?

2. Is pressure in the arterial line acceptable?

3. Is arterial blood adequately oxygenated?

4. Is systemic arterial pressure acceptable?

5. Is systemic venous pressure acceptable?

6. Is the heart adequately decompressed?

Once full stable cardiopulmonary bypass is established for at least 2 minutes, lung ventilation is discontinued, perfusion cooling may begin, and the aorta may be clamped for arresting the heart. Just as is seen with initiation of dialysis, it is not uncommon to see some vasodilation and early hypotension as the patient is first exposed to the artificial surfaces, particularly the oxygenator. This can usually be managed by the perfusionist with increased flows until the vasodilation resolves, although occassionally vasopressors such as neosynephrine may be transiently required.

Cardioplegia

Antegrade blood or crystalloid cardioplegia is administered directly into the aortic root at 60 to 100 mm Hg pressure proximal to the aortic cross-clamp by a dedicated cardioplegia roller pump (see Fig. 12-2). Blood entering the right atrium from the coronary sinus is captured by the right atrial or unsnared caval catheters. If the caval snares are tightened, the right atrium should be vented to prevent right ventricular distention. Many surgeons choose to monitor myocardial temperature and administer cardioplegia to cool the myocardium to a specific temperature range. Others deliver a specific amount of cardioplegia, or moniter the electrical activity to determine the delivered volume. With appropriate delivery of antegrade cardioplegia, the heart should usually arrest within 30 to 60 seconds, and failure to do so may indicate problems with delivery of the solution or unrecognized aortic regurgitation. Some surgeons monitor myocardial temperature or pH via direct needle sensors.144

The usual flow of retrograde cardioplegia is 200 to 400 mL/min at coronary sinus pressures between 30 and 50 mm Hg.145 Higher pressures may injure the coronary venous system119; low pressures usually indicate inadequate delivery owing to malposition of the catheter or leakage around the catheter cuff, but may also indicate a tear in the coronary sinus. Induction of electrical arrest is slower (2 to 4 minutes) than with antegrade delivery, and retrograde cardioplegia may provide incomplete protection of the right ventricle.117

Key Determinants of Safe Perfusion

The following offers rational guidelines for management of CPB, which uses manipulation of temperature, hematocrit, pressure, and flow rate to adequately support cellular metabolism during nonphysiologic conditions.

Blood Flow Rate

Under normal circumstances, basal cardiac output is determined by oxygen consumption, which is approximately 250 mL/min. It is impractical to measure oxygen consumption while on CPB, so a generally accepted flow rate at 35 to 37°C with a hematocrit of 25% is approximately 2.4 L/min/m2 in deeply anesthetized and muscle-relaxed patients. Hemodilution reduces blood oxygen content from approximately 20 to 10 to 12 mL/dL; consequently, flow rate must increase over resting normal cardiac output or oxygen demand must decrease. The resistance of venous catheters, turbulence, and loss of physiologic controls of the vasculature may also effect venous return and limit maximum pump flow.

Hypothermia reduces oxygen consumption by a factor of 0.5 for every 10°C decrease in temperature. However, at both normothermia and hypothermia maximal oxygen consumption falls with decreasing flow as described in the following equation:

Vo2 = 0.44 (Q − 62.7) ± 71.6

This relationship at various temperatures is depicted in Figure 12-8. For this reason Kirklin and Barratt-Boyes146 recommend that flows be reduced only to levels that permit at least 85% of maximal oxygen consumption. At 30°C this flow rate in adults is approximately 1.8 L/min/m2; at 25°C, 1.6 L/min/m2; and at 18°C, 1.0 L/min/m2.

As long as mean arterial pressure remains above 50 to 60 mm Hg (ie, above the autoregulatory range), cerebral blood flow is preserved even if systemic flow is less than normal. However, there is a hierarchal reduction of flow to other organs as total systemic flow is progressively reduced. First skeletal muscle flow falls, then abdominal viscera and bowel, and finally renal blood flow.

Pulsatile Flow

Theoretical benefits of pulsatile blood flow include increased transmission of energy to the microcirculation, which reduces critical capillary closing pressure, augments lymph flow, and improves tissue perfusion and cellular metabolism. Theoretically, pulsatile flow reduces vasocontrictive reflexes and neuroendocrine responses and may increase oxygen consumption, reduce acidosis, and improve organ perfusion. However, despite extensive investigation no one has convincingly demonstrated a benefit of pulsatile blood flow over nonpulsatile blood flow for short- or long-term CPB.71,147 Two studies reported the association of pulsatile flow with lower rates of mortality, myocardial infarction, and low cardiac output syndrome,148 but others failed to detect clinical benefits.149

Pulsatile CPB can reproduce the normal pulse pressure within the body, but is expensive, complicated, and requires a large-diameter aortic cannula. Higher nozzle velocities increase trauma to blood elements,150 and pulsations may damage micromembrane oxygenators.151 Thus for clinical CPB, nonpulsatile blood flow is an acceptable, nonphysiologic compromise with few disadvantages.

Arterial Pressure

Systemic arterial blood pressure is a function of flow rate, blood viscosity (hematocrit), and vascular tone. Perfusion of the brain is normally protected by autoregulation, but autoregulation appears to be lost somewhere between 55 and 60 mm Hg during CPB at moderate hypothermia and a hematocrit of 24%.84,152 Cerebral blood flow may still be adequate at lower arterial pressures,153 but the only prospective randomized study found a lower combined major morbidity/mortality rate when mean arterial pressure was maintained near 70 mm Hg (average 69 ± 7) rather than below 60 (average 52).154 In older patients, who may have vascular disease155 and/or hypertension, mean arterial blood pressure is generally maintained between 70 and 80 mm Hg at 37°C. Higher pressures are undesirable because collateral blood flow to the heart and lungs increases blood in the operative field.

Hypotension during CPB may be the result of low pump flow, aortic dissection, measurement error, or vasodilatation. Phenylephrine is most often used to elevate blood pressure, but arginine vasopressin (0.05 to 0.1 unit/min) has more recently been introduced. If anesthesia is adequate, hypertension can be treated with nitroprusside, an arterial dilator, or nitroglycerin, which predominantly dilates veins and pulmonary vessels.

Hematocrit

The ideal hematocrit during CPB remains controversial. Low hematocrits reduce blood viscosity and hemolysis, reduce oxygen-carrying capacity, and reduce the need for autologous blood transfusion. In general, viscosity remains stable when percent hematocrit and blood temperature (in degrees Celsius) are equal (ie, viscosity is constant at hematocrit 37%, temperature 37°C, or at hematocrit 20%, temperature 20°C). Hypothermia reduces oxygen consumption and permits perfusion at 26°C to 28°C with hematocrits between 18 and 22%, but at higher temperatures limits on pump flow may not satisfy oxygen demand.156,157 Hill158 found that hematocrit during CPB did not affect either hospital mortality or neurologic outcome, but DeFoe observed159 increasing hospital mortality with hematocrits below 23% during CPB; thus the issue remains unresolved.160 However, higher hematocrits (25 to 30%) during CPB appear justified157 in view of the increasing safety of autologous blood transfusion, improved neurologic outcomes with higher hematocrits in infant cardiac surgery,161 and more frequent operations near normothermia in older sicker patients.

Temperature

The ideal temperature for uncomplicated adult cardiac surgery is also an unsettled question.157 Until recently nearly all operations reduced body temperature to 25 to 30°C during CPB to protect the brain, support hypothermic cardioplegia, permit perfusion at lower flows and hematocrits, and increase the safe duration of circulatory arrest in case of emergency. Hypothermia, however, interferes with enzyme and organ function, aggravates bleeding, increases systemic vascular resistance, delays cardiac recovery, lengthens duration of bypass, increases the risk of cerebral hyperthermia, and is associated with higher levels of depression and anxiety postoperatively.162 Because the embolic risk of cerebral injury often is greater than perfusion risk, perfusion at higher temperatures (33 to 35°C), or "tepid" CPB, is recommended, in part because detrimental high blood temperatures are avoided during rewarming.163 Increasingly, efforts are made to avoid cerebral hyperthermia during and after operation, and one study suggests improved neuropsychometric outcomes if patients are rewarmed to only 34°C.164

pH/Pco2 Management

There are two strategies for managing pH/Pco2 during hypothermia: pH stat and alpha stat. During deep hypothermia and circulatory arrest (see the following) there is increasing evidence that pH-stat management may produce better neurologic outcomes during pediatric cardiac surgery.161 Alpha stat may be better in adults.165 pH stat maintains temperature-corrected pH 7.40 at all temperatures and requires the addition of Cc2 as the patient is cooled. Alpha stat allows the pH to increase during cooling so that blood becomes alkalotic. Cerebral blood flow is higher, and pressure is passive and uncoupled from cerebral oxygen demand with pH stat. With alpha stat, cerebral blood flow is lower, autoregulated, and coupled to cerebral oxygen demand.166

Arterial Pao2

Pao2 should probably be kept above 150 mm Hg to assure complete arterial saturation. Whether or not high levels (ie, >200 mm Hg) are detrimental has not yet been determined.

Glucose

Although Hill158 found no relationship between blood glucose concentrations during CPB and adverse neurologic outcome, others have been concerned that hyperglycemia (>180 mg/dL) aggravates neurologic injury138 and other morbidity/mortality,167 and recently many studies have documented the importance of tight glucose control in the prevention of infection, neurologic injury, renal and cardiac complications, as well as a reduction in ICU length of stay and overall mortality.168

Patient Monitors

Systemic arterial pressure is typically monitored by radial, brachial, or femoral arterial catheter. Central venous pressure is routinely monitored by a jugular venous catheter. Routine use of a Swan-Ganz pulmonary arterial catheter is controversial and not necessary for uncomplicated operations in low-risk patients.169 During CPB the pulmonary artery catheter should be withdrawn into the main pulmonary artery to prevent lung perforation and suture ensnarement.

Transesophageal Echocardiography

A comprehensive transesophageal echocardiography (TEE) examination 170 is an important monitor during most applications of CPB171 to assess catheter and vent insertion and location117,172,173; severity of regional atherosclerosis33; myocardial injury, infarction, dilatation, contractility, thrombi, and residual air; undiagnosed anatomic abnormalities170; valve function after repair or replacement; diagnosis of dissection41,174; and adequacy of de-airing at the end of CPB.175

Temperature

Bladder or rectal temperature is usually used to estimate temperature of the main body mass, but does not reflect brain temperature.176 Esophageal and pulmonary artery temperatures may be affected by local cooling associated with cardioplegia. The jugular venous bulb temperature is considered the best surrogate for brain temperature, but is more cumbersome to obtain.177 Nasopharyngeal or tympanic membrane temperatures are more commonly used, but tend to underestimate jugular venous bulb temperature during rewarming by 3 to 5°C.178 During rewarming, arterial line temperature correlates best with jugular venous bulb temperature.179

Neurophysiologic Monitoring

The efficacy of neurophysiologic monitoring during CPB is under investigation and not yet established as necessary. Techniques being investigated include jugular venous bulb temperature and saturation, transcranial Doppler ultrasound, near-infrared transcranial reflectance spectroscopy (NIRS), and the raw or processed electroencephalogram (EEG).180

Adequacy of Perfusion

During CPB oxygen consumption (Vo2) equals pump flow rate multiplied by the difference in arterial (Cao2) and venous oxygen content (Cvo2). For a given temperature, maintaining Vo2 at 85% predicted maximum during CPB assures adequate oxygen delivery (see Fig. 12-8).146 Oxygen delivery (Do2) equals pump flow multiplied by Cao2 and should be greater than 250 mL/min/m2 during normothermic perfusion.156 Mixed venous oxygen saturation (Svo2) assesses the relationship between Do2 and Vo2; values less than 60% indicate inadequate oxygen delivery. Because of differences in regional vascular tone, higher Svo2 does not assure adequate oxygen delivery to all vascular beds.181 Metabolic acidosis (base deficit) or elevated lactic acid levels may indicate inadequate perfusion, even in the face of "normal" Svo2 measurements.

Urine Output

Urine output is usually monitored but varies with renal perfusion, temperature, composition of the pump prime, diuretics, absence of pulsatility, and hemoconcentration. Urine production is reassuring during CPB and oliguria requires investigation.

Gastric Tonometry and Mucosal Flow

These Doppler and laser measurements gauge splanchnic perfusion but are rarely used clinically.

Weaning from Cardiopulmonary Bypass

Before stopping CPB the patient is rewarmed to 34 to 36°C, the heart is defibrillated if necessary, and the lungs are reexpanded and ventilated. The cardiac rhythm is monitored, and hematocrit, blood gases, acid-base status, and plasma electrolytes are reviewed. If the heart has been opened, TEE is recommended for detection and removal of trapped air before the heart is allowed to eject. Caval catheters are adjusted to ensure unobstructed venous return to the heart. If the need for inotropic drugs is anticipated, these are started at low flow rates. Vent catheters are removed, although sometimes an aortic root vent is placed on gentle suction to remove undiscovered air.

Once preparations are completed, the surgeon, anesthesiologist, and perfusionist begin to wean the patient off CPB. The perfusionist gradually occludes the venous line to allow filling of the right heart and ejection through the lungs to the left side, while simultaneously reducing pump input as cardiac rate and rhythm, arterial pressure and pulse, and central venous pressure are monitored and adjusted. Initially blood volume within the pump is kept constant, but as pump flow approaches zero, volume is added or removed from the patient to produce arterial and venous pressures within the physiologic ranges. During weaning, cardiac filling and contractility is often monitored by TEE, and intracardiac repairs and regional myocardial contractility are assessed. Pulse oximetry saturation near 100%, end-tidal CO2 greather than 25 mm Hg, and mixed venous oxygen saturation higher than 65% confirm satisfactory ventilation and circulation. When cardiac performance is satisfactory and stable, all catheters and cannulas are removed, protamine is given to reverse the heparin, and blood return from the surgical field is discontinued.

Once the patient is hemodynamically stable, as determined by surgeon and anesthesiologist, and after starting wound closure, the perfusate may be returned to the patient in several ways. The entire perfusate may be washed and returned as packed cells, excess fluid may be removed by a hemoconcentrator, or the perfusate, which still contains heparin, can be gradually pumped into the patient for hemoconcentration by the kidneys. Occasionally some of the perfusate must be bagged and given later. The heart-lung machine should not be completely disassembled until the chest is closed and the patient is ready to leave the operating room.

Special Topics

Special Applications of Extracorporeal Perfusion

Reoperations, surgery of the descending thoracic aorta, and minimally invasive procedures may be facilitated by surgical incisions other than midline sternotomy. These alternative incisions often require alternative methods for connecting the patient to the heart-lung machine. Some alternative applications of CPB are presented in the following.

Right Thoracotomy

Anterolateral incisions through the fourth or fifth interspaces provide easy access to the cavae and right atrium, adequate access to the ascending aorta, as well as exposure to the left atrium and mitral valve, but no direct access to the left ventricle. Adequate exposure of the ascending aorta is available for cross-clamping, aortotomy, and administration of cardioplegia by retracting the right atrial appendage. De-airing the left ventricle (eg, after mitral valve repair) is more difficult. External pads facilitate defibrillation.

Left Thoracotomy

Lateral or posterolateral incisions in the left chest are used for a variety of operations. Venous return may be captured by cannulating the pulmonary artery via a stab wound in the right ventricle, or by retrograde cannulation of the left pulmonary artery or cannulation of the left iliac or femoral vein. With iliac or femoral cannulation, venous return may be augmented by threading the cannula into the right atrium using TEE guidance.182 The descending thoracic aorta or left subclavian, iliac, or femoral arteries are accessible for arterial cannulation.

Left Heart Bypass

Left heart bypass uses the beating right heart to pump blood through the lungs to provide gas exchange.183 An oxygenator is not used and intake cannulation sites are exposed through a left thoracotomy. The left superior pulmonary vein–left atrial junction is an excellent cannulation site for capturing blood. The left atrial appendage can also be used, but may be more friable and therefore more difficult with which to work. The apex of the left ventricle is infrequently used because of the potential for myocardial injury. The tip of the intake catheter must be free in the left atrium and careful technique is required to avoid air entry during cannulation and perfusion. The extracorporeal circuit typically consists only of tubing and a centrifugal pump and does not include a reservoir, heat exchanger, or bubble trap. This reduces the thrombin burden and may permit reduced or no heparin if anticoagulation poses an additional risk (eg, in acute head injury). Otherwise, full heparin doses are recommended. The reduced perfusion circuit precludes the ability to add or sequester fluid, adjust temperature, or intercept systemic air emboli. Intravenous volume expanders may be needed to maintain adequate flows; temperature usually can be maintained without a heat exchanger.184

Full left heart bypass may be employed for left-sided coronary artery surgery by draining all of the pulmonary venous return out of the left atrium and leaving no blood for left ventricular ejection. If the heart fibrillates, blood can still passively pass through the right heart and lungs, but often an elevated central venous pressure is required.185

Partial left heart bypass is identical in configuration and cannulation to full left heart bypass and is used to facilitate surgery on the descending thoracic aorta. This accomplishes two goals by providing perfusion to the lower body beyond the aortic clamps, as well as allowing the perfusionist to remove preload as needed by increasing the flow, thereby controlling the perfusion pressure in the proximal aorta, preventing both hypotension, as well as hypertension and potential LV strain. The patient's left ventricle supplies blood to the aorta proximal to aortic clamps, and the circuit supplies blood to the distal body. Typically about two-thirds normal basal cardiac output (ie, 1.6 L/min/m2) is pumped to the lower body. Arterial pressure is monitored proximal (radial or brachial) and distal (right femoral, pedal) to the aortic clamps. Blood volume in the body and circuit is assessed by central venous pressure and TEE monitoring of chamber dimensions. Management is more complicated because of the single venous circulation and separated arterial circulations.183

Partial Cardiopulmonary Bypass

Partial CPB with an oxygenator is also used to facilitate surgery of the descending thoracic aorta. After left thoracotomy, systemic venous and arterial cannulas are placed as described in the preceding. The perfusion circuit includes a reservoir, pump, oxygenator, heat exchanger, and bubble trap. The beating left ventricle supplies the upper body and heart, so lungs must be ventilated and upper body oxygen saturation should be independently monitored. Blood flow to the separate upper and lower circulations must be balanced as described for partial left heart bypass.

Full Cardiopulmonary Bypass

Full CPB with peripheral cannulation is used when access to the chest is dangerous because of proximity of the heart, vital vessels (eg, mammary arterial graft), or pathologic condition (eg, ascending aortic mycotic aneurysm) abutting the anterior chest wall.3 The patient is supine and a complete extracorporeal perfusion circuit is prepared and primed. Venous cannulas may be inserted into the right atrium via the iliac or femoral vessels and/or the right jugular vein. The iliac, femoral, or axillary-subclavian arteries may be used for arterial cannulation. Initiation of CPB decompresses the heart, but profound cooling is usually deferred to keep the heart beating and decompressed until the surgeon can insert a vent catheter, unless the conduct and complexity of the operation dictate deep hypothermic circulatory arrest prior to dividing the sternum.

Femoral Vein to Femoral Artery Bypass

Femoral vein to femoral artery bypass with full CPB is used to initiate bypass outside the operating room for emergency circulatory assistance,3 supportive angioplasty,186 intentional (aneurysm repair) or accidental hypothermia. Femoral vessel cannulation is occasionally used during other operations to facilitate control of bleeding (eg, cranial aneurysm, tumor invading the inferior vena cava) or ensure oxygenation (eg, lung transplantation, upper airway reconstruction).

Cannulation for Minimally Invasive (Limited Access) Surgery

Off-pump coronary artery bypass (OP-CAB) describes construction of coronary arterial bypass grafts on the beating heart without CPB. Minimally invasive direct coronary artery bypass (MID-CAB) refers to coronary arterial bypass grafting with or without CPB through small, strategically placed incisions. Peripheral cannulation sites, described above, may be used, but often central cannulation of the aorta, atrium, or central veins is accomplished using specially designed or smaller cannulas placed through the operative incision or through a separate small incisions in the chest wall.187 Venous return may be augmented by applying negative pressure (see discussion of venous cannulation above); often soft tipped arterial catheters are used to minimize arterial wall trauma.20

The Port-Access System provides a means for full CPB, cardioplegia administration, and aortic cross-clamping without exposing the heart and can be used for both valvular and coronary arterial operations.173 Through the right internal jugular vein separate transcutaneous catheters are inserted into the coronary sinus for retrograde cardioplegia and the pulmonary artery for left heart venting. A multilumen catheter is inserted through the femoral artery and using TEE and/or fluoroscopy is positioned in the ascending aorta for arterial pump inflow, for balloon occlusion of the ascending aorta, and administration of antegrade cardioplegia into the aortic root. Venous return is captured by a femoral venous catheter advanced into the right atrium. The system allows placement of small skin incisions directly over the parts of the heart that require surgical attention.

Minimally invasive surgery using CPB is associated with potential complications that include perforation of vessels or cardiac chambers, aortic dissection, incomplete de-airing, systemic air embolism, and failure of the balloon aortic clamp. Because CO2 is heavier than air and more soluble in blood, the surgical field is sometimes flooded with CO2 at 5- to 10-L/min flow to displace air when the heart is open. The intra-aortic balloon occluder can leak, prolapse through the aortic valve, or move distally to occlude arch vessels. For safety the position of the occluding balloon is closely monitored by TEE, bilateral radial arterial pressures, and one of the following: transcranial Doppler ultrasound, cerebral near-infrared spectroscopy, or electroencephalogram.188

Deep Hypothermic Circulatory Arrest

Deep hypothermic circulatory arrest (DHCA) is commonly used for operations involving the aortic arch, a heavily calcified or porcelain aorta, thoracoabdominal aneurysms, pulmonary thromboendarterectomy, selected uncommon cardiovascular and neurologic procedures,189 and certain complex congenital heart procedures. The technology involves reducing body temperature to less than 20°C, arresting the circulation for a short period, and then rewarming to 37°C. Deep hypothermia reduces cerebral oxygen consumption (Fig. 12-9), and attenuates release of toxic neurotransmitters and reactive oxidants during ischemia and reperfusion.190

Because perfusion cooling produces differential temperatures within both the body and brain,176 more than one temperature is customarily monitored. Bladder, pulmonary artery, esophageal, or rectal temperatures are used to estimate body temperature. Nasopharyngeal and tympanic membrane temperatures are imperfect surrogates for mean brain temperature. Most surgical teams cool to either EEG silence, jugular venous saturation greater than 95%, or for at least 30 minutes before stopping circulation at nasopharyngeal or tympanic membrane temperatures below 20°C. Caloric exchange is proportional to body mass, rate of perfusion, and temperature differences between patient and perfusate; however, rates of perfusion cooling and rewarming are restricted (see the section on Heat Exchangers). Perfusion cooling is usually supplemented by surface cooling using hypothermia blankets and/or packing the head in ice. Hyperthermia is avoided by keeping arterial inflow temperature below 37°C during rewarming, and by avoiding gradients greater than 10° between the inflow blood temperature and the lowest monitored body temperature.

Changes in temperature affect acid-base balance, which must be monitored and managed during deep hypothermia. The pH-stat protocol (CO2 is added to maintain temperature corrected blood pH at 7.4) may be preferred over the alpha-stat protocol, which allows cold blood to become alkalotic. Compared with alpha-stat, pH-stat increases the rate and uniformity of brain cooling,191,192 slows the rate of brain oxygen consumption by 30 to 40% at 17°C,192 and improves neurologic outcomes in animal models161,193 and in infants,194 but not necessarily in adults.195 Hyperglycemia appears to increase brain injury and is avoided during deep hypothermia.196 The value of high-dose corticosteroids or barbiturates remains unproved.

The safe duration of circulatory arrest during deep hypothermia is unknown. In adults arrest times as short as 25 minutes are associated with poor performance on neuropsychologic tests of fine motor function and memory.197 Ergin198 found duration of arrest was a predictor of temporary neurologic dysfunction, which correlated with long-term neuropsychologic deficits.199 At 18°C, cerebral metabolism and oxygen consumption are 17 to 40% of normothermia200 and abnormal encephalographic patterns and cerebrovascular responses can be detected after 30 minutes of circulatory arrest.200 Most investigators,201 but not all202 report increased mortality and adverse neurologic outcomes after 40 to 65 minutes of circulatory arrest in adults. Most surgeons try to keep the period of arrest at less than 45 minutes and, if the operation allows, many perfuse for 10 to 15 minutes between serial arrest periods of 10 to 20 minutes. (For more details on DHCA, see Chapter 14.)

Antegrade and Retrograde Cerebral Perfusion

Antegrade cerebral perfusion is used in lieu of DHCA or as a supplement. Once the body has been appropriately cooled as for DHCA, the cerebral vessels can be cannulated separately and perfused together by a single pump203 or perfused collectively after a graft with a side branch is sewn to the top of the aortic arch from which the innominate, left carotid, and left subclavian arteries originate. Separate perfusion of separately cannulated vessels is rarely done. Perfusion is usually provided by a separate roller pump that receives blood from the arterial line. Line pressure is monitored and a microfilter may or may not be used. The cerebral vessels are collectively perfused with cold blood between 10 and 18°C and at approximate flows of 10 mL/kg/min; perfusion pressures are usually restricted to 30 to 70 mm Hg, though individual protocols vary widely.204 The adequacy of cerebral perfusion can be assessed by monitoring jugular venous saturation or near-infrared spectroscopy. Selective antegrade cerebral perfusion risks dislodging atheromatous emboli or causing air embolism, cerebral edema, or injury from excessive perfusion pressure.

Retrograde cerebral perfusion (RCP) was initially introduced in 1980 as emergency treatment for massive air embolism.205 Later, Ueda introduced continuous RCP for cerebral protection as an adjunct to deep hypothermic circulatory arrest during aortic surgery.206 During RCP and DHCA the superior vena cava is perfused at pressures usually between 25 and 40 mm Hg, temperatures between 8 and 18°C, and flows between 250 and 400 mL/min from a sideport off the arterial line, which is clamped downstream from the sideport. Some surgeons advocate much higher pressures and flows to compensate for runoff and have not shown detrimental effects.207 A snare is usually placed around the superior caval catheter cephalad to the azygous vein to reduce runoff. The IVC may or may not be occluded.208

Retrograde cerebral perfusion has been widely and safely used,207,209 but its effectiveness in protecting the brain is not clear.210 The method can wash out some particulate emboli entering from arteries, which is a major cause of brain injury after aortic surgery.211 However, it is not clear how adequately and completely all regions of the brain are perfused.210 Lin209 found cortical flows to be only 10% of control values. RCP slows but does not arrest the decrease in cerebral oxygen saturation203,207 and the decay in amplitude of somatosensory evoked potentials.212 Other clinical and animal studies have suggested RCP provides some cerebral protection over DHCA alone.207,209 A few studies report that antegrade cerebral perfusion provides better protection than the retrograde technique.203

Complications and Risk Management

Life-threatening incidents can occur in 0.4 to 2.7% of operations with CPB and the incidence of serious injury or death is between 0.06 and 0.08% (Table 12-4).61,92 Massive air embolism, aortic dissection, dislodgement of cannulas, and clotting within the circuit during perfusion are the principal causes of serious injury or death. Malfunctions of the heat exchanger, oxygenator, pumps, and electrical supply are the most common threatening incidents related to equipment. Others include premature takedown or clotting within the perfusion circuit.

Massive Air Embolism

The incidence of massive air embolism is between 0.003 to 0.007% with 50% of outcomes adverse.61,92 Air can enter any component of the perfusion circuit at any time during an operation if the integrity of the circuit is broken.213 Stopcocks, connections, vent catheters, empty reservoirs, pursestring sutures, cardioplegia infusion catheters, and unremoved air in opened cardiac chambers are the most common sources of air emboli. Uncommon sources include oxygenator membrane leaks, residual air in the circuit after priming, reversal of flow in venous, vent or arterial lines, and unexpected inspiration by the patient during cannula removal.

Massive air embolism during perfusion is a catastrophe, and management guidelines are evolving.14,205,213 Perfusion should stop immediately and clamps should be placed on both venous and arterial lines. Air in the circuit should be rapidly removed by recirculation and entrapment of all air in a reservoir or bubble trap. The patient should be immediately placed in steep Trendelenburg position and blood and air at the site of entry should be aspirated until no air is retrieved. TEE should be rapidly employed to search for air, but perfusion must resume promptly depending upon body temperature to prevent ischemic brain damage. Cooling to deep hypothermia should be considered to protect the brain and other organs while air is located and removed. As soon as possible, retrograde perfusion of the brain should be undertaken while the aortic arch is simultaneously aspirated with the patient in steep Trendelenburg position. Corticosteroids and/or barbiturates may be considered. Depending upon circumstances and availability, hyperbaric oxygen therapy may be helpful if patients can be treated within 5 hours of operation.214

Risk Management

Minimizing risks of extracorporeal perfusion requires strict attention to personnel training, preparation and training for emergencies, equipment function, and record keeping.14 All members of the operative team must be trained, certified, and recertified in their respective roles and participate in continuing education programs. A policy manual for the perfusion team and written protocols should be developed and continuously updated for various types of operations and emergencies. Emergency kits are prepared for out-of-operating-room (OR) crises. Adequate supplies are stocked in designated locations with sufficient inventory to support any operation or emergency for a specified period. An inventory of supplies is taken and recorded at regular intervals. Checklists are prepared and used for setting up the perfusion system and connecting to the patient. Equipment is inspected at regular intervals; worn, loose, or outdated parts are replaced; and preventive maintenance is provided and documented. New equipment is thoroughly checked before use and instructions are thoroughly digested by all user personnel. Safety alarms are optional; none replace the vigilance and attention of all OR personnel during an operation. Complete, signed written records are required for every perfusion; adverse events are recorded in a separate log and reviewed by the entire OR team. A continuous quality assurance program is desirable.215

During the procedure communication must be open among the surgeon, anesthetist, and perfusionist to coordinate activites. Statements are verbally acknowledged. Distractive conversations are discouraged. The entire OR team is committed to a zero-error policy, which can only be achieved by discipline and attention to details.216

Response of Humoral and Cellular Elements of Blood to Extracorporeal Circulation

Within the body the endothelial cell, the only surface in contact with circulating blood, simultaneously maintains the fluidity of blood and the integrity of the vascular system. This remarkable cell maintains a dynamic equilibrium by producing anticoagulants to maintain blood in a fluid state and generating procoagulant substances to enhance gel formation when perturbed. Blood proteins circulate as inert zymogens, which convert to active enzymes when stimulated. Likewise, blood cells remain quiescent until activated to express surface receptors and release proteins and enzymes involved in coagulation and inflammation. The continuous exposure of heparinized blood to the perfusion circuit and to cell tissues and fluid constituents of the wound during clinical cardiac surgery produces an intense thrombotic stimulus that involves both the tissue factor pathway (extrinsic coagulation pathway) in the wound and the contact and intrinsic coagulation pathways in the perfusion circuit. Thrombin is continuously generated and circulated despite massive doses of heparin in all applications of extracorporeal perfusion.217 This powerful enzyme along with tissue factor from the wound and many other cytokines also activate an inflammatory reaction, which can damage tissues and ultimately produce cell death by necrosis or apoptosis.

Thrombosis and Bleeding

Initial Reactions in the Perfusion Circuit

When heparinized blood contacts any biomaterial, plasma proteins are instantly adsorbed (<1 second) onto the surface to form a monolayer of selected proteins.218 Different biomaterials have different intrinsic surface activities for each plasma protein. The physical and chemical composition of the biomaterial surface determine the intrinsic surface activity of the biomaterial. Thus intrinsic surface activity differs among biomaterial surfaces, plasma proteins, and different bulk concentrations of plasma proteins. The composition of the protein monolayer is specific for the biomaterial and various concentrations of proteins in the plasma, but the topography of the adsorbed protein layer may not be uniform across the surface of the biomaterial.219 Thus it is not possible to predict the "thrombogenicity" of any biomaterial except by trial and error.

On most biomaterial surfaces fibrinogen is selectively adsorbed, but the adsorbed concentration of fibrinogen and other proteins may change over time.220 The complexity of blood–biomaterial interactions is further compounded by the fact that adsorbed proteins often undergo limited conformational changes221 that may expose "receptor" amino acid sequences that are recognized by specific blood cells or bulk plasma proteins.

Thus heparinized blood does not directly contact biomaterial surfaces in extracorporeal perfusion circuits, but contacts monolayers of densely packed, immobile plasma proteins arranged in undefined mosaics that differ between locations and possibly across time. All biomaterial surfaces, including heparin-coated surfaces, are procoagulant222; only the endothelial cell is truly nonthrombogenic (Fig. 12-10).

Anticoagulation

ECP and cardiopulmonary bypass (CPB) are not possible without anticoagulation; the large procoagulant surface quickly overwhelms natural circulating anticoagulants—antithrombin, proteins C and S, tissue factor pathway inhibitor, and plasmin— to produce thrombin and thrombosis within the circuit. Thrombin is produced in extracorporeal perfusion systems with small surface areas and high-velocity flow,223 but thrombosis may not be apparent if other procoagulants (eg, addition of blood from wounds) are absent. Generation of thrombin varies widely between applications of extracorporeal technology, but this powerful and potentially dangerous enzyme is produced whenever blood contacts a nonendothelial cell surface (Fig. 12-11).

During CPB and open heart surgery (OHS) high concentrations of heparin (3 to 4 mg/kg, initial dose) are needed to maintain the fluidity of blood. Heparin has both advantages and disadvantages; the most notable advantages are parenteral use, immediate onset of action, and rapid reversal by protamine or recombinant platelet factor 4.224 Heparin does not directly inhibit coagulation, but acts by accelerating the actions of the natural protease, antithrombin.225 Heparin-catalyzed antithrombin, however, does not inhibit thrombin bound to fibrin226 or factor Xa bound to platelets within clots227; thus, heparin only partially inhibits thrombin in vivo. Antithrombin primarily binds thrombin; its action on factors Xa and IXa is much slower. Heparin inhibits coagulation at the end of the cascade after nearly all other coagulation proteins have been converted to active enzymes. In addition, heparin to varying degrees activates several blood constituents: platelets,228 factor XII,229 complement, neutrophils, and monocytes.230 Thrombin concentrations cannot be measured in real time and only insensitive, indirect methods are available to regulate heparin anticoagulation in the operating room.231

Heparin is also associated with some clinical idiosyncrasies. In some patients recent, prolonged parenteral heparin may reduce antithrombin concentrations and produce heparin resistance.232 Insufficient antithrombin may also occur because of insufficient synthesis or increased consumption in cachectic patients and patients with advanced liver or renal disease. The deficiency in antithrombin prevents heparin from prolonging activated clotting times to therapeutic levels. In these patients fresh-frozen plasma or recombinant antithhrombin is needed to increase plasma antithrombin concentrations to inhibit thrombin. Heparin rebound is a delayed anticoagulant effect after protamine neutralization because of the rapid metabolism of protamine and delayed seepage of heparin into the circulation from lymphatic tissues and other deposits. Heparin is also associated with an allergic response in some patients that produces heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT). Lastly, heparin only partially suppresses thrombin formation during CPB and all applications of extracorporeal perfusion and mechanical circulatory and respiratory assistance despite doses two to three times those used for other indications (see Fig. 12-11).217

Potential alternatives for heparin during ECP include low molecular weight heparin, danaparoid (Organan), recombinant hirudin (Lepirudin), and the organic chemical, argatroban (Texas Biotechnology Corp.). All have important drawbacks and are approved for use in heparin-induced thrombocytopenia and in patients with circulating IgG anti-heparin–PF4 complex antibodies (see the following). Low molecular weight heparins have long half-lives in plasma (4 to 8 hours), require antithrombin as a cofactor, primarily inhibit factor Xa, and are not reversible by protamine.233 Danaparoid is a mixture of heparin sulfate, dermatan sulfate, and chrondroitin sulfate that catalyzes antithrombin to inhibit thrombin and factor Xa. The anticoagulant effect is long lasting (plasma half-life 4.3 hours)234 and is not reversed by protamine.

Recombinant hirudin (Lepirudin) is a direct inhibitor of thrombin, is effective rapidly, does not have an effective antidote, is monitored by the partial thromboplastin time, is cleared by the kidney, and has a relatively short half-life in plasma (40 minutes).235 This drug has been successfully used during CPB and open heart surgery, but in many instances bleeding after bypass has been troublesome and substantial. A newer drug is a semisynthetic bivalent thrombin inhibitor composed of 12 amino acids from hirudin.236 This drug, bivalirudin (Angiomax), has a shorter half-life than hirudin and therefore may be safer. Argatroban is also a direct thrombin inhibitor with rapid onset of action and short plasma half-life (40 to 50 minutes).237 Argatroban is metabolized in the liver and is without an antidote, but can be monitored with partial thromboplastin times or activated clotting times. At present there growing experience with the use of argatroban as an alternative anticoagulant when heparin cannot be used.238

Heparin-Associated Thrombocytopenia, Heparin-Induced Thrombocytopenia, and Heparin-Induced Thrombocytopenia and Thrombosis

Heparin-associated thrombocytopenia (HAT) is a benign, nonimmune, 5 to 15% decrease in platelet count that occurs within a few hours to 3 days after heparin exposure. Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis (HITT) are different manifestations of the same immune disease. Heparin binds to platelets in the absence of an antibody and releases small amounts of platelet factor 4 (as occurs in HAT). PF4 avidly binds heparin to form a heparin-PF4 (H-PF4) complex, which is antigenic in some people. In these individuals IgG antibodies to the H-PF4 complex are produced within 5 to 15 days after exposure to heparin and continue to circulate for approximately 3 to 6 months.239IgG-anti-H-PF4 antibodies plus H-PF4 complexes form HIT complexes, which unite IgG Fc terminals to platelet Fc receptors (Fig. 12-12). This binding strongly stimulates platelets to release more PF4.240 A self-perpetuating, accelerating cascade of platelet activation, release, and aggregation ensues. Since platelet granules contain several procoagulatory proteins (eg, thrombin, fibronectin, factor V, fibrinogen, von Willebrand factor), release also activates coagulation proteins to generate thrombin.

The intensity of the immune reaction varies between patients, but also varies by the indications for heparin use. Patients who do not have conditions that activate platelets have a low incidence of HIT after administration of heparin, because few PF4 molecules are available to form H-PF4 complexes. Large doses of heparin are given and huge numbers of platelets are activated during CPB. Thus after CPB, 50% of patients have IgG anti-H-PF4 antibodies; 2% have immune heparin-induced thrombocytopenia; and approximately 1% develop HITT.241 Because IgG antibodies are transient, a second heparin exposure 6 months after HIT is not likely to produce HIT or HITT,239 but will stimulate production of new IgG antibodies to the H-PF4 complex. The danger is a second heparin exposure when IgG anti-H-PF4 antibodies are still circulating.

IgG anti-H-PF4 antibodies are detected in two ways. The serotonin release test detects the release of radioactive serotonin from normal platelets washed by the patient's serum.242 An enzyme immunoassay measures IgG anti-H-PF4 antibodies directly. Both assays are equally sensitive in patients with clinical HIT, but the enzyme immunoassay is more sensitive in detecting IgG anti-H-PF4 antibodies in patients without other evidence of the disease.243

The clinical presentation of HIT may be insidious. If the platelet count was originally normal, the earliest sign is an abrupt decrease of at least 50% in platelet count (to <150,000/μL) in a patient who has had exposure to heparin within the past 5 to 15 days. This event is a preoperative stop sign for elective cardiac operations. After CPB, platelet counts less than 80,000/μL should trigger an order to stop all heparin, including heparin flushes, and obtain daily platelet counts. The patient should be thoroughly examined for deep vein thrombosis, extremity ischemia, stroke, myocardial infarction, or any evidence of intravascular thrombosis using ultrasound and appropriate radiographic technology. Any evidence of vascular thrombosis should prompt a plasma sample for IgG anti-H-PF4 antibodies. A positive antibody test confirms the diagnosis of HIT in patients with thrombocytopenia and HITT in those with either venous or arterial thrombosis or both. It is important to stress that HIT or HITT is a clinical diagnosis, and a positive antibody test is not required before stopping heparin.

Once the diagnosis of HIT or HITT is suspected, management must focus on prevention of further intravascular thrombosis. Bleeding is rarely the problem; intravascular thrombosis is. Neither heparin nor platelet transfusions should be given; platelet transfusions only add more PF4 if heparin and IgG anti-H-PF4 antibodies are still circulating. If heparin is proven absent from the circulation, platelet transfusions may be used very cautiously if the patient has significant nonsurgical bleeding. Surgical measures to reopen thrombosed large arteries are usually futile because the platelet-rich thrombus (white clot) often extends into small arteries and arterioles.

Modern management also includes full anticoagulation with recombinant hirudin (Lepirudin), argatroban, or possibly bivalirudin to prevent further extension of thrombosis or development of clinical intravascular thrombosis. This may occur in 40 to 50% of patients with HIT who are treated only with heparin cessation.244 At present there is little experience with argatroban in cardiac surgical patients with HITT, but the drug is a direct thrombin inhibitor, has attractive pharmokinetics, and is approved for patients with HITT.245 Full anticoagulation with hirudin in fresh postoperative cardiac surgical patients is recommended, but the safety zone between bleeding and thrombosis is narrow. The patient must be carefully monitored for pericardial tamponade and signs of hidden bleeding. Hirudin is monitored by aPTT and the range used is similar to that with intravenous heparin. Dose must be reduced in patients with renal failure because the kidney clears the drug. Argatroban is sometimes a better choice, but it should be remembered that it is difficult to manage in the presence of liver disease because it is metabolized in that organ. In most patients oral anticoagulation with warfarin is started at the same time as intravenous hirudin.

Emergency or urgent open heart surgery with CPB using hirudin is possible in patients with circulating IgG anti-HPF4 antibodies. The therapeutic level of drug should be between 3.5 and 4.5 μg/mL during CPB.246 Greinacher recommends bolus doses of 0.25 mg/kg IV and 0.2 mg/kg in the priming volume followed by an infusion of 0.5 mg/min until 15 minutes before stopping CPB. At that time 5 mg of hirudin is added to the perfusate to prevent clotting within the heart-lung machine.

Coagulation and Extracorporeal Perfusion: Thrombin Generation

Generation of thrombin during cardiopulmonary bypass and other applications of extracorporeal circulatory technology is the cause of the thrombotic and bleeding complications associated with ECP. Theoretically, if thrombin formation could be completely inhibited during ECP, the consumptive coagulopathy, which consumes coagulation proteins and platelets and causes bleeding complications, would not occur.

Thrombin generation and the fibrinolytic response primarily involve the extrinsic and intrinsic coagulation pathways, the contact and fibrinolytic plasma protein systems, and platelets, monocytes, and endothelial cells.

Contact System

The contact system includes four primary plasma proteins—factor XII, prekallikrein, high molecular weight kininogen (HMWK), and C-1 inhibitor and is activated during CPB and clinical cardiac surgery.247 This system is involved in complement and neutrophil activation and the inflammatory response to ECP, but is not involved in thrombin formation in vivo.

Intrinsic Coagulation Pathway

The intrinsic coagulation pathway probably does not generate thrombin in vivo, but does initiate thrombin formation when blood contacts nonendothelial cell surfaces such as perfusion circuits.248

Extrinsic (Tissue Factor) Coagulation Pathway

The extrinsic coagulation pathway is the major coagulation pathway in vivo and is a major source of thrombin generation during CPB and clinical cardiac surgery.249,250 Exposure of blood to tissue factor by direct contact in the wound or by wound blood aspirated into the ECP circuit initiates the extrinsic coagulation pathway.251 Tissue factor (TF) is a cell-bound glycoprotein that is constitutively expressed on the cellular surfaces of fat, muscle, bone, epicardium, adventia, injured endothelial cells, and many other cells except pericardium.252 Plasma TF associated with wound monocytes is a second source of TF and may be an important source during CPB and clinical cardiac surgery.253

Common Coagulation Pathway

Factor Xa is the gateway protein of the common coagulation pathway. Factor Xa slowly cleaves prothrombin to α-thrombin, the active enzyme, and a fragment, F1.2, and is the major pathway producing thrombin.251 F1.2 is a useful marker of the reaction.

Thrombin

Thrombin is a powerful enzyme that accelerates its own formation by several feedback loops.254 Thrombin is the major activator of factor XI and the exclusive activator of factor VIII in the intrinsic pathway. Thrombin is a secondary activator of factor VII, but once formed may be the most important activator in the wound.

Thrombin has both procoagulant and anticoagulant properties.254 Thrombin is the enzyme that cleaves fibrinogen to fibrin and in the process creates two fragments, fibrinopeptides A and B. Thrombin activates platelets via the platelet thrombin receptor and thus may be the major agonist for platelets both in the wound and in the perfusion circuit. Thrombin also activates factor XIII to cross-link fibrin to an insoluble form and attenuate fibrinolysis.

Thrombin also stimulates the production of anticoagulants. Surface glycosaminoglycans, such as heparan sulfate, inhibit thrombin and coagulation via antithrombin. Thrombin stimulates endothelial cells to produce tissue plasminogen activator, t-PA, which is the major enzyme that cleaves plasminogen to plasmin, and initiates fibrinolysis.

Thrombin Generation during Extracorporeal Perfusion

All applications of extracorporeal perfusion and exposure of blood to nonendothelial cell surfaces generate thrombin.217 F1.2 is a protein fragment that is formed when prothrombin is cleaved to thrombin; thus F1.2 is a measure of thrombin generation but not of thrombin activity. F1.2 and thrombin-antithrombin (TAT) complex increase progressively during clinical cardiac surgery with CPB, during applications of circulatory assist devices255 and during extracorporeal life support (ECLS) (Fig. 12-13). The amount of thrombin produced seems to vary with the intensity of the stimuli for thrombin production and may vary with age, comorbid disease, and clinical health of the patient. Complex cardiac surgery that requires several hours of CPB produces more F1.2 than short procedures with minimal exposure of circulating blood to the wound.256 Thrombin generation varies with the amount and type of anticoagulant used; surface area of the blood–biomaterial interface; duration of exposure to the surface; turbulence, stagnation, and cavitation within perfusion circuits; and to a lesser degree temperature and the "thromboresistant" characteristics of biomaterial surfaces.257

For many years blood contact with the biomaterials of the perfusion circuit was thought to be the major stimulus to thrombin formation during CPB and OHS. Increasing evidence indicates that the wound is the major source of thrombin generation during CPB and clinical cardiac surgery. This understanding has encouraged development of strategies to reduce the amounts of circulating thrombin during clinical cardiac surgery by either discarding wound blood258 or exclusively salvaging red cells by centrifugation and washing in a cell saver. The reduced thrombin formation in the perfusion circuit has also supported strategies for reducing the systemic heparin dose during first-time coronary revascularization procedures using heparin-bonded circuits.259 Although there is no good evidence that heparin-bonded circuits reduce thrombin generation, there is strong evidence that discarding wound plasma or limiting exposure of circulating blood to the wound (eg, less bleeding in the wound) does reduce the circulating thrombin burden.260

Cellular Procoagulants and Anticoagulants

Platelets

Platelets are activated by thrombin, contact with the surface of nonendothelial cells, heparin, and platelet-activating factor produced by a variety of cells during all applications of extracorporeal perfusion and/or recirculation of anticoagulated blood that has been exposed to a wound. Circulating thrombin and platelet contact with surface-adsorbed fibrinogen in the perfusion circuit are probably the earliest and strongest agonists. Circulating thrombin, although rapidly inhibited by antithrombin, is a powerful agonist and binds avidly to two specific thrombin receptors on platelets: PAR-1 and GPIbα.261 As CPB continues, complement, plasmin, hypothermia, epinephrine, and other agonists also activate platelets and contribute to their loss and dysfunction.

The initial platelet reaction to agonists is shape change. Circulating discoid platelets extend pseudopods, centralize granules, express GPIb and GPIIb/IIIa receptors,262 and secrete soluble and bound P selectin receptors from alpha granules.263 GPIIb/IIIa (αIIb β3) receptors almost instantaneously bind platelets to exposed binding sites on the α- and γ-chains on surface-adsorbed fibrinogen (Fig. 12-14),264 but the rough surfaces accumulate more platelets than smooth surfaces. Platelet adhesion and aggregate formation reduce the circulating platelet count, which is already reduced by dilution with pump priming solutions.

Plasma fibrinogen forms bridges between platelets expressing GPIIb/IIIa receptors to produce circulating platelet aggregates. Platelet bound P-selectin binds platelets to monocytes and neutrophils to form aggregates.265 During ECP the circulating platelet pool is reduced by dilution, adhesion, aggregation, destruction, and consumption. The platelet mass consists of a reduced number of morphologically normal platelets, platelets with pseudopod formation, new and larger platelets released from megakaryocytes, partially and completely degranulated platelets. Most of the circulating platelets appear structurally normal, but bleeding times increase and remain prolonged for several hours after protamine.266 The functional state of the circulating intact platelet during and early after CPB is reduced, but it is not clear whether this functional defect is intrinsic or extrinsic to the platelet. Flow cytometry studies of circulating intact platelets show little change in platelet membrane receptors.267

Monocytes

In the wound with calcium present, monocytes associate with plasma tissue factor to rapidly accelerate the conversion of factor VII to factor VIIa.268 This association is specific for monocytes as the reaction is essentially nil for platelets, neutrophils, and lymphocytes—and does not occur if monocytes, plasma tissue factor, or factor VII is not present. The major sources of tissue factor in the wound are the combination of monocytes, plasma tissue factor, and cell-bound tissue factor.

Endothelial Cells

Endothelial cells, charged with maintaining the fluidity of circulating blood and the integrity of the vascular system, are activated during CPB and clinical cardiac surgery by thrombin, C5a, IL-1, and TNF-α.269 Endothelial cells produce both procoagulants and anticoagulants. Procoagulant activities of endothelial cells include expression of tissue factor and production of a host of procoagulant proteins.270 Anticoagulant activities of endothelial cells include the production of tissue plasminogen activator (t-PA), heparin sulfate, tissue factor inhibitor protein, prostacyclin, nitric oxide, and adenosine.271

Fibrinolysis

Circulating thrombin activates endothelial cells to produce tissue plasminogen activator (t-PA), which binds avidly to fibrin.272 Endothelial cells are the principal source of t-PA.273 The combination of t-PA, fibrin, and plasminogen cleaves plasminogen to plasmin; plasmin cleaves fibrin. This reaction produces the protein fragment, D-dimer, which is a useful marker of fibrinolysis, and a marker of thrombin activity because fibrin is cleaved from fibrinogen by thrombin.274

Fibrinolysis is controlled by native protease inhibitors, α2-antiplasmin, α2-macroglobulin, and plasminogen activator inhibitor-1.274 Alpha 2-antiplasmin rapidly inhibits unbound plasmin, preventing the enzyme from circulating, but poorly inhibits plasmin bound to fibrin.

Consumptive Coagulopathy

Simultaneous and ongoing thrombin formation and fibrinolysis is by definition a consumptive coagulopathy275 and is present in all applications of ECP. In the normal state the fluidity of blood and the integrity of the vascular system are established and maintained by an equilibrium between procoagulants favoring clot and anticoagulants favoring liquidity (Fig. 12-15A). Blood contact with ECP systems and the wound disrupts this equilibrium to produce a massive procoagulant stimulus that overwhelms natural anticoagulants; therefore, an exogenous anticoagulant, heparin, is required for nearly all applications of ECP (Fig. 12-15B). Exceptions are only possible in applications that produce a relatively weak procoagulant stimulus and a minimal thrombin burden that can be contained by natural anticoagulants. Surgeons must realize that any blood exposure to nonendothelial cell surfaces, including prosthetic heart valves, produces a procoagulant stimulus whether or not a clot is produced. Except for the healthy endothelial cell, no nonthrombogenic surface exists.

This concept of an equilibrium between procoagulants and anticoagulants is helpful in managing the thrombotic and bleeding complications associated with all applications of ECP. During ECP procoagulant stimuli, manifested by thrombin formation that is not measurable in real time, must be balanced by either increased anticoagulation or a reduction in the thrombin burden to maintain equilibrium. After ECP, anticoagulants must be inhibited to avoid excessive bleeding. During consumptive coagulopathy, coagulation proteins and platelets are consumed and may become too deficient to generate thrombin and fibrin-platelet clots. In cardiac surgical patients many additional variables affect the coagulation equilibrium and impact the availability of coagulation proteins and functional platelets. These variables include the quantity of blood in contact with the wound; surface area of the perfusion system; duration of perfusion; circulating anticoagulants; and to lesser degrees temperature and the rheology and biomaterials of the perfusion system. Patient factors also affect the coagulation equilibrium; these include age, infection, history or presence of cardiogenic shock, massive blood losses and transfusions, platelet coagulation deficiencies, fibrinolysis, liver disease, cachexia, reoperation, and hypothermia.

Management of Bleeding

The cornerstone of bleeding management is meticulous surgical hemostasis during all phases of an operation. The surgical techniques, topical agents, and customary drugs used do not need reiteration for trained surgeons. Most cardiac surgical operations involving CPB are accompanied by net blood losses between 200 to 600 mL. Reoperations; complex procedures; prolonged (>3 hours) cardiopulmonary bypass; and patient factors listed above may be associated with excessive and ongoing blood losses. Most surgeons use an antifibrinolytic, such as tranexamic acid or epsilon amino caproic acid, to reduce fibrinolysis in prolonged or complex operations. Problem patients who bleed excessively after heparin neutralization require an attempt to rebalance procoagulants and anticoagulants to near normal, pre–CPB concentrations.

The most useful tests in the operating room are an activated clotting time or a protamine titration test to assess the presence of heparin; prothrombin time to uncover deficiency in the extrinsic coagulation pathway; and platelet count. If heparin is neutralized, the partial thromboplastin time may be measured to assess possible deficiency of coagulation proteins. Other tests such as measurements of fibrinogen, template bleeding time, and the thromboelastograph are controversial and/or difficult to obtain. Platelet counts below 80,000 to 100,000/μL should initiate platelet transfusions in bleeding patients, except those with IgG anti-H-PF4 antibodies, to add functioning platelets to the mass of partially dysfunctional platelets.

Measurements of F1.2 and D-dimer are two tests that can be very helpful and probably should be made available on an emergency basis in hospitals that perform complex procedures and offer mechanical circulatory and respiratory assistance. F1.2 measures thrombin formation by factor Xa, and if absent or low, there may be a deficiency in the concentrations of coagulation proteins; fresh-frozen plasma is needed. If F1.2 and D-dimer (a measurement of fibrinolytic activity) are both elevated, thrombin is being formed and an antifibrinolytic (Tranexamic acid or epsilon amino caproic acid) is needed to neutralize plasmin. If both markers or F1.2 remain elevated after the antifibrinolytic drug, this indicates continuing thrombin generation, and the cause (eg, infection usually) should be aggressively treated with antibiotics. Some thrombin is needed to stop bleeding, but excessive thrombin production feeds the consumptive coagulopathy. As with diffuse intravascular coagulopathy,275 no guaranteed therapeutic recipe is known; success requires patience, persistence, and judicious use of platelets, antifibrinolytics, specific clotting factors, and replacement transfusions to rebalance the coagulation equilibrium at near normal concentrations of the constituents.

The Inflammatory Response

Primary Blood Constituents

Complement

The complement system constitutes a group of more than 30 plasma proteins that interact to produce powerful vasoactive anaphylatoxins, C3a, C4a, and C5a, and the terminal complement cytotoxic complex, C5b-9.276 Complement is activated by three pathways, but only the classical and alternative pathways are involved in cardiopulmonary bypass. Direct contact between heparinized blood and the synthetic surfaces of the extracorporeal perfusion circuit activates the contact plasma proteins and the classical complement pathway. Activation of C1, possibly by activated factor XIIa, sequentially activates C2 and C4 to form C4b2a (classical C3 convertase) that cleaves C3 to form C3a and C3b (Fig. 12-16).

Generation of C3b activates the alternative pathway, which involves factors B and D in the formation of C3bBb, which is the alternative pathway C3 convertase that cleaves C3 to form C3a and C3b (see Fig. 12-16). Whereas the classical pathway proceeds in sequential steps, the alternative pathway contains a feedback loop that greatly amplifies cleavage of C3 by membrane-bound C3 convertase to membrane-bound C3b and C3a. During CPB complement is largely activated by the alternative pathway.277

The complement system is activated at three different times during CPB and cardiac surgery: during blood contact with nonendothelial cell surfaces278 and wound exudate–containing tissue factor279; after protamine administration and formation of the protamine–heparin complex280; and after reperfusion of the ischemic, arrested heart.281 CPB and myocardial reperfusion activate complement by both the classical and alternative pathways; the heparin-protamine complex activates complement by the classical pathway.

The two C3 convertases effectively merge the two complement pathways by producing C3b, which activates C5 to C5a and C5b (see Fig. 12-16). C3a and C5a are potent vasoactive anaphylatoxins. C5a, which avidly binds to neutrophils and therefore is difficult to detect in plasma, is the major agonist. C3b acts as an opsonin, which binds target cell hydroxyl groups and renders them susceptible to phagocytic cells expressing specific receptors for C3b.282,283 C5b is the first component of the terminal pathway that ultimately leads to formation of the membrane attack complex, C5b-9. In prokaryotic cells like erythrocytes, C5b-9 creates transmembrane pores, which cause death by intracellular swelling after loss of the intracellular/interstitial osmotic gradient. In eukaryotic cells, deposits of C5b-9 may not be immediately lethal but may eventually cause injury mediated by release of arachidonic acid metabolites (thromboxane A2, leukotrienes) and oxygen free radicals by macrophages and neutrophils, respectively.284

Neutrophils

Neutrophils are strongly activated during cardiopulmonary bypass (Fig. 12-17).285 The principal agonists are kallikrein and C5a produced by the contact and complement systems. Neutrophils are recruited to localized areas of injury or inflammation by chemokines, complement proteins (C5a), IL-1β, TNF-α, and adhesion molecules. During CPB thrombin stimulates endothelial cell production of platelet activating factor (PAF).286 Thrombin and PAF cause rapid expression of P-selectin by endothelial cells.287 Regional vasoconstriction mediated by PAF reduces blood flow rates within local vascular beds to allow neutrophils to marginate near endothelial cell surfaces. P-selectin weakly binds to neutrophils288; selectin binding causes the slowly passing neutrophils to roll and eventually stop (Fig. 12-18).289 Stronger adherence is produced by intracellular adhesion molecule-1 (ICAM-1) expressed on endothelial cells, which binds β2 neutrophil integrins, principally CD11b/CD18. These adhesion molecules from the immunoglobulin superfamily completely stop neutrophils and the process of transmigration begins in response to chemoattractants and cytotoxins produced in the extravascular space.290 This trafficking is strongly regulated by IL-8 produced by neutrophils, macrophages, and other cells.291

Using pseudopods and following the scent of complement proteins (C5a, C3b) and IL-8, neutrophils arrive at the scene of inflammation to begin the process of phagocytosis and release of cytotoxins. Organs and tissues experience periods of ischemia followed by reperfusion (lung, heart, brain) during CPB, and as a result express adhesion receptors and reactive oxidants, and are sources of neutrophil chemoattractants.292 Neutrophils vary considerably among individuals in expression of adhesive receptors293 and responsiveness to chemoattractants during CPB. The presence of diabetes, oxidative stress, and perhaps genetic factors (see the following) influences expression of cellular and soluble adhesive receptors and cytokines, which affect neutrophil adhesion and release of granule contents. Neutrophils contain a potent arsenal of proteolytic and cytotoxic substances. Azurophilic granules contain lysozyme, myeloperoxidase, cationic proteins, elastase, and collagenases.294 Activated neutrophils, in a "respiratory burst," also produce cytotoxic reactive oxygen and nitrogen intermediates including superoxide anion, hydrogen peroxide, hydroxyl radicals, singlet oxygen molecules. Finally, neutrophils produce arachidonate metabolites, prostaglandins, leukotrienes, and platelet-activating factor. During CPB these vasoactive and cytotoxic substances are produced and released into the extracellular environment and circulation. Circulation of these substances mediates many of the manifestations of the "whole body inflammatory response" or "systemic inflammatory response syndrome" (SIRS) associated with CPB and clinical cardiac surgery.295

Monocytes

Monocytes and macrophages (tissue monocytes) are relatively large, long-lived cells that are involved in both acute and chronic inflammation. Monocytes respond to chemical signals, are mobile, phagocytize microorganisms and cell fragments, produce and secrete chemical mediators, participate in the immune response, and generate cytotoxins.296 Monocytes are activated during CPB and have a major role in thrombin formation. Monocytes also produce and release many inflammatory mediators during acute inflammation, including proinflammatory cytokines, reactive oxygen and nitrogen intermediates, and prostaglandins.

Endothelial Cells

Endothelial cells are activated during CPB and OHS by a variety of agonists.297 The principal agonists for endothelial cell activation during CPB are thrombin, C5a, and the cytokines IL-1β and TNF-α. IL-1β and TNF-α induce the early expression of P-selectin and the later synthesis and expression of E-selectin, which are involved in the initial stages of neutrophil and monocyte adhesion. The two cytokines also induce expression of ICAM-1 and VCAM-1, which firmly bind neutrophils and monocytes to the endothelium and initiate leukocyte trafficking to the extravascular space (see Fig. 12-18). Experimentally ICAM-1 is upregulated during CPB in pulmonary vessels298 and there is evidence that selectins are upregulated during CPB and in myocardial ischemia-reperfusion sequences. IL-1β and TNF-α induce endothelial cell production of the chemotactic proteins IL-8 and MCP-1, and induce production of PGI2 (prostacyclin) by the cyclooxygenase pathway and NO by NO synthase. These two vasodilators reduce shear stress and increase vascular permeability and therefore enhance leukocyte adhesion and transmigration.

Platelets

Platelets are probably initially activated during CPB by thrombin, which is the most potent platelet agonist. Plasma epinephrine, PAF, vasopressin, from other cells, and internally generated thromboxane A2 contribute to activation as CPB continues. Platelets possess several protease-activated receptors to most of these agonists and to collagen, which has an important role in adhesion and thrombus formation. Platelets contribute to the inflammatory response by synthesis and release of eicosanoids299; serotonin from dense granules; chemokines, and other proteins.300 Platelets also produce and release acid hydrolases from membrane-bound lysozymes. Platelet-secreted cytokines may be particularly involved in the inflammatory response to CPB because of strong activation of platelets in both the wound and perfusion circuit.

Other Mediators of Inflammation

Anaphylatoxins

The anaphylatoxins C3a, C4a, and C5a are bioactive protein fragments released by cleavage of complement proteins C3, C4, and C5. These fragments have potent proinflammatory and immunoregulatory functions and contract smooth muscle cells, increase vascular permeability, serve as chemoattractants, and in the case of C5a, activate neutrophils and monocytes.301 Anaphylatoxins contribute to increased pulmonary vascular resistance, edema, and neutrophil sequestration and an increase in extravascular water during CPB. The duration of postoperative ventilation directly correlates with plasma C3a concentrations.302 C3a and C5a are important mediators in ischemia/reperfusion injuries.

Cytokines

Cytokines are small, cell-signaling peptides produced and released into blood or the extravascular environment by both blood and tissue cells. Cytokines stimulate specific receptors on other cells to initiate a response in that cell. All blood leukocytes and endothelium produce cytokines, but many tissue cells including fibroblasts, smooth muscle cells and cardiac monocytes also produce cytokines.303 IL-1β and TNF-α are early response cytokines that are produced by macrophages. These proteins stimulate surrounding cells to produce chemokines. The main anti-inflammatory cytokine observed during CPB is IL-10, which inhibits the production of chemokines from leukocytes.304 Proinflammatory cytokines increase during and after cardiac surgery using CPB with peak concentrations occurring 12 to 24 hours after CPB305 (Fig. 12-19). Some of the variation in measurements between studies also may be caused by patient factors such as age, left ventricular function, and genetic factors.306

Reactive Oxidants

Neutrophils, monocytes, and macrophages produce reactive oxidants, which are cytotoxic inside the phagosome, but act as cytotoxic mediators of acute inflammation outside. Four enzymes generate a large menu of reactive oxidants: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, superoxide dismutase, nitric oxide synthase, and myeloperoxidase.307 The four products produced by these enzymes, O2, H2O2, NO, and HOCL, generate all reactive oxidants from nonenzymatic reactions with other molecules or ions.

Endotoxins

Endotoxins, including lipopolysaccharides, and fragments of bacteria that are powerful agonists for complement, neutrophils, monocytes, and other leukocytes.308 Endotoxins have been detected during CPB and after aortic cross-clamping.309 Sources include contaminants within sterilized infusion solutions, the bypass circuit, and possibly the gastrointestinal tract owing to changes in microvascular intestinal perfusion, which may translocate bacteria.310

Metalloproteinases

CPB induces the synthesis and release of matrix metalloproteinases, 311 which are one of the four major classes of mammalian proteinases. These proteolytic enzymes have a major role in degradation of collagens and proteins in the pathogenesis of atherosclerosis and postinfarction left ventricular remodeling. The significance and possible injury produced by activation of these interstitial degradation enzymes over the long term remain to be determined.

Control of the Acute Inflammatory Response to Cardiopulmonary Bypass

Off-Pump Cardiac Surgery

Myocardial revascularization without either CPB or cardioplegia reduces the acute inflammatory response, but does not prevent it.312 The response to surgical trauma, myocardial ischemia, manipulation of the heart, pericardial suction, heparin, protamine, other drugs, and anesthesia activates the extrinsic clotting system and produces an increase in the markers of acute inflammation, C3a, C5b-9, proinflammatory cytokines (TNF-α, il-6, IL-9), neutrophil elastase, and reactive oxidants, but the magnitude of the response is significantly less than that observed with CPB.313 Although it has not been shown that the attenuated acute inflammatory response directly reduces organ dysfunction, elderly patients, and those with reduced renal and pulmonary function often tolerate off-pump surgery with less morbidity and mortality than patients created with CPB.314

Perfusion Temperature

Release of mediators of inflammation is temperature sensitive. Normothermic CPB increases the release of cytokines and other cellular and soluble mediators of inflammation,312 whereas hypothermia reduces production and release of these mediators until rewarming begins.315 Perfusion at tepid temperatures between 32 and 34oC is a reasonable compromise for many operations requiring 1 to 2 hours of CPB.316

Perfusion Circuit Coatings

Ionic- or covalent-bonded heparin perfusion circuits are the most widely used surface coatings and are often combined with reduced doses of systemic heparin in first-time myocardial revascularization patients.317 It is well established that heparin is an agonist for platelets, complement, factor XII, and leukocytes, but there is no reproducible evidence that heparin coating either produces a nonthrombogenic surface or reduces activation of the clotting cascade.318 Clinical trials that have combined heparin-coated circuits with reduced systemic heparin and exclusion of field-aspirated blood from the perfusion circuit have demonstrated significant clinical benefits319 (Fig. 12-20). New surface coatings are being developed or undergoing clinical studies.320 In clinical trials these surface coatings significantly reduced platelet loss and granule release, and reduced markers of thrombin generation.320,321 PMEA (poly-2- methylethylacrylate) is another manufactured surface coating designed to reduce surface adsorption of plasma proteins. Laboratory studies show reduced surface adsorption of fibrinogen and reduced bradykinin and thrombin generation in pigs.321 Clinical studies show significant reductions in C3a, C4D, and neutrophil elastase, but ambivalent effects on IL-6 and platelets.322

Modified Ultrafiltration

Modified ultrafiltration to remove intravascular (and extravascular) water and inflammatory substances has produced improved results in adults and children.323,324 Dialysis during CPB in adults may be beneficial in removing water, potassium, and protein wastes in patients with renal insufficiency.

Complement Inhibitors

The sequential activation cascade with convergence of the classical and alternative pathways at C3 offers many opportunities for inhabitation by recombinant proteins. Using a humanized, recombinant antibody to C5 (h5G1.1-scFv), Fitch et al. demonstrated that generation of C5b-9 was completely blocked in a dose-response manner (Fig. 12-21) and that neutrophil and monocyte CD11b/CD18 expression was attenuated in patients during and for several hours after clinical cardiac surgery using CPB.325 Large scale clinical trials that have followed have shown significant improvements in morbidity and mortality.326

Other complement recombinant protein inhibitors have been developed and are under active investigation because of the importance of this plasma protein system in CPB, ischemia/reperfusion, and injuries that summon the acute inflammatory response. Although any effective and safe inhibitor is welcome, C3 may be a better target for inhibition because both activation pathways are blocked at the point of convergence and because C3 concentrations in plasma are 15 times greater than C5.327

Glucocorticoids

Many investigators have used glucocorticoids to suppress the acute inflammatory response to CPB and clinical cardiac surgery, but beneficial effects in adult patients have been inconsistent.328 Steroids reduce release of rapid-response cytokines, TNF-α, and IL-1β from macrophages, enhance release of IL-10, and suppress expression of endothelial cell selectins and neutrophil integrins.329 Clinical results from a few randomized trials are conflicting: One study observed earlier extubation and reduced shivering,330 but another found increased blood glucose levels and delayed extubation.331 A recent large meta-analysis found that low-dose corticosteroids reduced atrial fibrillation incidence, and decreased ICU and hospital length of stay without increasing infectious complications.332

Organ Damage

Cardiopulmonary bypass can preempt normal reflex and chemoreceptor control of the circulation, initiate coagulation, activate blood cells, release circulating cell-signaling proteins, generate vasoactive and cytotoxic substances, and produce a variety of microemboli. Venous pressure can be elevated, plasma colloid osmotic pressure is reduced, flow is nonpulsatile, and temperature is manipulated. Tissues and organs may suffer from regional malperfusion that is independent of physiologic controls, and is caused by microemboli, increased interstitial water, and perfusion with a variable amount of cytotoxic substances. Reversible and irreversible cell injury may occur, but damage is diffusely distributed throughout the entire body as individual cells or small groups of cells are affected. Ischemia-reperfusion injury augments damage to the heart and on occasion to other organs. Amazingly, the body is able to withstand and for the most part repair the cellular damage, although some abnormalities may appear later. This section summarizes the reversible and permanent organ damage produced by cardiopulmonary bypass (CPB) and complements the preceding two sections of this chapter and the chapter on ischemia and reperfusion (see Chapter 3).

Mechanisms

Cardiac output during CPB is carefully monitored and synchronized with temperature and hemoglobin concentration to ensure that the entire body is adequately supplied with oxygen (see earlier section on extracorporeal perfusion systems). Excessive hemodilution reduces oxygen delivery,333 and hemoglobin concentrations significantly below 8 g/L cause organ dysfunction at temperatures above 30°C.334 However, regional hypoperfusion is not monitored; is independent of reflex and chemoreceptor controls; and is influenced by the inflammatory response, which produces circulating vasoactive substances. Regional perfusion is also influenced by acid-base relationships during cooling and may affect postoperative organ function. Alpha-stat management (pH increases during cooling) decreases cerebral perfusion during hypothermia; pH stat (pH 7.40 is maintained by adding CO2) improves organ perfusion but may increase embolic injury.335 Temperature differences within the body and within organs produce regional temperature-perfusion mismatch,336 which can precipitate regional hypoperfusion and acidosis caused by inadequate oxygen delivery.

The inflammatory response produces the cytotoxic compounds and activated neutrophils and monocytes that can and do destroy organ and tissue cells. These agents directly access the specialized cells of every organ by passing between endothelial cell junctions to reach the interstitial compartment. Reduced plasma colloid osmotic pressure, elevated venous pressure, and widened endothelial cell junctions337 increase the volume of the interstitial space during CPB in proportion to the duration of bypass, magnitude of the dissection, transfusions, and other factors. In prolonged complicated perfusions the interstitial compartment may increase 18 to 33%,338 but intracellular water does not increase during CPB.

Microemboli are defined as particles less than 500 microns in diameter. They enter the circulation during CPB from a variety of sources.339Table 12-2 summarizes sources of gas, foreign, and blood-generated microemboli, which are more fully discussed earlier. Air entry into the perfusion circuit produces the most dangerous gas emboli because nitrogen is poorly soluble in blood and is not a metabolite. Carbon dioxide is rapidly soluble in blood and is sometimes used to flood the surgical field to displace air. Foreign emboli, largely generated in the surgical wound, reach the circulation from the surgical field via the cardiotomy reservoir. The cardiotomy reservoir is the primary source of foreign emboli and the major source of blood-generated emboli, particularly fat emboli.340 Extensive activation and physical damage to blood elements produce a wide variety of emboli, which tend to increase with the duration of perfusion.335

Strategies for Reducing Microemboli

Although discussed in earlier sections, the principal methods for reducing circulating microemboli deserve emphasis and include the following: adequate anticoagulation; membrane oxygenator; washing blood aspirated from the surgical wound341; filtering the cardiotomy reservoir; secure pursestring sutures around cannulas; strict control of all air entry sites within the perfusion circuit; removal of residual air from the heart and great vessels; avoidance of atherosclerotic emboli; and selective filtration of cerebral vessels (Table 12-5).342,343

Many intraoperative strategies are available to reduce cerebral atherosclerotic embolization. These include routine epicardial echocardiography of the ascending aorta to detect both anterior and posterior atherosclerotic plaques and find sites free of atherosclerosis for placing the aortic cannula.344 Recently, special catheters with or without baffles or screens have been developed to reduce the number of atherosclerotic emboli that reach the cerebral circulation.345 In patients with moderate or severe ascending aortic atherosclerosis a single application of the aortic clamp as opposed to partial or multiple applications is strongly recommended and has been shown to reduce postoperative neuronal and neurocognitive deficits in a large clinical series.346 Retrograde cardioplegia is preferred over antegrade cardioplegia in these patients to avoid a sandblasting effect of the cardioplegic solution.347 No aortic clamp may be safe or even possible in some patients with severe atherosclerosis or porcelain aorta. If intracardiac surgery is required in these patients, deep hypothermia may be used with or without graft replacement of the ascending aorta. If only revascularization is needed, pedicled single or sequential arterial grafts,348 T or Y grafts from a pedicled mammary artery,349 or vein grafts anastomosed to arch vessels can be used.

In-depth or screen filters are essential for cardiotomy reservoirs and are usually used in arterial lines. The efficacy of arterial line filters is controversial because screen filters with a pore size less than 20 microns cannot be used because of flow resistance across the filter. However, air and fat emboli can pass through filters although 20 micron screen filters more effectivly trap microemboli than larger sizes.350

Cardiac Injury

It is difficult to separate postoperative cardiac dysfunction from injury owing to CPB, ischemia/reperfusion, direct surgical trauma, the disease being treated, and maladjustment of preload and afterload to myocardial contractile function. The heart, like all organs and tissues, is subject to microemboli, protease and chemical cytotoxins, activated neutrophils and monocytes, and regional hypoperfusion during CPB before and after cardioplegia or fibrillatory arrest. However, the heart is protected from CPB for at least one half of the case when the aorta is cross-clamped. Some degree of myocardial "stunning" during the period coronary blood flow is interrupted is inevitable,351 as is some degree of reperfusion injury after ischemia. Both myocardial edema and distention of the flaccid cardioplegic heart during aortic cross-clamping352 reduce myocardial contractility. Lastly, if myocardial contractility is weak, excessive preload or high afterload during weaning from CPB increases ventricular end-diastolic volume, myocardial wall stress, and oxygen consumption. Thus postoperative performance of the heart depends upon many variables and not just the injuries produced by CPB.

Neurologic Injury

The brain is the effecter organ for all behavior, innate and learned. It is the monarch of blood flow and will shut down all other vascular systems to preserve its own supply. Conversely, dysfunction in other organs can adversely affect brain function. It monitors other organ systems and is acutely sensitive and responsive to both the external and internal environment. Thus, even small injuries to the brain may produce symptomatic, functional losses that would not be detectable or important in other organs. Regional hypoperfusion, edema, microemboli, circulating cytotoxins or subtle changes in blood glucose, insulin, or calcium may result in changes in cognitive function, ranging from subtle to profound. A small 2-mm infarct may cause a disruption of behavioral patterns, physiologic and physical function changes can pass unnoticed, be accepted, and dismissed, or profoundly compromise the patient's quality of life. Move the lesion half a centimeter and the same volume lesion may result in a catastrophic stroke. Thus the brain is the most sensitive organ exposed to damage by CPB and also the organ that, with the heart, is most important to protect.

Assessment

Routine assessment of neurologic injury that occurs in the setting of cardiac surgery is not done for most patients because of the priority of the cardiac lesion as well as costs in time and money. General neurologic examinations by members of the surgical team or individuals lacking specialized training are not adequate to rule out subtle neurologic injuries, and this is the principal reason that the incidence of stroke, or neurologic or neuropsychological injury varies widely in the surgical literature.353

The most obvious neurologic abnormalities are paresis, loss of vital brain functions such as speech, vision, comprehension, or coma. These are commonly lumped under the general heading of stroke. Disorders of awareness or consciousness can include coma, delirium, and confusion, but transitory episodes of delirium and confusion are often dismissed as caused by anesthesia or medications. More subtle losses are determined by comparison of preoperative and postoperative performances using a standard battery of neuropsychological tests prepared by a group of neuropsychologists. A neuropsychological examination is basically an extension of the neurologic examination with a much greater emphasis on higher cortical function. Dysfunction is objectively defined as a deviation from the expected, relative to a large population. For example, although performing at a 95 IQ level is in the normal range, it is low for a physician, and a search for a neurologic impairment would be triggered by such a poor performance. A 20% decline in two or more of these tests, compared with the patient's own baseline, suggests a neuropsychological deficit that should be followed until resolved or not resolved.354 In studies involving long-term follow-up the inclusion of a control group of unoperated patients with the same disease and similar demographics helps define the causes of neuropsychological decline that occurs later than 3 to 6 months after surgery.355

Computed axial tomograms (CAT) or magnetic resonance imaging (MRI) scans are essential for the definitive diagnosis of stroke, delirium, or coma. Preoperative imaging is usually not necessary when new techniques such as diffusion-weighted MRI imaging, MRI spectroscopy, or MRI angiography are used to assess possible new lesions after operation.356 Biochemical markers of neurologic injury after cardiac surgery are relatively nonspecific and inconclusive. Neuron-specific enolase (NSE) is an intracellular enzyme found in neurons, normal neuroendocrine cells, platelets, and erythrocytes.357 S-100 is an acidic calcium-binding protein found in the brain.358 The beta dimer resides in glial and Schwann cells. Both S-100 and NSE increase in spinal fluid with neuronal death and may correlate with stroke or spinal cord injury after CPB.359 However, plasma levels are contaminated by aspiration of wound blood into the pump and hemolysis and are often elevated after prolonged CPB in patients without otherwise detectable neurologic injury.360 Newer blood-borne biochemical markers such as Tau have been identified, but as of yet have not been shown to be diagnostic for subtle neurologic injury.

Populations at Risk

Advancing age increases the risk of stroke or cognitive impairment in the general population, and surgery, regardless of type, increases the risk still higher.361 In 1986 Gardner and colleagues reported the risk of stroke during CABG surgery to be directly related to age.362 A European study compared 321 elderly patients without surgery to 1218 patients who had noncardiac surgery and found a 26% incidence of cognitive dysfunction 1 week after operation and a 10% incidence at 3 months.363 Between 1974 and 1990 the number of patients undergoing cardiac surgery over age 60 and over age 70 increased twofold and sevenfold, respectively364 (Fig. 12-22). Genetic factors also influence the incidence of cognitive dysfunction after cardiac surgery.365 The incidence of cognitive dysfunction at 1 week after cardiac surgery is approximately double that of noncardiac surgery.

As the age of cardiac surgical patients' increases, the number with multiple risk factors for neurologic injury also increases. Hypertension and diabetes occur in approximately 55 and 25% of cardiac surgical patients, respectively.366 Fifteen percent have carotid stenosis of 50% or greater, and up to 13% have had a transient ischemic attack or prior stroke. The total number of MRI atherosclerotic lesions in the brachiocephalic vessels adds to the risk of stroke or cognitive dysfunction,367 as does the severity of atherosclerosis in the ascending aorta as detected by epiaortic ultrasound scanning.368 Palpable ascending aortic atherosclerotic plaques markedly increase the risk of right carotid arterial emboli as detected by Doppler ultrasound.369 The incidence of severe aortic atherosclerosis is 1% in cardiac surgical patients less than 50 years old and is 10% in those aged 75 to 80.370

Mechanisms of Injury

The three major causes of neurologic dysfunction and injury during cardiac surgery are microemboli, hypoperfusion, and a generalized inflammatory reaction, which can occur in the same patient at the same time for different reasons. The vast majority of intraoperative strokes are caused by the embolization of atherosclerotic material from the aorta and brachiocephalic vessels. This occurs as a result of manipulation of the heart and major thoracic vasculature as well as dislodgement of atheromata from shearing forces directed at the walls of vessels from inflow cardiopulmonary bypass cannulae.371 Microemboli are distributed in proportion to blood flow20; thus reduced cerebral blood flow reduces microembolic injury but increases the risk of hypoperfusion.372 During CPB both alpha-stat acid-base management and phenylephrine reduce cerebral injury in adults, probably by causing cerebral vessel vasoconstriction and reducing the number of microemboli.373 Air, atherosclerotic debris, and fat are the major types of microemboli causing brain injury in clinical practice, and all cause neuronal necrosis by blocking cerebral vessels.374 Massive air embolism causes a large ischemic injury, but gaseous cerebral microemboli may directly damage endothelium in addition to blocking blood flow.375 The identification of unique small capillary arteriolar dilatations (SCADs) in the brain associated with fat emboli376 (Fig. 12-23) raises the possibility that these emboli not only block small vessels, but also release cytotoxic free radicals, which may significantly increase the damage to lipid-rich neurons.

Anemia and elevated cerebral temperature increase cerebral blood flow but may cause inadequate oxygen delivery to the brain,377 however, these conditions are easily avoided during clinical cardiac surgery. Although some investigators speculate that normothermic and/or hyperthermic CPB cause cerebral hypoperfusion,378 experimental studies indicate that cerebral blood flow increases with temperature. Brain injuries associated with this practice are more likely due to increased cerebral microemboli, which produce larger lesions at higher cerebral temperatures.376

Neuroprotective Strategies

Recommended conditions for protecting the brain during CPB include mild hypothermia (32 to 34°C) and hematocrit above 25%.161 Temporary increases in cerebral venous pressure caused by superior vena cava obstruction and excessive rewarming above blood temperatures of 37°C should be avoided.379 A randomized study in which patients were mildly rewarmed to 35°C core temperature demonstrated improved neurocognitive outcomes over patients rewarmed to 37°C. Either jugular venous bulb oxygen saturation or near-infrared cerebral oximetry are recommended for monitoring cerebral perfusion in patients who may be at high risk for cerebral injury.380

Barbiturates reduce cerebral metabolism by decreasing spontaneous synaptic activity and provide a definite neuroprotective effect during clinical cardiac surgery using CPB.381 Unfortunately, these agents delay emergence from anesthesia and prolong intensive care unit stays. NMDA (N-methyl-D-aspartate) antagonists, which are effective in animals, provide mild protection compared with control patients, but have a high incidence of neurologic side effects.382 A small study demonstrated a neuroprotective effect of lidocaine, but this beneficial effect has not been reproduced.383 Thus corticosteroids are the only drugs with potential neuroprotective effects that have significant evidence for a positive effect on outcomes.332

Off-pump myocardial revascularization theoretically avoids many of the causes of cerebral injury owing to CPB, but, as noted, many causes of neuronal injury are independent of CPB and related to atherosclerosis and air entry sites into the circulation. Nonrandomized measurements of carotid emboli by Doppler ultrasound indicate fewer emboli and slightly improved neurocognitive outcomes in high-risk patients who have off-pump surgery.384 Clinical trials of off-pump versus on-pump patients failed to show a significant difference in neurologic outcomes among methods.385

Prognosis

Patients with intraoperative stroke or those who develop stroke symptoms in the first week after surgery often improve in direct relation to the lesion size and location on imaging studies. Neuropsychologic deficits that are present after 3 months are almost always permanent.386 Assessments after that time are confounded by development of new deficits, particularly in aged patients.387,388

The difficulty of separating intraoperative brain injury from that which occurs in the early or late postoperative period has been recently addressed by a reanalysis of data published earlier. The authors tracked specific neuropsychological deficits that persisted unchanged for 6 months (persistent deficits) and separated them from new deficits that appeared after surgery389 (Fig. 12-24). Using this technique it is possible to accurately measure surgical brain injury and design techniques to eliminate this important cause of morbidity. Late follow-up studies should include a control group with similar risk factors but not having cardiac operations.390 This technique demonstrated similar outcomes in surgical and nonsurgical controls at 3 years, putting to rest the previous fear that surgical patients had recurrent neurocognitive deficits and were thus at greater risk for poor long-term outcomes. In a recent study, a group of surgical patients who were evaluated with preoperative and postoperative neuropsychological studies had rigid control of cardiovascular risk factors.391 They demonstrated no delayed or late cognitive decline offering hope that aggressive medical therapy can compliment skillful surgery in preventing neurological injury.

Lung Injury

Patient factors and the separate effects of operation and CPB combine to compromise lung function early after operation. Chronic smoking and emphysema are the most common patient factors, but muscular weakness, chronic bronchitis, occult pneumonia, preoperative pulmonary edema, and unrelated respiratory disease are other contributors to postoperative pulmonary dysfunction. Incisional pain, lack of movement, shallow respiratory sighs, increased work of breathing, reduced pulmonary compliance, weak cough, increased pulmonary arterial-venous shunting, and interstitial edema, to some degree, are consequences of anesthesia and any operation. CPB significantly adds to this injury.

During CPB the lungs are supplied by the bronchial arteries and pulmonary arterial blood flow may be absent or minimal. Whether or not alveolar cells suffer an ischemic/reperfusion injury is unclear, but the lungs are subject to many insults that combine to increase pulmonary capillary permeability and interstitial lung water. Hemodilution, reduced plasma oncotic pressure, and temporary elevation of left atrial or pulmonary venous pressure during CPB or during weaning from CPB increase extravascular lung water.392 Microemboli and circulating cellular, vasoactive, and cytotoxic mediators of the inflammatory response reach the lung via bronchial arteries during CPB and with resumption of the pulmonary circulation during weaning.393,394 These agents increase pulmonary capillary permeability, perivascular edema, and bronchial secretions, and perhaps cause observed changes in alveolar surfactant.395 The combination of increased interstitial lung water and bronchial secretions, altered surfactant, patient factors, and the consequences of operation reduces pulmonary compliance and functional residual capacity and increases the work of breathing.396 All of these changes combine to enhance regional atelectasis, increase susceptibility to infection, and increase the physiologic arterial-venous shunt, which reduces systemic arterial Pao2.

Postoperative respiratory care is based on restoring normal pulmonary capillary permeability and interstitial lung volume; preventing atelectasis; reinflating atelectatic segments; maintaining normal arterial blood gases; and preventing infection and facilitating removal of bronchial mucus. Improved postoperative respiratory care, an understanding of the mechanisms of lung injury during CPB, and efforts to prevent or control the causes of injury397 have markedly reduced the incidence of pulmonary complications in recent years. (See Chapter 16 for a more detailed discussion of postoperative care.)

Acute respiratory distress syndrome (ARDS) is a rare complication of lung injury during cardiopulmonary bypass and is usually caused by intrabronchial bleeding from traumatic injury by the endotracheal tube or pulmonary artery catheter or to extravasation of blood into alveoli from acute increases in pulmonary venous pressure or severe pulmonary capillary toxic injury.398

Renal Injury

As with other organs, the preoperative health of the kidneys is a major factor in the ability of that organ to withstand the microembolic, cellular, and regional malperfusion injuries caused by extracorporeal circulation. Risk factors include previous renal injury, increased age, and complex disease or cardiac operation.399 The incidence of acute renal failure requiring dialysis after CPB is remarkably low, averaging 1%; however, the incidence increases to 5% with complex operations.

Some degree of renal injury is inevitable during CPB and postperfusion proteinuria occurs in all patients.400 Renal blood and plasma flow, creatinine clearance, free water clearance, and urine volume decrease without hemodilution.401 Hemodilution attenuates most of these functional changes and also reduces the risk of hemoglobin precipitation in renal tubules if plasma-binding proteins become saturated with free hemoglobin during extracorporeal perfusion. Hemoglobin is toxic to renal tubules and precipitation can block both blood and urine flow to the tubules. Hemodilution dilutes plasma hemoglobin; improves flow to the outer renal cortex; improves total renal blood flow; increases creatinine, electrolyte, and water clearance; and increases glomerular filtration and urine volume.402

Perioperative periods of low cardiac output and/or hypotension added to the microembolic, cellular, and cytotoxic injuries of CPB and to any preoperative renal disease are the major cause of postoperative renal failure.403 Low cardiac output reduces renal perfusion pressure and causes angiotensin II production and renin release, which further decrease renal blood flow. Kidneys, already compromised by preoperative disease and the CPB injury, are particularly sensitive to ischemic injury secondary to low cardiac output and hypotension. Thus perioperative management includes efforts to maximize cardiac output using dopamine or dobutamine if necessary, avoiding renal arterial vasoconstrictive drugs, providing adequate crystalloid infusions to maintain urine volume, and alkalinizing urine to minimize precipitation of tubular hemoglobin if excessive hemolysis has occurred.

If perioperative low cardiac output and hypotension do not occur, the normal kidney has sufficient functional reserve to provide adequate renal function during and after operation. The appearance of oliguric renal failure is ominous and usually requires dialysis, which is generally permanent if required for more than 2 weeks. Oliguric renal failure markedly increases morbidity and mortality by approximately eightfold.

Injury to the Liver and Gastrointestinal Organs

Although subjected to microemboli, cytotoxins, and regional malperfusion during CPB, the enormous functional reserve and reparative processes of the normal liver nearly always overcome the injury without consequences. Often liver enzymes are mildly elevated, and 10 to 20% of patients are mildly jaundiced. Persistent and rising bilirubin 2 or more days after CPB may precede development of liver failure and is associated with increased morbidity and mortality.404 Catastrophic liver failure, however, occurs in patients with overwhelming sepsis, oliguric renal failure, anesthetic or drug toxicity, or after a prolonged period of low cardiac output or an episode of hemorrhagic shock and multiple blood transfusions and is uniformly fatal. The liver usually is involved in patients who develop multiorgan failure and is often presaged by sudden hypoglycemia.

Pancreatic Injury

Less than 1% of patients develop clinical pancreatitis after CPB, but approximately 30% develop a transitory, asymptomatic increase in plasma amylase and/or lipase.405 A history of recurrent pancreatitis, perioperative circulatory shock or hypotension, excessively prolonged CPB, and continuous, high doses of inotropic agents are risk factors for developing postoperative pancreatitis.406 Experimentally and clinically, high doses of calcium increase intracellular trypsinogen activation and histologic evidence of pancreatitis.407 Fulminant pancreatits is very rare, but is often fatal.

Stomach and Gut Injury

CPB at adequate flow rates does not decrease splanchnic blood flow.408 Risk factors for gastrointestinal complications include advanced age, emergency surgery, prolonged CPB, postoperative low cardiac output or shock, prolonged vasopressor therapy, and elevated preoperative systemic venous pressure.409

CPB decreases gastric pH, which declines further after operation. Before the advent of H2 blockers and regular use of antacids, duodenal and/or gastric erosion, ulcer, and bleeding were frequent complications after clinical cardiac surgery and were associated with mortality that approached 33 to 50%.410 These complications are now uncommon.

Several days to 1 week after operation very elderly patients rarely may develop mesenteric vasculitis or severe mesenteric vasoconstriction in response to vasopressors that proceeds to small bowel ischemia and/or infarction. New onset abdominal pain with a silent, rigid abdomen and abrupt rise in white count may be the only signs of this catastrophic complication, which is frequently fatal. If suspected before infarction, infusion of papaverine or alternative vasodilators directly into the mesenteric arteries may prevent or limit subsequent infarction.

The role of CPB in the etiology of gastrointestinal complications is not completely known. If the complications listed in the preceding develop, an increase in the morbidity and mortality may be expected.411