26 and

J. ERNESTO MOLINA f MD, PhD

CONTENTS

CARDIOPULMONARY BYPASS CARDIOPLEGIA REFERENCES

1. CARDIOPULMONARY BYPASS oxygenator that replaces the function of the lungs, and (3) a Extracorporeal circulation and cardiopulmonary bypass are pump that propels the oxygenated blood back into the patient's synonymous terms denoting a method by which the blood that arterial circulation. In this manner, the machine bypasses both usually returns directly to the is temporarily drained from the heart and the lungs while maintaining the functions of other the superior and inferior venae cavae. The blood is diverted organs during surgical intervention within the heart. into a reservoir, where it is oxygenated and subsequently returned to the patient's arterial circulation. This process 1.1. Venous Drainage effectually excludes the heart from the general circulation and The venous blood that is normally delivered to the right leaves it empty so that it can accommodate surgical interven- is commonly diverted to the heart-lung machine, either tion (Fig. 1). by cannulating the themselves or by cannulating the right The breakthrough technology that first allowed this type of atrial chamber. performed in or through the right atrial open heart operation was developed by two centers in the chamber requires that both the right atrium and right United States in the early 1950s. Importantly, Lillehei and be empty. To do so, cannulas are placed directly into the supe- Varco (1) at the University of Minnesota developed a cross- rior and inferior venae cavae. Constricting tourniquets are then circulation technique. This technique utilized a human donor, placed around the veins over the cannulas, and blood is diverted usually the parent of a child undergoing , who into the heart-lung machine (Fig. 1). These procedures consti- in essence functioned as an extracorporeal pump for the tute total cardiopulmonary bypass. patient's . This type of extracorporeal cir- Venous cannulation is normally performed in one of two culation also allowed the blood to be drained from the child's ways: (1) by placing a pursestring suture either directly in the venae cavae so that the surgical procedure could be performed or in the right atrium or (2) by advancing the within the empty heart. The subsequent development of the cannula into the superior vena cava. It should be noted that heart-lung machine by Gibbon (2) was considered revolution- direct cannulation of the superior vena cava generally provides ary in that it eliminated the need for a support donor (a second more room for any work that needs to be done inside the right patient). Gibbon's system has been improved since the mid- atrium. 1950s and has gradually evolved into the standardized, but A modification of this type of bypass can be used when the very complex and sophisticated, machine it is today. cardiac chambers are not surgically entered, such as in coronary The basic components of an extracorporeal circuit include: bypass operations involving procedures on the surface of the (1) a reservoir into which the patient's blood is diverted, (2) an heart. In such cases, a single cannula is placed in the right atrium, or a double-stage cannula is placed with the tip of the cannula in the inferior vena cava and the side drainage holes positioned From: Handbook of Cardiac Anatomy. Physiology, and Devices Edited by: P. A. laizzo © Humana Press Inc., Totowa, NJ at the level of the right atrium. Coronary bypass surgery does

371 372 PART IV: DEVICES AND THERAPIES / MOLINA

:T 1

.If ,~oxygenator ~"~.

pump filter Fig. 2. Left heart bypass showing a cannula inserted in the left atrium, draining approximately half of the cardiac output into the oxygenator, Fig. 1. Total pulmonary bypass showing the venous cannulas in the through the pump, and reinfusing in the distal for of the superior and inferior venae cavae with constrictions around the respec- abdominal organs. The excluded portion is only the descending thoracic tive veins. The venous blood is drained into the oxygenator and is pro- aorta (between clamps). The left heart continues to beat and pumps half pelled by the pump into the distal to maintain perfusion of the cardiac output to the head and upper organs. The graft is shown of the entire body. All chambers of the heart therefore are excluded from in the position in which it will be implanted after the aneurysm is the perfusion system. Ao, aorta; RA, right atrium; v, ventricle. resected. Ao, aorta; LA, left atrium; PA, pulmonary .

not involve direct vision of the inside of the cardiac chambers, . Then, the blood is infused back into the descending tho- so there is no need to constrict the superior or inferior venae racic aorta beyond the level of distal aortic cross-clamping. cavae. Doing so allows the heart to continue to beat normally and helps maintain the viability of the proximal organs (head, neck, 1.2. Arterial Return and arms) while the rest of the lower body is perfused by the Once the blood has been oxygenated in the heart-lung ma- pump. This technique is called left heart bypass because it chine, it is returned to the patient's general circulation via can- involves only the left side of the cardiac chambers. nulas placed directly in the arterial system (Fig. 1). The most After a thoracic aorta operation is completed, the bypass is common method involves the placement of a cannula in the discontinued. The clamps, which were placed to occlude the highest portion of the ascending aorta, below the origin of the aorta in the arch and the descending portion, are removed. The innominate artery. Depending on the type of surgery, other sites normal physiological perfusion of the body (which was inter- are also used, including cannulation of the femoral artery in the rupted during surgery without ever stopping the heartbeat) is groin and infusion of the arterial system in a retrograde manner. thus reestablished. The ascending aorta is cross-clamped at this point, so no sys- In contrast, total cardiopulmonary bypass involves com- temic blood enters the coronary artery circulation. The heart is, plete stoppage of the heart. After an operation employing total therefore, totally excluded from circulation. Thus, the heart cardiopulmonary bypass and cardiac arrest, the aortic clamp needs to be protected by using one of a number of methods to is released, which allows the general circulation to perfuse the infuse cardioplegic solutions (see Section 2). coronary and to rewarm the heart. After the air is In addition, any blood remaining in the operative field is expelled from the cardiac chambers, the heart usually devel- removed via suction lines, which aspirate it back to ops ventricular fibrillation. Such fibrillation normally requires the heart-lung machine, where it returns to bypass circulation with electric shock administered directly to the with the rest of the removed blood. myocardium, employing paddles that deliver currents that vary In some operations involving the descending thoracic aorta, from 20 to 30 W/s. The patient is then ventilated using the total cardiopulmonary bypass is not necessary. If the portion of endotracheal tube connected to the anesthesia machine, which the aorta that needs to be isolated lies between the left carotid reinflates the lungs. After the normal sinus rhythm of the heart artery and the diaphragm, only part of the total blood volume is reestablished, the patient is gradually weaned off the extra- needs to be removed, and partial bypass is implemented (Fig. 2). corporeal circulation until the heart takes over full function. The blood is removed by the heart-lung machine via a cannula At this point, the heart-lung machine is stopped, and all can- inserted in the left atrium or in the left superior pulmonary nulas are removed. CHAPTER 26 / CARDIOPULMONARY BYPASS AND CARDIOPLEGIA 373

In some complex surgical cases involving the aortic arch, a hypotension (6), so it is the drug of choice to neutralize the separate and independent perfusion of the arch vessels may effects of heparin. Naturally, the amount of protamine neces- require implementation, that is, in addition to the perfusion of sary to achieve neutralization depends on the amount of heparin the lower part of the body through the cannula inserted in the used. Initially, a test dose is given; if no reaction occurs, prota- femoral artery. This situation places a great demand on the mine is then administered in the appropriate amount. Its effects perfusionist operating the heart-lung machine. The perfusionist are monitored by measuring ACTs until the heparin has been must monitor two separate infusions to regulate pressures and neutralized. Diabetics are generally prone to be more sensitive make certain that balanced and sufficient perfusions are to protamine. If any reaction or side effect occurs, additional achieved in both the upper and lower areas of the patient's body. treatments are commonly employed, such as administration of Another specialized bypass method that needs description is epinephrine, calcium, steroids, or fluids (7). deep hypothermia and total circulatory arrest. This type of total Occasionally, patients cannot be given heparin because cardiopulmonary bypass employs decreases in body tempera- they have developed heparin antibodies from previous expo- tures to very low levels ( 15 to 20°C); this is accomplished using sure. Other anticoagulant agents studied and occasionally used heat exchangers installed in the heart-lung machine. Circula- in such cases include hirudin (lepirudin) (8), a potent antico- tion is stopped altogether, and the heart is empty for several agulant that is extracted from leeches and lampreys, or minutes, with the entire volume of the patient's blood remain- heparinoids (9) like Orgaran (Org10172, Organon Company, ing in the reservoir of the heart-lung machine. Once the target West Orange, NJ), for which a different monitoring protocol temperature is reached (usually 15°C), the pump is stopped, and is implemented. Unfortunately, to date no drug has been iden- arterial perfusion ceases. The venous return, however, is left tified that can reverse the effect of Orgaran; thus, it must be open to empty the patient's blood volume completely into the metabolized by the human body. For such patients, bleeding reservoir of the heart-lung machine. is a constant, and often very difficult, postoperative complica- This technique is used in special cases to allow repair of very tion. complicated conditions. The period of total circulatory arrest If the cardiopulmonary bypass takes an extended period of induced during deep hypothermia is usually less than 45 min time, coagulopathies are often a complication. In such cases, (3,4). This time restriction ensures that the patient does not the body, primarily the liver, is unable to produce the appropri- suffer neurological deterioration or central nervous system ate clotting factors to reverse the anticoagulation status. Other damage during such global . As soon as the repair is factors that can contribute to coagulopathies include ischemia completed, normal cardiopulmonary bypass is reestablished. of the abdominal organs, particularly if necrosis occurs in the The patient is gradually rewarmed to a normal core temperature liver cells or in the intestine. Bleeding, therefore, can be a very of 37°C prior to removal from extracorporeal circulation. serious and difficult complication to treat; multiple coagulation The use of such deep hypothermia always requires careful factors, platelets, and cryoprecipitates may be required. evaluation by the surgical team. In such clinical cases, the dan- ger of inducing neurological damage must be weighed against 1.4. Temperatures of Perfusion the benefits of correcting the cardiac anomaly. Since their inception, cardiopulmonary bypass and extracor- poreal circulation have been implemented using some degree of 1.3. Anticoagulation hypothermia. Lowering body temperature decreases the oxy- To prevent the formation of clots during cardiopulmonary gen demands of body tissues, an obviously desirable state of bypass procedures, both within the body and in the extracorpo- affairs during pulseless circulation as provided by the heart- real heart-lung machine, it is necessary to anticoagulate the lung machine. patient. The most common agent used for such anticoagulation Several degrees of hypothermia are commonly identifiable is heparin. It is commonly administered intravenously, before relative to extracorporeal circulation interventions. Normoth- cannulation, at a dose of 300 U/kg of the patient's weight. etwzia indicates that core body temperature is between 35.5 and There are two types of heparin: (1) the lung-beef type which 37°C (10); mild hypothermia is between 32 and 35°C; and is extracted from a bovine source, and (2) the porcine mucosal moderate hypothermia is between 24 and 32°C. An important type, which is from a swine source. Since the mid-1980s, the distinction must be made between mild and moderate hypoth- porcine mucosal heparin has been preferred because it is less ermia. If the heart is perfused at mild levels (above 3 l°C), the likely to lead to thrombocytopenia and production of heparin heart will continue to beat, although at a slower rate. This mild antibodies in the patient (5). level of hypothermia allows surgical correction of some con- The effectiveness of anticoagulation requires testing, usu- genital anomalies without arresting the heart. An additional ally by measuring the activated clotting time (ACT) of the level of hypothermia used occasionally is deep or profound patient's blood. The result is expressed in seconds, with normal hypothermia, that is, below 20°C. values ranging between 100 and 120 s. Heparinization is deemed Currently, most open cardiac operations are conducted adequate when the ACT runs above 300 s. At any time after such under conditions somewhere between moderate and mild values are achieved, the patient can undergo cannulation and be hypothermia and normothermia. Some centers routinely use placed on extracorporeal circulation. moderate hypothermia; others employ normothermia (11,12). The anticoagulant effects induced during such must One reason to maintain normothermic perfusion is to avoid be reversed postoperatively. Protamine, a macromolecule com- coagulopathies that may develop when body temperature is pound, may produce pulmonary vasoconstriction and severe lowered to the moderate levels and permit normal function of 374 PART IV: DEVICES AND THERAPIES / MOLINA the body's enzyme systems. Normothermic temperatures also Pulseless perfusion, as provided by the heart-lung machine, allow the kidneys to respond better to diuretics. and hemodilution invariably lead to a transfer of fluid across Several reports have indicated the safety of normothermic the capillary walls into the third space. Therefore, all patients perfusion (10-16), but an equal number have suggested compli- develop, to some degree, peripheral third spacing or edema, cations with this modality (17,18). As a result, spontaneous which is particularly seen in children and usually requires drifting to mild hypothermic levels is generally preferred. Deep several days to resolve completely. In an attempt to avoid this or profound hypothermia is associated with the implementation condition, plasma expanders (such as albumin, hetastarch, of total circulatory arrest, as mentioned. With this level of dextran, and mannitol) are usually added to the priming solu- hypothermia, body temperature is usually lowered to between tion of the heart-lung machine. 15 and 18°C. Such operations are thus usually prolonged given the time it takes to cool the body to those levels before surgery 1.7. Heart-Lung Machine Basics and to rewarm it afterward. The basic components of the heart-lung machine include an oxygenator, a reservoir for the perfusion solution, a perfu- 1.5. Perfusion Pressures sion pump, line filters, two heat exchangers, and monitoring Under normal physiological conditions, the heart provides devices. Although the bubble oxygenator has been used for a pulsatile pressure and flow. The peak systolic pressure many years, it has been largely supplanted by the membrane depends on the ventricular function. The diastolic pressure in oxygenator. The membrane oxygenator is associated with less normal states is primarily regulated by the blood volume and trauma to red blood cells and is less likely to produce micro- the vascular tonus. During cardiopulmonary bypass, the heart- bubbles that might pass into the patient's arterial system and lung machine facilitates pulseless perfusion; there is no sys- form an embolism. In addition, the newer centrifugal pumps tolic or diastolic pressure, but rather one steady mean pressure (Fig. 3), like the BioMedicus (Medtronic, Inc., Minneapolis, throughout the arterial circulatory system. This pressure MN), offer a distinct advantage over the older roller-type should be high enough to provide adequate blood oxygen pumps, such as the standard DeBakey. The older roller pumps supply to all organs of the body, particularly the brain and use occlusive pressure to propel the blood within the tub- kidneys. The patient is typically hypothermic, so oxygen ing and can cause damage to the red blood cells and dislodge requirements are lowered; the perfusion pressure is usually debris from the tubing material. The newer centrifugal pumps maintained around 70 mmHg. Occasionally, in patients with minimize trauma to the red blood cells because the motion severe obstructive carotid disease, a higher perfusion pressure required to move the blood does not constrict the tubing. is recommended to ensure proper perfusion of the brain. Yet, A typical modern heart-lung system uses gravity to divert this recommendation is somewhat debated because the brain venous blood from the right atrium or the venae cavae into a has its own autoregulatory system to maintain low resistance large reservoir, which acts as a membrane oxygenator (Fig. 3). near obstructed areas (12,14). To complete the circuit, the cardioplegic solution used to arrest During cardiopulmonary bypass, if the patient shows decreased the heart is injected back into the patient's arterial system by vascular tonus (despite adequate volumes of fluid), vasocon- two small roller pump heads (Fig. 4). strictors are routinely used; a typical therapy is a bolus or drips After the blood is oxygenated in the reservoir, it is passed of Neo-Synephrine (10). Decreased vascular tonus is common through heat exchangers that cool or rewarm it as necessary for in septic patients with bacterial endocarditis, for whom an the current stage of the operation. One heat exchanger provides emergency operation is necessary to replace the affected valve temperature control for systemic perfusion to the patient's and reverse the profound heart failure. In general, a mean per- body, whereas the other controls the temperature within the fusion pressure of around 70 mmHg during cardiopulmonary cardioplegia line. The temperature within each circuit is sepa- bypass should be maintained. rately controlled by a central regulation unit (Fig. 2). The blood is then filtered, which helps prevent microembolization when 1.6. Hemodilution it is returned to the patient's arterial system. In addition, Up to a certain level, hemodilution can be a desirable side two suction lines are employed to aspirate the blood from the effect of cardiopulmonary bypass. Lowering the hematocrit operative field into the reservoir, where it is oxygenated before prevents coagulation of the red cells, or "sludging," thereby it is pumped back into the patient's arterial system. providing better circulation at the capillary level; viscosity of The perfusionist monitors the general circulation flow, the the circulating blood is decreased, on the other hand, to ensure electrolyte parameters, the anticoagulation parameters, and the that oxygen is adequately delivered to the body's tissues during ultrafiltration system (which extracts fluid from the patient's cardiopulmonary bypass. Hematocrit levels are monitored and arterial system to avoid overhydration). The perfusionist is also maintained at a minimum between 22 and 26%. Toward the end in charge of maintaining the proper pressures within each cir- of the bypass operation, the perfusionist deliberately removes cuit and monitoring the temperature of the cardioplegic solu- some of the fluid from the patient's circulation to hemoconcen- tion. Normally, at 15-20-min intervals, the perfusionist apprises trate the blood toward more normal hematocrit levels (19,20), the surgeon of the elapsed time of perfusion and reinfuses the that is, usually above 30% by the time the patient is removed heart as necessary to maintain a temperature within the appro- from cardiopulmonary bypass. Subsequent diuresis or transfu- priate range (below 15°C). The perfusionist also remains in sion of red blood cells will further aid in reestablishing the direct communication with the anesthesiologist to coordinate hematocrit to normal levels. administration of any drugs or any other action necessary to CHAPTER 26 / CARDIOPULMONARY BYPASSAND CARDIOPLEGIA 375

Fig. 3. BioMedicus centrifugal pump. This unit propels the blood back into the arterial system. Two roller pumps (at left) are used for suction. The oxygenator reservoir is shown on the right.

Fig. 4. Typical setup of roller pumps. The three large pumps are used for suction, and the two smaller ones (left of center) are used for the mixing and infusion of cardioplegic solution during cold blood cardioplegia.

maintain the balance of the patient's other organ systems. At the is sometimes reinfused directly from the reservoir, or it may be end of cardiopulmonary bypass, the perfusionist administers concentrated and reinfused later. protamine in the amount sufficient to neutralize the effects of the heparin, thus returning the patient's coagulation system to 1.8. Heart-Lung Machine Priming normal function. Before cardiopulmonary bypass is undertaken, the heart- At the conclusion of the surgery, cardiopulmonary bypass is lung machine needs to be primed. For an adult patient, the discontinued, and the patient's heart resumes systemic blood priming fluid consists of about 1500 mL of fluid, based on a circulation. A small volume of blood often remains in the pump basic crystalloid solution. In our institution, Plasmalite is the and needs to be reinfused into the patient. This remaining blood preferred crystalloid solution to which albumin or hetastarch 376 PART IV: DEVICES AND THERAPIES/ MOLINA

(about 500 mL for a normal size patient) is added. Doing so trolyte to monitor is potassium, which after any major opera- helps maintain osmolality and volume in the intravascular tion usually rises above the normal level of 4.0 to 4.5 mEq/L space and helps prevent peripheral third spacing and edema. or higher. Potassium must be very strictly monitored to pre- Red cell sludging is prevented within the system by the addi- vent severe bradycardia or cardiac arrest. A dialysis system tion of 10,000 U heparin. For pediatric patients, these amounts can be used during cardiopulmonary bypass, if necessary, to are smaller, beginning with a priming of as little as 250 mL of prevent such serious complications. Even in large medical crystalloid solution. The addition of this priming solution centers, patients who are normally on dialysis rarely receive effects hemodilution, and the resultant lower blood viscosity potassium during cardiopulmonary bypass. allows it to better reach all vital areas of the body (as outlined In general, after weaning from cardiopulmonary bypass, in Section 1.6). At the end of the perfusion, the blood is hemo- most patients display various degrees of bradycardia, usually concentrated to normal levels by eliminating the extra fluid because of the persistent effect of the large amount of [~-blockers from circulation (19,20), and all the air is eliminated. Several administered preoperatively. Few patients will elicit heart rates areas of the heart-lung machine have an alarm system to pre- greater than 80 beats/min when taken off cardiopulmonary vent any air from entering into the circuitry. Once all the can- bypass. All patients are commonly provided with a temporary nulas are in place and the connections are properly made, the pacemaker system postoperatively. It consists of wires placed surgeon gives the order to begin cardiopulmonary bypass and on the surface of the heart (external leads) and connected to an the operative procedure. external pacemaker unit. Based on many years of research and experience, the optimal postcardiopulmonary bypass heart rate 1.9. Hemodynamics has been determined as 90 beats/min; atrial pacing is set at that As cardiopulmonary bypass is implemented, the patient's rate, with appropriate ventricular sensing. Pacing is usually systemic pressure usually drops briefly as the blood is diverted necessary for only 24 to 48 h. It provides higher cardiac output, from the heart to the heart-lung machine. This drop is precipi- significantly improves hemodynamics, and allows the patient tated by the cold (ambient) temperature of the fluid that the to eliminate the extra water that is usually third spaced during heart-lung machine is introducing into the patient's aorta. The the operation. drop should last no more than a minute or two before proper Ventricular leads are routinely implanted in all patients as a pressure and flow is reestablished. In general, it is preferable to very simple and safe prophylactic lifesaving measure (21). This maintain a systemic pressure of approx 70 mmHg and flows practice is highly advisable during the postoperative period between 1500 and 2500 mL/m 2 of body surface area throughout because serious problems such as complete heart block are the entire operation. If the systemic pressure tends to sag, which completely unpredictable regardless of the patient's age or can happen because of a variety of factors (e.g., loss of vascular general health. If serious problems occur, there is no substitute tonus), the anesthesiologist and the perfusionist must coordi- for the ability to pace the ventricle immediately. Once the acute nate administration of vasoconstrictor agents (such as Neo- recovery period is over and the patient is stable--typically 5 Synephrine). If the pressure is too high, vasodilators are days after surgery--the temporary pacemaker wires can usu- administered, or the rate of perfusion is decreased to restore ally be removed. In rare cases when heart block or severe brady- safe pressures. cardia occurs, a permanent pacemaker system may be necessary. Venous pressure and oxygen saturations are also monitored 1.1 0. Summary very carefully throughout a bypass procedure. An altered In summary, since its first implementation, cardiopulmo- venous pressure is one of the most important indicators that a nary bypass has improved significantly to become a very highly potential obstruction in the venous return has occurred, either sophisticated, but reliable, procedure. The near future promises at the level of the venous cannula or within the superior or even more improvements because research and innovations inferior vena cava. Such obstructions can often lead to major continue to make cardiac operations safer and more efficient. procedural complications if they are not monitored and imme- diately corrected. Typically, the perfusionist reports any con- 2. CARDIOPLEGIA cern to the surgeon so the surgeon can check whether any In the 1950s, the consensus among cardiac surgeons was that obstruction may exist. During cardiopulmonary bypass, the the results of the surgical methods at that time were satisfactory venous pressure should usually be zero and saturation above (22). Yet, numerous reports described low cardiac output syn- 70% because all the blood is completely diverted into the heart- drome occurring after surgical correction of congenital anoma- lung machine. Once the pressures are equilibrated, the tem- lies (23). Unfortunately, at that time, no definitive connection peratures must be maintained at the level of hypothermia that was provided between the lack of proper myocardial protection the surgeon has chosen. during surgery and the potential for postoperative cardiac dys- The records for the cardiopulmonary bypass are normally function or high mortality rates. called pump records. They must contain all pertinent informa- Not until the advent of coronary bypass in the late 1960s and tion, including: pressures, flows, temperatures, medications, early 1970s were intraoperative myocardial infarctions or periods of ischemia, and beginning and end times. Precise moni- deaths attributed to poor protection of the myocardium (24,25). toring during cardiopulmonary bypass is extremely important, At that time, several reports also noted that the levels of cardiac especially in patients with compromised renal function (i.e., enzymes after surgery were significantly elevated, indicating those who cannot produce urine to remove extra fluid from that additional myocardial damage had occurred during the their own system). In such patients, the most important elec- operations (25). CHAPTER 26 / CARDIOPULMONARY BYPASS AND CARDIOPLEGIA 377

As a result, surgeons of that era showed an increasing inter- est in attempting to protect the heart during the period of global ischemia (cross-clamping) via infusions of cold perfusates into the . Cold infusion is one of the methods known collectively as cardioplegia. Other modes for inducing cessation of cardiac activity employ chemical additions to perfusates or shocking the heart with electrical stimuli. After continued demonstration of its effectiveness, the use of hypo- thermic cardioplegia became quite widespread. Yet, today many issues still need to be investigated concern- ing optimizing cardioplegic methodologies, such as which type of solution to use, how much to inject, how often to reinfuse, how long to extend global ischemia safely using cardioplegia approaches, and how well a specific solution might protect the energy reserves of the myocardium. Operative settings that require cardioplegia involve aortic cross-clamping and coronary infusion (Fig. 5), usually of cold chemical solutions (26-30). Some surgeons prefer to inject warm (31,32) or tepid (33) solutions that have been mixed with chemical components (e.g., high-potassium concentrations). Ideally, normal myocardial cells require uninterrupted coro- nary perfusion. Therefore, the principles of applying cardiople- gia are aimed at: (1) conserving energy through the rapid induction of diastolic arrest; (2) slowing the metabolic demands and the degenerative processes that inevitably follow global myocardial ischemia; and (3) preventing unfavorable ischemic changes. Research over the past 30-plus years has provided several formulations of chemical components that have been used with ANTE~" or without cooling to obtain these three goals. Interestingly, these solutions still vary widely, likely because they have been Fig. 5. Antegrade (ANTE) cardioplegia. The ascending aorta is cross- independently developed at several separate institutions. clamped, and cardioplegia is infused into the root of the aorta. The solution runs through the coronary system and leaves the heart via the 2.1. Types of Solutions coronary sinus. At the upper right is an irrigating catheter that pro- vides topical hypothermia. This solution is removed by the suction Crystalloid solutions generally can be divided into two cat- line at the lower left. T, temperature probe (positioned in the interven- egories based on their formulations: extracellular or intracellu- tricular septum for monitoring purposes). lar. Extracellular solutions contain calcium and sodium, the primary determinants of transcellular calcium exchange. Cardioplegic cardiac arrest can still be achieved by extracellu- lar solutions containing only moderate amounts of potassium or magnesium. The cold blood cardioplegia solution (28-34), the advantage of intracellular-type solutions is that their minimal most common, is considered an extracellular ionic formula. or reduced levels of extracellular calcium will limit contrac- The principal advantage of extracellular-type solutions is that tion or restrict ischemia-induced calcium entry. The disad- they make it simpler to control equilibration characteristics vantage of such solutions is that the lack of sodium and calcium within the ischemic myocardial tissue. Because no calcium or may, under extreme conditions, predispose the heart to elicit sodium gradients exist in the extracellular fluid, subsequent the so-called calcium paradox. Another disadvantage is the replacement is easily achieved without any major reequilibra- potentially complex pattern of subsequent reequilibration tion with the intracellular fluid. The disadvantage of extracel- then required. As Hearse et al. (35) pointed out, low-volume lular solutions is that they are more easily washed out by infusion of intracellular solutions offers good protection, but noncoronary flow, but this effect can be counteracted by adding intermediate volumes offer only marginal protection, and high calcium channel blockers or procaine. volumes may actually exacerbate injury to the myocardium. Cardioplegia solutions that mimic intracellular ionic con- Each of the described crystalloid cardioplegic solutions is centration usually contain no sodium or calcium. Their advan- considered to contain several components that have been tage, at least in theory, is that the lack of sodium and calcium "proven" by these different researchers to provide enhanced generates a large osmolar space, which is available for other protection. For example, in one study published by Hearse and potentially protective components. This allows the solution to colleagues (26), the effects of changing the composition of a contain a high concentration of glucose, dextrose, mannitol, simple cardioplegic solution, when used during a 30-min period or histidine without excessive hyperosmolarity. Another of ischemia, were compared. It was shown that, at the end of a 378 PART IV: DEVICES AND THERAPIES / MOLINA

Table 1 Controversy persists regarding the "optimal" formulation to Composition of St. Thomas II Solution protect and prevent damage to the heart. The following solu- Sodium chloride 120 mmol/L tions are some of those most commonly used. Potassium 16 mmol/L Sodium bicarbonate 10 mmol/L 2.2. St. Thomas II Solution Calcium 1.2 mmol/L The formulation for the St. Thomas II (Plegisol, Abbott Phar- Magnesium 16 mmol/L maceutical Products Laboratories, Abbott Park, IL) solution Procaine 1 mmol/L originated with the published research of Hearse, Braimbridge, Osmolality 280 mosM/Kg H20 Stewart, and Jynge (26,35,39,40) from the St. Thomas Hospital Oncotic pressure 0.4 in London. The basic vehicle was Ringer's solution, to which pH 7.8 potassium chloride, procaine, and magnesium were added Table 2 (Table 1). Composition of Birmingham Solution St. Thomas II solution is an extracellular-type formulation. It is used extensively as an isolated clear cardioplegic solution Sodium 100 mmol/L Potassium 30 mmol/L and also as a base mix for the cold blood cardioplegia solution Calcium 0.7 mmol/L proposed by Buckberg and colleagues. It is usually injected into Glucose 5 g/L the root of the aorta at temperatures between 4 and 6°C (Fig. 5). Chloride 84 mmol/L Depending on the surgeon's preference, the initial volume is Albumin 50 g/L about 1000 mL for a 70-kg adult, followed by 100-mL infusions Mannitol 5 g/L intermittently every 15 to 20 min--combined with or with- Osmolality 300-335 mosM/L out topical hypothermia--to maintain the heart's temperature below 15°C. Table 3 Composition of Bretschneider The size of the catheter and the pressure for injecting the (Custodiol) Solution infusion are discussed in Section 2.8. Sodium 15 mM 2.3. Birmingham Solution Potassium 9 mM Various extracellular solutions were also developed in the Magnesium 4 mM United States. Most sought to attain relatively high extracellu- c~-Histidine 180 mM lar concentrations of potassium as an arrest-inducing drug. Bir- ct-Histidine HC1 18 mM Calcium chloride 0.015 mM mingham solution was developed by Conti and colleagues (41); Mannitol 30 mM its effectiveness was primarily demonstrated by the publica- Tryptophane 2 mM tions of Kirklin and colleagues (42). Ketoglutarate 1 mM The importance of Birmingham solution is that glucose pH 7.1-7.2 was included as a substrate for the myocardium (Table 2). The Osmolality 295-325 mosM/Kg H~0 development of this solution gave origin to many other formu- lations that used the basic additions of glucose, potassium, and insulin. 2.4. Bretschneider Solution (Custodiol) period of ischemia when no cardioplegia was used, the percent- During the early 1960s and 1970s, Bretschneider in Goet- age of ventricular function recovery was practically nil, only tingen, Germany published his studies introducing HTK about 3%. However, if potassium was added, the recovery (histidine-tryptophane-ketoglutarate) also known as Custodiol increased to about 30%. Furthermore, if both potassium and (Dr. F. K6hler Chemie GmbH, D-6146 Alsbach-H~ihnlein, magnesium were added, the recovery was even better, up to Germany) crystalloid cardioplegic solution (43,44) (Table 3). 68%. And, if potassium, magnesium, and adenosine triphos- This intracellular-type solution has also been shown to be very phate (ATP) were combined, the recovery reached 86%. Finally, effective in protecting the heart during surgery. It has been used if a combination of potassium, magnesium, ATP, creatine phos- extensively in Germany since its introduction. It is used not phate, and procaine was used, the recovery peaked at 93%. only as a protective solution for the heart during periods of After only crystalloid cardioplegia had been used for several surgical ischemia, but also as a preservation solution for years, it was reconsidered if the use of mixing cold blood with (45-4 7), livers, and kidneys (48) in the field of transplan- crystalloid solution (34) offered even better protection than the tation. crystalloid solution alone; this was considered so if the period According to Preusse et al. (44), the solution must be pro- of cardiac ischemia was more than 90 min. Although the idea of vided in large amounts, between 3000 and 4000 mL per organ. protecting the heart with blood cardioplegia originated in the Therefore, double cannulation of the right atrium is recom- early 1950s with Ebert and colleagues (36), it was not until 20 mended during surgery to open the right atrium and to eliminate years later when it was reintroduced by Buckberg and associ- the large volume of solution from the general circulation by ates (28,32,34,37,38) that it was popularized to use cold blood aspirating it from the coronary sinus orifice (Fig. 6). For cardioplegia among most surgeons in the United States and Custodiol to be most effective, the period of equilibration is throughout the world. crucial (43,44); that is, it takes about 7 min of infusion to equili- CHAPTER 26 / CARDIOPULMONARY BYPASSAND CARDIOPLEGIA 379 brate the extracellular and intracellular spaces before the patient's operation can proceed. This solution has also been used for both antegrade and retrograde (through the coronary sinus) perfusions. One of the considered significant advantages of this solution is its buffer- ing capacity, which even surpasses the buffering properties of blood. Custodiol needs to be stored at a specific temperature (12 to 16°C) to prevent denaturation of the components. 2.5. Glucose-Insulin-Potassium Solutions Most of the research performed on glucose-insulin-potas- sium (GIK) solutions was done in the United States. Multiple formulations with these basic components have been widely used for the past 30 years. Studies by Hewitt et al. (49) and later by Lolley et al. (50) demonstrated that continuous infusion of a solution containing 278 mmol/L of glucose, 20 mmol/L of potassium, and 20 U insulin with 69 mmol/L of mannitol dra- matically improved myocardial protection. Those studies illustrated that the combination of glucose, insulin, and potas- sium improved anaerobic glycolysis and the washout of toxic substances. A slight modification of this basic solution, which included albumin to increase osmolality, was used extensively HTK- ..... for many years at the University of Minnesota (Minneapolis, Fig. 6. Antegrade infusion of Bretschneider (HTK, histidine-tryp- MN) (51-53) (Table 4). The only concern with the use of GIK tophane-ketoglutarate) solution. The solution is infused in an solutions is the inevitable degradation of its constituent insulin antegrade manner into the aortic root while the aorta is cross-clamped. over time. Therefore, GIK solutions must be prepared fresh for Because this method requires a large volume of solution, the right each use and cannot be stored for prolonged periods. atrium is opened, and the solution exiting the coronary sinus is aspi- Many investigators contributed to the formulation of GIK rated and discarded. The superior and inferior venae cavae are indi- vidually cannulated to allow the right atrium to remain empty so that solutions, among them Follete and coworkers (34) and Todd the HTK solution can be evacuated. Topical hypothermia is shown, and Tyers (54); Roe et al.'s classical solution (30) also belongs with the irrigating cannula at the upper right and the suction catheter in this category. The common denominator among these formu- at the lower left. T, temperature probe. lations is the use of dextrose as the basic vehicle. Multiple pub- lications have shown protective effects. However, when used Table 4 alone, GIK solutions often provide insufficient protection dur- Composition of the Crystalloid ing long periods of ischemia (beyond 120 min) or when the left Potassium Insulin ventricular function is marginal. (University of Minnesota) Solution Several crystalloid potassium solutions have been formulated Dextrose 50 g/1000 mL without dextrose. The main difference among them is the basic Sodium 3.5 mEq/L vehicle, which could be formulated with Ringer's or Krebs- Potassium 30 mEq/L Chloride 30 mEq/L Henseleit. Potassium is commonly added at doses between 15 Sodium bicarbonate 3.5 mEq/L and 125 mmol/L. Some solutions in this group are the Univer- Regular insulin 10 U sity of Wisconsin (46,55) and Celsior (56) solutions, both used Mannitol 12.5 g to preserve organs for transplantation. Several agents are con- Albumin 12.5 g sidered also available to help increase the osmolality of Osmolality 364 mosM/L cardioplegic solutions (Table 5). For example, mannitol has pH 7.8 been included in such solutions both to stabilize osmolality and Oncotic pressure 3 to act as a potential scavenger for oxygen radicals. Table 5 2.6. Additional Components Components Used to Raise Osmolality Other components have been added to crystalloid cardio- Oncotic pressure Osmolality plegic solutions by various investigators based on their own Component (mmH g ) (mosm ) research. These include aspartate (38) as a substrate to generate Hespan (hetastarch) ATP; glutamate (38) as a substrate; procaine (35,40) as a mem- (6% in 0.9% saline solution) 18.4 311 brane stabilizer; nifedipine (57) to prevent calcium paradox; Mannitol 25% (12.5 g/50 mL) 0.1 -- phosphates (58-60) as a base for ATP regeneration; and ste- Albumin 25% >200 239 roids (methylprednisolone) (61-63) as a cellular wall stabilizer. Dextran (10% in dextrose) 130.2 319 Other elements found to help maintain an alkaline pH include Plasmanate (5% albumin) 16.86 239 tris hydroxymethyl aminomethane (THAM), as advocated by THAM" -- 370 Buckberg (28), and histidine, as in HTK solution. "THAM, Tris hydroxymethyl aminomethane. 380 PART IV: DEVICES AND THERAPIES / MOLINA

Table 6 rates less than 125 mL/min result in a higher incidence of cel- Composition of Buckberg's lular ischemia, focal necrosis, and uneven flow distribution (53). Cold Blood CardioplegicSolution Consequently, patients with obstructive coronary disease who 5% dextrose with 1/4 normal saline 422 mL undergo low-pressure or low-volume cardioplegic injection will Potassium chloride 2 mEq/mL inevitably experience an increase in flow distribution problems. THAM a 72 mL Conversely, pressures higher than 110 mmHg and peak flow Diluent volume 500 mL rates greater than 1500 mL/min may result in a higher incidence Blood hematocrit 22% = 500 mL Osmolality 360 mosM/kg of mechanical and physical trauma to the vascular endothelium Potassium 22 mEq/L (53). These higher levels, however, greatly enhance cellular pH 7.8 protection. It should be noted that the use of high pressures in Calcium 0.3 mEq/L the aortic root of patients with coronary obstructions does not Hematocrit 10% necessarily raise a concern. The rapid administration of aTHAM. Tris hydroxymethyl aminomethane. cardioplegic solutions causes the temperature of the myocar- dium to fall rapidly within the protective range below 15°C and induces cardiac arrest. Cardioplegic solutions are most commonly administered 2.7. Cold Blood Cardioplegia via an injection into the aortic root below the level of the aortic The mixture of blood with crystalloid cardioplegia has cross-clamp (Fig. 5). This site provides a normal antegrade become the most favored formulation for cardioplegia among flow to all areas of the heart. Several aortic valve procedures, cardiac surgeons, both in the United States and throughout the however, require the aortic root to remain open for prolonged world. It is considered superior to the use of any other periods. In such cases, cardioplegic solutions may be admin- cardioplegic solution alone. The standard proportion of blood istered retrograde, through the coronary sinus, while the valve to crystalloid solution has remained fairly constant, at 4:1 repair is performed. This option also continuously protects the (4 parts blood to 1 part crystalloid cardioplegia), yet the actual heart (Fig. 9). formulation of the crystalloid portion has varied across insti- Yet, this approach has several limitations that will be depen- tutions (64). dent on the degree of hypertrophy the myocardium may have Administration of cold blood cardioplegia in the propor- suffered because of a preexisting condition. The pressure in the tions proposed by Buckberg (Table 6) can be easily accom- coronary sinus must be intentionally kept below 50 mmHg to plished using the appropriate equipment available as a kit. The prevent possible injury to the vein, but such reduced pressures kit contains the necessary caliber of tubing, which is placed may be insufficient to perfuse all areas of the heart. As a result, into a roller pump that automatically mixes the blood with the left ventricular dysfunction is occasionally observed after long clear solution before injection into the root of the aorta (Fig. 7). periods of retrograde perfusion, even at myocardial tempera- The kit also includes a heat exchanger, which maintains the tures below 15°C. In such cases, decompression of the left ven- temperature of the solution between 4 and 6°C and allows the tricular chamber is considered essential to facilitate perfusion myocardial temperature to decrease even below 15 °C. The sig- of all areas of the heart (67). Therefore, some surgeons still nificant advantage of cold blood cardioplegia is that it is con- prefer antegrade perfusion through the coronary orifices requir- sidered to provide oxygen and nutrients to the ischemic ing handheld cannulas, even though this may cause interrup- myocardium and offers optimal buffering capacity. This mix- tions in the flow of the operation. ture can be injected antegrade (in the root of the aorta) or ret- Over the past 30 years, the use of cardioplegic solutions rograde (by coronary sinus cannulation using a self-inflating should be noted as one of the significant advances in cardiac balloon to perfuse the entire heart) (65) (Fig. 8). surgery to increase the safety of such operations. Nevertheless, Cold blood cardioplegia has endured many years of testing, researchers continue to look for better systems and methods to both in its initial form of providing cardioplegia at cold tem- provide even greater protection of the heart during cardiac sur- peratures and in its more recent adaptation to warm cardiople- gery. gia as promoted by Lichtenstein et al. (66). The cold blood 2.9. Adjunct Topical Hypothermia method is widely used in the pediatric population for correction The use of cardiac hypothermia has been one of the most of all types of congenital anomalies. important tools for increasing the safety of cardiac operations. 2.8. Cardioplegic Administration The application of topical hypothermia was introduced in the Our previous clinical work showed that cardioplegic solu- 1960s by Shumway, Lower, and Stofer (68,69) and was used tions should be administered at a rapid rate and under moderate exclusively through the 1970s until the introduction of crystal- pressure (29,51). Doing so shortens the prearrest period, pro- loid cardioplegia. vides better flow distribution, and accelerates the decrease in Topical hypothermia is considered to potentiate the use of myocardial temperature. Rapid injection results in a postopera- all methods of cardioplegic perfusion, keeping the tempera- tive level of cardiac isoenzymes that is lower than the level in ture of the heart in a safe range to tolerate global ischemia. The patients who undergo a slower cardioplegic injection (51). heart can be effectively cooled by a continuous flow of cold Experimental studies on normal of animals (6°C) saline or Ringer's solution over the heart; the remaining showed that low pressures (less than 30 mmHg) and peak flow solution is removed via wall suction (Figs. 5, 6, 8, and 9). This CHAPTER 26 / CARDIOPULMONARY BYPASS AND CARDIOPLEGIA 381

Fig. 7. Roller pumps of cardioplegia infusion system. The upper pump utilizes 1/4-in tubing to move the blood, and the lower pump runs crystalloid cardioplegic solution within 1/16-in tubing. The blood and cardioplegic solution are automatically mixed in a proportion of 4:1 in the outflow line before injection into the ascending aorta.

B LO-O / RETRO Fig. 8. Cold blood cardioplegia. This may be administered by antegrade infusion into the root of the aorta below the cross-clamp. It Fig. 9, Retrograde administration of crystalloid cardioplegia. This is may also be accomplished in a retrograde manner through a catheter accomplished via the coronary sinus, with the balloon inflated, to inserted in the coronary sinus, with the balloon inflated to prevent prevent reflux into the atrium. The solution eventually reaches the reflux into the right atrium. Topical hypothermia is used in conjunc- aortic root, where it is aspirated. It may also be allowed to drain into tion with cold blood cardioplegia to potentiate the hypothermic pro- the left ventricle, which is vented to the pump. Topical hypothermia tection of the heart. P, pressure monitoring of the coronary sinus; T, is shown using cold saline around the heart. P, pressure line monitor- temperature probe. ing; T, temperature probe. 382 PART IV: DEVICES AND THERAPIES / MOLINA technique is now preferred to the older method of applying observations with warm cardioplegia. Ann Thorac Surg. 59, 1429- slush ice over the heart; the latter method was attributed with 1433. 19. Naik, S.K., Knight, A., and Elliot, M. (1991) A prospective random- the induction of frostbite lesions, not only of the heart, but also ized study of a modified technique of ultrafiltration during pediatric of the phrenic nerve, which runs along the . Sev- open-heart surgery. Circulation. 84(Suppl), 111422-111431. eral types of plastic jackets have also been designed for appli- 20. Davies, M.J., Nguyen, K., Gaynor, J.W., and Elliott, M.J. (1998) cation around the heart for this purpose. 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