6 Myocardial Management in Arterial Revascularization 53 Provide Optimal Protection at These Levels [11, 12]

Chapter 6 Myocardial Management in Arterial 6 Revascularization B.S. Allen, G.D. Buckberg

The objectives of every cardiac operation must be a Table 6.1. Myocardial supply/demand balance during aortic technically perfect anatomic result and avoidance of in- cross-clamping traoperative damage in pursuit of this goal. Neverthe- Supply Demand less, perioperative myocardial damage remains the most common cause of morbidity and death following Noncoronary collaterals Electromechanical activity technically successful coronary bypass operation. This Intrinsic substrate stores Wall tension (glycogen) occurs whether the conduits are arterial or venous. Temperature (metabolic rate) Cardiac damage from inadequate myocardial protection leading to low output syndrome can prolong hos- principles are directly applicable to use of all arterial pital stay, and may also result in delayed myocardial fi- conduits during coronary revascularization. Issues of brosis leading to cardiac dysfunction months to years protection are important here, due to potential conduit later [1, 2]. Cardioprotective strategies, like cardiac op- discrepancy between arterial grafts and the coronary erations, have evolved to the point that it is essential to artery. Clearly, the long-term patency of arterial grafts understand various techniques in order to limit intrao- must be matched by absence of intraoperative damage perative damage during a complicated operation. Sur- whiletheyareconstructed. geons must refrain from using simplistic cardioplegic Table 6.1 lists the factors affecting the myocardial en- protection strategies for the very reason that simplicity ergy supply/demand balance during aortic clamping. and safety are not synonymous. As with technical as- The two factors affecting supply include oxygenated pects of the surgical repair, the primary object of pro- blood coming from noncoronary collateral blood flow, tection techniques is the use of the best strategy. Inte- and intrinsic or extrinsic substrate stores. All surgeons gration of surgical techniques is usually required to have noted noncoronary collateral flow during aortic perform the best technical operation. Similarly, opti- clamping, as blood appears in the coronary arteriotomy mal myocardial protection also requires integration of site during coronary revascularization despite a flaccid various techniques to achieve the best results. Most sur- aorta. The second determinant of supply is myocardial geons would not abandon a complex surgical proce- glycogen or exogenous glucose to provide anaerobic dure (like all arterial revascularization) that was metabolism to generate some energy during ischemia proved superior solely because of its lack of simplicity. to maintain cell membrane viability. Anaerobic glycoly- Likewise, we should not choose a protection strategy sis requires the presence of substrate (i.e., glucose or for simplicity, unless it provides optimal and complete glycogen), and a metabolic environment (i.e., buffer- myocardial protection. Optimal myocardial protection ing) to allow anaerobic energy production. Myocardial is as important as an excellent technical repair in oxygen demands are determined principally by electro- achieving the best long-term outcome with surgical mechanicalactivity.Cardiacarrestisusedbecausethe correction. Although, the surgeon might desire simplic- fibrillating or beating ischemic heart has a much higher ity,thepatientisonlyconcernedwithsuccess. energy requirement. The second determinant of de- This chapter describes how oxygenated cardioplegia mand is the wall tension within the myocardium, that is solutions can be delivered warm to allow their use for minimizedbyasystole,andthethirdthemyocardial active resuscitation before ischemia is imposed, cold to temperaturethatgovernsmetabolicratedirectly. limit damage, and again warm to avoid and reverse ischemic and reperfusion damage before and after aortic unclamping [1, 2]. It focuses primarily on the princi- 6.1 ples that form the basis for clinical strategies for cardio- Cardioplegic Prerequisites plegic delivery that can ensure that the selected cardioplegic solution can exert its desired effect, and it de- Essential clinical prerequisites for cardioplegia include scribes how these can be implemented. The described (1) a solution that is shown to be safe through testing 52 III Myocardial Protection During Coronary Bypass Surgery Using Arterial Grafts

under experimental conditions, in ischemic models, These solutions should be delivered according to estab- (2) the distribution of flow to all cardiac regions, (3) pe- lished experimental protocols, and, most importantly, riodic replenishment to counteract noncoronary collat- the aim must be complete preservation of metabolic eral washout, and (4) strategies for protection in vari- and functional parameters. A failure to reconstitute ous clinical conditions. creatine phosphate or other metabolic levels following aortic unclamping should be looked at as a protection failure, in the same way that a residual ventricular sep- 6.2 tal defect (VSD) or AVvalve regurgitation is a technical Cardioplegic Composition failure. Optimal protection is as important as the technical aspects of the repair in achieving the best long- The cardioplegic objectives are to stop the heart safely, term outcome for the patient. Using arterial grafts will allow continued energy production, and counteract not improve long-term survival if the patient is left deleterious effects of ischemia. The principles which with myocardial dysfunction as a result of poor protec- underlie the composition of any cardioplegic solution tion. are enumerated in Table 6.2. First, immediate arrest lowers energy demands to avoid depletion by ischemic electromechanical work, and high-energy stores are 6.3 enhanced with oxygenated solutions compared to crys- Blood Cardioplegia (Table 6.3) talloid solutions, that deplete adenosine triphosphate (ATP) before arrest [1, 2]. Second, reducing myocardial We have selected blood as the cardioplegic vehicle, temperature during perfusion lowers metabolic rate sincethisphysiologicsourceofoxygenisavailable duringischemia.Third,substrate(i.e.,glucoseorgly- readily in the extracorporeal circuit, and its use limits cogen) and Krebs cycle intermediates (i.e., glutamate or hemodilution when large volumes of cardioplegia are aspartate) [3] enhance anaerobic or aerobic energy needed. An additional advantage of a blood cardiople- production (or both) during aortic clamping. Fourth a gic vehicle is to ensure the buffering capacity of blood buffer such as TRIS (hydroxymethyl) aminoethane proteins, especially histidine imidazole groups [8]. Fur- (THAM), bicarbonate, phosphate, or perhaps some thermore, the rheologic benefits on the microvascula- other buffer optimizes the small energy output of an- ture afforded by erythrocytes enhance papillary mus- aerobic glycolysis during ischemia [1, 4]. Fifth, there cle perfusion compared with oxygenated crystalloid must be some degree of membrane stabilization with cardioplegia and reduce coronary vascular resistance exogenous additives or hypocalcemia [1, 5, 6]. Magne- and edema formation [9]. The erythrocytes of blood sium enrichment improves protection by preventing cardioplegia also contain abundant endogenous oxy- calcium influx, even in the presence of hypocalcemia. gen free radical scavengers (i.e., superoxide dismutase, The role of steroids, calcium channel blockers, and pro- catalase, and glutathione) [10], which may reduce oxy- caine is uncertain at this time. Oxygen radical scaven- gen-mediated injury during reperfusion. Their benefits gers (i.e., superoxide dismutase [5], catalase, allopuri- enumerate only the known benefits of using blood as nol, coenzyme Q10 [CoQ10], [6]) may counteract the cy- the vehicle for delivering oxygenated cardioplegia. We totoxic oxygen metabolites during ischemia and reper- are confident that further studies will reveal other nat- fusion [7]. Sixth, myocardial edema is limited by alter- urallyoccurringbloodcomponents(i.e.,enzymes,co- ing the osmolarity and colloid osmotic pressure of the factors, substrates, and electrolytes) that are important cardioplegic solution during infusions [7]. and would otherwise need to be added to any artificial- It is essential that only cardioplegic solutions de- ly constructed solution. signed and tested for a specific purpose be utilized. Blood cardioplegia is not just any crystalloid solution added to blood. Solutions like Plegisol (St. Thomas solution) were specifically developed to work best as a Table 6.2. Pharmacologic cardioplegia crystalloid solution, with the constituents adjusted to Principle Method

Immediate arrest K+,Mg2+,procaine Table 6.3. Blood cardioplegia Hypothermia 10°–20°C Oxygenation during arrest Substrate Oxygen, glucose, glutamate, Reoxygenation during replenishment aspartate Avoids reperfusion injury Avoids hemodilution Appropriate pH (buffer) THAM, bicarb., phosphate Endogenous Membrane stabilization Ca2+,steroids,procaine Oxygen radical scavengers Ca2+ antagonist, magnesium Buffers O2 radical scavenger Onconicity 6 Myocardial Management in Arterial Revascularization 53 provide optimal protection at these levels [11, 12]. Mix- 6.4 ing Plegisol (or other crystalloid cardioplegia solu- Operative Strategy tions) with blood alters the final (delivered) composition, and, as such, may not provide the same level of The strategies for clinical cardioplegia may be separat- protection. These solutions must be tested and com- ed into the phases of (1) induction, (2) maintenance pared to blood cardioplegic solutions that convey es- and distribution, and (3) reperfusion. tablished benefits. Conversely, blood cardioplegic solutions were developed to provide the ideal levels of the 6.4.1 various components only after they are mixed with Cardioplegic Induction blood [1, 3, 12, 13]. Therefore, it is important that the surgeon recognize the limitations of crystalloid solu- Cardioplegia may be given immediately after extracor- tions, and employ blood cardioplegic solutions that poreal circulation has begun, provided that the pulmo- have been specifically formulated for that purpose. nary artery is collapsed to attest to the adequacy of ve- The versatility of blood cardioplegia provides the nous return. Starting the infusion shortly before aortic cardiac surgeon with an extremely powerful tool to ac- clamping ensures aortic valve competence. We always tively treat the jeopardized myocardium as well as to deliver cardioplegia over time instead of by dose, as the prevent ischemic damage, provided attention is direct- heart takes up nutrients and is cooled over time. We do ed toward ensuring adequate delivery of the cardiople- not aim for a specific flow, but deliver the cardioplegia gicsolutions.Tables6.4and6.5enumeratetheprinci- at a continuously measured aortic root or coronary si- ples that underlie our experimentally and clinically nus pressure of 30–50 mm Hg. tested blood cardioplegic solutions [1, 2, 13, 14]. The cold cardioplegic solution contains 500–600 µM/l cal- 6.4.2 cium without glutamate or aspartate, but the cardiople- Cold Induction gic solution used for warm cardioplegic induction and warm reperfusion contains glutamate and aspartate Cardioplegic induction in operations on hearts with and a lower ionic calcium achieved by adding more cit- reasonably normal energy reserves is intended to (1) rate phosphate dextrose (CPD). stop the heart promptly to lower oxygen demands, (2) produce hypothermia to reduce O2 demands further, and (3) create an environment which allows continuous Table 6.4. Warm blood cardioplegia solution anaerobic energy production during intervals between Cardioplegia Volume Component Concentration cardioplegic replenishments in order to prevent ische- additive added (ml) modified delivereda mic damage (Table 6.6). An initial cold (4°–8°C) infusion containing a high concentration of potassium (i.e., KCl (2 mEq/ml) 10 K+ 8–10mEq/l THAM (0.3 mol/l) 225 pH pH 7.5–7.7 20–25 mEq/l, KCl) will produce asystole promptly. CPD 225 Ca2+ 0.2–0.3 mM/l Measurement of the aortic infusion pressure will allow 2+ MgCI2 (2 mEq/ml) 9 Mg 4–6mEq/l detection of aortic incompetence if it is caused inad- Aspartate/glutamate 250 Substrate 13 mmol/l each vertently. Cold induction is usually given from D50 W 40 Glucose <400 mg/dl D5 W 200 Osmolarity 380–400 mOsm 4–5 months to allow for uniform cooling throughout the myocardium. Cardioplegic solutions stop the heart 50 THAM tromethamine, CPD citrate-phosphate-dextrose; D W by depolarizing the cell membrane. Higher cardiople- 50% dextrose in water a When mixed in a 4:1 ratio with blood gic potassium concentrations (i.e., 15–30 mEq/l) are usually necessary to produce then to maintain asystole, but raising K+ >30 mEq/l is unnecessary during cardio- Table 6.5. Cold blood cardioplegia solution plegic induction, and only increases the potential for Cardioplegia Volume Component Concentration systemic hyperkalemia. Combining hypocalcemic and additive added (ml) modified delivereda magnesium enrichment with potassium will also

+ quicken arrest with blood or crystalloid cardioplegia KCl (2 mEq/ml) 5 K 8–10mEq/l + THAM (0.3 mol/l) 200 pH pH 7.6–7.8 [11, 15]. Cardioplegic K can be reduced to 8–10 mEq/l CPD 50 Ca2+ 0.5–0.6 mM/l during subsequent cold cardioplegic infusions (i.e., 2+ MgCI2 (2 mEq/ml) 9 Mg 4–6mEq/l multidose cardioplegia; see “Cardioplegic Mainte- D5 W 550 Osmolarity 340–360 mOsm nance” below) since perfusion or topical hypothermia THAM tromethamine, CPD citrate-phosphate-dextrose, D50 W potentiates the effectiveness of any cardioplegic potas- 50% dextrose in water sium concentration. a When mixed in a 4:1 ratio with blood Failure to produce arrest within 1–2 min may be due to (1) incomplete aortic clamping, (2) aortic insufficiency produced by distortion of the noncoronary cusp 54 III Myocardial Protection During Coronary Bypass Surgery Using Arterial Grafts

Table 6.6. Blood cardioplegic induction ventricular hypertrophy or dysfunction pose more dif- Cold Warm ficult problems in myocardial protection. Depletion of Global hypothermia “Active resuscitation” energy reserves and glycogen stores is common in such Prompt asystole hearts; they (1) are less tolerant to ischemia during aortic clamping, (2) cannot sustain cell metabolism when blood supply is interrupted, and (3) use oxygen ineffi- by a large right atrial cannula, (3) incomplete decom- ciently. The induction of warm blood cardioplegia in pression by the venous cannula resulting in admixture the energy depleted heart is, in a sense, the first phase of venous blood returning to the left heart and diluting of reperfusion. of the cardioplegic solution, and (4) inadvertent failure A brief (i.e., 5-min) infusion of warm oxygenated to add sufficient potassium to the cardioplegic solu- cardioplegic solution can be used as a form of active re- tion. Palpation of the left ventricle during cardioplegic suscitation in energy-depleted hearts [3, 17] which induction allows detection of left ventricular distention mustundergoprolonged(i.e.,2h)subsequentaortic that occurs if venous drainage is inadequate or aortic clamping. Normothermia optimizes the rate of cellular insufficiency has been produced. Corrective measures repair, and enrichment of the oxygenated cardioplegic include readjusting the position of the venous cannula solution with amino acid precursors of Krebs cycle in- within the right atrium and/or moving it away from the termediates (aspartate and glutamate) improves oxy- coronary cusp. Discontinuation of the cardioplegic in- gen utilization capacity. Substrate enriched warm fusion and immediate ventricular venting are neces- (37°C) blood cardioplegic induction results in myocar- sary if these maneuvers fail to produce decompression. dial oxygen uptake in energy depleted hearts (subject- Undueconcernshouldnotbedirectedtowardreducing ed to 45 min of normothermic global ischemia) which the temperature of the cardioplegic solution much be- exceeds basal requirements markedly (Fig. 6.1) and re- low 10°C since minor differences in solution tempera- sults in improved recovery despite two additional ture (i.e., between 5° and 10°C) will not produce major hours of aortic clamping with multidose blood cardio- differences in myocardial temperature or oxygen de- plegia (to simulate the time needed for operative re- mands during the brief interval of cardioplegic infu- pair) [18, 19] (Fig. 6.2). The extra oxygen may be used sion, especially after the heart is arrested. to repair cell damage and to replace the energy stores Cardioplegic infusions may cause myocardial edema (creatine phosphate) which can be used to sustain an- (especially if the myocardial cells are ischemic), if per- aerobic metabolism during the ischemic intervals until fusion pressure is allowed to become excessive (i.e., the next cardioplegic replenishment. Left ventricular >80 mmHg) since the myocardial contractile force and venting during warm induction lowers wall tension muscle tone which limit fluid flux mechanically are maximally [20]. overcome by pharmacologic asystole, and hypother- In contrast to cold cardioplegic induction, the dura- mia interferes with normal cell volume regulation tion of cardioplegic delivery during normothermic in- by decreasing the effectiveness of the Na+/K+ pump [2,7,16].Clinicalcardioplegicperfusionpressuresof 80–100 mmHg are probably safe during cardioplegic induction since myocardial electromechanical activity persists during part of the infusion, the full extent of perfusion hypothermia is not instantaneous, and the integrity of the capillary bed has not yet been altered by ischemic damage. Conversely, once the heart is arrested, keeping perfusion pressure at or below 50 mmHg during reinfusions and reperfusion will limit edema when cardioplegic replenishments are delivered to myocardial regions containing capillary endothelial cells that may have been damaged because they did not receiveadequatecardioplegicprotectionduringprevi- ous infusions.

6.4.3 Fig. 6.1. Oxygen consumption during induction of blood cardi- Warm Induction oplegia.Note:(1)twiceasmuchoxygenconsumedbyhearts given warm (37°C) glutamate blood cardioplegia compared to Cardiac operations upon ischemic hearts (i.e., cardio- cold (4°C) blood cardioplegia, (2) >threefold increase in oxy- genic shock, extending myocardial infarction, hemo- gen consumption by aspartate enrichment of warm glutamate dynamicinstability)orinpatientswithleftorright blood cardioplegia (MVO2 myocardial oxygen consumption) 6 Myocardial Management in Arterial Revascularization 55

environment, which can promote calcium influx leading to cell damage and (3) allows the same cardioplegic solution to be used during warm reperfusion (hot shot). Warm cardioplegic induction must be followed by the administration of cold cardioplegia to provide perfusion hypothermia to prevent ischemic damage during the subsequent period of aortic clamping. The prolonged aortic clamping during cardioplegic induction (5 min of warm and 3–5 min of cold blood cardioplegia) does not add ischemia when the cardioplegic in- gredients are mixed with blood or some other form of oxygen (i.e., fluorocarbons, bubbled oxygen, or stro- ma-free hemoglobin). A 5-min interval of warm blood cardioplegic induction has previously been used in he- modynamically unstable patients, particularly those in cardiogenic shock [22–24]. It is now apparent that many hearts not exhibiting cardiogenic shock may also be energy depleted, as decreased levels of ATP are re- Fig. 6.2. Left ventricular performance 30 min after blood reper- ported in hypertrophied hearts with pressure or vol- fusion. Note: (1) normal ventricular performance after warm umeoverloadandthosewithcoronaryarterydisease (37°C) induction of aspartate enriched glutamate blood cardi- [25, 26]. In addition, the risk profile of patients requir- oplegia; (2) moderate depression in ventricular performance ing operation is increasing and recent studies show that after warm induction with glutamate blood cardioplegia; (3) severe depression in ventricular failure after cold (4°C) blood there is increased uptake of oxygen and glucose during cardioplegia (LAP left atrial pressure, SWI stroke work index) warm substrate-enriched blood cardioplegic induction in noncardiogenic shock patients; this (1) is most pro- nounced in patients who were unstable preoperatively duction is more important than the volume of cardio- (CHF, left main disease, unstable angina) or who are plegia given because the heart takes up oxygen over hypertensive with or without left ventricular hypertro- time and not by dose. Whereas the basal myocardial ox- phy, (2) persists throughout normothermic induction, ygen requirements of the healthy heart subjected to and (3) correlates directly with the preoperative score normothermic arrest are only 1 ml/100 g per minute or described by Parsonnet that predicts higher periopera- 5 ml/100 g during 5 min, the energy-depleted heart tive mortality [27, 28]. The normothermic infusion is consumes approximately 25–30 ml O2 over a 5-min in- delivered both antegrade and retrograde to ensure car- duction interval under experimental conditions [3, 21]. dioplegic distribution as in cardiogenic shock patients Administration of this same cardioplegic volume for (to be described subsequently). 1 min would allow only 20% of the oxygen to be used compared to the fivefold greater O uptake which can 2 6.4.4 occur when the same volume of cardioplegia is given Cardioplegic Maintenance over 5 min. The operation does not need to be prolonged during All hearts receive some noncoronary collateral blood warm induction of oxygenated cardioplegia. Distal flow via pericardial connections. The volume of this anastomoses into occluded left anterior descending or flow is variable [29], but is sufficient to wash away all right coronary arteries can be constructed in coronary cardioplegic solutions with the exception of those given operations provided aortic insufficiency is not pro- to donor hearts excised for subsequent transplantation. duced by distorting the heart. More immediate arrest Myocardial temperature increases after the cardiople- during warm induction of blood cardioplegia occurs gic solution is discontinued, as the heart is rewarmed when the concentration of the cardioplegic agent is by the noncoronary collateral blood flow that has the transiently increased (i.e., to 25 mEq/l K+). The arrested same temperature as the systemic perfusate. Efforts at heart then tends to stay that way with a lower potassium controlling noncoronary collateral flow by reducing ei- concentration (8–10 mEq/l) especially in the presence ther systemic flow rate or systemic perfusion pressure, of hypocalcemia and elevated magnesium levels. Pri- or by using profound levels of systemic hypothermia marily using a warm cardioplegic solution with a potas- (<25°C), must be tempered by the recognition of the sium concentration of 8–10 mEq/l helps (1) prevent hy- possible hematologic consequences of deep hypother- perkalemia in longer operations requiring longer vol- mia, and the potential deleterious effects of hypoperfu- umes of cardioplegia, (2) prevents the ischemic cell sion of other vital organs (brain and kidney) at low sys- from being left in a high (20–30 mEq/l) hyperkalemic temic flow rates. 56 III Myocardial Protection During Coronary Bypass Surgery Using Arterial Grafts

Periodic replenishment of the cardioplegic solution at approximately 20-min intervals counteracts noncoronary collateral washout. Multidose cardioplegia is necessary even if electromechanical activity does not return since low-level electrical activity may precede recurrence of visible mechanical activity, and can lead to delayed recovery if cardioplegic replenishment is not provided [10]. Periodic replenishment (1) maintains arrest, (2) restores desired levels of hypothermia, (3) buffers acidosis, (4) washes acid metabolites away which inhibit continued anaerobiosis, (5) replenishes high-energy phosphates if the cardioplegic solution is oxygenated, (6) restores substrates depleted during ischemia [30] and (7) counteracts edema with hyperosmolarity. Cardioplegic replenishment with low-potassium Fig. 6.3. Left ventricular performance after blood cardioplegic (8–10 mg/l) solutions limits systemic hyperkalemia. infusion in dogs with no stenosis, and those where attempts Replenishment of oxygenated cardioplegic solutions at were made to distribute the cardioplegic solution beyond ste- 200–250 mL/min over 2 min ensures a gentle perfusion nosis. Note the partial recovery following 30 min of aortic clamping when no attempt was made to distribute the cardio- pressure (less than 50 mmHg) to avoid edema, and al- plegic solution, and the normal performance following lows enough time for the heart to use the delivered oxy- 120 min of aortic clamping when cardioplegic distribution was gen. Myocardial oxygen uptake may exceed basal de- unimpeded mandsbyasmuchastenfoldduringeach2-minreplen- ishment [31]. Asanguineous cardioplegic solutions ommend grafting any free grafts which will be anasto- without oxygen should be reinfused after similar inter- mosed to the aorta first to allow for improved cardio- vals, but anoxic solutions should be given as a fixed vol- plegic delivery. Conversely, with vein grafts we usually ume and as rapidly as possible to limit the duration of graft the largest area of remote myocardium first. anoxia, provided perfusion pressure does not exceed Possible strategies to ensure cardioplegic distribu- 50 mmHg. High perfusion pressure during cardiople- tion with arterial grafting include constructing both gic reinfusions should direct suspicion toward the pos- proximal anastomoses during a single period of aortic sibility of (1) obstruction of the infusion cannula or (2) clamping, or delivering retrograde cardioplegia. Most kinking or twisting of one of the grafts. operations will require both routes of delivery because many arterial grafts are left in situ (i.e., internal mammary artery, IMA), which prevents distribution of car- 6.4.5 dioplegia via the newly constructed grafts. Cardioplegic Distribution To ensure an adequate cardioplegic solution distribu- All Anastomoses During Aortic Clamping. This pro- tion is especially important in coronary patients where longs the duration of aortic clamping but ensures car- maldistribution of flow is the reason for operation. Our dioplegic delivery provided each proximal anastomosis studies show that it is safer to clamp the aorta for 2–4 h is accomplished immediately after each anastomosis. with good cardioplegic distribution than for as little as The obligatory prolongation of aortic clamping is 30 min when the same cold cardioplegic solution is giv- counterbalanced by the improved cardioplegic distri- en without attempts to deliver it beyond coronary ste- bution as shown in a recent report by Weisel et al. [34]. nosis [32, 33] (Fig. 6.3). Homogeneous hypothermia is Prolongation of aortic clamping may be problematic if not a necessary immediate goal provided the heart re- complete revascularization is not possible, or many in mains arrested. The myocardial oxygen requirements situ arterial grafts are utilized, as no protection can be of asystole are so low at 22°C (0.3 ml/100 g per minute) offered to these areas of contracting muscle that cannot that they cannot be reduced substantially by reducing be revascularized due to unsuitable distal vessels. Ret- temperature further. A prompt fall in myocardial tem- rograde cardioplegic administration circumvents this perature will be achieved by perfusion of cardioplegia problem by ensuring distribution to areas supplied by through the grafts after distal anastomoses are con- obstructed vessels as well as those receiving in situ ar- structed. However, this is only accomplished with arte- terial grafts [19, 35, 36], and can be delivered during rial grafts if they are connected to the aorta. Because construction of proximal anastomoses to further limit distribution of cardioplegia through grafts may not al- the ischemic duration while the aorta is clamped. The waysbepossiblewitharterialrevascularization,theor- construction of all anastomoses during a single period derofgraftingislessimportant;butwewouldstillrec- of aortic clamping also circumvents possible dislodge- 6 Myocardial Management in Arterial Revascularization 57 ment of atheromatous intra-aortic debris during appli- retrograde delivery, (2) the variability between calcu- cation of a tangential aortic clamp. lated and measured intravascular pressure increases as either antegrade or retrograde cardioplegic flow rate is raised, and (3) a precise measurement is essential, since 6.5 fingertip estimation is inaccurate. This discrepancy be- Cardioplegia Pressure tween the calculated and measured intravascular pressure probably results from differences related to cali- Antegrade cardioplegia is often delivered without di- bration with roller pumps, and wide fluctuations in rectly monitoring the infusion pressure. The surgeon cardioplegic delivery system pressure which can devel- or perfusionist can therefore only estimate the actual op when temperature, flow, and viscosity are varied in perfusion pressure [2, 16, 37]. This may result in cardi- systems containing rigid and compliant components. oplegia being delivered at a pressure, which is higher or Direct intravascular measurement circumvents this lower than desired. Furthermore, even if the pressure is problem and provides the surgeon with a more reliable monitored, the optimal cardioplegia infusion pressure pressure measurement. Direct aortic monitoring remains essentially unknown. Although a high cardio- should, therefore, be used to prevent inadvertent eleva- plegic perfusion pressure is thought to be deleterious, tionsinpressure,sinceevensmallchangesmaysignifi- especially to ischemic tissue, the definition of high re- cantly affect myocardial protection [16]. mains undefined. What pressure is required to insure distribution to all areas of the myocardium, and the consequences of even moderate elevation of cardiople- 6.6 gic infusion pressure, must be understood. Retrograde Cardioplegia To investigate this question, we protected hearts with blood cardioplegia delivered either at high This method has the theoretical advantages of (1) dis- (80–100 mmHg) or low (30–50 mmHg) pressure [16]. tributionofcardioplegiaindiffusecoronarydisease, In unstressed (nonischemic) hearts, there was com- especially when all areas cannot be revascularized, and plete preservation of myocardial and vascular function (2) the ability to distribute cardioplegia to areas receiv- using either low or high cardioplegia infusion pressure. ing in situ arterial grafts since with all arterial grafting, However, even in normal hearts there was still an in- techniques for perfusion of cardioplegia down vein crease in myocardial edema when an infusion pressure grafts are abandoned. One exception is with a long ra- of 80–100 mmHg was used. In contrast, the effect of cardioplegia infusion pressure was quite different if the heart was first stressed. In stressed hearts low cardioplegia infusion pressure protected the heart from further damage, and resulted in complete preservation of myocardial and vascular endothelial cell function. This implies that a cardioplegic infusion pressure of 30–50mmHgishighenoughtoensureadequatemyo- cardial distribution, since without adequate distribution, myocardial protection is poor. Conversely, when cardioplegic infusions were delivered at a slightly higher (80–100 mmHg) pressure, there was post bypass myocardial and vascular endothelial cell dysfunction, increased edema, and decreased ATP levels. We therefore always deliver cardioplegia at a measured pressure of 30–50 mmHg in arrested hearts. Direct intravascular pressure measurement is the only reliable method for determining either aortic or coronary sinus pressure during cardioplegic delivery [2, 16, 37]. This conclusion was reached by obtaining si- multaneous measurement of intravascular pressure in either the aorta or coronary sinus during cardioplegic infusions and comparing it to calculated pressure from the known pressure drop in the tubing system at various flow rates [2, 16, 37]. This demonstrated that: (1) calculated pressure does not accurately reflect the measured intravascular pressure during either antegrade or Fig. 6.4. Cardioplegic delivery system in current clinical use 58 III Myocardial Protection During Coronary Bypass Surgery Using Arterial Grafts

Fig. 6.5. Myocardial perfusion assessed by contrast echocardiography of the right and left ventricular (freewall and septum) a during retrograde cardioplegic delivery in 12 patients. Note the decreased right ventricular perfusion compared to the septum and left ventricular freewall

dial artry graft that can be perfused directly. The need for using both antegrade and retrograde cardioplegic delivery in coronary operations is emphasized by experimental and clinical data [35, 38]. Figure 6.4 depicts our current clinical method for antegrade and retrograde delivery. We have shown poor cardioplegic distribution to jeopardized myocardium with antegrade infusions under conditions of experimentally simulat- ed coronary stenosis [35, 36], as well as redistribution of cardioplegic flow away from vulnerable subendocardial muscle. Conversely, retrograde cardioplegia is di- b rected preferentially toward subendocardial muscle despite occlusion of the coronary artery supplying the jeopardized region. The right ventricle is not protected consistently by retrograde cardioplegia, as right ventricular cooling and post-bypass functional recovery are somewhat variable in experimental studies of iso- lated cold retrograde cardioplegia. These experimental findings have recently been confirmed clinically by contrast echocardiography that demonstrated poor right ventricular myocardial perfusion with retrograde delivery [39] (Fig. 6.5). Preliminary clinical observa- tions suggest also that antegrade and retrograde cardioplegia supply different vascular beds, because glucose c and O2 uptake increase, and lactate washout occurs Fig. 6.6a–c. Metabolic measurements during warm cardiople- when switching from antegrade to retrograde cardio- gic induction at the end of antegrade (solid bar) and at begin- plegia, or from retrograde to antegrade cardioplegia ning of retrograde (hatched bar) administration in 26 patients. a [40](Fig.6.6).Thereforeinpatientswithcompleteoc- Note: myocardial O2 uptake increase when switching from antegrade to retrograde delivery; b glucose consumption in- clusion of the RCA and right ventricular dysfunction creases; and c lactate consumption switches to production we believe an arterial graft (RIMA, or radial artery) di- when changing from antegrade to retrograde delivery. A simi- rectly anastomosed to the aorta should be utilized to al- lar pattern was observed when switching from retrograde to low antegrade distribution of cardioplegia. antegradedeliveryinseparatestudies We now routinely use both antegrade and retrograde cardioplegia in all patients undergoing coronary gory. This combined antegrade/retrograde approach has artery bypass grafting as well as other procedures. increased the safety of using IMA or other arterial grafts Overall mortality in a recent series was 2.8% (Table 6.7) in high risk patients who otherwise would have received and the majority of patients were in the high risk cate- vein grafts because of previous inability to provide ade- 6 Myocardial Management in Arterial Revascularization 59

Table 6.7. Antegrade/retrograde blood cardioplegia anastomosis. This includes (a) opening the radial ar- CABG 261 tery (to observe a large flow), while the proximal end is Shock or EF, 0.2 or AMI 49 intact,(b)thesamemaneuverwiththegastroepiploic Reops. 48 artery with papavarine, and (c) adding papavarine or a AVR and/or MVR 103 Fogerty dilator to the IMA if there is not abundant flow Dissecting aortic aneurysm 3 to supply a large vascular bed. Pediatric CHD 123 490 patients Failuretoensureadequateantegradeflowduetothe Mortality 2.8 % caliber of the prevailing arterial conduit may lead to ventricular failure caused by inadequate graft perfu- Types of operation where combined antegrade/retrograde blood cardioplegia was used sion, rather than inadequate myocardial protection. CABG coronary artery bypass grafting, AV R aortic valve re- Under these circumstances, an added vein graft may be placement, MVR mitral valve replacement, CHD congenital very useful (i.e., flow is enhanced by augmenting distal heart disease flow when a small IMA graft supplies large LAD vessels.) quate cardioplegic distribution to large myocardial segments. Normally we divide the blood cardioplegic volume delivered equally between antegrade and retro- 6.8 grade cardioplegia during all phases of cardioplegic ad- Reperfusion ministration (i.e., warm induction, multidose cold blood cardioplegic replenishments, and warm reperfu- Reperfusion injury is defined as the functional, meta- sion).Evenwithallarterialgrafts,antegradeinfusions bolic, and structural alterations caused by reperfusion are still delivered to ensure distribution to areas (i.e., after a period of temporary ischemia (i.e., aortic clamp- right ventricle) not perfused by retrograde delivery. ing) [19]. The potential for this damage exists during all cardiac operations because the aorta must be clamped to produce a quiet bloodless field. Reperfusion damage 6.7 is characterized by (1) intracellular calcium accumula- Specific Issues with all Arterial Conduits tion [41], (2) explosive cell swelling with reduction of postischemic blood flow and reduced ventricular com- Proponents of different techniques of intraoperative pliance [41, 42], and (3) inability to utilize delivered ox- myocardial protection have traditionally, and for un- ygen, even when coronary flow and oxygen content are certain reasons, taken adversarial positions (i.e.. ische- ample [13, 43]. Our studies show that the fate of myo- mic arrest versus ventricular fibrillation, blood versus cardium jeopardized by global and regional ischemia is crystalloid cardioplegia, antegrade versus retrograde determined more by the careful control of the condi- cardioplegia). The fundamental issue is the develop- tions of reperfusion and composition of the reperfusate ment of a thoughtful strategy for cardioplegic distribu- than by the duration of ischemia itself [44]. The cardiac tion, and this can be achieved by combining the bene- surgeon is in the unique position to counteract the po- fits of both antegrade and retrograde cardioplegic tech- tential of reperfusion damage since the conditions of niques (Table 6.8). We suspect that application of this reperfusion and the composition of the reperfusate are combined strategy will allow more critically ill patients under the surgeon’s immediate control. to undergo safe internal mammary artery grafting and Postischemic reperfusion damage after global ische- to experience the same complete immediate recovery of mia can be avoided or minimized by substituting a regional and global function shown in patients who re- brief (i.e., 3- to 5-min) warm (37°C) blood cardioplegic ceive vein grafts. A critical factor, if grafting large arte- infusion during the initial phase of reoxygenation for rial segments, supplying large myocardial regions is to the normal blood reperfusion which would be provid- be sure of adequate flow via the arterial conduit before ed by aortic unclamping [13] (Fig. 6.7). The principles (Table 6.9) that are addressed during controlled reperfusion include (1) reoxygenation with blood to start Table 6.8. Advantages of combined antegrade/retrograde cardioplegic techniques aerobic metabolism for energy production to repair cellular injury, (2) delivery of the reperfusion over time Prompt arrest rather than by dose to maximize O utilization [45], (3) Ensure distribution (IMA, AI, coronary occlusion) 2 Limit CP volume lowering energy demands by maintaining temporary Uninterrupted valve procedures cardioplegia to allow the limited O2 ability to be chan- Avoid ostial cannulation neled toward reparative processes [46], (4) replenish- Flush coronary debris/air ing substrate (i.e., glutamate) which allows optimal aer- IMA internal mammary artery, AI aortic insufficiency, CP car- obic energy production to occur [18], (5) making the dioplegia reperfusate pH alkalotic to counteract tissue acidosis 60 III Myocardial Protection During Coronary Bypass Surgery Using Arterial Grafts

mogeneous cardioplegic delivery was questionable. Starting systemic and cardioplegic rewarming about 5 min before unclamping the aorta ensures normothermia. Delivery of this warm cardioplegic reperfusate at 150 ml/min for 3–5 min avoids high reperfusion pressure (i.e., 50 mmHg). Longer infusions (i.e., 5–10 min) may be useful if there has been poor cardioplegic distribution during aortic clamping or if the cross-clamp interval has been prolonged, especially in the setting of preoperative myocardial dysfunction. Recurrence of cardiac electromechanical activity during reperfusion cardioplegia is rare despite the low potassium concentration. Return of ventricular activity is not problematic as oxygenated blood is being delivered and the rate is usually slow, limiting metabolic demands. Fig. 6.7. Left ventricular performance 30 min after 1 h of topical With all arterial grafting, increasing reliance is hypothermic ischemic arrest. Note the normal postischemic placed on retrograde delivery. Antegrade reperfusion is performance when a blood cardioplegic reperfusate contain- also provided, especially if a large right coronary artery ing low calcium, high pH, was given just prior to removal of the aortic clamp, and the depressed myocardial performance is grafted with the proximal anastomosis attached to when the reperfusate was unmodified the aorta attached to the aorta. However, if distribution is suboptimal, then rearrest is easily accomplished by + Table 6.9. Warm cardioplegic reperfusion starting a high K cardioplegic infusion to ensure arrest. Electromechanical activity resumes usually Principle Method 1–2 min after aortic unclamping unless there is sys-

Provide O2 Blood temic hyperkalemia. Failure to recover contractility re- Optimize metabolism Normothermia quires temporary ventricular pacing to avoid the myo- Duration 5–10 mm Maintain asystole KCl cardial edema that may follow prolonged perfusion of Replenish substrate Glutamate/aspartate the flaccid heart. Palpation of the left ventricle detects Reverse acidosis Buffer distention so that a vent can be inserted if necessary. Limit Ca2+ CPD Counteract edema Hyperosmolarity Gentle pressure 6.9 CPD citrate phosphate dextrose Topical Hypothermia

and optimize enzymatic and metabolic function dur- Topical cooling is a useful adjunct when problems in ing recovery [47], (6) temporarily reducing ionic calci- cardioplegic distribution are anticipated especially if um available to enter the cell (i.e., chelation with citrate there is right ventricular hypertrophy or pulmonary phosphate dextrose) [48], (7) inducing hyperosmolari- hypertension. Topical cooling retards the recurrence of ty and decreasing perfusion pressure (i.e., 50 mmHg to electromechanical activity by keeping myocardial tem- reduce and minimize reperfusion edema) [49, 50], and perature low and counteracts the effects of coronary (8) warming the reperfusate to 37°C to optimize the collateral washout of the cardioplegic solution. Surface rate of metabolic recovery [19, 51]. Hypothermic reper- cooling may not be essential with multidose cardiople- fusion is not used because it retards metabolic rate and gia since the oxygen requirements of the arrested heart slows repair [52, 53]. below 20°C are extremely low. The value of topical hy- Clinical studies by Teoh et al. [54] document the pothermia is limited most in coronary patients because metabolic and functional value of using a warm blood (1) the heart must be removed from the pericardial well cardioplegic reperfusate strategy in elective coronary forallbutveryproximalleftanteriordescendingand operations, and we use a warm blood reperfusate rightcoronaryanastomoses,and(2)injurytothe before aortic unclamping in all operations. The capaci- phrenic nerve (especially with ice slush) may cause un- ty to avoid or minimize reperfusion damage by reper- avoidable respiratory complications [55–57], which fusion cardioplegia makes this technique a valuable ad- may be problematic in elderly patients. We reviewed junct to the cardiac surgeon’s armamentarium, espe- 150 consecutive coronary patients undergoing coro- cially if cardioplegic distribution has been problematic, nary artery bypass grafting (50 with topical ice slush, or if aortic clamping has been prolonged. We have used 50 with 4°C saline, and 50 without topical cooling) [58]. reperfusion cardioplegia as the primary form of cardi- Patients that received ice slush topical hypothermia ac protection (to avoid reperfusion injury) when ho- had a higher incidence of phrenic nerve palsy (9/50 vs 6 Myocardial Management in Arterial Revascularization 61

3/50 vs 0/50, p<0.05), pleural effusion (25/50 vs 7/50 vs 9. Bodenhamer RM, DeBoer LWV, Geffin GA (1983) En- 9/50, p<0.05), and atelectasis (33/50 vs 34/50 vs 18/50, hanced myocardial protection during ischemic arrest. J p<0.05). Conversely, there was no improved protection Thorac Cardiovasc Surg 85:769–780 10. Ferguson TB, Smith PK, Buhrman WC (1983) Studies on afforded by the use of topical cooling as measured by the physiology of the conduction system during hyperka- postoperative cardiac outputs, ECG changes, postoper- lemic, hypothermic cardioplegic arrest. Surg Forum 34: ative enzymes, inotropic requirements or deaths. We 304 thereforedonotusetopicalhypothermiaduringcoro- 11. Hearse DJ, Stewart DA, Braimbridge MV (1978) Myocardi- al protection during ischemic cardiac arrest – the impor- nary operations if complete revascularization is possi- tance of magnesium in cardioplegic infusates. J Thorac ble unless cardioplegic distribution to the right ventri- Cardiovasc Surg 75:877–885 cle is suboptimal, as retrograde cardioplegia should al- 12. Bolling KS, Allen BS, Wang T, Ramon S, Feinberg H (1997) ways provide protection of the left ventricular myocar- Myocardial protection in normal and hypoxically stressed dium. neonatal hearts: the superiority of blood versus crystalloid cardioplegia. J Thorac Cardiovasc Surg 114:994–1005 13. Follette DM, Fey K, Buckberg GD (1981) Reducing postischemic damage by temporary modification of reperfusate 6.10 calcium, potassium, pH, and osmolarity. J Thorac Cardio- Conclusions vasc Surg 82:221–238 14. Bolling KS, Allen BS, Ramon S (1996) Myocardial protection in normal and hypoxically stressed neonatal hearts: In conclusion, significant advances have been made in The superiority of hypocalcemic versus normocalcemic protecting the heart against perioperative myocardial blood cardioplegia. J Thorac Cardiovasc Surg 112:1193– damage. These principles are readily applicable to all 1201 arterial grafting. The role of cardioplegic myocardial 15.KrononM,AllenBS,HernanJ,HalldorssonA,Rahman SK, Buckberg GD (1999) Superiority of magnesium cardi- protection has expanded to allow cardioplegic solu- oplegiainneonatalmyocardialprotection.AnnThorac tions to be used for active resuscitation, to prevent is- Surg 68:2285–2295 chemic injury, to avoid reperfusion damage and to re- 16. Kronon M, Bolling KS, Allen BS, Rahman SK, Wang T, verse ischemic and reperfusion damage. The persistent Feinberg H (1998) The importance of monitoring cardio- evidence of some enzymatic signs of myocardial necro- plegia infusion pressure in neonatal myocardial protection. Ann Thorac Surg 66:1358–1364 sis in patients who do not need postoperative circulato- 17. 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