Cardioplegia Solution

Cardioplegia Solution

Use in Cardiac Surgery

Hypothermic, hyperkalemic cardioplegia solution was first used in open heart surgery in the 1970s and enjoys widespread clinical use today. Cardioplegia solution is infused into the coronary vasculature to produce an elective diastolic cardiac arrest. Inducing cardiac arrest, or cardioplegia, helps protect the myocardium while providing the surgeon with a still, bloodless operative field and a flaccid heart on which to work. Cardioplegia solution is administered via the cardiopulmonary bypass pump (a heart-lung machine) through specialized circuits.

During open heart surgery, the heart is excluded from normal circulation by diverting venous blood away from the right atrium via gravity drainage and by clamping the aorta. Systemic circulation of blood is maintained through the use of the cardiopulmonary bypass pump; a cannula is placed in the aorta distal to the clamp and carries oxygenated blood from the pump to the patient. The blood circulates through the body and is returned to the cardiopulmonary bypass pump through cannulas inserted into the superior and inferior venae cava.

Delivery Methods

Cardioplegia solution is delivered to the coronary circulation by three approaches: antegrade, retrograde, or combination antegrade/retrograde. With antegrade administration, the solution is administered via a cannula placed in the aortic root, whereas with retrograde administration, the cannula is placed in the coronary sinus.⁸⁹ The commonly used combination approach eliminates problems such as the nonhomogeneous distribution of cardioplegia solution, which can occur with the antegrade approach, while still ensuring a rapid arrest (arrest produced by retrograde administration is not as fast as antegrade).^90,91 This approach has significantly reduced patient morbidity when compared with antegrade administration, especially in high-risk patients requiring reoperation.⁹⁰

Phases of Cardioplegia

Cardioplegia can be divided into three phases: induction of arrest, maintenance of arrest, and reperfusion (immediately before aortic unclamping). Cardioplegia solution is used routinely during the induction and maintenance phases, and reperfusion solution is used at the end of surgery before aortic unclamping. The solutions used in each phase may differ in composition and characteristics.

Goal of Treatment

Cardioplegia solution is used to prevent myocardial ischemic damage that can occur during the induction and maintenance of arrest, whereas reperfusion solution is used to help prevent and minimize the destructive phenomena that can occur during reperfusion. Myocardial ischemia can result in a number of detrimental changes to the heart, including rapid cellular conversion from aerobic to anaerobic metabolism, high-energy phosphate (e.g., adenosine triphosphate [ATP]) depletion, intracellular acidosis, calcium influx, and myocardial cell membrane disruption. Destructive changes that can occur during reperfusion include intracellular calcium accumulation, explosive cell swelling, and inability to use delivered oxygen.⁹² Chemical components are added to cardioplegia solution to counteract the specific cellular effects of ischemia and the cellular events that can occur during reperfusion.

Table 9-13 Advantages and Disadvantages of Cardioplegia Solution Vehicles

Vehicle Advantages Disadvantages Blood Oxygen-carrying capacity Possible sludging at low temperatures   Active resuscitation Possible unfavorable shift in oxyhemoglobin association curve   Reduction in systemic hemodilution Potential for poor distribution of solution beyond coronary stenoses   Minimize reperfusion damage Possible red blood cell crenation   Provision of inherent buffering, oncotic, and rheologic effects Impaired visualization   Provision of physiological calcium concentration     Presence of endogenous oxygen-free radical scavengers   Crystalloid History of effectiveness Minimal oxygen-carrying capacity   Ease of solution preparation Possible damage of coronary endothelium   Low cost Minimal potential for capillary obstruction Reduced efficacy (compared with blood) in preserving left ventricular function postoperatively     Systemic hemodilution     Possible role in production of late myocardial fibrosis Adapted from references 89, 90, and 93.

Cardioplegia Solution Vehicles

The chemical composition of a cardioplegia solution depends on the vehicle used: blood or crystalloid. Each has advantages and disadvantages, as can be seen in Table 9-13.^89,90,93 Blood, because of its many advantages, is the vehicle most commonly used. Blood cardioplegia provides oxygen while the heart is arrested, proteins in blood maintain osmotic pressures closer to normal and are capable of serving as buffers, and endogenous oxygen-free radical scavengers are beneficial during reperfusion.⁹³ The disadvantages listed for blood have not been shown to occur during clinical use of blood-based cardioplegia solution. The patient's own hemodiluted blood from the extracorporeal circuit is used. Blood-based cardioplegia solution delivery systems include commercially available microprocessor-controlled pumps that are capable of directly injecting an additive into the blood as well as more conventional systems that deliver a fixed ratio of blood with a premixed crystalloid cardioplegia solution. Ratios of blood to crystalloid composition range from 1:1 to 16:1. The concentration of additives in the crystalloid solution must be tailored to the specific delivery ratio used to prevent accidental overdosage or underdosage. A commonly used ratio in clinical practice today is 4:1; in other words, the blood-based cardioplegia solution being delivered to the patient contains four parts blood to one part crystalloid solution. Therefore, the concentration of additives contained in the crystalloid solution is five times greater than that actually delivered to the patient due to the dilution of this solution with blood before it reaches the patient. Furthermore, with blood-based cardioplegia solution, there is a reduced need to place additives in the crystalloid component of the solution. For example, calcium and magnesium need not be added to the crystalloid component because sufficient quantities are contained in blood.

Common Characteristics

Most cardioplegia solutions have certain basic characteristics in common. Crystalloid cardioplegia solutions are made hyperosmolar to help minimize myocardial edema associated with cardiac arrest and are usually made slightly basic to compensate for the metabolic acidosis that accompanies myocardial ischemia. Cardioplegia solutions are traditionally chilled to a temperature of 4°C to 8°C before being infused into the coronary circulation. Hypothermia decelerates the metabolic activity of the heart, reduces myocardial oxygen demand and the detrimental effects seen with myocardial ischemia, and helps maintain cardiac arrest.^94,95 However, hypothermia can also produce deleterious effects on the heart, including impaired mitochondrial energy generation and substrate utilization, membrane destabilization, and the need for a longer period of reperfusion to rewarm the heart, which can increase the chances of reperfusion injury. In an effort to minimize the adverse consequences of hypothermia, the use of normothermic cardioplegia solution for induction of arrest (with cardioplegia maintained with a hypothermic solution) and the administration of a normothermic reperfusion solution before aortic cross-clamp removal was demonstrated to improve myocardial metabolic and functional recovery in energy-depleted hearts.⁹³ The benefits seen with this technique prompted investigators to study the use of intermittent, normothermic (37°C) cardioplegia. Positive results were reported with this technique and included a decreased incidence of perioperative myocardial infarction (MI) and need for intra-aortic balloon pump (IABP) support, as well as a lower incidence of postoperative low cardiac output syndrome.^96,97 However, studies examining the use of normothermic cardioplegia solution have not consistently demonstrated a decrease in mortality or perioperative MI when compared with hypothermic cardioplegia solution. With normothermic cardioplegia, a major concern is that not as much protection from ischemia is provided during the time that cardioplegia solution is not being infused as that provided with the use of hypothermic solution. Furthermore, when compared with hypothermic cardioplegia solution, warm cardioplegia is associated with a greater use of crystalloid and α-agonists to maintain perfusion pressure, higher total volumes of cardioplegia, increased use of high-potassium cardioplegia to stop periodic episodes of electrical activity, a higher incidence of systemic hyperkalemia, and lower systemic vascular resistance.⁹⁸ In an attempt to reduce problems seen with normothermic cardioplegia, the use of tepid (29°C) cardioplegia solution has been advocated. When compared with hypothermic techniques, tepid cardioplegia resulted in greater left and right ventricular stroke work indices (slightly less than normothermic cardioplegia) and a much faster recovery of myocardial function.^99,100 Currently, a combination normothermic/hypothermic technique is still used more frequently in practice. Additional work is needed in this area.

Additives

Table 9-14 presents additives commonly used in cardioplegia and/or reperfusion solutions, the reason for their addition, and frequently used concentrations.^89,90 In addition to these additives, several other classes of agents continue to be examined for their usefulness in cardioplegia and/or reperfusion solutions.

Oxygen-free Radical Scavengers

Oxygen-free radicals (e.g., superoxide anion, hydrogen peroxide, free hydroxyl radical) are released during the sudden reintroduction of oxygen to ischemic tissue during reperfusion. They have been implicated in myocyte death, reperfusion-induced arrhythmias, and prolonged left ventricular dysfunction after reperfusion.⁹² The addition to reperfusion solution of drugs that inhibit oxygen-free radical production or degrade free radicals (e.g., mannitol, deferoxamine, allopurinol) has been demonstrated to reduce post-reperfusion myocardial injury and other free radical-induced surgical complications.^101,102,103 An advantage of using blood-based cardioplegia solution is that blood contains endogenous oxygen-free radical scavengers (e.g., catalase, superoxide dismutase, glutathione).¹⁰⁴

Adenosine

Adenosine is an endogenous nucleoside that is released from the ischemic myocardium during the catabolism of ATP. It protects the heart from ischemic and reperfusion injury and may have a role in ischemic preconditioning. Adenosine produces the majority of its effects through interaction at the adenosine A1, A2, and A3 receptors. Stimulation of A1 receptors causes activation of the ATP-sensitive potassium channel (K-ATP), ultimately resulting in positive chronotropic and dromotropic effects, antiadrenergic effects, stimulation of glycogenolysis, and stimulation of neutrophil adherence. Stimulation of A2 receptors results in vasodilation, renin release, inhibition of neutrophil adherence to endothelium, and inhibition of superoxide generation. The physiological effects of stimulation of A3 receptors include inhibition of neutrophil adherence to endothelium.¹⁰⁵ The cardioprotective effects during preconditioning are believed to be the result of K-ATP channel activation. Preliminary results of a phase II trial found that adenosine may improve postoperative hemodynamic function and possibly reduce morbidity and mortality when patients receive IV adenosine immediately before and after aortic cross-clamping in addition to cold blood cardioplegia containing 2 mM adenosine.¹⁰⁶ However, further multicenter studies are needed to identify patients who will benefit the most from adenosine and whether adenosine will definitively reduce the incidence of MI or death following open heart surgery.

L-Arginine

Ischemia results in decreased formation of nitric oxide; nitric oxide helps prevent neutrophils from adhering to the vascular endothelial cells. Neutrophil adhesion to the coronary endothelium is a prerequisite for neutrophil activation and accumulation in the myocardium. Activated neutrophils may be a major source of oxygen-free radical production. They enhance degranulation and the release of proteases, which cause cellular damage, and they adhere to microvascular endothelium or embolize in the microcirculation. Nitric oxide–dependent vasodilation and inhibition of neutrophil activity are believed to play important roles in preventing reperfusion damage after ischemia.

Table 9-14 Commonly Used Cardioplegia Solution Additives

Additive Frequently Used Concentrationa Function Amino acid substrates (glutamate/aspartateb) 11–12 mL/Lc Improves myocardial metabolism; improves metabolic and functional recovery in energy-depleted hearts Calcium At least trace amounts (0.1 mEq/L) Maintains integrity of myocardial cell membrane; prevents “calcium paradox”d Chloride 90–110 mEq/L Establishes a solution similar in composition to extracellular fluid CPD solution 12 mL/Le 45 mL/Lc Chelates calcium in blood-based cardioplegia solution to produce safe levels of hypocalcemia for rapid diastolic arrest; limits postischemic calcium accumulation and improves postischemic performance Glucose 5–10 g/L safely used Helps achieve desired osmolarity of solution; serves as a metabolic substrate for the heart Magnesium 32 mEq/L Reduces magnesium loss during ischemia; reduces calcium influx and potassium efflux during ischemia; has a weak arresting action on heart Potassium 15–30 mEq/Lf Induces rapid diastolic arrest Sodium 120–140 mEq/L Necessary for protective action of potassium; establishes a solution similar in composition to extracellular fluid Sodium bicarbonate or THAM Variable; added until desired pH is obtained Provides buffering capacity; helps maintain physiologically normal pH range; counters acidosis produced by ischemia aConcentration delivered to patient; concentration dependent on other cardioplegia solution additives (concentration of any one additive may be changed by inclusion of other additives). bNot commercially available in parenteral formulation; each milliliter of solution contains 178.4 mg monosodium L-glutamate and 163.4 mg monosodium L-aspartate (for preparation directions, see reference 89). cWarm, blood-based induction and reperfusion solutions. dCalcium paradox is a condition that results in rapid consumption of high-energy phosphates, extensive ultrastructural damage of myocardial cells, and myocardial contracture; it results from an influx of calcium into the myocardial cells, resulting from the introduction of a calcium-containing perfusate (i.e., blood) into the system during reperfusion after the use of a cardioplegia solution completely lacking in calcium. eCold, blood-based induction and maintenance solutions. fLower concentrations (5-10 mEq/L) used during maintenance phase. CPD, citrate-phosphate-dextrose; THAM, trishydroxymethylaminomethane. Adapted from references 89 and 90.

L-arginine is a nitric oxide donor and may have a role as a supplement to cardioplegia and/or reperfusion solutions. Animal studies have demonstrated benefits (reduction in oxygen-free radical formation, restoration of endothelial function) from the addition of L-arginine to cardioplegia solutions.^107,108,109 Limited trials in patients undergoing coronary artery bypass grafting have demonstrated that the addition of L-arginine (7.5 g/500 mL) to blood cardioplegia reduced the release of cardiac troponin T, a marker of myocardial ischemia.¹¹⁰

Potassium

16. W.D., a 64-year-old man, ASA-III, is scheduled to undergo a coronary artery bypass graft. W.D.'s serum potassium concentration is 4 mEq/L. A blood-based cardioplegia solution is ordered for the patient with the concentration of potassium in the crystalloid component to be 76 mEq/1,000 mL. Cold induction (e.g., chilled cardioplegia solution) using a delivery system of four parts blood to one part cardioplegia solution will be used. On administration of the solution to W.D., cardiac arrest was not achieved. A STAT chemical analysis of the crystalloid solution revealed that it contained no potassium. Why is this consistent with the findings in W.D.?

Failure to see immediate arrest within 1 to 2 minutes after the administration of cardioplegia solution can be due to several factors, including incomplete aortic clamping, aortic insufficiency, and failure to have a potassium concentration sufficient to produce arrest. Because W.D.'s cardioplegia solution contained no potassium, a direct cause-and-effect relationship can be made to the inability to achieve an arrest.

The major role of potassium in cardioplegia solution is to induce a rapid diastolic arrest by blocking the inward sodium current and initial phases of cellular depolarization. This results in cessation of electromechanical activity and helps preserve ATP and creatine phosphate stores for postischemic work. A delivered potassium concentration in the range of 15 to 20 mEq/L is used most commonly. This concentration has consistently produced asystole while minimizing adverse effects (e.g., tissue damage, systemic hyperkalemia). Potassium concentrations >40 mEq/L alter myocardial cell membranes, allow extracellular calcium to enter the cell, and raise energy demands.¹¹¹ In laboratory studies, high concentrations of potassium (>100 mEq/L) increase myocardial contracture and wall tension, a condition referred to as stone heart syndrome.¹¹² Varying concentrations of potassium are used in the cardioplegia solution, depending on the phase of cardioplegia. As previously discussed, a high concentration of potassium is required to induce arrest, whereas lower concentrations (e.g., 5-10 mEq/L) are sufficient to maintain arrest.¹¹³ On first glance, the concentration of potassium ordered in W.D.'s blood-based cardioplegia solution appears excessive. However, the concentration delivered to the coronary circulation is slightly <20 mEq/L if one considers that the potassium contribution from the blood component of this blood-based cardioplegia solution is approximately 4 mEq/L and that from the crystalloid component is approximately 15 mEq/L (76 mEq/L / 5). This highlights the importance of knowing the delivery ratio being used for the administration of blood-based cardioplegia solution.

Amino Acids: Normothermic, Blood-Based Cardioplegia Solution

17. T.E., a 55-year-old man, ASA-IV, is admitted to the hospital with an MI. He is currently in the coronary care unit and is scheduled for myocardial revascularization surgery. He has poor left ventricular function (cardiac output, 2.2 L/minute [normal, 4–6 L/minute]; pulmonary capillary wedge pressure, 25 mmHg [normal, 5–12 mmHg]; left ventricular ejection fraction, 25% [normal, >60%]), and is on an IABP for circulatory support. In addition to being on the IABP, he is receiving dopamine and milrinone. A diagnosis of cardiogenic shock is made. What type of cardioplegia solution should T.E. receive during his revascularization surgery?

Normothermic (37°C), blood-based cardioplegia and reperfusion solutions containing the amino acids glutamate and aspartate have been advocated for the induction and reperfusion phases of cardioplegia in patients with ischemic hearts (e.g., extending MI, cardiogenic shock, hemodynamic instability) or those with advanced left or right ventricular hypertrophy or dysfunction.^114,115,116 Glutamate and aspartate, Krebs' cycle precursors, are added to cardioplegia solution to counteract the depletion of Krebs' cycle intermediates during myocardial ischemia and to enhance energy production during reperfusion.^114,116,117 These agents enhance oxidative metabolism optimally at normothermia (37°C).¹¹⁷

With this technique, cardioplegia induction is accomplished with an infusion of the normothermic, blood-based cardioplegia solution over 5 minutes. Normothermia optimizes the rate of cellular repair, whereas glutamate and aspartate improve oxygen utilization capacity.¹⁰³ The normothermic solution is immediately followed by a 5-minute infusion of hypothermic, blood-based cardioplegia solution. Cardioplegia is maintained with hypothermic, blood-based solution. Normothermic reperfusion solution is administered for 3 to 5 minutes immediately before aortic unclamping (reperfusion). The administration of normothermic solution at the conclusion of surgery is referred to by some as a hot shot. It is believed to result in early resumption of temperature-dependent mitochondrial enzymatic function and to allow energy supplies to be channeled into cellular recovery rather than electromechanical work. This results in improved hemodynamic and myocardial metabolic recovery.^117,118

T.E., with his poor myocardial function, is a suitable candidate to receive amino acid–enriched, normothermic, blood-based cardioplegia solution and reperfusion solution during the induction and reperfusion phases of cardioplegia, respectively.

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