• Cardioplegia is a specialized solution that is delivered to the myocardium during cardiopulmonary bypass (CPB) to cease electrical activity and hence mechanical function. It
  • Brings the heart to a standstill and provides a quiet operating environment for the surgeon
  • Decreases oxygen (O₂) demand by decreasing electrical activity and mechanical contraction
  • Supplies the myocardium with O₂ and nutrients in order to protect it from ischemic injury

• Cardiac myocardium has a high O₂ demand and requires a high, sustained supply of O₂ and nutrients.
  • Normal myocardium: 8 mLO₂/100 g/min
  • Empty beating heart: 5.6 mLO₂/100 g/min
  • K⁺ arrested heart: 1.1 mLO₂/100 g/min
  • Myocardial arrest and cooling decreases consumption to 0.3 mLO₂/100 g/min (1,2).
• Ischemia results when there is an imbalance in O₂ supply and demand. O₂ delivery depends on the following:
  • Hemoglobin concentration
  • Arterial O₂ saturation
  • Blood flow to the heart. This is dependent on the coronary perfusion pressure and is equal to diastolic blood pressure minus the left ventricular end diastolic pressure.
• Cardiac contractility is dependent on adenosine triphosphate (ATP). Aerobic metabolism produces 36 ATP for each glucose molecule; anaerobic metabolism produces only 2 ATP and also results in lactic acid and H⁺ accumulating in the myocardium (suppresses glycolysis).
• Cardioplegia during CPB functions to:
  • Provide a quiet surgical field to facilitate the surgical procedure (arrest electrical activity and hence myocardial contractility).
  • Decrease myocardial energy requirements and O₂ demand in order to protect and preserve myocardial function during the period in which aortic cross-clamp is placed and myocardial perfusion is disrupted.
  • Provide O₂ and nutrients to the myocardium while it is ischemic (no coronary artery perfusion).
  • Of note: Myocardial arrest time can be prolonged or shortened by the administration of additional cardioplegia or washing out of cardioplegia.
• Composition of cardioplegia: Crystalloid or crystalloid and blood:
  • Crystalloid cardioplegia only contains dissolved O₂ due to the lack of hemoglobin. Its O₂ carrying capacity is sufficient to provide enough O₂ to cold myocardium, hence, it requires a hypothermic strategy for myocardial protection. Its composition can be altered by the addition of additives that replace substances present in blood cardioplegia.
    • Intracellular solutions have a [Na⁺] similar to the intracellular [Na⁺]; this abolishes the Na⁺ gradient and thereby prevents action potentials and myocardial contraction. The lack of Ca⁺⁺ further hinders myocardial contractility. Procaine chloride and magnesium chloride are added to provide membrane stability, and mannitol maintains the osmolarity of the solution. Today, it is mostly used for organ preservation in cardiac transplantation.
    • Extracellular solutions have a [Na⁺] similar to the extracellular [Na⁺] but with a high [K⁺], 8–30 mmol/L, that is responsible for causing diastolic arrest of cardiac action potentials. Today, it is more commonly used during CPB.
  • Blood cardioplegia is made by mixing blood and crystalloid cardioplegia. The ratio of blood:crystalloid is typically 4:1, but may vary based on the practitioner or institution. It has a higher O₂ carrying capacity because it contains hemoglobin and can be used for both cold and warm cardioplegia. Cold cardioplegia, however, causes a left-shift on the oxyhemoglobin saturation curve; thus, hemoglobin has an increased affinity and will not offload O₂ to tissues as readily. Benefits of blood cardioplegia include having natural buffers, free radical scavengers, and colloids, thus decreasing the need for additives. Blood cardioplegia solution is used more commonly than crystalloid cardioplegia. The most recent meta-analysis of the current literature indicates that blood cardioplegia is associated with a decreased incidence of low cardiac output state and creatine phosphokinase isoenzyme MB (CK-MB) release, but there is no difference in the incidence of myocardial infarction or mortality (3).
• Cardioplegia temperature, desired myocardial temperature, and protective strategies: The optimal myocardial temperature is dependent on the particular patient and surgery; it affects the choice between cold and warm cardioplegia as well as other protective strategies.
  • Cold (hypothermic) cardioplegia at a temperature of 4–10°C is typically administered to produce myocardial cooling. Myocardial metabolic rate and O₂ consumption decrease by 50% for every 10°C drop in temperature; the greatest benefit is achieved at a myocardial temperature of 25°C. Further cooling of the heart will result in smaller reductions in O₂ demand. Drawbacks of hypothermia include myocardial edema and injury that can result in post-CPB myocardial dysfunction (4).
  • Warm cardioplegia is used to achieve a "warm induction," or arrest prior to the initiation of ischemia. Electrical and mechanical arrest results from a high [K⁺] of 20–25 mEq/L (decreases O₂ consumption to ~1.1 mLO₂/100 g/min), while providing O₂ and nutrients to the myocardium (maintains O₂ supply). It can be used throughout the entire procedure if prolonged ischemia is not anticipated. However, because it is not hypothermic, it does not aid with decreasing cellular metabolism. It also requires blood cardioplegia (contains hemoglobin and hence a higher O₂ carrying capacity) and continuous administration. Studies have shown that warm cardioplegia results in a decreased incidence of myocardial dysfunction and impaired cardiac output in the post-bypass period, particularly in the setting of significant prebypass myocardial dysfunction and low ejection fraction (i.e., cardiogenic shock, progressing myocardial infarction, and advanced valvular disease) (4,5,6).
• Route of delivery:
  • Anterograde delivery is through a cannula placed in the ascending aorta proximal to the aortic cross-clamp. Flow is usually adjusted to achieve and maintain a pressure of 70–100 mm Hg in the aortic root. A rapid rate or low perfusion pressure will result in uneven distribution of cardioplegia.
  • Retrograde delivery is through a cannula placed in the coronary sinus (CS). Right ventricular (RV) venous return enters the CS near the CS ostium or directly into the right atrium (RA) which may result in inadequate RV myocardial protection through retrograde cardiolegia.
  • Additionally, cardioplegia can be delivered directly in the coronary ostia (Ostial), or through the bypass grafts to the distal coronary arteries (7).
• Frequency of delivery. Single dosing is appropriate when bypass time is short and there is no coronary disease. Multiple dose delivery is used in most cases, however, and is given to replace the solution washed away through noncoronary collateral flow. It is given for 1–2 minutes every 10–20 minutes. Advantages of multiple dose delivery include the following:
  • Maintain myocardial arrest
  • Maintain myocardial hypothermia (cold cardioplegia)
  • Supply substrates
  • Clear metabolites
  • Counteract myocardial edema
• Additives. Counteract the potential myocardial injury and dysfunction during myocardial arrest and reperfusion. Blood cardioplegia needs fewer additives in comparison to crystalloid cardioplegia, as previously discussed.
  • Calcium reduces the risk of reperfusion injury.
  • Magnesium not only stabilizes the myocardial cell membrane but also antagonizes the effect of calcium (preventing the need to eliminate Ca⁺⁺ from the solution). It has been shown that there is no benefit to adding magnesium to calcium-free cardioplegia.
  • Buffers. Natural (histidine, imidazole groups on proteins, bicarbonate) and synthetic buffers (THAM) are added to offset the accumulation of lactic acid in the myocardium during CPB. Blood cardioplegia contains only natural buffers.
  • Increasing osmolality to that of extracellular fluid helps prevent myocardial edema and preserve ventricular function. Mannitol, albumin, and glucose are used to increase the osmolarity of solutions.
  • Energy substrates. Addition of glutamate and aspartate can help replete the high-energy phosphates in the myocardium and preserve myocardial function.

• Anterograde cannula is placed just proximal to the site selected for aortic cross-clamp in the ascending aorta. The cannula has 3 ports, one for delivering cardioplegia, one for pressure monitoring, and one for venting. If the patient is undergoing aortic aneurysm repair or aortic valve surgery, anterograde cardioplegia can be delivered directly into the relative coronary ostia.
• Retrograde cannula is placed through a small incision through the RA after the placement of the venous cannula. The surgeon feels the inferior vena cava–right atrial junction and guides the tip of the cannula into the CS ostium. This can also be guided by transesophageal echocardiography. Presence of a large Thebesian valve in the entrance of the CS can prevent the placement of the cannula. The cannula is advanced until resistance is felt or a pressure of >20 mm Hg is measured. This means that the cannula is wedged and is at the junction of the CS and great coronary vein; it should be pulled back 1 cm and secured.
• The left ventricular free wall is perfused and cooled equally well by anterograde and retrograde techniques in the presence of a patent coronary vasculature. Subendocardial muscle is perfused as well as the epicardial muscle or even hyperperfused (Endo:Epi 1.4:1). If the left anterior descending artery is obstructed and anterograde cardioplegia is used, subendocardial muscle will be underperfused (Endo:Epi <0.2). Selective subendocardial hyperperfusion can be restored with retrograde cardioplegia (6).
• Left ventricular septal cooling is more profound with retrograde cardioplegia because it reduces the septal blood flow. It has been suggested that this effect is due to a rich network of venovenous collateral vessels. Retrograde flow passes this network and cools the septum without nourishing the capillary bed.
• Blood flow in the RV capillary bed is maintained with anterograde cardioplegia. Retrograde cardioplegia decreases RV perfusion by 20% in comparison to anterograde cardioplegia but moderate cooling (20°C) can be achieved.

In coronary artery bypass grafting, doses are alternatively given anterograde and retrograde. In mitral valve procedures, they are given mostly retrograde.

• Anterograde cardioplegia is used first to induce rapid arrest and limit the total amount of perfusate used. It is started after initiation of bypass and before cross-clamping the aorta to ensure aortic valve competency. Transesophageal echocardiography can be used to determine left ventricular distension at this time.
• A pressure of 70–100 mm Hg should be achieved during administration of anterograde cardioplegia. Pressure is transduced through the side port of the anterograde cardioplegia cannula. If the CS pressure rises during administration of anterograde cardioplegia, it indicates that the venous return from the coronary flow is entering the cannula tip. Pressure never exceeds 50 mm Hg because a portion of the venous return is drained directly into the RA and ventricle through the Thebesian veins. If arrest is not achieved within 1 minute, several reasons need to be considered:
  • Incomplete aortic cross-clamping. The cross-clamp may need to be adjusted or a new clamp used.
  • Aortic valve insufficiency (AI). If AI is mild, then increasing the cardioplegia flow to 500 cc/min will be sufficient. If significant, anterograde cardioplegia should be abandoned and switched to retrograde.
  • Distortion of the noncoronary cusp by the venous cannula. In this situation, the venous cannula should be repositioned.
  • Inadequate venous drainage. Cardioplegia should be started after the collapse of the pulmonary artery to confirm adequate drainage.
  • Insufficient potassium in the cardioplegia solution
• Retrograde cardioplegia is delivered at a rate of 200–250 cc/hr to achieve a pressure of 30–50 mm Hg. It is important that the pressure in the system and in the cannula be monitored closely. A CS pressure >20 mm Hg after insertion, or >50 mm Hg while on pump, means that the cannula is too far or wedged and needs to be pulled back and resecured. The cannula has a self-inflating balloon 1.8 cm in length with low intramural pressure and flows of 200–250 cc/hr to prevent barotrauma during infusions.
• Return of electromechanical activity after 2–5 minutes of administration of cardioplegia indicates that the cardioplegia solution was washed away by noncardioplegic blood. This could be due to inadequate venous drainage, low perfusate potassium concentration, or incomplete aortic clamping.
• Preparation for separation from CPB. The temperature is raised to 37°C and reperfusion is done with substrate enriched blood cardioplegia to buffer acidosis and limit the calcium load. Rewarming is started about 5 minutes before warm reperfusion. Warm reperfusate has a low potassium concentration (8–10 mmol/L) and is rich in substrates (aspartate, glutamate), CPD (to reduce calcium), and buffers (THAM). The first dose is given via anterograde cardioplegia and then alternated between anterograde and retrograde cardioplegia; the flow rate is 150 cc/hr for 3–5 minutes. The aortic cross-clamp is then removed and electromechanical activity usually resumes within 1–2 minutes. If this does not occur, it is indicative of a high serum and myocardial K⁺. Usually furosemide (0.5 mg/kg) and 1 g CaCl₂ are given to ease the return of rhythm and contractility.

Cardiopulmonary Bypass

Ali Salehi , MD