Cardiopulmonary Bypass: Cardioplegia, Cooling, Warming, and Deep Hypothermic Circulatory Arrest

History of Cardioplegia¹

• Modern-day cardioplegia was introduced in the 1950s, building on earlier experiments from the 1880s that achieved potassium-induced diastolic arrest in frogs. Significant advancements were made between 1950 and the mid-1970s.
• Melrose et al. pioneered the use of potassium citrate to induce cardioplegic arrest during cardiac surgery, thereby enhancing surgical precision and minimizing myocardial injury.
  • This solution led to calcium overload, which Hearse et al. later found to be one of the factors contributing to myocardial damage, along with adenosine triphosphate (ATP) depletion.
• In response, Reidemeister et al. developed Custodiol, a calcium-free, low-sodium crystalloid cardioplegic solution that promotes action potential loss.
• Concomitantly, Hearse introduced the St. Thomas’ Hospital cardioplegia, which mainly relies on depolarized hyperkalemic arrest.
• Concerns with hyperkalemic solutions led to the development of Bretschneider’s histidine-tryptophan-ketoglutarate solution (low potassium, low viscosity) as an alternative to organ preservation.
• In the mid-1970s, cardioplegic solutions with high-to-moderate potassium concentrations resurfaced. These solutions achieved diastolic arrest via membrane depolarization.
• Later, multi-dose 4:1 cold blood cardioplegia was introduced by Buckberg.
  • This remains a commonly used solution in cardiac surgery.

Cardioplegia

• Cardioplegia is an essential cardioprotective pharmacological therapy for electromechanical cardiac arrest during cardiac surgery.
  • The alteration of cellular electrochemical gradients reduces myocardial metabolic demands by inducing electrical quiescence.
• Cardioplegia is also indicated for the achievement of a bloodless and motionless operating field for a prolonged period.
• There are many forms of cardioplegia used in clinical practice; these are classified by parameters such as temperature (cold vs. warm), solution (crystalloid vs. blood), delivery method (antegrade, retrograde, or combined), continuous vs. intermittent, and the substances present in the solution.
• The principal goals of cardioplegia include:
  • Providing and maintaining electrochemical arrest of the myocardium.
  • Sustained cooling of the myocardium.
  • Flushing of metabolic waste and warm blood.
  • Limiting myocardial ischemia and providing buffering capacity.
  • Limiting ischemia-reperfusion injury to the myocardium.

Physiology of Cardioplegia¹

• To rapidly arrest the heart in diastole and maintain a depolarized state, voltage-gated channels need to be pharmacologically targeted.
  • Hyperkalemia induces diastolic arrest by establishing a new resting membrane potential (RMP) that is more depolarized than the normal RMP.
  • This cardioplegia-induced RMP doesn’t trigger the opening of voltage-gated sodium channels, which normally lead to an action potential.
  • In addition to the above, sodium and calcium depletion, extracellular potassium and magnesium elevation, and calcium antagonism contribute to the electrochemical arrest of the myocardium.
• On the other hand, reversal of cardiac arrest is achieved by cardioplegia washout and subsequent spontaneous restoration of electrical activity.
• If cardiac arrest is required for prolonged periods, re-dosing of cardioplegia is recommended.
  • A vast majority of surgeons use redosing intervals of 20-30 minutes or less.²
  • This varies by the type of cardioplegic solution and the surgeon’s preference.²

Cardioplegic Solutions

• Cardioplegic solutions can be divided into two main categories: intracellular or extracellular.
  • These classifications are based on the cellular environment they resemble.
  • Extracellular solutions are characterized by higher potassium and sodium concentrations and relatively normal calcium concentrations; these conditions prevent myocyte repolarization.
  • Intracellular solutions are characterized by high potassium concentrations and relatively low calcium and sodium concentrations; the decreased sodium-potassium concentration gradients lead to higher intracellular potassium and to inhibition of action potentials.

Cold vs Warm Cardioplegia¹

• Cardioplegic solutions can be administered at cold (4-10°C) or warm (35-37°C) temperatures.
• Potassium-induced electrochemical arrest reduces the myocardial oxygen demand by ~90%.
  • Lower temperatures of cardioplegic solutions further decrease the myocardial basal metabolic rate by 5-20%.
  • The additive effect of cardioplegic solution and low solution temperatures enables less frequent, intermittent dosing.
• Theoretically, cold cardioplegia may delay postoperative recovery of cardiac function by causing more profound inhibition of myocardial enzymes.
  • Colder solution temperatures have also been associated with myocardial cell membrane rupture, protein denaturation, and cellular edema via intracellular calcium sequestration.
  • Hypothermic conditions shift the oxygen-hemoglobin dissociation curve to the left, decreasing oxygen unloading and availability for the myocardium.
  • Cold cardioplegia can lead to sludging, cold agglutinin activation, and rouleaux formation, potentially leading to myocardial ischemia.
• Warm cardioplegia was introduced in the 1980s to avoid these perceived side effects of cold cardioplegia.
  • A warm solution has been associated with reduced reperfusion injury and improved postoperative cardiac index.
  • Lower 30-day mortality rates, reduced postoperative intra-aortic balloon pump requirement, and faster spontaneous return of normal sinus rhythm after cross-clamp removal have all been associated with warm cardioplegia.
  • The absence of hypothermic metabolic protection necessitates that warm cardioplegia be redosed more frequently or continuously, resulting in higher administered volumes, a higher risk of systemic hyperkalemia, and reduced systemic vascular resistance (SVR).

Blood vs Crystalloid Cardioplegia¹

• Blood cardioplegia solution resembles normal physiology, allowing rapid cardiac arrest while maintaining an oxygenated environment.
  • Intermittent myocardial oxygenation during blood cardioplegia infusion eliminates the need for substrates such as glucose and insulin.
  • Higher oxygen-carrying capacity ultimately increases oxygen delivery to the myocardium, as local ischemic and acidotic conditions during cardiac arrest cause oxygen offloading from hemoglobin.
  • Blood cardioplegia has been associated with reduced myocardial injury, low-output syndrome, and improved postoperative ventricular performance.
  • Other benefits include higher buffering capacity and oncotic pressure, which minimize myocardial edema and ease of preparation.
• On the other hand, crystalloid cardioplegia is widely used owing to its simplicity, lower cost, and improved visualization of the surgical field.
• The disadvantages of crystalloid-based cardioplegia include diminished oxygen-carrying capacity, decreased oncotic pressure, glycogen depletion, and myocardial edema and injury.
  • Large volumes of infused crystalloid cardioplegia can contribute to hemodilution.

Delivery of Cardioplegia

• Optimal myocardial protection relies on the homogenous distribution of cardioplegic solution, and this is achieved with either antegrade, retrograde, or a combination of both.
• The most common approach is antegrade delivery via the aortic root into the left and right main coronaries.
  • Distal delivery and distribution of cardioplegia to the myocardium might be limited by the presence of significant coronary artery disease.
  • In the presence of aortic regurgitation, incompetence of the aortic valve can lead to cardioplegia backflowing into the left ventricle, leading to inadequate myocardial protection and dilation of the ventricle.
  • In surgical cases that require aortotomy, or opening of the aorta, antegrade cardioplegia is commonly delivered directly via the coronary ostia.
• Retrograde cardioplegia consists of delivery via the coronary sinus into the cardiac venous system.
  • A balloon-tipped catheter is directly inserted and secured into the coronary sinus through a right atrial incision.
  • Retrograde cardioplegia is considered useful in settings in which antegrade cardioplegia is problematic, such as in the presence of aortic insufficiency or during procedures that could interfere with the timely infusion of antegrade cardioplegia (e.g., aortic surgery, aortic and mitral valve interventions).
  • In the setting of severe coronary artery disease, retrograde cardioplegia allows for the delivery of solution to areas of myocardium distal to the diseased coronaries.
  • Patients with a left internal mammary artery (LIMA) graft to the left anterior descending artery (LAD) may require retrograde cardioplegia for adequate myocardial protection of the anterior wall.³
    • LIMA blood flow originates from the subclavian artery to the LAD, distal to the graft site.
    • Presence of severe proximal LAD stenosis and competitive LIMA flow can wash out and prevent antegrade cardioplegia from flowing into the distal LAD.³
  • Retrograde perfusion pressure should not exceed 40 mmHg to prevent perivascular edema, venous rupture, and hemorrhage.
  • Several limitations of the retrograde approach include inadequate septal wall and right ventricular protection (due to shunting of cardioplegia via the thebesian veins and arteriosinusoidal connections) and the presence of anatomic variants, such as persistent left superior vena cava (SVC).
  • Total cardiac arrest is not achieved solely via retrograde cardioplegia; induction of arrest is achieved with antegrade cardioplegia, with retrograde cardioplegia used for maintenance of electromechanical silence.

Cooling during Cardiopulmonary Bypass^4,5

• Hypothermia, defined as a core body temperature below 35°C, is a commonly used technique in cardiac surgery.
• The protective effect of hypothermia is provided mainly by slowing of the cellular metabolism, decreasing oxygen consumption, and energy demand.
  • This leads to improved oxygen supply-demand ratio and enables safe circulatory arrest during cardiac surgical interventions.
  • Metabolic rates are reduced by 6-7% for each 1°C temperature drop.
• Other physiologic effects of hypothermia include:
  • Increased SVR
  • Increased blood viscosity
  • Reduced hepatic and renal drug metabolism; can prolong the action of anesthetics.
  • Coagulopathy caused by inhibition of the coagulation cascade and platelet dysfunction.
  • Increased arrhythmia risk as hypothermia deepens.
• The targeted degree of hypothermia can vary widely across institutions, but it is primarily determined by the nature of the surgical intervention and the expected ischemic time.

• Induced systemic hypothermia is achieved by active cooling via the heat exchanger in the cardiopulmonary bypass machine.
  • Additional myocardial cooling can be achieved by infusing cold cardioplegic solution and by applying ice slush directly to the mediastinum.
• Given the routine use of induced hypothermia in cardiac surgery, adequate temperature monitoring is imperative.⁶
  • Temperature gradients exist between the cerebral (e.g., brain), core (e.g., vital organs), and shell (e.g., muscle, fat, and bone) compartments.

Rewarming During Cardiopulmonary Bypass

• The rate of rewarming and the temperature gradient required to achieve it must be balanced against the known effects of prolonged cardiopulmonary bypass time.
• It is imperative to avoid cerebral hyperthermia during rewarming to prevent cerebral injury (Figure 1).
  • The cardiopulmonary bypass arterial outflow line temperature should not be set above 37°C by the perfusionist.⁷

Safe Rewarming Recommendations⁷

• The temperature difference between the cardiopulmonary bypass machine heat exchanger and the patient should be 10°C.
• The temperature difference between the bypass machine’s venous inflow line and arterial outflow line should not exceed 10°C to prevent the formation of gaseous emboli.
• Nasopharyngeal temperatures during rewarming should be maintained between 36 and 36.5°C.
• Tighter temperature control should be considered for hyperglycemic patients and in the presence of metabolic acidosis.
  • These factors will compound the potential risk and severity of cerebral injury.

Deep Hypothermic Circulatory Arrest (DHCA)⁸

• Deep hypothermic circulatory arrest is an organ and cerebral-preservation technique used during surgical interventions that require total cessation of blood flow.
• Deep hypothermia provides neuroprotection by inhibiting lactate accumulation and, hence, acidosis in neurons, thereby preserving ATP for energy-consuming processes.
  • There is a decrease in excitatory neurotransmitters (e.g., glutamate), inhibition of pro-apoptotic activity, and reduction in free radicals and inflammation.
• Some surgical procedures in which DHCA is employed routinely include aortic arch surgery (e.g., hemiarch, total arch replacement), pulmonary endarterectomy, and major thoracoabdominal reconstructions.
• As soon as cardiopulmonary bypass is established, induced hypothermia is initiated to achieve the target temperature within 30-40 minutes.

Selective Cerebral Perfusion^9,10

• In addition to induced deep hypothermia, selective antegrade and/or retrograde cerebral perfusion is utilized frequently during circulatory arrest.
• Retrograde cerebral perfusion (RCP) is administered via the SVC retrogradely into the cerebral venous system.
  • RCP increases cerebral ischemic tolerance, provides metabolic support, catabolite removal, washout of gaseous and particulate emboli, and prevents cerebral rewarming during the circulatory arrest period.
  • Because the RCP cannulas are in the SVC, they don’t interfere with the operative field.
  • Cold (10°C) retrograde cardioplegia has been utilized with moderate systemic hypothermia (22-26°C) to successfully repair proximal aortic disease within 30 minutes of circulatory arrest.¹⁰
  • RCP flow rate is maintained within 100-300 mL/min to maintain a pressure between 15-20 mmHg.
    • Pressures above this range can lead to cerebral edema.
    • Central venous pressure can be used to monitor retrograde perfusion pressure.
• Antegrade cerebral perfusion can be achieved by direct cannulation or side-graft anastomosis to the right axillary artery, left common carotid artery, or the brachiocephalic artery.
  • Flow is initiated at 10-15 mL/kg/min to maintain the cerebral arterial pressure between 50-60 mmHg.
  • Antegrade perfusion pressure is measured via a right radial arterial line.