Myocardial Protection

Anatomy and Physiology

Understanding myocardial protection requires grasping several anatomical and physiological concepts. A key principle is arresting the heart to suppress its energy needs while preserving cellular integrity. This approach provides a bloodless, motionless field and reduces the risk of air embolism when opening the heart's left side, forming the basis for developing the first cardioplegic solution. The solution, high in potassium, is administered directly into the coronary arteries to induce cardiac arrest.[2][3]

Intraoperative Myocardial Ischemia

During intraoperative myocardial ischemia, tissue hypoxia following aortic cross-clamping leads to acidosis and lactate accumulation within minutes, as adenosine triphosphate (ATP) is consumed faster than it can be produced in mitochondria. This proton accumulation activates the Na⁺/H⁺ exchanger and, subsequently, the Na⁺/Ca²⁺ exchanger, causing intracellular Ca²⁺ buildup. If ischemia persists without treatment, it disrupts cell membranes, resulting in leakage of intracellular components.

Mitochondrial Protection

Mitochondrial protection is crucial because mitochondria, while providing ATP to cardiomyocytes, also play a central role in activating cell death pathways. The mitochondrial permeability transition pore (mPTP) is a nonselective channel in the inner mitochondrial membrane that remains closed during ischemia-induced acidosis, offering some protection. However, if the mPTP opens, it leads to depolarization, uncoupling of oxidative phosphorylation, intracellular ATP depletion, and cell death. Protecting the heart during ischemia focuses on preventing mPTP opening and promoting the activation of the mitochondrial ATP-dependent potassium channel. This invokes 2 primary protective pathways: the reperfusion injury salvage kinase pathway, activated via G-protein-coupled receptors, and the survivor-activating factor enhancement pathway, which operates through tumor necrosis factor-alpha receptors.

Myocardial Reperfusion Injury

Myocardial reperfusion injury, occurring upon restoring blood flow to the myocardium, presents various challenges. Myocardial stunning refers to reversible mechanical impairment of cardiac muscle function, while lethal reperfusion injury is primarily driven by reactive oxygen species, intracellular calcium overload, and inflammatory processes. Reperfusion arrhythmias, often treatable with interventions like defibrillation, and the no-reflow phenomenon, where perfusion cannot be re-established in a previously ischemic region despite optimal revascularization, also pose significant risks.

Original Physiological Concepts of Cardioplegia

The original physiological foundation of cardioplegia is rooted in the need to protect the myocardium during cardiac surgery by inducing a state of reversible cardiac arrest, thereby minimizing myocardial energy consumption and preventing ischemic injury. This concept arose from the understanding that the heart requires a continuous supply of oxygen to maintain its function, and any interruption in blood flow could lead to tissue damage, especially during the complex and time-consuming procedures of open-heart surgery.

Understanding the interaction between potassium and the myocyte action potential was key in developing cardioplegia. The Nernst Equation, formulated by Walther Hermann Nernst in 1881, played a crucial role in this development. In the case of myocardial protection, the following can be calculated: the equilibrium potential (resting potential) of any given membrane (the myocyte membrane) given the concentration of any ion (electrolyte K) on both sides of the membrane. (see Image. Myocyte Action Potential). The equation is:

• E = 61.5 log 10 (C₁ / C₂)

This equation, in which E is the resting potential, C₁ is the concentration of K⁺ outside the membrane, and C₂ is the concentration of K⁺ inside, allows for calculating the equilibrium potential across the myocyte membrane. Typically, when extracellular potassium is 4 mmol/L, the resting membrane potential is approximately –90 mV. However, if extracellular potassium increases to 20 mmol/L, the resting potential shifts to around –50 mV. This shift in membrane potential effectively "traps" the myocyte in a state where the resting membrane potential is –50 mV, preventing the initiation of phase 0 of the cardiac action potential, as sodium channels require a threshold of –70 mV to open. This mechanism ensures the heart remains arrested, providing a bloodless and motionless field necessary for surgical precision and reducing the risks of complications such as air embolism when operating on the left side of the heart.

The extracellular and intracellular electrolyte composition is vital in the effectiveness of cardioplegia. For example, potassium typically exists at 144 mmol/L intracellularly and 4 mmol/L extracellularly, sodium at 10 to 15 mmol/L intracellularly and 144 mmol/L extracellularly, and calcium at less than or equal to 1 mmol/L intracellularly and 4 mmol/L extracellularly. These concentrations are critical in maintaining the myocyte's action potential, and manipulating them through cardioplegic solutions enables the controlled arrest of the heart during surgery. Overall, the physiological foundation of cardioplegia was the need to protect the heart from ischemic injury during surgery, ensure that the myocardium remained viable throughout the procedure, and enhance the overall outcomes of cardiac surgery.

More Recent Concepts of Myocardial Protection

Histological studies revealed that ischemia/reperfusion (I/R) injury can cause damage comparable to 24 hours of permanent coronary occlusion within just 30 to 60 minutes. This led to the realization that reperfusion itself contributes significantly to myocardial injury, giving rise to the term ischemia-reperfusion injury. While the full scope of I/R injury is beyond this discussion, 2 relevant elements are calcium overload and the calcium paradox.

When the first cardioplegic solutions were used, researchers observed cases of abnormal heart failure, intractable fibrillation, and widespread necrosis. Calcium overload was identified as a potential cause of this damage (see Image. Mechanism of Calcium Overload Phenomenon). Calcium-free solutions were proposed; however, these also led to similar damage upon reperfusion with physiological calcium levels, a phenomenon known as the calcium paradox. Various theories have been proposed to explain this, one of which is widely accepted and illustrated (see Image. Postulated Theory of Calcium Paradox). Notably, the observed effects of calcium handling issues preceded a complete understanding of the underlying mechanisms.

Cardioplegic solutions, while protective, were found to cause some degree of damage, leading researchers to examine their beneficial and detrimental effects carefully. A critical study by Follette et al and Dr Gerald D Buckberg investigated myocardial oxygen consumption in different states: beating decompressed hearts on cardiopulmonary bypass (CPB), fibrillating hearts, and electromechanically arrested hearts in comparison to normal hearts, which have a consumption rate of 10 mL/100 g/min. See Table. Myocardial Oxygen Consumption of the Heart in Different States below:  

Table. Myocardial Oxygen Consumption of the Heart in Different States

This study's results revealed that electromechanical arrest, regardless of temperature, is the most effective method for reducing myocardial oxygen consumption. A fibrillating heart reduces oxygen consumption more effectively than a decompressed beating heart, particularly at normothermia.

In his 1981 book, Protection of Ischemic Myocardium: Cardioplegia, DJ Hearse detailed the elements of myocardial protection, dividing them into 3 main components: 1) electromechanical arrest, 2) hypothermia, and 3) additive protective factors to counteract the harmful effects of the cardioplegic solution and hypothermia. These protective additives include magnesium citrate to counteract calcium overload, tromethamine or bicarbonate to counteract acidosis, mannitol or albumin to counteract cellular edema, local anesthetics such as procaine to counteract membrane instability, and amino acids or glucose to replenish energy substrates and nutrient stores.

Anatomical Concepts of Myocardial Protection

Understanding the coronary circulation and venous drainage of the heart is crucial for optimizing myocardial protection strategies during cardiac surgery. The coronary arteries supply oxygenated blood to the myocardium, while the coronary veins, including the coronary sinus and Thebesian veins, are responsible for venous drainage. This anatomy significantly influences the effectiveness of cardioplegia, a technique used to protect the heart muscle by temporarily arresting it during surgery.

Retrograde cardioplegia, where the cardioplegic solution is delivered through the coronary sinus, is often used in severe proximal coronary artery disease cases. This method is particularly effective in protecting the left ventricle, as the coronary sinus has widespread tributaries that facilitate the distribution of the solution beyond areas of coronary artery obstruction. This approach ensures that the left ventricle, which has a higher oxygen demand, receives adequate protection even when coronary arteries are severely blocked.

However, retrograde cardioplegia alone has limitations, especially concerning the right ventricle. The right ventricular muscle mass is less well-served by the coronary sinus tributaries, and its venous drainage relies more on the Thebesian veins, which directly drain into the heart chambers. As a result, the cardioplegic solution may not adequately reach the right ventricular myocardium, leading to suboptimal protection. This incomplete irrigation has been associated with perioperative right heart failure, a significant concern during cardiac surgery. Given these anatomical considerations, a combined approach using antegrade and retrograde cardioplegia is often recommended to ensure comprehensive myocardial protection. Antegrade cardioplegia, delivered directly into the coronary arteries, can reach the right ventricular myocardium more effectively, complementing the retrograde approach and enhancing overall myocardial protection during surgery.

Indications

Myocardial protection is crucial during cardiac procedures to maintain heart muscle viability while blood flow is temporarily interrupted. The indications for myocardial protection encompass a range of cardiac surgeries. For example, myocardial protection is essential during open-heart surgeries like aortic valve replacement and mitral valve repair to address intracardiac pathologies after arresting the heart using cardioplegia. 'Open-heart surgery' refers to the ability to access the inside heart chambers, which is only possible when the heart is arrested. Conversely, if the heart is not arrested, the procedure is not classified as open-heart surgery but rather as closed-heart surgery. This terminology has evolved, with 'closed-heart surgery' replaced by terms such as beating heart surgery or bypass surgery.

Notably, arresting the heart alone qualifies as 'open heart' surgery, even if the chambers are not directly accessed, such as in coronary artery bypass grafting. Additionally, myocardial protection is vital in congenital heart defect repairs, complex reconstructive procedures, heart transplantation, extracorporeal membrane oxygenation, or ventricular assist devices. The choice of myocardial protection technique, whether cardioplegia, hypothermia, or mechanical support, is tailored to the specific procedure and patient condition to minimize ischemia-reperfusion injury, prevent irreversible damage, and improve postoperative outcomes.

Contraindications

Certain myocardial protection strategies must be carefully evaluated for contraindications to avoid complications and ensure effective outcomes. Hypothermia, a technique used to reduce myocardial oxygen demand, is contraindicated in patients with cryoglobulinemia, where abnormal proteins cause blood to clump together at lower temperatures. In such cases, cooling can lead to severe intravascular clotting and exacerbate the patient's condition.

Similarly, using cross-clamping in the presence of a porcelain aorta is highly risky. A porcelain aorta is characterized by significant aortic calcification, which can make it brittle and prone to rupture. Applying a cross-clamp in this situation increases the risk of stroke and iatrogenic aortic dissection. Furthermore, patients with severe systemic or localized infections may not be ideal candidates for specific myocardial protection strategies, as the stress and potential complications of surgery could exacerbate their condition. For individuals with severe metabolic imbalances or congenital anomalies affecting cardiac function, tailored approaches to myocardial protection must be considered to minimize risks and address specific needs.

Equipment

The equipment required for effective cardioplegia encompasses a range of specialized tools and devices designed to ensure the delivery of cardioplegic solutions and the maintenance of myocardial protection during cardiac surgery. The key equipment includes:

• Cardioplegia delivery systems
  • These systems administer the cardioplegic solution directly into the coronary arteries. They typically consist of a cardioplegia pump, which controls the flow and pressure of the solution, and a set of cannulas and tubing to facilitate the delivery. Cardioplegia can be administered through various routes. Historically, crystalloid solutions were delivered via a straightforward infusion set from the anesthetic side. However, blood cardioplegia has recently become more popular and is considered superior due to its enhanced efficacy. Blood cardioplegia is delivered via a dedicated pump on the CPB machine, which enables precise control of infusion rate, temperature, and blood mixing ratios.
• Temperature management equipment
  • Hypothermia is often employed as a myocardial protection strategy. Temperature-controlled cooling devices, heat exchangers, and thermostatic blood warmer systems achieve and maintain the desired temperature. These devices regulate the temperature of the cardioplegic solution and the patient’s body to prevent overheating or overcooling.
• Oxygenators and pumps
  • During CPB, oxygenators and centrifugal or roller pumps oxygenate and circulate the blood. Although not directly part of cardioplegia, they are essential for maintaining systemic circulation while the heart is arrested.
• Monitoring systems
  • Advanced monitoring systems are crucial for tracking the effectiveness of cardioplegia and overall cardiac function. These systems may include pressure transducers, flow meters, and temperature sensors to continuously monitor the delivery of the cardioplegic solution and the state of myocardial protection.
• Cardioplegic solution preparation equipment
  • Equipment for preparing cardioplegic solutions includes mixing devices and sterile containers. These ensure the cardioplegic solution is correctly formulated and maintained under sterile conditions. The solution typically contains a high concentration of potassium to arrest the heart and various additives to mitigate the effects of ischemia.
• Cannulation devices
  • Cannulas are used to access the coronary arteries for cardioplegia delivery and to remove blood from the heart during surgery. Proper selection and placement of these cannulas are critical for effective myocardial protection.

Personnel

Effective myocardial protection during cardiac surgery involves a team of skilled personnel, each contributing essential expertise to ensure optimal patient outcomes. The key personnel required include:

• Cardiac surgeons
• Anesthesiologists
• Perfusionists
• Surgical nurses
• Cardiac surgical technologists
• Clinical perfusion scientists
• Biomedical engineers
• Pharmacists

Preparation

The myocardial protection circuit is part of the general CPB circuit. Please refer to our review article on CPB.[4]

Technique or Treatment

Techniques of Myocardial Protection

When Bigelow and Melrose proposed arresting the heart to enable surgery under direct vision, they recognized the need to protect both the heart (myocardial protection) and the body, particularly the brain (cerebral protection), if coronary circulation was to be interrupted with a cross-clamp. CPB machines, which maintained systemic circulation, decompressed the heart, and reduced its workload and oxygen consumption, contributed to two-thirds of the solution. The final piece was found through different approaches: Bigelow suggested hypothermia, while Melrose introduced cardioplegia, with non cardioplegic techniques emerging over time.

These methods are all forms of myocardial protection, and it's a common misconception to equate myocardial protection solely with cardioplegia. All techniques evolved; Bigelow's hypothermia concept laid the foundation for modern deep hypothermic arrest, while Melrose's cardioplegia technique became the basis for subsequent developments in cardioplegia. Noncardioplegic techniques emerged due to temporary setbacks in cardioplegia advancements. As cardioplegia composition and delivery methods evolved, each iteration revealed new flaws, prompting further innovation. Although some techniques became more popular, such as blood cardioplegia over crystalloid cardioplegia or extracellular over intracellular solutions, none were abandoned entirely. For example, retrograde cardioplegia is preferred in severe aortic regurgitation or tight proximal coronary stenosis. The following review will examine these techniques chronologically in their development.

Cardioplegic vs Noncardioplegic Techniques

Initially, a 2.5% potassium citrate cardioplegic solution was used to arrest the heart after decompressing it with the heart-lung machine. This solution was infused into the aortic root until a full arrest was achieved, with no fixed quantity specified. The safe period of arrest was limited to 30 minutes, after which redosing was mandatory. At the end of the operation, reperfusion was initiated using blood, calcium chloride, adrenaline, and neostigmine, occasionally supplemented by cardiac massage. While the heart consistently arrested and recovered, ventricular fibrillation was nearly universal, necessitating defibrillation. Researchers began to notice intractable fibrillation, poor contractility, and widespread myocardial necrosis. Various theories emerged to explain these poor outcomes, some attributing them to the citrate solution and others to the reperfusion method. Ultimately, these issues led to the abandonment of this approach, and for the next 15 years, non cardioplegic techniques became more prevalent, with 3 main methods being described.

Surgeons operated under 1 of 3 conditions:

• Beating heart
  • EB Kay, HT Bahnson, and JB Littlefield first described continuous antegrade coronary perfusion, while CW Lillehei and VL Gott introduced retrograde perfusion. This method was mainly used for aortic valve surgeries. However, it was less favored due to its cumbersome setup, the potential for coronary ostia injury, and its limitation to valvular heart surgery, particularly aortic valve procedures. Before the widespread use of CPB machines, almost all coronary artery bypass grafting surgeries were conducted with a beating heart. Recently, off-pump cardiac surgery has gained momentum again due to studies highlighting the negative effects of cardiopulmonary support.
• Hypothermia
  • Introduced in the 1950s by Bigelow et al, hypothermia has been a key technique in myocardial protection, with its primary protective mechanism being the reduction of metabolic rate and oxygen demand. Profound hypothermia (4 °C) combined with cardiac arrest can reduce myocardial oxygen consumption by approximately 97%. The relationship between oxygen consumption and temperature follows the van't Hoff law or the Q₁₀ effect, with a 50% decrease for every 10 °C reduction, particularly between 37 °C and 25 °C. Hypothermia increases ischemic tolerance and extends the "safe ischemic time" between cardioplegia infusions. At 4 °C, 45 minutes of global ischemia is tolerated, compared to just 15 minutes at normothermia. By lowering the metabolic rate, hypothermia delays ischemia and reperfusion injury.
• Ischemic preconditioning
  • This can be divided into local and remote ischemic preconditioning.
    • Local ischemic preconditioning
      • This type is often used with fibrillatory arrest, where the heart is electrically fibrillated before aortic cross-clamping, inducing global ischemia with fibrillation followed by anoxic arrest. Some degree of myocardial protection is provided by unloading the heart through CPB, which reduces myocardial work through fibrillation and provides ischemic preconditioning. The left ventricle is decompressed before placing the aortic cross-clamp to prevent myocardial distension, subendocardial ischemia, and myofibrillar disruption. Mild hypothermia (32-34 °C) increases permissible global ischemia time to approximately 15 minutes and reduces the amplitude of fibrillation. However, temperatures below 30 °C are avoided as it becomes difficult to defibrillate at such low temperatures.
    • Remote ischemic preconditioning 
      • This type is a protective strategy designed to mitigate ischemia-reperfusion injury in a target organ, such as the heart, by inducing brief, repeated episodes of ischemia followed by reperfusion in a remote organ or tissue, typically a limb, before the main ischemic event. The underlying mechanism of remote ischemic preconditioning (RIPC) involves releasing protective factors like adenosine, bradykinin, and opioids into the bloodstream during the remote tissue's ischemic episodes. These factors are believed to trigger signaling pathways that protect the heart by reducing cell death, preserving mitochondrial function, and decreasing oxidative stress during subsequent ischemic events. Additionally, neural pathways may play a role, where sensory nerves in the remote tissue detect ischemia and signal the brain, initiating protective responses in the target organ. RIPC is primarily used in cardiac surgery and interventional cardiology to reduce myocardial damage. The procedure typically involves inflating and deflating a blood pressure cuff on a limb for a few minutes, repeated several times before surgery. While some studies have shown that RIPC can reduce myocardial injury and improve outcomes, others have reported no significant benefit, leading to mixed results in the clinical application of RIPC. These varying outcomes may stem from differences in patient populations, surgical techniques, or the specific RIPC protocols used. Despite these inconsistencies, RIPC remains an active area of research, with ongoing studies exploring its potential benefits and underlying mechanisms.

In the past, ischemic arrest using intermittent aortic occlusion, where the surgeon cross-clamps the aorta at room temperature, was the most popular technique due to its simplicity and straightforward nature. However, this technique required a fast operator, as noted by Robicsek.[5] These methods continued until DA Cooley's famous paper described the phenomenon of intractable widespread myocardial contracture after anoxic arrest, known as "stone heart," which led to a renewed focus on cardioplegia and the search for better solutions.[6]

Although subsequent experimental studies refined cardioplegic techniques, noncardioplegic methods have resurfaced. For example, continuous coronary perfusion is used during aortic root surgery, or surgeons may omit the cross-clamp and induce fibrillatory arrest in cases of porcelain aorta. Intermittent aortic occlusion regained popularity after early studies on ischemic preconditioning. However, recent randomized controlled trials have shown that ischemic preconditioning, especially RIPC, offers no advantages over cardioplegic techniques.[7][8]

Extracellular vs Intracellular Crystalloid Cardioplegia

Simultaneously with Cooley's description of the stone heart phenomenon, advances in cardiac research led to a deeper understanding of myocardial conditions post-open-heart surgery. In the United States (US), the University of California, Los Angeles' pioneering research on microspheres allowed for accurate quantification of myocardial perfusion, revealing that non cardioplegic techniques were suboptimal, especially in high-risk cases or surgeries with prolonged operative times. This finding reignited the search for more effective cardioplegic solutions.

The result was the development of an intracellular crystalloid cardioplegic solution characterized by a sodium concentration equivalent to that of intracellular fluid (10-15 mmol/L). This low sodium concentration prevents the action potential initiation by inhibiting phase 0, keeping the myocyte in a hyperpolarized state and preventing depolarization. This approach offers several advantages: it prevents calcium release during phase 2 of the action potential, thereby avoiding the harmful calcium load phenomenon, and it circumvents the need for high potassium concentrations, which are chemically irritating and require frequent redosing, potentially interrupting the surgical flow.

Additionally, the hyponatremic intracellular solution is less irritating, allowing for its administration in larger quantities without frequent interruptions. Despite these benefits, the solution, known as the Brettschneider solution, was not without its faults, with the calcium paradox phenomenon being a significant issue.[9] Brettschneider and his colleagues refined the formula, ultimately producing a final version that included histidine, tryptophan, glutamate, and trace amounts of calcium. Histidine acted as a temperature-dependent buffer, maintaining a pH of 7.40 when the solution was at 4 °C.

Meanwhile, David Hearse and Mark Bainbridge developed a different cardioplegic solution in London. They recognized that the potassium concentration in the initial cardioplegic solutions was excessively high (around 200 mmol/L). They proposed a solution with a sodium concentration resembling extracellular fluid, supplemented with only 20 mmol/L of potassium. This extracellular cardioplegic solution was delivered via cold antegrade infusion, consistent with the consensus on cold cardiac surgery since Bigelow's proposal. While this method was primarily intended to enhance the action of histidine at low temperatures, exploring alternative delivery methods was still to come in the evolving field of cardioplegia.

Blood vs Crystalloid Cardioplegia

In the US, Buckberg and his colleagues were at the forefront of recognizing the harmful effects of non cardioplegic techniques, particularly normothermic intermittent aortic occlusion. Their research focused on improving subendocardial flow and reducing the incidence of ventricular fibrillation after cross-clamp removal. They proposed a series of maneuvers, including limiting hemodilution, venting, maintaining adequate perfusion pressures, decreasing hypothermia, and using perfusate resuscitation. This approach was termed the "integrated ischemic technique."

A key realization from their work was that blood could resuscitate the heart more effectively than crystalloid solutions used in cardioplegia. They suggested replacing the crystalloid portion of the cardioplegic solution with blood, leading to numerous benefits. Blood improves microvascular flow due to its rheologic properties, as coronary vessels are better suited to carry blood than crystalloid solutions. This adaptation allows for better cardioplegia distribution, even beyond stenotic areas. Additionally, blood reduces hemodilution and myocardial edema because of its plasma protein content and it contains endogenous scavengers that neutralize oxygen-free radicals. Blood also has superior acid-base buffering capacities to synthetic buffers and provides hemoglobin, enhancing oxygen delivery. Moreover, blood contains essential nutrients such as glucose, amino acids, fatty acids, and other minerals, supporting better myocardial recovery. Various experimental and clinical studies have demonstrated the superiority of blood cardioplegia, and surveys indicate that it has become the preferred technique among most surgeons in the United Kingdom (UK) and the US.[10][11]

The question has shifted from whether blood cardioplegia should be used t how it should be delivered. Surgeons employ various methods to administer blood cardioplegia, and certain clinical situations may favor specific delivery systems over others. Understanding the strengths and limitations of these systems enables surgeons to select the most appropriate approach for each situation.

Warm vs Cold Cardioplegia

The debate over the optimal temperature for blood cardioplegia began with the initial preference for normothermic (36 °C) blood cardioplegia, a natural progression from the resuscitation solutions Buckberg and colleagues used to enhance myocardial recovery after cross-clamp removal. Early studies were divided on this issue, with some favoring warm blood cardioplegia and others advocating for cold blood cardioplegia, supported by knowledge of the oxygen dissociation curve. In vitro study results demonstrated that in an arrested heart, the reduction in oxygen consumption is minimal at lower temperatures and almost negligible below 20 °C.[12][13] Additionally, the detrimental effects of hypothermia have been extensively documented, including inhibition of Na⁺-K⁺ ATP, reduced energy substrates, cellular edema, diminished nutrient stores, and impaired homeostatic abilities. Hypothermia also causes calcium sequestration, increased CO₂ production, and subsequent acidosis. Moreover, it can lead to sludging and rouleaux formation, which hinders the delivery of cardioplegic solutions to myocardial tissues.[14] 

Proponents of cold blood cardioplegia later countered these concerns by showing that hypothermia does not adversely affect hemoglobin's oxygen delivery capabilities. This is because myocardial acidosis and hypercarbia during arrest counteract the leftward shift of the oxygen dissociation curve caused by hypothermia and, in some cases, even shift it to the right.[15] The other detrimental effects of hypothermia were argued to be theoretical, as natural additives in the blood—such as magnesium, buffers, and plasma proteins—help counteract calcium sequestration, hypercarbic acidosis, and cellular edema, respectively. Furthermore, close control of hematocrit during CPB using hemofiltration limits sludging and rouleaux formation.[16] The addition of procaine helps counteract membrane instability, mitigating potential damage. While no significant harm is associated with cold blood cardioplegia, study results have shown its benefits, particularly in restoring baseline myocardial functions after prolonged aortic cross-clamping.[17][18] As a result, multiple surveys have indicated that most surgeons in the UK and US now prefer cold blood cardioplegia over warm blood cardioplegia.

Continuous vs Intermittent Cardioplegia

As cardioplegic techniques advanced, increasingly complex surgeries became feasible, leading to longer cross-clamp times. However, extended cross-clamp times, particularly those exceeding 120 minutes, revealed some limitations in traditional cardioplegia methods. This prompted the scientific community to revisit earlier techniques, such as continuous coronary perfusion, which had fallen out of favor after the Melrose technique failed. Unlike methods that protect the heart by reducing its metabolic demands through electromechanical arrest and hypothermia, continuous coronary perfusion protects the heart by maintaining a steady supply of a normothermic cardioplegic solution. This approach, often referred to as "warm heart surgery" or "aerobic heart surgery," focuses on "increasing supply" rather than "decreasing demand."

Three methods for delivering continuous cardioplegia are commonly employed, depending on the type of surgery being performed.[19] The proposed advantages of continuous cardioplegia include the elimination of time constraints associated with cross-clamping, the ability to bypass the need for hypothermia, improved delivery of cardioplegia beyond stenotic coronary lesions, more uniform myocardial perfusion, and reduced risk of subendocardial necrosis. Additionally, it can counteract the collateral coronary flow from pericardial vessels and coronary veins that might otherwise wash out the cardioplegia.[20][21]

Despite these benefits, the continuous cardioplegia concept has faced criticism. Dr Philippe Menasche, a French pioneer of retrograde cardioplegia, argued in a notable editorial that continuous cardioplegia is not truly continuous or aerobic. He pointed out that surgeons using this technique often have to pause the cardioplegia delivery for varying periods, particularly when visibility is obstructed during surgery.[22] During these pauses, the myocardium remains in an anoxic state without the protective effect of hypothermia, undermining the "aerobic" nature of the technique. However, the evolution of the ischemic preconditioning concept revealed that these brief interruptions might actually be beneficial, as they improved the myocardium's ability to clear lactate postreperfusion. This led to the development of the Calafiore technique in 1995 by Dr A Calafiore.

To date, no consensus has been reached on the optimal mode of cardioplegia delivery, with practice varying between the UK and the US; continuous infusion is more commonly used in the US. Continuous infusion is favored over intermittent in certain situations, such as aortic root surgery, complex pediatric surgeries, combined surgeries, or redo surgeries. Continuous infusion is particularly advantageous in complex operations where frequent interruptions for cardioplegia redosing could significantly prolong clamp time and disrupt the surgery flow. In aortic surgeries, where the aorta is often widely open, it is easier to use soft cardioplegia cannulas to deliver the solution directly to the coronary ostia without interrupting the procedure.

Antegrade vs Retrograde Cardioplegia

With advances in laboratory techniques, researchers gained deeper insights into the myocardial condition during CPB. Techniques such as microsphere research allowed for precise quantification of myocardial perfusion, while coronary effluent flow studies enabled the measurement of myocardial oxygen requirements. The development of animal models simulating ischemic hearts facilitated testing various concepts, including arterial grafts, ischemic preconditioning, and ischemia-reperfusion injury.

One of the concepts revisited was the route of cardioplegia delivery. The antegrade route was initially used largely because it was considered common sense and mimicked natural physiology. However, retrograde cardioplegia emerged as an evolution of retrograde coronary perfusion, a technique employed in earlier non cardioplegic methods.[23][24] Although retrograde cardioplegia and retrograde coronary perfusion are distinct techniques, the ability to insert a cannula into the coronary sinus and continuously infuse blood through it, as practiced in the late 1950s, inspired Menasché in the 1980s to apply the same principle to cardioplegia delivery. Menasché was further motivated by clinical studies highlighting the inadequate protection provided by antegrade cardioplegia in the presence of critical coronary stenosis, where the narrowing severely limits the cardioplegia reaching the myocardium. Additional clinical studies revealed significant issues with antegrade cardioplegia during aortic valve replacements, such as inadvertent damage to the coronary ostia during direct administration of the cardioplegic solution. Experimental studies also demonstrated that retrograde cardioplegia provided superior protection to the left ventricle in critical coronary stenosis.[25][26] 

Despite its benefits, retrograde cardioplegia was not without its challenges. Injuries to the coronary sinus were a particular concern, leading to the proposal of several remedies, including right atrial cardioplegia by Carpentier and pulsatile retrograde cardioplegia by Okike and colleagues.[27][28] Another significant concern was the reported inadequate protection of the right ventricle, a point of contention even among experts like Menasché. He attributed the delayed recovery of the right ventricle to the catheter balloon used in the early days of the technique. Initially, a small Foley catheter with a spherical and bulky balloon was employed, which Menasché believed obstructed the terminal 0.5 cm of the sinus before the right atrium, an area responsible for draining most of the right ventricle and the inferior interventricular septum. He later adopted a specially designed cannula with a discoid balloon to address this.

In the US, Buckberg proposed routinely combining antegrade and retrograde cardioplegia, termed the "integrated myocardial protection technique." Surveys indicated that this combined approach was favored by many surgeons in the US, while antegrade cardioplegia remained more commonly used in the UK. Certain situations, however, favor using retrograde; these include critical coronary stenosis, aortic regurgitation in non aortic surgeries, heavy calcifications occluding coronary ostia in aortic surgeries, or continuous cardioplegia (see Image. Direct Coronary Perfusion Techniques).

Diluted vs Microplegia

Following Buckberg's introduction of blood cardioplegia, the standard practice was to use a 4:1 ratio of blood to the cardioplegic solution. This mixture was designed to align with the concentrations of commercially available solutions and the tubing sizes used in CPB machines. The benefits of this hemodilution included reduced rouleaux formation and improved microvascular flow.

In 1996, Menasché, collaborating with Calafiore, proposed a shift to a method that minimized dilution by adding cardioplegic additives directly into the bloodstream. This approach had several advantages: it increased the hemoglobin concentration, enhanced oxygen delivery, and reduced the hemodilution effects associated with CPB. Additionally, this technique proved to be more cost-effective. Recently, an automated pump has been developed to streamline this method further.[29]

Complications

While crucial for successful cardiac surgery, myocardial protection strategies are associated with several potential complications affecting patient outcomes. These complications can arise from the myocardial protection methods and surgical procedures. Key complications include:

• Myocardial ischemia and reperfusion injury
  • Despite effective cardioplegia, myocardial ischemia during surgery and subsequent reperfusion can cause significant damage. Reperfusion injury is characterized by oxidative stress, inflammation, and calcium overload, which can lead to myocardial stunning, lethal reperfusion injury, and arrhythmias.
• Calcium overload and calcium paradox
  • Cardioplegic solutions, especially with high potassium concentrations, can induce calcium overload. This occurs when calcium levels become elevated within the cell, leading to cell damage and dysfunction. The calcium paradox refers to the phenomenon where a calcium-free cardioplegic solution followed by reperfusion with normal calcium levels can cause severe myocardial damage.
• Electrolyte imbalance
  • Cardioplegic solutions must be carefully balanced to avoid electrolyte imbalances. Excessive potassium levels can affect myocardial depolarization and repolarization, while imbalances in other electrolytes like calcium and sodium can disrupt normal cardiac function.
• Inadequate myocardial protection
  • Incomplete or ineffective delivery of cardioplegic solutions can result in areas of the myocardium not being adequately protected. This is particularly challenging in cases of severe coronary artery disease or complex anatomy where retrograde cardioplegia may not sufficiently cover the right ventricle.
• Complications from cooling
  • Hypothermia, used to reduce myocardial oxygen consumption, can cause complications such as coagulopathy, arrhythmias, and systemic hypothermia-related issues. Hypothermia is contraindicated in patients with cryoglobulinemia due to the risk of widespread intravascular clumping.
• Cardioplegia solution toxicity
  • Prolonged exposure to cardioplegic solutions can be toxic to myocardial cells. If not properly managed, components of these solutions, including preservatives and additives, may have deleterious effects on the myocardium.
• Intraoperative hemodynamic instability
  • The use of cardioplegia and CPB can lead to hemodynamic instability, including hypotension or arrhythmias, which may complicate the surgical procedure and impact patient recovery.
• Infection risk
  • The use of cardioplegia, particularly in a setting involving multiple intravenous lines and access points, increases the risk of infection. Proper sterile techniques and monitoring are essential to minimize this risk.

Clinical Significance

Myocardial protection is a crucial aspect of cardiac surgery involving CPB, pivotal in safeguarding the heart muscle during procedures such as valve replacements and coronary artery bypass grafting. The development of this procedure has significantly advanced heart surgery over the years, reflecting the evolution of both techniques and technology.[30][31] Although various myocardial protection strategies, such as hypothermia, cardioplegia, and regional perfusion, have become integral to surgical practice, none are without limitations.

Each approach has its own set of strengths and potential drawbacks, emphasizing the need for careful selection based on the specific clinical scenario. The history of myocardial protection is deeply intertwined with the history of heart surgery, as the evolution of protection techniques mirrors advancements in surgical capabilities. Thus, understanding the nuances of these techniques is essential for all cardiac surgeons. Surgeons must focus on executing surgical steps and prioritize myocardial protection during clamp time. Educating junior surgeons about the advantages and limitations of different myocardial protection methods is critical for improving surgical outcomes and advancing the field of cardiac surgery.

Enhancing Healthcare Team Outcomes

Effective myocardial protection during cardiac surgery requires a multidisciplinary approach, where skills, strategy, interprofessional communication, and care coordination are critical to enhancing patient-centered care and outcomes. Physicians and advanced clinicians must be adept at selecting and implementing the appropriate myocardial protection techniques based on patient-specific factors, such as the type of surgery, comorbidities, and coronary stenosis. Nurses are vital in monitoring patients' physiological parameters, ensuring that cardioplegic solutions are administered correctly, and promptly identifying deviations that could compromise myocardial protection. Pharmacists contribute by preparing and verifying the correct formulation and dosage of cardioplegic agents, ensuring that all medications are compatible and safe for the patient.

Interprofessional communication is essential for coordinating care across the surgical team, ensuring that each member understands their role and responsibilities in the myocardial protection strategy. Regular team briefings, clear communication during surgery, and collaborative decision-making are crucial to avoiding errors and enhancing patient safety. By working together and sharing expertise, the team can optimize myocardial protection, reduce the risk of complications, and improve overall surgical outcomes. This coordinated approach enhances patient safety and boosts team performance, leading to better care delivery and favorable patient outcomes.

Nursing, Allied Health, and Interprofessional Team Monitoring

After surgery, the nursing staff should be vigilant for any unintended issues with protecting the heart during the procedure and any other unexpected events. These issues may become apparent hours after leaving the operating room, so the charge nurse must be especially attentive in addressing them.[32]