Keywords

FormalPara High Yield Facts

  • The two pillars of myocardial protection during surgery on cardiopulmonary bypass are hypothermia and electromechanical cardiac arrest.

  • In the 1980s, blood-based potassium solutions were advocated to further improve myocardial protection and to reduce myocardial enzymes release.

  • Blood cardioplegia and combined antegrade and retrograde delivery is superior to crystalloid cardioplegia and antegrade delivery alone in terms of postoperative morbidity.

  • Current techniques of intraoperative myocardial protection are constantly evolving.

  • Additional adjuncts such as glutamate/aspartate enhancement, antioxidant supplementation, nitric oxide donors and maintenance of calcium homeostasis seem effective and associated with post-operative improved results.

Introduction

Cardiopulmonary bypass (CPB) is a cornerstone in the history of cardiac surgery because it makes the surgical treatment of most heart diseases possible [1]. CPB is however accompanied by deleterious effects caused by the activation of different pathways such as coagulation and proinflammatory cascades and pathologic oxidative balance [2, 3]. These pathways may explain postoperative dysfunctions in all organs [4] secondary to exposure to CPB. Systemic inflammatory response syndrome (SIRS) in particular remains the most important factor responsible for heart damage after CPB [5].

Despite major advances in technologies and clinical management, and improvements in the strategies for reducing the pro-inflammatory effects of CPB on the myocardium, during cardiac operations the heart suffers. Myocardial deterioration occurs due to organ ischemia caused by aortic cross clamping as well as additional damage secondary to heart reperfusion, or ischemia-reperfusion injury [4]. There is thus continuing debate about the safest and most effective strategy for myocardial protection during cardiac surgery.

Myocardial Injury After Cardiopulmonary Bypass

The exclusion of the heart from the systemic circulation after aortic cross clamping makes the myocardium ischemic, and after the release of aortic clamp and restoration of coronary perfusion post-ischemic myocardial dysfunction is triggered.

Severe hypoxemia during myocardial ischemia produces many deleterious reactions: conversion from aerobic to anaerobic cellular metabolism, high wasting of energy phosphate (i.e., adenosine diphosphate and adenosine triphosphate [ADP, ATP]), intracellular acidosis, and abnormal trans-membrane ionic homeostasis with a pathologic inflow of calcium leading to intracellular calcium ion deposition and phosphate crystals.

Cellular protection derived from the normal activity of free radical scavenging enzymes is lost during myocardial ischemia, and this leads to oxidative stress through the generation of reactive oxygen species (ROS) [6], usually detected in coronary venous blood after aortic clamp release. These radical products or lipid peroxides can cause reperfusion injury and can counteract myocardial recovery [4, 5]. Multifactorial origin is recognized in the pathogenesis of myocardial reperfusion injury [7]. The absence of the protective effect of free radical scavenging enzymes makes the myocardial cell more subject to the damage caused by the burst of free radical formation during reperfusion. Granulocyte-related mechanisms are also involved in myocardial reperfusion injury. These include increased neutrophil accumulation and adherence, leading to the release of dangerous proteolytic enzymes, vasoactive substances and free radicals, and culminating in the loss of the structural integrity of the endothelium. Anaerobic ATP production causes greater permeability of cell membrane with massive cellular calcium deposits, and myocardial contracture. Reperfusion may also manifest with the clinical occurrence of arrhythmias, reversible contractile dysfunction (myocardial stunning), and finally with irreversible reperfusion injury with myocardial cell death [8]. The key point in the pathophysiology of reperfusion injury appears to be the extent of damage sustained by the mitochondrion, which is related to the degree of opening of the mitochondrial permeability transition pore (MPTP) [9, 10] at the moment of reperfusion. During reperfusion, re-oxygenation causes a dangerous burst of ROS and the related opening of the MPTP, with a consequent pathologic modification of electrochemical gradients through mitochondrial membranes, and structural disruption of important membrane complexes as proton pumps, ATP synthase, and adenine nucleotide carriers. The degree of damage is proportional to the percentage of MPTP opened. Irreversible myocardial damage and cell necrosis occur when more than 50% of the mitochondria have MPTP open during reperfusion phase (Table 10.1).

Table 10.1 Factors contributing to myocardial damage during ischemia/reperfusion
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Myocardial Protection

Traditionally, the two pillars of myocardial protection during CPB are hypothermia [11] and electromechanical cardiac arrest [12]. Cardioplegia solutions have the dual aim of arresting the heart during diastole and minimizing myocardial energy requirements, in order to obtain an adequate balance between the need for a bloodless, motionless operating field, and the preservation of the myocardial function [13]. Electromechanical arrest has the aim of reducing myocardial metabolism, making it possible for the patient to tolerate intermittent ischemia periods [14, 15]. It is usually achieved with potassium infusion, which leads to diastolic cardiac arrest [13] (Table 10.2).

Table 10.2 Principal aims of cardioplegia
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The solutions are dissolved in crystalloid fluids or in the blood of the patient, and can be delivered intermittently or continuously, using either antegrade (aortic root or coronary ostia), or retrograde (coronary sinus), or both routes of administration.

Hypothermic Methods of Cardioplegic Protection

Hypothermic cardioplegia , introduced in the 1960s, is effective in decreasing myocardial metabolism [16], and in reducing myocardial oxygen consumption [17]. However, electromechanical arrest leads to a 90% reduction in oxygen consumption [13]. Therefore hypothermia offers an additional benefit of about 7% further reduction in oxygen consumption [14, 18].

However, several detrimental effects related to hypothermia have been described [13, 19], particularly the metabolic and functional recovery of the heart due to reduced mitochondrial respiration [20, 21]. In addition, hypothermia appears to adversely impact on the production of myocardial high energy phosphates [22, 23]. Hypothermia also affects several enzymes, such as sodium, potassium, and calcium adenylpyrophosphatase, with consequent modification of the ionic composition of the cell and water homeostasis [13, 20,21,22]. Other concerns are free radical generation damaging cellular membranes during reperfusion [24], an increase in hemoglobin affinity for oxygen [13, 19, 25], metabolic acidosis, increased plasma viscosity, and lower flow through the micro-capillaries [13]. Hypothermia alone, moreover, does not prevent injury in chronically “energy depleted” (ischemic) hearts.

A retrospective review [26] showed that hypothermic blood cardioplegia is superior to crystalloid based solutions in terms of clinical effects and enzyme release [26]. Hyperkalemic crystalloid cardioplegia is not completely cardioprotective, although it has been shown to be proved effective in causing electromechanical arrest [27]. In fact hematic cardioplegia guarantees better protection because its blood based composition makes its biological properties unique if compared to crystalloid solutions [28].

Normothermic Methods of Cardioplegic Protection

Normothermic myocardial protection is usually performed by the continuous delivery of hyperkalemic normothermic blood during the aortic cross-clamping time [29]. Lichtenstein et al. [30, 31] demonstrate that warm blood cardioplegia offers adequate myocardial protection throughout the cardiac surgery.

The benefits obtained by normothermia include a constant oxygen supply and the preservation of aerobic metabolism, higher oxygen transfer to myocardium, preserved enzymatic activity, normal plasma viscosity [13], low adrenergic response with consequent better cardiac index [32], and decreased CPB-related SIRS [33]. Moreover, low incidence of ventricular arrhythmias after cross-clamp release with the use of warm heart protection has been reported [34]. These benefits appear to be augmented when blood solutions during reperfusion are enriched by the amino acids glutamate and aspartate to replenish key Krebs cycle intermediates depleted by ischemia. These additions improve the reparative processes after a period of myocardial ischemia.

The safe duration of a cardioplegia administration during normothermia is still a matter of debate, and tepid cardioplegia constitutes an alternative method [35, 36]. Similar myocardial oxygen consumption, and less anaerobic lactate and acid washout than normothermic cardioplegia has been reported for this technique [37]. A matter of concern related to normothermia is that it protects the heart, but potentially affects negatively the brain [38]. In fact, neurological complications have been reported more frequently in the normothermic patients. A systemic temperature of 32–33 °C maintained via CPB, combined with tepid blood cardioplegia appears to be more protective for the brain and reduces the risks of neurologic complications [13, 16, 39]. Tepid hematic cardioplegia showed less myocardial injury, better functional myocardial recovery, and demonstrated coronary endothelium integrity [16].

Cardioplegic Solutions

Routes of Administration

All operations include the use of a dedicated pump on the CPB machine for cardioplegic perfusion, specific cannulas for antegrade and retrograde cardioplegia administration and a monitoring-infusion system.

An antegrade cardioplegia cannula is usually placed in the ascending aorta below the site chosen for the aortic cross-clamp (Fig. 10.1). This site can subsequently be used to anastomose the proximal end of a graft during coronary artery bypass grafting (CABG) operation. A 4-0 purse-string polyprolypene suture is used to secure the cannula. When the CPB is running and the heart is empty, thanks to effective systemic venous drainage, the aorta is clamped, and blood antegrade cardioplegia is delivered for 2 min at a rate of 200 mL/min. Sometimes, during CABG, additional antegrade cardioplegia doses can be administered through saphenous vein grafts.

Fig. 10.1
figure 1

Routes of cardioplegia administration. (a) Arterial cannula in ascending aorta; (b) Venous cannula in right atrium; (c) Antegrade cardioplegia cannula; (d) Retrograde cardioplegia cannula; (e) Pulmonary vein vent

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Retrograde delivery cardioplegia is performed through coronary sinus (Fig. 10.1). Coronary sinus cannulation can be performed before venous cannulation in order to prevent the venous cannula from being an obstacle to the insertion of the retrograde cannula. Otherwise, coronary sinus cannulation can be done on partial bypass with the right atrium slightly distended, with the aim of keeping the sinus ostium open. Transesophageal echocardiography (TOE) guided techniques or surgeon palpation are effective methods to guide the retrograde cannula into correct position. Commercially available retrograde cannulas usually have a malleable stylet and inflatable balloon cannula. The site of introduction on the atrial wall is secured with a 4-0 purse-string polypropylene suture around the cannula. The insertion of the cannula in the sinus should be easy and should make it possible to advance 2–3 cm within the coronary sinus. The correct position is confirmed by TOE images, the presence of dark blood emerging from the cannula, and by the retrograde pressure measuring line showing a “ventricle” like wave on the screen.

In the case of failure to insert the retrograde cannula into the coronary sinus (due to presence of Thebesian fenestrated valve or a narrow orifice), or in the case of surgical procedures requiring right atrium opening, like tricuspid repair/ replacement, transseptal approach to the mitral valve, or MAZE procedures, the right atrium is opened after bicaval cannulation, and retrograde cannula insertion is performed directly into the coronary sinus. Retrograde cardioplegia has proved to be effective in myocardial protection [40]. However, it may not be completely protective for the interventricular septum and the right ventricle [41] due to anatomical variations in the coronary vascular bed [42].

During retrograde infusions, the filling of the posterior descending vein with oxygenated blood is a confirmation of the good perfusion of the venous collateral network. Moreover, the presence of dark blood from the right coronary ostium (observed in the case of aortotomy) or from open coronary arteries incision during CABG means effective and nutritive retrograde blood flow.

Measuring infusion pressure of retrograde cardioplegia delivery prevents edema and endothelial damage and can confirm correct placement of the cannula. The permitted coronary sinus pressure range is from 30 to 40 mmHg at a cardioplegic infusion rate of 200–250 mL/min. If pressure rises over 50 mmHg it may be the result of incorrect positioning of the cannula or heart retraction during circumflex artery grafting which leads to kinking of the venous system. In this case it is mandatory to reduce the flow immediately, and to reposition the cannula, in order to avoid possible injury to the coronary sinus. In this case, a sudden low pressure occurs in the measuring line as a consequence of acute perforation, with the evidence of large amount of red blood within the pericardium. This damage can be repaired with 6-0 prolene sutures or with a pericardial patch. In other circumstances, hematomas may form, but these do not require surgical reparation because low venous pressure allows self-containment of the bleeding after heparin reversal. On the other hand, coronary sinus pressure of <20 mmHg means that the cannula is not inflated or not occluding the coronary sinus. This situation can be solved by palpation and repositioning the cannula tip and balloon.

Cardioplegia Composition and Timing of Delivery

Cardioplegic solutions are usually classified as crystalloid or blood based solutions. The solutions most frequently used in adult cardiac surgery are reported below.

St. Thomas’ Hospital solution no 1 (STH-1) is a crystalloid cardioplegic solution with moderately elevated potassium (20 mM) and magnesium (16 mM) and a small additive of procaine (1 mM) in an extracellular ionic matrix that was developed by Hearse and colleagues and introduced clinically by Braimbridge in 1975 [7, 18]. He reported encouraging initial experience in 1977. A comparison of patients undergoing valve replacements using STH-1 and hypothermia (1975–1976) with his previous (1972–1975) practice of coronary perfusion with blood, demonstrated a substantial benefit. The obvious advantages of working in a bloodless field were also acknowledged. Further preclinical studies confirmed the importance of maintaining near to normal extracellular concentrations of calcium and sodium avoiding major fluctuations in these key ions during and following coronary infusion of cardioplegic solutions. Based on the accumulated experience from ex vivo rat and in vivo dog studies an isosmolal St. Thomas’ Hospital solution no 2 (STH-2) was formulated with moderate elevations of potassium (16 mM) and magnesium (16 mM) together with near to normal sodium (120 mM) and calcium (1.2 mM) and a minor content of bicarbonate (10 mM) for initial pH control. This purely ionic and crystalloid solution can, without constraints concerning its administration, be applied for single-dose or multi-dose cardioplegia depending on the duration of aortic occlusion and on the washout by noncoronary collateral blood flow. Commercially available STH-2 (Plegisol™, Hospira Inc., Lake Forest, IL, USA) and STH-1 made up by local hospital pharmacies are still in broad clinical use, mostly for its simplicity of application (Table 10.3).

Table 10.3 Composition of the St. Thomas’ Hospital cardioplegic solutions
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Custodiol, Histidine-tryptophan-ketoglutarate (HTK) , or Bretschneider is an intracellular based crystalloid cardioplegic solution used for myocardial protection in long and complex cardiac surgery and for organ preservation in transplant surgery. It is easily manageable because it is administered as a single dose and has been proved to guarantee myocardial protection for a period of up to three hours [43, 44] without interruption. HTK was first proposed by Bretschneider in the 1970s [45]. It is an intracellular, crystalloid cardioplegia characterized by low sodium and calcium content. The mechanism of action is based on sodium depletion of the extracellular space, which causes a hyperpolarization of the myocyte membrane, inducing cardiac arrest in diastole. The components of Custodiol are listed in Table 10.4.

Table 10.4 Composition of Custodiol™ cardioplegia solution
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Cold blood cardioplegia is a method which appears to combine the advantages of hypothermia and blood solutions, and appears to complete myocardial recovery after long periods of ischemia in normal hearts. Blood cardioplegia consists of four parts of blood to one part of crystalloid solution. This limits the hemodilution occurring with crystalloid cardioplegia during repeated infusions. Table 10.5 summarizes flow rates usually employed in normal hearts. In the case of hypertrophied hearts, flow rates are increased by 50–100 mL/min. High-dose potassium (20–30 mEq/L) allows heart arrest during both warm and cold induction (Table 10.6). Some authors recommend enrichment with amino acids (glutamate/aspartate) in high-risk patients such as those affected by depressed left ventricular function, ongoing ischemia, or hypertrophy [46, 47]. Maintenance doses during cold cardioplegic infusion are based on low dose potassium solutions. At the end of surgical procedures, patients receive a terminal warm perfusate (“hot shot”). This solution is usually blood based and substrate enhanced, with no potassium, and is recommended in patients with poor ventricular function or after long cross-clamp times in complex surgical procedures.

Table 10.5 Methods of cold cardioplegia perfusion
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Table 10.6 Composition of cold blood cardioplegia solution
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Intermittent warm blood cardioplegia , first described by Calafiore et al., is based on intermittent doses of patient blood with potassium added. After the first dose (600 mL in 2 min), additional doses are given after construction of each distal CABG anastomosis or after 15 min. This proved to be a safe, reliable, and effective technique of myocardial protection, particularly in CABG procedures [48]. Delivery protocol is shown in Table 10.7.

Table 10.7 Delivery protocol for warm blood intermittent cardioplegia
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Adding retrograde perfusion to warm blood antegrade cardioplegia improves subendocardial perfusion, avoids direct ostial cannulation during aortic valve procedures, limits repositioning of retractors during mitral procedures, eliminates all the concerns related to the distribution of cardioplegia due to severe coronary artery stenosis and allows flushing of air bubbles and atheroma debris during coronary reoperations. Switching from antegrade to retrograde perfusion increases oxygen uptake and lactate washout, confirming that each strategy perfuses different areas. Therefore, both antegrade and retrograde perfusions are often required (Fig. 10.1), at least intermittently.

Continuous cardioplegic perfusion has been advocated by Salerno et al. to avoid ischemia caused by intermittent antegrade or retrograde delivery [49,50,51]. The heart is arrested using high-potassium blood cardioplegia, containing four portions of blood to one portion of high-potassium Fremes’ solution (Table 10.8). After the diastolic arrest, the perfusion system is switched to the retrograde flow. Low-potassium Fremes’ solution (same composition as high-potassium Fremes’ solution but KCI = 30 mEq/L) is administered in the same proportion of components at a maximum mean pressure of 40 mm Hg, measured in the coronary sinus cannula. Retrograde cardioplegic delivery should not exceed 250 mL/min. The infusion pressure and flows are constantly monitored. In the case of persistent electrical activity, additional high-potassium cardioplegia (usually 200–300 mL of high-potassium Fremes’ solution) can be delivered retrogradely or, otherwise, the surgeon can administer higher maintenance potassium concentration (40 mEq/L).

Table 10.8 Composition of Fremes’ solution
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Numerous adjuncts in cardioplegia solutions have been evaluated or are currently under investigation. They are summarized in Table 10.9.

Table 10.9 Adjuncts in cardioplegia solutions
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Conclusion

Since the beginning of cardiac surgery in the early 1950s, effective protection of the heart has been a mandatory step to counteract the risks and potential damage derived from myocardial ischaemia occurring during cardiac operations. Daily surgical practice is based on a consensus method with the use of hyperkalaemic cardioplegic solutions that allow satisfactory myocardial protection. This technique induces a cellular depolarized arrest and remains the cornerstone of cardiac protection regardless of chemical composition (crystalloid or blood solutions), temperature (hypothermic or warm solutions), or presence or absence of various additives. However it is widely acknowledged that the characteristics of cardiac surgery patients have changed considerably. Nowadays, patients are older and sicker, and present for surgery more frequently with a history of heart failure or acute coronary syndrome. New concepts in myocardial protection may bring various improvements. The new strategies however require further examination and investigation in order to respond to the new challenges that high-risk patients pose.