Circulatory Arrest and Cardiopulmonary Bypass Hypothermia

The incidence of congenital heart disease (CHD) is 2-10 cases per 1000 live births. The care of infants with congenital cardiac defects has continued to advance. Resultant abnormal physiology in many of these patients has led to management strategies emphasizing early complete repair. Currently, complete repair of congenital heart defects can be performed in infants smaller than 2 kg, with good outcomes. However, improved outcomes in even the sickest and smallest patients with CHD is not enough. Despite improved surgical techniques and operative results, CHD remains the leading cause of death among all patients with congenital defects.

In 1954, Lillehei first reported the effective use of extracorporeal circulation in the repair of CHD using cross circulation with the patient's parent functioning as the oxygenator. ^[1] Gibbon first described and used a mechanical extracorporeal oxygenator, which he termed the heart-lung machine. ^[2] On May 6, 1953, Gibbon performed the first successful open heart surgery using a heart-lung machine while repairing an atrial septal defect. Increasingly complex repairs subsequently became possible with the refinement of cardiopulmonary bypass (CPB) techniques and the use of hypothermic circulatory arrest that Barratt-Boyes et al (1971) and Castaneda et al (1974) popularized. ^{[3, 4]} Further refinements in CPB hardware and techniques, perfusion methods, myocardial and brain protection over the past seven decades contributed to improved outcomes of surgical treatment of CHD.

Major differences between adult and pediatric cardiopulmonary bypass (CPB) stem from anatomic, metabolic, and physiologic differences.

Anatomic differences

At the cellular level, the myocytes are relatively smaller, more circular, and less uniformly oriented in the neonate. ^[5] As they mature, the myocytes enlarge, become oblong, and become oriented in the longitudinal direction. Neonatal myocytes have less mitochondria and the calcium sequestration capabilities of the sarcoplasmic reticulum is significantly less. As the myocytes mature, the oxygen and contractile requirements create an increase in the number of mitochondria and the amount of sarcoplasmic reticulum. Its ability to sequester calcium (Ca²⁺) similarly increases in early development. Finally, the activity of the sodium-potassium (Na+/K+) adenosine triphosphatase (ATPase) increases with maturation, which affects the sodium-calcium exchange mechanism. ^[5] (For images depicting the morphology of fetal sheep myocytes, go here.)

These factors affect the way in which the immature heart handles calcium, which, in turn, contributes to the myocardial dysfunction observed after CPB. Immature calcium handling in immature myocardium raises intracellular calcium concentrations after ischemia and reperfusion. This change has been linked to activation of energy-consuming processes, which leads to decreased levels of adenosine triphosphatase (ATP) and a subsequent lack of energy sources for healthy cardiac function. Enzymes that calcium activates include phospholipases, proteases, ATPases, and endonucleases. Abnormal and uncontrolled activation of these enzymes lead to cellular damage after CPB.

Metabolic differences

After birth, increased oxygen requirements of the myocardium are associated with a switch from a relatively anaerobic metabolism in an immature heart to a more aerobic metabolism. The immature myocardium can use several substrates, such as carbohydrates, medium-chain and long-chain fatty acids, ketones, and amino acids. In the mature heart, long-chain fatty acids are the primary substrates, and several enzymes and an increased number of mitochondria are needed. Because of the increased ability of the immature myocardium to rely on anaerobic glycolysis, it can withstand ischemic injury better than adult myocardium can.

Physiologic differences

Given the relatively low circulating blood volume of newborns and infants compared with that of adults, the priming solution in the CPB circuit plays an important role in hemodilution. The prime volume may consist of as much as 3 times the blood volume of a healthy neonate. As a consequence, the effects of hemodilution are markedly enhanced in neonates compared with adults, as evidenced by decreased levels of plasma protein, coagulation factors, and hemoglobin. This reduction increases organ edema, coagulopathy, and transfusion requirements. In addition, infants and neonates have high oxygen-consumption rates and, therefore, require flow rates as high as 200 mL/kg/min at normal temperature to meet those requirements. Finally, intracardiac and extracardiac shunts and the reactive pulmonary vascular bed are unique anatomic and physiologic findings in patients with congenital cardiac disease that influence their response to CPB.

The pediatric myocyte is also unique from its adult counterpart. At birth, only 30% of the myocardial tissue is contractile compared to 60% in the adult. The pediatric ventricle has less compliance, less preload reserve, and less sensitivity to catecholamine. ^[6]  The metabolism of calcium also differs in pediatric patients. The immaturity of the sarcoplasmic reticulum leads to a diminished ability to sequester calcium, resulting in a predisposition to the calcium-mediated injury seen during ischemia and reperfusion for pediatric patients compared to adults. ^[7]

Cardiopulmonary bypass (CPB) exposes neonates to harmful effects that are more pronounced than those seen in adults because of the immaturity of the neonatal heart, peripheral tissues, and organ function. The disparity between the CPB circuit size and priming volume also increases the subsequent inflammatory reaction resulting from exposure to the foreign surface area of the CPB circuit.

The resultant systemic inflammatory response is complex and involves activation and interaction of many systems and cellular elements in the body. These include the complement system, neutrophils, cytokines, the arachidonic acid pathway, and the coagulation cascade. Capillary permeability and interstitial edema increase; the response is more pronounced in neonates, and pulmonary and renal function are affected.

Glucose metabolism

Hyperglycemia usually accompanies the stress response associated with CPB. The mechanism of this stress response is postulated to be a combination of decreased glucose uptake in skeletal and myocardial myocytes and a mismatch between oxygen delivery and consumption. Hyperglycemia occurs in approximately 25% of children after CPB and is especially prevalent in children with higher risk scores and more severe disease. ^[8] There have been conflicting results regarding hyperglycemia and its associations with higher postoperative morbidity and mortality. 

A study by Yates and colleagues in surgical patients of varying ages following congenital heart surgery reported that hyperglycemia in the postoperative period was associated with increased early morbidity and mortality. ^[9] However, other studies have not found a significant link between hyperglycemia and adverse outcomes in pediatric patients undergoing cardiac surgery using CPB compared to adults. Steward et al reported a worse neurologic outcome in patients with hyperglycemia who undergo deep hypothermic circulatory arrest (DHCA), but the results were not statistically significant. ^[10]

In the Boston Circulatory Arrest Study, intraoperative hyperglycemia was not predictive of worse neurodevelopmental outcome after the arterial switch operation. ^[11] A study by Ballweg et al examined the neurodevelopmental outcomes at age 1 year in 188 infants who underwent cardiac surgery when younger than 6 months. ^[12] They found that, although hyperglycemia was common in the initial 48 hours postoperatively, it was not associated with worse developmental outcome at age 1 year.

Insulin protocols and use of a glucose-insulin-potassium solution to ensure tight glucose control after cardiac surgery in adults have been associated with lower mortality, improved hemodynamics, and reduced need for reoperations, as well as less renal failure. However, randomized controlled trials in pediatric patients have produced inconsistent results and have even demonstrated increased morbidity from a higher incidence of hypoglycemia in the intervention group. What is being shown is that acute changes in glucose may be associated with neurologic sequelae. The clinical dilemma posed by postoperative hyperglycemia warrants continued investigation into the mechanism and potential interventions to improve patient care. ^[8]  

A more common complication of pediatric CPB is hypoglycemia. This is largely because of the decreased glycogen stores and reduced hepatic potential for gluconeogenesis. In patients with congenital heart disease (CHD), hepatic perfusion may be impaired further, which leads to compromised liver function. Neurologic consequences of hypoglycemia are aggravated by hypothermia and other factors that may modify cerebral perfusion. The management of hypoglycemia is also more well defined. Glucose monitoring during CPB and rapid correction of hypoglycemia with dextrose is essential for decreasing morbidity resulting from pediatric heart surgery. Close attention to postoperative glucose management in the intensive care unit (ICU) is also critical.

Hematologic effects

Pediatric patients develop an exaggerated response to CPB. The inflammatory response in patients undergoing CPB is inversely proportional to the patient's age. The synthetic surfaces of the bypass circuit are associated with activation of inflammatory mediators. Effects include activation of the complement system, including plasma-activated complement 3 (C3a). A potent stimulator of platelet aggregation, C3a causes the release of from mast cells and basophils, increases vascular permeability, and stimulates WBCs to release oxygen free radicals and lysosomal enzymes. Elevated levels of C3a are linked to the duration of CPB.

Neutrophil activation has been linked to this inflammatory reaction, with neutrophil expression linked to the duration of CPB. Their activation increases production of cytokines, such as interleukin (IL)-8 and IL-6 and tumor necrosis factor (TNF). Expression of binding proteins on endothelial surfaces leads to extravascular migration of neutrophils and subsequent tissue injury. Activated neutrophils may obstruct the capillaries, limiting reperfusion of ischemic tissue (ie, no-reflow phenomenon). In addition, neutrophil activation stimulates the release of lysosomal enzymes, such as elastase and proteinase, in addition to the release of oxygen free radicals.

The contact between the patient’s blood and the surface of the CPB circuit leads to an inflammatory cascade that activates platelets and increases thrombus formation. ^[13] The release of tissue factor leads to the generation of thrombin, which can initiate a viscous positive-feedback cycle of simultaneous coagulation and inflammatory cascade activation. If not corrected, this process leads to a hypercoagulable state and the consumption of coagulation factors, which, in addition to activation of fibrinolysis, can cause excessive bleeding.

Finally, activation of arachidonic acid cascade leads to the generation of leukotrienes, prostaglandins, and thromboxane A2. These factors interact and express various effects on the vascular reactivity and further activation of the inflammatory state caused by CPB.

Stress response

Low perfusion, hypothermia, anesthesia, and surgery cause the release of hormones and other substances, including catecholamines, cortisol, growth hormone, Glucagon, corticotropin (or adrenocorticotropic hormone [ACTH]), thyroid-stimulating hormone (TSH), and endorphins. Levels of thyroid hormone decreases the first few days after CPB. Decreased renal and hepatic function after CPB leads to decreased clearance of vasoactive inflammatory mediators from the kidneys and liver. The lung is normally responsible for metabolizing and clearing many of these hormones, particularly catecholamines. Exclusion of the lungs from the circulation after CPB leads to the accumulation and increased levels of circulating catecholamines.

Cardiac effects

Studies of immature animal hearts have demonstrated conflicting data regarding the relative sensitivity of the neonatal heart to ischemia compared with the adult heart. Reasons for improved tolerance to ischemia in the neonatal heart include the increased glycolytic capability of the immature myocardium and enhanced preservation of high-energy phosphates because of decreased levels of 5'-nucleotidase, which catalyzes the breakdown of adenosine monophosphate (AMP) to adenosine. Conversely, an accumulation of lactic acid because of anaerobic metabolism is hypothesized as a cause of ischemic intolerance in the neonatal heart.

Central nervous system (CNS) effects

Neurologic injury after routine CPB is an ongoing long-term issue in neonates, and the risk is increased when DHCA is required. Although permanent injury is relatively uncommon, evidence of neurologic injury is observed in as many as 25% of infants who undergo DHCA. Neurologic morbidity includes seizures, strokes, changed tone and mental status, motor disorders, abnormal cognitive functioning, and post-CPB choreoathetosis. Areas most vulnerable to ischemic injury include the neocortex, hippocampus, and striatum.

Another potential mechanism of brain injury involves binding of glutamate to the N -methyl-D-aspartate receptor (NMDAR). This binding increases the amount of intracellular calcium and subsequently activates proteases, phospholipases, and deoxyribonucleases (DNAses) and promotes generation of free radicals. The net result of these processes is cell injury, cell death, or both.

Benveniste et al demonstrated that the extracellular glutamate concentration was increased in rat hippocampus during ischemia. ^[14] Redmond et al found that areas with the highest concentration of NMDAR were most vulnerable to injury after circulatory arrest. ^[15]  Microemboli can be detected in patients during CPB. The long-term effect of these emboli is not well defined. The effect of DHCA on long-term neurodevelopment has been a potential concern; studies assessing the long-term effects of DHCA have not demonstrated significant differences in cognitive ability.

Spinal cord injury is a rare but serious complication caused by cessation of blood flow from DHCA or interruption of the spinal cord collateral network. This can lead to transient and permanent motor and sensor deficits.

Pulmonary effects

Lung injury is mediated in one of two ways. Leukocyte and complement activation cause an inflammatory response, or a mechanical effect leads to surfactant loss and atelectasis. These types of dysfunction reduce static and dynamic compliance and functional residual capacity and increase the alveolar-arterial (A-a) gradient. Hemodilution reduces oncotic pressure and causes extravasation of fluid into the lung parenchyma. CPB activates complement and leukocyte degranulation, causing injury to the capillary membrane and platelet activation, both of which eventually lead to increased pulmonary vascular resistance. On CPB, hemodilution can be managed through either the administration of albumin or the use of intraoperative cell salvage.

Renal effects

CPB leads to production of renin, angiotensin, catecholamines, and antidiuretic hormone. In turn, these substances cause renal vasoconstriction and reduce renal blood flow. Risk factors for postoperative renal dysfunction include preoperative renal disease, contrast-related renal injury, and profound post-CPB reduction in cardiac output. After CPB, more than 8% of patients have acute renal insufficiency, as indicated by oliguria and increased creatinine levels. After spontaneous urine output is observed, diuretics are effective for inducing diuresis and reversing renal cortical ischemia associated with CPB, but their use does not alter the time to the recovery of renal function.

A study by Ruf et al indicated that in infants undergoing CPB during cardiac surgery, oximetry measurement using near-infrared spectroscopy can be used to monitor these patients for the development of acute kidney injury. The study, which involved 59 infants who underwent CPB for univentricular or biventricular repair of congenital heart disease, found that patients who developed acute kidney injury tended to have significantly lower oximetry values during surgery and over the first 48 hours postoperatively. ^[16]

Different techniques can be used to moderate some of the potentially deleterious effects of cardiopulmonary bypass (CPB). These include miniaturization of the circuit and the oxygenator and the use of steroids and aprotinin; biocompatible circuitry; vacuum-assist venous drainage (VAVD); and modified ultrafiltration (MUF), which removes inflammatory mediator-rich fluid from the patient and bypass circuit. ^{[17, 18, 19]}

Noninvasive metabolic monitoring

Near-infrared spectroscopy (NIRS) is a noninvasive method to continuously monitor oxygen delivery perioperatively. NIRS provides regional oxygen saturation (rSO2), which reflects the balance between oxygen delivery (DO2) and oxygen consumption. The use of NIRS in pediatric cardiac surgery has dramatically increased since its inception and has been most extensively used as a method to measure cerebral perfusion. This can allow for a more precise measurement of brain oxygenation and thus provide more patient-tailored adjustment compared to body-surface–derived CPB flow rates. Relatively recent studies have suggested that NIRS can be predictive for neurologic complications and acute kidney injury, making it useful intra- and postoperatively. ^{[20, 21, 22]} However, its use remains controversial.

Allopurinol

Hypoxic-ischemic brain injury following CPB and DHCA can lead to potentially severe neurologic complications, especially for patients with high-acuity congenital heart disease (CHD) defects that present with perinatal asphyxia. Hypoxia and ischemia cause an increase in free radical production, namely superoxide, hydrogen peroxide, and the hydroxyl free radical. This process can be propagated by reperfusion (or “reperfusion injury”) leading to more neuronal damage. Allopurinol is a free-radical scavenger that has been demonstrated to reduce the incidence of postoperative coma, seizures, cardiac events, and death. Although the long-term neurodevelopmental benefits of allopurinol have not been clearly elucidated, its short term benefits are clear. ^[23]

Corticosteroids

Steroids have been used in conjunction with CPB for many years to moderate the inflammatory response and support any CPB-induced adrenal insufficiency. However, there is ongoing controversy regarding its usage. The inflammatory response mounted by pediatric patients is more severe than their adult counterparts. A rationale for steroid administration is hemodynamic support, as CPB is associated with disruption of the hypothalamic-pituitary-adrenal axis and can propagate hypotension intra- and postoperatively.

The present authors administer intravenous methylprednisolone at a dosage of 10 mg/kg 8 hours before surgery and repeat the dose just before surgery on all neonates. This treatment has been associated with a decreased post-CPB inflammatory response, as assessed by evaluating cytokine levels and the patient's clinical course. Several studies have showed that steroid use is associated with substantial reductions in post-CPB fluid gain, improvements in pulmonary compliance and pulmonary vascular resistance, and expedited postoperative convalescence. These benefits must be balanced with the potential harm of steroid administration. Steroid use intraoperatively has been associated with increased postoperative insulin use, infection, and increased length of stay. The dosage used by the authors is based on institutional experience that minimizes complications while maximizing the benefits of dexamethasone. However, further studies are needed to assess the value of corticosteroids and resolve the controversy.

Leukocyte-reduced blood

Leukocytes in transfused blood are associated with several posttransfusion immunomodulatory effects. At many cardiac centers, leukocyte-reduced blood is used to prime the bypass circuit to decrease any possible donor-versus-host reaction. Especially for children younger than 6 months, blood will be irradiated before priming.

Leukocyte filters

Clinical and experimental studies have shown that leukocyte filtration during CPB can ameliorate some of the inflammatory reaction associated with CPB. However, results of using leukocyte filters to remove WBCs during CPB have been inconsistent.

Biocompatible-coated circuits and oxygenators

At many cardiac centers, clinicians use special, available coated circuits designed to mitigate the systemic inflammatory response to CPB, with reduced complement activation, cytokine release, and fibrinolysis. However, the challenge has been in providing coated surfaces for oxygenators that improve the blood-surface interface without altering their gas-exchange performance.

Investigations of the effectiveness of a heparin-coated CPB circuit to reduce the inflammatory response have produced contradictory results. Ozawa et al reported decreased levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 in patients in whom heparin coating was used during surgery, but these reductions did not affect the patients' postoperative blood loss, intubation time, or length of stay in the intensive care unit (ICU) or hospital. ^[24] Grossi et al reported reduced C3a and IL-8 levels with heparin coating, which were correlated with improved peak airway pressures and prothrombin times. ^[25] However, others have not found a therapeutic benefit.

Poly-2-methoxyethyl acrylate (PMEA) is a synthetic blood-compatible polymer that has had promising ex vivo results. Interest in this compound is because of its ease of use, and it allows for avoidance of heparin-related complications (thrombocytopenia, allergic reactions, etc). However, the efficacy of a PMEA-coated CPB circuit has not been thoroughly investigated. In a randomized controlled trial that assigned 14 pediatric patients undergoing cardiac surgery to either a heparin-coated or PMEA-coated CPB circuit, investigators noted that the PMEA group had a significant transient leukopenia postoperatively and higher respiratory indices and C-reactive protein levels, indicating potential systemic inflammatory response syndrome. ^[26] A different randomized controlled trial found that PMEA-coated CPB circuits led to superior platelet inactivation but less complement inactivation compared with heparin-coated CPB circuits. ^[27] These results suggest PMEA circuits' higher rates of complement activation lead to leukocyte sequestration in the pulmonary vasculature and can produce pulmonary sequela.

Miniaturization of the cardiopulmonary bypass circuit

Different strategies can be applied to reduce circuit size and therefore decrease the blood-surface interface and reduce the prime volume and, therefore, hemodilution and the need for blood transfusion. These strategies involving decreasing the overall length and diameter of the tubing used. The size is kept as small as possible to reduce the prime volume but large enough to achieve effective flow rates and low line pressure. Tube length is kept as short as possible by optimizing the pump orientation in relationship to the surgical table and moving the pump heads closer to the patient.

These strategies help reduce the size of the circuit while maintaining adequate flows to enable safe repair of complex cardiac defects. In addition to these mentioned strategies, some components of the extracorporeal circuit, such as arterial-line filters and in-line blood cardioplegia, can sometimes be eliminated to further decrease the circuit.

More recently, oxygenators specifically designed for neonatal and pediatric patients have been brought to market. These oxygenators have built-in arterial line filters and can oxygenate 0.7 to 2 L per minute with a priming volume of only 31 to 50 mL. Some rat model systems work with no prime volume at all. This is a promising method to reduce the blood-surface interface and hemodilution. This will also reduce the use of VAVD and obviate its potential complications.

Vacuum-assisted venous drainage

Many centers use VAVD, which allows further miniaturization of the CPB circuit because VAVD allows the use of decreased-diameter cannulas and tubing while providing adequate and effective flow. Several reports describe major complications with VAVD, including air embolization. Although this is an important concern, many centers continue to use VAVD.

Modified ultrafiltration

An important cause of morbidity and mortality after CPB is total-body edema. A substantial amount of total-body water can occur after CPB, even in routine open cardiac procedures. This excessive fluid accumulation results in edema in the periphery and in organs such as the lungs, brain, heart, and gut. Effects include subsequent organ dysfunction and complex and prolonged postoperative care.

Two factors contribute to postoperative edema. First, hemodilution is related to the relatively large priming volumes compared with body weight in the pediatric age group. Consequently, decreased oncotic pressure leads to tissue edema and organ dysfunction. Second, exposure of the blood to the bypass circuit initiates an inflammatory response, increasing permeability and subsequent postoperative tissue edema.

Ultrafiltration relies on interposing a dialysis filter into the CPB circuit. During CPB, free water and soluble metabolites can be removed from the circuit by applying a negative pressure across the dialysis membrane. MUF is performed after the patient is weaned off CPB. Blood is withdrawn from the aortic cannula, passed through the filtration unit, and fed back to the patient through the venous line. To maintain hemodynamic stability, blood can be added to the circuit to further increase the hematocrit.

Endpoints of hemofiltration vary among institutions and can be defined by time, volume, or hematocrit. In the postoperative period, patients receiving MUF have smaller increases in total-body weight than do control subjects. In addition to decreasing edema, hemofiltration increases the hematocrit, which translates into increased oxygen-carrying capacity. Removed fluids also contain inflammatory mediators and vasoactive substances. Clinical studies have demonstrated that MUF is associated with increased ventricular systolic function; improved cerebral blood flow (CBF), cerebral metabolic activity, cerebral oxygen delivery, pulmonary function; and decreased duration of postoperative ventilation, postoperative bleeding, chest-tube drainage, and incidences of pleural effusions; and shortened hospital stays.

Pediatric and neonatal patients undergoing cardiopulmonary bypass (CPB) for cardiac surgery are prone to coagulopathy in the early postoperative period. ^[28] Contributing factors include hemodilution, depletion of platelets and decreased aggregation, decreased production of coagulation factors by the liver, decreased Von Wilbrand factor, immaturity of the coagulation system, increased fibrinolysis, and the complex nature of the surgical procedure (which often includes several suture sites and, therefore, an increased number of potential bleeding sites).

To avoid thrombus formation in the CPB machine, heparin is administered before cannulation, typically by using a loading dose of 300-400 U/kg. Heparin is chosen because it is a fast-acting anticoagulant and because protamine can rapidly inhibit its action. Heparin activates antithrombin III, which inhibits thrombin activity. Heparin can be stored in the vascular endothelium and smooth muscle, contributing to heparin rebound, which is observed after CPB is discontinued and heparinization reversed. Hepatic and renal function also determine the clearance of heparin.

Heparin activity is monitored by measuring activated clotting times (ACTs) and heparin levels. Newborns have only half the antithrombin III levels of adults and therefore require doses of heparin higher than those given to adults. The desired ACT is more than 450-480 seconds. However, this range is extremely controversial. Some clinicians use a much lower ACT. Monitoring of only ACTs or heparin levels methods may not reflect the full degree of anticoagulation. Factors unrelated to heparin concentration, including the patient's hematocrit and temperature, can affect ACT levels.

Another method of monitoring heparin activity is the use of a dose-response curve, which is somewhat cumbersome in a clinical setting. A heparin-protamine titration test can readily provide both ACTs and heparin levels. To perform this test, blood obtained from the patient is added to a series of tubes containing known amounts of protamine. Heparin and protamine are assumed to bind in a 1:1 ratio. If the amount of protamine and the volume of the blood sample are known, the heparin concentration can be calculated. Desired values are a heparin concentration of 3.0-3.5 U/mL and an ACT of 400 seconds.

Protamine binds to heparin and releases antithrombin III. One method of administering protamine is to administer 1-1.3 mg for each 100 U of heparin administered. This method does not account for the half-life of heparin or its clearance from circulation. Other methods include the use of ACT-heparin dose-response curves, direct measurement of heparin levels, and heparin-protamine titration, as stated before.

Adverse effects of protamine include the release of histamine, which can lead to a decrease in systemic vascular resistance; true anaphylaxis, which is mediated by antiprotamine immunoglobulin E (IgE) and is observed primarily in patients with a previous exposure to protamine (eg, neutral protamine Hagedorn [NPH] insulin) and in patients with fish allergy; and thromboxane release, which leads to pulmonary vasoconstriction and bronchoconstriction.

Bleeding after CPB is not unusual. Any source of obvious surgical bleeding should be identified because this is the most common cause of post-CPB bleeding. Next, assess the adequacy of the protamine dose. ^[29] If the dose appears sufficient, the next most common cause of bleeding is platelet dysfunction, platelet infusion is warranted, even if the platelet count is in reference range. Platelets in infants and children are often dysfunctional after CPB. Aprotinin can decrease requirements for blood transfusions in patients undergoing repeat surgeries and in patients with cyanosis. Other patient groups may also benefit. Desmopressin has antifibrinolytic activity and acts as a kallikrein inhibitor. Mild hypersensitivity reactions and anaphylactic reactions are reported. Furthermore, the temperature of the patient is important.

Neonates and infants undergoing complex repairs often need blood products, including platelets, fresh-frozen plasma, and cryoprecipitate to achieve hemostasis. Finally, factor VII concentrates have an emerging role in postoperative coagulopathy and bleeding refractory to the administration of several products after surgical bleeding sites are ruled out. However, experience with factor VII in children is limited, and further evaluation of its role is needed

Advantages of hypothermia

Hypothermia is frequently induced in infants and neonates because it offers several advantages. For example, hypothermia helps to protect organs against injury caused by the compromised substrate supply to tissues resulting from reduced flow. This protection occurs because of a reduced metabolic rate and decreased oxygen consumption. The metabolic rate is determined by enzymatic activity, which, in turn, depends on temperature. The decrease in metabolic rate is not the only factor involved in hypothermic protection. The safe period of hypothermic cardiopulmonary bypass (CPB) is longer than the period predicted on the basis of reduced metabolic activity alone.

The effect of hypothermia on the ionization constant of water and, therefore, its effect on the ionized-to-nonionized ratio of metabolic substrates mediates its effect on pH. In ischemic states, intracellular pH decreases because of the accumulation of hydrogen ions, which, in turn, causes a decrease in the ratio of ionized-to-nonionized metabolic substrates. Nonionized substrates can cross the cellular membrane and are lost. Hypothermia affects this loss by decreasing the metabolic rate, then by increasing the ionized-to-nonionized ratio. In addition, the transformation of a semiliquid cellular membrane to a semisolid membrane is postulated to decrease calcium influx.

The effect of hypothermia on the nervous system is multifactorial. In addition to decreasing the metabolic rate, hypothermia decreases the release of glutamate, which is involved in central nervous system (CNS) injury during CPB. A negative effect of hypothermia on brain function is the loss of autoregulation at extreme temperatures, which makes blood flow highly dependent on extracorporal perfusion. Studies in piglet models showed a decrease in both cerebral blood flow (CBF) and oxygen consumption at 45 minutes and at 3 hours after reperfusion; both of these parameters returned to preoperative values. In addition, hypothermia delays cardiac rewarming and contributes to myocardial protection during CPB.

Finally, hypothermia enables the perfusionist to decrease the flow rate, which decreases pulmonary venous and collateral return to the heart to improve exposure to the operative field, especially in patients with total anomalous venous connection repair and other cardiac reconstructions. In addition, decreased exposure to the CPB circuit with hypothermia decreases the inflammatory response to CPB, as evidenced by the findings of decreased inflammatory mediators and organ dysfunction in patients subjected to hypothermic arrest compared with those undergoing low-flow continuous CPB. At present, two surgical techniques are used in congenital heart surgery, namely, deep hypothermic circulatory arrest (DHCA) and hypothermic low-flow bypass (HLFB).

Deep hypothermic circulatory arrest

DHCA is typically defined as achieving a core temperature below 20ºC. It provides excellent surgical exposure by eliminating the need for several cannulas in the surgical field and by providing a motionless and bloodless field. Cooling is started before CPB by simply cooling the operating room. After systemic heparinization and cannulation are performed, CPB is started and cooling is begins for at least 20-30 minutes. The patient's body temperature is monitored by means of esophageal, tympanic, and rectal routes. After adequate cooling is achieved, the circulation is arrested to allow the surgeon to perform the critical part of the reconstruction. The duration of DHCA is limited to the shortest time possible. After circulation is restarted, the rest of the repair is performed during the rewarming phase. More recently, DHCA was used successfully for the approximation of the scimitar vein to a surgically created atrial septal defect during scimitar syndrome repair. ^[30]

Hypothermic low-flow cardiopulmonary bypass

The finding that DHCA was associated with neurologic morbidity led researchers to investigate the use of HLFB. This technique provides continuous low-flow perfusion to the organs during the operation to possibly increase the oxygen and nutrient supply.

Trials to compare the two methods have demonstrated lowered rates of neural dysfunction in patients undergoing HLFB. In particular, in 4-year-old patients receiving CPBs, DHCA was associated with low levels of motor coordination and planning but not with significantly lowered intelligence quotients (IQs) or worsened overall neurologic status. ^[31]

Many surgeons have adopted several modified surgical and perfusion techniques to allow for safe continuous HLFB in infants undergoing complex surgical cardiac repair, including arch reconstruction, and thus decrease the overall time for complete arrest.

Finally, some groups suggested combining the two approaches mentioned above in children undergoing complex cardiac repairs by using DHCA with intermittent low-flow perfusion for 1-2 minutes every 15-20 minutes.

Antegrade selective cerebral perfusion

Interest in selective hypothermic cerebral perfusion has increased. Several surgeons have pioneered various techniques. In the adult, selective antegrade perfusion of the brain is accomplished by using cannulas inserted into the innominate artery alone, into the innominate and left common carotid arteries, or into the right axillary artery.

In addition, antegrade cerebral perfusion (ACP) can be achieved by using an open end of a modified Blalock-Taussig shunt after the proximal anastomosis is constructed in neonates who require arch reconstruction (eg, in the Norwood operation). The perfusate temperature is usually set at 18°C, and the flow is set at 10-20 mL/kg/min or adjusted to maintain a pressure of 40-50 mm Hg in the right radial artery. Higher flows of 30-40 mL/kg/min are recommended for neonates.

Several drawbacks are associated with those various cannulation techniques and are mainly related to complications of direct cannulation of arch vessels. Examples include dissection of the arterial wall, air or atheromatous plaque embolization, malposition of the cannula, and overcrowding of the operative field with numerous cannulas. In addition, cannulation of the right axillary artery can cause complications, such as stenosis and dissection. Some groups report improved results by performing cannulation through a tube graft anastomosed to the axillary artery rather than by performing direct cannulation of the artery itself.

Studies by Goldberg et al and Visconti et al have failed to show a significant survival or functional neurodevelopmental advantage of selective cerebral perfusion over deep hypothermic arrest. ^{[32, 33]} Nonetheless, more research is needed to understand the ideal mode of administration of selective cerebral perfusion, the ideal perfusion rate, temperature, and ideal cooling to protect the remaining organs.

Kulyabin et al compared the outcomes of 121 infants who underwent aortic arch reconstruction between 2008 and 2018. Antegrade selective cerebral perfusion alone was used in 79 patients; 42 patients underwent repair with selective cerebral perfusion combined with continuous lower body perfusion with descending aortic cannulation. The patients who received continuous lower body perfusion had a lower mortality rate, a lower risk of acute kidney injury, and shorter hospital stays. There was no difference in neurological complications between the groups. The investigators concluded that selective cerebral perfusion combined with continuous lower body perfusion can effectively be used for improving early postoperative results among infants undergoing aortic arch reconstruction procedures. ^[34]

Retrograde cerebral perfusion (RCP)

The concept of RCP for cerebral protection originated in the treatment of massive air embolism during CPB. RCP has been successfully used in adult thoracic aortic surgery as an adjunct to DHCA to enhance cerebral protection.

The perfusion technique usually includes bicaval venous cannulation, with the arterial line containing Y-connectors with limbs to the venous line that may be clamped during antegrade cerebral flow. When retrograde perfusion is started, the superior vena cava is snared, antegrade arterial flow is terminated, and the arterial cannula is clamped while the limb connecting the arterial return line to the superior vena cava cannula is opened. Flow rate is usually 500-1000 mL/min, and the pressure in the superior vena cava is maintained at 15-20 mm Hg.

Mechanisms with which RCP may accomplish neuroprotection include the flushing of air and atheromatous embolic material from the cerebral circulation, the maintenance of cerebral hypothermia, and the provision of nutritive cerebral flow. RCP can be given continuously or intermittently. However, many institutions have moved away from this technique as incidents of cerebral edema after RCP, particularly when the perfusion pressure exceeds 25 mm Hg, are reported.

In addition, the nutritive value of retrograde brain perfusion remains controversial. Despite signs of oxygen uptake observed in several studies, the amount of perfusate that provides cerebral nutrition is low, corresponding to only about 5% of total retrograde flow. Most of this flow is drained from the superior vena cava into the inferior vena cava given the rich network of collaterals between the veins.

RCP remains a useful adjunct in adults requiring thoracic aortic surgery mainly because of its benefit in maintaining brain hypothermia and in flushing air and atheromatous debris. This technique is not commonly used in the pediatric population.

Spinal cord protection during DHCA

Prolonged DHCA and/or techniques that interrupt the network of spinal cord collaterals are risk factors for postoperative spinal cord injury. Although ACP and RCP can improve cerebral oxygen delivery, the susceptible spinal neurons are left unprotected. Increasing spinal cord perfusion in the immediate postoperative period is performed by manipulating the two variables that comprise spinal cord perfusion pressure: mean arterial pressure (MAP) and cerebral spinal fluid pressure (CSFP). Maintaining a relatively high MAP (70-90 mmHg) can aid in ensuring the spinal cord is perfused. Placement of a spinal cord drains in high-risk patients allows for a decrease CSFP and increases spinal cord perfusion pressure. ^[35]

Acid-base management and management of carbon dioxide pressure

At present, two strategies used to manage acid-base balance and carbon dioxide pressure (PCO₂) are the pH-stat and alpha-stat approached. During hypothermia, the solubility of carbon dioxide in blood increases, and for a given concentration of carbon dioxide in blood, PCO₂ decreases and the blood becomes alkalotic.

In pH-stat management to compensate for increased carbon dioxide solubility, carbon dioxide is added to the gas mixture in the oxygenator to maintain the hypothermic pH at 7.40 and the PCO₂ at 40 mm Hg. When blood samples are warmed to room temperature, blood gases are hypercapnic and acidotic.

The alpha-stat method allows blood pH to increase during cooling, which leads to hypocapnic and alkalotic blood in vivo. Blood samples warmed to room temperature have a pH of 7.4 and a PCO₂ of 40 mm Hg. These conditions allow the alpha-imidazole group of the histidine moiety on blood and cellular proteins to maintain a constant buffering capacity, which enhances enzyme function and metabolic activity. Furthermore, the increase in pH parallels the increase in the hydrogen ion dissociation constant of water during cooling, which can maintain a constant ratio of OH^- ions to H⁺ ions.

With the alpha-stat approach, CBF autoregulation is maintained, which allows for metabolism and blood flow coupling. CBF can be adjusted depending on the patient's cerebral metabolic activity and oxygen needs. Most studies of this approach have been performed in adults.

Prior experimental and retrospective single-center studies may suggest that the pH-stat strategy is best for the pediatric population. Findings included improved neurologic outcome, hastened electroencephalographic recovery times, and reduced number of postoperative seizures. Reasons for these improved outcomes include increased cortical oxygen saturation before arrest, decreased cortical oxygen metabolic rates during arrest, and increased brain-cooling rates. CBF during reperfusion also increases by using a pH-stat management strategy. However, the only randomized controlled trials specifically in the pediatric population have not found a significant difference in outcomes between the two methods. Therefore, this strategy is being revisited. ^{[36, 37]}

Potential harmful effects of the pH-stat method are increased CBF that can theoretically increase the potential for embolic events, high CBFs during reperfusion, and reperfusion injury.

Benefits of the pH-stat strategy might not be extrapolated to the adult population. Brain injury in adults is related to the number of microemboli that reach the brain. pH-stat management may increase the number of microemboli because of the increased CBF.

Microembolic injury has not been linked to cerebral injury in pediatric patients because microemboli are uncommon in pediatric heart surgery and because histopathologic features of brain damage in neonates are not consistent with microembolic injury. However, neurons of the CNS in pediatric patients are vulnerable to ischemia. This fact emphasizes that the need to improve the maintenance of CBF and the oxygen content is greater than the need to limit the risk of a microembolism reaching the cerebrum. Long-term clinical data are not available to categorically support one strategy over the other, and further studies and follow-up observations are necessary.

In addition, the acid load induced by using pH-stat strategy may impair enzymatic function and metabolic recovery after rewarming. To retain the benefits of the pH-stat method on cooling and to eliminate its negative effect on enzymatic function, several groups suggested use of a combined strategy to manage blood gases by combining both the pH-stat and the alpha-stat techniques in succession. That is, initial cooling is accomplished with the pH-stat method, which is then switched to alpha-stat method to normalize the pH in the brain before ischemic arrest is induced.

Myocardial-protection strategies are used to halt the mechanical contractions of the heart and to allow intracardiac procedures to be performed in a motionless, bloodless field. Because blood flow is interrupted and cardiac ischemia ensues, the myocardial-protection strategy is designed to sufficiently reduce myocardial oxygen consumption so that myocardial function can resume at the end of the procedure with minimal dysfunction.

Cardioplegia is typically categorized as either crystalloid or blood cardioplegia. Blood cardioplegia solution is typically a mixture of four (4) parts of oxygenated blood and one (1) part crystalloid solution. The addition of blood to the cardioplegic solution enhances oxygen delivery, especially at the microcirculation level. In addition, it contains buffers, leads to less hemodilution, and has a physiologic osmolality. The drawbacks of blood cardioplegia include sodium and calcium accumulation in neonates, who are already predisposed to calcium accumulation and subsequent myocyte injury. This leads to poorer myocardial recovery. 

The benefits of crystalloid cardioplegia include it is inexpensive, one dose is sufficient for arrest, and one dose can provide up to 2 hours of myocardial protection. Del Nido cardioplegia is a crystalloid cardioplegia that is the most commonly used myocardial protection agent in pediatric patients. ^[38] It contains lidocaine, a sodium channel blocker, and magnesium, which competes with calcium. These two agents help prevent the sodium and calcium accumulation seen with cardioplegia. In addition, magnesium has antiarrhythmic properties, and its administration during cardiopulmonary bypass (CPB) has been demonstrated to reduce postoperative arrhythmia incidence. Magnesium also aids in reducing sodium entry into the cell. ^[38]

Regardless of the agent utilized, minimizing the amount of calcium in the cardioplegia solution reduces the risk of the intracellular accumulation of calcium during ischemia and reperfusion. However, complete elimination of calcium from the solution is not advised because of the risk of the calcium paradox phenomenon, in which rapid calcium accumulation during reperfusion leads to acute contracture, also called a stone heart. The addition of magnesium provides a protective effect on the hypoxic-ischemic immature heart. 

Calcium channel blockers retard the entry of calcium into the cell, and the addition of verapamil and nicardipine to a standard potassium cardioplegic solution may improve postischemic cardiac performance. However, their long-term action may decrease cardiac function after surgery. Maintaining normal colloid pressure is also important. Low protein concentrations are associated with impaired lymphatic flow and increased capillary leak. Other additives include mannitol, which acts as an osmotic diuretic and an oxygen free-radical scavenger.

In 1990, the first utilization of myocardial perfusion in conjunction with antegrade cerebral perfusion (ACP) was performed in a neonate, allowing for beating heart (BH) surgery during a complex aortic arch repair. ^[39] Since then, the utilization of this technique has grown as multiple authors have reported improved biomarker levels, improved hemodynamic status, and clinical performance with BH surgery. For aortic arch surgery, ACP is typically placed via the innominate artery and a coronary perfusion catheter is placed in the aortic root. This technique allows for warmer temperatures to be utilized and can spare patients of some of the deep hypothermic circulatory arrest (DHCA)-related complications. ^[39]

Although there are no in-human randomized controlled trials (RCTs) comparing BH cardiac surgery with cardioplegia-induced arrest DHCA, Janssen and colleagues compared the two approaches in an RCT involving 20 piglets. ^[40] They found improved myocardial contractility in the BH group but similar ischemic damage in both groups. The BH group did have the benefit of less electrolyte derangement compared to the cardioplegia group, which may translate to clinical benefits. ^[40]