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 considerably advanced. Management of CHD emphasizes early complete repair before the heart and the patient deleteriously adapt to the abnormal physiology. Today, complete repair of congenital heart defects can be performed in infants smaller than 2 kg, with good outcomes. Nevertheless, 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.  Gibbon first described and used a mechanical extracorporeal oxygenator, which he termed the heart-lung machine.  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 2 decades contributed to improved outcomes of surgical treatment of CHD.
Major differences adult and pediatric cardiopulmonary bypass (CPB) stem from anatomic, metabolic, and physiologic differences in these 2 groups of patients.
In anatomic terms, myocytes enlarge and become oblong as they mature. As myofibrils increase in size, they become oriented in the longitudinal direction of the cell. The number of mitochondria increases as the oxygen requirements of the heart rises. The amount of sarcoplasmic reticulum and its ability to sequester calcium similarly increase in early development. Finally, the activity of Na+/K+ adenosine triphosphatase (ATPase) increases with maturation, and this affects the sodium-calcium exchange mechanism.
All of 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 leads to cellular damage after CPB.
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.
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.
Cardiopulmonary bypass (CPB) exposes neonates to harmful effects that are more pronounced than those seen in adults because of the immaturity of neonatal peripheral tissues and organ function. The disparity between the CPB circuit size and the patient also increases the subsequent inflammatory reaction resulting from exposure to the foreign surface area of the CPB circuit.
The systemic inflammatory response to CPB is complex and involves activation and interaction of many systems and cellular elements in the body, including the complement system, neutrophils, cytokines, the arachidonic acid pathway, and the coagulation cascade. The inflammatory response promotes increased capillary permeability and interstitial edema. This response is more pronounced in neonates than adults and contributes to pulmonary and renal dysfunction in the postoperative period.
Hyperglycemia usually accompanies the stress response associated with CPB. Hyperglycemia and impaired glucose control have been associated with worsened outcomes after myocardial infarction and acute coronary syndromes, stroke, postoperative wound infections, and severe head injury. 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 decreased need for reoperations, as well as less renal failure.
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.  However, other studies have not found a significant link between hyperglycemia and adverse outcomes in pediatric CPB compared with 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. 
In the Boston Circulatory Arrest Study, intraoperative hyperglycemia was not predictive of worse neurodevelopmental outcome after the arterial switch operation.  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.  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.
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 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. Glucose monitoring during CPB and rapid correction of hypoglycemia with dextrose is essential for decreasing morbidity resulting from pediatric heart surgery.
Pediatric patients develop an exaggerated response to CPB. The inflammatory response 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.
Contact of blood with the surface of the bypass machine activates platelets and increases thrombus formation. The release of tissue factor leads to the generation of thrombin, which can initiate a viscous cycle with positive-feedback activation of coagulation and inflammatory cascades. 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. All of these factors interact and express various effects on the vascular reactivity and further activation of the inflammatory state caused by CPB.
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.
Studies of immature animal hearts have demonstrated conflicting data with regard to 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 as a result of anaerobic metabolism is hypothesized as a cause of ischemic intolerance in the neonatal heart.
Neurologic injury after routine CPB is uncommon in neonates, but the risk is increased when deep hypothermic circulatory arrest (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 postpump 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.  Redmond et al found that areas with the highest concentration of NMDAR were most vulnerable to injury after circulatory arrest. 
Microemboli can be detected in patients during CPB. The long-term effect of these emboli is not well defined.
Lung injury is mediated in 1 of 2 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.
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, 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. 
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. [12, 13, 14]
Steroids have been used for many years with CPB. The present authors administer intravenous methylprednisolone at a dosage of 10 mg/kg 8 hours before surgery and repeat just before surgery on all neonates. This treatment has been associated with a decreased postbypass inflammatory response, as assessed by assessing cytokine levels and the patient’s clinical course. Several studies showed that steroids use is associated with substantial reductions in post-CPB fluid gain, improvements in pulmonary compliance and pulmonary vascular resistance, and expedited postoperative convalescence.
Aprotinin (Trasylol; Bayer Pharmaceutical, West Haven, Connecticut) is an antifibrinolytic serine protease inhibitor purified from bovine lung. Aprotinin was approved by the US Food and Drug Administration (FDA) to reduce perioperative blood loss in high-risk patients undergoing CPB for coronary artery bypass grafting in 1993. Aprotinin reduces bleeding by delaying the rapid plasmin-mediated lysis of the fibrin clot. Several randomized, prospective, placebo-controlled, carefully performed trials on aprotinin use have shown that it reduces requirements for blood transfusion in adult cardiac surgery. In addition to its effect on postoperative bleeding, some evidence suggests that the inflammatory response of CPB is attenuated with high-dose aprotinin, leading to a reduction in inotropic support, earlier extubation, a tendency toward reduced postoperative blood loss, and a reduced hospital stay.
As a result of those early trials, many pediatric cardiac surgery centers started routinely administering aprotinin as an intravenous infusion to neonates before initiation of CPB and continued the infusion through the duration of the bypass. The authors’ practice had been to routinely administer aprotinin to all patients undergoing deep hypothermic circulatory arrest (DHCA), neonates who required complex cardiac repairs, and, particularly, those in whom postoperative use of either ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO) was anticipated.
Nonetheless, the safety of aprotinin use in adult cardiac surgery has been called into question, particularly in 2 separate reports published by Mangano and colleagues. [15, 16] They reported that aprotinin use was associated with increased risk of perioperative acute kidney failure, cerebral vascular accidents, and long-term mortality. Subsequent to those reports, numerous responses and media attention were generated, with eventual voluntary withdrawal of aprotinin from the market.
Following that report, a study by Backer and colleagues from Chicago found that, in a retrospective cohort of pediatric patients undergoing cardiopulmonary bypass, no association was noted between the use of aprotinin and acute kidney failure, the need for dialysis, neurologic complications, and operative or late mortality;  they recommended the continuous use of aprotinin in pediatric cardiac surgery.
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.
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.
At many cardiac centers, clinicians use specially 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 ICU or hospital.  Grossi et al reported reduced C3a and IL-8 levels with heparin coating, which were correlated with improved peak airway pressures and prothrombin times.  However, others have not found a therapeutic benefit.
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.
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 possible complications with VAVD, including air embolization. Although this is an important concern, many centers continue to use VAVD with satisfactory results.
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. As a consequence, 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. 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. 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. 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.
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
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 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, 2 surgical techniques are used in congenital heart surgery, namely, deep hypothermic circulatory arrest (DHCA) and hypothermic low-flow bypass (HLFB).
DHCA 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.
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 2 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.
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 2 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.
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 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. [20, 21] 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. The authors, along with many other major cardiac centers, continue to use selective cerebral perfusion during arch reconstruction procedures in neonates and infants.
The concept of retrograde cerebral perfusion for cerebral protection originated in the treatment of massive air embolism during CPB. Retrograde cerebral perfusion 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 retrograde cerebral perfusion 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. Retrograde cerebral perfusion can be given continuously or intermittently. Several clinical series of adults have shown encouraging results with the retrograde cerebral perfusion technique. However, incidents of cerebral edema after retrograde cerebral perfusion, 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.
Retrograde cerebral perfusion 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.
At present, 2 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.
Data have suggested 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.
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.
Blood cardioplegia solution is typically a mixture of 4 parts of oxygenated blood and 1 part crystalloid solution. The addition of blood to the cardioplegic solution enhances oxygen delivery, especially at the microcirculation level.
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. This effect probably due to the antiarrhythmic effect of magnesium, inhibited entry of calcium into the myocytes, and decreased uptake of sodium by myocytes during ischemia. Magnesium is exchanged for calcium during reperfusion.
Manrique et al observed a decreased incidence of hypomagnesemia and junctional ectopic tachycardia when magnesium supplementation was administered during cardiopulmonary bypass.  The effect appeared to be dose related.
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.
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Bahaaldin Alsoufi, MD Consulting Surgeon, Department of Pediatric Surgery, King Faisal Heart Institute, King Faisal Specialist Hospital and Research Centre
Bahaaldin Alsoufi, MD is a member of the following medical societies: American College of Surgeons, Royal College of Physicians and Surgeons of Canada, Society of Thoracic Surgeons
Disclosure: Nothing to disclose.
Christopher A Caldarone, MD Chair, Division of Cardiac Surgery, Professor of Surgery, University of Toronto; Staff Surgeon, Cardiovascular Surgery, Hospital for Sick Children, Toronto
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Mary C Mancini, MD, PhD, MMM Surgeon-in-Chief and Director of Cardiothoracic Surgery, Christus Highland
Mary C Mancini, MD, PhD, MMM is a member of the following medical societies: American Association for Thoracic Surgery, American College of Surgeons, American Surgical Association, Phi Beta Kappa, Society of Thoracic Surgeons
Disclosure: Nothing to disclose.
Stuart Berger, MD Executive Director of The Heart Center, Interim Division Chief of Pediatric Cardiology, Lurie Childrens Hospital; Professor, Department of Pediatrics, Northwestern University, The Feinberg School of Medicine
Stuart Berger, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American College of Chest Physicians, American Heart Association, Society for Cardiovascular Angiography and Interventions
Disclosure: Nothing to disclose.
Jonah Odim, MD, PhD, MBA Section Chief of Clinical Transplantation, Transplantation Branch, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
Jonah Odim, MD, PhD, MBA is a member of the following medical societies: American College of Cardiology, American College of Chest Physicians, American Association for Physician Leadership, American College of Surgeons, American Heart Association, American Society for Artificial Internal Organs, American Society of Transplant Surgeons, Association for Academic Surgery, Association for Surgical Education, International Society for Heart and Lung Transplantation, National Medical Association, New York Academy of Sciences, Royal College of Physicians and Surgeons of Canada, Society of Critical Care Medicine, Society of Thoracic Surgeons, Canadian Cardiovascular Society
Disclosure: Nothing to disclose.
Chadi T Abouassaly, MD Resident, Physician, Department of General Surgery, Washington Hospital Center
Chadi T Abouassaly, MD is a member of the following medical societies: Iowa Medical Society
Disclosure: Nothing to disclose.
Stewart P Adams, MD, FRCPC Clinical Assistant Professor, Department of Medicine, University of Calgary Faculty of Medicine
Disclosure: Nothing to disclose.
Circulatory Arrest and Cardiopulmonary Bypass Hypothermia
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