Hypothermia, Circulatory Arrest and Cardiopulmonary Bypass



Incidence of congenital heart disease (CHD) has been reported in 2-10 per 1000 live births. Although the mortality rate resulting from CHD has been decreasing because of improved surgical repair techniques, CHD remains the leading cause of death in all congenital defects.

In 1954, Lillehei first reported the effective use of extracorporal circulation in repair of CHD using cross circulation with the patient's parent functioning as the oxygenator.

Gibbon first described and used a mechanical extracorporal oxygenator, which he termed the heart-lung machine. On May 6, 1953, Gibbon performed the first successful open heart surgery in the world using a heart-lung machine while repairing an atrial septal defect. Subsequent attempts to use the heart-lung machine to help correct congenital heart defects were met with high morbidity and mortality rates until Barratt-Boyes (1971) and Castaneda (1974) attempted correction using hypothermic circulatory arrest. This, plus the introduction of the concept of staged repair, dramatically improved the surgical outlook for patients with a wide variety of congential heart lesions.


Major differences exist between adult and pediatric cardiopulmonary bypass (CPB), stemming from anatomic, metabolic, and physiologic differences in these 2 groups of patients.

Anatomic differences

Anatomically, myocytes enlarge and become more oblong as they mature. As the size of the myofibrils increases, they become oriented in the longitudinal direction of the cell. The number of mitochondria increases as the oxygen requirements of the heart increase. Similarly, the amount of sarcoplasmic reticulum and its ability to sequester calcium also 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 calcium is handled by the immature heart, which in turn contributes to the myocardial dysfunction observed in individuals following CPB.

Immature calcium handling in immature myocardium leads to an increase in intracellular calcium concentration after ischemia and reperfusion. This has been linked to activation of energy-consuming processes, which causes a decrease in ATP and a subsequent lack of energy sources for healthy cardiac function. The enzymes known to be activated by calcium include phospholipases, proteases, ATPases, and endonucleases, and the abnormal and uncontrolled activation of these enzymes leads to cellular damage following 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 has the ability to use multiple substrates, such as carbohydrates, medium- and long-chain fatty acids, ketones, and amino acids. In the mature heart, long-chain fatty acids are the primary substrates and require several enzymes and the presence of an increased number of mitochondria. With its increased ability to rely on anaerobic glycolysis, the immature myocardium has a greater capability to withstand ischemic injury.

Physiologic differences

Considering the relatively low blood volume of newborns and infants compared to 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. Consequently, the effects of hemodilution are enhanced markedly in neonates compared to adults.

Glucose stores in infants and neonates are reduced compared to adult stores, making prevention of hypoglycemia a more important consideration in neonates than in adults.


During open heart surgery, CPB provides the surgeon with a clear field for cardiac manipulation and maintenance of pulmonary and hemodynamic stability. The objective of the heart-lung pump is to provide enough flow to maintain a sufficient cardiac index for tissue perfusion. Pump flow rates are based on the patient's weight and laboratory evidence of adequate perfusion. The addition of cardioplegia allows the surgeon to work in a motionless and bloodless field.

The addition of hypothermia to CPB has been standard practice since Bigelow demonstrated improved tolerance of the entire organism to ischemia accompanied by hypothermia.

Effects of cardiopulmonary bypass

Glucose metabolism

Hyperglycemia has not been linked to adverse outcomes in pediatric CPB. Steward et al reported a worse neurologic outcome in patients with hyperglycemia undergoing deep hypothermic circulatory arrest (DHCA), but the results were not statistically significant. Hyperglycemia usually accompanies the stress response associated with CPB, thus categorically stating that these complications were due only to hyperglycemia is difficult.

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 with dextrose is essential for decreasing morbidity resulting from pediatric heart surgery.

Hematologic effects

Pediatric patients develop a more exaggerated response to CPB. The inflammatory response is inversely proportional to the patient’s age. Interleukin (IL)–8 and IL-6 production have been linked to this inflammatory reaction, with their expression linked to the duration of CPB. The synthetic surfaces of the bypass circuit have been associated with activation of inflammatory mediators. These include activation of the complement system, including plasma-activated complement 3 (C3a). A potent stimulator of platelet aggregation, C3a causes histamine release from mast cells and basophils, increases vascular permeability, and stimulates WBCs to release oxygen free radicals and lysosomal enzymes. Elevated levels of C3a have been linked to the duration of CPB but not to the duration of extracorporeal membrane oxygenation.

Contact of blood with the bypass machine surface activates platelets and causes an increase in thrombus formation. If not corrected, activation of coagulation and fibrinolytic pathways can lead to excessive bleeding. Expression of binding proteins on endothelial surfaces leads to extravascular migration of neutrophils and subsequent tissue injury.

Activated neutrophils obstruct the capillaries, thus limiting reperfusion of ischemic tissue (ie, no-reflow phenomenon).

Stress response

Low perfusion, hypothermia, and exposure of the blood to the tubing and surface of the pump cause release of hormones and other substances, including catecholamines, cortisol, growth hormone, prostaglandins, complement, glucose, insulin, and endorphins. Other factors involved in secreting these substances include the type of anesthetic used and decreased renal and hepatic function leading to decreased clearance from the kidneys and liver. The lung normally is responsible for metabolizing and clearing many of these hormones, particularly catecholamines.

Cardiac effects

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

Central nervous system effects

Neurologic injury after routine CPB is uncommon in neonates, but the risk is increased when DHCA is required. Although permanent injury is less common, evidence of some neurologic injury is observed in as many as 25% of infants who have undergone DHCA. Neurologic morbidity includes seizures, strokes, changes in tone and mental status, motor disorders, abnormal cognitive functioning, and postpump choreoathetosis. Areas most vulnerable for 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 (DNAases) and promotes generation of free radicals. The net result of these processes is cell injury, cell death, or both. Benveniste et al demonstrated increased extracellular glutamate concentration in rat hippocampus during ischemia. Redmond et al found that areas with the highest concentration of NMDAR were the most vulnerable to injury after circulatory arrest.

Microemboli can be detected in patients on CPB. The long-term effect of these emboli is not well defined.

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 cause a reduction in static and dynamic compliance, reduced functional residual capacity, and an increased 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 capillary membrane injury and platelet activation, both of which eventually lead to increased pulmonary vascular resistance.

Renal effects

CPB leads to production of renin, angiotensin, catecholamines, and antidiuretic hormone. In turn, these substances cause renal vasoconstriction and reduced 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.

In the period following CPB, 8% of patients have acute renal insufficiency as indicated by oliguria and increased creatinine levels. After spontaneous urine output, diuretics are effective at inducing diuresis and reversing renal cortical ischemia associated with CPB, but their use does not alter the time to recovery of renal function.

Use of hypothermia

In a patient undergoing CPB, hypothermia helps protect against injury caused by the compromised substrate supply to tissues resulting from reduced flow. This protection occurs because of a reduction in 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 actual safe period of hypothermic CPB is longer than the period predicted by a sole reduction in metabolic activity. The effect of hypothermia on pH is mediated by its effect on the ionization constant of water and, therefore, its effect on the ionized-to-nonionized ratio of metabolic substrates.

In ischemia, the intracellular pH decreases because of the accumulation of hydrogen ions. In turn, the accumulation of hydrogen ions 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 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 has been demonstrated to decrease the release of glutamate, which, as stated above, 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 the blood flow highly dependent on extracorporal perfusion. Studies of piglet models report a decrease in both cerebral blood flow and oxygen consumption at 45 minutes after reperfusion, and at 3 hours, both of these parameters returned to preoperative values.



Currently, two surgical techniques are used in congenital heart surgery, namely, DHCA and hypothermic low-flow bypass (HLFB).

Deep hypothermic circulatory arrest

DHCA provides excellent surgical exposure by eliminating the need for multiple cannulas within the surgical field and by providing a motionless and bloodless field.

Surgical technique

  • Initiate the cooling phase prior to institution of CPB by simple cooling of the operating room environment.

  • After systemic heparinization and cannulation, initiate CPB.

  • Monitor body temperature via esophageal, tympanic, and rectal routes.

Potential problems

Obstruction of the inferior vena cava (IVC) by a misplaced IVC cannula can lead to increased venous pressure, which causes ascites and decreased perfusion pressure in mesenteric, hepatic, and vascular beds.

Monitor infants with ascites for GI tract, renal, and hepatic functioning. Misplacement of the cannula in the superior vena cava (SVC) can result in increased venous pressure in the cerebral venous system. Subsequent cerebral edema results from inadequate venous drainage and a consequent reduction in cerebral blood flow, potentially resulting in ischemia. In addition, when using DHCA techniques, the reduced cerebral blood flow can lead to inefficient cooling of the brain and neutralizes the cerebral protection afforded by systemic cooling. Consequently, ensure appropriate venous drainage, and investigate any large cooling gradients between the upper and lower body.

Arterial cannula misplacement also can occur. If the cannula inadvertently slips beyond the takeoff of the right innominate artery, preferential perfusion to the left side of the brain can be observed. Presence of any anomalous systemic-to-pulmonary shunts can lead to shunting of blood away from the systemic circulation, through the pulmonary circuit, and then through the venous cannula to the CPB machine. Thus, the systemic perfusion is shunted away from the body in a futile circuit back to the CPB machine. Anatomic lesions where such shunting can occur include an unrecognized patent ductus arteriosus and large aortopulmonary collaterals as found in pulmonary atresia.

Cardioplegic solution

Use myocardial protection strategies to halt the mechanical contractions of the heart and to allow intracardiac procedures to be performed in a motionless field. Since blood flow is interrupted and cardiac ischemia ensues, the myocardial protection strategy is designed to sufficiently reduce myocardial oxygen consumption so that resumption of myocardial function at the end of the procedure can occur with a minimum of dysfunction.

Typically, obtain a blood cardioplegia solution by mixing 4 parts of oxygenated blood to 1 part of crystalloid solution. Addition of blood to the cardioplegic solution enhances oxygen delivery, especially at the microcirculation level.

Minimizing calcium in the cardioplegia solution reduces the risk of intracellular accumulation of calcium during ischemia and reperfusion and, hence, prevents injury. 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 leading to cellular injury is observed. The addition of magnesium also adds a protective effect to the hypoxic-ischemic immature heart. This probably is the result of the antiarrhythmic effect of magnesium, its inhibition of calcium entry into the myocytes, and decreased uptake of sodium by myocytes during ischemia, which is exchanged for calcium during reperfusion.

Calcium channel blockers retard calcium entry into the cell, and use of verapamil and nicardipine added to a standard potassium cardioplegic solution may improve postischemic cardiac performance. However, their long-term action may decrease cardiac function postoperatively. 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 oxygen free radical scavenger.

Inflammatory response

Activation of the inflammatory pathway leads to serious complications, morbidity, and mortality. Investigations of the effectiveness of a heparin-coated CPB circuit to reduce the inflammatory response have produced contradictory results. Ozawa et al reported a decrease in tumor necrosis factor (TNF)–a, IL-6, and IL-8 in patients in whom heparin coating was used during surgery, but this reduction did not affect postoperative blood loss, intubation time, or length of stay in the ICU or hospital. Grossi et al reported reduced C3a and IL-8 with heparin coating, which correlated with improved peak airway pressures and prothrombin time. However, others have failed to detect a therapeutic benefit.

Modifying the blood cardioplegia solution has been investigated as a means of reducing inflammatory-mediated myocardial injury after intracardiac repair. Since neutrophils may mediate the local inflammatory response in the heart, a leukocyte-depleted blood cardioplegia (LDBC) has been postulated as a means for improving myocardial protection during CPB. Hayashi et al demonstrated that the use of LDBC in surgery for CHD conferred a protective advantage to the myocardium subject to ischemia-reperfusion injury.

Anticoagulation and heparin reversal

Pediatric and neonatal patients undergoing CPB for cardiac surgery are prone to coagulopathy in the early postoperative period. Contributing factors include hemodilution, immaturity of the coagulation system, depletion of platelets and other hemostatic proteins, and the complex nature of the operations performed, which often include multiple suture sites and, therefore, an increased number of potential bleeding sites. To avoid forming thrombi in the CPB machine, administer heparin prior to cannulation. Heparin is chosen because it is a fast-acting anticoagulant and its action can be inhibited rapidly by protamine. 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 discontinuation of CPB and heparin reversal. Clearance of heparin also is determined by hepatic and renal function.

Typically, use a loading dose of 200-300 U/kg and then monitor heparin activity by measuring activated clotting time (ACT) and heparin levels. Physicians at some centers administer 300 U/kg, check to see if this leads to an ACT of 450-480 seconds, then administer supplemental heparin based on subsequent ACT levels. The use of only one of these monitoring methods may not reflect the full degree of anticoagulation. ACT levels can be affected by factors unrelated to heparin concentration, including the patient's hematocrit and temperature.

Another method of monitoring heparin activity is via a dose-response curve, which is somewhat cumbersome in a clinical setting. A heparin-protamine titration test can provide both values readily. Add blood from the patient 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, heparin concentration can be calculated. Desired values for heparin are 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 take into account the half-life of heparin or its clearance from circulation. Other methods include ACT-heparin dose-response curves, direct measurement of heparin levels, and use of the heparin-protamine titration, as stated above.

Adverse effects of protamine include the following:

  • Release of histamine, which can lead to a decrease in systemic vascular resistance

  • True anaphylaxis, which is mediated by antiprotamine immunoglobulin E (IgE) and observed primarily in patients with prior exposure to protamine (eg, neutral protamine Hagedorn [NPH] insulin) and in patients with fish allergy

  • Thromboxane release, which leads to pulmonary vasoconstriction and bronchoconstriction

Bleeding after CPB is not unusual. Identify any sources of obvious surgical bleeding since this is the most common cause of post-CPB bleeding. Next, assess the adequacy of the protamine dose. If the dose appears to be sufficient, the next most common cause of bleeding is platelet dysfunction, and platelet infusion is warranted, even if the platelet count is within reference range. Often, platelets are dysfunctional after CPB in infants and children. Administration of aprotinin can decrease blood transfusion requirements in patients undergoing repeat surgeries and in patients who are cyanotic. Other patient groups also may benefit. Desmopressin has antifibrinolytic activity and acts as a kallikrein inhibitor. Mild hypersensitivity reactions and anaphylactic reactions are reported.

Acid-base and PCO2 management

Blood acid-base management during hypothermic CPB influences neurologic outcome. Currently, the 2 strategies used for such management are pH stat and alpha stat.

During hypothermia, the solubility of carbon dioxide in blood increases, and for a given concentration of carbon dioxide in blood, the PCO2 decreases and the blood becomes more alkalotic. In pH-stat management, to compensate for the increased carbon dioxide solubility, add carbon dioxide 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, the blood gas is 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 reveal a pH of 7.4 and a PCO2 of 40 mm Hg. This allows the alpha-imidazole group of the histidine moiety on blood and cellular proteins to maintain a constant buffering capacity, which allows for a better 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 OH-/H+ ratio.

With the alpha-stat approach, cerebral blood flow autoregulation is maintained, which allows metabolism and blood flow coupling. This allows adjustments of cerebral blood flow to be made depending on cerebral metabolic activity and oxygen needs. Most of these studies have been performed on adults.

Recent studies have suggested that treatment of the pediatric population is better using the pH-stat strategy. Findings included better neurologic outcome, faster electroencephalographic recovery times, and fewer postoperative seizures. Reasons for this better outcome include increased cortical oxygen saturation before arrest, decreased cortical oxygen metabolism rate during arrest, and an increased brain-cooling rate. Cerebral blood flow during reperfusion also increased while using a pH-stat management strategy.

Potential harmful effects of the pH-stat method are increased cerebral blood flow, leading to a theoretically increased potential for embolic events and higher cerebral blood flows during reperfusion, and a theoretical risk of increased reperfusion injury.

Benefits of the pH-stat strategy may not extrapolate 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 due to the increased cerebral blood flow.

Microembolic injury has not been linked to cerebral injury in pediatric patients. Evidence for this includes the facts that microemboli are uncommon in pediatric heart surgery and histopathologic features of brain damage in neonates are not consistent with microembolic injury. However, neurons of the CNS in pediatric patients are very vulnerable to ischemia, and this underlines that the need for better maintenance of cerebral blood flow and oxygen content is greater than the need to limit the risk of a microembolic event reaching the cerebrum. Long-term clinical data are not yet available to categorically support one strategy over the other, and further studies and follow-up observations are necessary.

Hypothermic low-flow cardiopulmonary bypass

The finding that DHCA was associated with neurologic morbidity has led researchers to investigate the use of HLFB. This technique allows continuous low-flow perfusion to the organs during the operation, which may lead to an increase in oxygen supply, better nutrient supply, and better achievement of homogeneous hypothermia during bypass. Recent trials comparing the 2 methods have reported lower rates of neural dysfunction in the group of patients undergoing HLFB. Specifically, when the patient with CPB is aged 4 years, DHCA is associated with lower levels of motor coordination and planning but not with significantly lower intelligence quotient (IQ) or a worse overall neurologic status.


An important cause of morbidity and mortality following CPB is total body edema. Two factors contribute to postoperative edema. First, hemodilution is related to the relatively large priming volumes compared to 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, leading to increased 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.

Modified ultrafiltration is performed after weaning the patient off CPB. Blood is withdrawn from the aortic canula, passed through the filtration unit, and then fed back to the patient through the venous line. To maintain hemodynamic stability, blood can be added to the circuit, further increasing the hematocrit, and crystalloids also can be added.

In the postoperative period, patients in whom modified ultrafiltration was used have less increase in total body weight than control subjects. In addition to decreasing edema, hemofiltration also increases the hematocrit, which translates into an increased oxygen-carrying capacity. Removed fluid also contains inflammatory mediators and vasoactive substances. Clinical studies have demonstrated an increase in ventricular systolic function; improved cerebral blood flow (CBF), cerebral metabolic activity, and cerebral oxygen delivery; reduced postoperative bleeding; decreased chest tube drainage; reduced incidence of pleural effusions; and shorter hospital stays in association with modified ultrafiltration.

Endpoints of hemofiltration vary among institutions and can be defined by time, volume, or hematocrit.