Cardiopulmonary Bypass and Management

The Circuit and Cannulas

Unfortunately, the circuit size cannot be reduced proportionately to the patient's size; this disproportion commonly leads to hemodilution and dilutional coagulopathies in children. Surgical procedures require extremes of temperature, hemodilution, and changes in flow rates. Because of the smaller vascular structures and greater flow rates (150–200 mL/kg per minute) in infants and children compared with flow rates of 2.2 to 2.4 L/minute per meter squared in adults, selection of appropriately sized cannulas is critical to maintain these flows. Shear stress is significant in small cannulas and several-fold greater than needed for activation of blood cells and platelets, leading to a disproportionately exaggerated systemic inflammatory response syndrome (SIRS).

Cardiopulmonary Bypass Pumps

The two pumps used most commonly for CPB are roller pumps and centrifugal pumps. Roller pumps have the advantages of simplicity, low cost, ease and reliability of flow calculation, and the ability to pump against increased resistance without reducing flow. Disadvantages include the need to assess occlusiveness, spallation or fragmentation of the inner tubing surface (potentially producing particulate arterial emboli), potential for pumping large volumes of air, and ability to create large positive and negative pressures. Compared with roller pumps, centrifugal pumps offer the advantages of less air pumping potential, less ability to create large positive and negative pressures, less blood trauma, and virtually no spallation. Disadvantages of centrifugal pumps include a greater cost, the lack of occlusiveness (creating the possibility of accidental patient exsanguination), and afterload-dependent flow that requires constant flow measurement. In the setting of short-term CPB for cardiac surgery, it remains uncertain whether the selection of a roller pump over a centrifugal pump, or of any specific centrifugal pump over another, has clinical importance. Pulsatile perfusion may prove to be beneficial in the future, but further outcome data and technical improvements are needed.

Cardiopulmonary Bypass Prime

The optimal priming fluid in cardiac surgery is a topic of enduring debate. Crystalloid solutions, colloids, and mixtures of both are used. Children appear to benefit from a colloid prime. If crystalloid is used for priming, it should not contain lactate or dextrose because CPB induces a metabolic acidosis that is iatrogenic, not splanchnic, in provenance. The addition of lactate to the prime increases the serum concentration of lactate postoperatively and should be avoided. Hyperchloremic metabolic acidosis is the second contributing component of a metabolic acidosis on CPB. This is often only detected by measuring the strong ion difference via the Stewart approach to the acid-base homeostasis. Both acidifying events are attenuated by the dilutional hypoalbuminemia induced by the pump prime. Because a hyperchloremic acidosis of a mild degree seems to be well tolerated and not associated with a poor outcome, no intervention seems necessary. Understanding the nature of CPB-associated acidosis, however, is likely to prevent unnecessary investigations or interventions.

The avoidance of dextrose is especially important during complex repairs using deep hypothermic cardiac arrest in which the risk of neurologic injury is substantive. The additives in banked blood, namely, glucose in citrate-phosphate-dextrose (CPD) storage solutions, also need to be considered as a source of glucose (together with the increased plasma concentrations of potassium in stored blood). We use a balanced electrolyte solution, such as PlasmaLyte, for the crystalloid component of our prime.

The proportionally large volume of the bypass circuit compared with the child's blood volume has a significant impact on the coagulation factors and cellular components. Platelet count decreases and coagulation factors, including fibrinogen, are diluted after bypass thereby contributing to a coagulopathy. The fibrinogen concentration at the end of bypass correlates with the 24-hour chest drainage in children who weigh less than 8 kg. This occurs more frequently in infants and neonates in whom the plasma concentrations of hemostatic proteins decrease postoperatively by 56% immediately upon initiation of bypass ; younger age represents the single most important risk factor for coagulopathy and bleeding complications.

One approach to offset this dilutional coagulopathy is the addition of whole blood to the circuit prime. Proponents cite two theoretical advantages: (1) improved hemostasis and (2) decreased SIRS with less edema formation and less organ dysfunction. However, one study challenged these perceived advantages when the researchers reported that the use of fresh whole blood actually increased perioperative fluid requirements, leading to a more prolonged duration of mechanical ventilation and ICU stay than in the single component group. The only advantage of whole blood prime was fewer donor exposures, a problem we obviate by matching packed red blood cells (PRBCs) and fresh frozen plasma (FFP) from the same donor. One retrospective analysis of donor exposures using fresh whole blood concluded that donor exposures were reduced in patients younger than 2 years of age compared with published reports using component therapy. Unfortunately, fresh whole blood is frequently unavailable. However, when a commitment to use fresh whole blood for pediatric cardiovascular surgery exists, it is possible to build a sustainable operating protocol to provide this resource. An alternative approach is to use FFP in the prime. Some investigators determined that the use of FFP led to greater fibrinogen concentrations at the end of surgery. On average, children in the FFP group needed 1.3 fewer donor exposures and tended to need fewer PRBCs. The reduced donor exposure was primarily the result of fewer transfusions of cryoprecipitate. FFP may be safely substituted by 5% albumin in the prime in children with less complex repairs and acyanotic lesions. Whenever possible, we prefer fresh blood that is less than 5 days old. Fresh PRBCs are presumably more balanced metabolically than stored PRBCs; the former contain less potassium, greater concentrations of glucose, reduced concentrations of lactate, and a greater pH. Also, postoperative morbidity increases with increasing age of red blood cells. Pulmonary complications, acute renal failure, and increased infection rates were among the main complications associated with increased red blood cell storage time. As far as potassium concentrations and acid-base balance are concerned, PRBC priming can be safely performed with stored PRBCs if the priming solution is circulated for 20 minutes before the initiation of CPB.

Depending on the size and age of the child and the complexity of the repair, a target hematocrit is chosen. Based on the child's blood volume and the prime volume, homologous blood is added using the following calculation:

The average prime volume of the circuits in use at Texas Children's Hospital is shown in Table 19.2 . Other prime additives are heparin, antifibrinolytics, antiinflammatory agents (corticosteroids), antibiotics, vasodilators, and, sometimes, diuretics (mannitol, furosemide). At the end of the case and before separation from bypass, a blood gas sample should be analyzed to ensure the electrolytes (including calcium and magnesium ions), glucose, and hematocrit are within a desired range. Acid-base changes and sodium concentration are corrected with sodium bicarbonate and wash solutions, and residual lactate is washed out using hemofiltration.

Antifibrinolytic Agents

Heparin-Induced Thrombocytopenia

The use of unfractionated heparin for anticoagulation for CPB in adults produces antiheparin antibodies in 25% to 50% of patients within 10 days postoperatively. In a small minority of these patients, high-titer immunoglobulin G (IgG) platelet-activating antibodies form and make immune complexes with heparin and platelet factor 4 (PF4). This results in activation of platelets (via their Fc receptors) and formation of procoagulant platelet microparticles, leading to thrombin generation and thrombosis. Thus the major problem in heparin-induced thrombocytopenia (HIT) is thrombocytopenia that occurs several days after heparin exposure accompanied by thrombosis, often in major vessels or structures. HIT appears to be less common, of milder course, and probably underrecognized in neonates and children. About 1% of children exposed to CPB have PF4 antibodies when tested before their second exposure to CPB, and actual HIT is much less common. When HIT is suspected, either PF4 enzyme-linked immunosorbent assay or a functional assay for HIT can be used to make the diagnosis; if positive, no further heparin should be given. If CPB is necessary, alternatives to heparin, such as the direct thrombin inhibitors argatroban, lepirudin, and bivalirudin, may be used. None of these agents is approved for use in children for anticoagulation for CPB, but case reports and small series have documented their successful use when HIT is diagnosed. The partial thromboplastin time (PTT), activated clotting time (ACT), and a specialized clotting time called the ecarin clotting time can be used to follow anticoagulation with these agents, but there is no reversal agent for them. Thus, treatment of post-CPB bleeding involves only administration of blood products and coagulation factors.

Antithrombin III Deficiency

Heparin produces anticoagulation by combining in a 1 : 1 ratio with antithrombin III (ATIII), which then binds to and inhibits thrombin, leading to anticoagulation. Of adult patients, 4% to 13% have a resistance to normal doses of heparin for CPB; most instances occur because of a partial deficiency of ATIII, rendering heparin less effective at producing anticoagulation. In children this is often unknown, and the first suspicion of ATIII deficiency may occur when the standard heparin dose of 300 to 400 units/kg fails to adequately anticoagulate before CPB; that is, the ACT remains less than 300 seconds. The usual response is to apply another dose of heparin from a different vial and remeasure the ACT, but if the ACT is still not adequately prolonged, a diagnosis of ATIII deficiency may be suspected. Infants younger than 6 months of age and children with congenital heart disease have decreased ATIII concentrations. Therefore heparin may not achieve adequate anticoagulation, and disorders in hemostasis and thrombosis and an exaggerated inflammatory response may occur. In this case, blood can be sent for ATIII levels, but to proceed with CPB, the ATIII must be increased. This can be accomplished in two ways: (1) by supplementing ATIII with 75 units/kg of recombinant ATIII and ensuring that the ACT is adequately prolonged before proceeding with CPB, or (2) by adding FFP (which has ample concentrations of ATIII) to the CPB prime or administering it to the child before bypass.

In the presence of reduced baseline concentrations of ATIII, the total dose of heparin, the amount of thrombin that was generated during bypass, and the fibrinogen that was consumed and fibrinolysis that was produced increased in infants undergoing cardiac surgery with CPB. This can exacerbate after bypass coagulopathy and transfusion requirements.

Recombinant Factor VIIa for Massive Hemorrhage

Recombinant factor VIIa (rFVIIa) was originally approved for use in patients with hemophilia who possess inhibitors to factors VIII or IX, and was shown to be effective in treating bleeding in these patients with doses of 90 µg/kg (see also Chapter 10 ). Endogenous factor VII circulates at small concentrations in the plasma. At a site of tissue or blood vessel injury, tissue factor (TF) is exposed, and the extrinsic coagulation pathway is activated by the binding of factor VII to TF, resulting in the activation of factor X to factor Xa, leading to the generation of thrombin from prothrombin, with further activation of platelets and the coagulation cascade. Large concentrations of rFVIIa activate the extrinsic pathway at the site of injury, theoretically without inducing systemic hypercoagulability. However, thrombotic complications are increased after its use. rFVIIa also activates platelets, adding to the potential benefit of this agent in significant hemorrhage. Thus this therapy seems appropriate for the treatment of surgical bleeding; a very complete review of the off-label uses of rFVIIa in pediatric cardiac surgery patients found no evidence to support the routine or prophylactic use of the therapy. However, rFVIIa may be beneficial as a rescue therapy for severe life-threatening refractory bleeding; the authors caution against the use of rFVIIa in children at risk for thromboembolic complications. A dose of 45 to 90 µg/kg, repeated every 2 hours, has been used. rFVIIa cannot produce hemostasis alone and should only be administered after the transfusion of sufficient amounts of platelets, plasma, and fibrinogen to form the substrate for hemostasis.

Fibrinogen Concentrate

Fibrinogen concentrate is an alternative to cryoprecipitate to replace fibrinogen after CPB. Compared with cryoprecipitate, fibrinogen concentrate, which is lyophilized and purified human plasma fibrinogen, has an improved safety profile because it has undergone viral inactivation and is devoid of microparticles that can cause vasoreactivity. In addition, fibrinogen concentrate contains a known amount of fibrinogen, and cryoprecipitate varies in the amount of fibrinogen per unit. One randomized pilot trial found no difference in the safety and efficacy of fibrinogen concentrate compared with cryoprecipitate when managing bleeding in children undergoing CPB. The dose of fibrinogen concentrate may be empiric (70 mg/kg), based on either the laboratory fibrinogen concentration or thromboelastometry.

Sickle Cell Disease

Sickle cell disease (SCD), one of the most common hemoglobinopathies among patients of African American or West Indian origin (with a prevalence of 0.2%–0.3% in that population), is the result of the substitution of valine for glutamic acid in position 6 of the β-hemoglobin chain. Normal adult hemoglobin is referred to as HbA, whereas hemoglobin containing the mutant β-hemoglobin chains is referred to as HbS. SCD is represented by a homozygous genotype (HbSS) with fractional concentrations of HbS in the range from 70% to 90%. Sickle cell trait, on the other hand, is a heterozygous manifestation (HbAS) with a prevalence of 8% to 10% in the same population. The definitive diagnosis of any sickle cell hemoglobinopathy is confirmed by hemoglobin electrophoresis (see Chapter 10 ).

Children with SCD are at particular risk for perioperative complications. Sickling can be triggered by hypoxia, dehydration, acidosis, hypothermia, stress, and infections. Hypoxia opens a Ca ²⁺ -activated K ⁺ channel (Gardos channel) that causes intracellular dehydration. Chain formation occurs that leads to increased blood viscosity with vasoocclusion. Opening of the Gardos channel, which is an important mechanism of sickle cell dehydration, depends on temperature, with greater potassium efflux at reduced temperatures. Shrinkage of sickle erythrocytes may also result from activation of a K ⁺ /Cl ⁻ cotransport pathway under acidotic conditions. Activation of this pathway can be blocked by increasing the abnormally low level of intracellular magnesium in sickled erythrocytes. The use of magnesium and hydroxyurea in the perioperative period therefore seems to be reasonable.

CPB, particularly for more complex surgical procedures, may involve periods of low flow or even circulatory arrest, as well as hypothermia with consequent local vasoconstriction, hypoxemia, and acidosis. There is some evidence that CPB can be safely undertaken in SCD. Flow conditions are an important determinant of sickle erythrocyte adherence to endothelium. Under low-flow conditions, the adhesion of sickled cells to endothelium increases with contact time in the absence of endothelium activation or adhesive proteins, whereas under low-flow conditions in venules, sickle cell adhesion occurs only after endothelial activation. During CPB, both low-flow conditions and endothelial activation may occur. Multiple triggers of sickling are likely to occur during CPB, and close attention should be paid to the conduct of all aspects of bypass.

In the past, routine exchange transfusion has been recommended to prevent these complications. More recent experience provides evidence that not all children require an exchange transfusion. The growing evidence of the harmful effects of blood transfusion adds to the need to carefully reconsider routine exchange transfusion. For uncomplicated bypass surgery without periods of cardiac arrest, the omission of exchange transfusion has led to good outcomes.

Guidelines have been proposed for the perioperative management of children with sickle cell disorders. It is essential to avoid hypothermia using tepid or warm CPB in its stead; blood transfusion only for a decrease in hematocrit to less than 20%; maintenance of intravascular volume and body temperature while on CPB; the avoidance of vasopressors; the use of postoperative multimodal pain therapy; and early incentive spirometry to prevent pulmonary complications. In our practice, we use cerebral near-infrared spectroscopy (NIRS) to help determine an acceptable lower limit of hemoglobin for the individual child.

For children undergoing hypothermia, successful management with and without partial or complete exchange transfusion on bypass has been reported. Exchange transfusion can be performed preoperatively or on initiation of CPB. For exchange transfusion during CPB, the extracorporeal circuit is primed with blood and the usual components. When CPB is commenced, the child's blood volume is drained into storage bags and separated. The platelet-rich plasma is reinfused at the end of CPB, and the concentrated sickle cells are discarded. Platelet and plasma sequestration in conjunction with exchange transfusion reduces the need for postoperative transfusion and protects the platelets from the negative effects of CPB.

There seems to be no consensus as to a suitable target concentration of HbS. Reducing the absolute level of HbS may provide a greater benefit than targeting a particular ratio of HbA to HbS because the remaining sickle cells are still 100% at risk for sickling. In SCD, exchange transfusion has been shown to favorably affect cerebral tissue oxygenation. Exchange transfusion decreases both the proportion and absolute amount of HbS, but it does not remove every cell that may sickle. It may also improve hypoxic pulmonary vasoconstriction. In this context, these children may benefit from continuous hemofiltration to reduce inflammatory mediators and improve pulmonary recovery. Inhaled nitric oxide also has been recommended as an adjunct to prevent sickle cell crisis. It may improve the binding of oxygen, thereby reducing the formation of sickle cells; reduce pulmonary hypertension; and improve pulmonary function without adverse effects on normal hemoglobin.