Effects of Cardiopulmonary Bypass

Glucose Regulation

A substantial amount of clinical and experimental data have shown conclusive evidence of the detrimental effects of hyperglycemia during complete, incomplete, and focal cerebral ischemia.^{[130] [131] [132]} The role of glucose in potentiating cerebral injury appears to rest on two factors: ATP utilization and lactic acidosis.^{[133] [134]} The anaerobic metabolism of glucose requires phosphorylation and the expenditure of two molecules of ATP before ATP production can occur. This initial ATP expenditure may result in a rapid depletion of ATP and may explain why hyperglycemia worsens neurologic injury. Lactic acidosis is also important in glucose-augmented cerebral injury.

2028

Hyperglycemia

A strong scientific argument can be made for the detrimental effects of hyperglycemia during ischemia, but there is very little evidence supporting a relationship between a worsening neurologic outcome and hyperglycemia during CPB or DHCA in children. Although a retrospective review of 34 children undergoing DHCA suggested a worse neurologic outcome in the hyperglycemic children, the results were reported as a nonsignificant statistical trend.^[136] A review of acquired neurologic lesions in patients undergoing the Norwood Stage I procedure for hypoplastic left heart syndrome suggested hyperglycemia as a significant associated finding in patients with extensive cerebral necrosis or intraventricular hemorrhage. A host of other potentially damaging factors (e.g., periods of hypoxia, low diastolic and systolic pressure, thrombocytopenia) were statistically associated with the observed neuropathology.^[137] Because hyperglycemia accompanies a generalized stress response, this literature failed to distinguish whether glucose directly contributes to neurologic injury or merely serves as a marker for a high-risk population that ultimately suffers neurologic insult as a result of other factors.

Hypoglycemia

Hypoglycemia is a frequent concern in neonates during the perioperative period. Reduced hepatic gluconeogenesis coupled with decreased glycogen stores places the newborn at increased risk for hypoglycemic events. In newborns with congenital heart disease, reduced systemic perfusion (e.g., critical coarctation, hypoplastic left heart syndrome, critical aortic stenosis) may result in worsening hepatic biosynthesis, further impairing glucose production. These patients may be fully dependent on exogenous glucose; therefore, it is not uncommon for them to require 20% to 30% dextrose infusions to maintain euglycemia in the pre-bypass period. Older children are not immune to hypoglycemic events and are therefore

TABLE 51-8 -- Sequelae of pediatric cardiopulmonary bypass

End-Organ Injury	Etiology/Signs
Renal injury	Organ immaturity, pre-existing renal disease
	Post-cardiopulmonary bypass low CO, use of DHCA
	Renal dysfunction characterized by reduced GFR and ATN
Pulmonary injury	Endothelial injury, increased capillary leak, complement activation, and leukocyte degranulation
	Pulmonary dysfunction characterized by reduced compliance, reduced FRC, and increased A-a gradient
Cerebral injury after DHCA	Loss of autoregulation, suppressed metabolism and cerebral blood flow, cellular acidosis, and cerebral vasoparesis
	CNS dysfunction characterized by seizures, reduced developmental quotients, choreoathetosis, learning disabilities, behavioral abnormalities
ATN, acute tubular necrosis; CNS, central nervous system; CO, cardiac output; DHCA, deep hypothermic circulatory arrest; FRC, functional residual capacity; GFR, glomerular filtration rate.

susceptible to hypoglycemia-induced neurologic injury. Patients with low cardiac output states (cardiomyopathies, pretransplant patients, critically ill postoperative patients) requiring reoperation and when on substantial inotropic support are at risk for reduced glycogen stores and intraoperative hypoglycemia.^[138]

The impact of hypoglycemia during CPB is further complicated by the consequences of hypothermia, CO₂ management, and other factors that may modify normal cerebrovascular responses during bypass. In a dog model, insulin-induced hypoglycemia to 30 mg/dL did not alter the electroencephalographic findings. However, after 10 minutes of hypocapnic hypoglycemia, the electroencephalogram became flat. ^[115] When regional blood flow was examined in these animals, cortical and hippocampal blood flow remained normal, whereas other regions of the brain had reduced flow. The loss of electroencephalographic activity from hypoglycemia alone does not normally occur above glucose levels of 8 mg/dL.^[139]

During deep hypothermic CPB and DHCA, CBF and metabolism are altered. The additive effect of hypoglycemia, even if mild, may cause alterations in cerebral autoregulation and culminate in increased cortical injury.^{[137] [140]} The common practice of using hyperventilation to reduce pulmonary vascular resistance in neonates and infants during weaning from CPB and in the early post-bypass period can further exacerbate hypoglycemic injury. Glucose monitoring and rigid maintenance of euglycemia are an important part of CPB management in the congenital heart patient.

Renal Effects

After CPB, the combined effects of hypothermia, nonpulsatile perfusion, and reduced mean arterial pressure cause release of angiotensin, renin, catecholamines, and antidiuretic hormones.^{[141] [142] [143]} These circulating hormones promote renal vasoconstriction and reduce renal blood flow. However, despite the negative impact of CPB on renal function, studies have been unable to link low-flow, low-pressure, nonpulsatile perfusion with postoperative renal dysfunction ( Table 51-8 ).^{[141] [144]} The factors that best correlate with postoperative renal dysfunction are preoperative renal dysfunction and profound reductions

2029

The incidence of acute renal insufficiency after pediatric cardiac surgery is approximately 8%. Multiple causative factors are involved and the final common result is oliguria and an elevated serum creatinine. Diuretics have been the mainstay of promoting urine flow after pediatric CPB. Furosemide in a dose of 1 to 2 mg/kg or ethacrynic acid 1 mg/kg every 4 to 6 hours, or both, induces a diuresis and may reverse renal cortical ischemia associated with CPB. After DHCA, it is not unusual to observe a 24-hour period of oliguria or anuria that resolves over the next 12- to 24-hour period. The use of diuretics is effective only after spontaneous urine output has been initiated in these patients.

Glomerular filtration rate, creatinine clearance, and medullary concentrating ability are substantially reduced in neonates and young infants. Therefore, the use of CPB in these patients is associated with greater fluid retention than is typically seen in older children and adult patients. The net result may be increased total body water, increased organ weight (e.g., lungs, heart), and greater difficulty with postoperative weaning from ventilatory support. The use of ultrafiltration during rewarming or after CPB is effective in reducing total body water, limiting the damaging effects of CPB, and decreasing the postoperative ventilation period. ^{[145] [146]}

Pulmonary Effects

Cardioplegia protects the heart, but there is no parallel protection afforded the lung during bypass. Pulmonary dysfunction is common after CPB, and its pathogenesis is poorly understood (see Table 51-8 ). In the broadest terms, lung injury is mediated in one of two ways: first, by an inflammatory response due to leukocyte and complement activation and, second, by a mechanical effect culminating in surfactant loss, atelectasis with resultant ventilation/perfusion mismatch, loss of lung volumes, and altered mechanics of breathing.

Pulmonary function after CPB is characterized by reduced static and dynamic compliance, reduced functional residual capacity, surfactant deficiency, and an increased A-a gradient.^{[147] [148]} Atelectasis and increased capillary leak due to hemodilution, and hypothermic CPB are the most likely etiologies. Hemodilution reduces circulating plasma proteins, reducing intravascular oncotic pressure, and favors water extravasation into the extravascular space. Hypothermic CPB causes complement activation and leukocyte degranulation.^[149] Leukocytes and complement are important in causing capillary-alveolar membrane injury and microvascular dysfunction through platelet plugging and release of mediators, which increase pulmonary vascular resistance. The technique of modified ultrafiltration is highly effective in reducing lung water and pulmonary morbidity during the postoperative period.

Stress Response and Cardiopulmonary Bypass

The release of a large number of metabolic and hormonal substances, including catecholamines, cortisol, growth hormone, prostaglandins, complement, glucose, insulin, endorphins, and other substances, characterizes the stress response during hypothermic CPB.^{[18] [150] [151]} The likely causes of the elaboration of these substances include contact of blood with the nonendothelialized surface of the pump tubing and oxygenator, nonpulsatile flow, low perfusion pressure, hemodilution, hypothermia, and light anesthesia depth. Other factors that may contribute to elevations of stress hormones include delayed renal and hepatic clearance during hypothermic CPB, myocardial injury, and exclusion of the pulmonary circulation from bypass. The lung is responsible for metabolizing and clearing many of these stress hormones. The stress response generally peaks during rewarming from CPB. There is strong evidence that the stress response can be blunted by increasing the depth of anesthesia.^{[18] [150] [151]}

It is unclear at what level elevated circulating stress hormones, a normal neonatal adaptive response, become detrimental. There is little question that these substances could mediate undesirable effects such as myocardial damage (catecholamines), systemic and pulmonary hypertension (catecholamines, prostaglandins), pulmonary endothelial damage (complement, prostaglandins), and pulmonary vascular reactivity (thromboxane). The benefits of controlling the stress response with fentanyl in premature infants undergoing PDA ligation and with sufentanil in neonates with complex congenital heart disease have been demonstrated.^{[85] [152]} Although blunting the stress response seems warranted, there is additional evidence suggesting that the newborn stress response, especially the endogenous release of catecholamines, may be an adaptive metabolic response necessary for survival at birth.^[153] Thus, the complete elimination of an adaptive stress response may not be desirable. To what extent acutely ill neonates with congenital heart disease are dependent on the stress response for maintaining hemodynamic stability is currently unknown.

It is, therefore, prudent to maintain a depth of anesthesia adequate to attenuate the stress response, but to attempt to block the response altogether may not be necessary. Acceptable anesthesia during CPB may be best accomplished by the continuous administration of an inhalation anesthetic via a vaporizer connected to the pump oxygenator, careful titration of incremental doses of opioids, or the precise administration of an opioid or opioid and benzodiazepine by a continuous infusion technique. Primary opioid anesthetic techniques result in reduced stress hormone release and decreased postoperative metabolic acidosis and lactate production compared with primary halothane anesthesia and may therefore be a preferred technique in complex congenital heart disease.^[85] If depth of anesthesia is accomplished by the administration of excessively large doses of opioids (e.g., fentanyl or sufentanil), postoperative mechanical ventilation will be necessary. By contrast, residual levels of inhalation anesthetic drugs (e.g., halothane or isoflurane) can produce transient myocardial depression at the termination of CPB, complicating separation from CPB.