Glucose and heart surgery: neonates are not just small adults.

DESPITE the many advances in cardiac surgery, neurologic complications continue to be recognized postoperatively. Cognitive deficits appear in about one-half of adults after coronary artery bypass grafting and in as many as one-third of children after neonatal heart surgery. Preoperative, intraoperative, and postoperative episodes of hypoxia-ischemia all seem to contribute to these complications. Hyperglycemia has been shown to worsen neurologic injury in adult ischemia models. Given the risk of ischemic neurologic injury in neonatal heart surgery and the role of hyperglycemia in ischemic brain injury in adults, de Ferranti et al. ’s examination of the relationship of blood glucose to neurologic outcome after neonatal heart surgery, published in this issue of the Journal, addresses an important and timely question. To appreciate the distinction between neonates and adults, it is useful to briefly review their differences in whole body and brain glucose metabolism. During development, brain metabolism changes markedly. Glucose crosses the blood-brain barrier through transporter proteins (GLUT1), and then enters the cell through a second glucose transporter system (GLUT3). Glycolysis then begins with the phosphorylation of glucose by hexokinase I. GLUT3 and hexokinase I increase fivefold from neonate to adult as cerebral metabolic rate increases. The developmental increase in cerebral glucose metabolic rate corresponds with an increase in synaptic activity, synaptogenesis, and myelination of specific brain regions. Cerebral glucose metabolism yields adenosine triphosphate, which provides energy to maintain ion gradients, support synaptic activity, and preserve cellular homeostasis. Unlike the adult brain, the neonatal brain is able to metabolize ketone bodies (acetoacetate and D-3hydroxybutyrate) and free fatty acids to generate adenosine triphosphate under physiologic conditions. The neonatal brain is also able to metabolize lactate to generate adenosine triphosphate for up to 60% of its energy requirements. Lactate permeability across the bloodbrain barrier is greater in neonates compared with adults, thus supporting brain lactate metabolism and limiting its build-up. During ischemia, the neonatal brain is able to use alternative substrates such as lactate and glycogen for energy. A wealth of information from animal models and clinical studies implicates hyperglycemia to be detrimental to the adult brain during global and focal ischemia. Although hyperglycemia supports adenosine triphosphate production through glycolysis and delays cellular energy failure during ischemia, the resultant lactic acidosis seems to be toxic to several intracellular processes, thereby hastening cell death and poisoning the repair mechanism of surviving cells. In contrast to the adult, hyperglycemia in the neonate seems to protect the brain from ischemic damage. In a neonatal rat model of hypoxia-ischemia, Vannucci et al. found that low-dose glucose treatment yielding mild hyperglycemia (270–360 mg/dl) did not exacerbate brain damage; unexpectedly, glucose treatment yielding moderate hyperglycemia (630–720 mg/dl) ameliorated the brain damage in this model. Studies in neonatal pigs involving hypothermic low-flow cardiopulmonary bypass or deep hypothermic circulatory arrest also demonstrated less brain damage with higher glucose levels. There are several reasons why hyperglycemia may help the neonatal brain. First, hyperglycemia increases cerebral high-energy reserves and glycogen stores. As a result, high-energy phosphates are sustained longer during ischemia in hyperglycemic compared to normoglycemic neonatal animals. Second, glucose uptake and metabolism is slower and lactate accumulates slower in the neonatal brain compared with the adult brain. Third, lactate clearance is enhanced, thereby avoiding the toxicity of lactacidosis. Although many studies have related serum glucose levels to ischemic neurologic outcome in adults, only one clinical study pertains to cardiac surgery. Ceriana et al. found that hyperglycemia was associated with adverse neurologic outcome in adults undergoing aortic arch reconstruction. As a result, many cardiac anesthesiologists treat hyperglycemia based on clinical studies of stroke or cardiac arrest and animal studies of ischemia. For pediatric cardiac surgery, the role of hyperglycemia in neurologic injury is even less clear. At the same time, neonates are at additional risk for hypoglycemic neurologic injury. In neonates, hypoglycemia during fasting or illness is This Editorial View accompanies the following article: de Ferranti S, Gauvreau K, Hickey PR, Jonas RA, Wypij D, du Plessis A, Bellinger DC, Kuban K, Newburger JW, Laussen PC: Intraoperative hyperglycemia during infant cardiac surgery is not associated with adverse neurodevelopmental outcomes at 1, 4, and 8 years. ANESTHESIOLOGY 2004; 100:1345–52.