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Cerebral Oxygenation and Transfusion for Severe Anemia: Searching for Functional Outcomes to Guide Transfusion.

The cerebrovascular circulation is different from other vascular beds, reflecting the high metabolic demand of brain tissue and need for tight regulation of water homeostasis because small changes in brain volume can lead to large changes in intracranial pressure. Cerebral blood flow (CBF) remains relatively constant for cerebral perfusion pressure (intra-arterial pressure – intracranial pressure) and should be maintained above 40 mm Hg in children from birth to age 5 years and above 50 mm Hg in those 6 to 17 years old.1 Cerebral blood flow also varies inversely with hematocrit and increases dramatically as the partial pressure of oxygen (PO2) falls below 50 mm Hg through direct effects on vascular cells in the cerebral arteries and arterioles and by the increased production of nitric oxide, which promotes vasodilatation. Increases in the partial pressure of carbon dioxide (PCO2) also cause an increase in CBF by a direct effect of extracellular hydrogen ions on vascular smooth muscle and may be seen with other causes of acidosis.2 If cerebral blood flow is inadequate, the oxygen extraction increases. This is to prevent tissue hypoxemia that is poorly tolerated by brain tissue and quickly leads to ischemia and often irreversible infarction and neurological impairment. Anemia causes a compensatory increase in CBF that is proportional to the decrease in hematocrit. Anemia also is associated with decreased cerebrovascular reactivity to hypercapnia both during normothermic cardiopulmonary bypass and in people with sickle cell disease (SCD).3 Severe anemia causes cerebral hyperemia, but this is inadequate to preserve cerebral oxygenation in some patients and may be blunted in children with malaria.3 In this issue of JAMA Pediatrics , Dhabangi and colleagues4 describe cerebral tissue oxygenation (cerebral tSO2) in 120 children 6 to 60 months old with hemoglobin concentration of less than 5.0 g/dL and a blood lactate level greater than 45.0 mg/dL (5mM). All children received transfusions with packed red blood cells, 10 mL/kg over 120 minutes with monitoring of cerebral tSO2 by near infrared spectroscopy. Most of the children had malaria (73%) or sickle cell disease (SCD) (21%) and were tachycardic and tachypneic but not hypotensive; 37% received a second transfusion. Prior to transfusion, cerebral tSO2 level was notably decreased (<65%) in 32 children including 17 of the 25 (75%) with SCD and 15 of 87 (17%) with malaria and mildly decreased (65%-75%) in another 49 children. Low cerebral tSO2 level was not associated with impaired level of consciousness, lower hemoglobin concentration, higher lactate level, or thigh tSO2 level in a subset of 72 children. Cerebral tSO2 level increased with transfusion in most participants, and these increases were the largest in those with low baseline values. However, a minority (21%) remained below normal values at the end of the transfusion. We do not know the effect of the low cerebral tSO2 on central nervous complications in these children, but low cerebral tSO2 level is a frequent finding in children and adults with sickle cell anemia. The initial study in adults with SCD reported average values substantially lower than healthy controls or people with other causes of anemia and only partial correction with transfusion.5 A recent pediatric study identified low cerebral tSO2 level (<65%) in 75% of children with sickle cell anemia and 35% with sickle beta plus thalassemia. In a subgroup of transfused children, cerebral tSO2 level increased to the normal range in 25%, but 60% still had cerebral tSO2 of less than 65%.6 In other studies, severe anemia has been associated with acute cerebral ischemia, likely secondary to inadequate perfusion to meet the high metabolic demand of the brain. Acute silent cerebral infarct was identified in 18% of children with sickle cell anemia (hemoglobin concentration <5.5 g/dL and >30% decrease from baseline) and in 7% of other children with severe anemia in a study7 that prospectively screened for acute cerebral infarction by magnetic resonance imaging of the brain. Silent cerebral infarctions are associated with cognitive impairment and school failure in children with SCD and may contribute to the cognitive impairment seen after severe anemia caused by malaria.8 Another possibility is that the severe anemia affects brain development and cognition without ischemia detectable by magnetic resonance imaging. This clearly occurs with some chronic anemias including sickle cell disease and the anemia of renal failure.9 This study suggests that many children with severe anemia have inadequate oxygen delivery to the brain, and measurement of oxygenation in other tissues and other clinical parameters (other than a concomitant diagnosis of SCD) do not help identify these children. Transfusion quickly improves cerebral tissue oxygenation. Hopefully, further study of participants in this recently completed randomized clinical study is possible to evaluate the relationship between cerebral tissue oxygenation, cerebral ischemia, and cognitive development. In addition, we still have much to learn about the interactions among SCD, malaria, and severe anemia. With that information, cerebral oximetry may become a true surrogate marker to guide transfusions for severe anemia. Related article Opinion