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To the Editor.—
It is the purpose of this letter to (1) define poor circulation in very premature newborns, (2) discuss the concept of stagnant hypoxia and its relation to early brain injury, and (3) discuss the potential role of adult packed red cell transfusion as an acute intervention for poor circulation.
POOR CIRCULATION
There is no simple definition of poor circulation in newborns. It may be pragmatically described by the presence of 1 of the following: low cardiac output (CO) on echocardiography,1 profound hypotension with capillary refill time of 
3 seconds,2 or hypoxemia resulting in elevated serum lactate.3
STAGNANT HYPOXIA
There are a number of different forms of hypoxia, namely, stagnant (inadequate flow), anemic (inadequate hemoglobin concentration), hypoxic (inadequate inspired oxygen), and histotoxic hypoxia. Barcroft first described stagnant hypoxia in 19204 with the sentence "[the] blood is normal but is supplied to the tissues in insufficient quantities."
The principal determinants of systemic oxygen transport are CO, hemoglobin concentration, and hemoglobin saturation.5 Final tissue oxygen extraction depends on the oxygen diffusion gradient, the diffusion distance between the capillary and the cell, and cellular uptake mechanisms.
The degree of oxygen extraction varies between tissues but never reaches 100%. When oxygen delivery decreases to a critical level, oxygen extraction increases but reaches a maximum. Oxygen consumption is subsequently limited by the supply. An oxygen debt develops, and anaerobic metabolism results in lactic acidemia.6
Mixed venous oxygen saturation is the saturation of blood in the pulmonary artery. It is an indicator of whole-body oxygen equilibrium because it represents the residual oxygen in systemic blood after circulation through the tissues. It has been used as a predictor of mortality in infants after cardiac surgery.7,8 It has been calculated9 but not directly measured in premature newborns. Right atrial saturation has been used for newborns10,11 but is confounded by incomplete atrial mixing. Animal models demonstrate that critical mixed venous oxygen saturation, when oxygen consumption is limited by supply, is highest in stagnant hypoxia,12–15 which we believe highlights the importance of CO in oxygen delivery. Fetal tolerance of low saturation states is primarily the result of high placental blood flow.16
Blood pressure is often used as a clinical measure of circulation in newborns; however, it is only weakly correlated with CO (r = 0.38).17 Measurement of ventricular output is significantly complicated by the presence of ductal and atrial shunts, which are almost universal in the preterm population. Superior vena cava (SVC) flow is blood flow returning from the brain and upper body and is unaffected by cardiac shunts. Measurement of SVC flow has been validated as a noninvasive measurement of CO in preterm infants, and a "normal range" has been defined.1
EARLY BRAIN INJURY
Kluchow and Evans18 demonstrated an association between low SVC flow and intraventricular hemorrhage in a cohort of very low birth weight infants, and Kissack et al19 described sequential increases in CO with a simultaneous fall in cerebral fractional oxygen extraction (FOE) in the first 3 days of life in a similar cohort. Infants in this study who developed intraventricular hemorrhage had a larger variation in cerebral FOE than their non–brain-injured counterparts, with the highest FOE in 2 infants with hemorrhagic parenchymal infarction.20
It is not possible to determine if infants developing early brain injury have failed compensation despite higher FOE without a measure of oxygen consumption. The interaction of cerebral autoregulation, partial pressure of carbon dioxide,20 and possibly hemoglobin-oxygen affinity (HOA) may also contribute to the risk in each newborn.
PACKED RED BLOOD CELL TRANSFUSION
Transfusion of adult packed red blood cells (PRBCs) offers a number of theoretical benefits in the setting of poor circulation, including (1) improvement of CO, (2) increasing oxygen-carrying capacity without increasing oxygen consumption, and (3) alteration of HOA to favor tissue unloading.
Trials from the pre–surfactant era show improved oxygenation and survival after early exchange transfusion versus plasma expansion or control21,22; however, there are methodologic issues with these trials. Other work in ventilated preterm infants has shown similar benefit in oxygenation after transfusion.23 A comparison of PRBC transfusion and adrenaline infusion in normovolemic children after cardiac surgery showed that those receiving PRBCs had the benefit of improved oxygen delivery without the burden of increased oxygen consumption, which was seen with adrenaline infusion.24 In newborn lambs randomly allocated to control or isovolemic exchange with maternal blood, lambs allocated to exchange with low-affinity maternal blood were more able to adequately oxygenate tissues during severe progressive anemia despite increases in CO.25 This is primarily a result of alteration of HOA with adult hemoglobin favoring tissue oxygen unloading.
Our own work has shown a more complex interaction between CO, FOE, and HOA in newborns. During episodes of low SVC flow there was a small increase in FOE with a simultaneous increase in lactate. Many of the smallest infants received an early transfusion, resulting in a change to HOA. Infants with higher HOA had significantly lower FOE irrespective of CO.26
Trials of transfusion in premature newborns have focused on hemoglobin thresholds rather than support of circulation. A recent study of liberal- versus restricted-transfusion thresholds demonstrated increased brain injury in those in the restrictive-transfusion group with no difference in the number of transfusions.27 The higher hemoglobin-transfusion threshold resulted in earlier transfusion (median: day 3 vs 8), which, we suggest, may have improved circulation and possibly protected against subsequent brain injury.
Despite the theoretical advantages, there is clearly a need to balance the risk of blood exposure against these potential benefits in a population at risk of brain injury and transfusion-related illnesses.
CONCLUSIONS
We suggest that the brain injury in premature newborns with low CO is not simply an injury of flow but rather a hypoxic injury after exhaustion of compensatory mechanisms. It is important that the components of systemic oxygen transport are not viewed in isolation, because physiologic adaptation occurs in combination. PRBC transfusion as an intervention for poor circulation offers the opportunity to change multiple factors within oxygen delivery without increasing oxygen consumption and may contribute to protection against early brain injury in premature newborns.
REFERENCES
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