We show that daytime Hb saturation is a determinant of TCD velocity in children with Hb SS. Desaturation is associated with increased cerebral artery blood flow velocities and increased odds of abnormal TCD velocities, thus increased risk of stroke. A similar inverse relationship between Hb saturation and TCD velocity was shown in a small (N=30), uncontrolled study of determinants of intellectual function in children with Hb SS (Hogan, et al 2006
). Here we control for confounders of TCD velocity in a much larger sample and show that about 5% of the variation in TCD velocity can be ascribed to Hb saturation alone. Although stenosis itself is the dominant risk factor, our study adds to growing body of evidence for an additional role of Hb desaturation in the pathophysiology of stroke in Hb SS (Hogan, et al 2006
, Kirkham and Datta 2006
, Kirkham, et al 2001
, Quinn and Sargent 2008
, Setty, et al 2003
). We propose that desaturation, which decreases arterial oxygen content, limits oxygen delivery to the brain and predisposes to stroke, especially in regions distal to stenotic cerebral vasculopathy where compensatory increases in blood flow may be blunted. Moreover, the compensatory increase in cerebral blood flow due to desaturation could increase the turbulence of blood flow at the site of stenosis and further predispose to vessel injury and stroke.
Our findings do not yet directly affect clinical practice, but they add to our knowledge about the genesis of stroke in Hb SS and have at least two additional implications. First, the measurement of cerebral artery blood flow velocity by TCD is more complex than a simple measure of the degree of stenosis in a blood vessel. Although stenosis is a dominant factor, TCD is actually a composite measure that integrates a number of related factors that could increase the risk of stroke in children with Hb SS, including the degree of anaemia and Hb saturation. Second, Hb saturation is a potentially modifiable risk factor. Supplemental oxygen would be cumbersome to use, but treatment with hydroxyurea (Singh, et al 2008
) or red blood cell transfusions (Kress, et al 1999
) can alleviate desaturation in Hb SS, which might be part of therapeutic benefit of both agents.
Our study has a number of limitations. First, we cannot ascribe a causal relationship between Hb desaturation and TCD velocity because this is a cross-sectional study. Even so, our findings are consistent with controlled physiologic experiments in animal models (Jones, et al 1981
) and humans without Hb SS (Gupta, et al 1997
). Second, we used a novel proxy measure of degree of stenosis (MCA:VB). We used this proxy because there is no appropriate “gold standard” for children with Hb SS. Nevertheless, this proxy is supported by biologic rationale, and it performed as expected for a measure of degree of stenosis. Additionally, the significant inverse relationship between SpO2
and TCD velocity remains if we remove this proxy measure from the models entirely (data not shown). That is, our conclusions are the same with or without the use of MCA:VB as a covariate, but the inclusion of MCA:VB may improve the accuracy of our models. Third, we retrospectively assembled data that were obtained and documented for the purposes of routine clinical practice, so there were missing data and the possibility of different types of bias, such as ascertainment bias. However, we analysed every patient in our cohort who had a screening TCD study, and 92 and 100% of patients had measurements of SpO2
and Hct. Fourth, the measurements of SpO2
and Hct were not simultaneous with the TCD study, because this is not our clinical practice, but the median interval between the TCD and these measurements was short (1 – 1.5 months). Finally, we did not ascertain patients’ oxy-haemoglobin dissociation curves, so we do not know whether desaturated patients are hypoxaemic and cannot quantify oxygen extraction. Nevertheless, Hb concentration and saturation are the dominant determinants of arterial oxygen content, so anemia and Hb desaturation will greatly limit the bulk delivery of oxygen to the brain irrespective of dissolved oxygen content.
In conclusion, Hb saturation is a determinant of TCD velocity in children with Hb SS. Desaturation is associated with increased cerebral artery blood flow velocities and increased odds of abnormal TCD velocities, thus increased risk of stroke. Hb saturation is an easily measured and potentially modifiable risk factor. It could be studied as a potential therapeutic target to prevent stroke.