Abstract
Stroke is a serious but increasingly preventable complication of sickle cell anemia (SS). Steady-state hemoglobin (Hb) desaturation, which is common in SS and once thought to be benign, could contribute to the risk of stroke because it can perturb endothelial function and limit oxygen delivery to the brain. We recently showed that daytime Hb desaturation is associated with overt stroke in SS patients (BJH2008;140:336–9). To corroborate and study potential mechanisms of this association, we examined the relationship between daytime Hb saturation and cerebral artery blood flow velocity measured by transcranial Doppler ultrasonography (TCD), an established risk factor for overt stroke in children with SS. We hypothesized that daytime steady-state Hb saturation correlated inversely with TCD velocity, because Hb desaturation would cause a compensatory increase in cerebral blood flow to maintain oxygen delivery to the brain. Therefore, we performed a cross-sectional study of all Dallas Newborn Cohort subjects with SS or sickle-β0-thalassemia who had screening TCD studies. For each subject we collected the time-averaged maximum mean velocities (TAMMV) in the right and left middle cerebral arteries (RMCA, LMCA), age at TCD study, and the most recent (relative to the TCD) hematocrit (Hct) and daytime steady-state oxygen saturation by pulse oximetry (SpO2). Only the first TCD study of any subject was used for this analysis. We identified 169 subjects (54% male; 98% SS) with a mean age of 8 years (range 2 – 20). SpO2 correlated significantly with TAMMV in both the RMCA (Pearson r −0.28; p=0.001) and the LMCA (−0.23; p=0.003) in the direction hypothesized. To control for two important determinants of TCD velocity, age and Hct, we performed multiple linear regression. We defined the dependent variable to be the TAMMV in either the RMCA or LMCA and the independent variables to be the SpO2 closest to the TCD study, Hct closest to TCD, and age at time of TCD. SpO2 remained a statistically significant predictor of TAMMV in both the RMCA (p=0.001) and LMCA (p=0.039) while simultaneously controlling for age and Hct (Table). These models explained 20 to 30% of the variation in TAMMV in the LMCA and RMCA, respectively. In summary, daytime steady-state Hb desaturation in children with SS is associated with increased cerebral artery blood flow velocity as measured by TCD. Thus, Hb saturation is a novel determinant of TCD velocity, an established risk factor for overt stroke in children with SS. We previously showed that Hb desaturation is also associated with overt stroke. Therefore, we propose that daytime steady-state Hb desaturation predisposes children with SS to overt ischemic stroke by limiting oxygen delivery to the brain. Hb saturation is an easily measured, potentially modifiable risk factor that could be used with TCD to better identify children with SS at highest risk of stroke.
TAMMV in RMCA: TAMMV in LMCA: β Partial r 2 p β Partial r 2 p (Constant) 464.05 — <0.001 414.39 — <0.001 Recent SpO 2 −2.44 −0.25 0.001 −1.85 −0.16 0.039 Recent Hct −2.51 −0.32 <0.001 −2.99 −0.33 <0.001 Age −3.61 −0.43 <0.001 −2.27 −0.25 0.001 model r2= 0.29 model r2= 0.19
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