Quantifying the Cerebral Hemometabolic Response to Blood Transfusion in Pediatric Sickle Cell Disease With Diffuse Optical Spectroscopies

Abstract

Red blood cell transfusions are common in patients with sickle cell disease who are at increased risk of stroke. Unfortunately, transfusion thresholds needed to sufficiently dilute sickle red blood cells and adequately restore oxygen delivery to the brain are not well defined. Previous work has shown that transfusion is associated with a reduction in oxygen extraction fraction and cerebral blood flow, both of which are abnormally increased in sickle patients. These reductions are thought to alleviate hemometabolic stress by improving the brain's ability to respond to increased metabolic demand, thereby reducing susceptibility to ischemic injury. Monitoring the cerebral hemometabolic response to transfusion may enable individualized management of transfusion thresholds. Diffuse optical spectroscopies may present a low-cost, non-invasive means to monitor this response. In this study, children with SCD undergoing chronic transfusion therapy were recruited. Diffuse optical spectroscopies (namely, diffuse correlation spectroscopy combined with frequency domain near-infrared spectroscopy) were used to quantify oxygen extraction fraction (OEF), cerebral blood volume (CBV), an index of cerebral blood flow (CBFi), and an index of cerebral oxygen metabolism (CMRO2i) in the frontal cortex immediately before and after transfusion. A subset of patients receiving regular monthly transfusions were measured during a subsequent transfusion. Data was captured from 35 transfusions in 23 patients. Transfusion increased median blood hemoglobin levels (Hb) from 9.1 to 11.7 g/dL (p < 0.001) and decreased median sickle hemoglobin (HbS) from 30.9 to 21.7% (p < 0.001). Transfusion decreased OEF by median 5.9% (p < 0.001), CBFi by median 21.2% (p = 0.020), and CBV by median 18.2% (p < 0.001). CMRO2i did not statistically change from pre-transfusion levels (p > 0.05). Multivariable analysis revealed varying degrees of associations between outcomes (i.e., OEF, CBFi, CBV, and CMRO2i), Hb, and demographics. OEF, CBFi, and CBV were all negatively associated with Hb, while CMRO2i was only associated with age. These results demonstrate that diffuse optical spectroscopies are sensitive to the expected decreases of oxygen extraction, blood flow, and blood volume after transfusion. Diffuse optical spectroscopies may be a promising bedside tool for real-time monitoring and goal-directed therapy to reduce stroke risk for sickle cell disease.

Hybrid diffuse optical appraisal of peripheral and cerebral changes in critically ill patients receiving red blood cell transfusion

“…Both rPMRO 2 and rCMRO 2 raised due to RBCT, with a greater median increase in the muscle than in the brain and with a statistically significant difference between the two. This result is in disagreement with what was found in some literature related to infants where, for instance, a decrease [15] or no change (p>0.05) [39, 49] had been found in CMRO 2 by optical methods. Likewise, no rCMRO 2 change was found in SAH patients by PET [41] nor in children with sickle cell anemia by MRI [43].…”

“…However, this is in contrast with the results obtained on the brain in ill but young populations (i.e. sickle cell disease, very preterm infants) where a decrease in the CBF was found after the intake of blood [15, 20, 39]. For instance, in Reference [20], the decrease of cerebral blood volume (CBV) was 0.5 mL/100g, while in Reference [39] CBV decreased by median 18.2% and CBF by median 21.2%.…”

“…sickle cell disease, very preterm infants) where a decrease in the CBF was found after the intake of blood [15, 20, 39]. For instance, in Reference [20], the decrease of cerebral blood volume (CBV) was 0.5 mL/100g, while in Reference [39] CBV decreased by median 18.2% and CBF by median 21.2%. However, we acknowledge that the populations, the age, the origin of their anemia and the etiology are not fully relatable and may account for these discrepancies.…”

“…However, in Reference [37] a correction method was outlined for the BFI in phantom experiments. This approach is currently under validation against MRI measurements [39] by the same group and, if confirmed in vivo , it would be a further step to implement in the future. Therefore, our calculations of the BFI should be considered as preliminary.…”

Novel approaches to measure transfusion effectiveness

“…Increased CBF and OEF have been shown to predispose individuals with SCD to stroke and are reduced following RBC transfusion, thereby reducing cerebral metabolic demands that predispose to ischemic injury [17]. Frequency-domain NIRS and DCS have been used in a study of 35 chronic transfusion events in children with SCD to show significant decreases in CBF index, cerebral blood volume, and cerebral OEF immediately after a single transfusion, without change in CMRO 2 [18 ▪▪ ]. Novel MRI sequences, specifically arterial spin labeling (ASL) for CBF and asymmetric spin echo for OEF quantification may also be used to assess the cerebroprotective goals of chronic transfusions in SCD.…”