Cerebral hemodynamic changes during vaso-occlusive episodes in pediatric sickle cell disease

Abstract

Abstract Introduction: Vaso-occlusive pain episodes (VOE) are one of the most common and debilitating complications in people with sickle cell disease (SCD). VOEs are the number one cause for hospitalizations and emergency visits annually in this population, and they affect quality of life physically, psychologically, and socially (McClish et al. Pain 2024). The episodes are known to be associated with increased risk for acute chest syndrome, hepatic and renal involvement, and multi-organ failure. However, little is known about the cerebral hemodynamics during VOE, in part due to the challenge of studying the brain with existing tools during pain events. Neuroimaging modalities capable of capturing cerebrovascular hemodynamics such as MRI are time-consuming, costly, and unsuitable for acutely ill patients experiencing high levels of discomfort and pain. There is a need for better understanding of cerebral hemodynamics during VOE to improve our understanding of pain mechanisms and develop more targeted and effective pain management. Diffuse optical spectroscopies (DOS), specifically frequency domain near-infrared spectroscopy coupled with diffuse correlation spectroscopy, are novel, non-invasive optical tools that have the potential to fill this need. DOS provide a rapid, bedside quantification of regional oxygen extraction, cerebral blood volume, and indices of cerebral blood flow and oxygen metabolism. In this pilot study, we demonstrate the feasibility of DOS measurements during VOE, and we use DOS to test the hypothesis that cerebral hemodynamics are altered in children with SCD during VOE (SCD-VOE) compared to those without. Methods: This is a secondary analysis of data collected as part of ED-based clinical trials enrolling children and young adults with SCD and pain, evaluating mechanisms of hemolysis. Data was collected in the ED or within 24 hours of presentation in subjects 3-21 years old with SCD hospitalized for pain receiving parenteral opioids. Patients were assessed with DOS bilaterally over the prefrontal cortex, as in Lee et al. (Front. Neurol. 2022). A control group of children with SCD at steady-state (no VOE admission for at least 2 weeks) were used for comparison. This control cohort was derived from a study investigating differences in cerebral hemodynamics in patients with SCD and silent cerebral infarct. Differences between groups in each DOS-measured cerebral hemodynamic marker (i.e., oxygen extraction, cerebral blood volume, and indices of cerebral blood flow and oxygen metabolism) were assessed with Wilcoxon ranked sum tests at the 0.05 level. Within the SCD-VOE group, linear regression was used to assess correlation between each cerebral hemodynamic marker and self-reported pain score (on a scale of 1-10). For the whole cohort, linear models accounting for group (VOE, control) were used to assess the effects of hemoglobin on each hemodynamic marker. Results: Fifteen patients with SCD-VOE (median [interquartile range]) age (12.4 [11.1, 18.0]y, 53% male) and 32 control SCD patients (13.9 [11.0, 15.1]y, 37% male) were enrolled. No differences in age or hemoglobin levels (SCD-VOE 8.6 [7.9, 9.9] vs. controls 8.4 [7.8, 9.5] g/dL) were observed between groups. In the SCD-VOE cohort 80% of patients were on hydroxyurea (HU), and in the control cohort 78.1% of patients were on HU. DOS-measured oxygen extraction fraction and cerebral blood flow index were significantly decreased in SCD-VOE compared to SCD controls (p<0.05). In the SCD-VOE group, oxygen extraction was inversely associated with self-reported pain score (R=-0.55 p=0.009). All the other correlations with cerebral hemodynamics were not statistically significant. Oxygen extraction was inversely correlated with hemoglobin in the SCD control group (R=-0.5, p=0.002), but not in the SCD-VOE group (p>0.05). Conclusions: These findings support the feasibility of using DOS to monitor patients in pain. Our results suggest that VOE in SCD is associated with reduced cerebral blood flow and oxygen extraction, which together would be expected to impair oxygen delivery to the brain. Studies evaluating the implications of altered cerebrovascular hemodynamics during VOE are warranted as well as the impact of therapies on DOS over time. Insight into potential mechanisms driving these changes is also needed. There may be value in expanding therapeutic targets beyond pain to address aberrant cerebrovascular hemodynamics during VOE.