Dynamic Cerebral Autoregulation and Blood Pressure Oscillations Reveal the Severity of Autoregulatory Dysfunction in Sickle Cell Disease

Introduction

Sickle Cell Disease (SCD) is an inherited blood disorder that causes the production of sickle hemoglobin (HbS), which can polymerize and cause red blood cells to become rigid and sickle-shaped, leading to the blockage of small blood vessels and impeding microvascular blood flow and oxygen delivery to various tissues. This disruption in microvascular function can cause chronic microvascular ischemia and significant tissue damage. In the brain, this may lead to impairments in dynamic cerebral autoregulation (CA), which is critical for maintaining stable blood flow to the brain during changes in blood pressure (BP). When dynamic CA is impaired, blood pressure fluctuations can lead to mismatches between oxygen supply and metabolic demands, affecting tissue oxygen saturation (StO₂) levels in patients with SCD. Understanding the relationship between dynamic CA due to blood pressure oscillations in SCD could provide insights into the severity of autoregulatory dysfunction in patients with SCD. To evaluate this relationship, we adopted a phase delay to quantify the lag between BP changes and oscillations in the difference between oxyhemoglobin (O) and deoxyhemoglobin (D) (diffHb) in the brain, a surrogate measure of cerebral blood flow, measured by frequency domain near-infrared spectroscopy (FD-NIRS). We expect lower phase values (-180° to -250°) to represent a healthy physiological relationship between diffHb and blood pressure oscillations.

Methods

We enrolled 15 controls and 13 patients with SCD in an IRB-approved prospective study at the UPMC Adult SCD Clinic. Using a commercial FD-NIRS device (ISS Oxiplex^TM, Champaign, IL), we measured cerebral changes in concentrations of O, D, total hemoglobin and StO₂. Optical probes were placed on the left forehead. Participants underwent three 2-minute blocks of paced breathing at 0.09, 0.1, and 0.125 Hz (F1, F2, F3) with screen prompts for inhalation and exhalation synchronization to induce changes in vascular tone for phase delay measurements. Respiration and blood pressure (BP) were continuously monitored with a respiration belt and a BP cuff on the chest and right arm, respectively, using a BIOPAC device synced with optical data (sampled at 50 Hz). We assessed cerebral hemodynamic differences by calculating the difference in phase delay between BP and hemoglobin NIRS data (BP-diffHb) using circular statistics, adjusting values to a -180° to -360° range for better interpretation. Mean and standard deviation values for each breathing block were analyzed using the Mann-Whitney U Test to determine statistical significance (p<0.05).

Results

We noticed fluctuations in the phase delay as the paced breathing frequency increased and observed a similar pattern in our previous findings from Wood et al, 2020. Our results demonstrated a lower phase delay (BP-NIRS) for controls (F1 = -225.08°, F2 = -246.47°, and F3 = -214.25°), as compared to patients with SCD (F1 = -297.10°, F2 = -272.38°, and F3 = -308.85°) with a significant change at F3 (p = 0.038) when including continuous blood pressure measurements. Our StO₂ results revealed a significant difference in cerebral oxygenation between controls and SCD at F1, with an increase in StO₂ (+1.09 %) in controls and a decrease in StO₂ (-3.09 %) in patients with SCD (p=0.022).

Discussion

We anticipated a greater phase delay with increased paced breathing frequency but observed a decrease in phase values from F1 to F2 and an increase from F2 to F3 in patients. This may suggest that while the brain was attempting to maintain blood flow during the task, impaired CA resulted in challenges for patients to compensate quickly for the heightened oxygen demand and continuous blood pressure changes, leading to a significant increase in phase values from F2 to F3.The greater phase delays observed in patients with SCD indicate impaired cerebral autoregulation, which may result in difficulty maintaining stable cerebral blood flow. The StO₂ results support our phase delay findings and suggest that the paced breathing task induces a oxygen demand that is not adequately met in patients with SCD.

Conclusion

Our study utilized phase delay measurements via NIRS to investigate how variations in blood flow timing are influenced by blood pressure, offering insights into the complex mechanisms underlying SCD-related cerebrovascular disease.

Xu:GSK: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy.