Sickle Cell Patients Have Exagerated Autonomic Response to Transient Hypoxia
Authors: Sangkatumvong Suvimol , Khanna Rachna , Khoo Michael , Coates Thomas D. 
Published: April 2020

Abstract
Sickle cell anemia (SCA) is a devastating disorder that results from a single amino acid substitution in the beta chain of hemoglobin causing polymerization of hemoglobin S when oxygen is removed. This causes normally flexible sickle red cells (SRBC) to become rigid, obstruct vasculature resulting in ischemic organ damage and decreased longevity. Anything which decreases microvasculature flow will promote the sickling process. Inflammation and adhesion of cellular elements to the vessel wall are known to increase the probability of vasoocclusive crisis (VOC). However, the precise event that triggers the cascade called “crisis” is not known. Microvascular flow changes rapidly in response to autonomic signals which can be assessed by measurement of heart rate variability (HRV). These autonomic signals may be the trigger that causes regional decrease in flow and initiates the events resulting in crisis.
We have established a model of induced hypoxia in human subjects that was designed to mimic the transient hypoxia occuring naturally during sleep. Calibrated tidal volume, O2 saturation, and electrocardiogram, were recorded up to 200 times per second using a LifeShirt physiological monitoring garment and tissue oxygenation and microvascular blood flow was assessed by laser Doppler flowmetry or magnetic resonance imaging. The report focuses on safety and on HRV results. Subjects breathed 5 breaths of 100% N2 twice separated by a 5 to 10 minte recovery period on up to 4 separate days per subject. 15 SCA had two hypoxic exposures on 38 days.
Subjects were contacted 1, 12, and 24 hrs and 7 to 14 days later and symptom questionnaires completed. On only 4 occasions, subjects reported mild transient sicklelike pain that required no or non-narcotic treatment within 24 hours of hypoxia and was deemed possibly related to the hypoxic exposure. About sixty percent of the exposures were associated with lightheadedness lasting 10 to 15 seconds at the nadir of the SpO2. The drop in SpO2 was greater in the SCA patients (p&lt;.05) and lasted 15 to 20 seconds. However, when we used the subjects’ individually measured oxyhemoglobin saturation curve to calculate change in pO2, there was no difference between SCA and normals.
Using a novel algorithm we developed which allows second to second comparison of autonomic nervous system (ANS) balance to change in SaO2, we found that the high frequency component of HRV representing parasympathetic (HFP) and low frequency component representing mixed sympathetic activity (LFP) were significantly different between SCA and control (p&lt;.001). SCA patients have a dramatic loss of parasympathetic signal in response to transient hypoxia resulting in significant loss of heart rate variability. These data suggest than SCA patients have a greatly amplified autonomic nervous system response, at least to hypoxia. Since these same ANS signals are also responsible for control of regional microvascular blood flow, it is reasonable to speculate that this hyperactive ANS response leads to regional drop in perfusion which, on a background of hyper-adhesiveness, nitric oxide depletion, inflammation, and dehydration, triggers the sickling cascade. It is important to note that loss of HRV is a powerful predicator of sudden death in several other settings of vascular disease and that 15 to 20% of SCA deaths are otherwise unexplained sudden deaths.
These data demonstrate that
transient hypoxia can be safely induced in SCA subjects and used to study the relation between hypoxia and physiological responses and SCA patients have a marked abnormality in autonomic nervous system regulation in response to transient hypoxia that likely plays a role in the pathophysiology of this disorder.