Thermal Pain and Pain Anticipation Induce a Decrease in Microvascular Perfusion in Sickle Cell and Normal Subjects

Abstract

INTRODUCTION: Sickle cell disease is an inherited blood disorder characterized by vaso-occlusive crises (VOC). HbS in red blood cells (RBC) polymerizes rapidly after it releases oxygen to tissues, causing RBC to become rigid. Anything that decreases flow in the microvasculature increases the chance that this flexible-to-rigid transformation occurs causing the rigid blood cell to lodge in the microvasculature, therefore increasing the chance of vaso-occlusion and the risk of VOC. Although hypoxia and stress are known risk factors for crises, the exact mechanism that initiates VOC events is not well known. We have previously shown that transient hypoxia causes parasympathetic withdrawal and sighs cause vasoconstriction more frequently in SCD subjects than in normal controls. Pain is the hallmark of SCD and is a consequence of VOC but has not been considered as a possible trigger of vasoconstriction that may lead to VOC. OBJECTIVES: To determine if heat induced pain causes decrease in peripheral blood flow (PBF) in SCD. METHODS: 30 SCD and 30 control subjects (healthy and sickle cell traits) were recruited at Children's Hospital Los Angeles (CHLA). Quasi-periodic pulses of pain were induced on the right forearm using TSA-II neuro analyzer heating thermode. We implemented a technique using cross correlation analysis to detect changes in complex microvascular flow signals measured bilaterally on the hands, using laser-Doppler flowmeter (LDF), Peripheral Arterial Tonometer (PAT) and photo-plethysmography (PPG). We also measured the average drop from baseline in the microvascular flow during the heat pain. Data were analyzed using one- and two- sample Student t-test. RESULTS: Data on 53 subjects were analyzed. There was a significant correlation between heat pain pulses and PBF responses, as well as a significant drop in blood flow in all study participants (PPG signal, both p<0.001), indicating that heat pain pulses lead to vasoconstriction. Males had higher correlation (p<0.005) and stronger vasoconstriction (p<0.05) during heat stimuli compared to females. Other Signals (LDF and PAT) had a similar pattern but were less significant. The vasoconstriction response consisted of two components, the first one occurred prior to administration of the painful stimulus indicating that anxiety or anticipation of pain causes significant vasoconstriction. Application of the painful stimulus causes further vasoconstriction. CONCLUSIONS: The findings demonstrate a significant decrease in PBF in both SCD and controls in response to heat pain and possibly to pain anticipation. The decrease in PBF could play a critical role in the genesis of VOC in SCD by markedly prolonging microvascular transit time, increasing the likelihood of red cell entrapment when sickle red cells transform from flexible to rigid. Furthermore, the potent vasoconstriction response to pain in SCD means that pain resulting from VOC could potentially trigger a cascade effect in which vasoconstriction could lead to even more serious VOC. Since regional blood flow is regulated by the autonomic nervous system (ANS), which has been described to be dysfunctional in SCD, our study calls attention to the ANS as a factor in the genesis of crisis in this disorder. Disclosures No relevant conflicts of interest to declare.

Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease

“…We previously reported that SCD subjects had stronger vasoconstriction in response to heat-induced pain than non-SCD controls [ 7 ]. Since pain triggers rapid changes in blood pressure and respiration, and these auxiliary changes can also lead to peripheral vasoconstriction, we sought to quantify the relative contributions of these additional inputs to pain-induced vasoconstriction, and thus determine how these contributions were different in SCD vs controls.…”

“…Although the model showed reasonably good fit, the assumption of linear relationships between the inputs and the vasoconstriction response is necessarily a simplification of the underlying reality. Lastly, Khaleel et al [ 7 ] reported vasoconstriction due to anticipation prior to receiving pain. The anticipatory effect was in part accounted for in the model by changes in blood pressure, although this could not be directly measured.…”

“…Pain is known to activate the sympathetic nervous system, as demonstrated by studies measuring muscle sympathetic nerve activity [ 4 – 6 ], and the increase in sympathetic drive can lead to peripheral vasoconstriction. We previously found that pain, induced through the delivery of dynamic pulses of heat to the skin, led to stronger phasic vasoconstriction responses in SCD compared to non-SCD subjects [ 7 ]. So while pain is thought to be a consequence of VOC, the pain itself may trigger a cascade of events that leads to full-scale VOC by promoting regional vasoconstriction.…”

The effect of hypnosis on pain and peripheral blood flow in sickle-cell disease: a pilot study

“…Parametric testing used Cohen’s d as the effect size (small = 0.2, medium = 0.5, large = 0.8). 19 Nonparametric testing used Pearson’s r as the effect size (small = 0.1, medium = 0.3, large = 0.5). 20 All analyses were conducted in RStudio (version 3.2.1).…”

Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain

“…Sickle cell disease (SCD) is an inherited blood disorder resulting from the substitution of the amino acid valine at the sixth position of the β‐globin chain to a glutamine, forming sickle hemoglobin (HbS) . HbS, unlike normal hemoglobin, polymerizes in the deoxy‐state causing red blood cells (RBC) to become rigid and obstruct microvascular blood flow .…”