No abstract

The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure and pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser-Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (p < 0.01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso-reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (p = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso-occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady-state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.

Significance : Intracranial pressure (ICP), variability in perfusion, and resulting ischemia are leading causes of secondary brain injury in patients treated in the neurointensive care unit. Continuous, accurate monitoring of cerebral blood flow (CBF) and ICP guide intervention and ultimately reduce morbidity and mortality. Currently, only invasive tools are used to monitor patients at high risk for intracranial hypertension. Aim: Diffuse correlation spectroscopy (DCS), a noninvasive near-infrared optical technique, is emerging as a possible method for continuous monitoring of CBF and critical closing pressure (CrCP or zero-flow pressure), a parameter directly related to ICP. Approach: We optimized DCS hardware and algorithms for the quantification of CrCP. Toward its clinical translation, we validated the DCS estimates of cerebral blood flow index ( ) and CrCP in ischemic stroke patients with respect to simultaneously acquired transcranial Doppler ultrasound (TCD) cerebral blood flow velocity (CBFV) and CrCP. Results: We found CrCP derived from DCS and TCD were highly linearly correlated (ipsilateral , ; contralateral , ). We found weaker correlations between and CBFV (ipsilateral , ; contralateral , ) probably due to the different vasculature measured. Conclusion: Our results suggest DCS is a valid alternative to TCD for continuous monitoring of CrCP.

Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α‐globin protein from loss of up to four α‐globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co‐inherit the loss of one or two α‐globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α‐globin gene deletions affect sickle red cell deformability, the α‐globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α‐globin due to α‐thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow‐mediated dilation and microvascular post‐occlusive reactive hyperemia in 27 human subjects (15 missing one or two α‐globin genes and 12 healthy controls). Flow‐mediated dilation was significantly higher in subjects with α‐trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α‐globin gene status. This may explain the beneficial effect of α‐globin gene loss in sickle cell disease and suggests that α‐globin gene status may play a role in other vascular diseases.

In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects. Percent increase in heart rate from baseline was used to quantify cardiac ANS response, while percent decrease in PPG amplitude represented degree of peripheral vasoconstriction. After employing cluster analysis to determine threshold levels, the HUT responses were classified into four phenotypes: (CP) increased heart rate and peripheral vasoconstriction; (C) increased heart rate only; (P) peripheral vasoconstriction only; and (ST) subthreshold cardiac and peripheral vascular responses. Multinomial logistic regression (MLR) was used to relate these phenotypic responses to various parameters representing blood properties and baseline cardiovascular activity. The most common phenotypic response, CP, was found in 82% of non-SCD subjects, including those with chronic anemia. In contrast, 70% of SCD subjects responded abnormally to HUT: C-phenotype = 22%, P-phenotype = 37%, or ST-phenotype = 11%. MLR revealed that the HUT phenotypes were significantly associated with baseline cardiac parasympathetic activity, baseline peripheral vascular variability, hemoglobin level and SCD diagnosis. Low parasympathetic activity at baseline dramatically increased the probability of belonging to the P-phenotype in SCD subjects, even after adjusting for hemoglobin level, suggesting a characteristic autonomic dysfunction that is independent of anemia. Further analysis using a mathematical model of heart rate variability revealed that the low parasympathetic activity in P-phenotype SCD subjects was due to impaired respiratory-cardiac coupling rather than reduced cardiac baroreflex sensitivity. By having strong peripheral vasoconstriction without compensatory cardiac responses, P-phenotype subjects may be at increased risk for vaso-occlusive crisis. The classification of autonomic phenotypes based on HUT response may have potential use for guiding therapeutic interventions to alleviate the risk of adverse outcomes in SCD.

Sickle cell disease (SCD) subjects exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crisis by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. As SCD subjects have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity towards vasoconstriction. We exposed 17 SCD and 16 control subjects to a sequence of predetermined threshold temperatures for cold and heat detection as well as cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand using photo-plethysmography, and cardiac autonomic balance was assessed using heart rate variability. Thermal stimuli at both detection and pain thresholds caused significant decrease in MBF in the contralateral hand within seconds of stimulus application, with SCD subjects showing significantly stronger vasoconstriction (p=0.019). Furthermore, SCD subjects showed greater progressive decrease in blood flow than controls, with poor recovery between episodes of thermal stimulation (p=0.042). SCD subjects had faster vasoconstriction than controls (p=0.033), especially with cold detection stimulus; individuals with higher anxiety also vasoconstricted faster (p=0.007). Augmented vasoconstriction responses and progressive decrease in perfusion with repeated thermal stimulation in SCD is indicative of autonomic hypersensitivity in the microvasculature. This is likely to increase red cell entrapment in response to clinical triggers like cold or stress that have been associated with vaso-occlusive crisis in SCD.

Objectives: Real-time noninvasive monitoring of cerebral blood flow (CBF) during surgery is key to reducing mortality rates associated with adult cardiac surgeries requiring hypothermic circulatory arrest (HCA). We explored a method to monitor cerebral blood flow during different brain protection techniques using diffuse correlation spectroscopy (DCS), a noninvasive optical technique which, combined with frequency-domain near-infrared spectroscopy (FDNIRS), also provides a measure of oxygen metabolism.Methods: We used DCS in combination with FDNIRS to simultaneously measure hemoglobin oxygen saturation (SO 2 ), an index of cerebral blood flow (CBF i ), and an index of cerebral metabolic rate of oxygen (CMRO 2i ) in 12 patients undergoing cardiac surgery with HCA.