Cerebral Artery Blood Flow Velocity Research Articles

Association of Hemodynamic and Cerebrovascular Responses to Exercise With Symptom Severity in Adolescents and Young Adults With Concussion.

Aerobic exercise has become a useful method to assist with postconcussion management. Exercise can exacerbate concussion symptoms even when symptoms are not apparent at rest. Few studies have examined the reasons for symptom exacerbation during exercise following a concussion. We had 2 primary objectives: (1) to delineate cardiopulmonary and cerebrovascular responses to exercise in adolescents and young adults with a concussion and healthy controls and (2) to determine the association between cerebrovascular responses and symptom burden. We recruited participants with a recent concussion from a sport concussion clinic between September 1, 2018, and February 22, 2020. They were included if their concussion occurred <3 weeks before initial testing and if they were symptomatic at rest. Participants were excluded if they sustained a concussion in the past year (excluding index injury), reported history of neurologic disorders, or were using medications/devices that may alter neurologic function. Participants completed a progressive, symptom-limited, submaximal exercise protocol on a stationary bicycle. We assessed heart rate, blood pressure, fraction of end tidal CO2 (FETCO2), and middle cerebral artery blood flow velocity (CBF) and cerebrovascular function (vasoactivity and autoregulation) at seated rest and during exercise. We conducted 107 exercise tests (40 concussed, 37 healthy participants initially; 30 concussed at follow-up). Concussed participants were tested initially (mean 17.6 ± 2.2 [SD] years of age; 55% female; mean 12.5 ± 4.7 days postconcussion) and again 8 weeks later (mean 73.3 ± 9.5 days postconcussion). Control participants (mean 18.3 ± 2.4 years; 62% female) were tested once. FETCO2 increased throughout the exercise protocol as heart rate increased, reached a plateau, and declined at higher exercise intensities. CO2 explained >25% of the variation in resting CBF (R 2 > 0.25; p < 0.01) in most (73% individuals). Within the concussion group, resting symptom severity and the heart rate at which FETCO2 reached a plateau explained ∼2/3s of variation in exercise-induced symptom exacerbation (R 2 = 0.65; FETCO2 β = -1.210 ± 0.517 [SE], p < 0.05). There was a moderate, statistically significant relationship between cerebrovascular responses to CO2 at rest (cerebral vasoactivity) and cerebrovascular responses to exercise-induced changes in FETCO2 (R 2 = 0.13, p = 0.01). The arterial CO2 response and symptom exacerbation relationship during postconcussion aerobic exercise may be mediated by increased sensitivity of cerebral vasculature to exercise-related increase in CO2.

Impaired dynamic cerebral autoregulation in young adults with mild depression.

The incidence of depression is increasing, especially in the young adult population. Impaired cognitive function is one of the characteristics of depression, which may be related to impaired cerebral autoregulation (CA). We investigated the characteristics of CA in young adults with mild depression, as well as its validity for identifying patients with depression. Patients (aged 18-35years) with Hamilton Depression Rating Scale (HAMD) scores ranging from 8 to 17 and a first episode of mild depression were enrolled in this study. Healthy volunteers were recruited as controls. Noninvasive continuous arterial blood pressure and bilateral middle cerebral artery blood flow velocity were simultaneously recorded from each subject. Transfer function analysis was applied to derive phase difference, gain, coherence and rate of recovery for the assessment of CA. Forty-three patients and 43 healthy controls were enrolled. Phase difference values were significantly compromised in young adults with mild depression and were negatively correlated with HAMD scores. Rate of recovery values estimated from depressed patients was significantly lower. The validity in identifying patients with depression was favorable for the phase difference. The cutoff phase difference value was 29.66. Our findings suggest that dynamic CA was impaired in young patients with mild depression and negatively correlated with HAMD scores. CA represented by phase difference can be used as an objective auxiliary examination of depression, and has clinical diagnostic value for the early identification of patients with depression.

Concussion history in rugby union players is associated with depressed cerebrovascular reactivity and cognition.

Recurrent contact and concussion in rugby union remains a significant public health concern given the potential increased risk of neurodegeneration in later life. This study determined to what extent prior-recurrent contact impacts molecular-hemodynamic biomarkers underpinning cognition in current professional rugby union players with a history of concussion. Measurements were performed in 20 professional rugby union players with an average of 16 (interquartile range [IQR] 13-19) years playing history reporting 3 (IQR 1-4) concussions. They were compared to 17 sex-age-physical activity-and education-matched non-contact controls with no prior history of self-reported concussion. Venous blood was assayed directly for the ascorbate free radical (A•- electron paramagnetic resonance spectroscopy) nitric oxide metabolites (NO reductive ozone-based chemiluminescence) and select biomarkers of neurovascular unit integrity (NVU chemiluminescence/ELISA). Middle cerebral artery blood flow velocity (MCAv doppler ultrasound) was employed to determine basal perfusion and cerebrovascular reactivity (CVR) to hyper/hypocapnia ( ). Cognition was assessed by neuropsychometric testing. Elevated systemic oxidative-nitrosative stress was confirmed in the players through increased A•- (p<0.001) and suppression of NO bioavailability (p<0.001). This was accompanied by a lower CVR range ( ; p=0.045) elevation in neurofilament light-chain (p=0.010) and frontotemporal impairments in immediate-memory (p=0.001) delayed-recall (p=0.048) and fine-motor coordination (p<0.001). Accelerated cognitive decline subsequent to prior-recurrent contact and concussion history is associated with a free radical-mediated suppression of CVR and neuronal injury providing important mechanistic insight that may help better inform clinical management.

Ten days of high dietary sodium does not impair cerebral blood flow regulation in healthy adults.

High dietary sodium impairs cerebral blood flow regulation in rodents and is associated with increased stroke risk in humans. However, the effects of multiple days of high dietary sodium on cerebral blood flow regulation in humans is unknown. Therefore, the purpose of this study was to determine whether ten days of high dietary sodium impairs cerebral blood flow regulation. Ten participants (3F/7M; age: 30±10years; blood pressure (BP): 113±8/62±9mmHg) participated in this randomized, cross-over design study. Participants were placed on 10-day diets that included either low- (1000mg/d), medium- (2300mg/d) or high- (7000mg/d) sodium separated by ≥four weeks. Urinary sodium excretion, beat-to-beat BP (finger photoplethysmography), middle cerebral artery velocity (transcranial Doppler), and end-tidal carbon dioxide (capnography) was measured. Dynamic cerebral autoregulation during a ten-minute baseline was calculated and cerebrovascular reactivity assessed by determining the percent change in middle cerebral artery blood flow velocity to hypercapnia (8% CO2, 21% oxygen, balance nitrogen) and hypocapnia (via mild hyperventilation). Urinary sodium excretion increased in a stepwise manner (ANOVA P=0.001) from the low, to medium, to high condition. There were no differences in dynamic cerebral autoregulation between conditions. While there was a trend for a difference during cerebrovascular reactivity to hypercapnia (ANOVA P=0.06), this trend was abolished when calculating cerebrovascular conductance (ANOVA: P=0.28). There were no differences in cerebrovascular reactivity (ANOVA P=0.57) or conductance (ANOVA: P=0.73) during hypocapnia. These data suggest that ten days of a high sodium diet does not impair cerebral blood flow regulation in healthy adults.

Dynamic cerebral autoregulation during early orthostatic exercise in patients with severe traumatic brain injury: Further exploratory analyses from a randomized clinical feasibility trial

In patients with severe traumatic brain injury, there is limited evidence of the clinical effect of early orthostatic exercise, although such exercise may strengthen systemic or cerebral hemodynamic responses to head-up tilt, thereby minimizing orthostatic intolerance. We measured dynamic cerebral autoregulation (dCA) and the occurrence of orthostatic intolerance after four weeks of regular orthostatic exercise by head-up tilt using a tilt table with integrated stepping using the ERIGO® tilt-table and comparing it to standard care. Thirty-four patients with severe traumatic brain injury admitted to a neurocritical care unit were included in this randomized clinical trial. Middle cerebral artery blood flow velocity (MCAv), non-invasive mean arterial pressure, heart rate and PaCO2 were recorded; dCA was measured by the non-invasive mean flow index (nMxa). Transition from the supine position to head-up tilt triggered a 10–16% decrease in MCAv and increased nMxa in both groups at all time points (P < 0.05), with no differences between groups. There was no difference in the number of episodes with orthostatic intolerance (5 vs 3; 1 vs 2; 1 vs 0) at baseline, two weeks and four weeks, respectively, and no association between changes in PaCO2-adjusted nMxa and the occurrence of orthostatic reactions (P = 0.35). Early orthostatic exercise does not affect dynamic cerebral autoregulation and does not protect against orthostatic intolerance in patients with severe traumatic brain injury. Trial registration: ClinicalTrials.gov identifier: NCT02924649. Registered on 3rd October 2016.

Reader Response: Association of Ventricular Arrhythmias With Dementia: The Atherosclerosis Risk in Communities (ARIC) Study

Norby et al.1 report their interesting findings on the relationship between ventricular arrhythmias and dementia. As they note, speculative mechanisms underlying the observed relationship may include brain hypoperfusion. We previously had the opportunity to directly measure the effects of premature ventricular contractions (PVC) on intracranial hemodynamics.2 Using simultaneous transcranial Doppler ultrasound and electrocardiography, we measured middle cerebral artery blood flow velocity during PVC in comparison to blood flow velocity before and after PVC. Compared with the preceding beat, we found significant reductions in peak, mean, and diastolic velocities (30.7%, 34.2%, and 29.6%, respectively) for PVC. Compared with the following beat, we also found significant reductions in peak, mean, and diastolic velocities (37.1%, 30.3%, and 36.2%, respectively) for PVC. Moreover, using similar measurement techniques, we found substantial intracranial hemodynamic effects of atrial fibrillation, including dramatic changes before and immediately after cardioversion.3 We believe that these findings offer some mechanistic perspectives on the epidemiologic observations of the link between cardiac arrhythmias and dementia.1,4

The Effect of K ATP Channel Blocker Glibenclamide on CGRP-Induced Headache and Hemodynamic in Healthy Volunteers.

BackgroundCalcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (KATP) channels. Here, we investigated the effect of the KATP channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.MethodsIn a randomized, double-blind, placebo-controlled, cross-over study, 20 healthy volunteers aged 18–27 years were randomly allocated to receive an intravenous infusion of 1.5 μg/min CGRP after oral pretreatment with glibenclamide (glibenclamide-CGRP day) or placebo (placebo-CGRP day). The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0–14 h) between glibenclamide and placebo. The secondary endpoints were the difference in AUC for middle cerebral artery blood flow velocity (VMCA), superficial temporal artery (STA) and radial artery (RA) diameter, facial flushing, heart rate (HR) and mean arterial blood pressure (MAP) (0–4 h) between glibenclamide and placebo.ResultsWe found no significant difference in the incidence of headache between glibenclamide-CGRP day (14/20, 70%) and placebo-CGRP day (19/20, 95%) (P = 0.06). The AUC for headache intensity, VMCA, STA, RA, facial skin blood flow, HR, and MAP did not differ between glibenclamide-CGRP day compared to placebo-CGRP day (P > 0.05).ConclusionPretreatment with a non-selective KATP channel inhibitor glibenclamide did not attenuate CGRP-induced headache and hemodynamic changes in healthy volunteers. We suggest that CGRP-induced responses could be mediated via activation of specific isoforms of sulfonylurea receptor subunits of KATP channel.

Head Trauma not Associated with Long Term Effects on Autonomic Function

Contact-sports can elicit concussions, which impacts autonomic function, as well as elicit repetitive head trauma, where autonomic function has not yet been assessed. Purpose To determine if differences in autonomic function exist among three groups (CTRL: healthy non-contact-sport participant; RHT: repetitive head trauma contact-sport participant; CONC: previous concussion). Methods Forty men (16) and women (24), aged 18-37 (22±3), participated. Participants were grouped based on their sport and concussion history (CTRL, RHT, CONC). The participant was outfitted with equipment to evaluate heart rate, blood pressure, and cerebral-artery blood flow velocity (CBFv), as the participant performed three stimuli: deep breathing, Valsalva maneuver, and a 70° head-up tilt test. All group comparisons were analyzed using a one-way ANOVA; all data are presented as means ± standard deviation. Results The groups did not differ in respiratory sinus arrhythmia (CTRL: 22±6bpm, RHT: 21±8bpm, CONC: 19±7bpm; p=0.471), Valsalva ratio (CTRL: 2.19±0.39, RHT: 2.09±0.37, CONC: 2.00±0.47; p=0.519), CBFv (CTRL: 47.74±25.28cm/s, RHT: 40.99±10.93cm/s, CONC: 43.97±17.55cm/s; p=0.657), or tilt time (CTRL: 806.09±368.37sec, RHT: 943.07±339.54sec, CONC: 978.40±387.98sec; p=0.479). However, CONC (113.24±11.64mmHg) had a significantly higher mean systolic blood pressure during the tilt test than CTRL (102.66±7.79mmHg; p=0.026), while RHT (107.9±9.0mmHg) was not significantly different than CTRL (p=0.39) or CONC (p=0.319). Conclusion Concussions do not seem to have lasting effects on autonomic function. Overwhelmingly, dysautonomia is not present during chronic recovery from concussions or in individuals with RHT from contact-sports.

Cerebrovascular Neuroprotection after Acute Concussion in Adolescents.

To assess acute cerebrovascular function in concussed adolescents (14-21 years of age), whether it is related to resting cerebral hemodynamics, and whether it recovers chronically. Cerebral vasoreactivity and autoregulation, based on middle cerebral artery blood flow velocity, was assessed in 28 concussed participants (≤14 days of injury) and 29 matched controls. The participants in the concussion group returned for an 8-week follow-up assessment. Over the course of those 8-weeks, participants recorded aerobic exercise frequency and duration. Between groups, demographic, clinical, and hemodynamic variables were not significantly different. Vasoreactivity was significantly higher in the concussed group (p=0.02). Within the concussed group, 60% of the variability in resting cerebral blood flow velocity was explained by vasoreactivity and two components of autoregulation - falling slope and effectiveness of autoregulation (adjusted R2 =0.60, p < 0.001). Moreover, lower mean arterial pressure, lower responses to increases in arterial pressure, and lower vasoreactivity were significantly associated with larger symptom burden (adjusted R2 =0.72, p < 0.01). By the 8-week timepoint, symptom burden, but not vasoreactivity, improved in all but four concussed participants (p < 0.01). 8-week change in vasoreactivity was positively associated with aerobic exercise volume (adjusted R2 =0.19, p=0.02). Concussion resulted in changes in cerebrovascular regulatory mechanisms, which in turn explained the variability in resting cerebral blood flow velocity and acute symptom burden. Furthermore, these alterations persisted chronically despite symptom resolution, but was positively modified by aerobic exercise volume. These findings provide a mechanistic framework for further investigation into underlying cerebrovascular related symptomatology. ANN NEUROL 2021;90:43-51.

Are acute sitting-induced changes in inflammation and cerebrovascular function related to impaired mood and cognition?

PurposeSedentary behaviour is negatively associated with mood and cognition, yet how acute sitting contributes to these overall associations is unknown. Since sitting heightens inflammation and impairs cerebrovascular function, this study investigated the hypothesis that these sitting-induced changes are related to impaired mood and cognition.MethodsTwenty-five healthy desk workers (18 male, 28.3 ± 7.5 years, BMI: 24.2 ± 3.3 kg∙m−2) were recruited. During laboratory visit one, participants were familiarised with cognitive performance tests measuring executive function, attention and working memory. During laboratory visit two, participants completed 6 h of continuous, uninterrupted sitting. At baseline and after 6 h, serum markers of inflammation, middle cerebral artery blood flow velocity (MCAv), cerebrovascular carbon dioxide reactivity (CVR), dynamic cerebral autoregulation (CA), cognitive performance and mood (positive and negative affect, alert, contented and calm) were assessed. Data were analysed using paired-samples t tests and correlation analyses.ResultsFollowing sitting, C-reactive protein (∆-1.0 µg/ml) and tissue plasminogen activator (∆-360.4 pg/ml) decreased (p < 0.05), MCAv reduced (∆-2.9 cm∙s−1, p = 0.012) and normalised gain increased in the very low frequency range, indicating impaired CA (∆ + 0.22%·mmHg−1, p = 0.016). Positive affect (∆-4.6, p < 0.001), and alert (∆-10.6 p = 0.002) and contented (∆-7.4, p = 0.006) mood states also decreased following sitting. No significant changes in interleukin-6, tumour necrosis factor-alpha, von Willebrand factor, CVR or cognitive performance were observed (p > 0.05). The observed changes in inflammation and cerebrovascular function were not related to changes in mood (p > 0.05).ConclusionAlterations in inflammation or cerebrovascular function following six hours of prolonged, uninterrupted sitting are not related to the observed reductions in mood, indicating other mechanisms underlie the relationship between acute sitting and mood disturbances.

Opening of BKCa channels causes migraine attacks: a new downstream target for the treatment of migraine.

Migraine is a common and frequently disabling neurological disorder, but the initiating migraine mechanisms are still poorly understood. Potassium channel opening may cause migraine, and we therefore examined the migraine-inducing effect of MaxiPost, a large (big)-conductance calcium-activated potassium (BKCa) channel opener, on migraine induction and cephalic vasodilation in individuals with migraine. Twenty-six patients with migraine without aura were randomly allocated to receive an infusion of MaxiPost or placebo on 2 study days separated by at least 1 week. The primary endpoint was the difference in incidence of migraine attacks after MaxiPost compared with placebo. The secondary endpoints were the difference in incidence of headaches and the difference in area under the curve for headache intensity scores (0-12 hours), for middle cerebral artery blood flow velocity (VMCA) (0-2 hours), and for superficial temporal artery and radial artery diameter. Twenty-two patients completed the study. Twenty-one of 22 (95%) developed migraine attacks after MaxiPost compared with none after placebo (P < 0.0001); the difference of incidence is 95% (95% confidence interval 86%-100%). The incidence of headache over the 12-hour observation period was higher after MaxiPost day (n = 22) than after placebo (n = 7) (P < 0.0001). We found a significant increase of VMCA and superficial temporal and radial arteries' diameter. Because BKCa channel opening initiates migraine attacks, we suggest that BKCa channel blockers could be potential candidates for novel antimigraine drugs.

Effects of delayed cord clamping in intrauterine growth-restricted neonates: a randomized controlled trial.

The time of cord clamping in intrauterine growth-restricted (IUGR) neonates remains an area of uncertainty. This assessor-blinded randomized controlled trial compared the effects of delayed cord clamping (DCC) with early cord clamping (ECC) on the systemic blood flow (SBF) and cerebral hemodynamics in IUGR neonates of gestational age ≥28 weeks, not requiring resuscitation. Eligible newborns were randomized to DCC (cord clamping after 60 s; n=55) or ECC (cord clamping within 30 s; n=55) group immediately after delivery. The primary outcome variable was superior vena cava (SVC) blood flow at 24±2 h. The secondary outcome variables were right ventricular output (RVO), anterior cerebral artery (ACA) blood flow velocity (BFV), superior mesenteric artery (SMA)-BFV and venous hematocrit at 24±2 h, peak total serum bilirubin (TSB), incidences of polycythemia, intraventricular hemorrhage, respiratory distress, feeding intolerance, and necrotizing enterocolitis, outcome, duration of hospital stay, screening audiometry, and serum ferritin levels at the postnatal age of 3 months. Compared to ECC, DCC was associated with significantly higher SVC flow (101.22±21.02 and 81.27±19.12 mL/kg/min, in DCC and ECC groups, respectively; p<0.0001), and significantly increased RVO, SMA-BFV, venous hematocrit, and serum ferritin levels. Though peak TSB was significantly higher with DCC, duration of phototherapy was comparable. ACA-BFV, incidence of polycythemia, and other outcomes were comparable between the groups.Conclusions: DCC was a safe and beneficial intervention in IUGR infants with an improved SBF and SMA-BFV and an increased hematocrit and serum ferritin levels without higher incidences of polycythemia and requirement of phototherapy for significant hyperbilirubinemia.Trial registration: Clinical Trials Registry of India (CTRI/2019/05/018904) What is Known: • Delayed cord clamping (DCC) increases superior vena cava (SVC) blood flow in preterm neonates. • DCC increases hematocrit and serum ferritin in intrauterine growth-restricted (IUGR) neonates, but there may be an associated risk of polycythemia and neonatal hyperbilirubinemia. What is New: • DCC increases SVC blood flow, right ventricular output, superior mesenteric artery blood flow velocity, venous hematocrit, and serum ferritin in IUGR neonates. • Incidences of polycythemia and duration of phototherapy for significant neonatal hyperbilirubinemia do not increase with DCC.

Reliability of the transcranial Doppler ultrasound-derived mean flow index for assessing dynamic cerebral autoregulation in healthy volunteers

The transcranial Doppler ultrasound-derived mean flow index (Mxa) is widely used for assessing dynamic cerebral autoregulation (dCA) in different clinical populations. This study aimed at estimating the relative and absolute reliability of Mxa in healthy participants in the supine position and during head-up tilt (HUT). Fourteen healthy participants were examined on two separate occasions during which, mean middle cerebral artery blood flow velocity (MCAv), non-invasive blood pressure, and heart rate were continuously recorded in the supine position and during HUT. Mxa was calculated as the correlation coefficient between mean arterial blood pressure and MCAv using either 3-, 5-, or 10-second averages collected over a 300 second period. Intraclass correlation coefficient (ICC1.1) was calculated to assess relative reliability, while the standard error of measurement (SEM), and limits of agreement (LOA) were used to assess absolute reliability. Mxa-based 3-second averages yielded a similar relative and absolute reliability in both positions. When Mxa was calculated from 5-second averages, the most reliable values were obtained during HUT. The poorest reliability was achieved using 10-second averages, regardless of posture. The Mxa shows fair reliability with acceptable LOA in healthy volunteers when based on 3-second averages, both in the supine position and during HUT.

Cognitive Impairment During Combined Normobaric vs. Hypobaric and Normoxic vs. Hypoxic Acute Exposure.

INTRODUCTION: Exposure to hypoxia has a deleterious effect on cognitive function; however, the putative effect of hypobaria remains unclear. The present study aimed to evaluate cognitive performance in pilot trainees who were exposed to acute normobaric (NH) and hypobaric hypoxia (HH). Of relevance for military pilots, we also aimed to assess cognitive performance in hypobaric normoxia (HN).METHODS: A total of 16 healthy pilot trainees were exposed to 4 randomized conditions (i.e., normobaric normoxia, NN, altitude level of 440 m; HH at 5500 m; NH, altitude simulation of 5500 m; and HN). Subjects performed a cognitive assessment (KLT-R test). Cerebral oxygen delivery (cDO₂) was estimated based middle cerebral artery blood flow velocity (MCAv) and pulse oxygen saturation (Spo₂) monitored during cognitive assessment.RESULTS: Percentage of errors increased in NH (14.3 9.1%) and HH (12.9 6.4%) when compared to NN (6.5 4.1%) and HN (6.0 4.0%). Number of calculations accomplished was lower only in HH than in NN and HN. When compared to NN, cDO₂ decreased in NH and HH.DISCUSSION: Cognitive performance was decreased similarly in acute NH and HH. The cDO₂ reduction in NH and HH implies insufficient MCAv increase to ensure cognitive performance maintenance. The present study suggests negligible hypobaric influence on cognitive performance in hypoxia and normoxia.Aebi MR, Bourdillon N, Noser P, Millet GP, Bron D. Cognitive impairment during combined normobaric vs. hypobaric and normoxic vs. hypoxic acute exposure. Aerosp Med Hum Perform. 2020; 91(11):845851.

Effect of phenylephrine on cerebral oxygen saturation and cardiac output in adults when used to treat intraoperative hypotension: a systematic review.

The objective of this review was to examine the effect of phenylephrine on cerebral oxygen saturation, cardiac output, and middle cerebral artery blood flow velocity when used to treat intraoperative hypotension. While the etiology of postoperative cognitive dysfunction in adults following surgery is likely multifactorial, intraoperative cerebral hypoperfusion is a commonly proposed mechanism. Research evidence and expert opinion are emerging that suggest phenylephrine adversely affects cerebral oxygen saturation and may also adversely affect cerebral perfusion via a reduction in cardiac output or cerebral vascular vasoconstriction. The administration of phenylephrine to treat intraoperative hypotension is common anesthesia practice, despite a lack of evidence to show it improves cerebral perfusion. Therefore, a systematic review of the effect of phenylephrine on cerebral hemodynamics has significant implications for anesthesia practice and future research. Studies of adults 18 years and over undergoing elective, non-neurosurgical procedures involving anesthesia were included. In these studies, participants received phenylephrine to treat intraoperative hypotension. The effect of phenylephrine on cerebral oxygen saturation, cardiac output, or middle cerebral artery blood flow velocity was measured. Key information sources searched included MEDLINE (Ovid), Embase, CINAHL (EBSCO), and Google Scholar. The scope of the search was limited to English-language studies published from 1999 through 2017. The recommended JBI approach to critical appraisal, study selection, data extraction, and data synthesis were used. This systematic review found that phenylephrine consistently decreased cerebral oxygen saturation values despite simultaneously increasing mean arterial pressure to normal range. Results also found that ephedrine and dopamine were superior to phenylephrine in maintaining or increasing values. Phenylephrine was found to be similar to vasopressin in the extent to which both decreased cerebral oxygen saturation values. Results also showed that phenylephrine resulted in statistically significant declines in cardiac output, or failed to improve abnormally low preintervention values. The effect of phenylephrine on middle cerebral artery blood flow velocity was only measured in one study and showed that phenylephrine increased flow velocity by about 20%. Statistical pooling of the study results was not possible due to the gross variation in how the intervention was administered and how effect was measured. This review found that phenylephrine administration resulted in declines in cerebral oxygen saturation and cardiac output. However, the research studies were ineffective in informing phenylephrine's mechanism of action or its impact on postoperative cognitive function. PROSPERO (CRD42018100740).

Opening of BKCa channels alters cerebral hemodynamic and causes headache in healthy volunteers.

Preclinical data implicate large conductance calcium-activated potassium (BKCa) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BKCa channels would cause headache and vascular effects in healthy volunteers. In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18-39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BKCa channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0-12 hours) and for middle cerebral artery blood flow velocity (VMCA) (0-2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0-2 hours) between MaxiPost and placebo. Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo (p = 0.0005); the difference of incidence is 60% (95% confidence interval 36-84%). The area under the curve for headache intensity (AUC0-12 hours, p = 0.0003), for mean VMCA (AUC0-2 hours, p = 0.0001), for superficial temporal artery diameter (AUC0-2 hours, p = 0.003), and for radial artery diameter (AUC0-2 hours, p = 0.03) were significantly larger after MaxiPost compared to placebo. MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BKCa channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.

Age-related cerebrovascular carbon dioxide reactivity in children with ventricular septal defect younger than 3years.

Impaired cerebrovascular reactivity to carbon dioxide was proposed to contribute to neurological morbidity in children undergoing cardiac surgery. The objective of this study was to assess carbon dioxide reactivity and regional cerebral oxygen saturation in children younger than 3years. This study enrolled children younger than 3years undergoing ventricular septal defect repair. The cohort was divided into three age groups: younger than 6months, 6-12months, and 12-36months. Under steady-state anesthesia, carbon dioxide reactivity was calculated by measuring changes in middle cerebral artery blood flow velocity using transcranial Doppler sonography. Regional cerebral oxygen saturation changes were measured by near-infrared spectroscopy while endtidal carbon dioxide pressure was adjusted from 30 to 45mmHg. Carbon dioxide reactivity showed a statistically significant increasing relationship with age (younger than 6months group: 4.42%±2.73%, 6-12months group: 5.86%±1.91%, 12-36months group: 7.58%±1.49%; P<.001). Regional cerebral oxygen saturation showed a statistically significant increasing relationship with age (younger than 6months group: 65%±6%, 6-12months group: 68%±5%, 12-36months group: 70%±5%; P=.027). Regional cerebral oxygen saturation showed a statistically significant increasing relationship with endtidal carbon dioxide pressure in all children (P<.001). Abnormal carbon dioxide reactivity is prevalent in children younger than 3years and the degree varies according to age.

A new index of ultrasonography for estimating cerebral circulation in newborn infants.

To quantitatively estimate the influence of ductal shunt on cerebral blood flow and establish a new index of ultrasonography for estimating cerebral circulation without the influence of ductal shunt in newborn infants. We retrospectively examined the records of anterior cerebral artery (ACA) and left pulmonary artery (LPA) blood flow velocity curves recorded by pulsed Doppler ultrasonography within 6h after birth in 123 newborn infants without asphyxia (normal group) and in 31 newborn infants with asphyxia (asphyxia group). In the normal group, the resistance index (RI) of the ACA showed a positive correlation with the ratio of LPA diastolic-to-systolic flow velocities (LPAD/LPAS) (P < 0.001, r = 0.58), and the estimated RI (eRI) of the ACA was calculated using the following formula: Y = 0.47X + 0.67 (Y estimated RI; X LPAD/LPAS). In the asphyxia group, the RI of the ACA showed a weak correlation to base excess (BE) (P < 0.05, r = 0.46). The eRI of the ACA was calculated by the LPAD/PLAS in the asphyxia group, and the difference between the RI and eRI showed a better correlation to BE than RI (P < 0.001, r = 0.64). We determined the relation between cerebral blood flow RI and ductal shunt, and (RI - eRI) may be a new useful ultrasonographic index indicating cerebral circulation without the influence of ductal shunt in newborn infants.

Inspiratory muscle training improves cerebrovascular and postural control responses during orthostatic stress in older women.

We aimed to investigate the effect of inspiratory muscle training (IMT) on, hemodynamic, cerebrovascular and postural balance responses during orthostatic stress, in older women. Fourteen elderly women were assigned to perform IMT at 50% of maximal inspiratory pressure (MIP) (IMT group, n = 8) or placebo training at 5% MIP (Sham group, n = 6), in a counter-balanced order, using an inspiratory threshold device for 4weeks. During the protocol, MIP was tested weekly once. In a second visit, blood pressure, heart rate, stroke volume, cardiac output, middle cerebral artery blood flow velocity (MCAv), and ventilation parameters were recorded continuously at rest and during orthostatic stress testing, which was conducted on a force plate to measure center-of-pressure (COP) oscillations (postural balance) and the electromyographic activity of the right medial gastrocnemius and tibialis anterior. IMT increased MIP from second to 4thweek. The drops in MCAv, stroke volume, and cardiac output, as well as COP displacements during initial orthostasis decreased post-IMT. IMT improves the interplay of the respiratory pump, hemodynamic, cerebrovascular and postural balance responses during orthostatic stress in older women.

Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women.

Observed sex differences in the epidemiology of cardiovascular disease incidence and the efficacy of clinical intervention strategies, coupled with recent mandates from the National Institutes of Health (NIH), and its international counterparts to consider sex as a biological variable in all preclinical and clinical work (15), have led to increased enrollment of women in human physiology studies of vascular function with the goal of improving external validity and clinical applicability of the findings. However, standard practice in these studies is to test women during the early follicular phase (~days 1-5) of the menstrual cycle, during which estrogen and progesterone concentrations are lowest, and either exclude or limit testing of women who use hormonal contraceptives to the placebo phase. This approach seeks to control for, or limit, differences in circulating hormone concentrations between men and women and is based on the dogmatic theory that cyclic changes in estrogen and progesterone concentrations lead to greater variability in study outcomes and uninterpretable datasets. Contrary to this common approach, we propose that limiting testing of women to this single phase 1) decreases external validity of the findings, 2) obfuscates potential physiological differences contributable to differences in sex hormone concentrations between men and women, and 3) is, in many instances, contradicted by literature that demonstrates limited or no variability in vascular measurements across the menstrual cycle.