Effects of Hypovolemia on Cerebral Blood Velocity and Autoregulation During Upright Tilt: Implications for Post-Spaceflight Orthostasis

Orthostatic stability depends on maintenance of adequate cerebral blood flow. Orthostatic instability experienced by returning astronauts is associated with microgravity-induced hypovolemia, suggesting that hypovolemia may disrupt the ability of the cerebral vasculature to regulate blood flow. PURPOSE: To test the hypothesis that hypovolemia reduces cerebral blood velocity and impairs cerebral autoregulation (CA) during upright tilt. METHODS: Nine males (age 23 ± .5 yrs; height 172 ± 2 cm; weight 87 ± 3 kg; mean ± SE) were tilted head-up to 70° on two occasions separated by at least 5 days under euhydration (EUH) and dehydration (DEH) conditions. Dehydration was induced with 40 mg Furosemide and 8 h water restriction. Plasma volumes (PV) and blood volumes (BV) were estimated from venous hemoglobin and hematocrit. ECG, beat-by-beat finger arterial pressures, and cerebral blood velocity (CBV) were measured during a five min supine baseline, and during the first (T1) and last (T2) five min of upright tilt. Dynamic CA was assessed in the frequency domain with cross-spectral analysis of mean arterial pressure (MAP) and mean CBV within the frequency range of 0.07-0.2 Hz. RESULTS: Furosemide reduced PV by 10 ± 2 % and BV by 6 ± 2 % (P = .005 and P = .07). MAP decreased during tilt (P \u3c .007), but the reduction was similar between hydration conditions. CBV during DEH was lower during the entire 10-min tilt by about 7 cm/s (P \u3c .004) compared with EUH. Low frequency coherence was higher during DEH T1 compared with EUH T1 (.67 ± .04 vs .51 ± .04; P = .02), but coherence decreased as tilt continued, and was similar to EUH during T2 (P = 0.7). CONCLUSIONS: Increased coherence during the first 5 min of tilt suggests that reductions of CBV with hypovolemia might be explained by a reduced autoregulatory capacity. However, maintenance of lower CBV despite reduced coherence during the second 5 min of tilt suggests that disruptions of autoregulatory capacity with hypovolemia are transient. Our results provide evidence that hypovolemic astronauts may be at greatest risk for orthostatic intolerance immediately upon assumption of upright posture

Ovarian Hormones and Cerebral Hemodynamics During Upright Tilt

The cerebral vasculature is a specific target for ovarian hormones. Estrogens in particular activate endothelial factors that decrease vessel tone and increase blood flow. Changes in cerebral blood flow across the menstrual cycle could underlie the observation that women experience orthostatic instability more often than men, but the influence of ovarian hormone levels on cerebral hemodynamics in the upright posture is unclear. PURPOSE: To test the hypothesis that cerebral blood velocity and cerebral autoregulatory capacity change in parallel with ovarian hormone concentrations. METHODS: Nine healthy eumenorrheic women (mean age 24 ± 1 yr, height 166 ± 3 cm, weight 68 ± 2 kg; mean ± SE) were studied during the early and late follicular (EF and LF) and early and late luteal (EL and LL) phases of the menstrual cycle. We recorded the ECG, beat-by-beat arterial pressure, end-tidal CO2, and cerebral blood velocity from the middle cerebral artery (transcranial Doppler). Plasma ovarian hormone concentrations were assessed with high performance liquid chromatography. Subjects breathed in time to a metronome for 10 min (15 breaths/min) in the supine position, and were then tilted head-up to 70° for an additional 10 min of controlled breathing. Cerebral autoregulation was assessed in the frequency domain with cross-spectral analysis of mean arterial pressure (MAP) and mean CBV within the frequency range of 0.07-0.2 Hz. RESULTS: Upright tilt decreased CBV (supine 74 ± 1.7; tilt 65 ± 1.8 cm ∙ s-1; P=.005 pooled across phases) and end-tidal CO2 (P\u3c.001) but did not affect MAP. Coherence increased from .45 ± .02 to .67 ± .03 with tilt (P\u3c .001 pooled across phases) and was significantly higher during LF (.61 ± .03) compared with LL (.48 ± .03; P = .04). Lower coherence during LL compared with LF was associated with higher concentrations of progesterone (P \u3c .001). CONCLUSIONS: Upright tilt decreases CBV, and the magnitude of reduction is not related to ovarian hormone concentrations. Lower coherence during LL compared with LF suggests improved autoregulatory capacity mediated by higher concentrations of progesterone. These results have implications for orthostatic stability in women

No Influence of Ovarian Hormones on Cerebrovascular Responses to the Valsalva Maneuver

Cerebral blood flow is modulated in part by arterial perfusion pressure and autonomic neural activity. Valsalva straining drives increases in cerebral perfusion pressure that may challenge cerebrovascular regulatory mechanisms. These challenges may be even greater during the normal menstrual cycle due to vasoactive influences of ovarian hormones. PURPOSE: To test the hypothesis that cerebral vascular responses to Valsalva straining are enhanced with increased plasma concentrations of estrogen and progesterone. METHODS: Twelve healthy eumenorrheic females (mean age 25 ± 1 yr; height 165 ± 3 cm; weight 66 ± 2 kg; mean ± SE) were studied during the early and late follicular (EF and LF) and early and late luteal (EL and LL) phases of the menstrual cycle. We recorded the ECG, beat-by-beat arterial pressure (Finometer), end-tidal CO2, and cerebral blood velocity (CBV) from the middle cerebral artery (transcranial Doppler ultrasound). Plasma ovarian hormone concentrations were assessed with high performance liquid chromatography. Supine subjects strained to an expiratory pressure of 40 mmHg for 15 seconds, and we recorded magnitudes of changes in arterial pressure and CBV. RESULTS: Compared with EF, estrogen was significantly higher during LF (111 ± 20 pg/ml) and EL (113 ± 27 pg/ml) (both P\u3c0.05). During EL (12 ± 6 pg/ml) and LL (7 ± 2 pg/ml), progesterone was significantly higher when compared with EF(1 ± .3 pg/ml) and LF(1 ± .2 pg/ml) (both P\u3c0.05). The magnitude of arterial pressure overshoot at the release of strain (an indirect indicator of peripheral sympathetic neural activation during straining) was significantly higher during LF (54 ± 9 mmHg) compared to EL and EF (both phases = 35 ± 4 mmHg; P=0.003). Changes in CBV during Valsalva straining and during release from strain were statistically identical across menstrual phases (P\u3e0.05). CONCLUSIONS: Despite indirect evidence that sympathetic neural activity during the Valsalva maneuver is increased when plasma estrogen concentrations are high, responses of the cerebral vasculature to Valsalva straining are unaffected by cycling ovarian hormones

Thermographic Imaging to Detect Reductions of Central Volume Induced by Simulated Hemorrhage

Hemorrhage is the leading cause of death on the battlefield, but the magnitude of blood loss can be difficult to determine. Therefore, medics would benefit from advanced tools to detect blood loss. As skin temperature likely decreases with peripheral vasoconstriction, a portable thermographic imaging (TI) device capable of measuring skin temperature may assist in the detection hemorrhage. PURPOSE: To determine whether skin temperature measured with TI track stroke volume reductions during simulated hemorrhage. METHODS: We studied fifteen healthy volunteers (7 female and 8 male; 24±1 yrs; 171±3 cm; 69±3 kg). ECG, beat-by-beat finger arterial pressure (Finometer), respiratory rate (pneumobelt and TI at the nose), stroke volume (inert rebreathing) and continuous TI skin temperatures were measured during progressive lower body negative pressure (LBNP; -3mmHg/min) to -60 mmHg. Changes of stroke volume, respiratory rate, and skin temperature were determined with repeated measures ANOVA and linear regression. RESULTS: Respiratory rates were consistent during LBNP, and were not significantly different between the pneumobelt (13.5 ± .2) and TI (14.3 ± .3). Stroke volumes decreased directly with negative pressure applied at a rate of -1.3 ml/mmHg (R2=0.96) from a baseline value of 123 ± 8 ml to 41 ± 3 ml at -60 mmHg (P\u3c0.001). Skin temperature (assessed from the ear) did not change with LBNP (P=.17). Skin temperature was 97.06 Fo at baseline, 97.14 Fo at – 60 mmHg, and did not correlate with stroke volume (R2=0.13). CONCLUSIONS: Changes in temperature measured at the nose with TI are sensitive enough to detect inspiration and expiration, and therefore such measures have utility as a method to detect respiratory rate. Progressive LBNP of a magnitude sufficient to decrease stroke volume by 66% does not change skin temperature at the ear, and therefore TI imaging may not be a good candidate technology to pursue for hemorrhage detection

Arterial Pulse Wave Velocities are Unchanged Following 12 Weeks of Circuit Weight Training

Arterial stiffness is decreased after vigorous endurance training and increased after high-intensity resistance training. The effects of a combined program of moderate endurance and resistance exercise on arterial stiffness have not been determined. PURPOSE: To determine whether12 weeks of circuit weight training will decrease both central and peripheral arterial stiffness as estimated from pulse wave velocity (PWV). METHODS: Thirteen males and eight females (age 22 ± 2, height 162 ± 8 cm, weight 78 ± 20 kg) were assigned to control (n = 10) or exercise (n = 11) groups. Aerobic capacity and muscular strength were assessed before and at the end of the 12 week period. Arterial pressures and PWV (Doppler) were recorded every four weeks. Velocities from the carotid to femoral artery and from the femoral to dorsalis pedis artery were used as estimates of central and peripheral stiffness. RESULTS: Muscular strength increased by 26% (P = .001) and VO2 max increased by 17% (P = .06) following circuit training in the exercise group, but was unchanged for controls. Circuit weight training did not affect arterial pressures, (systolic = 117 ± 3, diastolic = 74 ± 3 mmHg; pooled across groups), or central and peripheral PWV (central PWV = 6.2 ± 0.6, peripheral PWV = 9.5 ± 0.7 m ∙ s-1; pooled across groups). CONCLUSIONS: In contrast to other reports of increases in arterial stiffness following high-intensity resistance training, increases in muscular strength following moderate-intensity exercise in the current study were not associated with increased arterial stiffness. Circuit training may be an appropriate exercise prescription to increase muscular strength for patients at risk for peripheral artery disease

Substitutions for Hydrophobic Amino Acids in the N-terminal Domains of IGFBP-3 and -5 Markedly Reduce IGF-I Binding and Alter Their Biologic Actions

Insulin-like growth factor-binding protein-3 and -5 (IGFBP-3 and -5) have been shown to bind insulin-like growth factor-I and -II (IGF-I and -II) with high affinity. Previous studies have proposed that the N-terminal region of IGFBP-5 contains a hydrophobic patch between residues 49 and 74 that is required for high affinity binding. These studies were undertaken to determine if mutagenesis of several of these residues resulted in a reduction of the affinity of IGFBP-3 and -5 for IGF-I. Substitutions for residues 68, 69, 70, 73, and 74 in IGFBP-5 (changing one charged residue, Lys(68), to a neutral one and the four hydrophobic residues to nonhydrophobic residues) resulted in an approximately 1000-fold reduction in the affinity of IGFBP-5 for IGF-I. Substitutions for homologous residues in IGFBP-3 also resulted in a >1000-fold reduction in affinity. The physiologic consequence of this reduction was that IGFBP-3 and -5 became very weak inhibitors of IGF-I-stimulated cell migration and DNA synthesis. Likewise, the ability of IGFBP-5 to inhibit IGF-I-stimulated receptor phosphorylation was attenuated. These changes did not appear to be because of alterations in protein folding induced by mutagenesis, because the IGFBP-5 mutant was fully susceptible to proteolytic cleavage by a specific IGFBP-5 protease. In summary, residues 68, 69, 70, 73, and 74 in IGFBP-5 appear to be critical for high affinity binding to IGF-I. Homologous residues in IGFBP-3 are also required, suggesting that they form a similar binding pocket and that for both proteins these residues form an important component of the core binding site. The availability of these mutants will make it possible to determine if there are direct, non-IGF-I-dependent effects of IGFBP-3 and -5 on cellular physiologic processes in cell types that secrete IGF-I

A waitlist-controlled trial of group cognitive behavioural therapy for depression and anxiety in Parkinson’s disease

Background: The aim of this study was to evaluate the efficacy of a group Cognitive Behavioural Therapy (CBT) treatment for depression and anxiety in Parkinson’s disease (PD). Methods: A waitlist-controlled trial design was used. Eighteen adults with PD and a comorbid DSM-IV-TR diagnosis of depression and/or anxiety were randomised to either Intervention (8-week group CBT treatment) or Waitlist (8-week clinical monitoring preceding treatment). The Depression, Anxiety, Stress Scale-21 (DASS-21) was the primary outcome. Assessments were completed at Time 1 (pretreatment), Time 2 (posttreatment/post-waitlist) and 1-month and 6-month follow-ups. Results: At Time 2, participants who received CBT reported greater reductions in depression (Mchange = -2.45) than Waitlist participants (Mchange = .29) and this effect was large, d = 1.12, p = .011. Large secondary effects on anxiety were also observed for CBT participants, d = .89, p = .025. All treatment gains were maintained and continued to improve during the follow-up period. At 6-month follow-up, significant and large effects were observed for both depression (d = 2.07) and anxiety (d = 2.26). Conclusions: Group CBT appears to be an efficacious treatment approach for depression and anxiety in PD however further controlled trials with larger numbers of participants are required

Update of Bisphosphonate Flight Experiment

Elevated bone resorption is a hallmark of human spaceflight and bed rest indicating that elevated remodeling is a major factor in the etiology of space flight bone loss. In a collaborative effort between the NASA and JAXA space agencies, we are testing whether an antiresorptive drug would provide additional benefit to in-flight exercise to ameliorate bone loss and hypercalciuria during long-duration spaceflight. Measurements of bone loss include DXA, QCT, pQCT, urinary and blood biomarkers. We have completed analysis of R+1year data from 7 crewmembers treated with alendronate during flight, as well as immediate post flight (R+<2wks) data from 6 of 10 concurrent controls without treatment. The treated astronauts used the Advanced Resistive Exercise Device (ARED) during their missions. The purpose of this report is twofold: 1) to report the results of inflight, post flight and one year post flight bone measures compared with available controls with and without the use of ARED; and 2) to discuss preliminary data on concurrent controls. The figure below compares the BMD changes in ISS crewmembers exercising with and without the current ARED protocol and the alendronate treated crewmembers also using the ARED. This shows that the use of ARED prevents about half the bone loss seen in early ISS crewmembers and that the addition of an antiresorptive provides additional benefit. Resorption markers and urinary Ca excretion are not impacted by exercise alone but are significantly reduced with antiresorptive treatment. Bone measures for treated subjects, 1 year after return from space remain at or near baseline. DXA data for the 6 concurrent controls using the ARED device are similar to DXA data shown in the figure below. QCT data for these six indicate that the integral data are consistent with the DXA data, i.e., comparing the two control groups suggests significant but incomplete improvement in maintaining BMD using the ARED protocol. Biochemical data of the concurrent control group await sample return and analysis. The preliminary conclusion is that an antiresorptive may be an effective adjunct to exercise during long-duration spaceflight

Global REACH 2018: Andean Highlanders, Chronic Mountain Sickness and the Integrative Regulation of Resting Blood Pressure

High‐altitude maladaptation syndrome chronic mountain sickness (CMS) is characterised by excessive erythrocytosis and frequently accompanied by accentuated arterial hypoxaemia. Whether altered autonomic cardiovascular regulation is apparent in CMS is unclear. Therefore, we assessed integrative control of blood pressure (BP) and determined basal sympathetic vasomotor outflow and arterial baroreflex function in 8 Andean natives with CMS ([Hb] 22.6 ± 0.9 g/dL) and 7 healthy highlanders ([Hb] 19.3 ± 0.8 g/dL) at their resident altitude (Cerro de Pasco, Peru; 4383 m). R‐R interval (RRI, electrocardiogram), beat‐by‐beat BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest and during pharmacologically‐induced changes in BP (modified Oxford test). Although [Hb] and blood viscosity (7.8 ± 0.7 vs 6.6 ± 0.7cP; d = 1.7, P = 0.01) were elevated in CMS compared to healthy highlanders, cardiac output, total peripheral resistance and mean BP were similar between groups. The vascular sympathetic baroreflex MSNA set‐point (i.e. MSNA burst incidence) and reflex gain (i.e. responsiveness) were also similar between groups (MSNA set‐point; d = 0.75, P = 0.16, gain; d = 0.2, P = 0.69). In contrast, in CMS the cardiovagal baroreflex operated around a longer RRI (960 ± 159 vs 817 ± 50msec; d = 1.4, P = 0.04) with a greater reflex gain (17.2 ± 6.8 vs 8.8 ± 2.6msec·mmHg−1; d = 1.8, P = 0.01) versus healthy highlanders. Basal sympathetic vasomotor activity was also lower compared to healthy highlanders (33 ± 11 vs 45 ± 13bursts·min−1; d = 1.0, P = 0.08). In conclusion, our findings indicate adaptive differences in basal sympathetic vasomotor activity and heart rate compensate for the haemodynamic consequences of excessive erythrocyte volume and contribute to integrative blood pressure regulation in Andean highlanders with mild CMS

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]