External to internal cranial perfusion shifts during simulated weightlessness: Results from a randomized cross-over trial.

The exact pathophysiology of the spaceflight-associated neuro-ocular syndrome (SANS) has so far not been completely elucidated. In this study we assessed the effect of acute head-down tilt position on the mean flow of the intra- and extracranial vessels. Our results suggest a shift from the external to the internal system that might play an important role in the pathomechanism of SANS.

Simulated Hypergravity Activates Hemostasis in Healthy Volunteers.

Background Hypergravity may promote human hemostasis thereby increasing thrombotic risk. Future touristic suborbital spaceflight will expose older individuals with chronic medical conditions, who are at much higher thromboembolic risk compared with professional astronauts, to hypergravity. Therefore, we tested the impact of hypergravity on hemostasis in healthy volunteers undergoing centrifugation. Methods and Results We studied 20 healthy seated men before and after 15 minutes under 3 Gz hypergravity on a long-arm centrifuge. We obtained blood samples for hemostasis testing before, immediately after, and 30 minutes after centrifugation. Tests included viscoelastic thromboelastometry, platelet impedance aggregometry, endothelial activation markers, blood rheology testing, microparticle analyses, and clotting factor analysis. Exposure to hypergravity reduced plasma volume by 12.5% (P=0.002) and increased the red blood cell aggregation index (P<0.05). With hypergravity, thrombelastographic clotting time of native blood shortened from 719±117 seconds to 628±89 seconds (P=0.038) and platetet reactivity increased (P=0.045). Hypergravity shortened partial thromboplastin time from 28 (26-29) seconds to 25 (24-28) seconds (P<0.001) and increased the activity of coagulation factors (eg, factor VIII 117 [93-134] versus 151 [133-175] %, P<0.001). Tissue factor concentration was 188±95 pg/mL before and 298±136 pg/mL after hypergravity exposure (P=0.023). Antithrombin (P=0.005), thrombin-antithrombin complex (P<0.001), plasmin-alpha2-antiplasmin complex (0.002), tissue-plasminogen activatior (P<0.001), and plasminogen activator inhibitor-1 (P=0.002) increased with centrifugation. Statistical adjustment for plasma volume attenuated changes in coagulation. Conclusions Hypergravity triggers low-level hemostasis activation through endothelial cell activation, increased viscoelasticity, and augmented platelet reactivity, albeit partly counteracted through endogenous coagulation inhibitors release. Hemoconcentration may contribute to the response.

Sleeping with Elevated Upper Body Does Not Attenuate Acute Mountain Sickness: Pragmatic Randomized Clinical Trial.

PURPOSE: Acute mountain sickness commonly occurs following ascent to high altitude and is aggravated following sleep. Cephalad fluid shifts have been implicated. We hypothesized that sleeping with the upper body elevated by 30º reduces the risk of acute mountain sickness. METHODS: In a pragmatic, randomized, observer-blinded field study at 4554 meters altitude, we investigated 134 adults aged 18-70 years with a Lake Louise score between 3 and 12 points on the evening of their arrival at the altitude. The individuals were exposed to sleeping on an inflatable cushion elevating the upper body by 30º or on a sham pillow in a horizontal position. The primary endpoint was the change in the Acute Mountain Sickness-Cerebral (AMS-C) score in the morning after sleeping at an altitude of 4554 meters compared with the evening before. Sleep efficiency was the secondary endpoint. RESULTS: Among 219 eligible mountaineers, 134 fulfilled the inclusion criteria and were randomized. The AMS-C score increased by 0.250 ± 0.575 in the control group and by 0.121 ± 0.679 in the intervention group (difference 0.105; 95% confidence interval, -0.098-0.308; P = .308). Oxygen saturation in the morning was 79% ± 6% in the intervention group and 78% ± 6% in the control group (P = .863). Sleep efficiency did not differ between groups (P = .115). CONCLUSIONS: Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms or hypoxemia at high altitude.

Effects of Prolonged Head-Down Bed Rest on Cardiac and Vascular Baroreceptor Modulation and Orthostatic Tolerance in Healthy Individuals.

Orthostatic intolerance commonly occurs after prolonged bed rest, thus increasing the risk of syncope and falls. Baroreflex-mediated adjustments of heart rate and sympathetic vasomotor activity (muscle sympathetic nerve activity - MSNA) are crucial for orthostatic tolerance. We hypothesized that prolonged bed rest deconditioning alters overall baroreceptor functioning, thereby reducing orthostatic tolerance in healthy volunteers. As part of the European Space Agency Medium-term Bed Rest protocol, 10 volunteers were studied before and after 21 days of -6° head down bed rest (HDBR). In both conditions, subjects underwent ECG, beat-by-beat blood pressure, respiratory activity, and MSNA recordings while supine (REST) and during a 15-min 80° head-up tilt (TILT) followed by a 3-min -10 mmHg stepwise increase of lower body negative pressure to pre-syncope. Cardiac baroreflex sensitivity (cBRS) was obtained in the time (sequence method) and frequency domain (spectrum and cross-spectrum analyses of RR interval and systolic arterial pressure - SAP, variability). Baroreceptor modulation of sympathetic discharge activity to the vessels (sBRS) was estimated by the slope of the regression line between the percentage of MSNA burst occurrence and diastolic arterial pressure. Orthostatic tolerance significantly decreased after HDBR (12 ± 0.6 min) compared to before (21 ± 0.6 min). While supine, heart rate, SAP, and cBRS were unchanged before and after HDBR, sBRS gain was slightly depressed after than before HDBR (sBRS: -6.0 ± 1.1 versus -2.9 ± 1.5 burst% × mmHg-1, respectively). During TILT, HR was higher after than before HDBR (116 ± 4 b/min versus 100 ± 4 b/min, respectively), SAP was unmodified in both conditions, and cBRS indexes were lower after HDBR (α index: 3.4 ± 0.7 ms/mmHg; BRSSEQ 4.0 ± 1.0) than before (α index: 6.4 ± 1.0 ms/mmHg; BRSSEQ 6.8 ± 1.2). sBRS gain was significantly more depressed after HDBR than before (sBRS: -2.3 ± 0.7 versus -4.4 ± 0.4 burst% × mmHg-1, respectively). Our findings suggest that baroreflex-mediated adjustments in heart rate and MSNA are impaired after prolonged bed rest. The mechanism likely contributes to the decrease in orthostatic tolerance.

Cardiac and Vascular Sympathetic Baroreflex Control during Orthostatic Pre-Syncope.

We hypothesized that sympathetic baroreflex mediated uncoupling between neural sympathetic discharge pattern and arterial pressure (AP) fluctuations at 0.1 Hz during baroreceptor unloading might promote orthostatic pre-syncope. Ten volunteers (32 ± 6 years) underwent electrocardiogram, beat-to-beat AP, respiratory activity and muscle sympathetic nerve activity (MSNA) recordings while supine (REST) and during 80° head-up tilt (HUT) followed by -10 mmHg stepwise increase of lower body negative pressure until pre-syncope. Cardiac and sympathetic baroreflex sensitivity were quantified. Spectrum analysis of systolic and diastolic AP (SAP and DAP) and calibrated MSNA (cMSNA) variability assessed the low frequency fluctuations (LF, ~0.1 Hz) of SAP, DAP and cMSNA variability. The squared coherence function (K2) quantified the coupling between cMSNA and DAP in the LF band. Analyses were performed while supine, during asymptomatic HUT (T1) and at pre-syncope onset (T2). During T2 we found that: (1) sympathetic baroreceptor modulation was virtually abolished compared to T1; (2) a progressive decrease in AP was accompanied by a persistent but chaotic sympathetic firing; (3) coupling between cMSNA and AP series at 0.1 Hz was reduced compared to T1. A negligible sympathetic baroreceptor modulation during pre-syncope might disrupt sympathetic discharge pattern impairing the capability of vessels to constrict and promote pre-syncope.

Sleep Is Compromised in -12° Head Down Tilt Position.

Recent studies are elucidating the interrelation between sleep, cranial perfusion, and cerebrospinal fluid (CSF) circulation. Head down tilt (HDT) as a simulation of microgravity reduces cranial perfusion. Therefore, our aim was to assess whether HDT is affecting sleep (clinicaltrials.gov; identifier NCT02976168). 11 male subjects were recruited for a cross-over designed study. Each subject participated in two campaigns each comprising 3 days and 2 nights. Intervention started on the second campaign day and consisted of maintenance of horizontal position or -12° HDT for 21 h. Ultrasound measurements were performed before, at the beginning and the end of intervention. Polysomnographic measurements were assessed in the second night which was either spent in horizontal posture or at -12° HDT. Endpoints were sleep efficiency, sleep onset latency, number of sleep state changes and arousals, percentages of N3, REM, light sleep stages and subjective sleep parameters. N3 and REM sleep reduced by 25.6 and 19.1 min, respectively (P = 0.002, g = -0.898; P = 0.035, g = -0.634) during -12° HDT. Light sleep (N1/2) increased by 33.0 min at -12° HDT (P = 0.002, g = 1.078). On a scale from 1 to 9 subjective sleep quality deteriorated by 1.3 points during -12° HDT (P = 0.047, g = -0.968). Ultrasonic measurement of the venous system showed a significant increase of the minimum (P = 0.009, P < 0.001) and maximum (P = 0.004, P = 0.002) cross-sectional area of the internal jugular vein at -12° HDT. The minimum cross-sectional area of the external jugular vein differed significantly between conditions over time (P = 0.001) whereas frontal skin tissue thickness was not significantly different between conditions (P = 0.077, P = 0.811). Data suggests venous congestion at -12° HDT. Since subjects felt comfortable with lying in -12° HDT under our experimental conditions, this posture only moderately deteriorates sleep. Obviously, the human body can almost compensate the several fold effects of gravity in HDT posture like an affected CSF circulation, airway obstruction, unusual patterns of propioception and effects on the cardiovascular system.

Modeling human orthostatic responses on the Moon and on Mars.

PURPOSE: Since manned missions to the Moon and Mars are planned, we conducted active standing tests with lunar, Martian, terrestrial, and 1.8 loads of inertial resistance (+Gz) modeled through defined parabolic flight maneuvers. We hypothesized that the cardiovascular response to active standing is proportional to the +Gz load. METHODS: During partial-+Gz parabolic flights, 14 healthy test subjects performed active stand-up maneuvers under 1 +Gz, lunar (0.16 +Gz), Martian (0.38 +Gz), and hyper inertial resistance (1.8 +Gz) while heart rate and finger blood pressure were continuously monitored. We quantified amplitudes and timing of orthostatic response immediately following standing up. RESULTS: The maximum early heart rate increase was 21 (SD ± 10) bpm with lunar, 23 (± 11) bpm with Martian, 34 (± 17) bpm with terrestrial +Gz, and 40 (± 11) bpm hyper +Gz. The time to maximum heart rate increased gradually with increasing loads of inertial resistance. The transient blood pressure reduction was most pronounced with hyper +Gz but did not differ significantly between lunar and Martian +Gz. The mean arterial pressure nadir was reached significantly later with Martian and lunar compared to 1 +Gz. Paradoxically, the time for blood pressure to recover was shortest with terrestrial +Gz. CONCLUSION: While load of inertial resistance directly affects the magnitude of the transient blood pressure reduction and heart rate response to active standing, blood pressure stabilization is most rapidly attained during terrestrial +Gz. The observation might suggest that the human cardiovascular system is tuned to cope with orthostatic stress on earth.

Partial weight bearing of the tibia.

INTRODUCTION: Partial weight bearing is part of treatment schemes in orthopedic surgery and traumatology. The aim of the present study was to explore to what degree ground reaction forces during partial weight bearing of the lower leg are related to given instructions and to tibia deformation. MATERIALS AND METHODS: Tibia deformation (torsion, medio-lateral and anterio-posterior bending) was measured for rear foot and forefoot loading, 10kg, 20kg and half body weight instructions compared to full loading in five healthy male subjects using the "Optical Segment Tracking" approach, a motion-capturing based method that uses monocortically fixed bone screws. RESULTS: 1. Ground reaction force was a good indicator of tibia deformation. 2. Participants significantly under-loaded during half-body weight instructions (P<0.001) while they overloaded when loading the forefoot only. 3. Partial-loading instructions led to a highly significant and systematic reduction in peak ground reaction force (GRFpk) in all three types of tibia deformation with substantial variation between measurements. 4. Forefoot usage was associated with significant, albeit moderate increases in GRFpk (P=0.0031), in AP-bending (P=0.0027) and in torsion (P<0.001), compared to rear foot loading. DISCUSSION: These findings result in the following clinical "lessons learned": 1. GRF is a good reflection of loading-induced deformation of the tibia. 2. GRFs are hard to control by subjects/patients. 3. The expectation that forefoot-loading results in larger tibia deformation could not be confirmed in our study. 4. When aiming at a reduction in tibia deformation, rear-foot loading is more preferable than forefoot loading.

Influence of bed rest on plasma galanin and adrenomedullin at presyncope.

BACKGROUND: The role of hormones in reduced orthostatic tolerance following long-term immobilization remains uncertain. We have previously shown that plasma concentrations of adrenomedullin and galanin, two peptides with vasodepressor properties, rise significantly during orthostatic challenge. We tested the hypothesis that bedrest immobilization increases the rise in adrenomedullin and galanin during orthostatic challenge leading to presyncope. MATERIALS AND METHODS: We measured baseline (supine), presyncope and recovery (10 min postpresyncope, supine) levels of adrenomedullin and galanin in 8 healthy men, before and after 21 days of -6° head-down bed rest (HDBR). Presyncope was elicited using a combined head-up tilt and graded lower body negative pressure protocol. Orthostatic tolerance was defined as the time taken from the commencement of head-up tilt to the development of presyncope. RESULTS: Orthostatic tolerance time after HDBR reduced by 8·36 ± 5·39 min (P = 0·0032). HDBR increased plasma adrenomedullin concentration to orthostatic challenge (P = 0·0367). Compared to pre-HDBR, a significant rise in post-HDBR presyncopal (P < 0·001) and recovery adrenomedullin concentration (P < 0·01) was demonstrated. In contrast, we observed no change in pre- and post-HDBR galanin levels to orthostatic challenge. CONCLUSIONS: Bedrest immobilization appears to affect adrenomedullin levels in that greater increases in adrenomedullin occur at presyncope following bedrest immobilization. Due to its peripheral vasculature hypotensive effect, the greater levels of adrenomedullin at presyncope following bedrest immobilization may have contributed to the reduced orthostatic capacity postbedrest.

Cardiovascular parameters and neural sympathetic discharge variability before orthostatic syncope: role of sympathetic baroreflex control to the vessels.

We tested the hypothesis that altered sympathetic baroreceptor control to the vessels (svBRS) and disrupted coupling between blood pressure (BP) fluctuations and muscle sympathetic activity (MSNA) discharge pattern in the low frequency band (LF, around 0.1 Hz) precede vasovagal syncope. Seven healthy males underwent ECG, BP, respiratory, and MSNA recordings at baseline (REST) and during a 15 min 80° head-up tilt, followed by a -10 mmHg step wise increase of lower body negative pressure up to presyncope. Spectral and coherence analyses of systolic arterial pressure (SAP) and MSNA variability provided the indexes of vascular sympathetic modulation, LFSAP, and of the linear coupling between MSNA and SAP in the low frequency band (around 0.1 Hz), K(2)MSNA-SAP(LF). svBRS was assessed as the slope of the regression line between MSNA and diastolic arterial pressure (DAP). Data were analyzed at REST, during asymptomatic and presyncope periods of tilt. svBRS declined during presyncope period compared to REST and asymptomatic tilt. The presyncope period was characterized by a decrease of RR interval, LFMSNA, LFSAP, and K(2)MSNA-SAP(LF) values compared to the asymptomatic one, whereas MSNA burst rate was unchanged. The reduction of svBRS producing an altered coupling between MSNA and SAP variability at 0.1 Hz, may provoke circulatory changes leading to presyncope.

Pulse contour methods to estimate cardiovascular indices in micro- and hypergravity.

BACKGROUND: The importance of noninvasive health monitoring in space increased as a result of the long-duration missions on the International Space Station (ISS). In order to monitor changes in cardiovascular indices such as cardiac output (CO) and total peripheral resistance (TPR), many methods have been developed using signal processing and mathematical modeling techniques. However, their performance in various gravitational conditions has not been known. METHODS: The present study compared 10 methods to estimate CO and TPR by processing peripheral arterial blood pressure signals recorded from 8 subjects in multiple gravity levels (1 G, 0 G, and 1.8 G) during parabolic flights. For reference data sets, CO and TPR were simultaneously obtained by an inert gas rebreathing technique. Root normalized mean square errors and Bland-Altman plots were used to evaluate the estimation methods. RESULTS: The corrected impedance method achieved the lowest estimation errors (20.0% CO error and 23.5% TPR error) over the three gravity levels. In microgravity, mean arterial pressure was also demonstrated to be an indicator of CO (24.5% error). DISCUSSION: The corrected impedance method achieved low estimation errors for a wide range of the gravity levels. Gravity-dependent performance was observed in the mean arterial pressure method that achieved low errors in the short-term 0 G.

The financial burden of mandibular trauma.

PURPOSE: Patients with mandibular trauma in the greater Seattle region are frequently transferred to Harborview Medical Center (HMC) despite trained providers in the surrounding communities. HMC receives poor reimbursement for these services, creating a disproportionate financial burden on the hospital. In this study we aim to identify the variables associated with increased cost of care, measure the relative financial impact of these variables, and quantify the revenue loss incurred from the treatment of isolated mandibular fractures. MATERIALS AND METHODS: A retrospective chart review was conducted of patients treated at HMC for isolated mandibular fractures from July 1999 through June 2010, using International Classification of Diseases, Ninth Revision and Current Procedural Terminology coding. Data collected included demographics, injury, hospital course, treatment, outcomes, and billing. RESULTS: The study included 1,554 patients. Total billing was $22.1 million. Of this, $6.9 million was recovered. We found that there are multiple variables associated with the increased cost of treating mandibular fractures; 4 variables--length of hospital stay, treatment modality, service providing treatment, and method of arrival--accounted for 49.1% of the total variance in the amount billed. In addition, we found that the unsponsored portion of our patient population grew from 6.7% to 51.4% during the study period. CONCLUSIONS: Our results led to specific cost-efficiency recommendations: 1) perform closed reduction whenever possible; 2) encourage performing procedures with patients under local anesthesia (closed reductions and arch bar removals); 3) provide improved and shared training among the services treating craniofacial trauma; 4) encourage arrival by privately owned vehicle; 5) provide outpatient treatment, when applicable; 6) offer provider incentives to take trauma call; and 7) offer hospital incentives to treat patients and not transfer them.

Upright cardiac output measurements in the transition to weightlessness during parabolic flights.

OBJECTIVE: Aims of this study were: 1) to determine cardiac output by inert gas rebreathing (CO(reb)) during transition into 0 Gz in the standing position; and 2) to compare impedance cardiography (ICG) and pulse contour method (PCM) with CO(reb) as a reference method. METHODS: We measured baseline CO(reb) and heart rate (HR) on the ground, and CO(reb), CO(pcm), CO(icg), and HR in standing and supine positions in the transition to weightlessness in six subjects. We conducted repeated measures ANOVA, Bland and Altman analysis, and analysis of percentage error of each data set. RESULTS: CO(reb) rose from 5.03 +/- 0.7 upright ground control to 11.45 +/- 3.6 L x min(-1) in 0 Gz. HR and stroke volume (SV) rose from 83 +/- 14 to 113 +/- 19 bpm and from 61 +/- 6 to 99 +/- 18 ml, respectively. Mean CO(reb), CO(pcm), and CO(icg) across all conditions were 10.45 +/- 3.04, 7.42 +/- 1.71, and 6.57 +/- 2.46 L x min(-1), respectively. Overall Bland and Altman analysis showed poor agreement for CO(pcm) and CO(icg) compared to CO(reb). DISCUSSION: Large bias for both comparisons indicated that both PCM and ICG underestimate the true CO value. Paired CO values of individual subjects showed a better correlation between methods and a broad bias range, indicating a preponderant role for large between-subjects variability. Repeated CO(reb) determinations in 1 Cz (i.e., when the cardiovascular system is in a steady state) should be used for calibration of the PCM and of ICG data. PCM and ICG can then be used to track CO dynamics during rapid changes of acceleration profiles.

Effect of change in intrathoracic pressure on thermoregulatory responses during -6 degree head-down bed rest.

We investigated the effect of change in intrathoracic pressure by total body negative pressure (TBNP) or positive pressure (TBPP) on thermoregulatory responses during -6 degree head-down bed rest (HDBR). Eight healthy male subjects participated to three of the following interventions in a randomised sequence: 1) HDBR, 2) HDBR with TBNP of -15 cmH2O, 3) HDBR with TBPP of +15 cmH2O. A rapid decrease of cutaneous blood flow occurred after the start of TBNP. In contrast, cutaneous blood flow increased slightly at TBPP. Sweat rate decreased immediately after the start of TBNP. Immediately after the TBPP was started, tympanic temperature greatly decreased. It is concluded that combination of HDBR and intrathoracic pressure changes thermoregulatory responses through the cardiopulmonary baroreceptor to reduce the wall stretch.