Non-invasive biomarkers for detecting progression toward hypovolemic cardiovascular instability in a lower body negative pressure model.

Occult hemorrhages after trauma can be present insidiously, and if not detected early enough can result in patient death. This study evaluated a hemorrhage model on 18 human subjects, comparing the performance of traditional vital signs to multiple off-the-shelf non-invasive biomarkers. A validated lower body negative pressure (LBNP) model was used to induce progression towards hypovolemic cardiovascular instability. Traditional vital signs included mean arterial pressure (MAP), electrocardiography (ECG), plethysmography (Pleth), and the test systems utilized electrical impedance via commercial electrical impedance tomography (EIT) and multifrequency electrical impedance spectroscopy (EIS) devices. Absolute and relative metrics were used to evaluate the performance in addition to machine learning-based modeling. Relative EIT-based metrics measured on the thorax outperformed vital sign metrics (MAP, ECG, and Pleth) achieving an area-under-the-curve (AUC) of 0.99 (CI 0.95-1.00, 100% sensitivity, 87.5% specificity) at the smallest LBNP change (0-15 mmHg). The best vital sign metric (MAP) at this LBNP change yielded an AUC of 0.6 (CI 0.38-0.79, 100% sensitivity, 25% specificity). Out-of-sample predictive performance from machine learning models were strong, especially when combining signals from multiple technologies simultaneously. EIT, alone or in machine learning-based combination, appears promising as a technology for early detection of progression toward hemodynamic instability.

Effect of lower body negative pressure on cardiac and cerebral function in postural orthostatic tachycardia syndrome: A pilot MRI assessment.

Postural orthostatic tachycardia syndrome (POTS) is characterized by an excessive heart rate (HR) response upon standing and symptoms indicative of inadequate cerebral perfusion. We tested the hypothesis that during lower body negative pressure (LBNP), individuals with POTS would have larger decreases in cardiac and cerebrovascular function measured using magnetic resonance (MR) imaging. Eleven patients with POTS and 10 healthy controls were studied at rest and during 20 min of -25 mmHg LBNP. Biventricular volumes, stroke volume (SV), cardiac output (Qc), and HR were determined by cardiac MR. Cerebral oxygen uptake (VO2 ) in the superior sagittal sinus was calculated from cerebral blood flow (CBF; MR phase contrast), venous O2 saturation (SvO2 ; susceptometry-based oximetry), and arterial O2 saturation (pulse oximeter). Regional cerebral perfusion was determined using arterial spin labelling. HR increased in response to LBNP (p < 0.001) with no group differences (HC: +9 ± 8 bpm; POTS: +13 ± 11 bpm; p = 0.35). Biventricular volumes, SV, and Qc decreased during LBNP (p < 0.001). CBF and SvO2 decreased with LBNP (p = 0.01 and 0.03, respectively) but not cerebral VO2 (effect of LBNP: p = 0.28; HC: -0.2 ± 3.7 mL/min; POTS: +1.1 ± 2.0 mL/min; p = 0.33 between groups). Regional cerebral perfusion decreased during LBNP (p < 0.001) but was not different between groups. These data suggest patients with POTS have preserved cardiac and cerebrovascular function.

Validity and reliability of deriving the autoregulatory plateau through projection pursuit regression from driven methods.

To compare the construct validity and between-day reliability of projection pursuit regression (PPR) from oscillatory lower body negative pressure (OLBNP) and squat-stand maneuvers (SSMs). Nineteen participants completed 5 min of OLBNP and SSMs at driven frequencies of 0.05 and 0.10 Hz across two visits. Autoregulatory plateaus were derived at both point-estimates and across the cardiac cycle. Between-day reliability was assessed with intraclass correlation coefficients (ICCs), Bland-Altman plots with 95% limits of agreement (LOA), coefficient of variation (CoV), and smallest real differences. Construct validity between OLBNP-SSMs were quantified with Bland-Altman plots and Cohen's d. The expected autoregulatory curve with positive rising and negative falling slopes were present in only ~23% of the data. The between-day reliability for the ICCs were poor-to-good with the CoV estimates ranging from ~50% to 70%. The 95% LOA were very wide with an average spread of ~450% for OLBNP and ~350% for SSMs. Plateaus were larger from SSMs compared to OLBNPs (moderate-to-large effect sizes). The cerebral pressure-flow relationship is a complex regulatory process, and the "black-box" nature of this system can make it challenging to quantify. The current data reveals PPR analysis does not always elicit a clear-cut central plateau with distinctive rising/falling slopes.

Lower body negative pressure identifies altered central vein characteristics without accompanying changes to baroreflexes in astronauts within hours of landing.

Cardiovascular deconditioning and altered baroreflexes predispose returning astronauts to Orthostatic Intolerance. We assessed 7 astronauts (1 female) before and following long-duration spaceflight (146 ± 43 days) with minimal upright posture prior to testing. We applied lower body negative pressure (LBNP) of up to - 30 mmHg to supine astronauts instrumented for continual synchronous measurements of cardiovascular variables, and intermittent imaging the Portal Vein (PV) and Inferior Vena Cava (IVC). During supine rest without LBNP, postflight elevations to total peripheral resistance (TPR; 15.8 ± 4.6 vs. 20.8 ± 7.1 mmHg min/l, p < 0.05) and reductions in stroke volume (SV; 104.4 ± 16.7 vs. 87.4 ± 11.5 ml, p < 0.05) were unaccompanied by changes to heart rate (HR) or estimated central venous pressure (CVP). Small increases to systolic blood pressure (SBP) and diastolic blood pressure (DBP) were not statistically significant. Autoregressive moving average modelling (ARMA) during LBNP did not identify differences to either arterial (DBP → TPR and SBP → HR) or cardiopulmonary (CVP → TPR) baroreflexes consistent with intact cardiovascular control. On the other hand, IVC and PV diameter-CVP relationships during LBNP revealed smaller diameter for a given CVP postflight consistent with altered postflight venous wall dynamics.

COMPARISON BETWEEN ACTIVE ABDOMINAL COMPRESSION-DECOMPRESSION CARDIOPULMONARY RESUSCITATION AND STANDARD CARDIOPULMONARY RESUSCITATION IN ASPHYCTIC CARDIAC ARREST RATS WITH MULTIPLE RIB FRACTURES.

ABSTRACT: Background: Active abdominal compression-decompression cardiopulmonary resuscitation (AACD-CPR) is potentially more effective for cardiac arrest (CA) with multiple rib fractures. However, its effect on survival rates and neurological outcomes remains unknown. This study aimed to assess if AACD-CPR improves survival rates and neurological outcomes in a rat model of asphyctic CA with multiple rib fractures. Methods: Adult male Sprague-Dawley rats were randomized into three groups-AACD group (n = 15), standard cardiopulmonary resuscitation (STD-CPR) group (n = 15), and sham group (n = 10)-after bilateral rib fractures were surgically created and endotracheal intubation was performed. AACD-CPR and STD-CPR groups underwent 8 min of asphyxia followed by different CPR techniques. The sham group had venous catheterization only. Physiological variables and arterial blood gases were recorded at baseline and during a 4-h monitoring period. Neurological deficit scores (NDSs) and cumulative survival rates were assessed at 24, 48, and 72 h. NDS, serum biomarkers, and hippocampal neuron analysis were used to evaluate neurological outcomes. Results: No statistical differences were observed in the return of spontaneous circulation (ROSC), 24-, 48-, and 72-h survival rates between the AACD-CPR and STD-CPR groups. AACD-CPR rats had lower serum levels of neuron-specific enolase and S100B at 72 h post-ROSC, and higher NDS at 72 h post-ROSC compared with STD-CPR animals. Cellular morphology analysis, hematoxylin and eosin staining, and TUNEL/DAPI assays showed more viable neurons and fewer apoptotic neurons in the AACD-CPR group than in the STD-CPR group. Conclusions: AACD-CPR can achieve similar survival rates and better neurological outcome after asphyxial CA in rats with multiple rib fractures when compared with STD-CPR.

Acute fasting reduces tolerance to progressive central hypovolemia in humans.

Potential health benefits of an acute fast include reductions in blood pressure and increases in vagal cardiac control. These purported health benefits could put fasted humans at risk for cardiovascular collapse when exposed to central hypovolemia. The purpose of this study was to test the hypothesis that an acute 24-h fast (vs. 3-h postprandial) would reduce tolerance to central hypovolemia induced via lower body negative pressure (LBNP). We measured blood ketones (ß-OHB) to confirm a successful fast (n = 18). We recorded the electrocardiogram (ECG), beat-to-beat arterial pressure, muscle sympathetic nerve activity (MSNA; n = 7), middle cerebral artery blood velocity (MCAv), and forearm blood flow. Following a 5-min baseline, LBNP was increased by 15 mmHg until -60 mmHg and then increased by 10 mmHg in a stepwise manner until onset of presyncope. Each LBNP stage lasted 5-min. Data are expressed as means ± SE ß-OHB increased (ß-OHB; 0.12 ± 0.04 fed vs. 0.47 ± 0.11, P < 0.01 mmol/L fast). Tolerance to central hypovolemia was decreased by ∼10% in the fasted condition measured via total duration of negative pressure (1,370 [Formula: see text] 89 fed vs. 1,229 ± 94 s fast, P = 0.04), and was negatively associated with fasting blood ketones (R = -0.542, P = 0.02). During LBNP, heart rate and MSNA increased similarly, but in the fasted condition forearm vascular resistance was significantly reduced. Our results suggest that acute fasting reduces tolerance to central hypovolemia by blunting increases in peripheral resistance, indicating that prolonged fasting may hinder an individual's ability to compensate to a loss of blood volume.NEW & NOTEWORTHY An acute 24 h fasting reduces tolerance to central hypovolemia, and tolerance is negatively associated with blood ketone levels. Compared with a fed condition (3-h postprandial), fasted participants exhibited blunted peripheral vasoconstriction and greater reductions in stroke volume during stepwise lower body negative pressure. These findings suggest that a prolonged fast may lead to quicker decompensation during central hypovolemia.

Facial fanning reduces heart rate but not tolerance to a simulated hemorrhagic challenge following exercise heat stress in young healthy humans.

We investigated whether reducing face skin temperature alters arterial blood pressure control and lower body negative pressure (LBNP) tolerance after exercise heat stress. Eight subjects (1 female; age, 27 ± 9 yr) exercised at ∼63% V̇o2max until core temperature had increased ∼1.5°C before undergoing LBNP to presyncope either with fanning to return face skin temperature to baseline (Δ-5°C, Fan trial) or without (No Fan trial). LBNP tolerance was quantified as cumulative stress index (CSI; mmHg·min). Before LBNP, whole body and face skin temperatures were elevated from baseline in both trials (38.0 ± 0.5°C and 36.3 ± 0.5°C, respectively, both P < 0.001). During LBNP, face skin temperature decreased in the Fan trial (30.9 ± 1.0°C) but was unchanged in the No Fan trial (36.1 ± 0.6°C, between trials P < 0.001). Mean arterial pressure was not different between trials (P = 0.237) and was similarly reduced at presyncope in both trials (from 82 ± 7 to 67 ± 8 mmHg, P < 0.001). During LBNP, heart rate was attenuated in the Fan trial at Mid LBNP (146 ± 16 vs. 158 ± 12 beats/min, P = 0.036) and at peak heart rate (158 ± 15 vs. 170 ± 15 beats/min; P < 0.001). LBNP tolerance was not different between trials (321 ± 248 vs. 328 ± 115 mmHg·min, P = 0.851). In exercise heat-stressed individuals, lowering face skin temperature to normothermic values suppressed heart rate thereby altering cardiovascular control during a simulated hemorrhagic challenge without reducing tolerance.

The effect of oscillatory hemodynamics on the cardiovascular responses to simulated hemorrhage during isocapnia.

During cerebral hypoperfusion induced by lower body negative pressure (LBNP), cerebral tissue oxygenation is protected with oscillatory arterial pressure and cerebral blood flow at low frequencies (0.1 Hz and 0.05 Hz), despite no protection of cerebral blood flow or oxygen delivery. However, hypocapnia induced by LBNP contributes to cerebral blood flow reductions, and may mask potential protective effects of hemodynamic oscillations on cerebral blood flow. We hypothesized that under isocapnic conditions, forced oscillations of arterial pressure and blood flow at 0.1 Hz and 0.05 Hz would attenuate reductions in extra- and intracranial blood flow during simulated hemorrhage using LBNP. Eleven human participants underwent three LBNP profiles: a nonoscillatory condition (0 Hz) and two oscillatory conditions (0.1 Hz and 0.05 Hz). End-tidal (et) CO2 and etO2 were clamped at baseline values using dynamic end-tidal forcing. Cerebral tissue oxygenation (ScO2), internal carotid artery (ICA) blood flow, and middle cerebral artery velocity (MCAv) were measured. With clamped etCO2, neither ICA blood flow (ANOVA P = 0.93) nor MCAv (ANOVA P = 0.36) decreased with LBNP, and these responses did not differ between the three profiles (ICA blood flow: 0 Hz: 2.2 ± 5.4%, 0.1 Hz: -0.4 ± 6.6%, 0.05 Hz: 0.2 ± 4.8%; P = 0.56; MCAv: 0 Hz: -2.3 ± 7.8%, 0.1 Hz: -1.3 ± 6.1%, 0.05 Hz: -3.1 ± 5.0%; P = 0.87). Similarly, ScO2 did not decrease with LBNP (ANOVA P = 0.21) nor differ between the three profiles (0 Hz: -2.6 ± 3.3%, 0.1 Hz: -1.6 ± 1.5%, 0.05 Hz: -0.2 ± 2.8%; P = 0.13). Contrary to our hypothesis, cerebral blood flow and tissue oxygenation were protected during LBNP with isocapnia, regardless of whether hemodynamic oscillations were induced.NEW & NOTEWORTHY We examined the role of forcing oscillations in arterial pressure and blood flow at 0.1 Hz and 0.05 Hz on extra- and intracranial blood flow and cerebral tissue oxygenation during simulated hemorrhage (using lower body negative pressure, LBNP) under isocapnic conditions. Contrary to our hypothesis, both cerebral blood flow and cerebral tissue oxygenation were completely protected during simulated hemorrhage with isocapnia, regardless of whether oscillations in arterial pressure and cerebral blood flow were induced. These findings highlight the protective effect of preventing hypocapnia on cerebral blood flow under simulated hemorrhage conditions.

Influence of sex on the reliability of cerebral blood velocity regulation during lower body negative pressure and supine cycling with considerations of the menstrual cycle.

Objective.To evaluate sex differences in the reliability of absolute and relative cerebral blood velocity (CBv) during concurrent supine cycling with lower body negative pressure (LBNP).Approach. A total of 19 participants (11 females; aged 20-33 years) completed five testing sessions, occurring on 7 d intervals. Visit 1 was a maximal-ramp-cycle test to ascertain peak CBv wattage. During visits 2-5, supine cycling protocol occurred at individualized peak CBv wattages with progressive decreases in LBNP from 0 to -20, -40, -60, -70, and -80 Torr. Menstrual cycle day was self-reported via the Rhinessa Women's Questionnaire. Transcranial Doppler ultrasound insonated bilateral middle cerebral artery velocity (MCAv). Two-way ANOVA assessed potential day- and sex-differences at each LBNP stage. Reliability was determined using intraclass correlation coefficients (ICC) and coefficient of variation (CoV).Main results. For all physiological measures, no main-effects were present for day- or interaction-terms (p> 0.067; negligible-to-small effect sizes), while sex differences were noted for MCAv, blood pressure, and heart rate (p< 0.046). Across visits, males and females displayed excellent and good-to-excellent levels of reliability for MCAv metrics, respectively (ICC range: 0.745-0.999; CoV range: 0.33%-9.90%).Significance. During the current investigation, both relative and absolute CBv demonstrated high reliability in both male and female participants during a supine LBNP cycling protocol. An exploratory analysis revealed increased variance was found in female participants dependent on contraceptive use. Despite this, results indicate future LBNP studies may include females at any menstrual cycle stage.

Rapid onset vasodilation during baroreceptor loading and unloading.

The purpose of these experiments was to determine if the increase in vascular conductance following a single muscle contraction (50% of maximal voluntary contraction) (6 male and 6 female subjects) was altered during baroceptor loading and unloading. Rapid onset vasodilation (ROV) was determined by measuring brachial artery blood flow (Doppler ultrasound) and blood pressure (Finapress monitor). Brachial artery vascular conductance was calculated by dividing blood flow by mean arterial pressure. ROV was described by the area under the Δvascular conductance (VC)-time curve during the 30 s following muscle contraction. ROV was determined using chamber pressures of +20, +10, 0, -10, -20, and -40 mmHg (lower body positive and negative pressure, LBPP, and LBNP). We tested the hypothesis that the impact of baroreceptor loading and unloading produces a proportion change in ROV. The level of ROV following each contraction was proportional to the peak force (r2 = 0.393, P = 0.0001). Peak force was therefore used as a covariate in further analysis. ROV during application of -40 mmHg LBNP (0.345 ± 0.229 mL·mmHg-1) was lower than that observed at Control (0.532 ± 0.284 mL·mmHg-1, P = 0.034) and +20 mmHg LBPP (0.658 ± 0.364 mL·mmHg-1, P = 0.0008). ROV was linearly related to chamber pressure from -40 to +20 mmHg chamber pressure (r2 = 0.512, P = 0.022, n = 69) and from -20 to +10 mmHg chamber pressure (r2= 0.973, P < 0.0425, n = 45), Overall, vasoconstrictor tone altered with physiologically relevant baroreceptor loading and unloading resulted in a proportion change in ROV.NEW & NOTEWORTHY Rapid onset vasodilation (ROV) was linearly related to the peak force of each single 1-s muscle contraction. In addition, ROV is reduced by baroreceptor unloading (LBNP: -10, -120, and -40 mmHg) and increased by baroreceptor loading (LBPP: +10 and +20 mmHg). Without accounting for peak force and the level of baroreceptor engagement makes comparison of ROV in subjects of differing muscle size or strength untenable.

Cerebral blood velocity during concurrent supine cycling, lower body negative pressure, and head-up tilt challenges: implications for concussion rehabilitation.

Introduction. The effect of concurrent head-up tilt and lower body negative pressure (LBNP) have been examined on middle cerebral artery velocity (MCAv) at rest; however, it is unknown the superimposed effect these factors have on blunting the elevation in cerebral blood velocity associated with moderate-intensity exercise.Methods. 23 healthy adults (11 females / 12 males, 20-33 years) completed three visits. The first consisted of a maximal ramp supine cycling test to identify the wattage associated with individualized maximal MCAv. Subsequent visits included randomized no LBNP (control) or LBNP at -40 Torr (experimental) with successively increasing head-up tilt stages of 0, 15, 30, and 45 degrees during the pre-described individualized wattage. Transcranial Doppler ultrasound was utilized to quantify MCAv. Two-factorial repeated measures analysis of variance with effect sizes were used to determine differences between days and tilt stages.Results. Between-day baseline values for MCAv, heart rate, and blood pressure displayed low variability with <5% variation. With no LBNP, MCAv was above baseline on average for all participants; however, 15 degrees and 30 degrees tilt with concurrent -40 Torr LBNP was sufficient to return MCAv to 100% of baseline values in females and males, respectively. Body-weight did not impact the association between tilt and pressure (R2range: 0.01-0.12).Conclusion. Combined LBNP and tilt were sufficient to reduce the increase in MCAv associated with moderate-intensity exercise. This exercise modality shows utility to enable individuals with a concussion to obtain the positive physiological adaptions associated with exercise while minimizing symptom exacerbation due to the notion of the Monro-Kellie doctrine.

The effect of supine cycling and progressive lower body negative pressure on cerebral blood velocity responses.

Moderate-intensity aerobic exercise increases cerebral blood velocity (CBv) primarily due to hyperpnea-induced vasodilation; however, the integrative control of cerebral blood flow (CBF) allows other factors to contribute to the vasodilation. Although lower body negative pressure (LBNP) can reduce CBv, the exact LBNP intensity required to blunt the aforementioned exercise-induced CBv response is unknown. This could hold utility for concussion recovery, allowing individuals to exercise at higher intensities without symptom exacerbation. Thirty-two healthy adults (age: 20-33 yr; 19 females/13 males) completed a stepwise maximal exercise test during a first visit to determine each participant's wattage associated with their exercise-induced maximal CBv increase. During the second visit, following supine rest, participants completed moderate-intensity exercise at their determined threshold, while progressive LBNP was applied at 0, -20, -40, -60, -70, -80, and ∼88 Torr. Bilateral middle cerebral artery blood velocities (MCAvs), mean arterial pressure (MAP), heart rate, respiratory rate, and end-tidal carbon dioxide levels were measured continuously. Two-way analysis of variance with effect sizes compared between sexes and stages. Compared with resting supine baseline, averaged MCAv was elevated during 0 and -20 Torr LBNP (q value > 7.73; P < 0.001); however, no differences were noted between baseline and -40 to -70 Torr (q value < |4.24|; P > 0.262). Differences were present between females and males for absolute MCAv measures (q value > 11.2; P < 0.001), but not when normalized to baseline (q value < 0.03; P > 0.951). Supine cycling-elicited increases in MCAv are able to be blunted during the application of LBNP ranging from -40 to -70 Torr. The blunted CBv response demonstrates the potential benefit of allowing individuals to aerobically train (moderate-intensity supine cycling with LBNP) without exacerbating symptoms during the concussion recovery phase.NEW & NOTEWORTHY The current investigation demonstrated that moderate-intensity supine cycling-induced increases in cerebral blood velocities were balanced by the lower body negative pressure-induced decreases in cerebral blood velocity. Although performed in a healthy population, the results may lend themselves to a potential treatment option for individuals recovering from concussion or experience persistent concussion symptoms.

Superiority of compensatory reserve measurement compared with the Shock index for early and accurate detection of reduced central blood volume status.

BACKGROUND: Shock index (SI) equals the ratio of heart rate (HR) to systolic blood pressure (SBP) with clinical evidence that it is more sensitive for trauma patient status assessment and prediction of outcome compared with either HR or SBP alone. We used lower body negative pressure (LBNP) as a human model of central hypovolemia and compensatory reserve measurement (CRM) validated for accurate tracking of reduced central blood volume to test the hypotheses that SI: (1) presents a late signal of central blood volume status; (2) displays poor sensitivity and specificity for predicting the onset of hemodynamic decompensation; and (3) cannot identify individuals at greatest risk for the onset of circulatory shock. METHODS: We measured HR, SBP, and CRM in 172 human subjects (19-55 years) during progressive LBNP designed to determine tolerance to central hypovolemia as a model of hemorrhage. Subjects were subsequently divided into those with high tolerance (HT) (n = 118) and low tolerance (LT) (n = 54) based on completion of 60 mm Hg LBNP. The time course relationship between SI and CRM was determined and receiver operating characteristic (ROC) area under the curve (AUC) was calculated for sensitivity and specificity of CRM and SI to predict hemodynamic decompensation using clinically defined thresholds of 40% for CRM and 0.9 for SI. RESULTS: The time and level of LBNP required to reach a SI = 0.9 (~60 mm Hg LBNP) was significantly greater ( p < 0.001) compared with CRM that reached 40% at ~40 mm Hg LBNP. Shock index did not differ between HT and LT subjects at 45 mm Hg LBNP levels. ROC AUC for CRM was 0.95 (95% CI = 0.94-0.97) compared with 0.91 (0.89-0.94) for SI ( p = 0.0002). CONCLUSION: Despite high sensitivity and specificity, SI delays time to detect reductions in central blood volume with failure to distinguish individuals with varying tolerances to central hypovolemia. LEVEL OF EVIDENCE: Diagnostic Test or Criteria; Level III.

Using the ear photoplethysmographic waveform as an early indicator of central hypovolemia in healthy volunteers utilizing LBNP induced hypovolemia model.

Objective. To study the photoplethysmographic (PPG) waveforms of different locations (ear and finger) during lower body negative pressure (LBNP) induced hypovolemia. Then, to determine whether the PPG waveform can be used to detect hypovolemia during the early stage of LBNP.Approach. 36 healthy volunteers were recruited for progressive LBNP induced hypovolemia, with an endpoint of -60 mmHg or development of hypoperfusion symptoms, whichever comes first. Subjects tolerating the entire protocol without symptoms were designated as high tolerance (HT), while symptomatic subjects were designated as low tolerance (LT). Subjects were monitored with an electrocardiogram, continuous noninvasive blood pressure monitor, and two pulse oximetry probes, one on the ear (Xhale) and one the finger (Nellcor). Stroke volume was measured non-invasively utilizing Non-Invasive Cardiac Output Monitor (NICOM, Cheetah Medical). The waveform morphology was analyzed using novel PPG waveforms indices, including phase hemodynamic index (PHI) and amplitude hemodyamaic index and were evaluated from the ear PPG and finger PPG at different LBNP stages.Main results. The PHI, particularly the phase relationship between the second harmonic and the fundamental component of the ear PPG denoted as∇φ2,during the early stage of LBNP (-15 mmHg) in the HT and LT groups is statistically significantly different (pvalue = 0.0033) with the area under curve 0.81 (CI: 0.616-0.926). The other indices are not significantly different. The 5 fold cross validation shows that∇φ2during the early stage of LBNP (-15 mmHg) as the single index could predict the tolerance of the subject with the sensitivity, specificity, accuracy andF1 as 0.771 ± 0.192, 0.71 ± 0.107, 0.7 ± 0.1 and 0.771 ± 0.192 respectively.Significance. The ear's PPG PHI which compares the phases of the fundamental and second harmonic has the potential to be used as an early predictor of central hypovolemia.

Wearable Sensing System for NonInvasive Monitoring of Intracranial BioFluid Shifts in Aerospace Applications.

The alteration of the hydrostatic pressure gradient in the human body has been associated with changes in human physiology, including abnormal blood flow, syncope, and visual impairment. The focus of this study was to evaluate changes in the resonant frequency of a wearable electromagnetic resonant skin patch sensor during simulated physiological changes observed in aerospace applications. Simulated microgravity was induced in eight healthy human participants (n = 8), and the implementation of lower body negative pressure (LBNP) countermeasures was induced in four healthy human participants (n = 4). The average shift in resonant frequency was -13.76 ± 6.49 MHz for simulated microgravity with a shift in intracranial pressure (ICP) of 9.53 ± 1.32 mmHg, and a shift of 8.80 ± 5.2097 MHz for LBNP with a shift in ICP of approximately -5.83 ± 2.76 mmHg. The constructed regression model to explain the variance in shifts in ICP using the shifts in resonant frequency (R2 = 0.97) resulted in a root mean square error of 1.24. This work demonstrates a strong correlation between sensor signal response and shifts in ICP. Furthermore, this study establishes a foundation for future work integrating wearable sensors with alert systems and countermeasure recommendations for pilots and astronauts.

Acute regulation of erythropoietin via lower body negative pressure: Influence of sex and age.

The regulation of erythropoiesis via hemodynamic stimuli such as reduced central blood volume (CBV) remains uncertain in women and elderly individuals. This study assessed the acute effects of lower body negative pressure (LBNP) on key endocrine biomarkers regulating erythropoiesis, that is, erythropoietin (EPO) and copeptin, in young and older women and men (n = 87). Transthoracic echocardiography and hemodynamics were assessed throughout incremental LBNP levels for 1 hour, or until presyncope, with established methods. Venous blood samples were collected at baseline and immediately after termination of the orthostatic tolerance (OT) test for subsequent hormone analyses. The average age of young women and men (33.1 ± 6.0 vs. 29.5 ± 6.9 yr) and older women and men (63.8 ± 8.0 vs. 65.3 ± 8.9 yr) as well as their physical activity levels were matched within each age and sex group. CBV, as determined by right atrial volume, was reduced in all individuals at the end of the OT test (p < 0.001). The average OT time ranged from 50.1 to 58.1 min in all individuals. LBNP increased circulating EPO in young women (p = 0.023) but not in young men or older individuals. Copeptin was increased in all individuals with LBNP but was exclusively associated with EPO in men (r = 0.39, p = 0.013). The present study indicates that the acute hemodynamic regulation of EPO production is both sex- and age-dependent.

Cardio-respiratory interactions in response to lower-body negative pressure.

The relationship between heart rate and blood pressure, as well as cardiorespiratory coupling, play a critical role in maintaining blood pressure and organ perfusion during conditions of blood loss. Traditional vital signs such as blood pressure, breathing rate, and oxygen saturation are poor markers of blood loss, making it difficult for medics to assess the severity of central hypovolemia. Monitoring hemorrhage is further complicated by the fact that some patients have a low tolerance to hemorrhage and would reach the point of cardiovascular collapse in less time than high tolerant individuals. Therefore, this study aimed to investigate the potential of the physiological interaction between heart rate and blood pressure, and cardiorespiratory coupling to track the progression of simulated hemorrhage, as well as distinguish individuals with low tolerance (LT) from the ones with high tolerance (HT) to hypovolemia. Nineteen subjects (age: 28 ± 6 years; height: 170 ± 7 cm; weight: 68 ± 10 kg) underwent a progressive lower body negative pressure (LBNP) protocol in which the participant was supine inside the chamber for 12 min (baseline) before 12 min of chamber decompression at -20, -30, -40, -50 and -60 mmHg followed by a 12 min recovery period. Twelve subjects reached presyncope before or during -60 mmHg LBNP stage and were considered low tolerant (LT, 12 participants), while the ones who completed -60 mmHg were considered high tolerant (HT, 7 participants). Continuous blood pressure (BP), respiration (RSP), and electrocardiogram (ECG) signals were acquired simultaneously during baseline and each LBNP stage. RR interval was calculated using ECG, while systolic blood pressure (SBP), and pulse pressure were derived from BP waveform. Wavelet transform coherence and convergent cross-mapping techniques were employed to study the physiological interdependence and the causal relationship between heart rate, blood pressure, and respiration. The interaction between blood pressure and heart rate in terms of gain, active gain, and fraction time active(SBP↔RR,PP↔RR)to maintain homeostasis was higher in the LT group during baseline, and LBNP simulated mild, moderate, and severe hemorrhage. The significant time of interaction between SBP and RSP, and the causal effect of blood pressure on respiration were higher in the HT group during baseline compared to the LT group. HT participants also had a higher causal effect of respiration on blood pressure(RSP→SBP,RSP→PP)during -30 and -40 mmHg compared to LT. Moreover, the HT group displayed a higher causal drive of respiratory-related changes in heart rate(RSP→RR)and heart rate mediated changes in respirationRR→RSPduring severe simulated hemorrhage (-40 mmHg) compared to the LT group. The calculated metrics to distinguish between individual LT from HT subjects achieved a sensitivity of 58%-83%, an accuracy of 63%-84%, and an area under the ROC curve of 74%-86%, while the overlap of LT individual responses with HT was 0%-33%. These results indicate the potential of cardiorespiratory coupling, and heart rate and blood pressure interaction toward tracking the progression of hemorrhage and distinguishing individuals with low tolerance to hypovolemia from those with high tolerance. Measurements of such interactions could improve clinical outcomes for patients with low tolerance to hypovolemia and therefore reduce morbidity and mortality through early implementation of life-saving interventions.

Amplitude and phase measurements from harmonic analysis may lead to new physiologic insights: lower body negative pressure photoplethysmographic waveforms as an example.

The photoplethysmographic (PPG) waveform contains hemodynamic information in its oscillations. We provide a new method for quantitative study of the waveform morphology and its relationship to the hemodynamics. A data adaptive modeling of the waveform shape is used to describe the PPG waveforms recorded from ear and finger. Several indices, based on the phase and amplitude information of different harmonics, are proposed to describe the PPG morphology. The proposed approach is illustrated by analyzing PPG waveforms recorded during a lower body negative pressure (LBNP) experiment. Different phase and amplitude dynamics are observed during the LBNP experiment. Specifically, we observe that the phase difference between the high order harmonics and fundamental components change more significantly when the PPG signal is recorded from the ear than the finger at the beginning of the study. In contrast, the finger PPG amplitude changes more when compared to the ear PPG during the recovery period. A more complete harmonic analysis of the PPG appears to provide new hemodynamic information when used during a LBNP experiment. We encourage other investigators who possess modulated clinical waveform data (e.g. PPG, arterial pressure, respiratory, and autonomic) to re-examine their data, using phase information and higher harmonics as a potential source of new insights into underlying physiologic mechanisms.

Compensatory hemodynamic changes in response to central hypovolemia in humans: lower body negative pressure: updates and perspectives.

Central hypovolemia is accompanied by hemodynamic compensatory responses. Understanding the complex systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia-as induced by standing up and/or lower body negative pressure (LBNP)-in humans are important. LBNP has been widely used to understand the integrated physiological responses, which occur during sit to stand tests (orthostasis), different levels of hemorrhages (different levels of LBNP simulate different amount of blood loss) as well as a countermeasure against the cephalad fluid shifts which are seen during spaceflight. Additionally, LBNP application (used singly or together with head up tilt, HUT) is useful in understanding the physiology of orthostatic intolerance. The role seasonal variations in hormonal, autonomic and circulatory state play in LBNP-induced hemodynamic responses and LBNP tolerance as well as sex-based differences during central hypovolemia and the adaptations to exercise training have been investigated using LBNP. The data generated from LBNP studies have been useful in developing better models for prediction of orthostatic tolerance and/or for developing countermeasures. This review examines how LBNP application influences coagulatory parameters and outlines the effects of temperature changes on LBNP responses. Finally, the review outlines how LBNP can be used as innovative teaching tool and for developing research capacities and interests of medical students and students from other disciplines such as mathematics and computational biology.

Real-Time Magnetic Resonance Imaging to Study Orthostatic Intolerance Mechanisms in Human Beings: Proof of Concept.

Background Discerning the mechanisms driving orthostatic symptoms in human beings remains challenging. Therefore, we developed a novel approach combining cardiac and cerebral real-time magnetic resonance imaging, beat-to-beat physiological monitoring, and orthostatic stress testing through lower-body negative pressure (LBNP). We conducted a proof-of-concept study in a patient with severe orthostatic hypotension. Methods and Results We included a 46-year-old man with pure autonomic failure. Without and during -30 mmHg LBNP, we obtained 3T real-time magnetic resonance imaging of the cardiac short axis and quantitative flow measurements in the pulmonary trunk and middle cerebral artery. Blood pressure was 118/74 mmHg during supine rest and 58/35 mmHg with LBNP. With LBNP, left ventricular stroke volume decreased by 44.6%, absolute middle cerebral artery flow by 37.6%, and pulmonary trunk flow by 40%. Conclusions Combination of real-time magnetic resonance imaging, LBNP, and continuous blood pressure monitoring provides a promising new approach to study orthostatic intolerance mechanisms in human beings.