Central Hypovolemia Research Articles

Peaks and valleys: oscillatory cerebral blood flow at high altitude protects cerebral tissue oxygenation

Introduction. Oscillatory patterns in arterial pressure and blood flow (at ∼0.1 Hz) may protect tissue oxygenation during conditions of reduced cerebral perfusion and/or hypoxia. We hypothesized that inducing oscillations in arterial pressure and cerebral blood flow at 0.1 Hz would protect cerebral blood flow and cerebral tissue oxygen saturation during exposure to a combination of simulated hemorrhage and sustained hypobaric hypoxia. Methods. Eight healthy human subjects (4 male, 4 female; 30.1 ± 7.6 year) participated in two experiments at high altitude (White Mountain, California, USA; altitude, 3800 m) following rapid ascent and 5–7 d of acclimatization: (1) static lower body negative pressure (LBNP, control condition) was used to induce central hypovolemia by reducing chamber pressure to −60 mmHg for 10 min (0 Hz), and; (2) oscillatory LBNP where chamber pressure was reduced to −60 mmHg, then oscillated every 5 s between −30 mmHg and −90 mmHg for 10 min (0.1 Hz). Measurements included arterial pressure, internal carotid artery (ICA) blood flow, middle cerebral artery velocity (MCAv), and cerebral tissue oxygen saturation (ScO2). Results. Forced 0.1 Hz oscillations in mean arterial pressure and mean MCAv were accompanied by a protection of ScO2 (0.1 Hz: −0.67% ± 1.0%; 0 Hz: −4.07% ± 2.0%; P = 0.01). However, the 0.1 Hz profile did not protect against reductions in ICA blood flow (0.1 Hz: −32.5% ± 4.5%; 0 Hz: −19.9% ± 8.9%; P = 0.24) or mean MCAv (0.1 Hz: −18.5% ± 3.4%; 0 Hz: −15.3% ± 5.4%; P = 0.16). Conclusions. Induced oscillatory arterial pressure and cerebral blood flow led to protection of ScO2 during combined simulated hemorrhage and sustained hypoxia. This protection was not associated with the preservation of cerebral blood flow suggesting preservation of ScO2 may be due to mechanisms occurring within the microvasculature.

Safety of anesthesia in acute blood loss moderate hypovolemia

Acute blood loss is the most common cause of death in armed conflicts. During the great Patriotic war, 37.2% of the wounded died on the battlefield from acute blood loss and its consequences. According to statistics of military surgeons in local wars, the percentage of deaths from bleeding on the battlefield has remained quite high in recent decades: in Afghanistan, 43% due to untimely first aid for gunshot and mine-explosive wounds, of which 27% died from acute blood loss. During counter-terrorism operations in the North Caucasus, acute blood loss was the cause of death in 26.6% of cases. Analysis of recent armed conflicts shows that the main causes of death on the battlefield are the consequences of penetrating wounds, in particular blood loss with combined traumatic brain injuries of various origins. The issue of analgesia for a lack of circulating blood volume, as well as for continuing bleeding, is complex due to the need to prevent the development of shock conditions against the background of possible side effects of anesthesia. The paper presents pharmacometric and toxicometric characteristics of a model agonist of opioid receptors in acute blood loss of moderate hypovolemia in an experiment. It was shown that the sensitivity of white rats and rabbits to intravenous anesthesia according to the criteria of deep anesthesia increased by 7.3 and 7.5 times, respectively; there were no changes in the mortality criterion for acute blood loss of moderate hypovolemia. A decrease in the speed of action and an increase in the duration of the effect of deep anesthesia in hypovolemia after intravenous administration of a model opioid receptor agonist at doses of 1 ED50 was revealed. An assessment of the breadth of therapeutic action of the model agonist of opioid receptors was made, according to the results of which an increase in this indicator was revealed. It is shown that it is necessary to clarify the anaesthetic manual for more severe variations of polytrauma with blood loss.

Impact of Sleep Quality on Cardiovascular Responses to Simulated Hemorrhage in Humans

Introduction Sleep is an important determinant of cardiovascular health. Poor sleep quality, including sleep restriction, is associated with impairments in cardiovascular function, and may limit cardiovascular responsiveness to physiological stress. As hemorrhage is one of the leading causes of preventable civilian death, and a major cause of death from trauma in the military, it is important to assess the impact of sleep quality on cardiovascular responses to this stress. We hypothesize that human subjects who report poor sleep quality will be less tolerant to simulated hemorrhage, which will be associated with lower arterial pressure and cerebral blood flow, and higher heart rates compared to subjects who report good sleep quality. Methods Healthy human subjects (10F; 10M) participated in a graded pre-syncopal lower body negative pressure (LBNP) protocol to simulate hemorrhage. Sleep quality was assessed pre-experiment using the Pittsburgh Sleep Quality Index (PSQI). Subjects were categorized in two groups: POOR sleep quality (Global PSQI score ≥ 5) or GOOD sleep quality (Global PSQI score < 5). Arterial pressure, heart rate, stroke volume, and middle cerebral artery velocity (MCAv) were measured continuously throughout the LBNP protocol. The protocol was terminated if systolic arterial pressure was < 80 mmHg, or if subjects reported symptoms such as lightheadedness, nausea, dizziness, or vision disturbances. Results Of the 20 subjects tested, 5 were in the POOR sleep quality group (5M; 0F), and 15 were in the GOOD sleep quality group (5M; 10F). Sleep quality had no effect on tolerance to LBNP (POOR: 1453 ± 223 s vs. GOOD: 1535 ± 88 s; P = 0.34), and there were no differences in the magnitude of central hypovolemia at presyncope (%Δ stroke volume, POOR: -53 ± 8 % vs. GOOD: -49 ± 4 %; P = 0.32). However, there were differences in the magnitude of hypotension (%Δ mean arterial pressure, POOR: -18 ± 3 % vs. GOOD: -22 ± 2 %; P = 0.08), cerebral blood flow reduction (%Δ MCAv, POOR: -19 ± 6 % vs. GOOD: -28 ± 2 %; P = 0.03), and reflex tachycardia (% Δ heart rate, POOR: 103 ± 30 % vs. GOOD: 72 ± 9 %; P = 0.09). There was a moderate association between sleep quality and the magnitude of MCAv reduction at presyncope (r = 0.53; P = 0.02), where poorer sleep quality was associated with a smaller reduction in MCAv at presyncope. All 5 (100%) subjects in the POOR group terminated the experiment based on subjective symptoms (i.e., they did not reach the systolic arterial pressure threshold of 80 mmHg), compared to 2 of the 15 subjects (13%) in the GOOD group (P=0.001). Conclusion: Sleep quality did not affect tolerance to simulated hemorrhage in healthy human subjects. While there were differences in hemodynamic responses, this may be related to premature termination of the LBNP protocol based on the early onset of subjective presyncopal symptoms. A larger sample size may help to further investigate these observations.

Time‐Frequency Analysis of Hemodynamics Oscillations during Presyncopal Lower Body Negative Pressure (LBNP)

Introduction Greater low frequency (LF) oscillations (~0.1 Hz) in mean arterial pressure (MAP) and cerebral blood flow (indexed by middle cerebral artery velocity; MCAv) have been associated with higher tolerance to central hypovolemia. As the fast Fourier transform approach was used in these prior studies, measuring exact timing of oscillatory amplitude was not possible. In the present study, the continuous wavelet transform was used for time localization and measurement of the magnitude of LF oscillations during application of lower body negative pressure (LBNP) to presyncope to reduce cerebral perfusion. We hypothesized that the magnitude of LF oscillations in MAP and MCAv would be higher in subjects with greater tolerance to this stress. We also hypothesized that the time of instantaneous maximum magnitude of LF oscillations would be further from baseline for high tolerant subjects. Methods 31 healthy human subjects (14 F: 17 M; 25.1 ± 3.0 y) underwent a stepwise LBNP protocol to presyncope. Subjects were classified as high tolerant (HT) if they completed the -60 mmHg stage of LBNP, and low tolerant (LT) if they did not. Continuous beat-to-beat MAP and mean MCAv were recorded. The continuous wavelet transform was used to extract magnitude of oscillations within the LF range (0.07-0.15 Hz) over time for both MAP and mean MCAv. The instantaneous maximum magnitude of LF oscillations was then extracted. Pearson's correlation was calculated for instantaneous LF magnitude of MAP and mean MCAv versus presyncopal time. A t-test was then used to compare magnitude and relative time of LF oscillations between HT and LT subjects. Results The maximum magnitude of MAP LF oscillations was positively correlated with presyncopal time (R = 0.39, P = 0.03). The maximum magnitude of MCAv LF oscillations, however, was not correlated with presyncopal time (R = -0.03, P = 0.86). When assessing HT and LT subjects, no differences were observed for maximum magnitude of LF oscillations in MAP (HT 4.3 ± 1.0, LT 3.7 ± 1.2, P=0.15) or MCAv (HT 3.1 ± 0.9, LT 3.1 ± 0.7, P=0.91). Time to maximum magnitude of LF oscillations was greater in high tolerant subjects for both MAP (HT 1384.5 ± 329.6 s, LT 798.6 ± 416.8 s, P<0.01) and MCAv (HT 1064.3 ± 431.6 s, LT 662.4 ± 380.1 s, P=0.01). When expressing the time of maximum amplitude as a percent of presyncopal time, the average time in all subjects for MAP was 73.6 ± 22.0 % and 59.6 ± 26.1 % for MCAv, and there were no differences between tolerance groups in either MAP (HT 79.5 ± 14.0 %, LT 67.4 ± 27.3 %, P=0.14) or MCAv (HT 61.8 ± 24.8 %, LT 57.3 ± 28.1 %, P=0.64). Conclusions Using wavelet analysis, only the maximum magnitude of MAP LF oscillations was modestly correlated to presyncopal time. Contrary to previous measures using fast Fourier transform, there was no difference in instantaneous maximum magnitude of oscillations in MAP and mean MCAv between high and low tolerant subjects indicating that both groups could mount similar responses. Interestingly, the relative timing of maximum magnitude of oscillations in MAP and MCAv was no different between tolerance groups.

Sympathetic Response to Resistance Breathing During Simulated Hemorrhage in Humans

Background Resistance breathing increases venous return and stroke volume by amplifying the respiratory pump during inspiration. Breathing with resistance devices augments reflex compensatory mechanisms to improve tolerance to hypovolemic stress, such as hemorrhage. We tested the hypothesis that protection of arterial pressure with resistance breathing during simulated hemorrhage is due to the mechanical effect of the respiratory pump, and not due to increases in sympathetic nervous system activity. Methods Lower body negative pressure (LBNP) was used to simulate hemorrhage in eight human subjects (4M, 3F; 27.5±1.6 y). Two experiments were conducted (randomized order): 1) a control condition in which ramp LBNP was applied at 3 mmHg/min until the onset of presyncope, and 2) a resistance breathing condition in which the same LBNP protocol was used, but subjects breathed through a resistance device during the final stages of the protocol. Mean arterial pressure and stroke volume were monitored continuously, and blood samples were collected every 5-min for measurement of plasma norepinephrine and epinephrine. Results There were no differences in the reduction in stroke volume (control, -36.9±13.8% vs. resistance breathing, -33.5±17.1%, P=0.31) or mean arterial pressure (control, -5.5±4.2% vs. resistance breathing, -6.3±7.4%, P=0.63) between conditions. LBNP induced increases in both norepinephrine (P=0.03) and epinephrine (P=0.003), but there was no main effect of resistance breathing on these responses (norepinephrine, P=0.8; epinephrine, P=0.48). Conclusion These data support the hypothesis that, based on circulating catecholamine responses, resistance breathing has no direct effect on sympathetic drive to compensate for central hypovolemia.

The impact of acute central hypovolemia on cerebral hemodynamics: does sex matter?

Trauma-induced hemorrhage is a leading cause of disability and death due, in part, to impaired perfusion and oxygenation of the brain. It is unknown if cerebrovascular responses to blood loss are differentiated based on sex. We hypothesized that compared to males, females would have reduced tolerance to simulated hemorrhage induced by maximal lower body negative pressure (LBNP), and this would be associated with an earlier reduction in cerebral blood flow and cerebral oxygenation. Healthy young males (n = 29, 26 ± 4 yr) and females (n = 23, 27 ± 5 yr) completed a step-wise LBNP protocol to presyncope. Mean arterial pressure (MAP), stroke volume (SV), middle cerebral artery velocity (MCAv), end-tidal CO2 (etCO2), and cerebral oxygen saturation (ScO2) were measured continuously. Unexpectedly, tolerance to LBNP was similar between the sexes (males, 1,604 ± 68 s vs. females, 1,453 ± 78 s; P = 0.15). Accordingly, decreases (%Δ) in MAP, SV, MCAv, and ScO2 were similar between males and females throughout LBNP and at presyncope (P ≥ 0.20). Interestingly, although decreases in etCO2 were similar between the sexes throughout LBNP (P = 0.16), at presyncope, the %Δ etCO2 from baseline was greater in males compared to females (-30.8 ± 2.6% vs. -21.3 ± 3.0%; P = 0.02). Contrary to our hypothesis, sex does not influence tolerance, or the central or cerebral hemodynamic responses to simulated hemorrhage. However, the etCO2 responses at presyncope do suggest potential sex differences in cerebral vascular sensitivity to CO2 during central hypovolemia.NEW & NOTEWORTHY Tolerance and cerebral blood velocity responses to simulated hemorrhage (elicited by lower body negative pressure) were similar between male and female subjects. Interestingly, the change in etCO2 from baseline was greater in males compared to females at presyncope, suggesting potential sex differences in cerebral vascular sensitivity to CO2 during simulated hemorrhage. These findings may facilitate development of individualized therapeutic interventions to improve survival from hemorrhagic injuries in both men and women.

Pivotal Role of Heart for Orthostasis: Left Ventricular Untwisting Mechanics and Physical Fitness.

Augmentation of left ventricular (LV) untwisting due to central hypovolemia is likely to be a compensatory mechanism for maintaining stroke volume, which is reduced by a decrease in cardiac filling during orthostatic stress. Orthostatic intolerance observed in both high and low fitness levels may be explained by the impaired response of LV untwisting due to central hypovolemia.

Optical Hemodynamic Imaging of Jugular Venous Dynamics During Altered Central Venous Pressure.

An optical imaging system is proposed for quantitatively assessing jugular venous response to altered central venous pressure. The proposed system assesses sub-surface optical absorption changes from jugular venous waveforms with a spatial calibration procedure to normalize incident tissue illumination. Widefield frames of the right lateral neck were captured and calibrated using a novel flexible surface calibration method. A hemodynamic optical model was derived to quantify jugular venous optical attenuation (JVA) signals, and generate a spatial jugular venous pulsatility map. JVA was assessed in three cardiovascular protocols that altered central venous pressure: acute central hypovolemia (lower body negative pressure), venous congestion (head-down tilt), and impaired cardiac filling (Valsalva maneuver). JVA waveforms exhibited biphasic wave properties consistent with jugular venous pulse dynamics when time-aligned with an electrocardiogram. JVA correlated strongly (median, interquartile range) with invasive central venous pressure during graded central hypovolemia (r=0.85, [0.72, 0.95]), graded venous congestion (r=0.94, [0.84, 0.99]), and impaired cardiac filling (r=0.94, [0.85, 0.99]). Reduced JVA during graded acute hypovolemia was strongly correlated with reductions in stroke volume (SV) (r=0.85, [0.76, 0.92]) from baseline (SV: 79 ± 15mL, JVA: 0.56 ± 0.10a.u.) to -40mmHg suction (SV: 59 ± 18mL, JVA: 0.47 ± 0.05a.u.; p 0.01). The proposed non-contact optical imaging system demonstrated jugular venous dynamics consistent with invasive central venous monitoring during three protocols that altered central venous pressure. This system provides non-invasive monitoring of pressure-induced jugular venous dynamics in clinically relevant conditions where catheterization is traditionally required, enabling monitoring in non-surgical environments.

Physiology of Human Hemorrhage and Compensation.

Hemorrhage is a leading cause of death following traumatic injuries in the United States. Much of the previous work in assessing the physiology and pathophysiology underlying blood loss has focused on descriptive measures of hemodynamic responses such as blood pressure, cardiac output, stroke volume, heart rate, and vascular resistance as indicators of changes in organ perfusion. More recent work has shifted the focus toward understanding mechanisms of compensation for reduced systemic delivery and cellular utilization of oxygen as a more comprehensive approach to understanding the complex physiologic changes that occur following and during blood loss. In this article, we begin with applying dimensional analysis for comparison of animal models, and progress to descriptions of various physiological consequences of hemorrhage. We then introduce the complementary side of compensation by detailing the complexity and integration of various compensatory mechanisms that are activated from the initiation of hemorrhage and serve to maintain adequate vital organ perfusion and hemodynamic stability in the scenario of reduced systemic delivery of oxygen until the onset of hemodynamic decompensation. New data are introduced that challenge legacy concepts related to mechanisms that underlie baroreflex functions and provide novel insights into the measurement of the integrated response of compensation to central hypovolemia known as the compensatory reserve. The impact of demographic and environmental factors on tolerance to hemorrhage is also reviewed. Finally, we describe how understanding the physiology of compensation can be translated to applications for early assessment of the clinical status and accurate triage of hypovolemic and hypotensive patients. © 2021 American Physiological Society. Compr Physiol 11:1531-1574, 2021.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.

Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use.

Postural orthostatic tachycardia syndrome: A respiratory disorder?

Postural orthostatic tachycardia syndrome (POTS) is a disorder epitomized by the story of the blind men and the elephant. Patients may see primary care internists or pediatricians due to fatigue, be referred to neurologists for “spells”, to cardiologists for evaluation of pre-syncope or chest pain, to gastroenterologists for nausea or dyspepsia, and even pulmonologists for dyspnea. Adoption of a more systematic approach to their evaluation and better characterization of patients has led to greater understanding of comorbidities, hypotheses prompting mechanistic investigations, and pharmacologic trials. Recent work has implicated disordered sympathetic nervous system activation in response to central (thoracic) hypovolemia. It is this pathway that leads one zero in on a putative focal point from which many of the clinical manifestations can be explained – specifically the carotid body. Despite heterogeneity in etiopathogenesis of a POTS phenotype, we propose that aberrant activation and response of the carotid body represents one potential common pathway in evolution. To understand this postulate, one must jettison isolationist or reductionist ideas of chemoreceptor and baroreceptor functions of the carotid body or sinus, respectively, and consider their interaction and interdependence both locally and centrally where some of its efferents merge. Doing so enables one to connect the dots and appreciate origins of diverse manifestations of POTS, including dyspnea for which the concept of neuro-mechanical uncoupling is wanting, thereby expanding our construct of this symptom. This perspective expounds our premise that POTS has a prominent respiratory component.

Wearable Sensors Incorporating Compensatory Reserve Measurement for Advancing Physiological Monitoring in Critically Injured Trauma Patients.

Vital signs historically served as the primary method to triage patients and resources for trauma and emergency care, but have failed to provide clinically-meaningful predictive information about patient clinical status. In this review, a framework is presented that focuses on potential wearable sensor technologies that can harness necessary electronic physiological signal integration with a current state-of-the-art predictive machine-learning algorithm that provides early clinical assessment of hypovolemia status to impact patient outcome. The ability to study the physiology of hemorrhage using a human model of progressive central hypovolemia led to the development of a novel machine-learning algorithm known as the compensatory reserve measurement (CRM). Greater sensitivity, specificity, and diagnostic accuracy to detect hemorrhage and onset of decompensated shock has been demonstrated by the CRM when compared to all standard vital signs and hemodynamic variables. The development of CRM revealed that continuous measurements of changes in arterial waveform features represented the most integrated signal of physiological compensation for conditions of reduced systemic oxygen delivery. In this review, detailed analysis of sensor technologies that include photoplethysmography, tonometry, ultrasound-based blood pressure, and cardiogenic vibration are identified as potential candidates for harnessing arterial waveform analog features required for real-time calculation of CRM. The integration of wearable sensors with the CRM algorithm provides a potentially powerful medical monitoring advancement to save civilian and military lives in emergency medical settings.

Coagulation Changes during Central Hypovolemia across Seasons.

Lower body negative pressure (LBNP) application simulates hemorrhage. We investigated how seasons affect coagulation values at rest and during LBNP. Healthy participants were tested in cold (November–April) and warm (May–October) months. Following a 30-min supine period, LBNP was started at −10 mmHg and increased by −10 mmHg every five minutes until a maximum of −40 mmHg. Recovery was for 10 min. Blood was collected at baseline, end of LBNP, and end of recovery. Hemostatic profiling included standard coagulation tests, calibrated automated thrombogram, thrombelastometry, impedance aggregometry, and thrombin formation markers. Seven men (25.0 ± 3.6 years, 79.7 ± 7.8 kg weight, 182.4 ± 3.3 cm height, and 23.8 ± 2.3 kg/m2 BMI) and six women (25.0 ± 2.4 years, 61.0 ± 8.4 kg weight, 167 ± 4.7 cm height, and 21.8 ± 2.4 kg/m2 BMI) participated. Baseline levels of prothrombin (FII), tissue factor (TF) and markers for thrombin generation F1+2 and the thrombin/antithrombin complex (TAT) were higher during summer. Factor VIII, prothrombin fragment 1+2 (F1+2), TAT and the coagulation time showed significant increases during LBNP in both seasons. Some calibrated automated thrombography variables (Calibrated automated thrombography (CAT): lag, time to peak (ttPeak), peak) shifted in a procoagulant direction during LBNP in summer. Red blood cell counts (RBC), hemoglobin and white blood cell counts (WBC) decreased during LBNP. LBNP application reduced prothrombin time in winter and activated partial thromboplastin time in summer. Greater levels of FII, TF, F1+2, and TAT—a more pronounced LBNP-induced procoagulative effect, especially in CAT parameters (lag time (LT), Peak, ttPeak, Velindex)—were seen in summer. These results could have substantial medical implications.

Low-dose ketamine affects blood pressure, but not muscle sympathetic nerve activity, during progressive central hypovolemia without altering tolerance.

Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low-dose ketamine, one of three analgesics employed in the pre-hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown. For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult. Increases in muscle sympathetic nerve activity during progressive lower-body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double-blinded, randomized, placebo-controlled trial. A pre-syncopal limited progressive lower-body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two-tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage]×drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360mmHg‧min, p=0.77). Increases in MSNA burst frequency (time: P<0.01, trial: p=0.27, interaction: p=0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P<0.01, trial: P<0.01, interaction: p=0.01) and heart rate (time: P<0.01, trial: P<0.01, interaction: P<0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P<0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low-dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP.

Menstrual Phase Affects Coagulation and Hematological Parameters during Central Hypovolemia.

Background: It has been reported that women have a higher number of heart attacks in the “follicular phase” of the menstrual cycle. We, therefore, tested the hypothesis that women in the follicular phase exhibit higher coagulability. As lower body negative pressure (LBNP) has been used previously to assess coagulation changes in whole blood (WB) samples in men and women, effects of menstrual phase on coagulation was assessed during LBNP. Methods: Seven women, all healthy young participants, with no histories of thrombotic disorders and not on medications, were tested in two phases of the menstrual cycle (early follicular (EF) and mid-luteal (ML)). LBNP was commenced at −10 mmHg and increased by −10 mmHg every 5 min until a maximum of −40 mmHg. Recovery up to 10 min was also monitored. Blood samples were collected at baseline, at end of LBNP, and at end of recovery. Hemostatic profiling included comparing the effects of LBNP on coagulation values in both phases of the menstrual cycle using standard coagulation tests, calibrated automated thrombogram, thrombelastometry, impedance aggregometry, and markers of thrombin formation. Results: LBNP led to coagulation activation determined in both plasma and WB samples. During both phases, coagulation was affected during LBNP, as reflected in their decreased partial thromboplastin time (PTT) and elevated coagulation factor VIII FVIII, F1 + 2, and thrombin-antithrombin (TAT) levels. Additionally, during the ML phase, greater PT [%] and shorter time to peak (ttPeak) values (implying faster maximum thrombin formation) suggest that women in the ML phase are relatively hypercoagulable compared to the early follicular phase. Conclusions: These results suggest that thrombosis occurs more during the midluteal phase, a finding with substantial medical implications.

Effect of novel short-arm human centrifugation-induced gravitational gradients upon cardiovascular responses, cerebral perfusion and g-tolerance.

Key points The aim of this study was to determine the effect of rotational axis position (RAP and thus g‐gradient) during short‐arm human centrifugation (SAHC) upon cardiovascular responses, cerebral perfusion and g‐tolerance.In 10 male and 10 female participants, 10 min passive SAHC runs were performed with the RAP above the head (P1), at the apex of the head (P2), or at heart level (P3), with foot‐level Gz at 1.0 g, 1.7 g and 2.4 g.We hypothesized that movement of the RAP from above the head (the conventional position) towards the heart might reduce central hypovolaemia, limit cardiovascular responses, aid cerebral perfusion, and thus promote g‐tolerance.Moving the RAP footward towards the heart decreased the cerebral tissue saturation index, calf circumference and heart rate responses to SAHC, thereby promoting g‐tolerance.Our results also suggest that RAP, and thus g‐gradient, warrants further investigation as it may support use as a holistic spaceflight countermeasure. Artificial gravity (AG) through short‐arm human centrifugation (SAHC) has been proposed as a holistic spaceflight countermeasure. Movement of the rotational axis position (RAP) from above the head towards the heart may reduce central hypovolaemia, aid cerebral perfusion, and thus promote g‐tolerance. This study determined the effect of RAP upon cardiovascular responses, peripheral blood displacement (i.e. central hypovolaemia), cerebral perfusion and g‐tolerance, and their inter‐relationships. Twenty (10 male) healthy participants (26.2 ± 4.0 years) underwent nine (following a familiarization run) randomized 10 min passive SAHC runs with RAP set above the head (P1), at the apex of the head (P2), or at heart level (P3) with foot‐level Gz at 1.0 g, 1.7 g and 2.4 g. Cerebral tissue saturation index (cTSI, cerebral perfusion surrogate), calf circumference (CC, central hypovolaemia), heart rate (HR) and digital heart‐level mean arterial blood pressure (MAP) were continuously recorded, in addition to incidence of pre‐syncopal symptoms (PSS). ΔCC and ΔHR increases were attenuated from P1 to P3 (ΔCC: 5.46 ± 0.54 mm to 2.23 ± 0.42 mm; ΔHR: 50 ± 4 bpm to 8 ± 2 bpm, P < 0.05). In addition, ΔcTSI decrements were also attenuated (ΔcTSI: −2.85 ± 0.48% to −0.95 ± 0.34%, P < 0.05) and PSS incidence lower in P3 than P1 (P < 0.05). A positive linear relationship was observed between ΔCC and ΔHR with increasing +Gz, and a negative relationship between ΔCC and ΔcTSI, both independent of RAP. Our data suggest that movement of RAP towards the heart (reduced g‐gradient), independent of foot‐level Gz, leads to improved g‐tolerance. Further investigations are required to assess the effect of differential baroreceptor feedback (i.e. aortic–carotid g‐gradient).

Effect of Blood Volume Shift Simulated via Head-up Tilt on Photoplethysmography Morphology.

PPG can provide information on cardiovascular responses to fluid shifts from upper to lower part of body under the condition of orthostatic stress. The current study investigated ability of PPG derived LVET and other PPG derived features to identify progressive central hypovolemia induced by head up tilt (HUT) and evaluated potential use of LVET as early noninvasive indicator of blood loss. Continuous finger PPG, blood pressure, and electrocardiography were recorded simultaneously during 5-minutes of baseline and HUT of 20°, 40°, and 60° from 15 participants (age: 26.5 ± 3 years; height: 177 ± 8 cm; weight: 72 ± 10 kg, mean ± SD). Beat-by-beat pulse rate (PR), systolic amplitude (SA), systolic time (ST), diastolic time (DT), and PP Interval (PPI) and Ratio of pulse rate over systolic amplitude (PR/SA) were derived for each stage. LVET was derived from each stage. Friedman test followed by post-hoc analysis using Tukey-HSD was conducted to highlight the significance of changes induced by HUT. Application of 60° HUT (i.e. moderate category simulated hypovolemia) resulted in a significant change in PR (80±3 bpm vs 68±3 bpm, p=0.0008), DT (264±7 ms vs 303±4 ms, p=0.0008), ST (110±6 ms vs 117±7 ms, p=0.02), PP interval (764±39 ms vs 869±25 ms, p=0.0045), PR/SA (112±16 vs 82±21, p=0.012) , SA (0.875± 0.2 vs 1.69±0.6, p=0.012) and LVET(292 vs 351ms,p=0.0008) compared to baseline. LVET has a strong association with the change in central blood volume and may be used as a sensitive early marker of progressive hypovolemia. The findings of the study support the hypothesis of differentiating simulated hypovolemia based on PPG alone. Keywords: Hypovolemia, HUT, LVET.

Similar hemostatic responses to hypovolemia induced by hemorrhage and lower body negative pressure reveal a hyperfibrinolytic subset of non-human primates.

To study central hypovolemia in humans, lower body negative pressure (LBNP) is a recognized alternative to blood removal (HEM). While LBNP mimics the cardiovascular responses of HEM in baboons, similarities in hemostatic responses to LBNP and HEM remain unknown in this species. Thirteen anesthetized baboons were exposed to progressive hypovolemia by HEM and, four weeks later, by LBNP. Hemostatic activity was evaluated by plasma markers, thromboelastography (TEG), flow cytometry, and platelet aggregometry at baseline (BL), during and after hypovolemia. BL values were indistinguishable for most parameters although platelet count, maximal clot strength (MA), protein C, thrombin anti-thrombin complex (TAT), thrombin activatable fibrinolysis inhibitor (TAFI) activity significantly differed between HEM and LBNP. Central hypovolemia induced by either method activated coagulation; TEG R-time decreased and MA increased during and after hypovolemia compared to BL. Platelets displayed activation by flow cytometry; platelet count and functional aggregometry were unchanged. TAFI activity and protein, Factors V and VIII, vWF, Proteins C and S all demonstrated hemodilution during HEM and hemoconcentration during LBNP, whereas tissue plasminogen activator (tPA), plasmin/anti-plasmin complex, and plasminogen activator inhibitor-1 did not. Fibrinolysis (TEG LY30) was unchanged by either method; however, at BL, fibrinolysis varied greatly. Post-hoc analysis separated baboons into low-lysis (LY30 <2%) or high-lysis (LY30 >2%) whose fibrinolytic state matched at both HEM and LBNP BL. In high-lysis, BL tPA and LY30 correlated strongly (r = 0.95; P<0.001), but this was absent in low-lysis. In low-lysis, BL TAFI activity and tPA correlated (r = 0.88; P<0.050), but this was absent in high-lysis. Central hypovolemia induced by either LBNP or HEM resulted in activation of coagulation; thus, LBNP is an adjunct to study hemorrhage-induced pro-coagulation in baboons. Furthermore, this study revealed a subset of baboons with baseline hyperfibrinolysis, which was strongly coupled to tPA and uncoupled from TAFI activity.

Evidence for misleading decision support in characterizing differences in tolerance to reduced central blood volume using measurements of tissue oxygenation.

The physiological response to hemorrhage includes vasoconstriction in an effort to shunt blood to the heart and brain. Hemorrhaging patients can be classified as "good" compensators who demonstrate high tolerance (HT) or "poor" compensators who manifest low tolerance (LT) to central hypovolemia. Compensatory vasoconstriction is manifested by lower tissue oxygen saturation (StO2 ), which has propelled this measure as a possible early marker of shock. The compensatory reserve measurement (CRM) has also shown promise as an early indicator of decompensation. Fifty-one healthy volunteers (37% LT) were subjected to progressive lower body negative pressure (LBNP) as a model of controlled hemorrhage designed to induce an onset of decompensation. During LBNP, CRM was determined by arterial waveform feature analysis. StO2 , muscle pH, and muscle H+ concentration were calculated from spectrum using near-infrared spectroscopy (NIRS) on the forearm. These values were statistically indistinguishable between HT and LT participants at baseline (p ≥ 0.25). HT participants exhibited lower (p = 0.01) StO2 at decompensation compared to LT participants. Lower StO2 measured in patients during low flow states associated with significant hemorrhage does not necessarily translate to a more compromised physiological state, but may reflect a greater resistance to the onset of shock. Only the CRM was able to distinguish between HT and LT participants early in the course of hemorrhage, supported by a significantly greater ROC AUC (0.90) compared with STO2 (0.68). These results support the notion that measures of StO2 could be misleading for triage and resuscitation decision support.

Peripheral Chemoreceptors Hemodynamic Responses During Simulated Hemorrhage Under Hypoxia Conditions

BackgroundMaintaining baroreflex sensitivity is integral to ensuring blood pressure maintenance and end‐organ perfusion during hemorrhage. This is especially true under conditions of hypoxemia, where decreased tolerance to central hypovolemia is commonly observed. Hypoxia activates peripheral chemoreceptors and reduces baroreceptor‐vascular resistance reflex sensitivity. However, a direct role for the peripheral chemoreceptors in the hemodynamic response to hemorrhage in hypoxia remains unclear.ObjectiveWe tested the hypothesis that attenuation of peripheral chemoreceptor activity (low‐dose dopamine; 1–2 μg/kg/min) during acute hypoxia would promote maintenance of mean arterial pressure, pulse pressure, and other hemodynamic markers [heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR)] during simulated hemorrhage.MethodsTen healthy men (35±3 years, BMI 25±1 kg/m2) participated in a randomized, double‐blind, placebo controlled study. Participants completed two experimental visits (saline and low‐dose dopamine) at which lower body negative pressure (LBNP) was conducted during hypoxia (SpO2 ~85%; PaO2 ~52 mmHg) delivered via a non‐rebreather mask. Ventilation [V̇ (turbine transducer)], arterial blood pressure (brachial artery catheter), HR (ECG), and central venous pressure (peripherally inserted central catheter) were measured continuously and SV, CO, and TPR were calculated. Following a 5‐min rest, participants underwent LBNP for 5‐min at 3 intervals (−15, −30, and −45 mmHg). Outcome values were analyzed and compared using a mixed linear model (SAS PROC MIXED) with a direct product AR(1) covariance structure using indicator variables for saline vs. dopamine. Data from the mixed linear model are reported as an estimated change per 15 mmHg of LBNP.ResultsDopamine had no effect on hypoxia PaO2, PaCO2, V̇ or respiratory rate (all P&gt;0.05) and this relationship persisted throughout all LBNP stages. The mixed linear model showed no effect of dopamine vs. saline on changes in: central venous pressure (−1.1±0.4 vs −1.3±0.3 mmHg, P=0.15), mean arterial pressure (−4.7±2.3 vs −5.3±1.4 mmHg, P=0.25), pulse pressure (−6.7±1.5 vs −8.3±1.4 mmHg, P=0.50), HR (7.8±1.5 vs 6.1±1.5 bpm, P=0.41), SV (−10.9±1.9 vs −11.6±3.3 mL, P=0.41), CO (−0.3±0.2 vs −0.4±0.4 L · min−1, P=0.31) or TPR (0.2±0.4 vs 0.7±0.6 mmHg · L · min−1P=0.27).DiscussionIntravenous infusion of low‐dose dopamine designed to attenuate peripheral chemoreflex activity during acute hypoxia did not alter the integrated hemodynamic response to simulated hemorrhage. Our data suggests that peripheral chemoreceptors have a limited role during hypoxic central hypovolemia. More research is needed to understand the sensitivity and cross‐talk between chemoreceptors and baroreceptors during hemorrhage.Support or Funding InformationFunding: W81XWH‐13‐2‐0038 (DOD), DK90541 (NIH), UL1 TR000135 (NIH).