Hemorrhage at high altitude: impact of sustained hypobaric hypoxia on cerebral blood flow, tissue oxygenation, and tolerance to simulated hemorrhage in humans.

With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4 M) participated in LBNP protocols to presyncope at LA (1130 m) and 5-7 days following ascent to HA (3800 m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO2) through the ICA, and cerebral tissue oxygen saturation (ScO2) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304 s vs. HA: 1208 ± 306 s; P = 0.58). Overall, ICA blood flow and CDO2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P < 0.0001), but there was no effect of altitude on ScO2 responses (P = 0.59). Thus, sustained exposure to hypobaric hypoxia did not negatively impact tolerance to simulated hemorrhage. These data demonstrate the robustness of compensatory physiological mechanisms that preserve human cerebral blood flow and oxygen delivery during sustained hypoxia, ensuring cerebral tissue metabolism and neuronal function is maintained.

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.

Transfer function analysis of dynamic cerebral autoregulation: A CARNet white paper 2022 update.

Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.

On the use and misuse of cerebral hemodynamics terminology using transcranial Doppler ultrasound: a call for standardization.

Cerebral hemodynamics, e.g., cerebral blood flow, can be measured and quantified using many different methods, with transcranial Doppler ultrasound (TCD) being one of the most commonly used approaches. In human physiology, the terminology used to describe metrics of cerebral hemodynamics are inconsistent and in some instances technically inaccurate; this is especially true when evaluating, reporting, and interpreting measures from TCD. Therefore, this perspective article presents recommended terminology when reporting cerebral hemodynamic data. We discuss the current use and misuse of the terminology in the context of using TCD to measure and quantify cerebral hemodynamics and present our rationale and consensus on the terminology that we recommend moving forward. For example, one recommendation is to discontinue the use of the term "cerebral blood flow velocity" in favor of "cerebral blood velocity" with precise indication of the vessel of interest. We also recommend clarity when differentiating between discrete cerebrovascular regulatory mechanisms, namely, cerebral autoregulation, neurovascular coupling, and cerebrovascular reactivity. This will be a useful guide for investigators in the field of cerebral hemodynamics research.

The potential therapeutic benefits of low frequency haemodynamic oscillations.

Haemodynamic oscillations occurring at frequencies below the rate of respiration have been observed experimentally for more than a century. Much of the research regarding these oscillations, observed in arterial pressure and blood flow, has focused on mechanisms of generation and methods of quantification. However, examination of the physiological role of these oscillations has been limited. Multiple studies have demonstrated that oscillations in arterial pressure and blood flow are associated with the protection in tissue oxygenation or functional capillary density during conditions of reduced tissue perfusion. There is also evidence that oscillatory blood flow can improve clearance of interstitial fluid, with a growing number of studies demonstrating a role for oscillatory blood flow to aid in clearance of debris from the brain. The therapeutic potential of these haemodynamic oscillations is an important new area of research which may have beneficial impact in treating conditions such as stroke, cardiac arrest, blood loss injuries, sepsis, or even Alzheimer's disease and vascular dementia.

Functional optical coherence tomography at altitude: retinal microvascular perfusion and retinal thickness at 3,800 meters.

Cerebral hypoxia is a serious consequence of several cardiorespiratory illnesses. Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into cerebral hypoxia in critical illness. In addition, although sex-specific differences in cardiovascular diseases are strongly supported, few have focused on differences in ocular blood flow. We evaluated the retinal microvasculature in males (n = 11) and females (n = 7) using functional optical coherence tomography at baseline (1,130 m) (day 0), following rapid ascent (day 2), and prolonged exposure (day 9) to high altitude (3,800 m). Retinal vascular perfusion density (rVPD; an index of total blood supply), retinal thickness (RT; reflecting vascular and neural tissue volume), and arterial blood were acquired. As a group, rVPD increased on day 2 versus day 0 (P < 0.001) and was inversely related to [Formula: see text] (R2 = 0.45; P = 0.006). By day 9, rVPD recovered to baseline but was significantly lower in males than in females (P = 0.007). RT was not different on day 2 versus day 0 (P > 0.99) but was reduced by day 9 relative to day 0 and day 2 (P < 0.001). RT changes relative to day 0 were inversely related to changes in [Formula: see text] on day 2 (R2 = 0.6; P = 0.001) and day 9 (R2 = 0.4; P = 0.02). RT did not differ between sexes. These data suggest differential time course and regulation of the retina during rapid ascent and prolonged exposure to high altitude and are the first to demonstrate sex-specific differences in rVPD at high altitude. The ability to assess intact microvasculature contiguous with the brain has widespread research and clinical applications.NEW & NOTEWORTHY Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into consequence of cerebral hypoxia in critical illness. This study demonstrates dynamic regulation of the retina during rapid ascent and prolonged exposure to high altitude and is the first to demonstrate sex-specific differences in retinal microvasculature at high altitude. The ability to dynamically assess intact microvasculature contiguous with the brain has widespread research and clinical applications.

The reciprocal relationship between cardiac baroreceptor sensitivity and cerebral autoregulation during simulated hemorrhage in humans.

A reciprocal relationship between the baroreflex and cerebral autoregulation (CA) has been demonstrated at rest and in response to acute hypotension. We hypothesized that the reciprocal relationship between cardiac baroreflex sensitivity (BRS) and CA would be maintained during sustained central hypovolemia induced by lower body negative pressure (LBNP), and that the strength of this relationship would be greater in subjects with higher tolerance to this stress. Healthy young adults (n = 51; 23F/28M) completed a LBNP protocol to presyncope. Subjects were classified as high tolerant (HT; completion of -60 mmHg LBNP stage, ≥20-min) or low tolerant (LT; did not complete -60 mmHg LBNP stage, <20-min). R-R intervals (RRI), systolic arterial pressure (SAP), mean arterial pressure (MAP), and middle cerebral artery velocity (MCAv) were measured continuously. Cardiac BRS was calculated in the time domain (ΔHR/ΔSAP) and frequency domain (RRI-SAP low frequency (LF) transfer function gain), and CA was calculated in the time domain (ΔMCAv/ΔMAP) and frequency domain (MAP-mean MCAv LF transfer function gain). There was a moderate relationship between cardiac BRS and CA for the group of 51 subjects in both the time (R = -0.54, P < 0.0001) and frequency (R = 0.61, P < 0.001) domains; there was a stronger relationship in the HT group (R = 0.73) compared to the LT group (R = 0.31) in the frequency domain (P = 0.08), but no difference between groups in the time domain (HT: R = -0.73 vs. LT: R = -0.63; P = 0.27). These findings suggest that an interaction between BRS and CA may be an important compensatory mechanism that contributes to tolerance to simulated hemorrhage in young healthy adults.

Integrative physiological assessment of cerebral hemodynamics and metabolism in acute ischemic stroke.

Restoring perfusion to ischemic tissue is the primary goal of acute ischemic stroke care, yet only a small portion of patients receive reperfusion treatment. Since blood pressure (BP) is an important determinant of cerebral perfusion, effective BP management could facilitate reperfusion. But how BP should be managed in very early phase of ischemic stroke remains a contentious issue, due to the lack of clear evidence. Given the complex relationship between BP and cerebral blood flow (CBF)-termed cerebral autoregulation (CA)-bedside monitoring of cerebral perfusion and oxygenation could help guide BP management, thereby improve stroke patient outcome. The aim of INFOMATAS is to 'identify novel therapeutic targets for treatment and management in acute ischemic stroke'. In this review, we identify novel physiological parameters which could be used to guide BP management in acute stroke, and explore methodologies for monitoring them at the bedside. We outline the challenges in translating these potential prognostic markers into clinical use.

Integrative cerebral blood flow regulation in ischemic stroke.

Optimizing cerebral perfusion is key to rescuing salvageable ischemic brain tissue. Despite being an important determinant of cerebral perfusion, there are no effective guidelines for blood pressure (BP) management in acute stroke. The control of cerebral blood flow (CBF) involves a myriad of complex pathways which are largely unaccounted for in stroke management. Due to its unique anatomy and physiology, the cerebrovascular circulation is often treated as a stand-alone system rather than an integral component of the cardiovascular system. In order to optimize the strategies for BP management in acute ischemic stroke, a critical reappraisal of the mechanisms involved in CBF control is needed. In this review, we highlight the important role of collateral circulation and re-examine the pathophysiology of CBF control, namely the determinants of cerebral perfusion pressure gradient and resistance, in the context of stroke. Finally, we summarize the state of our knowledge regarding cardiovascular and cerebrovascular interaction and explore some potential avenues for future research in ischemic stroke.

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 ScO2during combined simulated hemorrhage and sustained hypoxia. This protection was not associated with the preservation of cerebral blood flow suggesting preservation of ScO2may be due to mechanisms occurring within the microvasculature.

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.

Time course and magnitude of ventilatory and renal acid-base acclimatization following rapid ascent to and residence at 3,800 m over nine days.

Rapid ascent to high altitude imposes an acute hypoxic and acid-base challenge, with ventilatory and renal acclimatization countering these perturbations. Specifically, ventilatory acclimatization improves oxygenation, but with concomitant hypocapnia and respiratory alkalosis. A compensatory, renally mediated relative metabolic acidosis follows via bicarbonate elimination, normalizing arterial pH(a). The time course and magnitude of these integrated acclimatization processes are highly variable between individuals. Using a previously developed metric of renal reactivity (RR), indexing the change in arterial bicarbonate concentration (Δ[HCO3-]a; renal response) over the change in arterial pressure of CO2 (Δ[Formula: see text]; renal stimulus), we aimed to characterize changes in RR magnitude following rapid ascent and residence at altitude. Resident lowlanders (n = 16) were tested at 1,045 m (day [D]0) prior to ascent, on D2 within 24 h of arrival, and D9 during residence at 3,800 m. Radial artery blood draws were obtained to measure acid-base variables: [Formula: see text], [HCO3-]a, and pHa. Compared with D0, [Formula: see text] and [HCO3-]a were lower on D2 (P < 0.01) and D9 (P < 0.01), whereas significant changes in pHa (P = 0.072) and RR (P = 0.056) were not detected. As pHa appeared fully compensated on D2 and RR did not increase significantly from D2 to D9, these data demonstrate renal acid-base compensation within 24 h at moderate steady-state altitude. Moreover, RR was strongly and inversely correlated with ΔpHa on D2 and D9 (r≤ -0.95; P < 0.0001), suggesting that a high-gain renal response better protects pHa. Our study highlights the differential time course, magnitude, and variability of integrated ventilatory and renal acid-base acclimatization following rapid ascent and residence at high altitude.NEW & NOTEWORTHY We assessed the time course, magnitude, and variability of integrated ventilatory and renal acid-base acclimatization with rapid ascent and residence at 3,800 m. Despite reductions in [Formula: see text] upon ascent, pHa was normalized within 24 h of arrival at 3,800 m through renal compensation (i.e., bicarbonate elimination). Renal reactivity (RR) was unchanged between days 2 and 9, suggesting a lack of plasticity at moderate steady-state altitude. RR was strongly correlated with ΔpHa, suggesting that a high-gain renal response better protects pHa.

Reducing intracranial pressure by reducing central venous pressure: assessment of potential countermeasures to spaceflight-associated neuro-ocular syndrome.

Spaceflight-associated neuro-ocular syndrome (SANS) involves unilateral or bilateral optic disc edema, widening of the optic nerve sheath, and posterior globe flattening. Owing to posterior globe flattening, it is hypothesized that microgravity causes a disproportionate change in intracranial pressure (ICP) relative to intraocular pressure. Countermeasures capable of reducing ICP include thigh cuffs and breathing against inspiratory resistance. Owing to the coupling of central venous pressure (CVP) and intracranial pressure, we hypothesized that both ICP and CVP will be reduced during both countermeasures. In four male participants (32 ± 13 yr) who were previously implanted with Ommaya reservoirs for treatment of unrelated clinical conditions, ICP was measured invasively through these ports. Subjects were healthy at the time of testing. CVP was measured invasively by a peripherally inserted central catheter. Participants breathed through an impedance threshold device (ITD, -7 cmH2O) to generate negative intrathoracic pressure for 5 min, and subsequently, wore bilateral thigh cuffs inflated to 30 mmHg for 2 min. Breathing through an ITD reduced both CVP (6 ± 2 vs. 3 ± 1 mmHg; P = 0.02) and ICP (16 ± 3 vs. 12 ± 1 mmHg; P = 0.04) compared to baseline, a result that was not observed during the free breathing condition (CVP, 6 ± 2 vs. 6 ± 2 mmHg, P = 0.87; ICP, 15 ± 3 vs. 15 ± 4 mmHg, P = 0.68). Inflation of the thigh cuffs to 30 mmHg caused no meaningful reduction in CVP in all four individuals (5 ± 4 vs. 5 ± 4 mmHg; P = 0.1), coincident with minimal reduction in ICP (15 ± 3 vs. 14 ± 4 mmHg; P = 0.13). The application of inspiratory resistance breathing resulted in reductions in both ICP and CVP, likely due to intrathoracic unloading.NEW & NOTEWORTHY Spaceflight causes pathological changes in the eye that may be due to the absence of gravitational unloading of intracranial pressure (ICP) under microgravity conditions commonly referred to as spaceflight-associated neuro-ocular syndrome (SANS), whereby countermeasures aimed at lowering ICP are necessary. These data show that impedance threshold breathing acutely reduces ICP via a reduction in central venous pressure (CVP). Whereas, acute thigh cuff inflation, a popular known spaceflight-associated countermeasure, had little effect on ICP and CVP.

A comparison of protocols for simulating hemorrhage in humans: step versus ramp lower body negative pressure.

Lower body negative pressure (LBNP) elicits central hypovolemia, and it has been used to simulate the cardiovascular and cerebrovascular responses to hemorrhage in humans. LBNP protocols commonly use progressive stepwise reductions in chamber pressure for specific time periods. However, continuous ramp LBNP protocols have also been utilized to simulate the continuous nature of most bleeding injuries. The aim of this study was to compare tolerance and hemodynamic responses between these two LBNP profiles. Healthy human subjects (N = 19; age, 27 ± 4 y; 7 female/12 male) completed a 1) step LBNP protocol (5-min steps) and 2) continuous ramp LBNP protocol (3 mmHg/min), both to presyncope. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), middle and posterior cerebral artery velocity (MCAv and PCAv), cerebral oxygen saturation (ScO2), and end-tidal CO2 (etCO2) were measured. LBNP tolerance, via the cumulative stress index (CSI, summation of chamber pressure × time at each pressure), and hemodynamic responses were compared between the two protocols. The CSI (step: 911 ± 97 mmHg/min vs. ramp: 823 ± 83 mmHg/min; P = 0.12) and the magnitude of central hypovolemia (%Δ SV, step: -54.6% ± 2.6% vs. ramp: -52.1% ± 2.8%; P = 0.32) were similar between protocols. Although there were no differences between protocols for the maximal %Δ HR (P = 0.88), the %Δ MAP during the step protocol was attenuated (P = 0.05), and the reductions in MCAv, PCAv, ScO2, and etCO2 were greater (P ≤ 0.08) when compared with the ramp protocol at presyncope. These results indicate that when comparing cardiovascular responses to LBNP across different laboratories, the specific pressure profile must be considered as a potential confounding factor.NEW & NOTEWORTHY Ramp lower body negative pressure (LBNP) protocols have been utilized to simulate the continuous nature of bleeding injuries. However, it unknown if tolerance or the physiological responses to ramp LBNP are similar to the more common stepwise LBNP protocol. We report similar tolerance between the two protocols, but the step protocol elicited a greater increase in cerebral oxygen extraction in the presence of reduced blood flow, presumably facilitating the matching of metabolic supply and demand.

Responses of cerebral blood velocity and tissue oxygenation to low-frequency oscillations during simulated haemorrhagic stress in humans.

NEW FINDINGS: What is the central question of this study? Do low-frequency oscillations in arterial pressure and cerebral blood velocity protect cerebral blood velocity and oxygenation during central hypovolaemia? What is the main finding and its importance? Low-frequency oscillations in arterial pressure and cerebral blood velocity attenuate reductions in cerebral oxygen saturation but do not protect absolute cerebral blood velocity during central hypovolaemia. This finding indicates the potential importance of haemodynamic oscillations in maintaining cerebral oxygenation and therefore viability of tissues during challenges to cerebral blood flow and oxygen delivery. ABSTRACT: Tolerance to both real and simulated haemorrhage varies between individuals. Exaggerated low-frequency (∼0.1 Hz) oscillations in mean arterial pressure and brain blood flow [indexed via middle cerebral artery velocity (MCAv)] have been associated with improved tolerance to reduced central blood volume. The mechanism for this association has not been explored. We hypothesized that inducing low-frequency oscillations in arterial pressure and cerebral blood velocity would attenuate reductions in cerebral blood velocity and oxygenation during simulated haemorrhage. Fourteen subjects (11 men and three women) were exposed to oscillatory (0.1 and 0.05 Hz) and non-oscillatory (0 Hz) lower-body negative pressure profiles with an average chamber pressure of -60 mmHg (randomized and counterbalanced order). Measurements included arterial pressure and stroke volume via finger photoplethysmography, MCAv via transcranial Doppler ultrasound, and cerebral oxygenation of the frontal lobe via near-infrared spectroscopy. Tolerance was higher during the two oscillatory profiles compared with the 0 Hz profile (0.05 Hz, P = 0.04; 0.1 Hz, P = 0.09), accompanied by attenuated reductions in stroke volume (P < 0.001) and cerebral oxygenation of the frontal lobe (P ≤ 0.02). No differences were observed between profiles for reductions in mean arterial pressure (P = 0.17) and MCAv (P = 0.30). In partial support of our hypothesis, cerebral oxygenation, but not cerebral blood velocity, was protected during the oscillatory profiles. Interestingly, more subjects tolerated the oscillatory profiles compared with the static 0 Hz profile, despite similar arterial pressure responses. These findings emphasize the potential importance of haemodynamic oscillations in maintaining perfusion and oxygenation of cerebral tissues during haemorrhagic stress.

Hemorrhage simulated by lower body negative pressure provokes an oxidative stress response in healthy young adults.

IMPACT STATEMENT: We characterize the systemic oxidative stress response in young, healthy human subjects with exposure to simulated hemorrhage via application of lower body negative pressure (LBNP). Prior work has demonstrated that LBNP and actual blood loss evoke similar hemodynamic and immune responses (i.e. white blood cell count), but it is unknown whether LBNP elicits oxidative stress resembling that produced by blood loss. We show that LBNP induces a 29% increase in F2-isoprostanes, a systemic marker of oxidative stress. The findings of this investigation may have important implications for the study of hemorrhage using LBNP, including future assessments of targeted interventions that may reduce oxidative stress, such as novel fluid resuscitation approaches.

Ischaemic and hypoxic conditioning: potential for protection of vital organs.

NEW FINDINGS: What is the topic of this review? Remote ischaemic preconditioning (RIPC) and hypoxic preconditioning as novel therapeutic approaches for cardiac and neuroprotection. What advances does it highlight? There is improved understanding of mechanisms and signalling pathways associated with ischaemic and hypoxic preconditioning, and potential pitfalls with application of these therapies to clinical trials have been identified. Novel adaptations of preconditioning paradigms have also been developed, including intermittent hypoxia training, RIPC training and RIPC-exercise, extending their utility to chronic settings. ABSTRACT: Myocardial infarction and stroke remain leading causes of death worldwide, despite extensive resources directed towards developing effective treatments. In this Symposium Report we highlight the potential applications of intermittent ischaemic and hypoxic conditioning protocols to combat the deleterious consequences of heart and brain ischaemia. Insights into mechanisms underlying the protective effects of intermittent hypoxia training are discussed, including the activation of hypoxia-inducible factor-1 and Nrf2 transcription factors, synthesis of antioxidant and ATP-generating enzymes, and a shift in microglia from pro- to anti-inflammatory phenotypes. Although there is little argument regarding the efficacy of remote ischaemic preconditioning (RIPC) in pre-clinical models, this strategy has not consistently translated into the clinical arena. This lack of translation may be related to the patient populations targeted thus far, and the anaesthetic regimen used in two of the major RIPC clinical trials. Additionally, we do not fully understand the mechanism through which RIPC protects the vital organs, and co-morbidities (e.g. hypercholesterolemia, diabetes) may interfere with its efficacy. Finally, novel adaptations have been made to extend RIPC to more chronic settings. One adaptation is RIPC-exercise (RIPC-X), an innovative paradigm that applies cyclical RIPC to blood flow restriction exercise (BFRE). Recent findings suggest that this novel exercise modality attenuates the exaggerated haemodynamic responses that may limit the use of conventional BFRE in some clinical settings. Collectively, intermittent ischaemic and hypoxic conditioning paradigms remain an exciting frontier for the protection against ischaemic injuries.

Vive la résistance! The role of inspiratory resistance breathing on cerebral blood flow.

Prolonging the therapeutic window for treatment is imperative for survival from a multitude of life-threatening events such as hemorrhage, cardiac arrest, and stroke. Inspiratory resistance breathing is a therapeutic approach that augments the reduction in intrathoracic and intracranial pressure during inspiration, facilitating improvements in vital organ perfusion under conditions of ischemia, such as blood loss and cardiac arrest. In this review a series of studies will be presented assessing the role of inspiratory resistance breathing on responses of cerebral blood flow and cerebral tissue oxygenation under conditions of cardiac arrest and blood loss in animal models, and simulated hemorrhage in humans. Knowledge gaps in this field of investigation will be presented, and future research directions will be discussed.

Impact of environmental stressors on tolerance to hemorrhage in humans.

Hemorrhage is a leading cause of death in military and civilian settings, and ~85% of potentially survivable battlefield deaths are hemorrhage-related. Soldiers and civilians are exposed to a number of environmental and physiological conditions that have the potential to alter tolerance to a hemorrhagic insult. The objective of this review is to summarize the known impact of commonly encountered environmental and physiological conditions on tolerance to hemorrhagic insult, primarily in humans. The majority of the studies used lower body negative pressure (LBNP) to simulate a hemorrhagic insult, although some studies employed incremental blood withdrawal. This review addresses, first, the use of LBNP as a model of hemorrhage-induced central hypovolemia and, then, the effects of the following conditions on tolerance to LBNP: passive and exercise-induced heat stress with and without hypohydration/dehydration, exposure to hypothermia, and exposure to altitude/hypoxia. An understanding of the effects of these environmental and physiological conditions on responses to a hemorrhagic challenge, including tolerance, can enable development and implementation of targeted strategies and interventions to reduce the impact of such conditions on tolerance to a hemorrhagic insult and, ultimately, improve survival from blood loss injuries.

Time course of compensatory physiological responses to central hypovolemia in high- and low-tolerant human subjects.

Lower body negative pressure (LBNP) simulates hemorrhage in human subjects. Most subjects (67%) exhibited high tolerance (HT) to hypovolemia, while the remainder (33%) had low tolerance (LT). To investigate the mechanisms for decompensation to central hypovolemia in HT and LT subjects, we characterized the time course of total peripheral resistance (TPR), heart rate (HR), and muscle sympathetic nerve activity (MSNA) during LBNP to tolerance determined by the onset of decompensation (presyncope, PS). We hypothesized that 1) maximum (Max) TPR, HR, and MSNA would coincide, and 2) PS would result from simultaneous decreases in TPR, HR, and MSNA in LT and HT subjects but occur earlier in LT than in HT subjects. Max TPR was lower and occurred earlier in LT ( n = 59) than in HT ( n = 113) subjects (LT: 24 ± 1 mmHg·min·1-1 at 756 ± 31 s; HT: 28 ± 1 mmHg·min·1-1 at 1,265 ± 37 s, P < 0.01). Max TPR occurred several minutes before PS. During subsequent decrease in TPR, HR and MSNA continued to increase. Max HR (LT: 111 ± 2 beat/min at 923 ± 27 s; HT: 130 ± 2 beats/min at 1489 ± 23 s, P < 0.01) occurred several seconds before PS. Higher MSNA ( P < 0.01) was attained in HT ( n = 10; 51 ± 5 bursts/min at max TPR; 54 ± 5 bursts/min at max HR) than LT subjects ( n = 4; 41 ± 8 bursts/min at max TPR; 39 ± 8 bursts/min at max HR). The onset of cardiovascular decompensation is a biphasic process in which vasodilation occurs before bradycardia and sympathetic withdrawal. This pattern was similar in LT and HT but occurred earlier in LT subjects. We conclude that sudden bradycardia plays a critical role in the determination of tolerance to central hypovolemia.