Differential effects of lower body negative pressure and upright tilt on splanchnic blood volume

Upright posture and lower body negative pressure (LBNP) both induce reductions in central blood volume. However, regional circulatory responses to postural changes and LBNP may differ. Therefore, we studied regional blood flow and blood volume changes in 10 healthy subjects undergoing graded lower-body negative pressure (-10 to -50 mmHg) and 8 subjects undergoing incremental head-up tilt (HUT; 20 degrees , 40 degrees , and 70 degrees ) on separate days. We continuously measured blood pressure (BP), heart rate, and regional blood volumes and blood flows in the thoracic, splanchnic, pelvic, and leg segments by impedance plethysmography and calculated regional arterial resistances. Neither LBNP nor HUT altered systolic BP, whereas pulse pressure decreased significantly. Blood flow decreased in all segments, whereas peripheral resistances uniformly and significantly increased with both HUT and LBNP. Thoracic volume decreased while pelvic and leg volumes increased with HUT and LBNP. However, splanchnic volume changes were directionally opposite with stepwise decreases in splanchnic volume with LBNP and stepwise increases in splanchnic volume during HUT. Splanchnic emptying in LBNP models regional vascular changes during hemorrhage. Splanchnic filling may limit the ability of the splanchnic bed to respond to thoracic hypovolemia during upright posture.     

Lower body negative pressure as a tool for research in aerospace physiology and military medicine

Lower body negative pressure (LBNP) has been extensively used for decades in aerospace physiological research as a tool to investigate cardiovascular mechanisms that are associated with or underlie performance in aerospace and military environments. In comparison with clinical stand and tilt tests, LBNP represents a relatively safe methodology for inducing highly reproducible hemodynamic responses during exposure to footward fluid shifts similar to those experienced under orthostatic challenge. By maintaining an orthostatic challenge in a supine posture, removal of leg support (muscle pump) and head motion (vestibular stimuli) during LBNP provides the capability to isolate cardiovascular mechanisms that regulate blood pressure. LBNP can be used for physiological measurements, clinical diagnoses and investigational research comparisons of subject populations and alterations in physiological status. The applications of LBNP to the study of blood pressure regulation in spaceflight, groundbased simulations of low gravity, and hemorrhage have provided unique insights and understanding for development of countermeasures based on physiological mechanisms underlying the operational problems.     

Comparison of muscle sympathetic responses to hemorrhage and lower body negative pressure in humans

We compared changes in muscle sympathetic nerve activity (SNA) during graded lower body negative pressure (LBNP) and 450 ml of hemorrhage in nine healthy volunteers. During LBNP, central venous pressure (CVP) decreased from 6.1 +/- 0.4 to 4.5 +/- 0.5 (LBNP -5 mmHg), 3.4 +/- 0.6 (LBNP -10 mmHg), and 2.3 +/- 0.6 mmHg (LBNP -15 mmHg), and there were progressive increases in SNA at each level of LBNP. The slope relating percent change in SNA to change in CVP during LBNP (mean +/- SE) was 27 +/- 11%/mmHg. Hemorrhage of 450 ml at a mean rate of 71 +/- 5 ml/min decreased CVP from 6.1 +/- 0.5 to 3.7 +/- 0.5 mmHg and increased SNA by 47 +/- 11%. The increase in SNA during hemorrhage was not significantly different from the increase in SNA predicted by the slope relating percent change in SNA to change in CVP during LBNP. These data show that nonhypotensive hemorrhage causes sympathoexcitation and that sympathetic responses to LBNP and nonhypotensive hemorrhage are similar in humans.     

Forebrain regions associated with postexercise differences in autonomic and cardiovascular function during baroreceptor unloading

The cortical regions representing peripheral autonomic reactions in humans are poorly understood. This study examined whether changes in forebrain activity were associated with the altered physiological responses to lower body negative pressure (LBNP) following a single bout of dynamic exercise (POST-EX). We hypothesized that, compared with the nonexercised condition (NO-EX), POST-EX would elicit greater reductions in stroke volume (SV) and larger increases in heart rate (HR) and muscle sympathetic nerve activity (MSNA) during LBNP (5, 15, and 35 mmHg). Forebrain neural activity (n = 11) was measured using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. HR, SV, arterial blood pressure (ABP), and MSNA were collected separately. Compared with NO-EX, baseline ABP was reduced, whereas HR and total vascular conductance (TVC) were elevated in POST-EX (P < 0.05). In both conditions, 5 mmHg LBNP did not elicit a change (from baseline) in any physiological parameter. Compared with NO-EX, 35 mmHg LBNP-mediated decreases in SV and TVC produced greater increases in HR and MSNA during POST-EX (P < 0.05). The right posterior insula and dorsal anterior cingulate cortex demonstrated a larger decrease in BOLD at 5 mmHg LBNP but greater BOLD increase at 15 and 35 mmHg LBNP POST-EX vs. NO-EX (P < 0.005). Conversely, the thalamus and ventral medial prefrontal cortex displayed the opposite BOLD activity pattern (i.e., larger increase at 5 mmHg LBNP but greater decrease at 15 and 35 mmHg LBNP POST-EX vs. NO-EX). Our findings suggest that discrete forebrain regions may be involved with the generation of baroreflex-mediated sympathetic and cardiovascular responses elicited by moderate LBNP.     

The cardiovascular response to lower body negative pressure in humans depends on seal location

We tested whether seal location at iliac crest (IC) or upper abdomen (UA), before and during lower body negative pressure (LBNP), would affect thoracic electrical impedance, hepatic blood flow, and central cardiovascular responses to LBNP. After 30 min of supine rest, LBNP at -40 mm Hg was applied for 15 min, either at IC or UA, in 14 healthy males. Plasma density and indocyanine green concentrations assessed plasma volume changes and hepatic perfusion. With both sealing types, LBNP-induced effects remained unchanged for mean arterial pressure (-3.0+/-1.1 mm Hg), cardiac output (-1.0 l min(-1)), and plasma volume (-11 %). Heart rate was greater during UA (80.6+/-3.3 bpm) than IC (76.0+/-2.5 bpm) (p<0.01) and thoracic impedance increased more using UA (3.2+/-0.2 Omega) than IC (1.8+/-0.2 Omega) (p<0.0001). Furthermore, during supine rest, UA was accompanied by lower thoracic impedance (26.9+/-1.1 vs 29.0+/-0.8 Omega, p<0.001) and hepatic perfusion (1.6 vs 1.8 l.min(-1), p<0.05) compared to IC. The data suggest that the reduction in central blood volume in response to LBNP depends on location of the applied seal. The sealing in itself altered blood volume distribution and hepatic perfusion in supine resting humans. Finally, application of LBNP with the seal at the upper abdomen induced a markedly larger reduction in central blood volume and greater increases in heart rate than when the seal was located at the iliac crest.     

The physiological changes of cumulative hemorrhagic shock in conscious rats

Summary Hemorrhagic shock is a common cause of death in emergency rooms. Current animal models of hemorrhage encounter a major problem that the volume and the rate of blood loss cannot be controlled. In addition, the use of anesthesia obscures physiological responses. Our experiments were designed to establish an animal model based on the clinical situation for studying hemorrhagic shock. Hemorrhagic shock was induced by withdrawing blood from a femoral arterial catheter. The blood volume withdrawn was 40% of the total blood volume for group 1 and 30% for group 2 and 3. Group 3 was anesthetized with sodium pentobarbital (25 mg/kg, i.v.) at the beginning of blood withdrawal. Our data showed that the survival rate was 87.5% at 48 h in the conscious group and 0% at 9 h in anesthetic group after hemorrhage. The levels of mean arterial pressure, heart rate, white blood count, TNF-, IL1-, CPK, and LDH after blood withdrawal in the anesthetic group were generally lower than those in conscious groups. These results indicated that anesthetics significantly affected the physiology of experimental animals. The conscious, unrestrained and cumulative volume-controlled hemorrhagic shock model was a good experimental model to investigate the physical phenomenon without anesthetic interfernce.     

Cardiopulmonary effects of hemorrhagic shock in splenic autotransplanted pigs: a new surgical model

The spleen is an important organ for hemodynamic compensation during hemorrhagic shock. The aim of the study was to compare the hemodynamic and metabolic responses of sham-operated pigs with intact spleen, splenectomized pigs, and splenic autotransplanted pigs during hemorrhagic shock. Hemorrhagic shock was induced by 30% total blood volume bleed in sham-operated, splenectomized and splenic autotransplanted pigs (n = 20). Cardiopulmonary and metabolic variables were measured before, immediately after, and at 20, 60 and 100 minutes after hemorrhage. Upon hemorrhagic shock induction, body temperature, mean arterial pressure, mean pulmonary arterial pressure, cardiac output, cardiac index and oxygen delivery decreased, while lactate and shock index increased. Hemoglobin and hematocrit were significantly lower in the splenectomized and splenic autotransplant groups as compared with the control group at 60 and 100 minutes after hemorrhage (p < 0.05). Unlike intact spleen, splenic autotransplant could not improve hemodynamic parameters in hemorrhagic shock in pigs. In comparison to mice, rats or dogs, this species could be an interesting investigation model to test new surgical procedures during splenic related hemorrhagic shock, with potential applications in human medicine.     

Teaching fluid shifts during orthostasis using a classic paper by Foux et al

Hypovolemic and orthostatic challenge can be simulated in humans by the application of lower body negative pressure (LBNP), because this perturbation leads to peripheral blood pooling and, consequently, central hypovolemia. The classic paper by Foux and colleagues clearly shows the effects of orthostasis simulated by LBNP on fluid shifts and homeostatic mechanisms. The carefully carried out experiments reported in this paper show the interplay between different physiological control systems to ensure blood pressure regulation, failure of which could lead to critical decreases in cerebral blood flow and syncope. Here, a teaching seminar for graduate students is described that is designed in the context of this paper and aimed at allowing students to learn how Foux and colleagues have advanced this field by addressing important aspects of blood regulation. This seminar is also designed to put their research into perspective by including important components of LBNP testing and protocols developed in subsequent research in the field. Learning about comprehensive protocols and carefully controlled studies can reduce confounding variables and allow for an optimal analysis and elucidation of the physiological responses that are being investigated. Finally, in collaboration with researchers in mathematical modeling, in the future, we will incorporate the concepts of applicable mathematical models into our curriculum.     

Using thermal stress to model aspects of disease states

Exposure to acute heat or cold stress elicits numerous physiological responses aimed at maintaining body temperatures. Interestingly, many of the physiological responses, mediated by the cardiovascular and autonomic nervous systems, resemble aspects of, or responses to, certain disease states. The purpose of this Perspective is to highlight some of these areas in order to explore how they may help us better understand the pathophysiology underlying aspects of certain disease states. The benefits of using this human thermal stress approach are that (1) no adjustments for inherent comparative differences in animals are needed, (2) non-medicated healthy humans with no underlying co-morbidities can be studied in place of complex patients, and (3) more mechanistic perturbations can be safely employed without endangering potentially vulnerable populations. Cold stress can be used to induce stable elevations in blood pressure. Cold stress may also be used to model conditions where increases in myocardial oxygen demand are not met by anticipated increases in coronary blood flow, as occurs in older adults. Lower-body negative pressure has the capacity to model aspects of shock, and the further addition of heat stress improves and expands this model because passive-heat exposure lowers systemic vascular resistance at a time when central blood volume and left-ventricular filling pressure are reduced. Heat stress can model aspects of heat syncope and orthostatic intolerance as heat stress decreases cerebral blood flow and alters the Frank–Starling mechanism resulting in larger decreases in stroke volume for a given change in left-ventricular filling pressure. Combined, thermal perturbations may provide in vivo paradigms that can be employed to gain insights into pathophysiological aspects of certain disease states.     

Construction of a lower body negative pressure chamber

Lower body negative pressure (LBNP) is an established and important technique used to physiologically stress the human body, particularly the cardiovascular system. LBNP is most often used to simulate gravitational stress, but it has also been used to simulate hemorrhage, alter preload, and manipulate baroreceptors. During experimentation, the consequences of LBNP and the reflex increases in heart rate and blood pressure can be manipulated and observed in a well-controlled manner, thus making LBNP an important research tool. Numerous laboratories have developed LBNP devices for use in research settings, and a few devices are commercially available. However, it is often difficult for new users to find adequately described design plans. Furthermore, many available plans require sophisticated and expensive materials and/or technical support. Therefore, we have created an affordable design plan for a LBNP chamber. The purpose of this article was to share our design template with others. In particular, we hope that this information will be of use in academic and research settings. Our pressure chamber has been stress tested to 100 mmHg below atmospheric pressure and has been used successfully to test orthostatic tolerance and physiological responses to -50 mmHg.     

Beat-to-beat cardiovascular responses to rapid, low-level LBNP in humans

The hypothesis tested was that there are significant transient changes in the cardiovascular variables after rapid onset and release of mild lower body negative pressure (LBNP, -20 mmHg), even in experimental situations where there is no detectable change in steady-state values. Twelve subjects participated in the study. Heart rate, stroke volume (SV), cardiac output, mean arterial pressure (MAP), total peripheral resistance (TPR), acral and nonacral skin blood flow, and blood flow velocity in the brachial artery were continuously recorded during the pre-LBNP period (0-120 s), during LBNP (120-420 s), and during the post-LBNP period (420-600 s). The main finding was that MAP is transiently but strongly affected by rapid changes in LBNP as small as -20 mmHg. There was also a characteristic asymmetry in cardiovascular responses to the onset and release of LBNP, particularly in the responses in SV. The transient changes in MAP indicate that the neural responses that affect TPR are not fast enough to compensate for the rapid changes in LBNP. In this case, the arterial baroreceptors will be activated as well as the low-pressure baroreceptors that sense central venous pressure. This must be taken into consideration in future discussions of the results of LBNP protocols.     

Aspects of control of the cardiovascular-respiratory system during orthostatic stress induced by lower body negative pressure

This paper considers a model developed to study the cardiovascular control system response to orthostatic stress as induced by two variations of lower body negative pressure (LBNP) experiments. This modeling approach has been previously applied to study control responses to transition from rest to aerobic exercise, to transition to non-REM sleep and to orthostatic stress as produced by the head up tilt (HUT) experiment. LBNP induces a blood volume shift because negative pressure changes the volume loading characteristics of the compartment which is subject to the negative pressure. This volume shift induces a fall in blood pressure which must be counteracted by a complicated control response involving a variety of mechanisms of the cardiovascular control system. There are a number of medical issues connected to these questions such as orthostatic intolerance in the elderly resulting in dizziness or fainting during the transition from sitting to standing. The model presented here is used to study the interaction of changes in systemic resistance, unstressed venous volume, venous compliance, heart rate, and contractility in the control of orthostatic stress. The overall short term response depends on a combination of these physiological reactions which may vary from individual to individual. There remain open questions about which factors have greater importance. The model simulations are compared to experimental data collected for LBNP exerted from the hips to feet and from ribs to feet.     

Simulated acute hemorrhage through lower body negative pressure as an activator of the hypothalamic-pituitary-adrenal axis

While insulin induced hypoglycemia is the principle method of producing hypothalamic-pituitary-adrenal stress response, the mechanism by which this occurs may be different from that produced by other stressors. In a pilot study, we explored ways to standardize lower body negative pressure (LBNP), as a simulator of hemorrhage, to determine its utility for future studies of hypothalamic-pituitary-adrenal (HPA) axis function. Reduced atmospheric pressure of -40 mmHg applied at the level of the iliac crests during LBNP rapidly lowers blood pressure in most subjects, simulating acute hemorrhage. In 6 normal subjects, ACTH and cortisol values were measured before, during and after the application LBNP at 0800, 1600 and 2300 hours in the baseline state and at 1600 hours on the day following 1 mg of dexamethasone. Peak ACTH values of 60-250 pg/ml occurred 2 to 10 minutes after the cessation of the stimulus in subjects experiencing presyncope or having a systolic or diastolic blood pressure decrease of greater than 20 mmHg with a rise in pulse of 30 beats per minute or more. There was no significant difference between ACTH responses at different times of day. Peak cortisol values of 25-30 micrograms/dl occurred 15-20 minutes after cessation of the stimulus. In all subjects, administration of dexamethasone greatly attenuated the ACTH response and decreased but did not ablate the cortisol response. In conclusion, these data indicate that LBNP may be used to simulate hemorrhage as a stimulus of the HPA axis. HPA axis changes occur only when physiologic evidence of hypovolemic stress is present. Dexamethasone may be used to modulate the response to this stress paradigm.     

Cardiovascular adaptations following detraining

We have recently summarized our data concerning endurance exercise training and its effect on blood pressure regulation during lower body negative pressure (LBNP). We found that endurance trained (ET) subjects were less tolerant to LBNP than their untrained (UT) counterparts. This decreased tolerance to LBNP was linked to a fitness related adaptation in cardiac compliance, an attenuated cardiopulmonary reflex regulation of peripheral vasoconstriction and an attenuated aortic-cardiac reflex. More recently we have found that 15 days of bed rest deconditioning (a severe form of detraining) in UT subjects resulted in a more responsive aortic-cardiac reflex. In severe detraining investigations, spaceflight and bed rest deconditioning a reduction in total blood and plasma volume were the manifest physiological changes. Therefore, we postulate that the increased aortic-reflex responsiveness was a compensation for the blood and plasma volume losses associated with detraining. Subsequently, we hypothesized that a generalized reduction of the normal daily aerobic activities of a healthy, young adult population would produce a moderate reduction in total blood and plasma volume and an up-regulation of the reflex blood pressure regulatory mechanisms.     

Hemodynamic response to LBNP during the 14 month MIR spaceflight (94-95)

Lower body negative pressure (LBNP) was used during the Mir spaceflight in a study of orthostatic tolerance. Hemodynamic responses were measured including heart rate, blood pressure, cerebral artery blood flow, and lower limb vascular resistance. Results showed that femoral flow volume decreased, which may be due to hypovolemia and reduced cardiac output. Additional changes in femoral vascular response and cerebral to femoral blood flow are discussed.     

Effects of leg venous hemodynamics on cardiovascular responses to lower body negative pressure and aging

In aged people, decreases in stroke volume and cardiac output during orthostatic challenge are less. It is suggested that the stiffness of blood vessels is greater in the elderly, blunting leg venous pooling and drop in central blood volume in an upright position. Leg venous hemodynamics plays an important role in human cardiovascular homeostasis against gravitational stress. This study aimed to clarify how aging influences the leg venous hemodynamics and its contribution to cardiovascular homeostasis during lower body negative pressure (LBNP) in humans.     

Effects of pericardial constraint and ventricular interaction on left ventricular hemodynamics in the unloaded heart

Pericardial constraint and ventricular interaction influence left ventricular (LV) performance when preload is high. However, it is unclear if these constraining forces modulate LV filling when the heart is unloaded, such as during upright posture, in humans. Fifty healthy individuals underwent right heart catheterization to measure pulmonary capillary wedge (PCWP) and right atrial pressure (RAP). To evaluate the effects of pericardial constraint on hemodynamics, transmural filling pressure (LVTMP) was defined as PCWP-RAP. Beat-to-beat blood pressure (BP) waveforms were recorded, and stroke volume (SV) was derived from the Modelflow method. After measurements at -30 mmHg lower body negative pressure (LBNP), which approximates the upright position, LBNP was released, and beat-to-beat measurements were performed for 15 heartbeats. At -30 mmHg LBNP, RAP and PCWP were significantly decreased. During the first six beats of LBNP release, heart rate (HR) was unchanged, while BP increased from the fourth beat. RAP increased faster than PCWP resulting in an acute decrease in LVTMP from the fourth beat. A corresponding drop in SV by 3% was observed with no change in pulse pressure. From the 7th to 15th beats, LVTMP and SV increased steadily, followed by a decreased HR due to the baroreflex. A decreased TMP, but not PCWP, caused a transient drop in SV with no changes in HR or pulse pressure during LBNP release. These results suggest that the pericardium constrains LV filling during LBNP release, enough to cause a small but significant drop of SV, even at low cardiac filling pressure in healthy humans.     

The effect of blood volume loss on cardiovascular response to lower body negative pressure using a mathematical model

Different mathematical models of varying complexity have been proposed in recent years to study the cardiovascular (CV) system. However, only a few of them specifically address the response to lower body negative pressure (LBNP), a stress that can be applied in weightlessness to predict changes in orthostatic tolerance. Also, the simulated results produced by these models agree only partially with experimental observations. In contrast, the model proposed by Melchior et al., and modified by Karam et al. is a simple representation of the CV system capable of accurately reproducing observed LBNP responses up to presyncopal levels. There are significant changes in LBNP response due to a loss of blood volume and other alterations that occur in weightlessness and related one-g conditions such as bedrest. A few days of bedrest can cause up to 15% blood volume loss (BVL), with consequent decreases in both stroke volume and cardiac output, and increases in heart rate, mean arterial pressure, and total peripheral resistance. These changes are more pronounced at higher levels of LBNP. This paper presents the results of a simulation study using our CV model to examine the effect of BVL on LBNP response.     

Effect of heat stress on cardiac output and systemic vascular conductance during simulated hemorrhage to presyncope in young men

During moderate actual or simulated hemorrhage, as cardiac output decreases, reductions in systemic vascular conductance (SVC) maintain mean arterial pressure (MAP). Heat stress, however, compromises the control of MAP during simulated hemorrhage, and it remains unknown whether this response is due to a persistently high SVC and/or a low cardiac output. This study tested the hypothesis that an inadequate decrease in SVC is the primary contributing mechanism by which heat stress compromises blood pressure control during simulated hemorrhage. Simulated hemorrhage was imposed via lower body negative pressure (LBNP) to presyncope in 11 passively heat-stressed subjects (increase core temperature: 1.2 ± 0.2°C; means ± SD). Cardiac output was measured via thermodilution, and SVC was calculated while subjects were normothermic, heat stressed, and throughout subsequent LBNP. MAP was not changed by heat stress but was reduced to 45 ± 12 mmHg at the termination of LBNP. Heat stress increased cardiac output from 7.1 ± 1.1 to 11.7 ± 2.2 l/min (P < 0.001) and increased SVC from 0.094 ± 0.018 to 0.163 ± 0.032 l·min(-1)·mmHg(-1) (P < 0.001). Although cardiac output at the onset of syncopal symptoms was 37 ± 16% lower relative to pre-LBNP, presyncope cardiac output (7.3 ± 2.0 l/min) was not different than normothermic values (P = 0.46). SVC did not change throughout LBNP (P > 0.05) and at presyncope was 0.168 ± 0.044 l·min(-1)·mmHg(-1). These data indicate that in humans a cardiac output adequate to maintain MAP while normothermic is no longer adequate during a heat-stressed-simulated hemorrhage. The absence of a decrease in SVC at a time of profound reductions in MAP suggests that inadequate control of vascular conductance is a primary mechanism compromising blood pressure control during these conditions.     

A model of hemorrhagic shock and acute lung injury in Landrace-Large White Swine

Traumatic injury is a leading cause of death worldwide for people between 5 and 44 y of age, and it accounts for 10% of all deaths. The incidence of acute lung injury, a life-threatening complication in severely injured trauma patients remains between 30% and 50%. This study describes an experimental protocol of volume-controlled hemorrhage in Landrace-Large White swine. The experimental approach simulated the clinical situation associated with hemorrhagic shock in the trauma patient while providing controlled conditions to maximize reproducibility. The duration of the protocol was 8 h and was divided into 5 distinct phases-stabilization, hemorrhage, maintenance, resuscitation, and observation-after which the swine were euthanized. Lung tissue samples were analyzed histologically. All swine survived the protocol. The hemodynamic responses accurately reflected those seen in humans, and the development of acute lung injury was consistent among all swine. This experimental protocol of hemorrhagic shock and fluid resuscitation in Landrace-Large White swine may be useful for future study of hemorrhagic shock and acute lung injury.