Assessment Of Blood Pressure Regulatory Controls To Detect Hypovolemia And Orthostatic Intolerance

Regulation of blood pressure is vital for maintaining organ perfusion and homeostasis. A significant decline in arterial blood pressure could lead to fainting and hypovolemic shock. In contrast to young and healthy, people with impaired autonomic control due to aging or disease find regulating blood pressure rather demanding during orthostatic challenge. This thesis performed an assessment of blood pressure regulatory controls during orthostatic challenge via traditional as well as novel approaches with two distinct applications 1) to design a robust automated system for early identification of hypovolemia and 2) to assess orthostatic tolerance in humans. In chapter 3, moderate intensity hemorrhage was simulated via lower-body negative pressure (LBNP) with an aim to identify moderate intensity hemorrhage (-30 and -40 mmHg LBNP) from resting baseline. Utilizing features extracted from common vital sign monitors, a classification accuracy of 82% and 91% was achieved for differentiating -30 and -40 mmHg LBNP, respectively from baseline. In chapter 4, cause-and-effect relationship between the representative signals of the cardiovascular and postural systems to ascertain blood pressure homeostasis during standing was performed. The degree of causal interaction between the two systems, studied via convergent cross mapping (CCM), showcased the existence of a significant bi-directional interaction between the representative signals of two systems to regulate blood pressure. Therefore, the two systems should be accounted for jointly when addressing physiology behind fall. Further, in chapter 5, the potential of artificial gravity (2-g) induced via short-arm human centrifuge at feet towards evoking blood pressure regulatory controls analogous to standing was investigated. The observation of no difference in the blood pressure regulatory controls, during 2-g centrifugation compared to standing, strongly supported the hypothesis of artificial hypergravity for mitigating cardiovascular deconditioning, hence minimizing post-flight orthostatic intolerance

Impacts of Microgravity Analogs to Spaceflight on Cerebral Autoregulation.

It is well known that exposure to microgravity in astronauts leads to a plethora physiological responses such as headward fluid shift, body unloading, and cardiovascular deconditioning. When astronauts return to Earth, some encounter problems related to orthostatic intolerance. An impaired cerebral autoregulation (CA), which could be compromised by the effects of microgravity, has been proposed as one of the mechanisms responsible for orthostatic intolerance. CA is a homeostatic mechanism that maintains cerebral blood flow for any variations in cerebral perfusion pressure by adapting the vascular tone and cerebral vessel diameter. The ground-based models of microgravity are useful tools for determining the gravitational impact of spaceflight on human body. The head-down tilt bed rest (HDTBR), where the subject remains in supine position at -6 degrees for periods ranging from few days to several weeks is the most commonly used ground-based model of microgravity for cardiovascular deconditioning. head-down bed rest (HDBR) is able to replicate cephalic fluid shift, immobilization, confinement, and inactivity. Dry immersion (DI) model is another approach where the subject remains immersed in thermoneutral water covered with an elastic waterproof fabric separating the subject from the water. Regarding DI, this analog imitates absence of any supporting structure for the body, centralization of body fluids, immobilization and hypokinesia observed during spaceflight. However, little is known about the impact of microgravity on CA. Here, we review the fundamental principles and the different mechanisms involved in CA. We also consider the different approaches in order to assess CA. Finally, we focus on the effects of short- and long-term spaceflight on CA and compare these findings with two specific analogs to microgravity: HDBR and DI

Non-linear Heart Rate and Blood Pressure Interaction in Response to Lower-Body Negative Pressure

Early detection of hemorrhage remains an open problem. In this regard, blood pressure has been an ineffective measure of blood loss due to numerous compensatory mechanisms sustaining arterial blood pressure homeostasis. Here, we investigate the feasibility of causality detection in the heart rate and blood pressure interaction, a closed-loop control system, for early detection of hemorrhage. The hemorrhage was simulated via graded lower-body negative pressure (LBNP) from 0 to -40 mmHg. The research hypothesis was that a significant elevation of causal control in the direction of blood pressure to heart rate (i.e., baroreflex response) is an early indicator of central hypovolemia. Five minutes of continuous blood pressure and electrocardiogram (ECG) signals were acquired simultaneously from young, healthy participants (27 ± 1 years, N = 27) during each LBNP stage, from which heart rate (represented by RR interval), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were derived. The heart rate and blood pressure causal interaction (RR SBP and RR MAP) was studied during the last 3 min of each LBNP stage. At supine rest, the non-baroreflex arm (RR SBP and RR MAP) showed a significantly (p \u3c 0.001) higher causal drive toward blood pressure regulation compared to the baroreflex arm (SBP RR and MAP RR). In response to moderate category hemorrhage (-30 mmHg LBNP), no change was observed in the traditional marker of blood loss i.e., pulse pressure (p = 0.10) along with the RR SBP (p = 0.76), RR MAP (p = 0.60), and SBP RR (p = 0.07) causality compared to the resting stage. Contrarily, a significant elevation in the MAP RR (p = 0.004) causality was observed. In accordance with our hypothesis, the outcomes of the research underscored the potential of compensatory baroreflex arm (MAP RR) of the heart rate and blood pressure interaction toward differentiating a simulated moderate category hemorrhage from the resting stage. Therefore, monitoring baroreflex causality can have a clinical utility in making triage decisions to impede hemorrhage progression

Proceedings of the First Joint NASA Cardiopulmonary Workshop

The topics covered include the following: flight echocardiography, pulmonary function, central hemodynamics, glycerol hyperhydration, spectral analysis, lower body negative pressure countermeasures, orthostatic tolerance, autonomic function, cardiac deconditioning, fluid and renal responses to head-down tilt, local fluid regulation, endocrine regulation during bed rest, autogenic feedback, and chronic cardiovascular measurements. The program ended with a general discussion of weightlessness models and countermeasures

Neural regulation of cardiovascular response to exercise: role of central command and peripheral afferents

During dynamic exercise, mechanisms controlling the cardiovascular apparatus operate to provide adequate oxygen to fulfill metabolic demand of exercising muscles and to guarantee metabolic end-products washout. Moreover, arterial blood pressure is regulated to maintain adequate perfusion of the vital organs without excessive pressure variations. The autonomic nervous system adjustments are characterized by a parasympathetic withdrawal and a sympathetic activation. In this review, we briefly summarize neural reflexes operating during dynamic exercise. The main focus of the present review will be on the central command, the arterial baroreflex and chemoreflex, and the exercise pressure reflex. The regulation and integration of these reflexes operating during dynamic exercise and their possible role in the pathophysiology of some cardiovascular diseases are also discusse

AUTONOMIC OUTPUT IN HEALTH AND DISEASE: CLOSED-LOOP DYNAMICS OF BAROREFLEX CHANGES

Introduction Sympathetic\u2013parasympathetic interaction plays a critical role in the evolution and outcome of many cardiovascular disorders. It is well established that the sympathetic activation has an arrhythmogenic potential, contrariwise the vagal activation has an opposite effect. These findings are summarised in the generic concept of the \u201cautonomic balance\u201d, which generate the common perception that the loss of autonomic balance is a potentially proarrhythmic condition, and therapeutic strategies that aim at modulating the autonomic nervous system might increase the cardiac electrical stability. Several tools have been proposed to investigate the activity of the autonomic nervous system, and the analysis of the arterial baroreflex is considered an indirect measure of the cardiac vagal activity. In fact the spontaneous baroreflex sensitivity (BRS) is viewed as an index of the rise in the cardiac vagal efferent activity in response to an increase in arterial blood pressure. BRS has been assessed in a variety of conditions and with a variety of experimental techniques, focusing mostly on the cardiac-chronotropic efferent branch. Healthy subjects and several cardiovascular diseases have been extensively investigated by the analysis of baroreflexes with either a closed-loop and/or an open-loop approach. The latter allows computation of the characteristic parameters of the baroreflex curve, i.e. the centring point, the operating point, and the maximal gain. This approach can be applied only in steady state conditions, at rest and during exercise, since it make use of external factors (mechanical or pharmacological) to modify the operating range and to construct the responding range, in terms of heart rate (HR) or arterial blood pressure (BP) responses. Contrariwise, the closed-loop approach analyses the relationship between HR and BP to define the sensitivity of the baroreflex close to the operating point, which could be displaced toward the \u201cthreshold\u201d of the baroreflex curves in some conditions, i.e. during exercise. In closed-loop condition, Bertinieri and colleagues (1988) proposed the so-called sequence method which they applied in steady state condition. In practice, they computed the mean slope of several BRS sequences, of at least three beats, in which the R-R interval (RRi) of the ECG varied consensually to BP, regardless of the direction. Recently, this method was applied also in unsteady state conditions (Adami et al., 2013, Bringard et al., 2017; Fagoni et al., 2015; Sivieri et al. 2015); the only a-priori assumption behind the sequence method is that each heart beat has a biunivocal effect on the following beat: no upper limit was imposed to the length of baroreflex sequences (minimum three beats). Moreover, the BRS analysis was applied to estimate the prognosis in patients affected by cardiovascular diseases (Head, 1995; Korner et al., 1974; La Rovere et al., 1998, 2008, 2011). Autonomic output is different in health and disease and the BRS can be used to analyse these differences in several conditions. Thus, the purpose of this project was to perform a closed-loop baroreflex analysis, under different dynamic conditions (rest, exercise, apnoeas), in healthy subjects and in patients affected by mild arterial hypertension. The closed-loop approach was used to this aim, in order to deeply investigate the dynamics of the arterial baroreflex in the following unsteady state conditions: i) at exercise onset and ii) during apnoeas, in healthy volunteers; iii) during exercise, comparing healthy subjects and hypertensive patients. Commonly, the sequence method is computed starting from the R-R interval (RRi) of the ECG, and the systolic blood pressure (SAP). In literature, both HR and RRi are used to calculate BRS, even though RRi is the reciprocal of HR, and these two parameters provided two different information. To clarify this challenging point, a further detailed paper will be proposed to discuss this topic. In this thesis, we decided to use the relationship between HR and MAP to compute BRS. While HR has been an a-priori choice, the use of MAP was a consequence of the typology of experiments we carried out. The beginning of physical activity is accomplished by the sudden change in the total peripheral resistances (TPR), which predominantly acts on DAP; this modification affects more MAP than SAP, thus the former parameter was chosen to define the BRS. First study: baroreflex at exercise onset This first experiment analysed the dynamics of baroreflex resetting at exercise onset. Baroreflex resetting is generally studied at steady state, by means of open-loop procedures, and it was demonstrated that during exercise the operating point is displaced upward and rightward with respect to rest, and its maximal gain is invariant (Rowell et al. 1996; DiCarlo and Bishop 2001; Raven et al. 2002; Raven et al. 2006; Raven 2008; Fadel and Raven 2012; Mitchell 2013). Notwithstanding, the dynamics of baroreflex displacement from rest to exercise was never described so far. We aimed at investigating the temporal components of the mechanisms that intervene in determining baroreflex resetting during transient. Ten healthy volunteers took parts in the experiments. They performed three repetition of a 50 W exercise on a cycle ergometer, lasting seven minutes, in supine and upright position; the different posture was used to have an a-priori displacement the BRS operating point (Schwartz et al., 2013) even at rest. HR was continuously recorded, on single beat basis, by electrocardiography. Arterial pressure was continuously recorded by a non-invasive finger pressure cuff. From pulse pressure profiles, we determined cardiac output (CO) by Modelflow, and we computed MAP; TPR was derived as the ratio between the former two parameters. We performed the closed-loop analysis of HR vs MAP relationship at rest before starting the exercise (BRS computed as the average of the mean slopes of all analysed sequences of each single subject, over one minute), during the transient (HR vs MAP relationship), and during exercise (BRS over one minute steady state recording). At exercise onset, HR was higher than in quiet rest. As exercise started, MAP fell to a minimum (MAPmin) of about 73 mmHg in both posture, while HR increased. The initial HR versus MAP relationship was linear, with flatter slope than resting baroreflex sensitivity, in both postures. TPR fell and CO increased. After MAPmin, both HR and MAP increased toward exercise steady state, with further CO increase. The sensitivity of baroreflex during steady state at exercise resulted lower than at rest, in both posture, and invariant compared to the beginning of exercise. These results suggest that, at exercise onset, the falling of MAP was corrected by a HR reduction along a baroreflex curve; the sensitivity of the baroreflex changed immediately during the transient, with lower sensitivity than at rest, and then BRS remained unchanged during the exercise steady state. After reaching MAPmin, the baroreflex resetting took place, yet with a delay after the beginning of exercise. Thus, the baroreflex resetting starts after the exercise onset, but the sensitivity of the baroreflex changes immediately, and this process is compatible with the central command hypothesis. However, the central command theory may not explain the resetting process, that lasted one minute upright, but not supine (it took more time), compatibly with a possible role of increasing sympathetic stimulation of the sinus node during exercise (Fagraeus and Linnarsson, 1976; Orizio et al., 1988). Second study: baroreflex in apnoea. The cardiovascular response to apnoea is characterised by three phases (Fagoni et al., 2015, 2017; Perini et al., 2008; Sivieri et al., 2015). The first dynamic phase (\u3c61) of the cardiovascular response to apnoea is characterised by a sudden drop in MAP, accompanied by an increase HR (Costalat et al, 2015; Fagoni et al., 2015; Perini et al, 2008, 2010; Sivieri et al., 2015). It was interpreted as a baroreflex attempt at correcting a MAP fall due to a reduction in venous return caused by an increase in intrathoracic pressure occurring at elevated lung volumes. The purpose was to perform the analysis of the HR vs MAP relationship during the \u3c61 of apnoeas performed at lung volumes close to the total lung capacity, at rest and during exercise. Indeed, during exercise apnoeas, the characteristics of \u3c61 would be different than in resting apnoeas, because the BRS slope at exercise is lower than at rest, and the operating point of the baroreflex should be displaced. We calculated BRS in steady state condition before apnoeas, during phase II (\u3c62), and we analysed the HR vs MAP relationship during \u3c61, before and after attainment MAPmin, in resting and exercise apnoeas. Ten healthy divers performed resting and exercise (30 W) apnoeas. HR and MAP were recorded on a beat-by-beat basis by means of an electrocardiography and the Portapres\uae, respectively. The resulting slopes of the linear regression line of the HR versus MAP relationship, at rest, during steady \u3c62, before and after the attainment of MAPmin, were computed in both conditions. We also analysed the modification of the prevailing HR and MAP from the first part of \u3c61, before the MAPmin, and after MAPmin, to investigate if baroreflex resetting took place after attainment of MAPmin. Before the beginning of apnoeas, BRS was lower (p<0.05) during exercise than in resting apnoeas (-1.23 \ub1 0.23 and -0.87 \ub1 0.21 b min-1 mmHg-1, respectively). This difference was also reported for the HR vs MAP relationship in all the investigated conditions. In either resting and exercise apnoeas, slopes were lower at the beginning of \u3c61 (-0.49 \ub1 0.20 and -0.31 \ub1 0.08 b min-1 mmHg-1, resting and exercise, respectively), compared to rest, \u3c62 (-1.12 \ub1 0.33 and -0.82 \ub10.27 b min-1 mmHg-1, resting and exercise, respectively) and after MAPmin (-0.96 \ub1 0.24 and -0.70\ub1 0.31 b min-1 mmHg-1, resting and exercise, respectively). The prevailing HR and MAP at the beginning of apnoeas resulted different compared to after attainment of MAPmin, then both HR and MAP increased consensually to attain new levels: whereas at rest both HR and MAP increased, during exercise MAP was displaced upward and rightward, whilst the HR remained unchanged. The novelty of this study is that during the dynamic phase of apnoeas, the HR vs MAP relationship showed a baroreflex dynamic characterized by a sudden modification in the sensitivity compared to rest and to the steady phase II. After the attainment of MAPmin, a parallel rise in HR and MAP took place, which we interpreted as due to baroreflex resetting. Indeed, the prevailing HR and MAP resulted shifted upward and rightward during exercise compared to rest. During exercise, this process caused an increase in MAP after MAPmin, compared to before MAPmin, with an invariant HR: the prevailing sympathetic output during exercise might affects much more the vasomotor component of the cardiovascular responses compared to the cardiac one, resulting in higher TPR and lower HR values (Fagoni et al., 2015; Sivieri et al., 2015) Third study: baroreflex in hypertensive patients. The BRS in hypertensive patients is impaired (Bristow et al., 1969; Head, 1995; Korner et al., 1974; Mancia et al., 1978), and the modification in BRS is associated with worst outcome in cardiovascular patients (La Rovere et al., 1998, 2008, 2011; Osculati et al., 1990). Studies concerning the implantation of continuous baroreflex stimulators as a tool to diminish central sympathetic outflow (Mohaupt et al., 2007) and the introduction of catheter-based renal selective denervation for resistant hypertension show a significantly reduction in blood pressure (DiBona and Esler, 2010; Esler, 2011; Schlaich et al., 2009). These data suggest that the overall cardiovascular regulation in hypertensive patients may be different from normal, and the analysis of the dynamics of the baroreflex response to exercise might be different from healthy subjects. We aimed at investigating the steady-state and the dynamics of the HR vs MAP relationship in response to exercise in patients affected by essential hypertension compared to age-matched healthy controls, carried out in supine and upright postures, at two different workloads, 50 and 75W. Ten patients affected by grade I or II of arterial hypertension were age-matched with ten healthy controls. HR and MAP were recorded on a beat-by-beat basis by means of an electrocardiography and the Portapres\uae, respectively. The resulting slopes of the linear regression line of the HR versus MAP relationship, at rest, during the transient and at steady state during exercise, were computed in supine and upright position. Data were compared between patients and healthy volunteers, between positions, and among the different phases before and during exercises. BRS resulted steeper in controls than in hypertensive patients (supine -1.43 \ub1 0.19 and -1.16 \ub1 0.33 b min-1 mmHg-1 for controls and hypertensive patients, respectively; upright -1.22 \ub1 0.2 and -0.99 \ub1 0.19 b min-1 mmHg-1 for controls and hypertensive patients, respectively), as well as the linear relationship between HR and MAP at the beginning of exercise at 50 W, in both positions, resulted higher in controls than in patients. In supine position controls showed higher slopes at rest than at the beginning and during exercise. In controls and hypertensive patients, at the beginning of exercise at 75 W the slopes were lower in upright than supine. These data showed a trend characterised by a reduced baroreflex sensitivity in all conditions with sympathetic hyperactivity: hypertension versus control, exercise versus rest, and upright versus supine. Moreover, several slopes resulted lower at the beginning of exercise and during steady state exercise compare to rest, confirming previous findings. It is noteworthy that during the transient at 75 W the baroreflex response was absent in several patients in supine position, probably due to sympathetic overactivity which limited the MAP fall demonstrated at the exercise onset because of the sudden drastic fall in TPR (Elstad et al., 2009; Faisal et al., 2010; Lador et al., 2006, 2008; Wieling et al., 1996). Conclusion The analysis of the relationship between HR and MAP by means of the closed-loop approach is a non-invasive method that can be easily applied in health and disease, and it can be used as an indirect measure of the autonomic nervous system activity. The reported results on the patterns of baroreflex changes in dynamic states suggested that the baroreflex resetting started after the beginning of exercise, but the modification of the sensitivity was almost immediate, as soon as the MAP fell and the baroreflex activity tried to counteract by increasing the HR. After the attainment of the MAPmin, which might be considered a trigger MAP value, the resetting phase took place. The change in slope at exercise onset might be attributed to the sudden vagal withdrawal, and compatibly more with the central command theory. Contrariwise, the resetting process may well be mediated by other neural mechanisms (Raven et al., 2006), and it is possible that the activation of the sympathetic efferent branch of the autonomic nervous system plays a role in the phase of the exercise transient after attainment MAPmin (Lador et al., 2006). At the same time, apnoea provided interesting information about the baroreflex function, since the first phase is characterized by dynamic and deep modifications in MAP, sustained for several beats, counteracted by adjustments in HR. In exercise apnoeas BRS was lower than resting apnoeas, in all the investigated conditions. In \u3c61, rapid cardiovascular adjustments affect the baroreflex responses with different pattern before and after MAPmin, showing higher values of the HR vs MAP slopes after the attainment of MAPmin compared to the onset of \u3c61. The baroreflex sensitivity restored immediately after reaching the MAPmin in \u3c61, indeed BRS in \u3c62 was similar to the one computed at the beginning of apnoea. Finally, the prevailing HR and MAP points during exercise apnoeas were displaced rightward and upward compared to resting apnoeas. During \u3c62, HR decreased, and the TPR increased, thus a modification in the autonomic output can occur, with a dissociation between heart (characterised by predominant vagal activity) and vascular system (with predominant sympathetic activity), that may explain why these modifications did not affect the baroreflex sensitivity during \u3c62 apnoeas. In the hypertension study, patients presented a reduced baroreflex gain, in agreement with previous findings (Bristow et al., 1969; Head, 1995; Korner et al., 1974; Mancia et al., 1978). The baroreflex sensitivity, in healthy and hypertensive subjects, changed immediately at the exercise onset, in both positions, and remained unchanged during the steady state of light-mild exercises: the baroreflex resetting acted in the same manner in healthy and hypertensive patients, but with a reduced gain in the latter compared to the former. The closed-loop approach allows the analysis of the BRS in several conditions, such as rest, exercise, apnoea and in pathologies (hypertension, orthostatic intolerance, dysautonomic diseases). BRS could be a useful tool, i.e. to assess improvements after rehabilitation in neurological as well as in cardiorespiratory diseases, or after prolonged bed rest, in healthy volunteers and in patients after prolonged hospital stay. The application of this technique might be used to monitor the efficacy of the undertaken treatment, whether behavioural or pharmacological. Thus, the modification in BRS might be considered as a mirror of cardiovascular adjustments following a different stimulation of the two branches of the autonomic nervous system, in health and disease

Cardiovascular Deconditioning Resulting from 28-hour Bed-rest and the Efficacy of the Fluid Loading Countermeasure

This study tested the hypotheses that 1) 28h head-down bed-rest (HDBR) would result in significant hypovolemia and cardiovascular deconditioning, and that 2) NASA’s fluid loading protocol (ingestion of 15 ml/kg water with a 1g NaCl for every 125ml of water consumed) would restore normovolemia and prevent cardiovascular deconditioning resulting from 28h HDBR. Nine healthy men were tested in 5 testing scenarios, with a progressive lower body negative pressure (LBNP) protocol performed before and after each scenario to measure the subjects’ cardiovascular responses to orthostasis. Subjects were tested in two 28h HDBR conditions, without fluid loading (NFL) and with fluid loading (FL), as well as in three 4-hour control conditions to isolate the effects of circadian rhythm, HDBR, and fluid loading. After 28h NFL HDBR, plasma volume was reduced by 8%. There were no symptoms of syncope during orthostatic testing following 28h NFL HDBR, however cardiovascular deconditioning was apparent as there were significant increases in heart rate, reductions in central venous pressure, and reductions in portal vein diameter during LBNP testing. There were no changes in stroke volume, cardiac output, systemic vasoconstriction, cardiac measures, and arterial and cardiopulmonary baroreflex responses, and no evidence of splanchnic or venous pooling. This study also found that NASA’s fluid loading protocol was ineffective at restoring normovolemia after 28h HDBR, as there were no differences in plasma volume between 28h FL HDBR post and 28h NFL HDBR post tests (p=0.22). Cardiovascular deconditioning was not prevented by fluid loading as the heart rate response remained elevated and central venous pressure remained reduced after 28h FL HDBR. In addition, four of the nine subjects experienced nausea during administration of the fluid loading protocol prescription and two subjects vomited, further evidence that NASA’s fluid loading protocol is not effective at preventing orthostatic hypotension. Investigation of control models verified that deconditioning was the result of HDBR. It was also concluded that circadian rhythm did not affect the measured cardiovascular responses and the fluid loading protocol was ineffective at increasing blood volume in the absence of HDBR

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 349)

This bibliography lists 149 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during April, 1991. Subject coverage includes: aerospace medicine and psychology, life support systems and controlled environments, safety equipment, exobiology and extraterrestrial life, and flight crew behavior and performance