Stages Of Lower Body Negative Pressure Research Articles

Physiologic validation of the compensatory reserve metric obtained from pulse oximetry: A step towards advanced medical monitoring on the battlefield.

The Compensatory Reserve Metric (CRM) provides a time sensitive indicator of hemodynamic decompensation. However, its in-field utility is limited due to the size and cost-intensive nature of standard vital sign monitors or photoplethysmographic volume-clamp (PPGVC) devices used to measure arterial waveforms. In this regard, photoplethysmographic measurements obtained from pulse oximetry (PPGPO) may serve as a useful, portable alternative. This study aimed to validate CRM values obtained using PPGPO. Forty-nine healthy adults (25 females) underwent a graded lower body negative pressure (LBNP) protocol to simulate hemorrhage. Arterial waveforms were sampled using PPGPO and PPGVC. The CRM was calculated using a one-dimensional convolutional neural network. Cardiac output and stroke volume were measured using PPGVC. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. Log-rank analyses were used to examine differences in shock determination during LBNP between monitored hemodynamic parameters. The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 47±12% reduction in stroke volume, 64±27% increase in heart rate, and 21±7% reduction in systolic blood pressure (P<0.001 for all). CRM values obtained with both PPGPO and PPGVC were associated with changes in heart rate (P<0.001), stroke volume (P<0.001), and pulse pressure (P<0.001). Furthermore, they provided an earlier detection of hemodynamic shock relative to the traditional metrics of shock index (P<0.001 for both), systolic blood pressure (P<0.001 for both), and heart rate (P=0.001 for both). The CRM obtained from PPGPO provides a valid, time-sensitized prediction of hemodynamic decompensation, opening the door to provide military medical personnel noninvasive in-field advanced capability for early detection of hemorrhage and imminent onset of shock. Diagnostic Tests or Criteria, Level IV.

Sublingual sufentanil does not decrease tolerance to progressive central hypovolemia

Hemorrhage is a leading cause of death in both civilian and battlefield settings. Since pain often accompanies a hemorrhagic insult, the administered pain medication must not interfere with critical autonomic responses beneficial to maintaining arterial blood pressure and thus organ perfusion. Sublingual sufentanil is currently available for administration on the battlefield, but its effect on hemorrhage tolerance is unknown. This study tested the hypothesis that sufentanil impairs tolerance to progressive central hypovolemia in awake humans. METHODS: 29 participants, 15 males and 14 females (aged: 29 ± 5, weight: 74 ± 8 kg, BMI: 25 ± 2 kg/m2) participated in this double-blinded, randomized, placebo-controlled trial. Following sublingual administration of sufentanil (30 μg) or placebo, participants completed a progressive lower-body negative pressure (LBNP) protocol starting at 40 mmHg that was further reduced by 10 mmHg every three minutes until presyncope. Presyncope was defined as: continued reports of feeling faint and/or nauseous, a rapid decline in blood pressure resulting in systolic blood pressure &lt;80 mmHg, and/or relative bradycardia accompanied by a narrowing of pulse pressure. Tolerance to LBNP, quantified as cumulative stress index (mmHg*min), was compared between sufentanil and placebo trials using a Wilcoxon Signed rank test. Arterial blood pressure, heart rate, and plasma catecholamine concentrations were compared using mixed effects models (LBNP stage x Drug). RESULTS: Tolerance to LBNP was not different between trials (sufentanil: 518 ± 203 vs. placebo: 594 ± 267, p = 0.495). Mean blood pressure decreased similarly between the two trials during LBNP (sufentanil: -23 ± 9 mmHg vs. placebo: -22 ± 10 mmHg, p&lt; 0.001), with no main effect of drug (p = 0.498) or interaction (p = 0.935). Increases in heart rate with LBNP were similar between the two trials (sufentanil: 44 ± 25 bpm vs. placebo: 52 ± 23 bpm, time: p &lt; 0.001) with no main effect of drug (p=0.626) or interaction (p = 0.424). Epinephrine (drug: p = 0.004, time: p &lt; 0.001, interaction: p = 0.031) and norepinephrine (drug: p = 0.017, time: p &lt; 0.001, interaction: p = 0.161), concentrations increased to LBNP, with post hoc analysis revealing that epinephrine concentrations were higher at LBNP 50 and presyncope (p ≤ 0.05) with sufentanil. CONCLUSION: These data demonstrate that sublingual sufentanil does not impair tolerance to simulated hemorrhage or alter the assessed mechanisms responsible for maintaining arterial blood pressure. W81XWH-22-C-0004. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex Differences in Sympathetic Responses to Lower-Body Negative Pressure.

Trauma-induced hemorrhage is a leading cause of death in prehospital settings. Experimental data demonstrate that females have a lower tolerance to simulated hemorrhage (i.e., central hypovolemia). However, the mechanism(s) underpinning these responses are unknown. Therefore, this study aimed to compare autonomic cardiovascular responses during central hypovolemia between the sexes. We hypothesized that females would have a lower tolerance and smaller increase in muscle sympathetic nerve activity (MSNA) to simulated hemorrhage. Data from 17 females and 19 males, aged 19-45 yr, were retrospectively analyzed. Participants completed a progressive lower-body negative pressure (LBNP) protocol to presyncope to simulate hemorrhagic tolerance with continuous measures of MSNA and beat-to-beat hemodynamic variables. We compared responses at baseline, at two LBNP stages (-40 and -50 mmHg), and at immediately before presyncope. In addition, we compared responses at relative percentages (33%, 66%, and 100%) of hemorrhagic tolerance, calculated via the cumulative stress index (i.e., the sum of the product of time and pressure at each LBNP stage). Females had lower tolerance to central hypovolemia (female: 561 ± 309 vs male: 894 ± 304 min·mmHg [time·LBNP]; P = 0.003). At LBNP -40 and -50 mmHg, females had lower diastolic blood pressures (main effect of sex: P = 0.010). For the relative LBNP analysis, females exhibited lower MSNA burst frequency (main effect of sex: P = 0.016) accompanied by a lower total vascular conductance (sex: P = 0.028; main effect of sex). Females have a lower tolerance to central hypovolemia, which was accompanied by lower diastolic blood pressure at -40 and -50 mmHg LBNP. Notably, females had attenuated MSNA responses when assessed as relative LBNP tolerance time.

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

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

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

Objective. To study the photoplethysmographic (PPG) waveforms of different locations (ear and finger) during lower body negative pressure (LBNP) induced hypovolemia. Then, to determine whether the PPG waveform can be used to detect hypovolemia during the early stage of LBNP. Approach. 36 healthy volunteers were recruited for progressive LBNP induced hypovolemia, with an endpoint of −60 mmHg or development of hypoperfusion symptoms, whichever comes first. Subjects tolerating the entire protocol without symptoms were designated as high tolerance (HT), while symptomatic subjects were designated as low tolerance (LT). Subjects were monitored with an electrocardiogram, continuous noninvasive blood pressure monitor, and two pulse oximetry probes, one on the ear (Xhale) and one the finger (Nellcor). Stroke volume was measured non-invasively utilizing Non-Invasive Cardiac Output Monitor (NICOM, Cheetah Medical). The waveform morphology was analyzed using novel PPG waveforms indices, including phase hemodynamic index (PHI) and amplitude hemodyamaic index and were evaluated from the ear PPG and finger PPG at different LBNP stages. Main results. The PHI, particularly the phase relationship between the second harmonic and the fundamental component of the ear PPG denoted as during the early stage of LBNP (−15 mmHg) in the HT and LT groups is statistically significantly different (p value = 0.0033) with the area under curve 0.81 (CI: 0.616–0.926). The other indices are not significantly different. The 5 fold cross validation shows that during the early stage of LBNP (−15 mmHg) as the single index could predict the tolerance of the subject with the sensitivity, specificity, accuracy and F1 as 0.771 ± 0.192, 0.71 ± 0.107, 0.7 ± 0.1 and 0.771 ± 0.192 respectively. Significance. The ear’s PPG PHI which compares the phases of the fundamental and second harmonic has the potential to be used as an early predictor of central hypovolemia.

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

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

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 -60mmHg LBNP stage, ≥20-min) or low tolerant (LT; did not complete -60mmHg 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.

Sympathetic transduction of blood pressure during graded lower body negative pressure

IntroductionCross‐sectional work has demonstrated that participants with high resting muscle sympathetic nerve activity (MSNA) have lower resting sympathetic transduction of blood pressure (BP), and a larger proportion of sympathetic bursts firing above the BP set‐point (or mean BP). However, to date, most of these observations have been evaluated between participants with different levels of resting MSNA. The objective of the current study is to evaluate the influence of acute elevations in MSNA on sympathetic transduction of BP in young healthy adults using graded lower body negative pressure (LBNP). We hypothesize that sympathetic transduction will decrease during acute elevations in MSNA due to an increased proportion of MSNA bursts firing above the BP set‐point.MethodsTen (1 female) young healthy participants underwent 8 minutes of quiet rest, followed by a graded LBNP protocol consisting of 8‐minute stages at ‐10, ‐20, and ‐30mmHg. Beat‐to‐beat heart rate and BP were quantified using single‐lead electrocardiography and finger photoplethysmography, respectively, while MSNA was quantified using fibular nerve microneurography. Sympathetic transduction was quantified in the time (signal‐averaging) and frequency (MSNA‐diastolic BP low frequency [LF: 0.04‐0.15 Hz] transfer function magnitude) domains. Tertiles of diastolic BP were determined for each participant, and the proportion of MSNA bursts firings within each BP tertile were quantified.ResultsMSNA burst frequency increased progressively during graded LBNP (from 15±7 to 17±7, 22±7, and 27±9 bursts/min; P&lt;0.01), while the proportion of MSNA bursts firing in the highest BP tertile remained stable (19±7, 18±9, 19±9, 19±7 %; P=0.72). Sympathetic transduction of BP was unchanged during LBNP (from 2.1±1.1 to 2.3±1.5, 2.1±1.2, and 2.0±1.1 mmHg; P=0.51), while the BP responses to non‐burst cardiac cycles decreased progressively (from ‐0.7±0.5 to ‐0.9±0.5, ‐1.0±0.4, and ‐1.4±0.7 mmHg; P&lt;0.01). The difference between burst and non‐burst cardiac cycles (from 2.8±1.4 to 3.2±1.9, 3.1±1.5, and 3.4±1.3 mmHg; P=0.26) and the MSNA‐diastolic BP transfer function magnitude (from 0.14±0.09 to 0.14±0.06, 0.14±0.06, and 0.13±0.07 au/mmHg; P=0.40) were also unchanged during LBNP. Lastly, the change in the proportion of MSNA bursts firing in the largest BP tertile was associated with the change in signal‐averaged sympathetic transduction across each stage of LBNP (r= ‐0.79, ‐0.78, ‐0.81; P≤0.01).ConclusionSympathetic transduction of diastolic BP is unchanged during graded LBNP due to the heterogenous inter‐individual responses in the gating of bursts to diastolic BP. The proportion of bursts firing at high BPs are associated with changes in sympathetic transduction of BP. The determinants of gating MSNA burst occurrence by the arterial baroreflex and its capacity for modulation warrant further study.

Lower blood pressure, but not muscle sympathetic nerve activity, in female compared to male adults during progressive central hypovolemia

INTRODUCTIONRapid adjustments in cardiac output and sympathetically‐mediated vasoconstriction are critical to prevent blood pressure (BP) from falling during central hypovolemia. Female adults have a reduced ability to tolerate central hypovolemia (i.e., orthostatic hypotension), potentially due to reduced sympathetically‐mediated vasoconstriction. However, there are minimal data evaluating sex differences in muscle sympathetic nerve activity (MSNA) during pre‐syncopal limited central hypovolemia. Therefore, the purpose of this study was to compare autonomic cardiovascular responses during central hypovolemia between sexes. We tested the hypothesis that young healthy female, compared to male, adults would have a lower tolerance to progressive hypovolemia, accompanied by attenuated MSNA responses.METHODSTwenty‐eight female (28±8 years old, 170±7 cm, 75±8 kg, BMI: 26±3 kg/m2) and 31 male (age: 30±5 years old, height: 176±6 cm, mass: 82±9 kg, BMI: 26±3 kg/m2) adults completed a staged lower‐body negative pressure (LBNP) protocol. The LBNP protocol started at minus 40 mmHg (LBNP40) and was further reduced by 10 mmHg every 3 minutes until the participant reached pre‐syncope. MSNA (radial nerve), heart rate, and BP were collected continuously throughout the protocol. LBNP tolerance was quantified as a cumulative stress index (mmHg*min) and was compared between sexes using a two‐tailed Mann‐Whitney test. MSNA, heart rate, and BP responses during LBNP were compared between sexes (LBNP stage [repeated measure] x sex) using mixed‐model analysis of variance tests.RESULTSConsistent with prior findings, female adults had a lower tolerance to progressive LBNP (female: 513±283 vs. male: 929±357 mmHg*min, p&lt;0.0001). Due to more females reaching pre‐syncope sooner in the protocol, we compared responses during the early stages of LBNP. At these early LBNP stages (LBNP40 &amp; LBNP50), significant interactions for heart rate and BP were observed (heart rate: p&lt;0.0001, BP: p=0.0464). Post‐hoc analyses revealed a significantly higher heart rate (98±20 vs. 82±15 bpm, p&lt;0.0001) and lower mean BP (80±11 vs. 87±7 mmHg, p = 0.0343) in females at LBNP50. However, MSNA burst frequency responses were not different between sexes at the assessed time points (female vs. male; Baseline: 14±9 vs. 17±10, LBNP40: 29±14 vs. 34±12, LBNP50: 34±16 vs. 35±16 bursts/min; sex: p=0.2685, interaction: p=0.2334, stage: p&lt;0.0001).DISCUSSIONConsistent with previous reports, this study demonstrated a lower tolerance to progressive central hypovolemia in female compared to male adults. However, contrary to our hypothesis, there was no difference in MSNA burst frequency between sexes, despite lower BP in female adults during the early stages of LBNP. These findings support the need for future studies to explore other mechanisms contributing to sex differences in tolerance to central hypovolemia.

Low-dose morphine reduces tolerance to central hypovolemia in healthy adults without affecting muscle sympathetic outflow.

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Low-dose (i.e., an analgesic dose) morphine is recommended for use in the prehospital (i.e., field) setting. Morphine administration reduces hemorrhagic tolerance in rodents. However, it is unknown whether morphine impairs autonomic cardiovascular regulation and consequently reduces hemorrhagic tolerance in humans. Thus, the purpose of this study was to test the hypothesis that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thirty adults (15 women/15 men; 29 ± 6 yr; 26 ± 4 kg·m-2, means ± SD) completed this randomized, crossover, double-blinded, placebo-controlled trial. One minute after intravenous administration of morphine (5 mg) or placebo (saline), we used a presyncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (mmHg·min), which was compared between trials using a Wilcoxon matched-pairs signed-rank test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat blood pressure (photoplethysmography) during the LBNP test using mixed-effects analyses [time (LBNP stage) × trial]. Median LBNP tolerance was lower during morphine trials (placebo: 692 [473-997] vs. morphine: 385 [251-728] mmHg·min, P < 0.001, CI: -394 to -128). Systolic blood pressure was 8 mmHg lower during moderate central hypovolemia during morphine trials (post hoc P = 0.02; time: P < 0.001, trial: P = 0.13, interaction: P = 0.006). MSNA burst frequency responses were not different between trials (time: P < 0.001, trial: P = 0.80, interaction: P = 0.51). These data demonstrate that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that tolerance to simulated hemorrhage was lower after low-dose morphine administration. Such reductions in hemorrhagic tolerance were observed without differences in MSNA burst frequency responses between morphine and placebo trials. These data, the first to be obtained in conscious humans, demonstrate that low-dose morphine reduces hemorrhagic tolerance. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.

The Doppler shock index measured by a wearable ultrasound patch accurately detects moderate-to-severe central hypovolemia during lower body negative pressure.

ObjectiveModerate‐to‐severe hemorrhage is a life‐threatening condition, which is challenging to detect in a timely fashion using traditional vital signs because of the human body's robust physiologic compensatory mechanisms. Measuring and trending blood flow could improve diagnosis of clinically significant exsanguination. A lightweight, wireless, wearable Doppler ultrasound patch that captures and trends blood flow velocity could enhance hemorrhage detection.MethodsIn 11 healthy volunteers undergoing simulated hemorrhage and resuscitation during graded lower body negative pressure (LBNP) and release, we studied the relationship between stroke volume (SV) and common carotid artery velocity time integral (VTI) and corrected flow time (FTc). We assessed the diagnostic accuracy of 2 variations of a novel metric, the Doppler shock index (ie, the DSIVTI and DSIFTc), at capturing moderate‐to‐severe central hypovolemia defined as a 30% reduction in SV. The DSIVTI and DSIFTc are calculated as the heart rate divided by either the VTI or FTc, respectively.ResultsA total of 17,822 cardiac cycles were analyzed across 22 LBNP protocols. The average SV reduction to the lowest tolerated LBNP stage was 40%; there was no clinically significant fall in the mean arterial pressure. Correlations between changing SV and the common carotid artery VTI and FTc were strong (R 2 of 0.87, respectively) and concordant. The DSIVTI and DSIFTc accurately detected moderate‐to‐severe central hypovolemia with values for the area under the receiver operator curves of 0.96 and 0.97, respectively.ConclusionIn a human model of hemorrhage and resuscitation, measures from a wearable Doppler ultrasound patch correlated strongly with SV and identified moderate‐to‐severe central hypovolemia with excellent diagnostic accuracy.

Carotid Doppler Measurement Variability in Functional Hemodynamic Monitoring: An Analysis of 17,822 Cardiac Cycles.

OBJECTIVES:Carotid Doppler ultrasound is used as a measure of fluid responsiveness, however, assessing change with statistical confidence requires an adequate beat sample size. The coefficient of variation helps quantify the number of cardiac cycles needed to adequately detect change during functional hemodynamic monitoring.DESIGN:Prospective, observational, human model of hemorrhage and resuscitation.SETTING:Human physiology laboratory at Mayo Clinic.SUBJECTS:Healthy volunteers.INTERVENTIONS:Lower body negative pressure.MEASUREMENTS AND MAIN RESULTS:We measured the coefficient of variation of the carotid artery velocity time integral and corrected flow time during significant cardiac preload changes. Seventeen-thousand eight-hundred twenty-two cardiac cycles were analyzed. The median coefficient of variation of the carotid velocity time integral was 8.7% at baseline and 11.9% during lowest-tolerated lower body negative pressure stage. These values were 3.6% and 4.6%, respectively, for the corrected flow time.CONCLUSIONS:The median coefficient of variation values measured in this large dataset indicates that at least 6 cardiac cycles should be averaged before and after an intervention when using the carotid artery as a functional hemodynamic measure.

The Reciprocal Relationship Between Cardiac Baroreceptor Sensitivity and Cerebral Autoregulation During Simulated Hemorrhage in Humans

Tolerance to reduced central blood volume (e.g., via hemorrhage) depends upon cardiovascular and cerebrovascular mediated compensatory mechanisms to preserve cerebral perfusion. Prior studies have demonstrated a reciprocal relationship between the arterial baroreflex and cerebral autoregulation (CA) at rest and in response to acute hypotension. It is unknown if this reciprocal relationship persists during progressive and sustained hypotension simulating hemorrhage. We hypothesized that the reciprocal relationship between cardiac baroreceptor sensitivity (BRS) and CA would be maintained during a simulated hemorrhage induced by maximal 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, 26 ± 4 y) completed a step-wise LBNP protocol until the onset of presyncope. Subjects were classified as high tolerant (HT) if they completed at least the -60 mmHg stage of LBNP (≥ 20-min), and low tolerant (LT) if they became presyncopal prior to completing the -60 mmHg stage of LBNP (< 20-min), as previously defined by our group. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), and middle cerebral artery velocity (MCAv) were measured continuously. The absolute change from baseline to presyncope (Δ) was calculated for each variable. Cardiac BRS was calculated as ΔHR divided by ΔMAP, and CA was calculated as ΔMCAv divided by ΔMAP. The relationship between BRS and CA was assessed with Pearson's correlation coefficients for the entire group of 51 subjects, and within the HT and LT sub-groups. Absolute change values for the hemodynamic responses were also compared between the two tolerance groups. By design, tolerance to LBNP was different between the groups (HT (n=30): 1775 ± 225 s vs. LT (n=21): 1184 ± 253 s; P<0.0001). Accordingly, HT subjects demonstrated a greater ΔSV (HT: -51 ± 17 ml vs. LT: -41 ± 13 ml; P=0.03) and a greater ΔHR (HT: +56 ± 17 bpm vs. LT: +34 ± 20 bpm; P<0.0001) in response to maximal LBNP. Interestingly, ΔMAP (HT: -18 ± 7 mmHg vs. LT: -19 ± 9 mmHg; P=0.51), ΔMCAv (HT: -17 ± 8 cm/s vs. LT: -19 ± 10 cm/s; P=0.52), BRS (HT: 4 ± 3 bpm/mmHg vs. LT: 3 ± 4 bpm/mmHg; P=0.24), and CA (HT: 1.2 ± 0.9 cm/s.mmHg-1 vs. LT: 1.5 ± 1.8 cm/s.mmHg-1; P=0.45) were similar between HT and LT subjects. In support of our hypothesis, there was a strong reciprocal relationship (R=0.77; P<0.0001) between BRS and CA in the group of 51 subjects. When independently assessing this relationship within each tolerance group, however, there was a stronger relationship in LT subjects (R=0.94; P<0.0001) compared to HT subjects (R=0.57; P<0.001). In support of our hypothesis, the reciprocal relationship between cardiac BRS and CA was maintained during sustained and progressive hypotension, but this relationship was stronger in subjects with lower tolerance to this stress. These findings suggest that despite a strong overall relationship in the interaction between BRS and CA, it may not be a primary compensatory mechanism that dictates tolerance to simulated hemorrhage in young healthy adults.

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

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

Exogenous Infusion of Epinephrine Augments Cardiac Output during Simulated Hemorrhage in Humans

BackgroundLower body negative pressure (LBNP) simulates hemorrhage, evoking compensatory cardiovascular mechanisms of increased heart rate (HR) while stroke volume (SV) and cardiac output (CO) progressively decline, ultimately leading to presyncope. Previous work has shown that circulating levels of plasma epinephrine are elevated during LBNP; however, the role of early administration of epinephrine in compensatory cardiovascular mechanisms to simulated hemorrhage is not well understood.PurposeWe hypothesized that during simulated hemorrhage, a low‐dose exogenous infusion of epinephrine in humans would: 1) augment HR response, 2) attenuate the decline of SV and CO, and 3) prolong time to tolerance.MethodsNine healthy subjects (5M/4F, 35±9yrs, BMI 25±1 kg·m−2) participated in LBNP on two separate study days. Protocols on each day consisted of a 10‐minute pre‐infusion baseline, 15‐minute infusion period (randomized to saline or epinephrine, dose = 0.1 μg·kg−1·min−1, delivered through a peripherally inserted central catheter), 10‐minute post‐infusion baseline, and 5 minute stages of progressive LBNP with stepwise increases of 10–15 mmHg negative pressure until tolerance (systolic blood pressure less than 80 mmHg, bradycardia, or voluntary termination due to presyncopal symptoms). Heart rate (HR; electrocardiogram) and blood pressure (BP; radial arterial catheter) were recorded continuously. Cardiovascular function (HR, SV, CO, and systemic vascular resistance (SVR)) was determined using arterial waveform analysis. Data were analyzed via percent tolerance using repeated measures ANOVA with student method for pairwise comparisons.ResultsInfusion of exogenous epinephrine lowered MAP (p&lt;0.01) and diastolic blood pressure (DBP; p&lt;0.001), but raised systolic blood pressure (SBP; p=0.019) throughout all stages of LBNP. Epinephrine compared to saline augmented mean HR, SV and CO to the penultimate stage of LBNP (p≤0.01 for all cardiac measures) and concurrently reduced SVR (p=0.002). However, time to tolerance was not significantly different between epinephrine and saline conditions (1415 ± 79 vs. 1475 ± 150s, respectively; p=0.69).DiscussionOur findings suggest that during simulated hemorrhage exogenous epinephrine can augment cardiac function without increasing tolerance to progressive central hypovolemia. During the epinephrine infusion, benefits to cardiac function may have been limited by reduced vascular resistance.Support or Funding InformationThe United States Department of Defense W81XWH‐13‐2‐0038

Detecting central hypovolemia in simulated hypovolemic shock by automated feature extraction with principal component analysis.

Assessment of the volume status by blood pressure (BP) monitoring is difficult, since baroreflex control of BP makes it insensitive to blood loss up to about one liter. We hypothesized that a machine learning model recognizes the progression of central hypovolemia toward presyncope by extracting information of the noninvasive blood pressure waveform parametrized through principal component analysis. This was tested in healthy volunteers exposed to simulated hemorrhage by lower body negative pressure (LBNP).Fifty‐six healthy volunteers were subjected to progressive central hypovolemia. A support vector machine was trained on the blood pressure waveform. Three classes of progressive stages of hypovolemia were defined. The model was optimized for the number of principal components and regularization parameter for penalizing misclassification (cost): C. Model performance was expressed as accuracy, mean squared error (MSE), and kappa statistic (inter‐rater agreement).Forty‐six subjects developed presyncope of which 41 showed an increase in model classification severity from baseline to presyncope. In five of the remaining nine subjects (1 was excluded) it stagnated. Classification of samples during baseline and end‐stage LBNP had the highest accuracy (95% and 50%, respectively). Baseline and first stage of LBNP demonstrated the lowest MSE (0.01 respectively 0.32). Model MSE and accuracy did not improve for C values exceeding 0.01. Adding more than five principal components did not further improve accuracy or MSE. Increment in kappa halted after 10 principal components had been added. Automated feature extraction of the blood pressure waveform allows modeling of progressive hypovolemia with a support vector machine. The model distinguishes classes between baseline and presyncope.

Inferior Vena Cava Diameter Reductions Precede Changes in Traditional Vital Signs during Simulated Blood Loss

Hemorrhage is a leading cause of trauma deaths. Many of these deaths could be prevented with early detection and appropriate treatment. Traditional vital signs such as heart rate (HR) and mean arterial pressure (MAP) can remain relatively normal despite the central hypovolemia that occurs during blood loss. Ultrasound measurements of the inferior vena cava diameter (IVCD) have been used clinically as gross indicators of central hypovolemia. However, it is not known if reductions in IVCD occur prior to changes in traditional vital signs during blood loss in humans. PURPOSE: To test the hypothesis that reductions in IVCD occur prior to changes in traditional vital signs during central hypovolemia. METHODS: Blood loss was stimulated using lower body negative pressure (LBNP) in fourteen healthy men (22±2 years). Pressure within the LBNP chamber was reduced by 10 mmHg every four minutes until the pressure reached -80 mmHg or subjects experienced pre-syncopal signs. Sagittal view images of maximum and minimum IVCD were obtained using B-mode ultrasonography between minutes two and four of each stage. The mean HR (ECG), MAP, pulse pressure (PP) and stroke volume (SV) (photoplethysmography) were obtained during the last minute of each stage. RESULTS: Maximum IVCD was lower than baseline (1.5±0.4 cm) at -20 mmHg (1.0±0.3 cm, P<0.01) and throughout LBNP (P<0.01). Minimum IVCD was lower than baseline (0.9±0.3 cm) at -20 mmHg (0.5±0.3 cm, P<0.01) and throughout LBNP (P<0.01). HR was only higher than baseline (70±16 bpm) at the final stage of LBNP (94±19 bpm, p<0.01). MAP was only lower than baseline (91±7 mmHg) at the final stage of LBNP (78±17 mmHg, p<0.0001). PP was lower than baseline (62±5 mmHg) starting at -40 mmHg (53±9 mmHg, P=0.03) and throughout LBNP (P<0.03). SV was lower than baseline (93±28 ml) starting at -50 mmHg (65±14 ml, P=0.01) and throughout LBNP (P<0.01). CONCLUSIONS: Reductions in maximum and minimum IVCD preceded changes in tradition vital signs during graded simulated blood loss. IVCD may be a useful tool to identify blood loss and guide treatment in patients prior to the development of vital sign abnormalities.

Renal Medullary Oxygenation Decreases in a Dose‐Dependent Manner with Graded Lower Body Negative Pressure in Healthy Young Adults

BackgroundIncrease in sympathetic nerve activity (SNA) evokes a renal vasoconstrictor response that is powerfully opposed by autoregulatory influences. In the renal medulla, increases in SNA serve to increase Na+/K+‐ATPase activity (an oxygen dependent process) in the distal tubule, a process contributing to salt and water retention. In this report, we engaged SNA with lower body negative pressure (LBNP) as we employed magnetic resonance imaging to examine an index of renal medullary oxygenation, T2*. At a separate time we applied LBNP as we measured changes in renal blood flow velocity. This is an index that largely reflects changes in renal cortical blood flow.MethodsThirteen healthy (mean age 28 ± 1 yr) men (n = 7) and women (n = 6) participated in one or both of the experimental visits. Graded negative pressure (−10, −20, and −30 mmHg) was applied during 2 visits; visit 1 was for Doppler and visit 2 for MRI. Blood pressure (BP) and heart rate (HR) were also measured at baseline and at each stage of LBNP and recovery. RBV was obtained in all 13 subjects while T2* was obtained in 8 of 13 subjects.ResultsLBNP −30 mmHg led to a lower T2* (−0.65 ± 0.14 ms; P &lt; 0.001). RBV decreased and renal vascular resistance (RVR) increased at −30 mmHg (ΔRBV −7.44 ± 3.87 cm/s, P = 0.041; ΔRVR arbitrary units 0.28 ± 0.11, P = 0.028). During recovery, T2* remained below baseline for the first and the second minutes of the recovery.ConclusionsThese data suggest that −30 mmHg LBNP leads to renal vasoconstriction and medullary deoxygenation. We suspect that changes in T2* are due to a sympathetically mediated, oxygen requiring, accentuation of Na/K ATP activity in the distal tubule. We postulate that this leads to salt and water retention as the SNS is engaged.Support or Funding InformationCommonwealth Universal Research Enhancement Program (CURE); P01 HL134609 (Sinoway)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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 < 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.

Measurement of the Compensatory Reserve Predicts Racial Differences in Orthostatic Tolerance

The Compensatory Reserve Index (CRI) has recently been established to accurately measure the body's integrated capacity to compensate for physiological conditions of reduced central blood volume, and predict hemodynamic decompensation. We previously demonstrated that African American (AA) women have a higher tolerance to orthostatic stress. Therefore, we tested the hypothesis that the CRI would identify racial differences in orthostatic tolerance prior to the onset of traditional signs and symptoms. We measured beat‐by‐beat blood pressure (BP) and heart rate (HR) in 23 AA (22 ± 1 years; 24 ± 1 kg/m2) and 31 Caucasian women (20 ± 1 years; 23 ± 1 kg/m2) during progressive lower body negative pressure (LBNP) to presyncope. Blood pressure waveforms were analyzed using a machine‐learning algorithm to derive the CRI at each LBNP stage; stroke volume (SV) was derived from the Finometer (Model flow). Resting mean arterial BP (AA, 78 ± 3 vs. Caucasian, 74 ± 2 mmHg) and HR (AA, 68 ± 2 vs. Caucasian, 65 ± 2 bpm) were similar between groups. The CRI progressively decreased during LBNP in both groups, however the CRI in Caucasian women was 4% lower than AA women at −15 mmHg LBNP and decreased to 21% lower at −50 mmHg LBNP (P&lt;0.05). The rate of decline in SV during LBNP was greater in Caucasian women (ANOVA P&lt;0.05), and differences were noted as early as −20 mmHg. However changes in BP and HR during LBNP were not different between groups. At presyncope, mean arterial BP (AA, 66 ± 3 vs. white, 65 ± 4 mmHg) and HR (AA, 102 ± 4 vs. white, 97 ± 3 bpm) were similar between groups, as was the change in SV (AA, Δ −33 ± 2 vs. white, Δ −35 ± 3 mL). Finally, the time to presyncope was 1.6 minutes longer in AA women. These data support the notion that greater tolerance to the orthostatic stress induced by LBNP in AA women can be explained by their greater reserve to compensate for progressive central hypovolemia compared to Caucasian women. An important clinical translation is that the CRI provides a more sensitive and specific measure for early assessment of differences in orthostatic tolerance in comparison to traditional vital signs and symptoms or changes in hemodynamics.Support or Funding InformationResearch supported by funding from the Combat Casualty Care Research Program of the US Army Medical Research and Materiel Command and NIH HL071159.