Relationship Between Environmental Air Quality and Congenital Heart Defects.

BACKGROUND: Congenital heart defects (CHDs) affect 40,000 U.S. infants annually. One fourth of these infants have a critical CHD, requiring intervention within the first year of life for survival. Over 80% of CHDs have an unknown etiology. Fine particulate matter ≤2.5 (PM2.5) and ozone (O3) may be air pollutants associated with CHD. OBJECTIVES: The purpose of this study was to explore relationships between first-trimester maternal exposure to air pollutants PM2.5 and O3 and a critical CHD diagnosis. METHODS: A retrospective cohort study with nested case controls was conducted using data from January 1, 2014, to December 31, 2016, and consisted of 199 infants with a diagnosed critical CHD and 550 controls. Air pollution data were obtained from the U.S. Environmental Protection Agency air monitors. Geographic information system software was used to geocode monitoring stations and infant residential locations. Data analysis included frequencies, chi-square, independent t-test analysis, and binary logistic regression for two time periods: the entire first trimester (Weeks 1-12) and the critical exposure window (Weeks 3-8 gestation). RESULTS: Critical CHD odds were not significantly increased by exposure during the first trimester. However, weekly analyses revealed CHD odds were higher in Weeks 5 and 8 as PM2.5 increased and decreased in Week 11 with increased O3 exposure. DISCUSSION: Our study shows no evidence to support the overall association between air pollutants PM2.5 and O3 and a critical CHD diagnosis. However, analyses by week suggested vulnerability in certain weeks of gestation and warrant additional surveillance and study.

Acute effects of electronic cigarettes on arterial pressure and peripheral sympathetic activity in young nonsmokers.

Electronic cigarettes (e-cigarettes) are marketed as an alternative to smoking for those who want to decrease the health risks of tobacco. Tobacco cigarettes increase heart rate (HR) and arterial pressure, while reducing muscle sympathetic nerve activity (MSNA) through sympathetic baroreflex inhibition. The acute effects of e-cigarettes on arterial pressure and MSNA have not been reported: our purpose was to clarify this issue. Using a randomized crossover design, participants inhaled on a JUUL e-cigarette containing nicotine (59 mg/mL) and a similar placebo e-cigarette (0 mg/mL). Experiments were separated by ∼1 mo. We recorded baseline ECG, finger arterial pressure (n = 15), and MSNA (n = 10). Subjects rested for 10 min (BASE) and then inhaled once every 30 s on an e-cigarette that contained nicotine or placebo (VAPE) for 10 min followed by a 10-min recovery (REC). Data were expressed as Δ means ± SE from BASE. Heart rate increased in the nicotine condition during VAPE and returned to BASE values in REC (5.0 ± 1.3 beats/min nicotine vs. 0.1 ± 0.8 beats/min placebo, during VAPE; P < 0.01). Mean arterial pressure increased in the nicotine condition during VAPE and remained elevated during REC (6.5 ± 1.6 mmHg nicotine vs. 2.6 ± 1 mmHg placebo, during VAPE and 4.6.0 ± 1.7 mmHg nicotine vs. 1.4 ± 1.4 mmHg placebo, during REC; P < 0.05). MSNA decreased from BASE to VAPE and did not restore during REC (-7.1 ± 1.6 bursts/min nicotine vs. 2.6 ± 2 bursts/min placebo, during VAPE and -5.8 ± 1.7 bursts/min nicotine vs. 0.5 ± 1.4 bursts/min placebo, during REC; P < 0.05). Our results show that acute e-cigarette usage increases mean arterial pressure leading to a baroreflex-mediated inhibition of MSNA.NEW & NOTEWORTHY The JUUL e-cigarette is the most popular e-cigarette in the market. In the present study, inhaling on a JUUL e-cigarette increased mean arterial pressure and heart rate, and decreased muscle sympathetic nerve activity (MSNA). In contrast, inhaling on a placebo e-cigarette without nicotine elicited no sympathomimetic effects. Although previous tobacco cigarette studies have demonstrated increased mean arterial pressure and MSNA inhibition, ours is the first study to report similar responses while inhaling on an e-cigarette. Listen to this article's corresponding podcast at @ https://ajpheart.podbean.com/e/aerosolized-nicotine-and-cardiovascular-control/.

Association of serum levels of p,p'- Dichlorodiphenyldichloroethylene (DDE) with type 2 diabetes in African American and Caucasian adult men from agricultural (Delta) and non-agricultural (non-Delta) regions of Mississippi.

Epidemiological associations were reported in several studies between persistent organochlorine organic pollutants and type 2 diabetes mellitus (T2D). Mississippi is a highly agricultural state in the USA, particularly the Delta region, with previous high usage of organochlorine (OC) insecticides such as p,p'- dichlorodiphenyltrichloroethane (DDT). In addition, there is a high proportion of African Americans who display elevated prevalence of T2D. Therefore, this State provides an important dataset for further investigating any relationship between OC compounds and metabolic diseases. The aim of this study was to assess whether soil and serum levels of OC compounds, such as p,p'- dichlorodiphenyldichloroethylene (DDE), arising from the heavy historical use of legacy OC insecticides, might serve as an environmental public health indicator for T2D occurrence. Soil samples from 60 Delta and 60 non-Delta sites randomly selected were analyzed for the presence of OC compounds. A retrospective cohort study of adult men (150 from each region) was recruited to provide a blood sample for OC compound quantitation and select demographic and clinical information including T2D. Using multivariable logistic regression, an association was found between increasing serum DDE levels and T2D occurrence in non-Delta participants (those subjects with lower serum DDE levels), as opposed to Delta participants (individuals with higher serum DDE levels). Thus, while there was a relationship between serum DDE levels and T2D in those with lower burdens of DDE, the lack of association in those with higher levels of DDE indicates a complex non-monotonic correlation between serum DDE levels and T2D occurrence complicating the goal of finding a public health marker for T2D. Abbreviations: BMI, body mass index; CVD, cardiovascular disease; CDC, Center for Disease Control, United States of America; DDE, p,p'- dichlorodiphenyldichloroethylene; DDT, p,p'- dichlorodiphenyltrichloroethane; GC/MS, gas chromatography/mass spectrometry; GIS, geographic information system; GPS, global positioning system; HDL, high-density lipoprotein; HTN, hypertension; IDW, inverse distance weighting; IRB, Institutional Review Board; LDL, low-density lipoprotein; LOQ, limit of quantitation; NHANES, National Health and Nutrition Examination Surveys; POPs, persistent organic pollutants; OC, organochlorine; PCB, polychlorinated biphenyl; SIM, single-ion monitoring; T2D, type 2 diabetes mellitus; USA, United States of America.

Respiratory modulation of human autonomic function on Earth.

KEY POINTS: We studied healthy supine astronauts on Earth with electrocardiogram, non-invasive arterial pressure, respiratory carbon dioxide concentrations, breathing depth and sympathetic nerve recordings. The null hypotheses were that heart beat interval fluctuations at usual breathing frequencies are baroreflex mediated, that they persist during apnoea, and that autonomic responses to apnoea result from changes of chemoreceptor, baroreceptor or lung stretch receptor inputs. R-R interval fluctuations at usual breathing frequencies are unlikely to be baroreflex mediated, and disappear during apnoea. The subjects' responses to apnoea could not be attributed to changes of central chemoreceptor activity (hypocapnia prevailed); altered arterial baroreceptor input (vagal baroreflex gain declined and muscle sympathetic nerve burst areas, frequencies and probabilities increased, even as arterial pressure climbed to new levels); or altered pulmonary stretch receptor activity (major breathing frequency and tidal volume changes did not alter vagal tone or sympathetic activity). Apnoea responses of healthy subjects may result from changes of central respiratory motoneurone activity. ABSTRACT: We studied eight healthy, supine astronauts on Earth, who followed a simple protocol: they breathed at fixed or random frequencies, hyperventilated and then stopped breathing, as a means to modulate and expose to view important, but obscure central neurophysiological mechanisms. Our recordings included the electrocardiogram, finger photoplethysmographic arterial pressure, tidal volume, respiratory carbon dioxide concentrations and peroneal nerve muscle sympathetic activity. Arterial pressure, vagal tone and muscle sympathetic outflow were comparable during spontaneous and controlled-frequency breathing. Compared with spontaneous, 0.1 and 0.05 Hz breathing, however, breathing at usual frequencies (∼0.25 Hz) lowered arterial baroreflex gain, and provoked smaller arterial pressure and R-R interval fluctuations, which were separated by intervals that were likely to be too short and variable to be attributed to baroreflex physiology. R-R interval fluctuations at usual breathing frequencies disappear during apnoea, and thus cannot provide evidence for the existence of a central respiratory oscillation. Apnoea sets in motion a continuous and ever changing reorganization of the relations among stimulatory and inhibitory inputs and autonomic outputs, which, in our study, could not be attributed to altered chemoreceptor, baroreceptor, or pulmonary stretch receptor activity. We suggest that responses of healthy subjects to apnoea are driven importantly, and possibly prepotently, by changes of central respiratory motoneurone activity. The companion article extends these observations and asks the question, Might terrestrial responses to our 20 min breathing protocol find expression as long-term neuroplasticity in serial measurements made over 20 days during and following space travel?

Respiratory modulation of human autonomic function: long-term neuroplasticity in space.

KEY POINTS: We studied healthy astronauts before, during and after the Neurolab Space Shuttle mission with controlled breathing and apnoea, to identify autonomic changes that might contribute to postflight orthostatic intolerance. Measurements included the electrocardiogram, finger photoplethysmographic arterial pressure, respiratory carbon dioxide levels, tidal volume and peroneal nerve muscle sympathetic activity. Arterial pressure fell and then rose in space, and drifted back to preflight levels after return to Earth. Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations rose and then fell in space, and descended to preflight levels upon return to Earth. Sympathetic burst frequencies (but not areas) were greater than preflight in space and on landing day, and astronauts' abilities to modulate both burst areas and frequencies during apnoea were sharply diminished. Spaceflight triggers long-term neuroplastic changes reflected by reciptocal sympathetic and vagal motoneurone responsiveness to breathing changes. ABSTRACT: We studied six healthy astronauts five times, on Earth, in space on the first and 12th or 13th day of the 16 day Neurolab Space Shuttle mission, on landing day, and 5-6 days later. Astronauts followed a fixed protocol comprising controlled and random frequency breathing and apnoea, conceived to perturb their autonomic function and identify changes, if any, provoked by microgravity exposure. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, tidal carbon dioxide concentrations and volumes, and peroneal nerve muscle sympathetic activity on Earth (in the supine position) and in space. (Sympathetic nerve recordings were made during three sessions: preflight, late mission and landing day.) Arterial pressure changed systematically from preflight levels: pressure fell during early microgravity exposure, rose as microgravity exposure continued, and drifted back to preflight levels after return to Earth. Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations (root mean square of successive normal R-R intervals; and proportion of successive normal R-R intervals greater than 50 ms, divided by the total number of normal R-R intervals) rose significantly during early microgravity exposure, fell as microgravity exposure continued, and descended to preflight levels upon return to Earth. Sympathetic mechanisms also changed. Burst frequencies (but not areas) during fixed frequency breathing were greater than preflight in space and on landing day, but their control during apnoea was sharply altered: astronauts increased their burst frequencies from already high levels, but they could not modulate either burst areas or frequencies appropriately. Space travel provokes long-lasting sympathetic and vagal neuroplastic changes in healthy humans.

Acute inhalation of vaporized nicotine increases arterial pressure in young non-smokers: a pilot study.

PURPOSE: Electronic cigarettes are growing in popularity, but the physiological consequences of vaporized nicotine are unknown. METHODS: Twenty healthy non-smokers inhaled vaporized nicotine and placebo (randomized). RESULTS: Nicotine inhalation was associated with higher arterial pressures in the seated position, and increased arterial pressures in the head-up positions with no other effects on autonomic control. CONCLUSIONS: Our results show that vaporized nicotine inhalation is not innocuous. Longitudinal studies in otherwise healthy non-smokers should be conducted.

Acute fasting reduces tolerance to progressive central hypovolemia in humans.

Potential health benefits of an acute fast include reductions in blood pressure and increases in vagal cardiac control. These purported health benefits could put fasted humans at risk for cardiovascular collapse when exposed to central hypovolemia. The purpose of this study was to test the hypothesis that an acute 24-h fast (vs. 3-h postprandial) would reduce tolerance to central hypovolemia induced via lower body negative pressure (LBNP). We measured blood ketones (ß-OHB) to confirm a successful fast (n = 18). We recorded the electrocardiogram (ECG), beat-to-beat arterial pressure, muscle sympathetic nerve activity (MSNA; n = 7), middle cerebral artery blood velocity (MCAv), and forearm blood flow. Following a 5-min baseline, LBNP was increased by 15 mmHg until -60 mmHg and then increased by 10 mmHg in a stepwise manner until onset of presyncope. Each LBNP stage lasted 5-min. Data are expressed as means ± SE ß-OHB increased (ß-OHB; 0.12 ± 0.04 fed vs. 0.47 ± 0.11, P < 0.01 mmol/L fast). Tolerance to central hypovolemia was decreased by ∼10% in the fasted condition measured via total duration of negative pressure (1,370 [Formula: see text] 89 fed vs. 1,229 ± 94 s fast, P = 0.04), and was negatively associated with fasting blood ketones (R = -0.542, P = 0.02). During LBNP, heart rate and MSNA increased similarly, but in the fasted condition forearm vascular resistance was significantly reduced. Our results suggest that acute fasting reduces tolerance to central hypovolemia by blunting increases in peripheral resistance, indicating that prolonged fasting may hinder an individual's ability to compensate to a loss of blood volume.NEW & NOTEWORTHY An acute 24 h fasting reduces tolerance to central hypovolemia, and tolerance is negatively associated with blood ketone levels. Compared with a fed condition (3-h postprandial), fasted participants exhibited blunted peripheral vasoconstriction and greater reductions in stroke volume during stepwise lower body negative pressure. These findings suggest that a prolonged fast may lead to quicker decompensation during central hypovolemia.

Beyond the Baroreflex: A New Measure of Autonomic Regulation Based on the Time-Frequency Assessment of Variability, Phase Coherence and Couplings.

For decades the role of autonomic regulation and the baroreflex in the generation of the respiratory sinus arrhythmia (RSA) - modulation of heart rate by the frequency of breathing - has been under dispute. We hypothesized that by using autonomic blockers we can reveal which oscillations and their interactions are suppressed, elucidating their involvement in RSA as well as in cardiovascular regulation more generally. R-R intervals, end tidal CO2, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion. The measurements were repeated during spontaneous and fixed-frequency breathing, and apnea. The power spectra, phase coherence and couplings were calculated to characterise the variability and interactions within the cardiovascular system. Atropine reduced R-R interval variability (p < 0.05) in all three breathing conditions, reduced MSNA power during apnea and removed much of the significant coherence and couplings. Propranolol had smaller effect on the power of oscillations and did not change the number of significant interactions. Most notably, atropine reduced R-R interval power in the 0.145-0.6 Hz interval during apnea, which supports the hypothesis that the RSA is modulated by a mechanism other than the baroreflex. Atropine also reduced or made negative the phase shift between the systolic and diastolic pressure, indicating the cessation of baroreflex-dependent blood pressure variability. This result suggests that coherent respiratory oscillations in the blood pressure can be used for the non-invasive assessment of autonomic regulation.

Arterial pressure oscillations are not associated with muscle sympathetic nerve activity in individuals exposed to central hypovolaemia.

The spectral power of low frequency oscillations of systolic arterial pressure (SAP(LF)) has been used as a non-invasive surrogate of muscle sympathetic nerve activity (MSNA) in both experimental and clinical situations. For SAP(LF) to be used in this way, a relationship must exist between SAP(LF) and MSNA within individuals during sympathetic activation. Using progressive central hypovolaemia to induce sympathetic activation, we hypothesised that SAP(LF) would correlate with MSNA in all subjects. ECG, beat-by-beat arterial pressure and MSNA were recorded in humans (n = 20) during a progressive lower body negative pressure (LBNP) protocol designed to cause presyncope in all subjects. Arterial pressure oscillations were assessed in the low frequency (LF; 0.04-0.15 Hz) domain using a Fourier transform. For the entire group, SAP(LF), MSNA burst frequency, and total MSNA increased during LBNP. Values for coefficients of determination (r(2)) describing the linear associations of SAP(LF) with MSNA burst frequency and total MSNA were 0.73 and 0.84, but rose to 0.89 and 0.98 when curvilinear fits were used, indicating that the relationship is curvilinear rather than linear. Associations between SAP(LF) and MSNA within each individual subject, however, varied widely for both MSNA burst frequency and total MSNA, whether derived by linear (r(2) range, 1.7 × 10(-6) to 0.99) or polynomial (r(2) range, 0.09 to 1.0) regression analysis. Similar results were obtained when relationships between low frequency oscillations in diastolic arterial pressure and MSNA were evaluated. These results do not support the use of low frequency oscillations in arterial pressure as a non-invasive measure of sympathetic outflow for individual subjects during sympathetic activation.

Linear mixed-effects modeling of the relationship between heart rate variability and fatigue arising from sleep deprivation.

INTRODUCTION: Fatigue degrades cognitive performance, yet there is no universally accepted objective measure of fatigue. We tested whether fatigue arising from sleep deprivation can be quantified objectively using heart rate variability (HRV). METHODS: There were 35 male subjects (mean +/- SD; age = 21.4 +/- 2.6 yr) who were assigned to one of two experimental groups: (1) control (N = 16), or (2) 48-h sleep-deprived (N=19). Using 3-h sampling intervals, we simultaneously tracked fatigue level, cognitive performance, and HRV. Linear mixed-effects (LME) models were used to evaluate linear relationships between fatigue level and cognitive performance, as well as between fatigue level and HRV. RESULTS: Significant negative slopes were observed in LME models of cognitive performance and fatigue level. Of the several HRV parameters examined during standing and supine rest, the ratio of low-frequency to high-frequency R-R interval in the supine position had the clearest significant relationship when modeled against fatigue level. DISCUSSION: In summary, our results suggest that HRV tracks fatigue arising from sleep deprivation. This noninvasive, objective tool can quantify fatigue in real time.

Controlled breathing and autonomic rhythms: Influence of auditory versus visual cues.

We compared standard metrics of autonomic control in 20 humans (10 female) during spontaneous and controlled breathing. Subjects controlled breathing at 0.25 Hz following a metronome (auditory) or scrolling waveforms (visual). Respiratory rates and heart rates were lower during spontaneous breathing compared with auditory and visual. One heart rate variability metric was higher during visual compared with spontaneous breathing, but baroreflex sensitivity and muscle sympathetic nerve activity were not affected by breathing cues. A majority of subjects (86%) perceived that breathing to auditory cues was more difficult compared with visual cues, but this elevated perceived stress did not manifest physiologically.

Muscle sympathetic nerve activity during intense lower body negative pressure to presyncope in humans.

Activation of sympathetic efferent traffic is essential to maintaining adequate arterial pressures during reductions of central blood volume. Sympathetic baroreflex gain may be reduced, and muscle sympathetic firing characteristics altered with head-up tilt just before presyncope in humans. Volume redistributions with lower body negative pressure (LBNP) are similar to those that occur during haemorrhage, but limited data exist describing arterial pressure-muscle sympathetic nerve activity (MSNA) relationships during intense LBNP. Responses similar to those that occur in presyncopal subjects during head-up tilt may signal the beginnings of cardiovascular decompensation associated with haemorrhage. We therefore tested the hypotheses that intense LBNP disrupts MSNA firing characteristics and leads to a dissociation between arterial pressure and sympathetic traffic prior to presyncope. In 17 healthy volunteers (12 males and 5 females), we recorded ECG, finger photoplethysmographic arterial pressure and MSNA. Subjects were exposed to 5 min LBNP stages until the onset of presyncope. The LBNP level eliciting presyncope was denoted as 100% tolerance, and then data were assessed relative to this normalised maximal tolerance by expressing LBNP levels as 80, 60, 40, 20 and 0% (baseline) of maximal tolerance. Data were analysed in both time and frequency domains, and cross-spectral analyses were performed to determine the coherence, transfer function and phase angle between diastolic arterial pressure (DAP) and MSNA. DAP-MSNA coherence increased progressively and significantly up to 80% maximal tolerance. Transfer functions were unchanged, but phase angle shifted from positive to negative with application of LBNP. Sympathetic bursts fused in 10 subjects during high levels of LBNP (burst fusing may reflect modulation of central mechanisms, an artefact arising from our use of a 0.1 s time constant for integrating filtered nerve activity, or a combination of both). On average, arterial pressures and MSNA decreased significantly the final 20 s before presyncope (n = 17), but of this group, MSNA increased in seven subjects. No linear relationship was observed between the magnitude of DAP and MSNA changes before presyncope (r = 0.12). We report three primary findings: (1) progressive LBNP (and presumed progressive arterial baroreceptor unloading) increases cross-spectral coherence between arterial pressure and MSNA, but sympathetic baroreflex control is reduced before presyncope; (2) withdrawal of MSNA is not a prerequisite for presyncope despite significant decreases of arterial pressure; and (3) reductions of venous return, probably induced by intense LBNP, disrupt MSNA firing characteristics that manifest as fused integrated bursts before the onset of presyncope. Although fusing of integrated sympathetic bursts may reflect a true physiological compensation to severe reductions of venous return, duplication of this finding utilizing shorter time constants for integration of the nerve signal is required.

Heart rate variability to assess combat readiness.

Chronic fatigue/physical exhaustion (FPE) impacts combat readiness but is difficult to identify. We tested the hypothesis that resting heart rate variability (HRV), including both time- and frequency-domain assessments, would correlate with hydration status and aerobic capacity in military recruit-age men and women with varying fitness levels. Cardiac interbeat intervals were recorded using a heart R-R monitor during 20 minutes of quiet, supine rest with paced breathing (0.25 Hz). HRV metrics included average R-R interval (RRIavg), R-R interval standard deviation (RRISD), the percentage of adjacent R-R intervals varying by > or = 50 ms (pNN50), and integrated areas of R-R interval spectral power at the high (0.15-0.4 Hz) (RRIHF) and low (0.04-0.15 Hz) (RRILF) frequencies. Treadmill maximal oxygen uptake (VO2 max), segmental bioimpedance estimates of total body water (TBW), and urine specific gravity (USG) were also assessed. All dependent variables of interest were within expected ranges, although absolute ranges of individual values were considerable. RRI correlated with VO2 max (r = 0.49; p < 0.001), with TBW (r = 0.38; p < 0.001), and inversely with USG (r = -0.23; p = 0.02). RRISD correlated with VO2 max (r = 0.21; p = 0.03), but not with TBW or USG. pNN50 correlated inversely with USG (r = -0.21; p = 0.03) but not with VO2 max or TBW. R-R interval spectral power at the high and low frequencies did not correlate with VO2 max, TBW, or USG. We have demonstrated that fitness level and hydration status may affect cardiac function via changes in autonomic tone, highlighting the potential of field-based assessment of heart rate variability metrics to identify FPE and other aspects of combat readiness.

Autonomic compensation to simulated hemorrhage monitored with heart period variability.

OBJECTIVE: To test the hypothesis that components of heart period variability track autonomic function during simulated hemorrhage in humans. DESIGN: Prospective experimental laboratory intervention. SETTING: Human physiology laboratory. SUBJECTS: A total of 33 healthy, nonsmoking, volunteer subjects (23 men, ten women). INTERVENTIONS: Progressive lower body negative pressure was applied in 5-min stages until the onset of impending cardiovascular collapse. MEASUREMENTS AND MAIN RESULTS: The electrocardiogram, beat-by-beat finger arterial pressure, and muscle sympathetic nerve activity from the peroneal nerve were recorded continuously. Pulse pressure was calculated from the arterial pressure waveform and used as an estimate of relative changes of central blood volume. Heart period variability was assessed in both time and frequency domains. Application of lower body negative pressure caused progressive reductions of R-R interval and pulse pressure and progressive increases of muscle sympathetic nerve activity. Arterial pressures changed minimally and late. R-R interval time domain variability measures and spectral power at the high frequency (0.15-0.4 Hz) decreased progressively with lower body negative pressure (p < .001). Both R-R interval high-frequency power and time domain variability measures correlated inversely with muscle sympathetic nerve activity and directly with pulse pressure (all amalgamated R2 > .88, all p < or = .001). CONCLUSIONS: Components of heart period variability track early compensatory autonomic and hemodynamic responses to progressive reduction in central blood volume. Such analyses, interpreted in conjunction with standard vital signs, may contribute to earlier assessments of the magnitude of blood volume loss during hemorrhage.

Oxygen saturation determined from deep muscle, not thenar tissue, is an early indicator of central hypovolemia in humans.

OBJECTIVE: To compare the responses of noninvasively measured tissue oxygen saturation (StO2) and calculated muscle oxygen tension (PmO2) to standard hemodynamic variables for early detection of imminent hemodynamic instability during progressive central hypovolemia in humans. DESIGN: Prospective study. SETTING: Research laboratory. SUBJECTS: Sixteen healthy human volunteers. INTERVENTIONS: Progressive lower body negative pressure (LBNP) to onset of cardiovascular collapse. MEASUREMENTS AND MAIN RESULTS: Noninvasive measurements of blood pressures, heart rate, and stroke volume were obtained during progressive LBNP with simultaneous assessments of StO2, PmO2, and muscle oxygen saturation (SmO2). Forearm SmO2 and PmO2 were determined with a novel near infrared spectroscopic measurement device (UMMS) and compared with thenar StO2 measured by a commercial device (HT). All values were normalized to the duration of LBNP exposure required for cardiovascular collapse in each subject (i.e., LBNP maximum). Stroke volume was significantly decreased at 25% of LBNP maximum, whereas blood pressure was a late indicator of imminent cardiovascular collapse. PmO2 (UMMS) was significantly decreased at 50% of maximum LBNP while SmO2 (UMMS) decreased at 75% of maximum LBNP. Thenar StO2 (HT) showed no statistical change throughout the entire LBNP protocol. CONCLUSIONS: Spectroscopic assessment of forearm muscle PO2 and SmO2 provides noninvasive and continuous measures that are early indicators of impending cardiovascular collapse resulting from progressive reductions in central blood volume.

Breathing through an inspiratory threshold device improves stroke volume during central hypovolemia in humans.

Inspiratory resistance induced by breathing through an impedance threshold device (ITD) reduces intrathoracic pressure and increases stroke volume (SV) in supine normovolemic humans. We hypothesized that breathing through an ITD would also be associated with a protection of SV and a subsequent increase in the tolerance to progressive central hypovolemia. Eight volunteers (5 men, 3 women) were instrumented to record ECG and beat-by-beat arterial pressure and SV (Finometer). Tolerance to progressive lower body negative pressure (LBNP) was assessed while subjects breathed against either 0 (sham ITD) or -7 cmH(2)O inspiratory resistance (active ITD); experiments were performed on separate days. Because the active ITD increased LBNP tolerance time from 2,014 +/- 106 to 2,259 +/- 138 s (P = 0.006), data were analyzed (time and frequency domains) under both conditions at the time at which cardiovascular collapse occurred during the sham experiment to determine the mechanisms underlying this protective effect. At this time point, arterial blood pressure, SV, and cardiac output were higher (P < or = 0.005) when breathing on the active ITD rather than the sham ITD, whereas indirect indicators of autonomic activity (low- and high-frequency oscillations of the R-to-R interval) were not altered. ITD breathing did not alter the transfer function between systolic arterial pressure and R-to-R interval, indicating that integrated baroreflex sensitivity was similar between the two conditions. These data show that breathing against inspiratory resistance increases tolerance to progressive central hypovolemia by better maintaining SV, cardiac output, and arterial blood pressures via primarily mechanical rather than neural mechanisms.

Physiological and medical monitoring for en route care of combat casualties.

BACKGROUND: Most prehospital medical interventions during civilian and military trauma casualty transport fail to utilize advanced decision-support systems for treatment and delivery of medical interventions, particularly intravenous fluids and oxygen. Current treatment protocols are usually based on standard vital signs (eg, blood pressure, arterial oxygen saturation) which have proven to be of limited value in detecting the need to implement an intervention before cardiovascular collapse. A primary objective of the US Army combat casualty care research program is to reduce mortality and morbidity during casualty transport from the battlefield through advanced development of a semiautomated decision-support capability for closed-loop resuscitation and oxygen delivery. METHODS: To accomplish this goal, the Trauma Informatics Research Team at the US Army Institute of Surgical Research has developed two models for evidence-based decision support 1) a trauma patient database for capture and analysis of prehospital vital signs for identification of early, novel physiologic measurements that could improve the control of closed-loop systems in trauma patients; and, 2) a human experimental model of central hypovolemia using lower body negative pressure to improve the understanding and identification of physiologic signals for advancing closed-loop capabilities with simulated hemodynamic responses to hemorrhage. RESULTS: In the trauma patient database and lower body negative pressure studies, traditional vital sign measurements such as systolic blood pressure and oxygen saturation fail to predict mortality or indicate the need for life saving interventions or reductions in central blood volume until after the onset of cardiovascular collapse. We have evidence from preliminary analyses, however, that indicators of reduced central blood volume in the presence of stable vital signs include 1) reductions in pulse pressure; 2) changes in indices of autonomic balance derived from calculation of heart period variability (ie, linear and non-linear analyses of R-R intervals); and 3) reductions in tissue oxygenation. CONCLUSIONS: We propose that derived indices based on currently available technology for continuous monitoring of specific hemodynamic, autonomic, and/or metabolic responses could provide earlier recognition of hemorrhage than current standard vital signs and allow intervention before the onset of circulatory shock. Because of this, such indices could provide improved feedback for closed-loop control of patient resuscitation and oxygen delivery. These technological advances could prove instrumental in advancing decision-support capabilities for prehospital trauma care during transport to higher levels of care in both the military and civilian environments.

Combat stress or hemorrhage? Evidence for a decision-assist algorithm for remote triage.

INTRODUCTION: In the setting of remote military triage, when physical access to the patient is not possible, traditional physiological measurements available to a combat medic may not differentiate between a wounded soldier and an active soldier. We tested the hypothesis that changes in high-frequency R-R interval spectral power (RRI HF) and pulse pressure (PP) would differ between progressive central hypovolemia (simulated hemorrhage) and exercise to evaluate their potential for remotely distinguishing active from bleeding soldiers. The RRI HF and PP were used because of their ability to track central hypovolemia. METHODS: There were 12 (8 female/4 male) healthy, normotensive, nonsmoking subjects (age 27 +/- 2 yr; height 169 +/- 3 cm; weight 68 +/- 5 kg) who were exposed to progressive lower body negative pressure (LBNP) and a supine cycle ergometer protocol. ECG and blood pressure were measured continuously. Exercise workloads were determined by matching the heart rate (HR) responses to each LBNP level. Data were analyzed in time and frequency domains. RESULTS: HR increased from 67 +/- 3 bpm at rest to 101 +/- 4 bpm by -60 mmHg LBNP and was matched within 5% during exercise. By the final stage, RRI HF decreased by a similar magnitude during both LBNP (-78 +/- 7%) and exercise (-85 +/- 6%). PP decreased by 30 +/- 4% with LBNP compared with an increase of 20 +/- 6% during exercise. CONCLUSION: Monitoring PP in combination with RRI HF would distinguish a bleeding from an active soldier. Technologies that incorporate telemetry to track these derived vital signs would provide a combat medic with remote decision support to assess soldier status on the battlefield.

Inspiratory resistance, cerebral blood flow velocity, and symptoms of acute hypotension.

INTRODUCTION: Symptoms of orthostatic intolerance, e.g., following prolonged bed rest and microgravity exposure, are associated with reductions in cerebral blood flow. We tested the hypothesis that spontaneously breathing through an impedance threshold device (ITD) would attenuate the fall in cerebral blood flow velocity (CBFV) during a hypotensive orthostatic challenge and reduce the severity of reported symptoms. METHODS: While breathing through either an active ITD (-7 cm H2O inspiratory impedance) or a sham ITD (no impedance), 19 subjects performed a squat stand test (SST). Symptoms upon stand were recorded on a 5-point scale (1 = normal; 5 = faint) of subject-perceived rating (SPR). To address our hypothesis, only data from symptomatic subjects (SPR > 1 during the sham trial) were analyzed (N = 9). Mean arterial blood pressure (MAP) and mean CBFV were measured continuously throughout the SST and analyzed in time and frequency domains. RESULTS: Breathing with the active ITD during the SST reduced the severity of orthostatic symptoms in eight of the nine symptomatic subjects (sham ITD SPR, 1.9 +/- 0.1; active ITD SPR, 1.1 +/- 0.1), but there was no statistically distinguishable difference in the reduction of mean CBFV between the two trials (sham ITD, -39 +/- 3% vs. active ITD, -44 +/- 3%). High frequency oscillations in mean CBFV, however, were greater during the active ITD trial (7.8 +/- 2.6 cm x s(-2)) compared with the sham ITD trial (2.5 +/- 0.9 cm x s(-2)). CONCLUSIONS: Higher oscillations in CBFV while breathing with the active ITD may account for the reduction in symptom severity during orthostatic hypotension despite the same fall in absolute CBFV.