Caroline A. Rickards

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.

Assessment of cerebral autoregulation: the quandary of quantification.

We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject relationships among low-frequency (LF; 0.07-0.2 Hz) and very-low-frequency (VLF; 0.02-0.07 Hz) transfer function coherence, phase, gain, and normalized gain, we performed retrospective transfer function analysis on spontaneous blood pressure and middle cerebral artery blood velocity recordings from 105 individuals. We characterized the relationships (n = 29) among spontaneous transfer function metrics and the rate of regulation index and autoregulatory index derived from bilateral thigh-cuff deflation tests. In addition, we analyzed data from subjects (n = 29) who underwent a repeated squat-to-stand protocol to determine the relationships between transfer function metrics during forced blood pressure fluctuations. Finally, data from subjects (n = 16) who underwent step changes in end-tidal P(CO2) (P(ET)(CO2) were analyzed to determine whether transfer function metrics could reliably track the modulation of CA within individuals. CA metrics were generally unrelated or showed only weak to moderate correlations. Changes in P(ET)(CO2) were positively related to coherence [LF: β = 0.0065 arbitrary units (AU)/mmHg and VLF: β = 0.011 AU/mmHg, both P < 0.01] and inversely related to phase (LF: β = -0.026 rad/mmHg and VLF: β = -0.018 rad/mmHg, both P < 0.01) and normalized gain (LF: β = -0.042%/mmHg(2) and VLF: β = -0.013%/mmHg(2), both P < 0.01). However, Pet(CO(2)) was positively associated with gain (LF: β = 0.0070 cm·s(-1)·mmHg(-2), P < 0.05; and VLF: β = 0.014 cm·s(-1)·mmHg(-2), P < 0.01). Thus, during changes in P(ET)(CO2), LF phase was inversely related to LF gain (β = -0.29 cm·s(-1)·mmHg(-1)·rad(-1), P < 0.01) but positively related to LF normalized gain (β = 1.3% mmHg(-1)/rad, P < 0.01). These findings collectively suggest that only select CA metrics can be used interchangeably and that interpretation of these measures should be done cautiously.

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.

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.

Use of advanced machine-learning techniques for noninvasive monitoring of hemorrhage.

BACKGROUND Hemorrhagic shock is a leading cause of death in both civilian and battlefield trauma. Currently available medical monitors provide measures of standard vital signs that are insensitive and nonspecific. More important, hypotension and other signs and symptoms of shock can appear when it may be too late to apply effective life-saving interventions. The resulting challenge is that early diagnosis is difficult because hemorrhagic shock is first recognized by late-responding vital signs and symptoms. The purpose of these experiments was to test the hypothesis that state-of-the-art machine-learning techniques, when integrated with novel non-invasive monitoring technologies, could detect early indicators of blood volume loss and impending circulatory failure in conscious, healthy humans who experience reduced central blood volume. METHODS Humans were exposed to progressive reductions in central blood volume using lower body negative pressure as a model of hemorrhage until the onset of hemodynamic decompensation. Continuous, noninvasively measured hemodynamic signals were used for the development of machine-learning algorithms. Accuracy estimates were obtained by building models using signals from all but one subject and testing on that subject. This process was repeated, each time using a different subject. RESULTS The model was 96.5% accurate in predicting the estimated amount of reduced central blood volume, and the correlation between predicted and actual lower body negative pressure level for hemodynamic decompensation was 0.89. CONCLUSIONS Machine modeling can accurately identify reduced central blood volume and predict impending hemodynamic decompensation (shock onset) in individuals. Such a capability can provide decision support for earlier intervention.

Tolerance to central hypovolemia: the influence of oscillations in arterial pressure and cerebral blood velocity

Higher oscillations of cerebral blood velocity and arterial pressure (AP) induced by breathing with inspiratory resistance are associated with delayed onset of symptoms and increased tolerance to central hypovolemia. We tested the hypothesis that subjects with high tolerance (HT) to central hypovolemia would display higher endogenous oscillations of cerebral blood velocity and AP at presyncope compared with subjects with low tolerance (LT). One-hundred thirty-five subjects were exposed to progressive lower body negative pressure (LBNP) until the presence of presyncopal symptoms. Subjects were classified as HT if they completed at least the -60-mmHg level of LBNP (93 subjects; LBNP time, 1,880 ± 259 s) and LT if they did not complete this level (42 subjects; LBNP time, 1,277 ± 199 s). Middle cerebral artery velocity (MCAv) was measured by transcranial Doppler, and AP was measured at the finger by photoplethysmography. Mean MCAv and mean arterial pressure (MAP) decreased progressively from baseline to presyncope for both LT and HT subjects (P < 0.001). However, low frequency (0.04-0.15 Hz) oscillations of mean MCAv and MAP were higher at presyncope in HT subjects compared with LT subjects (MCAv: HT, 7.2 ± 0.7 vs. LT, 5.3 ± 0.6 (cm/s)(2), P = 0.075; MAP: HT, 15.3 ± 1.4 vs. 7.9 ± 1.2 mmHg(2), P < 0.001). Consistent with our previous findings using inspiratory resistance, high oscillations of mean MCAv and MAP are associated with HT to central hypovolemia.

Pulse Oximeter Plethysmographic Waveform Changes in Awake, Spontaneously Breathing, Hypovolemic Volunteers

BACKGROUND:The primary objective of this study was to determine whether alterations in the pulse oximeter waveform characteristics would track progressive reductions in central blood volume. We also assessed whether changes in the pulse oximeter waveform provide an indication of blood loss in the hemorrhaging patient before changes in standard vital signs. METHODS:Pulse oximeter data from finger, forehead, and ear pulse oximeter sensors were collected from 18 healthy subjects undergoing progressive reduction in central blood volume induced by lower body negative pressure (LBNP). Stroke volume measurements were simultaneously recorded using impedance cardiography. The study was conducted in a research laboratory setting where no interventions were performed. Pulse amplitude, width, and area under the curve (AUC) features were calculated from each pulse wave recording. Amalgamated correlation coefficients were calculated to determine the relationship between the changes in pulse oximeter waveform features and changes in stroke volume with LBNP. RESULTS:For pulse oximeter sensors on the ear and forehead, reductions in pulse amplitude, width, and area were strongly correlated with progressive reductions in stroke volume during LBNP (R2 ≥ 0.59 for all features). Changes in pulse oximeter waveform features were observed before profound decreases in arterial blood pressure. The best correlations between pulse features and stroke volume were obtained from the forehead sensor area (R2 = 0.97). Pulse oximeter waveform features returned to baseline levels when central blood volume was restored. CONCLUSIONS:These results support the use of pulse oximeter waveform analysis as a potential diagnostic tool to detect clinically significant hypovolemia before the onset of cardiovascular decompensation in spontaneously breathing patients.

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.

Inspiratory resistance maintains arterial pressure during central hypovolemia: Implications for treatment of patients with severe hemorrhage

Objective:To test the hypothesis that an impedance threshold device would increase systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure and delay the onset of symptoms and cardiovascular collapse associated with severe central hypovolemia. Design:Prospective, randomized, blinded trial design. Setting:Human physiology laboratory. Patients:Nine healthy nonsmoking normotensive subjects (five males, four females). Interventions:Central hypovolemia and impending cardiovascular collapse were induced in human volunteers by applying progressive lower body negative pressure (under two experimental conditions: a) while breathing with an impedance threshold device set to open at −7 cm H2O pressure (active impedance threshold device); and b) breathing through a sham impedance threshold device (control). Measurements and Main Results:Systolic blood pressure (79 ± 5 mm Hg), diastolic blood pressure (57 ± 3 mm Hg), and mean arterial pressure (65 ± 4 mm Hg) were lower (p < .02) when subjects (n = 9) breathed through the sham impedance threshold device than when they breathed through the active impedance threshold device at the same time of cardiovascular collapse during sham breathing (102 ± 3, 77 ± 3, 87 ± 3 mm Hg, respectively). Elevated blood pressure was associated with 23% greater lower body negative pressure tolerance using an active impedance threshold device (1639 ± 220 mm Hg-min) compared with a sham impedance threshold device (1328 ± 144 mm Hg-min) (p = .02). Conclusions:Use of an impedance threshold device increased systemic blood pressure and delayed the onset of cardiovascular collapse during severe hypovolemic hypotension in spontaneously breathing human volunteers. This device may provide rapid noninvasive hemodynamic support in patients with hypovolemic hypotension once the blood loss has been controlled but before other definitive therapies are available.

Oxygen transport characterization of a human model of progressive hemorrhage

BACKGROUND Hemorrhage continues to be a leading cause of death from trauma sustained both in combat and in the civilian setting. New models of hemorrhage may add value in both improving our understanding of the physiologic responses to severe bleeding and as platforms to develop and test new monitoring and therapeutic techniques. We examined changes in oxygen transport produced by central volume redistribution in humans using lower body negative pressure (LBNP) as a potential mimetic of hemorrhage. METHODS AND RESULTS In 20 healthy volunteers, systemic oxygen delivery and oxygen consumption, skeletal muscle oxygenation and oral mucosa perfusion were measured over increasing levels of LBNP to the point of hemodynamic decompensation. With sequential reductions in central blood volume, progressive reductions in oxygen delivery and tissue oxygenation and perfusion parameters were noted, while no changes were observed in systemic oxygen uptake or markers of anaerobic metabolism in the blood (e.g., lactate, base excess). While blood pressure decreased and heart rate increased during LBNP, these changes occurred later than the reductions in tissue oxygenation and perfusion. CONCLUSIONS These findings indicate that LBNP induces changes in oxygen transport consistent with the compensatory phase of hemorrhage, but that a frank state of shock (delivery-dependent oxygen consumption) does not occur. LBNP may therefore serve as a model to better understand a variety of compensatory physiological changes that occur during the pre-shock phase of hemorrhage in conscious humans. As such, LBNP may be a useful platform from which to develop and test new monitoring capabilities for identifying the need for intervention during the early phases of hemorrhage to prevent a patients progression to overt shock.