A Lumped-Parameter Model of the Cardiovascular System Response for Evaluating Automated Fluid Resuscitation Systems.

Physiological closed-loop controlled (PCLC) medical devices, such as those designed for blood pressure regulation, can be tested for safety and efficacy in real-world clinical settings. However, relying solely on limited animal and clinical studies may not capture the diverse range of physiological conditions. Credible mathematical models can complement these studies by allowing the testing of the device against simulated patient scenarios. This research involves the development and validation of a low-order lumped-parameter mathematical model of the cardiovascular system's response to fluid perturbation. The model takes rates of hemorrhage and fluid infusion as inputs and provides hematocrit and blood volume, heart rate, stroke volume, cardiac output and mean arterial blood pressure as outputs. The model was calibrated using data from 27 sheep subjects, and its predictive capability was evaluated through a leave-one-out cross-validation procedure, followed by independent validation using 12 swine subjects. Our findings showed small model calibration error against the training dataset, with the normalized root-mean-square error (NRMSE) less than 10% across all variables. The mathematical model and virtual patient cohort generation tool demonstrated a high level of predictive capability and successfully generated a sufficient number of subjects that closely resembled the test dataset. The average NRMSE for the best virtual subject, across two distinct samples of virtual subjects, was below 12.7% and 11.9% for the leave-one-out cross-validation and independent validation dataset. These findings suggest that the model and virtual cohort generator are suitable for simulating patient populations under fluid perturbation, indicating their potential value in PCLC medical device evaluation.

Multivariate physiological recordings in an experimental hemorrhage model.

In this paper we describe a data set of multivariate physiological measurements recorded from conscious sheep (N = 8; 37.4 ± 1.1 kg) during hemorrhage. Hemorrhage was experimentally induced in each animal by withdrawing blood from a femoral artery at two different rates (fast: 1.25 mL/kg/min; and slow: 0.25 mL/kg/min). Data, including physiological waveforms and continuous/intermittent measurements, were transformed to digital file formats (European Data Format [EDF] for waveforms and Comma-Separated Values [CSV] for continuous and intermittent measurements) as a comprehensive data set and stored and publicly shared here (Appendix A). The data set comprises experimental information (e.g., hemorrhage rate, animal weight, event times), physiological waveforms (arterial and central venous blood pressure, electrocardiogram), time-series records of non-invasive physiological measurements (SpO2, tissue oximetry), intermittent arterial and venous blood gas analyses (e.g., hemoglobin, lactate, SaO2, SvO2) and intermittent thermodilution cardiac output measurements. A detailed explanation of the hemodynamic and pulmonary changes during hemorrhage is available in a previous publication (Scully et al., 2016) [1].

Physician-Directed Versus Computerized Closed-Loop Control of Blood Pressure Using Phenylephrine in a Swine Model.

BACKGROUND: Vasopressors provide a rapid and effective approach to correct hypotension in the perioperative setting. Our group developed a closed-loop control (CLC) system that titrates phenylephrine (PHP) based on the mean arterial pressure (MAP) during general anesthesia. As a means of evaluating system competence, we compared the performance of the automated CLC with physicians. We hypothesized that our CLC algorithm more effectively maintains blood pressure at a specified target with less blood pressure variability and reduces the dose of PHP required. METHODS: In a crossover study design, 6 swine under general anesthesia were subjected to a normovolemic hypotensive challenge induced by sodium nitroprusside. The physicians (MD) manually changed the PHP infusion rate, and the CLC system performed this task autonomously, adjusted every 3 seconds to achieve a predetermined MAP. RESULTS: The CLC maintained MAP within 5 mm Hg of the target for (mean ± standard deviation) 93.5% ± 3.9% of the time versus 72.4% ± 26.8% for the MD treatment (P = .054). The mean (standard deviation) percentage of time that the CLC and MD interventions were above target range was 2.1% ± 3.3% and 25.8% ± 27.4% (P = .06), respectively. Control statistics, performance error, median performance error, and median absolute performance error were not different between CLC and MD interventions. PHP infusion rate adjustments by the physician were performed 12 to 80 times in individual studies over a 60-minute period. The total dose of PHP used was not different between the 2 interventions. CONCLUSIONS: The CLC system performed as well as an anesthesiologist totally focused on MAP control by infusing PHP. Computerized CLC infusion of PHP provided tight blood pressure control under conditions of experimental vasodilation.

Automated closed-loop resuscitation of multiple hemorrhages: a comparison between fuzzy logic and decision table controllers in a sheep model.

BACKGROUND: Hemorrhagic shock is the leading cause of trauma-related death in the military setting. Definitive surgical treatment of a combat casualty can be delayed and life-saving fluid resuscitation might be necessary in the field. Therefore, improved resuscitation strategies are critically needed for prolonged field and en route care. We developed an automated closed-loop control system capable of titrating fluid infusion to a target endpoint. We used the system to compare the performance of a decision table algorithm (DT) and a fuzzy logic controller (FL) to rescue and maintain the mean arterial pressure (MAP) at a target level during hemorrhages. Fuzzy logic empowered the control algorithm to emulate human expertise. We hypothesized that the FL controller would be more effective and more efficient than the DT algorithm by responding in a more rigid, structured way. METHODS: Ten conscious sheep were submitted to a hemorrhagic protocol of 25 ml/kg over three separate bleeds. Automated resuscitation with lactated Ringer's was initiated 30 min after the first hemorrhage started. The endpoint target was MAP. Group differences were assessed by two-tailed t test and alpha of 0.05. RESULTS: Both groups maintained MAP at similar levels throughout the study. However, the DT group required significantly more fluid than the FL group, 1745 ± 552 ml (42 ± 11 ml/kg) versus 978 ± 397 ml (26 ± 11 ml/kg), respectively (p = 0.03). CONCLUSION: The FL controller was more efficient than the DT algorithm and may provide a means to reduce fluid loading. Effectiveness was not different between the two strategies. Automated closed-loop resuscitation can restore and maintain blood pressure in a multi-hemorrhage model of shock.

Closed-Loop Control of FiO2 Rapidly Identifies Need For Rescue Ventilation and Reduces ARDS Severity in a Conscious Sheep Model of Burn and Smoke Inhalation Injury.

Pulmonary injury can be characterized by an increased need for fraction of inspired oxygen or inspired oxygen percentage (FiO2) to maintain arterial blood saturation of oxygenation (SaO2). We tested a smart oxygenation system (SOS) that uses the activity of a closed-loop control FiO2 algorithm (CLC-FiO2) to rapidly assess acute respiratory distress syndrome (ARDS) severity so that rescue ventilation (RscVent) can be initiated earlier. After baseline data, a pulse-oximeter (noninvasive saturation of peripheral oxygenation [SpO2]) was placed. Sheep were then subjected to burn and smoke inhalation injury and followed for 48 h. Initially, sheep were spontaneously ventilating and then randomized to standard of care (SOC) (n = 6), in which RscVent began when partial pressure of oxygen (PaO2) < 90 mmHg or FiO2 < 0.6, versus SOS (n = 7), software that incorporates and displays SpO2, CLC-FiO2, and SpO2/CLC-FiO2 ratio, at which RscVent was initiated when ratio threshold < 250. RscVent was achieved using a G5 Hamilton ventilator (Bonaduz, Switzerland) with adaptive pressure ventilation and adaptive support ventilation modes for SOC and SOS, respectively. OUTCOMES: the time difference from when SpO2/FiO2 < 250 to RscVent initiation was 4.7 ±â€Š0.6 h and 0.2 ±â€Š0.1 h, SOC and SOS, respectively (P < 0.001). Oxygen responsiveness after RscVent, defined as SpO2/FiO2 > 250 occurred in 4/7, SOS and 0/7, SOC. At 48 h the SpO2/FiO2 ratio was 104 ±â€Š5 in SOC versus 228 ±â€Š59 in SOS (P = 0.036). Ventilatory compliance and peak airway pressures were significantly improved with SOS versus SOC (P < 0.001). Data suggest that SOS software, e.g. SpO2/CLC-FiO2 ratio, after experimental ARDS can provide a novel continuous index of pulmonary function that is apparent before other clinical symptoms. Earlier initiation of RscVent translates into improved oxygenation (reduces ARDS severity) and ventilation.

Peripheral Venous Pressure as an Indicator of Preload Responsiveness During Volume Resuscitation from Hemorrhage.

BACKGROUND: Fluid resuscitation of hypovolemia presumes that peripheral venous pressure (PVP) increases more than right atrial pressure (RAP), so the net pressure gradient for venous return (PVP-RAP) rises. However, the heart and peripheral venous system function under different compliances that could affect their respective pressures during fluid infusion. In a porcine model of hemorrhage resuscitation, we examined whether RAP increases more than PVP, thereby reducing the venous return pressure gradient and blood flow. METHODS: Anesthetized pigs (n = 8) were bled to a mean arterial blood pressure of 40 mm Hg and resuscitated with stored blood and albumin for pulmonary artery occlusion pressures (PAOPs) of 5, 10, 15, and 20 mm Hg. Venous pressures, inferior vena cava blood flow (ultrasonic flowprobe), and left ventricular diastolic compliance (Doppler echocardiography) were measured. Stroke volume variability was calculated. RESULTS: With volume resuscitation, the slope of RAP exceeded PVP (P ≤ 0.0001) when PAOP is 10 to 20 mm Hg, causing the pressure gradient for venous return to progressively decrease. Inferior vena cava blood flow did not further increase after PAOP > 10 mm Hg. The E/e' ratio increased (P = 0.001) during resuscitation indicating reduced diastolic compliance. A significant curvilinear relationship was found between PVP and stroke volume variability (R = 0.62; P < 0.001), where fluid responders had PVP < 15 mm Hg. CONCLUSIONS: Fluid resuscitation above a PAOP 10 mm Hg reduces myocardial compliance and reduces the venous return pressure gradient. The hemodynamic response to fluid resuscitation becomes limited by diastolic properties of the heart. PVP measurement during hemorrhage resuscitation may predict fluid responsiveness and nonresponsiveness.

Effect of hemorrhage rate on early hemodynamic responses in conscious sheep.

Physiological compensatory mechanisms can mask the extent of hemorrhage in conscious mammals, which can be further complicated by individual tolerance and variations in hemorrhage onset and duration. We assessed the effect of hemorrhage rate on tolerance and early physiologic responses to hemorrhage in conscious sheep. Eight Merino ewes (37.4 ± 1.1 kg) were subjected to fast (1.25 mL/kg/min) and slow (0.25 mL/kg/min) hemorrhages separated by at least 3 days. Blood was withdrawn until a drop in mean arterial pressure (MAP) of >30 mmHg and returned at the end of the experiment. Continuous monitoring includedMAP, central venous pressure, pulmonary artery pressure, pulse oximetry, and tissue oximetry. Cardiac output by thermodilution and arterial blood samples were also measured. The effects of fast versus slow hemorrhage rates were compared for total volume of blood removed and stoppage time (whenMAP < 30 mmHg of baseline) and physiological responses during and after the hemorrhage. Estimated blood volume removed whenMAPdropped 30 mmHg was 27.0 ± 4.2% (mean ± standard error) in the slow and 27.3 ± 3.2% in the fast hemorrhage (P = 0.47, pairedttest between rates). Pressure and tissue oximetry responses were similar between hemorrhage rates. Heart rate increased at earlier levels of blood loss during the fast hemorrhage, but hemorrhage rate was not a significant factor for individual hemorrhage tolerance or hemodynamic responses. In 5/16 hemorrhages MAP stopping criteria was reached with <25% of blood volume removed. This study presents the physiological responses leading up to a significant drop in blood pressure in a large conscious animal model and how they are altered by the rate of hemorrhage.

Blood pressure and heart rate from the arterial blood pressure waveform can reliably estimate cardiac output in a conscious sheep model of multiple hemorrhages and resuscitation using computer machine learning approaches.

BACKGROUND: This study was a first step to facilitate the development of automated decision support systems using cardiac output (CO) for combat casualty care. Such systems remain a practical challenge in battlefield and prehospital settings. In these environments, reliable CO estimation using blood pressure (BP) and heart rate (HR) may provide additional capabilities for diagnosis and treatment of trauma patients. The aim of this study was to demonstrate that continuous BP and HR from the arterial BP waveform coupled with machine learning (ML) can reliably estimate CO in a conscious sheep model of multiple hemorrhages and resuscitation. METHODS: Hemodynamic parameters (BPs, HR) were derived from 100-Hz arterial BP waveforms of 10 sheep records, 3 hours to 4 hours long. Two models (mean arterial pressure, Windkessel) were then applied and merged to estimate COVS. ML was used to develop a rule for identifying when models required calibration. All records contained 100-Hz recording of pulmonary arterial blood flow using Doppler transit time (COFP). COFP and COVS were analyzed using equivalence tests and Bland-Altman analysis, as well as waveform and concordance plots. RESULTS: Baseline COFP varied from 3.0 L/min to 5.4 L/min, while posthemorrhage COFP varied from 1.0 L/min to 1.8 L/min. A total of 315,196 pairs of data were obtained. Equivalence tests for individual records showed that COVS was statistically equivalent to COFP (p < 0.05). Smaller equivalence thresholds (<0.3 L/min) indicated an overall high COFP accuracy. The agreement between COFP and COVS was -0.13 (0.69) L/min (Bland-Altman). In an exclusion zone of 12%, trending analysis found a 92% concordance between 5-minute changes in COFP and COVS. CONCLUSION: This study showed that CO can be reliably estimated using BPs and HR from the arterial BP waveform in combination with ML. A next step will be to test this approach using noninvasive BPs and HR.

Is heart-rate complexity a surrogate measure of cardiac output before, during, and after hemorrhage in a conscious sheep model of multiple hemorrhages and resuscitation?

BACKGROUND: Despite its medical utility, continuous cardiac output (CO) monitoring remains a practical challenge on the battlefield and in the prehospital environment. Measuring a CO surrogate, perhaps heart-rate complexity (HRC), might be a viable solution when no direct monitoring of CO is available. Changes in HRC observed before and during hemorrhagic shock may be able to track the simultaneous changes in CO. The goal of this study was to test whether HRC is a surrogate measure of CO before, during, and after hemorrhage in a conscious sheep model of multiple hemorrhages and resuscitation. METHODS: HRC was derived from 100-Hz electrocardiograms of 10 sheep records, 3 hours to 4 hours long, using the method of sample entropy. A real-time detection algorithm was used to detect the R-R interval sequences for HRC calculations. All records contained 100-Hz recordings of pulmonary arterial blood flow using Doppler transit time (criterion standard CO). Gold CO and estimated HRC values were analyzed using overlaid time-synchronized waveform plots as well as Bland-Altman, regression, and four-quadrant analysis. RESULTS: Baseline CO varied from 3.0 L/min to 5.4 L/min, while posthemorrhage CO varied from 1.0 L/min to 1.8 L/min. Importantly, overlaid plots demonstrated an overall high similarity between CO and HRC waveforms before and during hemorrhage, but not during resuscitation. When the electrocardiogram quality was high, the correlation between CO and HRC within the first 45 minutes was greater than 0.75 (p < 0.0001; maximum r, 0.972). Scatter plots also depicted high linearity before and during hemorrhage. Four-quadrant analysis showed that instantaneous changes between consecutive beat-to-beat HRC measurements followed CO measurements (100% concordance rate), while 5-minute time points yielded a 76.19% concordance rate. CONCLUSION: HRC has potential utility as a noninvasive tool for assessing the response of CO to life-threatening injuries such as hemorrhagic shock. However, further investigation and other animal models or human studies are needed.

Intrathoracic Pressure Regulation Augments Stroke Volume and Ventricular Function in Human Hemorrhage.

Obtaining intravenous (i.v.) access for fluid administration is a critical step in treating hemorrhage. However, expertise, supplies, and personnel to accomplish this task can be delayed or even absent in austere environments. An alternative approach that can "buy time" and improve circulation when i.v. fluids are absent is needed. Preclinical studies show that intrathoracic pressure regulation (ITPR) can increase perfusion in hypovolemia in the absence of i.v. fluid. We compared ITPR with placebo in humans undergoing a 15% hemorrhage under general anesthesia. Paired healthy volunteers (n = 7, aged 21 - 35 years) received either ITPR or placebo on different study days. Institutional review board informed consent was obtained. Subjects were anesthetized using propofol, intubated, and mechanically ventilated and hemorrhaged (10 mL/kg). Twenty minutes after hemorrhage, ITPR (-12 cm H2O vacuum) or placebo (device but no vacuum) was administered for another 60 min. Intravenous fluid was administered when systolic blood pressure was less than 85 mmHg. Hemodynamics, cardiac function by echocardiography, and volumetric data were compared. Data were expressed in Δmean ± SEM before and after ITPR/placebo intervention. There were no differences in mean arterial pressure (ITPR, 2.1 ± 3 mmHg; placebo, -0.7 ± 3 mmHg) or fluid infused (ITPR, 17.4 ± 4 mL/kg; placebo, 18.6 ± 5 mL/kg). Urinary output and plasma volume also were not significantly different. Intrathoracic pressure regulation augmented stroke volume (ITPR, 22 ± 5 mL, placebo, 6 ± 4 mL; P < 0.05), ejection fraction (ITPR, 4% ± 1%; placebo, 0% ± 1%), and diastolic function (ΔE/e') (ITPR, -0.8 ± 0.4 vs. placebo, +0.81 ± 0.6; P < 0.05). Intrathoracic pressure regulation did not improve mean arterial pressure in healthy volunteers aged 21 to 35 years. However, ITPR augmented stroke volume, which could be caused by improved ventricular function.

Continuous measurement of cerebral oxygen saturation (rSO2) for assessment of cardiovascular status during hemorrhagic shock in a swine model.

BACKGROUND: Early trauma care is dependent on subjective assessments and sporadic vital sign assessments. We hypothesized that near-infrared spectroscopy-measured cerebral oxygenation (regional oxygen saturation [rSO2]) would provide a tool to detect cardiovascular compromise during active hemorrhage. We compared rSO2 with invasively measured mixed venous oxygen saturation (SvO2), mean arterial pressure (MAP), cardiac output, heart rate, and calculated pulse pressure. METHODS: Six propofol-anesthetized instrumented swine were subjected to a fixed-rate hemorrhage until cardiovascular collapse. rSO2 was monitored with noninvasively measured cerebral oximetry; SvO2 was measured with a fiber optic pulmonary arterial catheter. As an assessment of the time responsiveness of each variable, we recorded minutes from start of the hemorrhage for each variable achieving a 5%, 10%, 15%, and 20% change compared with baseline. RESULTS: Mean time to cardiovascular collapse was 35 minutes ± 11 minutes (54 ± 17% total blood volume). Cerebral rSO2 began a steady decline at an average MAP of 78 mm Hg ± 17 mm Hg, well above the expected autoregulatory threshold of cerebral blood flow. The 5%, 10%, and 15% decreases in rSO2 during hemorrhage occurred at a similar times to SvO2, but rSO2 lagged 6 minutes behind the equivalent percentage decreases in MAP. There was a higher correlation between rSO2 versus MAP (R² =0.72) than SvO2 versus MAP (R² =0.55). CONCLUSIONS: Near-infrared spectroscopy-measured rSO2 provided reproducible decreases during hemorrhage that were similar in time course to invasively measured cardiac output and SvO2 but delayed 5 to 9 minutes compared with MAP and pulse pressure. rSO2 may provide an earlier warning of worsening hemorrhagic shock for prompt interventions in patients with trauma when continuous arterial BP measurements are unavailable.