Muzna N. Khan

Continuous measurement of cerebral oxygen saturation (rSO 2) 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.

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.

ABSTRACT 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 ± 0.6 h and 0.2 ± 0.1 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 ± 5 in SOC versus 228 ± 59 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.

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 included MAP, 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 (when MAP < 30 mmHg of baseline) and physiological responses during and after the hemorrhage. Estimated blood volume removed when MAP dropped 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, paired t test 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.

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

ABSTRACT 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 &Dgr;mean ± 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 (&Dgr;E/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.

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 r2, 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.

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.

Optoacoustic monitoring of central and peripheral venous oxygenation during simulated hemorrhage

Circulatory shock may be fatal unless promptly recognized and treated. The most commonly used indicators of shock (hypotension and tachycardia) lack sensitivity and specificity. In the initial stages of shock, the body compensates by reducing blood flow to the peripheral (skin, muscle, etc.) circulation in order to preserve vital organ (brain, heart, liver) perfusion. Characteristically, this can be observed by a greater reduction in peripheral venous oxygenation (for instance, the axillary vein) compared to central venous oxygenation (the internal jugular vein). While invasive measurements of oxygenation are accurate, they lack practicality and are not without complications. We have developed a novel optoacoustic system that noninvasively determines oxygenation in specific veins. In order to test this application, we used lower body negative pressure (LBNP) system, which simulates hemorrhage by exerting a variable amount of suction on the lower body, thereby reducing the volume of blood available for central circulation. Restoration of normal blood flow occurs promptly upon cessation of LBNP. Using two optoacoustic probes, guided by ultrasound imaging, we simultaneously monitored oxygenation in the axillary and internal jugular veins (IJV). LBNP began at -20 mmHg, thereafter was reduced in a step-wise fashion (up to 30 min). The optoacoustically measured axillary oxygenation decreased with LBNP, whereas IJV oxygenation remained relatively constant. These results indicate that our optoacoustic system may provide safe and rapid measurement of peripheral and central venous oxygenation and diagnosis of shock with high specificity and sensitivity.

Automatic Control of Arterial Pressure for Hypotensive Patients using Phenylephrine

Abstract Developed in this paper is an automated closed-loop system that regulates the target blood pressure and maintains haemodynamic stability in hypotensive patients using the vasopressor drug phenylephrine. First, experimental studies are conducted on several healthy swine to identify dynamic mathematical models that quantify and predict blood pressure response to infusion of vasopressors. A first-order plus time-delay model structure has been selected to capture mean arterial pressure (MAP) response of patient’s subject to drug injection. Intra- and inter-patient variabilities of the model parameters have been identified and characterized. Then, an anti-windup proportional integral controller is designed, taking patient response variation in account. A nonlinear stochastic simulation environment has been developed to investigate the controller under diverse scenarios. Finally, automatic control of blood pressure is applied for the treatment of eight anesthetized swine subjected to hypotension induced by standard haemorrhage, spinal cord injury, and vasodilator injection. Results from clinical evaluations show that the proposed automated closed-loop control system is able to keep MAP near target and its performance is superior to that of manual control of infusion.

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].