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.

A Mathematical Model for Simulation of Vasoplegic Shock and Vasopressor Therapy.

OBJECTIVE: To develop a high-fidelity mathematical model intended to replicate the cardiovascular (CV) responses of a critically ill patient to vasoplegic shock-induced hypotension and vasopressor therapy. METHODS: The mathematical model consists of a lumped-parameter CV physiology model with baroreflex modulation feedback and a phenomenological dynamic dose-response model of a vasopressor. The adequacy of the proposed mathematical model was investigated using an experimental dataset acquired from 10 pigs receiving phenylephrine (PHP) therapy after vasoplegic shock induced via sodium nitroprusside (SNP). RESULTS: Upon calibration, the mathematical model could (i) faithfully replicate the effects of PHP on dynamic changes in blood pressure (BP), cardiac output (CO), and systemic vascular resistance (SVR) (root-mean-squared errors between measured and calibrated mathematical responses: mean arterial BP 2.5+/-1.0 mmHg, CO 0.2+/-0.1 lpm, SVR 2.4+/-1.5 mmHg/lpm; r value: mean arterial BP 0.96+/-0.01, CO 0.65+/-0.45, TPR 0.92+/-0.10) and (ii) predict physiologically plausible behaviors of unmeasured internal CV variables as well as secondary baroreflex modulation effects. CONCLUSION: This mathematical model is perhaps the first of its kind that can comprehensively replicate both primary (i.e., direct) and secondary (i.e., baroreflex modulation) effects of a vasopressor drug on an array of CV variables, rendering it ideally suited to pre-clinical virtual evaluation of the safety and efficacy of closed-loop control algorithms for autonomous vasopressor administration once it is extensively validated. SIGNIFICANCE: This mathematical model architecture incorporating both direct and baroreflex modulation effects may generalize to serve as part of an effective platform for high-fidelity in silico simulation of CV responses to vasopressors during vasoplegic shock.

Development and validation of a mathematical model of heart rate response to fluid perturbation.

Physiological closed-loop controlled (PCLC) medical devices monitor and automatically adjust the patient's condition by using physiological variables as feedback, ideally with minimal human intervention to achieve the target levels set by a clinician. PCLC devices present a challenge when it comes to evaluating their performance, where conducting large clinical trials can be expensive. Virtual physiological patients simulated by validated mathematical models can be utilized to obtain pre-clinical evidence of safety and assess the performance of the PCLC medical device during normal and worst-case conditions that are unlikely to happen in a limited clinical trial. A physiological variable that plays a major role during fluid resuscitation is heart rate (HR). For in silico assessment of PCLC medical devices regarding fluid perturbation, there is currently no mathematical model of HR validated in terms of its predictive capability performance. This paper develops and validates a mathematical model of HR response using data collected from sheep subjects undergoing hemorrhage and fluid infusion. The model proved to be accurate in estimating the HR response to fluid perturbation, where averaged between 21 calibration datasets, the fitting performance showed a normalized root mean square error (NRMSE) of [Formula: see text]. The model was also evaluated in terms of model predictive capability performance via a leave-one-out procedure (21 subjects) and an independent validation dataset (6 subjects). Two different virtual cohort generation tools were used in each validation analysis. The generated envelope of virtual subjects robustly met the defined acceptance criteria, in which [Formula: see text] of the testing datasets presented simulated HR patterns that were within a deviation of 50% from the observed data. In addition, out of 16000 and 18522 simulated subjects for the leave-one-out and independent datasets, the model was able to generate at least one virtual subject that was close to the real subject within an error margin of [Formula: see text] and [Formula: see text] NRMSE, respectively. In conclusion, the model can generate valid virtual HR physiological responses to fluid perturbation and be incorporated into future non-clinical simulated testing setups for assessing PCLC devices intended for fluid resuscitation.

Heart Rate Variability Can Detect Blunt Traumatic Brain Injury Within the First Hour.

INTRODUCTION: In patients with multi-organ system trauma, the diagnosis of coinciding traumatic brain injury can be difficult due to injuries from the hemorrhagic shock that confound clinical and radiographic signs of traumatic brain injury. In this study, a novel technique using heart rate variability was developed in a porcine model to detect traumatic brain injury early in the setting of hemorrhagic shock without the need for radiographic imaging or clinical exam. METHODS: A porcine model of hemorrhagic shock was used with an arm of swine receiving hemorrhagic shock alone and hemorrhagic shock with traumatic brain injury. High-resolution heart rate frequencies were collected at different time intervals using waveforms based on voltage delivered from the heart rate monitor. Waveforms were analyzed to assess statistically significant differences between heart rate variability parameters in those with hemorrhagic shock and traumatic brain injury versus those with only hemorrhagic shock. Stochastic analysis was used to assess the validity of results and create a model by machine learning to better assess the presence of traumatic brain injury. RESULTS: Significant differences were found in several heart rate variability parameters between the two groups. Additionally, significant differences in heart rate variability parameters were found in swine within 1 hour of inducing hemorrhage in those with traumatic brain injury versus those without. These results were confirmed with stochastic analysis and machine learning was used to generate a model which determined the presence of traumatic brain injury in the setting of hemorrhage shock with 91.6% accuracy. CONCLUSIONS:  Heart rate variability represents a promising diagnostic tool to aid in the diagnosis of traumatic brain injury within 1 hour of injury.

The physiologic responses to a fluid bolus administration in old and young healthy adults.

BACKGROUND: Organ function is known to decline with age. Optimizing cardiac, pulmonary and renal function in older adults has led to significant improvements in perioperative care. However, when substantial blood loss and fluid shifts occur, perioperative outcomes still remains poor, especially in older adults. We suspect that this could be due to age-related changes in endothelial function-an organ controlling the transport of fluid and solutes. The capillary filtration coefficient (CFC) is an important determinant of fluid transport. The CFC can be measured in vivo, which provides a tool to estimate endothelial barrier function. We have previously shown that the CFC increases when giving a fluid bolus resulting in increased vascular and extravascular volume expansion, in young adults. This study aimed to compare the physiologic determinants of fluid distribution in young versus older adults so that clinicians can best optimize perioperative fluid therapy. METHODS: Ten healthy young volunteers (ages 21-35) and nine healthy older volunteers (ages 60-75) received a 10 mL/kg fluid bolus over the course of twenty minutes. Hemodynamics, systolic and diastolic heart function, fluid volumetrics and microcirculatory determinants were measured before, during, and after the fluid bolus. RESULTS: Diastolic function was reduced in older versus younger adults before and after fluid bolus (P < 0.01). Basal CFC and plasma oncotic pressure were lower in the older versus younger adults. Further, CFC did not increase in older adults following the fluid bolus, whereas it did in younger adults (p < 0.05). Cumulative urinary output, while lower in older adults, was not significantly different (p = 0.059). Mean arterial pressure and systemic vascular resistance were elevated in the older versus younger adults (p < 0.05). CONCLUSION: Older adults show a less reactive CFC to a fluid bolus, which could reduce blood to tissue transport of fluid. Diastolic dysfunction likely contributes to fluid maldistribution in older adults.

Collective Variational Inference for Personalized and Generative Physiological Modeling: A Case Study on Hemorrhage Resuscitation.

OBJECTIVE: Individual physiological experiments typically provide useful but incomplete information about a studied physiological process. As a result, inferring the unknown parameters of a physiological model from experimental data is often challenging. The objective of this paper is to propose and illustrate the efficacy of a collective variational inference (C-VI) method, intended to reconcile low-information and heterogeneous data from a collection of experiments to produce robust personalized and generative physiological models. METHODS: To derive the C-VI method, we utilize a probabilistic graphical model to impose structure on the available physiological data, and algorithmically characterize the graphical model using variational Bayesian inference techniques. To illustrate the efficacy of the C-VI method, we apply it to a case study on the mathematical modeling of hemorrhage resuscitation. RESULTS: In the context of hemorrhage resuscitation modeling, the C-VI method could reconcile heterogeneous combinations of hematocrit, cardiac output, and blood pressure data across multiple experiments to obtain (i) robust personalized models along with associated measures of uncertainty and signal quality, and (ii) a generative model capable of reproducing the physiological behavior of the population. CONCLUSION: The C-VI method facilitates the personalized and generative modeling of physiological processes in the presence of low-information and heterogeneous data. SIGNIFICANCE: The resulting models provide a solid basis for the development and testing of interpretable physiological monitoring, decision-support, and closed-loop control algorithms.

Mathematical Modeling, In-Human Evaluation and Analysis of Volume Kinetics and Kidney Function After Burn Injury and Resuscitation.

OBJECTIVE: Existing burn resuscitation protocols exhibit a large variability in treatment efficacy. Hence, they must be further optimized based on comprehensive knowledge of burn pathophysiology. A physics-based mathematical model that can replicate physiological responses in diverse burn patients can serve as an attractive basis to perform non-clinical testing of burn resuscitation protocols and to expand knowledge on burn pathophysiology. We intend to develop, optimize, validate, and analyze a mathematical model to replicate physiological responses in burn patients. METHODS: Using clinical datasets collected from 233 burn patients receiving burn resuscitation, we developed and validated a mathematical model applicable to computer-aided in-human burn resuscitation trial and knowledge expansion. Using the validated mathematical model, we examined possible physiological mechanisms responsible for the cohort-dependent differences in burn pathophysiology between younger versus older patients, female versus male patients, and patients with versus without inhalational injury. RESULTS: We demonstrated that the mathematical model can replicate physiological responses in burn patients associated with wide demographic characteristics and injury severity, and that an increased inflammatory response to injury may be a key contributing factor in increasing the mortality risk of older patients and patients with inhalation injury via an increase in the fluid retention. CONCLUSION: We developed and validated a physiologically plausible mathematical model of volume kinetic and kidney function after burn injury and resuscitation suited to in-human application. SIGNIFICANCE: The mathematical model may provide an attractive platform to conduct non-clinical testing of burn resuscitation protocols and test new hypotheses on burn pathophysiology.

Sex differences in the effects of adolescent intermittent ethanol exposure on exploratory and anxiety-like behavior in adult rats.

Adolescent intermittent ethanol (AIE) exposure in rodents has been shown to alter adult behavior in several domains, including learning and memory, social interaction, affective behavior, and ethanol self-administration. AIE has also been shown to produce non-specific behavioral changes that compromise behavioral efficiency. Many studies of these types rely on measuring behavior in mazes and other enclosures that can be influenced by animals' activity levels and exploratory behavior, and relatively few such studies have assessed sex as a biological variable. To address the effects of AIE and its interaction with sex on these types of behavioral assays, male and female adolescent rats (Sprague Dawley) were exposed to 10 doses of AIE (5 g/kg, intra-gastrically [i.g.]), or control vehicle, over 16 days (postnatal day [PND] 30-46), and then tested for exploratory and anxiety-like behaviors on the novelty-induced hypophagia (NIH) task in an open field, the elevated plus (EPM) maze, and the Figure 8 maze. AIE reduced activity/exploratory behaviors in males on the anxiety-producing NIH and EPM tasks, but reduced activity in both males and females in the Figure 8 maze, a task designed to create a safe environment and reduce anxiety. Independent of AIE, females engaged in more rearing behavior than males during the NIH task but less in the EPM, in which they were also less active than males. AIE also increased EPM open arm time in females but not in males. These findings demonstrate previously unrecognized sex differences in the effects of AIE on activity, exploratory behavior, and anxiety-like behavior; additionally, they underscore the need to design future behavioral studies of AIE using sex as a variable and with rigorous attention to how AIE alters these behaviors.

Accuracy assessment methods for physiological model selection toward evaluation of closed-loop controlled medical devices.

Physiological closed-loop controlled (PCLC) medical devices are complex systems integrating one or more medical devices with a patient's physiology through closed-loop control algorithms; introducing many failure modes and parameters that impact performance. These control algorithms should be tested through safety and efficacy trials to compare their performance to the standard of care and determine whether there is sufficient evidence of safety for their use in real care setting. With this aim, credible mathematical models have been constructed and used throughout the development and evaluation phases of a PCLC medical device to support the engineering design and improve safety aspects. Uncertainties about the fidelity of these models and ambiguities about the choice of measures for modeling performance need to be addressed before a reliable PCLC evaluation can be achieved. This research develops tools for evaluating the accuracy of physiological models and establishes fundamental measures for predictive capability assessment across different physiological models. As a case study, we built a refined physiological model of blood volume (BV) response by expanding an original model we developed in our prior work. Using experimental data collected from 16 sheep undergoing hemorrhage and fluid resuscitation, first, we compared the calibration performance of the two candidate physiological models, i.e., original and refined, using root-mean-squared error (RMSE), Akiake information criterion (AIC), and a new multi-dimensional approach utilizing normalized features extracted from the fitting error. Compared to the original model, the refined model demonstrated a significant improvement in calibration performance in terms of RMSE (9%, P = 0.03) and multi-dimensional measure (48%, P = 0.02), while a comparable AIC between the two models verified that the enhanced calibration performance in the refined model is not due to data over-fitting. Second, we compared the physiological predictive capability of the two models under three different scenarios: prediction of subject-specific steady-state BV response, subject-specific transient BV response to hemorrhage perturbation, and leave-one-out inter-subject BV response. Results indicated enhanced accuracy and predictive capability for the refined physiological model with significantly larger proportion of measurements that were within the prediction envelope in the transient and leave-one-out prediction scenarios (P < 0.02). All together, this study helps to identify and merge new methods for credibility assessment and physiological model selection, leading to a more efficient process for PCLC medical device evaluation.

Mathematical model of volume kinetics and renal function after burn injury and resuscitation.

This paper presents a mathematical model of blood volume kinetics and renal function in response to burn injury and resuscitation, which is applicable to the development and non-clinical testing of burn resuscitation protocols and algorithms. Prior mathematical models of burn injury and resuscitation are not ideally suited to such applications due to their limited credibility in predicting blood volume and urinary output observed in wide-ranging burn patients as well as in incorporating contemporary knowledge of burn pathophysiology. Our mathematical model consists of an established multi-compartmental model of blood volume kinetics, a hybrid mechanistic-phenomenological model of renal function, and novel lumped-parameter models of burn-induced perturbations in volume kinetics and renal function equipped with contemporary knowledge on burn-related physiology and pathophysiology. Using the dataset collected from 16 sheep, we showed that our mathematical model can be characterized with physiologically plausible parameter values to accurately predict blood volume kinetic and renal function responses to burn injury and resuscitation on an individual basis against a wide range of pathophysiological variability. Pending validation in humans, our mathematical model may serve as an effective basis for in-depth understanding of complex burn-induced volume kinetic and renal function responses as well as development and non-clinical testing of burn resuscitation protocols and algorithms.

Fluid volumes infused during burn resuscitation 1980-2015: A quantitative review.

INTRODUCTION: 'Fluid creep' or excessive fluid delivered to burn patients during early resuscitation has been suggested by several studies from individual burn centers. METHODS: We performed a Medline search from 1980 to 2015 in order to identify studies of burn patients predominantly resuscitated with lactated Ringers with infusion adjusted per urinary output. Data was abstracted for 48 publications (3196 patients) that met entry criteria. RESULTS: Higher resuscitation volumes compared to Parkland estimates were reported, but the trend of increasing resuscitation volumes over the last 30 years is not supported by regression of total fluid infused versus year of study. Mean 24h fluid infused for all studies was 5.2±1.1mL/kg per %TBSA. The mean 24h urinary output reported in 30 studies was 1.2±0.5mL/kg per hr. Burns with inhalation injuries (5 studies) received significantly more fluid than non-inhalation injured burn patients (5.0±1.3 versus 3.9±0.9mL/kg per %TBSA). Fluid infused and urinary outputs were similar for adults and pediatric patients. The most striking finding of our analyses was the great ranges of the means and high standard deviations of volumes infused compared to the original Baxter publication that introduced the Parkland formula CONCLUSIONS: These analyses suggest that burn units currently administer volumes larger than Parkland formula with great patient variability. Individual patient hourly data is needed to better understand the record of burn resuscitation and Fluid Creep.

Operational Advantages of Enteral Resuscitation Following Burn Injury in Resource-Poor Environments: Palatability of Commercially Available Solutions.

BACKGROUND: In recent combat operations, 5% to 15% of casualties sustained thermal injuries, which require resource-intensive therapies. During prolonged field care or when caring for patients in a multidomain battlefield, delayed transport will complicate the challenges that already exist in the burn population. A lack of resources and/or vascular access in the future operating environment may benefit from alternative resuscitation strategies. The objectives of the current report are 1) to briefly review actual and potential advantages/caveats of resuscitation with enteral fluids and 2) to present new data on palatability of oral rehydration solutions. METHODS: A review of the literature and published guidelines are reported. In addition, enlisted US military active duty Servicemembers (N = 40) were asked to taste/rank five different oral rehydration solutions on several parameters. RESULTS AND CONCLUSIONS: There are several operational advantages of using enteral fluids including ease of administration, no specialized equipment needed, and the use of lightweight sachets that are easily reconstituted/ administered. Limited clinical data along with slightly more extensive preclinical studies have prompted published guidelines for austere conditions to indicate consideration of enteral resuscitation for burns. Gatorade® and Drip-Drop® were the overall preferred rehydration solutions based on palatability, with the latter potentially more appropriate for resuscitation. Taken together, enteral resuscitation may confer several advantages over intravenous fluids for burn resuscitation under resource-poor scenarios. Future research needs to identify what solutions and volumes are optimal for use in thermally injured casualties.

The Medical Student Summer Research Program at the University of Texas Medical Branch at Galveston: building research foundations.

BACKGROUND: Interest in incorporating research into the medical school curriculum has grown over the years. One of the challenges involved with providing research to medical students is developing programs that allow a large number of students to perform research. This involves securing faculty to mentor students in the design of research projects. In order to accommodate students with research interests, well-established research programs must be implemented. OBJECTIVE: This article describes the design and implementation of a curriculum-based research program for medical students at the University of Texas Medical Branch (UTMB) at Galveston. The main objective of this article is to describe the program for the purpose of assisting other medical schools to develop a similar student research program. DESIGN: At UTMB we established a Medical Student Summer Research Program (MSSRP) that occurred between the first year and the second year of medical school. Between the years 2000-2017, MSSRP accommodated a minimum of 39 and a maximum of 90 students during an 8 week period. Two surveys were conducted to collect students' views on how MSSRP affected their interest in research. We performed a proportion statistical analysis on the data from both surveys in order to determine the significance of the responses. RESULTS: The benefit of MSSRP is that it provided medical students with an exposure to research. According to the proportions test, the responses were statistically significant with 85% of 26 third and fourth year students stating they would continue to incorporate research into their medical careers; 75% stating that MSSRP increased their interest in research; and 85% responding that MSSRP helped them to understand research methodology. CONCLUSIONS: MSSRP is a curriculum-based program that provides a framework to other medical institutions interested in the development of similar student research programs and provides students the exposure and option to continue with research as a component of their medical profession.

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].

Control-oriented physiological modeling of hemodynamic responses to blood volume perturbation.

This paper presents a physiological model to reproduce hemodynamic responses to blood volume perturbation. The model consists of three sub-models: a control-theoretic model relating blood volume response to blood volume perturbation; a simple physics-based model relating blood volume to stroke volume and cardiac output; and a phenomenological model relating cardiac output to blood pressure. A unique characteristic of this model is its balance for simplicity and physiological transparency. Initial validity of the model was examined using experimental data collected from 11 animals. The model may serve as a viable basis for the design and evaluation of closed-loop fluid resuscitation controllers.

Effectiveness of Colonic Fluid Resuscitation in a Burn-Injured Swine.

To determine the effectiveness of colonic fluid absorption as a route for fluid resuscitation of a major burn. In order to assess the feasibility and performance of colonic resuscitation, the authors compared plasma volume expansion and hemodynamic parameters of animals submitted to colonic or intravenous fluid resuscitation. Twelve anesthetized swine were submitted to a 40% full thickness flame burn. Thirty minutes later fluid resuscitation was initiated with either intravenous or colonic infusion of crystalloid based on the Parkland formula. This treatment lasted 4.5 hours. The volume of fluid infused was 86 ± 18 ml/kg for the intravenous treatment and 89 ± 14 ml/kg for the colonic treatment. The percentage of fluid absorbed by the colon at the end of the protocol was 30 ± 13% of the infused fluid. Enteral resuscitation was equally effective in expanding plasma volume at the end of the protocol. Laboratorial and hemodynamic parameters were similar between the two resuscitation strategies throughout the study. Urine output was significantly higher in the intravenous group (7.9 ± 4.2 ml/kg/hr vs 0.9 ± 0.3 ml/kg/hr, P = .03). This study demonstrates that colonic infusion of normal saline in a severe burn injury model can restore hemodynamic stability and expand plasma volume to a degree that rivals the effect of direct intravenous infusion for early burn resuscitation in a swine model.

In-human subject-specific evaluation of a control-theoretic plasma volume regulation model.

The goal of this study was to conduct a subject-specific evaluation of a control-theoretic plasma volume regulation model in humans. We employed a set of clinical data collected from nine human subjects receiving fluid bolus with and without co-administration of an inotrope agent, including fluid infusion rate, plasma volume, and urine output. Once fitted to the data associated with each subject, the model accurately reproduced the fractional plasma volume change responses in all subjects: the error between actual versus model-reproduced fractional plasma volume change responses was only 1.4 ± 1.6% and 1.2 ± 0.3% of the average fractional plasma volume change responses in the absence and presence of inotrope co-administration. In addition, the model parameters determined by the subject-specific fitting assumed physiologically plausible values: (i) initial plasma volume was estimated to be 36 ± 11 mL/kg and 37 ± 10 mL/kg in the absence and presence of inotrope infusion, respectively, which was comparable to its actual counterpart of 37 ± 4 mL/kg and 43 ± 6 mL/kg; (ii) volume distribution ratio, specifying the ratio with which the inputted fluid is distributed in the intra- and extra-vascular spaces, was estimated to be 3.5 ± 2.4 and 1.9 ± 0.5 in the absence and presence of inotrope infusion, respectively, which accorded with the experimental observation that inotrope could enhance plasma volume expansion in response to fluid infusion. We concluded that the model was equipped with the ability to reproduce plasma volume response to fluid infusion in humans with physiologically plausible model parameters, and its validity may persist even under co-administration of inotropic agents.

Closed-Loop- and Decision-Assist-Guided Fluid Therapy of Human Hemorrhage.

OBJECTIVES: We sought to evaluate the efficacy, efficiency, and physiologic consequences of automated, endpoint-directed resuscitation systems and compare them to formula-based bolus resuscitation. DESIGN: Experimental human hemorrhage and resuscitation. SETTING: Clinical research laboratory. SUBJECTS: Healthy volunteers. INTERVENTIONS: Subjects (n = 7) were subjected to hemorrhage and underwent a randomized fluid resuscitation scheme on separate visits 1) formula-based bolus resuscitation; 2) semiautonomous (decision assist) fluid administration; and 3) fully autonomous (closed loop) resuscitation. Hemodynamic variables, volume shifts, fluid balance, and cardiac function were monitored during hemorrhage and resuscitation. Treatment modalities were compared based on resuscitation efficacy and efficiency. MEASUREMENTS AND MAIN RESULTS: All approaches achieved target blood pressure by 60 minutes. Following hemorrhage, the total amount of infused fluid (bolus resuscitation: 30 mL/kg, decision assist: 5.6 ± 3 mL/kg, closed loop: 4.2 ± 2 mL/kg; p < 0.001), plasma volume, extravascular volume (bolus resuscitation: 17 ± 4 mL/kg, decision assist: 3 ± 1 mL/kg, closed loop: -0.3 ± 0.3 mL/kg; p < 0.001), body weight, and urinary output remained stable under decision assist and closed loop and were significantly increased under bolus resuscitation. Mean arterial pressure initially decreased further under bolus resuscitation (-10 mm Hg; p < 0.001) and was lower under bolus resuscitation than closed loop at 20 minutes (bolus resuscitation: 57 ± 2 mm Hg, closed loop: 69 ± 4 mm Hg; p = 0.036). Colloid osmotic pressure (bolus resuscitation: 19.3 ± 2 mm Hg, decision assist, closed loop: 24 ± 0.4 mm Hg; p < 0.05) and hemoglobin concentration were significantly decreased after bolus fluid administration. CONCLUSIONS: We define efficacy of decision-assist and closed-loop resuscitation in human hemorrhage. In comparison with formula-based bolus resuscitation, both semiautonomous and autonomous approaches were more efficient in goal-directed resuscitation of hemorrhage. They provide favorable conditions for the avoidance of over-resuscitation and its adverse clinical sequelae. Decision-assist and closed-loop resuscitation algorithms are promising technological solutions for constrained environments and areas of limited resources.

Progression and variability of physiologic deterioration in an ovine model of lung infection sepsis.

In this study, a lung infection model of pneumonia in sheep (n = 12) that included smoke inhalation injury followed by methicillin-resistant Staphylococcus aureus placement into the lungs was used to investigate hemodynamic and pulmonary dysfunctions during the course of sepsis progression. To assess the variability in disease progression, animals were retrospectively divided into survivor (n = 6) and nonsurvivor (n = 6) groups, and a range of physiological indexes reflecting hemodynamic and pulmonary function were estimated and compared to evaluate variability in dynamics underlying sepsis development. Blood pressure and heart rate variability analyses were performed to assess whether they discriminated between the survivor and nonsurvivor groups early on and after intervention. Results showed hemodynamic deterioration in both survivor and nonsurvivor animals during sepsis along with a severe oxygenation disruption (decreased peripheral oxygen saturation) in nonsurvivors separating them from survivor animals of this model. Variability analysis of beat-to-beat heart rate and blood pressure reflected physiologic deterioration during infection for all animals, but these analyses did not discriminate the nonsurvivor animals from survivor animals.NEW & NOTEWORTHY Variable pulmonary response to injury results in varying outcomes in a previously reported animal model of lung injury and methicillin-resistant Staphylococcus aureus-induced sepsis. Heart rate and blood pressure variability analyses were investigated to track the varying levels of physiologic deterioration but did not discriminate early nonsurvivors from survivors.