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.

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.

Intramuscular versus Intraosseous Delivery of Nerve Agent Antidote Pralidoxime Chloride in Swine.

OBJECTIVE: Exposure to nerve agents requires prompt treatment. We hypothesized that intraosseous (IO) injections of drug antidotes into the vascularized bone marrow will provide a more rapid and effective means to treat exposure to nerve agents than standard intramuscular (IM) injections. We compared the pharmacokinetics of IM and IO administration of pralidoxime chloride (2-PAM Cl) during normovolemia and hypovolemia, as well as their combined administration during normovolemia in swine. METHODS: Ten normovolemic swine were randomly administered 2 mL, 660 mg 2-PAM Cl via the IM or IO route and monitored for 180 minutes. IM versus IO also was compared in 8 hypovolemic swine bled to a mean arterial pressure of 50 mmHg. In a combined group, an IO injection was administered followed by an IM injection 60 minutes later. Blood samples were collected at times over a 180-minute period to calculate standard pharmacokinetic variables to compare the 2 routes of administration. RESULTS: In the normovolemic swine, IM injection achieved therapeutic levels (4 µg/mL) in 2 minutes, whereas IO infusion achieved these levels in less than 15 seconds. 2-PAM-Cl concentrations fell below these levels at 60 minutes post-injection in both groups. In the hypovolemic swine, IM injection achieved therapeutic levels in 4 minutes compared to less than 15 seconds in the IO group. 2-PAM-Cl concentrations fell below therapeutic levels at 12 and 90 minutes post-injection in the IM and IO groups, respectively. In the combined IO-IM treatment, plasma levels remained above therapeutic levels for the entire experiment and had two concentration peaks that corresponded to IO and IM injections. CONCLUSIONS: The IO route for the delivery of 2-PAM Cl provides a significant time and high initial blood concentrations advantage compared to the IM route for the prehospital treatment of nerve agent exposure even under hypovolemic conditions. The initial concentration peak associated with IO, but not IM, may provide greater initial therapy at the most critical time.

Passive leg raising during pregnancy.

OBJECTIVE: To determine if passive leg raising (PLR) significantly increases cardiac output in a cohort of healthy pregnant women during the third trimester. STUDY DESIGN: Using a noninvasive monitor, baseline hemodynamic measurements for arterial blood pressure, systolic and diastolic blood pressure, heart rate, cardiac output, cardiac index, stroke volume, and systemic vascular resistances were obtained with patients in the semirecumbent position. Measurements were repeated after a 3-minute PLR maneuver in supine, right lateral decubitus, and left lateral decubitus positions. RESULTS: After 10 minutes of bed rest, the cohort's mean baseline heart rate was 80 ± 12 beats/minute. Baseline stroke volume was 98 ± 14 mL, mean cardiac output was 7.8 ± 1.2 L/min, and mean cardiac index was 4.32 ± 0.63 L/min. The baseline systemic vascular resistance value was 893 ± 160 dynes/sec/cm(5). Baseline mean arterial blood pressure was 84 ± 11 mm Hg. Following a PLR maneuver in the supine position, heart rate decreased significantly. No difference was noted in other measurements. Findings were similar with PLR in the left lateral decubitus. PLR in the right lateral decubitus resulted in significantly decreased heart rate, cardiac output, and cardiac index. CONCLUSIONS: PLR did not result in cardiac output recruitment in a cohort of healthy pregnant women during the third trimester.

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.

Fluid resuscitation using the intraosseous route: infusion with lactated Ringer's and hetastarch.

OBJECTIVE: The effectiveness of the intraosseous (IO) route for fluid resuscitation remains uncertain. This study compares IO infusion rates and estimated volume expansion using clinically relevant infusion pressures with lactated Ringer's (LR) and hetastarch (HES). METHODS: IO needles were placed in the sternum or tibia for infusion of HES and LR in 8 Yorkshire pigs. Pressures were recorded at variable flow rates and linear regression used to identify flow rates at 100 and 400 mm Hg. Volume expansion was calculated for a 10-minute infusion. RESULTS: Mean LR flow rates (mL x min(-1)) were 24/111 (tibia--100/400 mm Hg) and 8/34 (sternum--100/400 mm Hg). The HES flow rates (mL x min(-1)) of 10/44 (tibia--100/400 mm Hg) and 6/26 (sternum--100/400 mm Hg) were significantly lower or -40% (p < 0.01) of the LR flow rates into the tibia and -70% (p < 0.05) into the sternum. Mean volume expansion (mL) for a 10-min infusion of LR was estimated to be 80/369 (tibia--100/400 mm Hg) and 27/112 (sternum--100/400 mm Hg). In comparison, HES volume expansion was -20% higher for the tibia (p > 0.05) and 110% to 120% higher for the sternum (p < 0.05). CONCLUSION: HES flow rates are lower than LR flow rates in the sternum and tibia of swine. Sternal infusion of HES is likely to provide greater estimated intravascular volume expansion than LR despite the lower infusion rates.

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.

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.

Computerized decision support system improves fluid resuscitation following severe burns: an original study.

OBJECTIVE: Several formulas have been developed to guide resuscitation in severely burned patients during the initial 48 hrs after injury. These approaches require manual titration of fluid that may result in human error during this process and lead to suboptimal outcomes. The goal of this study was to analyze the efficacy of a computerized open-loop decision support system for burn resuscitation compared to historical controls. DESIGN: Fluid infusion rates and urinary output from 39 severely burned patients with >20% total body surface area burns were recorded upon admission (Model group). A fluid-response model based on these data was developed and incorporated into a computerized open-loop algorithm and computer decision support system. The computer decision support system was used to resuscitate 32 subsequent patients with severe burns (computer decision support system group) and compared with the Model group. SETTING: Burn intensive care unit of a metropolitan Level 1 Trauma center. PATIENTS: Acute burn patients with >20% total body surface area requiring active fluid resuscitation during the initial 24 to 48 hours after burn. MEASUREMENTS AND MAIN RESULTS: We found no significant difference between the Model and computer decision support system groups in age, total body surface area, or injury mechanism. Total crystalloid volume during the first 48 hrs post burn, total crystalloid intensive care unit volume, and initial 24-hr crystalloid intensive care unit volume were all lower in the computer decision support system group. Infused volume per kilogram body weight (mL/kg) and per percentage burn (mL/kg/total body surface area) were also lower for the computer decision support system group. The number of patients who met hourly urinary output goals was higher in the computer decision support system group. CONCLUSIONS: Implementation of a computer decision support system for burn resuscitation in the intensive care unit resulted in improved fluid management of severely burned patients. All measures of crystalloid fluid volume were reduced while patients were maintained within urinary output targets a higher percentage of the time. The addition of computer decision support system technology improved patient care.

Gastric emptying and intestinal transit of various enteral feedings following severe burn injury.

BACKGROUND: Burn-induced delayed gastric emptying and intestinal transit limits enteral feeding/resuscitation. AIMS: To study (1) the effects of burn injury on gastric emptying and intestinal transit at different time points following enteral feeding/fluids, and (2) the effects of enteral resuscitative fluids on gastric emptying, intestinal transit, and plasma volume expansion. METHODS: Rats were randomized into sham-burn and burn groups. They were either enterally untreated or treated by a gavage of one or multiple doses of oral rehydration solution (ORS) or, Vivonex(®), all mixed with phenol red as a marker, at different time points from 1 to 6 h after burn. Gastric emptying, intestinal transit and hematocrit values were assessed. Gastric emptying of a semi-solid methylcellulose meal served as a standard control for gastric emptying studies. RESULTS: We found that (1) burn did not alter the gastric emptying of ORS, but delayed its intestinal transit at all time points; (2) burn delayed the gastric emptying of both methylcellulose or Vivonex and the intestinal transit of Vivonex, 6 h after burn; and (3) multiple doses of ORS normalized the elevated post-burn hematocrit values. The percentage of plasma volume expansion at 6 h resulting from the multiple-dose ORS was superior to that of Vivonex by 50%. Addition of Erythromycin to Vivonex improved its gastric emptying, intestinal transit, and plasma volume expansion. CONCLUSIONS: Burn delays the gastric emptying of semi-solids, but not the ORS. Enteral electrolyte solution (ORS) and feeding (Vivonex) provided plasma volume expansion. Prokinetic drugs may be able to maximize the effectiveness of early post-burn feeding.

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.

Effect of esmolol on fluid therapy in normovolemia and hypovolemia.

beta-Adrenergic agonists can enhance vascular volume expansion after a fluid bolus. The present study addresses how the beta-adrenergic antagonist esmolol influences volume expansion and fluid balance during normovolemia (series 1) and hypovolemia (series 2). Sheep were instrumented, and the spleen was removed. For series 1, continuous infusion of 50 to 100 microg.kg(-1).min(-1) esmolol (n = 6) or control (no drug; n = 6) was begun 30 min before administration of a 24-mL kg(-1) 20-min bolus of 0.9% NaCl. For series 2, anesthetized sheep were infused with 50 to 100 microg.kg(-1).min(-1) esmolol (n = 6) or control (no drug; n = 6) 30 min before a-20 mL kg(-1) hemorrhage. Fluid resuscitation (0.9% NaCl) was begun 30 min after hemorrhage. The 24-mL kg(-1) 20-min bolus was followed by titrated fluid therapy. Hemoglobin, fluid in, and urinary output were used to calculate changes in plasma volume (DeltaPV), extravascular volume (DeltaEVV = fluid in - urinary output - DeltaPV), volume expansion efficiency (VEE = fluid in / DeltaPV), and fluid distribution ratio (DeltaPV/DeltaEVV). Hemodynamics for both series were similar with the exception of heart rate. In series 1, peak DeltaPV was 9.1 +/- 1.0 mL kg(-1) in control and 3.7 +/- 1.0 mL kg(-1) at study end. Esmolol resulted in a lower peak DeltaPV (6.4 +/- 2.0 mL kg(-1)) and a negative DeltaPV (-0.4 +/- 0.6 mL kg(-1)) at study's end. Urinary output was lower, and EVV was greater with esmolol. In series 2, esmolol increased fluid requirements (67 +/- 7 mL kg(-1)) compared with control (54 +/- 5 mL kg(-1)). Esmolol reduced DeltaPV/DeltaEVV. These data suggest that esmolol impairs the vascular retention of fluid and may increase the amount of volume support during fluid resuscitation.

Closed-loop and decision-assist resuscitation of burn patients.

Effective resuscitation is critical in reducing mortality and morbidity rates of patients with acute burns. To this end, guidelines and formulas have been developed to define infusion rates and volume requirements during the first 48 hours postburn. Even with these standardized resuscitation guidelines, however, over- and under-resuscitation are not uncommon. Two approaches to adjust infusion rate are decision-assist and closed-loop algorithms based on levels of urinary output. Specific decision assist guidelines or a closed-loop system using computer-controlled feedback technology that supplies automatic control of infusion rates can potentially achieve better control of urinary output. In a properly designed system, closed-loop control has the potential to provide more accurate titration rates, while lowering the incidence of over- and under-resuscitation. Because the system can self-adjust based on monitoring inputs, the technology can be pushed to environments such as combat zones where burn resuscitation expertise is limited. A closed-loop system can also assist in the management of mass casualties, another scenario in which medical expertise is often in short supply. This article reviews the record of fluid balance of contemporary burn resuscitation and approaches, as well as the engineering efforts, animal studies, and algorithm development of our most recent autonomous systems for burn resuscitation.

Closed-loop control of fluid therapy for treatment of hypovolemia.

Closed-loop algorithms and resuscitation systems are being developed to control IV infusion rate during early resuscitation of hypovolemia. Although several different physiologic variables have been suggested as an endpoint to guide fluid therapy, blood pressure remains the most used variable for the initial assessment of hemorrhagic shock and the treatment response to volume loading. Closed-loop algorithms use a controller function to alter infusion rate inversely to blood pressure. Studies in hemorrhaged conscious sheep suggest that: (1) a small reduction in target blood pressure can result in a significant reduction in volume requirement; (2) nonlinear algorithms may reduce the risk of increased internal bleeding during resuscitation; (3) algorithm control functions based on proportional-integral, fuzzy logic, or nonlinear decision tables were found to restore and maintain blood pressure equally well. Proportional-integral and fuzzy logic algorithms reduced mean fluid volume requirements compared with the nonlinear decision table; and (4) several algorithms have been constructed to the specific mechanism of injury and the volume expansion properties of different fluids. Closed-loop systems are undergoing translation from animal to patient studies. Future smart resuscitation systems will benefit from new noninvasive technologies for monitoring blood pressure and the development of computer controlled high flow intravenous pumps.

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].