Predicting Inter-individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study.

INTRODUCTION: Intravenous lipid emulsions (ILE) have been credited for successful resuscitation in drug intoxication cases where other cardiac life-support methods have failed. However, inter-individual variability can function as a confounder that challenges our ability to define the scope of efficacy for lipid interventions, particularly as relevant data are scarce. To address this challenge, we developed a quantitative systems pharmacology model to predict outcome variability and shed light on causal mechanisms in a virtual population of rats subjected to bupivacaine toxicity and ILE intervention. MATERIALS AND METHODS: We combined a physiologically based pharmacokinetic-pharmacodynamic model with data from a small study in Sprague-Dawley rats to characterize individual-specific cardiac responses to lipid infusion. We used the resulting individual parameter estimates to posit a population distribution of responses to lipid infusion. On that basis, we constructed a large virtual population of rats (N = 10,000) undergoing lipid therapy following bupivacaine cardiotoxicity. RESULTS: Using unsupervised clustering to assign resuscitation endpoints, our simulations predicted that treatment with a 30% lipid emulsion increases bupivacaine median lethal dose (LD50) by 46% when compared with a simulated control fluid. Prior experimental findings indicated an LD50 increase of 48%. Causal analysis of the population data suggested that muscle accumulation rather than liver accumulation of bupivacaine drives survival outcomes. CONCLUSION: Our results represent a successful prediction of complex, dynamic physiological outcomes over a virtual population. Despite being informed by very limited data, our mechanistic model predicted a plausible range of treatment outcomes that accurately predicts changes in LD50 when extrapolated to putatively toxic doses of bupivacaine. Furthermore, causal analysis of the predicted survival outcomes indicated a critical synergy between scavenging and direct cardiotonic mechanisms of ILE action.

BurnCare tablet trainer to enhance burn injury care and treatment.

BACKGROUND: Applied Research Associates (ARA) and the United States Army Institute of Surgical Research (USAISR) have been developing a tablet-based simulation environment for burn wound assessment and burn shock resuscitation. This application aims to supplement the current gold standard in burn care education, the Advanced Burn Life Support (ABLS) curriculum. RESULTS: Subject matter experts validate total body surface area (TBSA) identification and analysis and show that the visual fidelity of the tablet virtual patients is consistent with real life thermal injuries. We show this by noting that the error between their burn mapping and the actual patient burns was sufficiently less than that of a random sample population. Statistical analysis is used to confirm this hypothesis. In addition a full body physiology model developed for this project is detailed. Physiological results, and responses to standard care treatment, are detailed and validated. Future updates will include training modules that leverage this model. CONCLUSION: We have created an accurate, whole-body model of burn TBSA training experience in Unreal 4 on a mobile platform, provided for free to the medical community. We hope to provide learners with more a realistic experience and with rapid feedback as they practice patient assessment, intervention, and reassessment.

A Whole-Body Mathematical Model of Sepsis Progression and Treatment Designed in the BioGears Physiology Engine.

Sepsis is a debilitating condition associated with a high mortality rate that greatly strains hospital resources. Though advances have been made in improving sepsis diagnosis and treatment, our understanding of the disease is far from complete. Mathematical modeling of sepsis has the potential to explore underlying biological mechanisms and patient phenotypes that contribute to variability in septic patient outcomes. We developed a comprehensive, whole-body mathematical model of sepsis pathophysiology using the BioGears Engine, a robust open-source virtual human modeling project. We describe the development of a sepsis model and the physiologic response within the BioGears framework. We then define and simulate scenarios that compare sepsis treatment regimens. As such, we demonstrate the utility of this model as a tool to augment sepsis research and as a training platform to educate medical staff.

Open Source Pharmacokinetic/Pharmacodynamic Framework: Tutorial on the BioGears Engine.

BioGears is an open-source, lumped parameter, full-body human physiology engine. Its purpose is to provide realistic and comprehensive simulations for medical training, research, and education. BioGears incorporates a physiologically based pharmacokinetic/pharmacodynamic (PK/PD) model that is designed to be applicable to a diversity of drug classes and patients and is extensible to future drugs. In addition, BioGears also supports drug interactions with various patient insults and interventions allowing for a realistic research framework and accurate dose-patient responses. This tutorial will demonstrate how the generic BioGears PK/PD model can be extended to a new substance for prediction of drug administration outcomes.

A Full-Body Model of Burn Pathophysiology and Treatment Using the BioGears Engine.

We have created a model of systemic burn pathophysiology by incorporating a mathematical model of acute inflammation within the BioGears Engine. This model produces outputs consistent with burns of varying severities and leverages existing BioGears functionality to simulate the effect of treatment on virtual patient outcome. The model performs well for standard resuscitation scenarios and we thus expect it to be useful for educational and training purposes.

Comparing in situ removal strategies for improving styrene bioproduction.

As an important conventional monomer compound, the biological production of styrene carries significant promise with respect to creating novel sustainable materials. Since end-product toxicity presently limits styrene production by previously engineered Escherichia coli, in situ product removal by both solvent extraction and gas stripping were explored as process-based strategies for circumventing its inhibitory effects. In solvent extraction, the addition of bis(2-ethylhexyl)phthalate offered the greatest productivity enhancement, allowing net volumetric production of 836 ± 64 mg/L to be reached, representing a 320 % improvement over single-phase cultures. Gas stripping rates, meanwhile, were controlled by rates of bioreactor agitation and, to a greater extent, aeration. A periodic gas stripping protocol ultimately enabled up to 561 ± 15 mg/L styrene to be attained. Lastly, by relieving the effects of styrene toxicity, new insight was gained regarding subsequent factors limiting its biosynthesis in E. coli and strategies for future strain improvement are discussed.

The effect of intravenous indigo carmine on near-infrared cerebral oximetry.

The effects of IV-administered dyes on pulse oximetry have been well described. However, the effects on near-infrared cerebral oximetry have not been well documented. We report a series of four patients undergoing radical prostatectomy who were monitored with cerebral oximetry during surgery. After the administration of indigo carmine, intraoperative desaturations were observed for an extended period. Because clinical use of near-infrared cerebral oximetry is increasing, anesthesiologists should be aware of this issue.