Credibility Assessment of a Subject-Specific Mathematical Model of Blood Volume Kinetics for Prediction of Physiological Response to Hemorrhagic Shock and Fluid Resuscitation

Subject-specific mathematical models for prediction of physiological parameters such as blood volume, cardiac output, and blood pressure in response to hemorrhage have been developed. In silico studies using these models may provide an effective tool to generate pre-clinical safety evidence for medical devices and help reduce the size and scope of animal studies that are performed prior to initiation of human trials. To achieve such a goal, the credibility of the mathematical model must be established for the purpose of pre-clinical in silico testing. In this work, the credibility of a subject-specific mathematical model of blood volume kinetics intended to predict blood volume response to hemorrhage and fluid resuscitation during fluid therapy was evaluated. A workflow was used in which: (i) the foundational properties of the mathematical model such as structural identifiability were evaluated; (ii) practical identifiability was evaluated both pre- and post-calibration, with the pre-calibration results used to determine an optimal splitting of experimental data into calibration and validation datasets; (iii) uncertainty in model parameters and the experimental uncertainty were quantified for each subject; and (iv) the uncertainty was propagated through the blood volume kinetics model and its predictive capability was evaluated via validation tests. The mathematical model was found to be structurally identifiable. Pre-calibration identifiability analysis led to splitting the 180 min of time series data per subject into 50 and 130 min calibration and validation windows, respectively. The average root mean squared error of the mathematical model was 12.6% using the calibration window of (0 min, 50 min). Practical identifiability was established post-calibration after fixing one of the parameters to a nominal value. In the validation tests, 82 and 75% of the subject-specific mathematical models were able to correctly predict blood volume response when predictive capability was evaluated at 180 min and at the time when amount of infused fluid equals fluid loss.

RADI-05. Metastatic Neoplasm Volume Kinetics Following Two-Staged Stereotactic Radiosurgery

Introduction Multisession staged stereotactic radiosurgery (2-SSRS) represents an alternative approach for management of large brain metastases (LBMs), with potential theoretical advantages over fractionated SRS and represents an alternative to surgery in poor surgical candidates. We aimed to investigate the clinical efficacy and safety of 2-SSRS in patients with LBMs. Methods LBMs of patients treated with 2-SSRS between 2014 and 2020 were evaluated. Demographic, clinical, and radiologic information was obtained. Volumetric measurements at first SSRS, second SSRS, and follow-up imaging studies were obtained. Results Twenty-six patients with 28 LBMs were included in the study. Fifteen patients (58%) were male. Median age at 2-SSRS was 61 years (range: 31–84). Median marginal doses for first and second SSRS were 15 Gy (range: 12–18 Gy) and 15 Gy (range: 12–16 Gy), respectively. Median duration between sessions was 32 days. Two patients (8%) failed to receive their second SSRS due to local progression. Median tumor volumes at first SSRS, second SSRS, 3-month follow-up, and 6-month follow-up were 8.7 cm3 (range: 1.5–34.7 cm3), 3.3 cm3 (range: 0.8–26.1 cm3), 1.7 cm3 (range: 0.2–10.1 cm3), and 1.4 cm3 (range: .04–20.7 cm3), respectively. The median absolute and relative decrement between S-SRS sessions was 3.7 cm3 (range: 2.8–16.5 cm3) and 49.5% (range: 17.1- 87.1%), respectively. Overall, 26 of the 28 lesions (93%) demonstrated early local control following the first SSRS with 18 lesions (69%) demonstrating a decrease in volume of >30% and 3 lesions (12%) remaining stable. Six lesions (23%) showed disease progression. There were no grade 3 adverse events. Conclusions Our study supports the effectiveness and safety of 2-SSRS as a treatment modality for patients with large, symptomatic brain metastases, especially in non-surgical candidates. The local failure rate and low occurrence of adverse effects are comparable to other staged radiosurgery series.

Understanding Volume Kinetics: The Role of Pharmacokinetic Modeling and Analysis in Fluid Therapy

Fluid therapy is a rapidly evolving yet imprecise clinical practice based upon broad assumptions, species-to-species extrapolations, obsolete experimental evidence, and individual preferences. Although widely recognized as a mainstay therapy in human and veterinary medicine, fluid therapy is not always benign and can cause significant harm through fluid overload, which increases patient morbidity and mortality. As with other pharmaceutical substances, fluids exert physiological effects when introduced into the body and therefore should be considered as “drugs.” In human medicine, an innovative adaptation of pharmacokinetic analysis for intravenous fluids known as volume kinetics using serial hemoglobin dilution and urine output has been developed, refined, and investigated extensively for over two decades. Intravenous fluids can now be studied like pharmaceutical drugs, leading to improved understanding of their distribution, elimination, volume effect, efficacy, and half-life (duration of effect) under various physiologic conditions, making evidence-based approaches to fluid therapy possible. This review article introduces the basic concepts of volume kinetics, its current use in human and animal research, as well as its potential and limitations as a research tool for fluid therapy research in veterinary medicine. With limited evidence to support our current fluid administration practices in veterinary medicine, a greater understanding of volume kinetics and body water physiology in veterinary species would ideally provide some evidence-based support for safer and more effective intravenous fluid prescriptions in veterinary patients.

RADT-06. VOLUME KINETICS FOLLOWING TWO-SESSION GAMMA KNIFE RADIOSURGERY FOR LARGE BRAIN METASTASES (BM)

INTRODUCTION Resection is a well-established treatment for BM ≥ 2 cm, albeit with potential for perioperative complications and delays in systemic treatment. Staged stereotactic radiosurgery (S-SRS) may improve outcomes versus traditional SRS, representing an alternative to surgery in responders. We reviewed institutional outcomes using 2-session S-SRS, focusing on lesion volume kinetics. METHODS 25 patients with 27 lesions underwent S-SRS at our institution between 2014 and 2020. Tumor volumes (TV) were measured at both S-SRS sessions and on follow-up MRI studies. RESULTS Median age at S-SRS was 61 years (range (r:) 31–84). Nine patients (10 BM) were lost to follow-up. Two patients failed to receive their second S-SRS due to local progression. The median margin tumor doses at first and second S-SRS were 15 Gy (r: 12–18 Gy) and 15 Gy (r: 12–16 Gy). The median interval between stages was 32 days (r: 8–63), and median TV at the first and second stages were 9.3 cm3 (r: 1.5–34.7 cm3) and 3.3 cm3 (r: 0.76–26.1 cm3), respectively. The median absolute and relative decrement between S-SRS sessions was 3.7 cm3 (r: 2.8-16.5 cm3) and 49.5% (r: 17.1-87.1%), respectively. [1-2]-month, [3-5]-month, and [6-12]-month MRI scans were available for 17, 10, and 15 lesions. The median decrease in TV compared to baseline was 50.2%, 78.2%, 74.9%. Two of 17 lesions (12%) had initial control but subsequently experienced volumetric progression and required resection. There were no G3+ adverse events (AE). Crude tumor control was achieved in 14 of 17 individual lesions (82%). CONCLUSION Two-session S-SRS is an effective treatment modality for treating patients with large BM, which is feasible in over 80% of patients with sustained tumor control and early volumetric regression.

Effects of Custom-made Mouthguards on Cardiopulmonary Exercise Capacity

The importance of using mouthguards as well as their low acceptance rate have been demonstrated. The aim of this study was to investigate the influence of customized mouthguards on hemodynamics.. This randomized crossover study used data from 13 subjects (23.5±1.4 years). The cardiopulmonary and metabolic parameters were observed during ergometer tests without mouthguard (control) in comparison to two types of mouthguards (with and normal without breathing channels). Maximum ventilation was significantly decreased with the normal mouthguard (113.3±30.00 l ∙ min−1) in contrast to the mouthguard with breathing channels (122.5±22.9 l ∙ min−1) and control (121.9±30.8 l ∙ min−1). Also the inspiration time was longer when using the normal mouthguard (0.70±0.11 s) compared to the mouthguard with breathing channels (0.63±0.11 s) and control (Co 0.64±0.10 s). Lactate was also increased under the influence of the mouthguard with breathing channels (10.72±1.4 mmol ∙ l−1) compared to the control (9.40±1.77 mmol ∙ l−1) and the normal mouthguard (9.02±1.67 mmol ∙ l−1). In addition, stroke volume kinetics (p=0.048) and maximum heart rates (p=0.01) show changes. Despite equal levels of oxygen uptake and performances under all three conditions, the use of mouthguards showed differences in cardiopulmonary parameters. The use of mouthguards during exercise does not affect physical performance and can be recommended for injury prevention.