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<italic>Objective:</italic> 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. <italic>Methods:</italic> 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. <italic>Results:</italic> 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. <italic>Conclusion:</italic> 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. <italic>Significance:</italic> The mathematical model may provide an attractive platform to conduct non-clinical testing of burn resuscitation protocols and test new hypotheses on burn pathophysiology.

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