Pediatric sepsis is a heterogeneous disease with varying physiological dynamics associated with recovery, disability, and mortality. Using risk scores generated from a sepsis prediction model to define illness states, we used Markov chain modeling to describe disease dynamics over time by describing how children transition among illness states. We analyzed 18,666 illness state transitions over 157 pediatric intensive care unit admissions in the 3 days following blood cultures for suspected sepsis. We used Shannon entropy to quantify the differences in transition matrices stratified by clinical characteristics. The population-based transition matrix based on the sepsis illness severity scores in the days following a sepsis diagnosis can describe a sepsis illness trajectory. Using the entropy based on Markov chain transition matrices, we found a different structure of dynamic transitions based on ventilator use but not age group. Stochastic modeling of transitions in sepsis illness severity scores can be useful in describing the variation in transitions made by patient and clinical characteristics.

Background: Heart rate characteristics aid early detection of late-onset sepsis (LOS), but respiratory data contain additional signatures of illness due to infection. Predictive models using cardiorespiratory data may improve early sepsis detection. We hypothesized that heart rate (HR) and oxygenation (SpO 2 ) data contain signatures that improve sepsis risk prediction over HR or demographics alone. Methods: We analyzed cardiorespiratory data from very low birth weight (VLBW, <1500g) infants admitted to three NICUs. We developed and externally validated four machine learning models to predict LOS using features calculated every 10m: mean, standard deviation, skewness, kurtosis of HR and SpO 2 , and cross-correlation. We compared feature importance, discrimination, calibration, and dynamic prediction across models and cohorts. We built models of demographics and HR or SpO 2 features alone for comparison with HR-SpO 2 models. Results: Performance, feature importance, and calibration were similar among modeling methods. All models had favorable external validation performance. The HR-SpO 2 model performed better than models using either HR or SpO 2 alone. Demographics improved the discrimination of all physiologic data models but dampened dynamic performance. Conclusions: Cardiorespiratory signatures detect LOS in VLBW infants at 3 NICUs. Demographics risk-stratify, but predictive modeling with both HR and SpO 2 features provides the best dynamic risk prediction.

Illness dynamics and patterns of recovery may be essential features in understanding the critical illness course. We propose a method to characterize individual illness dynamics in patients who experienced sepsis in the pediatric intensive care unit. We defined illness states based on illness severity scores generated from a multi-variable prediction model. For each patient, we calculated transition probabilities to characterize movement among illness states. We calculated the Shannon entropy of the transition probabilities. Using the entropy parameter, we determined phenotypes of illness dynamics based on hierarchical clustering. We also examined the association between individual entropy scores and a composite variable of negative outcomes. Entropy-based clustering identified four illness dynamic phenotypes in a cohort of 164 intensive care unit admissions where at least one sepsis event occurred. Compared to the low-risk phenotype, the high-risk phenotype was defined by the highest entropy values and had the most ill patients as defined by a composite variable of negative outcomes. Entropy was significantly associated with the negative outcome composite variable in a regression analysis. Information-theoretical approaches to characterize illness trajectories offer a novel way of assessing the complexity of a course of illness. Characterizing illness dynamics with entropy offers additional information in conjunction with static assessments of illness severity. Additional attention is needed to test and incorporate novel measures representing the dynamics of illness.

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