Continuous Learning in Model-Informed Precision Dosing: A Case Study in Pediatric Dosing of Vancomycin.

Model-informed precision dosing (MIPD) leverages pharmacokinetic (PK) models to tailor dosing to an individual patient's needs, improving attainment of therapeutic drug exposure targets and thus potentially improving drug efficacy or reducing adverse events. However, selection of an appropriate model for supporting clinical decision making is not trivial. Error or bias in dose selection may arise if the selected model was developed in a population not fully representative of the intended MIPD population. One previously proposed approach is continuous learning, in which an initial model is used in MIPD and then updated as additional data becomes available. In this case study of pediatric vancomycin MIPD, the potential benefits of the continuous learning approach are investigated. Five previously published models were evaluated and found to perform adequately in a data set of 273 pediatric patients in the intensive care unit. Additionally, two predefined simple PK models were fitted on separate populations of 50-350 patients in an approach mimicking clinical implementation of automated continuous learning. With these continuous learning models, prediction error using population PK parameters could be reduced by 2-13% compared with previously published models. Sample sizes of at least 200 patients were found suitable for capturing the interindividual variability in vancomycin at this institution, with limited benefits of larger data sets. Although comprised mostly of trough samples, these sparsely sampled routine clinical data allowed for reasonable estimation of simulated area under the curve (AUC). Together, these findings lay the foundations for a continuous learning MIPD approach.

Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care: Sedation, Analgesia and Muscle Relaxant.

OBJECTIVE: This article reviews pharmacotherapies currently available to manage sedation, analgesia, and neuromuscular blockade for pediatric cardiac critical patients. DATA SOURCES: The knowledge base of an expert panel of pharmacists, cardiac anesthesiologists, and a cardiac critical care physician involved in the care of pediatric cardiac critical patients was combined with a comprehensive search of the medical literature to generate the data source. STUDY SELECTION: The panel examined all studies relevant to management of sedation, analgesia, and neuromuscular blockade in pediatric cardiac critical patients. DATA EXTRACTION: Each member of the panel was assigned a specific subset of the studies relevant to their particular area of expertise (pharmacokinetics, pharmacodynamics, and clinical care) to review and analyze. DATA SYNTHESIS: The panel members each crafted a comprehensive summary of the literature relevant to their area of expertise. The panel, as a whole, then collaborated to cohesively summarize all the available, relevant literature. CONCLUSIONS: In the cardiac ICU, management of the cardiac patient requires an individualized sedative and analgesic strategy that maintains hemodynamic stability. Multiple pharmacological therapies exist to achieve these goals and should be selected based on the patient's underlying physiology, hemodynamic vulnerabilities, desired level of sedation and analgesia, and the projected short- or long-term recovery trajectory.

Dopamine-resistant hypotension and severe retinopathy of prematurity.

OBJECTIVE: To examine the relationship between the cause or severity of hypotension and the development of severe ROP (sROP) (≥stage 3 or stage 2 with plus disease in zone I or II). STUDY DESIGN: Infants (<28 weeks' gestation, n = 242) were observed for hypotension and treated with a standardized hypotension-treatment protocol. Hypotension was classified as resulting from one of the following causes: (1) culture-positive infection and/or necrotizing enterocolitis; (2) patent ductus arteriosus ligation; or (3) "idiopathic" (no cause identified other than prematurity), and as being either dopamine responsive or dopamine resistant. Cortisol levels were measured for infants with dopamine-resistant hypotension. Eye examinations were performed until the retinopathy of prematurity resolved or the vasculature matured. Multivariable logistic regression analysis was performed to determine the relationship between the cause/severity of hypotension and sROP. RESULTS: Overall, 66% of infants developed hypotension (41% were dopamine responsive and 25% were dopamine resistant). sROP developed in 19% of infants. "Idiopathic" dopamine-resistant hypotension was the only cause significantly related to sROP. Of the infants with dopamine-resistant hypotension, 66% had low serum cortisol (≤10 µg/dL). Low cortisol, in the presence of dopamine-resistant hypotension, was significantly associated with sROP and accounted for the relationship between "idiopathic" hypotension and sROP. When low cortisol was included in statistical models, other known risk factors, such as immature gestation, were no longer significantly related to sROP. CONCLUSION: Low cortisol, in the presence of dopamine-resistant hypotension, has the greatest magnitude of association with sROP.