INITIAL DUAL COMPARED TO MONO THERAPY FOR SEDATION AND ANALGESIA IN MECHANICALLY-VENTILATED, CRITICALLY ILL CHILDREN

Kanecia O. Zimmerman: Initial dual compared to mono therapy for sedation and analgesia in mechanically-ventilated, critically ill children (Under the direction of Til Stürmer) Mechanical ventilation is a lifesaving therapy for critically ill children with cardiopulmonary failure. Sedatives and analgesics are often required in mechanically-ventilated children to reduce pain and anxiety as well as related outcomes of hemodynamic instability, oxygen consumption, immunosuppression, ventilator asynchrony, and unplanned extubation. However, sedatives and analgesics are also associated with adverse outcomes such as drug tolerance, delirium, iatrogenic withdrawal syndrome, and prolonged hospitalization, especially as exposure to sedatives and analgesics increases. To date, the optimal strategy to minimize adverse effects while maintaining adequate sedation and analgesia remains unclear. The objective of this study is to examine the causal effect of initial administration of dual compared to mono sedative or analgesic therapy on sedative and analgesic exposure, sedation levels, and adverse outcomes in mechanically ventilated, critically ill children. We extracted data from the electronic health record at Duke University to answer the study question. We characterized the study population using descriptive statistics and used stabilized inverse probability of treatment weighting to evaluate the effect of initial sedative strategy on study outcomes during and after mechanical ventilation. Our point estimates suggest increased risk for sedative and analgesic exposure during mechanical ventilation, decreased risk of death, and elevated WAT-1 scores in the week after extubation in dual compared to monotherapy patients; however, we did not observe a similar increase in risk for more concerning outcomes such as prolonged duration of mechanical ventilation, need for reintubation, or prolonged hospitalization. We also observed heterogeneity in results within age, baseline probability of death, and neurologic subgroups. Based on our findings, we conclude that further evaluation of initial dual compared to monotherapy maybe warranted, particularly as it pertains to the most clinically relevant finding around incidence of death in the two treatment groups.Doctor of Philosoph

Determinants of Access to Care and Subsequent Emergency Department Use: The Experience of Latino Participants in Durham County's LATCH Program

Introduction: The health care sector has become the focal point of health and is increasingly viewed as the necessary factor for decreased morbidity and mortality. As several studies have linked increases in health care costs to poor access to ambulatory care and subsequent utilization of the Emergency Department (ED), programs have been implemented to increase access to ambulatory care and reduce inappropriate utilization of the ED. Despite the existence of these programs, it is unclear from existing literature what factors determine access to ambulatory care and subsequent utilization of the ED, particularly for Latino persons with low levels of ambulatory care access and poorer health outcomes when compared to non-Latino whites. In this report, we evaluate factors associated with access to ambulatory care for Latino participants of Durham Count's LATCH program and determine whether access to care is associated with utilization of the ED. Methods: We collected connnunity-based data from 448 participants in the LATCH program. We evaluated the individual associations between patient characteristics (age, gender, duration lived in the U.S., birthplace, language concordance with a health care provider, satisfaction with health care, existence of a usual source of care, perceived racial discrimination, self-rated health status, insurance status, and care management status) and access to ambulatory health care. We then evaluated these patient characteristics in relation to utilization of the ED. Analyses were performed for a subgroup of participants with at least one ambulatory sensitive condition (asthma, diabetes, hypertension) and for participants without a condition. Results: For participants without an ambulatory sensitive condition, care management and language discordance with a health care provider were significantly associated with access to ambulatory care. For those with a condition, self-rated health status and insurance status were significantly associated with access to health care. For those without an ambulatory sensitive condition, self-rated health status was significantly associated with use of the ED. No factors were significantly associated with use of the ED among those with an ambulatory sensitive condition. Conclusions: In both persons with ambulatory sensitive conditions and those without, the factors that mediate access to ambulatory care do not appear to be similar to those that mediate visits to the emergency department. A larger study is needed to clarify these important questions.Master of Public Healt

Pharmacologic studies in vulnerable populations: Using the pediatric experience

Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. However, federal legislation targeted at pediatric therapeutics, innovative clinical trial design, use of quantitative clinical pharmacology methods, and pediatric thought leadership and collaboration have successfully overcome many existing barriers. This success has resulted in improved knowledge on pharmacokinetics, safety, and efficacy of therapeutics in children. To date, research in pregnant women has not been characterized by similar success. Wide gaps in knowledge remain despite the common use of therapeutics in pregnancy. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women

Sedation, Analgesia, and Paralysis during Mechanical Ventilation of Premature Infants

To characterize administration of sedatives, analgesics, and paralytics in a large cohort of mechanically ventilated, premature infants

Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval

Over the last decade, few novel antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval

Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure–Response Relationships in Renal Transplant Patients

Sirolimus, an immunosuppressant agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially due to inconsistencies in sirolimus exposure-response relationships

Sedatives and Analgesics Given to Infants in Neonatal Intensive Care Units at the End of Life

To describe the administration of sedatives and analgesics at the end of life in a large cohort of infants in North American neonatal intensive care units (NICUs)

Population Pharmacokinetics of Olanzapine in Children

Aims The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. Methods The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. Results Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2–19.2) and 14.1 kg (4.2–111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or \u3c15 kg and fixed doses for children ≥15 kg. Conclusion We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance

A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation:

Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI)

Community SARS-CoV-2 Surge and Within-School Transmission

OBJECTIVES: When the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic began, experts raised concerns about in-person instruction in the setting of high levels of community transmission. We describe secondary transmission of SARS-CoV-2 within North Carolina (NC) K-12 school districts during a winter surge to determine if mitigation strategies can hinder within-school transmission. METHODS: From 10/26/2020–02/28/2021, 13 NC school districts participating in the ABC Science Collaborative were open for in-person instruction, adhered to basic mitigation strategies, and tracked community- and school-acquired SARS-CoV-2 cases. Public health officials adjudicated each case. We combined these data with that from August 2020 to evaluate the effect of the SARS-CoV-2 winter surge on infection rates, as well as weekly community- and school-acquired cases. We evaluated the number of secondary cases generated by each primary case, as well as the role of athletic activities in school-acquired cases. RESULTS: More than 100,000 students and staff from 13 school districts attended school in-person; of these, 4,969 community-acquired SARS-CoV-2 infections were documented by molecular testing. Through contact tracing, NC local health department staff identified an additional 209 infections among >26,000 school close contacts (secondary attack rate <1%). Most within-school transmissions in high schools (75%) were linked to school-sponsored sports. School-acquired cases slightly increased during the surge; however, within-school transmission rates remained constant, from pre-surge to surge, with approximately 1 school-acquired case for every 20 primary cases. CONCLUSIONS: With adherence to basic mitigation strategies, within-school transmission of SARS-CoV-2 can be interrupted, even during a surge of community infections