Clinical Pharmacology Studies in Critically Ill Children

Developmental and physiological changes in children contribute to variation in drug disposition with age. Additionally, critically ill children suffer from various life-threatening conditions that can lead to pathophysiological alterations that further affect pharmacokinetics (PK). Some factors that can alter PK in this patient population include variability in tissue distribution caused by protein binding changes and fluid shifts, altered drug elimination due to organ dysfunction, and use of medical interventions that can affect drug disposition (e.g., extracorporeal membrane oxygenation and continuous renal replacement therapy). Performing clinical studies in critically ill children is challenging because there is large inter-subject variability in the severity and time course of organ dysfunction; some critical illnesses are rare, which can affect subject enrollment; and critically ill children usually have multiple organ failure, necessitating careful selection of a study design. As a result, drug dosing in critically ill children is often based on extrapolations from adults or non-critically ill children. Dedicated clinical studies in critically ill children are urgently needed to identify optimal dosing of drugs in this population. This review will summarize the effect of critical illness on pediatric PK, the challenges associated with performing studies in this vulnerable subpopulation, and the clinical PK studies performed to date for commonly used drugs

Risk Factors and In-Hospital Outcomes following Tracheostomy in Infants

To describe the epidemiology, risk factors, and in-hospital outcomes of tracheostomy in infants in the neonatal intensive care unit (NICU)

Tracheostomy after Surgery for Congenital Heart Disease: An Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database

Background Information concerning tracheostomy after operations for congenital heart disease has come primarily from single-center reports. We aimed to describe the epidemiology and outcomes associated with postoperative tracheostomy in a multi-institutional registry. Methods The Society of Thoracic Surgeons Congenital Heart Database (2000 to 2014) was queried for all index operations with the adverse event “postoperative tracheostomy” or “respiratory failure, requiring tracheostomy.” Patients with preoperative tracheostomy or weighing less than 2.5 kg undergoing isolated closure of patent ductus arteriosus were excluded. Trends in tracheostomy incidence over time from January 2000 to June 2014 were analyzed with a Cochran-Armitage test. The patient characteristics associated with operative mortality were analyzed for January 2010 to June 2014, including deaths occurring up to 6 months after transfer of patients to long-term care facilities. Results From 2000 to 2014, the incidence of tracheostomy after operations for congenital heart disease increased from 0.11% in 2000 to a high of 0.76% in 2012 (p < 0.0001). From 2010 to 2014, 648 patients underwent tracheostomy. The median age at operation was 2.5 months (25th, 75th percentile: 0.4, 7). Prematurity (n = 165, 26%), genetic abnormalities (n = 298, 46%), and preoperative mechanical ventilation (n = 275, 43%) were common. Postoperative adverse events were also common, including cardiac arrest (n = 131, 20%), extracorporeal support (n = 87, 13%), phrenic or laryngeal nerve injury (n = 114, 18%), and neurologic deficit (n = 51, 8%). The operative mortality was 25% (n = 153). Conclusions Tracheostomy as an adverse event of operations for congenital heart disease remains rare but has been increasingly used over the past 15 years. This trend and the considerable mortality risk among patients requiring postoperative tracheostomy support the need for further research in this complex population

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

Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants

Abstract Background The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood. Objectives The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants. Methods We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model. Results We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC 24,SS ) and maximum concentration of sildenafil (C max,SS,SIL ) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC 24,SS ; 1.19 (0.78, 1.82) for C max,SS,SIL . Conclusions We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK)

Medication Use in the Neonatal Intensive Care Unit

We provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time

Comparative Effectiveness of Surfactant Preparations in Premature Infants

To compare effectiveness of three surfactant preparations (beractant, calfactant, and poractant alpha) in premature infants for preventing three outcomes: (1) air leak syndromes; (2) death; and (3) bronchopulmonary dysplasia (BPD) or death (composite outcomes)

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