Sedation Research in Critically Ill Pediatric Patients: Proposals for Future Study Design From the Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research IV Workshop.

OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.

Urinary Tract Infection Epidemiology in NICUs in the United States.

OBJECTIVE: Our objective was to characterize the incidence, associated clinical factors, timing of infection, microbiology, and incidence of concordant blood culture of urinary tract infections (UTIs) in very low birth weight (VLBW <1,500g) infants. STUDY DESIGN: Multicenter observational cohort study of VLBW infants with gestational age (GA) ≤32 weeks, still hospitalized on postnatal day 7, and discharged 2010 to 2018 from Pediatrix Medical Group neonatal intensive care units. Demographic and clinical characteristics of infants with and without UTI were compared. Multivariable logistic regression evaluated adjusted odds of UTI diagnosis. RESULTS: Of 86,492 included infants, 5,988 (7%) had a UTI. The most common pathogen was Enterococcus spp. (20%), followed by Escherichia coli (19%) and Klebsiella spp. (18%). Candida spp. (6%) was the most common nonbacterial pathogen. Concordant-positive blood culture was present in 8% of infants with UTI diagnoses. UTI was associated with lower GA, male sex, vaginal delivery, prenatal steroid exposure, and longer duration of hospitalization. CONCLUSION: UTI is a common cause of infection in VLBW infants, especially among the smallest, most premature, male infants, and those with a longer duration of hospitalization. Neonatal clinicians should consider obtaining urine culture in the setting of late-onset sepsis evaluations in VLBW infants. KEY POINTS: · UTI is a common cause of LOS in VLBW infants.. · The most common pathogens are Enterococcus spp. and E. coli.. · UTI risk varies among different VLBW infant populations.. · Next steps should include evaluation of preventative measures..

Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018.

OBJECTIVE: To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time. STUDY DESIGN: We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies. RESULTS: The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem + cilastatin, and amikacin. CONCLUSION: Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.

Association Between Digoxin Use and Cardiac Function in Infants With Single-Ventricle Congenital Heart Disease During the Interstage Period.

OBJECTIVES: To examine the association between digoxin use and cardiac function assessed by echocardiographic indices in infants with single-ventricle (SV) congenital heart disease (CHD) during the interstage period. DESIGN: Retrospective cohort study. SETTING: Fifteen North American hospitals. PATIENTS: Infants discharged home following stage 1 palliation (S1P) and prior to stage 2 palliation (S2P). Infants with no post-S1P and pre-S2P echocardiograms were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 373 eligible infants who met inclusion criteria, 140 (37.5%) were discharged home on digoxin. In multivariable linear and logistic regressions, we found that compared with infants discharged home without digoxin, those discharged with digoxin had a smaller increase in end-systolic volume (ß = -8.17 [95% CI, -15.59 to -0.74]; p = 0.03) and area (ß = -1.27 [-2.45 to -0.09]; p = 0.04), as well as a smaller decrease in ejection fraction (ß = 3.38 [0.47-6.29]; p = 0.02) and fractional area change (ß = 2.27 [0.14-4.41]; p = 0.04) during the interstage period. CONCLUSIONS: Digoxin may partially mitigate the expected decrease in cardiac function during the interstage period through its positive inotropic effects. Prospective clinical trials are needed to establish the pharmacokinetics, safety, and efficacy of digoxin use in SV CHD.

Developing lay summaries and thank you notes in paediatric pragmatic clinical trials.

INTRODUCTION: Better transparency of research results and participant engagement may help address poor participant accrual in paediatric clinical research. We conducted formative research to assess the acceptability of lay summaries and thank you notes, as well as to refine and expand guidance on participant and family engagement in Pediatric Trials Network's (PTN) pragmatic paediatric clinical research. METHODS: Informed by draft PTN guidance, we conducted in-depth qualitative interviews with adolescent clinical trial participants and caregivers of paediatric participants in four trials conducted by PTN across eight sites. Participants were shown multiple versions of mock lay summaries and thank you notes and asked questions on their preferences for content and layout, and on trial communications. We used applied thematic analysis to analyse the data. RESULTS: We interviewed 27 individuals engaged in PTN research: 24 caregivers and 3 adolescents. During a trial, participants want regular updates on study progress, reminders of the study purpose and reassurances of data confidentiality. After the trial, participants want to learn the aggregated results, particularly medication effectiveness. Participants reported that lay summaries should include a review of the study's purpose, methods and length, and that they expect to learn individual-level results. Participants stated that thank you notes must be of sufficient length to be meaningful. CONCLUSIONS: This is the first study to describe stakeholder preferences for thank you note content and layout. Using these findings, we finalized PTN's trial communication guidance for use in future PTN trials. Research is needed to determine the effect of lay summaries and thank you notes on improving public transparency regarding clinical trials and paediatric trial recruitment and completion. PATIENT OR PUBLIC CONTRIBUTION: By design, stakeholders (adolescent trial participants and caregivers of pediatric trial participants) contributed to PTN's guidance on the content and layout of lay summaries and thank you notes through their participation in the in-depth interviews.

Prescribing Patterns of Amantadine During Pediatric Inpatient Rehabilitation After Traumatic Brain Injury: A Multicentered Retrospective Review From the Pediatric Brain Injury Consortium.

OBJECTIVES: To describe dosing practices for amantadine hydrochloride and related adverse effects among children and young adults with traumatic brain injury (TBI) admitted to pediatric inpatient rehabilitation units. SETTING: Eight pediatric acute inpatient rehabilitation units located throughout the United States comprising the Pediatric Brain Injury Consortium. PARTICIPANTS: Two-hundred thirty-four children and young adults aged 2 months to 21 years with TBI. DESIGN: Retrospective data revie. MAIN OUTCOME MEASURES: Demographic variables associated with the use of amantadine, amantadine dose, and reported adverse effects. RESULTS: Forty-nine patients (21%) aged 0.9 to 20 years received amantadine during inpatient rehabilitation. Forty-five percent of patients admitted to inpatient rehabilitation with a disorder of consciousness (DoC) were treated with amantadine, while 14% of children admitted with higher levels of functioning received amantadine. Children with DoC who were not treated with amantadine were younger than those with DoC who received amantadine (median 3.0 vs 11.6 years, P = .008). Recorded doses of amantadine ranged from 0.7 to 13.5 mg/kg/d; the highest total daily dose was 400 mg/d. Adverse effects were reported in 8 patients (16%); nausea/abdominal discomfort and agitation were most common, each reported in 3 patients. The highest reported dose without an adverse effect was 10.1 mg/kg/d. CONCLUSION: During pediatric inpatient rehabilitation, amantadine was prescribed to children across a range of ages and injury severity and was most commonly prescribed to older children with DoC. Dosing varied widely, with weight-based dosing for younger/smaller children at both lower and higher doses than what had been previously reported. Prospective studies are needed to characterize the safety and tolerability of higher amantadine doses and optimize amantadine dosing parameters for children with TBI.

The relationship between simulated milrinone exposure and hypotension in children.

INTRODUCTION: Hypotension is an adverse event that may be related to systemic exposure of milrinone; however, the true exposure-safety relationship is unknown. METHODS: Using the Pediatric Trials Network multicentre repository, we identified children ≤17 years treated with milrinone. Hypotension was defined according to age, using the Pediatric Advanced Life Support guidelines. Clinically significant hypotension was defined as hypotension with concomitant lactate >3 mg/dl. A prior population pharmacokinetic model was used to simulate milrinone exposures to evaluate exposure-safety relationships. RESULTS: We included 399 children with a median (quarter 1, quarter 3) age of 1 year (0,5) who received 428 intravenous doses of milrinone (median infusion rate 0.31 mcg/kg/min [0.29,0.5]). Median maximum plasma milrinone concentration was 110.7 ng/ml (48.4,206.2). Median lowest systolic and diastolic blood pressures were 74 mmHg (60,85) and 35 mmHg (25,42), respectively. At least 1 episode of hypotension occurred in 178 (45%) subjects; clinically significant hypotension occurred in 10 (2%). The maximum simulated milrinone plasma concentrations were higher in subjects with clinically significant hypotension (251 ng/ml [129,329]) versus with hypotension alone (86 ng/ml [44, 173]) versus without hypotension (122 ng/ml [57, 208], p = 0.002); however, this relationship was not retained on multivariable analysis (odds ratio 1.01; 95% confidence interval 0.998, 1.01). CONCLUSIONS: We successfully leveraged a population pharmacokinetic model and electronic health record data to evaluate the relationship between simulated plasma concentration of milrinone and systemic hypotension occurrence, respectively, supporting the broader applicability of our novel, efficient, and cost-effective study design for examining drug exposure-response and -safety relationships.

Evaluation of effect of scheduled fresh frozen plasma on ECMO circuit life: A randomized pilot trial.

BACKGROUND: Factor consumption is common during ECMO complicating the balance of pro and anticoagulation factors. This study sought to determine whether transfusion of coagulation factors using fresh frozen plasma (FFP) increased ECMO circuit life and decreased blood product transfusion. Secondly, it analyzed the association between FFP transfusion and hemorrhagic and thrombotic complications. STUDY DESIGN AND METHODS: Thirty-one pediatric ECMO patients between October 2013 and January 2016 at a quaternary care institution were included. Patients were randomized to FFP every 48 hours or usual care. The primary outcome was ECMO circuit change. Secondary outcomes included blood product transfusion, survival to decannulation, hemorrhagic and thrombotic complications, and ECMO costs. RESULTS: Median (interquartile range [IQR]) number of circuit changes was 0 (0, 1). No difference was seen in percent days without a circuit change between intervention and control group, P = .53. Intervention group patients received median platelets of 15.5 mL/kg/d IQR (3.7, 26.8) vs 24.8 mL/kg/d (12.2, 30.8) for the control group (P = .16), and median packed red blood cells (pRBC) of 7.7 mL/kg/d (3.3, 16.3) vs 5.9 mL/kg/d (3.4, 18.7) for the control group, P = .60. FFP transfusions were similar with 10.2 mL/kg/d (5.0, 13.9) in the intervention group vs 8.8 (2.5, 17.7) for the control group, P = .98. CONCLUSION: In this pilot randomized study, scheduled FFP did not increase circuit life. There was no difference in blood product transfusion of platelets, pRBCs, and FFP between groups. Further studies are needed to examine the association of scheduled FFP with blood product transfusion.

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 <15 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.

Cognitive Recovery During Inpatient Rehabilitation Following Pediatric Traumatic Brain Injury: A Pediatric Brain Injury Consortium Study.

OBJECTIVES: To characterize the demographics, clinical course, and predictors of cognitive recovery among children and young adults receiving inpatient rehabilitation following pediatric traumatic brain injury (TBI). DESIGN: Retrospective observational, multicenter study. SETTING: Eight acute pediatric inpatient rehabilitation facilities in the United States with specialized programs for treating patients with TBI. PARTICIPANTS: Children and young adults (0-21 years) with TBI (n = 234) receiving inpatient rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Admission and discharge status assessed by the WeeFIM Cognitive Developmental Functional Quotient (DFQ) and Cognitive and Linguistic Scale (CALS). RESULTS: Patients admitted to pediatric inpatient rehabilitation are diverse in cognitive functioning. While the majority of patients make improvements, cognitive recovery is constrained for those admitted with the most severe cognitive impairments. Age, time since injury to rehabilitation admission, and admission WeeFIM Cognitive DFQ are significant predictors of cognitive functioning at discharge from inpatient rehabilitation. CONCLUSIONS: This work establishes a multicenter Pediatric Brain Injury Consortium and characterized the demographics and clinical course of cognitive recovery during inpatient rehabilitation of pediatric patients with TBI to aid in prospective study design.

Impact of COVID-19-related School Closures on the Drivers of Child Health.

The COVID-19 pandemic resulted in large-scale school closures in an effort to reduce the spread of disease. This article reviews the potential impact of COVID-19-related school closures on the health of children in North Carolina, with particular attention to the impact of school closures on drivers of child health.

Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.

PURPOSE: Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease. METHODS: We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated. RESULTS: Eleven patients with IPD (n = 7) or LOPD (n = 4) were treated with higher doses of up to 40 mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40 mg/kg weekly compared with lower doses (p < 0.05). No safety or immunogenicity concerns were observed at higher doses. CONCLUSION: Higher rhGAA doses are safe, improve gross motor outcomes, lingual strength, pulmonary function measures, and biochemical markers in early-onset Pompe disease, and should be considered in patients with clinical and functional decline.

Detection of iron deficiency in children with Down syndrome.

PURPOSE: Current American Academy of Pediatrics guidelines for children with Down syndrome (DS) recommend a complete blood count (CBC) at birth and hemoglobin annually to screen for iron deficiency (ID) and ID anemia (IDA) in low-risk children. We aimed to determine if macrocytosis masks the diagnosis of ID/IDA and to evaluate the utility of biochemical and red blood cell indices for detecting ID/IDA in DS. METHODS: We reviewed data from 856 individuals from five DS specialty clinics. Data included hemoglobin, mean corpuscular volume, red cell distribution width (RDW), percent transferrin saturation (TS), ferritin, and c-reactive protein. Receiver operating characteristic curves were calculated. RESULTS: Macrocytosis was found in 32% of the sample. If hemoglobin alone was used for screening, all individuals with IDA would have been identified, but ID would have been missed in all subjects. RDW had the highest discriminability of any single test for ID/IDA. The combination of RDW with ferritin or TS led to 100% sensitivity, and RDW combined with ferritin showed the highest discriminability for ID/IDA. CONCLUSION: We provide evidence to support that a CBC and ferritin be obtained routinely for children over 1 year old with DS rather than hemoglobin alone for detection of ID.

Altered Folate Homeostasis in Children with Down Syndrome: A Potential Basis for Enhanced Methotrexate Toxicity.

Methotrexate is used to treat autoimmune and oncologic diseases in children with Down syndrome. However, increased methotrexate-related toxicity is reported in this population. We evaluated differences in the concentrations and distribution of erythrocyte folates in children with Down syndrome as a potential basis for this enhanced toxicity.

Probiotic Use and Safety in the Neonatal Intensive Care Unit: A Matched Cohort Study.

OBJECTIVE: To determine the prevalence of probiotic administration in infants born preterm over time, as well as the association between probiotic administration and select adverse outcomes. STUDY DESIGN: We performed a multicenter cohort study of infants 23-29 weeks of gestational age admitted to 289 neonatal intensive care units from 1997 to 2016. We evaluated the type of probiotics given and prevalence of exposure to probiotics over time and by site. We matched infants exposed to probiotics by several factors to unexposed infants receiving enteral feeds on the same postnatal day. We performed conditional logistic regression to evaluate the association between probiotics exposure and adverse outcomes, including necrotizing enterocolitis (NEC), bloodstream infections, meningitis, and death. RESULTS: Of 78 076 infants, 3626 (4.6%) received probiotics. Probiotic use increased over the study period and varied among neonatal intensive care units. We matched 2178 infants exposed to probiotics to 33 807 without exposure. Probiotic administration was associated with a decrease in NEC (OR 0.62, 95% CI 0.48-0.80) and death (OR 0.52, 95% CI 0.39-0.70), an increase in Candida infection (OR 2.23, 95% CI 1.29-3.85), but no increase in bloodstream infection (OR 0.86, 95% CI 0.70-1.05) or meningitis (OR 1.18, 95% CI 0.40-3.46). CONCLUSIONS: Probiotic use increased over time and was associated with decreased odds of NEC and death. Prospective, randomized-controlled studies of specific probiotic products are needed to further investigate the safety and efficacy of probiotics in preterm infants.

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020.

BACKGROUND: Infants with moderate-to-severe CHD frequently undergo cardiopulmonary bypass surgery in childhood. Morbidity and mortality are highest in those who develop post-operative low cardiac output syndrome. Vasoactive and inotropic medications are mainstays of treatment for these children, despite limited evidence supporting their use. METHODS: To help inform clinical practice, as well as the conduct of future trials, we performed a systematic review of existing literature on inotropes and vasoactives in children after cardiac surgery using the PubMed and EMBASE databases. We included studies from 2000 to 2020, and the patient population was defined as birth - 18 years of age. Two reviewers independently reviewed studies to determine final eligibility. RESULTS: The final analysis included 37 papers. Collectively, selected studies reported on 12 different vasoactive and inotropic medications in 2856 children. Overall evidence supporting the use of these drugs in children after cardiopulmonary bypass was limited. The majority of studies were small with 30/37 (81%) enrolling less than 100 patients, 29/37 (78%) were not randomised, and safety and efficacy endpoints differed widely, limiting the ability to combine data for meta-analyses. CONCLUSION: Vasoactive and inotropic support remain critical parts of post-operative care for children after cardiopulmonary bypass surgery. There is a paucity of data for the selection and dosing of vasoactives and inotropes for these patients. Despite the knowledge gaps that remain, numerous recent innovations create opportunities to rethink the conduct of clinical trials in this high-risk population.

Association between preoperative respiratory support and outcomes in paediatric cardiac surgery.

BACKGROUND: Preoperative mechanical ventilation is associated with morbidity and mortality following CHD surgery, but prior studies lack a comprehensive analysis of how preoperative respiratory support mode and timing affects outcomes. METHODS: We retrospectively collected data on children <18 years of age undergoing cardiac surgery at an academic tertiary care medical centre. Using multivariable regression, we examined the association between modes of preoperative respiratory support (nasal cannula, high-flow nasal cannula/noninvasive ventilation, or invasive mechanical ventilation), escalation of preoperative respiratory support, and invasive mechanical ventilation on the day of surgery for three outcomes: operative mortality, postoperative length of stay, and postoperative complications. We repeated our analysis in a subcohort of neonates. RESULTS: A total of 701 children underwent 800 surgical procedures, and 40% received preoperative respiratory support. Among neonates, 243 patients underwent 253 surgical procedures, and 79% received preoperative respiratory support. In multivariable analysis, all modes of preoperative respiratory support, escalation in preoperative respiratory support, and invasive mechanical ventilation on the day of surgery were associated with increased odds of prolonged length of stay in children and neonates. Children (odds ratio = 3.69, 95% CI 1.2-11.4) and neonates (odds ratio = 8.97, 95% CI 1.31-61.14) on high-flow nasal cannula/noninvasive ventilation had increased odds of operative mortality compared to those on room air. CONCLUSION: Preoperative respiratory support is associated with prolonged length of stay and mortality following CHD surgery. Knowing how preoperative respiratory support affects outcomes may help guide surgical timing, inform prognostic conversations, and improve risk stratification models.

Dexmedetomidine extraction by the extracorporeal membrane oxygenation circuit: results from an in vitro study.

BACKGROUND: Dexmedetomidine is a sedative administered to minimize distress and decrease the risk of life threatening complications in children supported with extracorporeal membrane oxygenation. The extracorporeal membrane oxygenation circuit can extract drug and decrease drug exposure, placing the patient at risk of therapeutic failure. OBJECTIVE: To determine the extraction of dexmedetomidine by the extracorporeal membrane oxygenation circuit. MATERIALS AND METHODS: Dexmedetomidine was studied in three closed-loop circuit configurations to isolate the impact of the oxygenator, hemofilter, and tubing on circuit extraction. Each circuit was primed with human blood according to standard practice for Duke Children's Hospital, and flow was set to 1 L/min. Dexmedetomidine was dosed to achieve a therapeutic concentration of ~600 pg/mL. Dexmedetomidine was added to a separate tube of blood to serve as a control and evaluate for natural drug degradation. Serial blood samples were collected over 24 hours and concentrations were quantified with a validated assay. Drug recovery was calculated at each time point. RESULTS: Dexmedetomidine was highly extracted by the oxygenator evidenced by a mean recovery of 62-67% at 4 hours and 23-34% at 24 hours in circuits with an oxygenator in-line. In contrast, mean recovery with the oxygenator removed was 96% at 4 hours and 93% at 24 hours. Dexmedetomidine was stable over time with a mean recovery in the control samples of 102% at 24 hours. CONCLUSION: These results suggest dexmedetomidine is extracted by the oxygenator in the extracorporeal membrane oxygenation circuit which may result in decreased drug exposure in vivo.

Dexmedetomidine Pharmacokinetics and a New Dosing Paradigm in Infants Supported With Cardiopulmonary Bypass.

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.

Neonatal Therapeutics: Considerations for Dosing.

Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures to drugs that lack adequate data on safety, efficacy, and appropriate dosing in this population. Key physiologic differences between neonates and older children and adults affect drug absorption, distribution, metabolism, and elimination. Adequate understanding and consideration of these differences is essential to ensure optimal dosing of therapeutic agents in this vulnerable population. Moreover, direct study of neonates through appropriately designed pharmacokinetic and pharmacodynamic studies can ensure the development of safe and effective therapeutics in our youngest populations of patients.