Felice Su

Population pharmacokinetics of dexmedetomidine in infants after open heart surgery.

BACKGROUND: Dexmedetomidine is a highly selective &agr;2-agonist with hypnotic, analgesic, and anxiolytic properties. In adults, it provides sedation while preserving respiratory function facilitating extubation. Only limited pharmacokinetic data are available for pediatric patients. The primary aim of this study was to determine the pharmacokinetics of dexmedetomidine in infants after open heart surgery. METHODS: We evaluated 36 infants, aged 1 to 24 months, after open heart surgery. Cohorts of 12 infants requiring mechanical ventilation after open heart surgery were enrolled sequentially to 1 of the 3 initial loading dose—continuous IV infusion (CIVI) regimens: 0.35–0.25, 0.7–0.5, or 1–0.75 &mgr;g/kg-&mgr;g/kg/h. The initial loading dose was administered over 10 minutes immediately postoperatively followed by a CIVI of up to 24 hours. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. RESULTS: Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight on drug clearance, intercompartmental clearance, central and peripheral volume of distributions, total bypass time as a covariate on clearance and central volume of distribution, and age and ventricular physiology as covariates on clearance. Infants demonstrated a clearance of 28.1 mL/min/kg0.75, intercompartmental clearance of 93.4 mL/min/kg0.75, central volume of distribution of 1.2 L/kg, and peripheral volume of distribution of 1.5 L/kg. CONCLUSIONS: Dexmedetomidine clearance increased with weight, age, and single-ventricle physiology, whereas total bypass time was associated with a trend toward decreasing clearance, and central volume of distribution increased as a function of total bypass time. The dependence of clearance on body weight supports current practice of weight-based dexmedetomidine dosing, whereas the clinical impact of the remaining covariate effects requires further investigation. Initial loading doses in the range of 0.35 to 1 &mgr;g/kg over 10 minutes and CIVI of 0.25 to 0.75 &mgr;g/kg/h were well tolerated in this infant population.

Dexmedetomidine: pediatric pharmacology, clinical uses and safety

Importance of the field: Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic and analgesic properties. It is used off-label in pediatric patients due to its efficacy and lack of adverse respiratory effects. Dexmedetomidine may cause severe circulatory complications in adults. Despite its popularity, the safety of dexmedetomidine in the pediatric population has not been extensively studied. Areas covered in this review: This article reviews the current literature (up to 2010) focusing on applications and safety of dexmedetomidine administered to pediatric patients. What the reader will gain: Dexmedetomidine is a useful sedative and anxiolytic drug in the pediatric intensive care unit as well as during diagnostic and therapeutic procedures. Deleterious effects of dexmedetomidine include hypotension and bradycardia. Additionally, hypertension may occur during the “loading dose” or with high infusion rates. Few studies have been performed to evaluate the safety of dexmedetomidine in pediatrics. The development of tolerance and withdrawal has not been studied in children. Take home message: Despite its favorable respiratory profile, dexmedetomidine may cause deleterious cardiovascular effects. Close monitoring of circulatory dynamics and judicious titration is recommended. Further studies are needed to better define adverse effects following long-term infusions as well as in special populations such as pre-term infants.

Association between vancomycin trough concentration and area under the concentration-time curve in neonates.

ABSTRACT National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC0–24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC0–24 of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC0–24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC0–24 achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC0–24 of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC0–24 of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC0–24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.

A Dose-Response Study of Dexmedetomidine Administered as the Primary Sedative in Infants Following Open Heart Surgery

Objective: To evaluate the dose-response relationship of dexmedetomidine in infants with congenital heart disease postoperative from open heart surgery. Design: Prospective open-label dose-escalation pharmacokinetic-pharmacodynamic study. Setting: Tertiary pediatric cardiac ICU. Patients: Thirty-six evaluable infants, 1–24 months old, postoperative from open heart surgery requiring mechanical ventilation. Interventions: Cohorts of 12 infants were enrolled sequentially to one of the three IV loading doses of dexmedetomidine (0.35, 0.7, and 1 mcg/kg) over 10 minutes followed by respective continuous infusions (0.25, 0.5, and 0.75 mcg/kg/hr) for up to 24 hours. Measurements and Main Results: Dexmedetomidine plasma concentrations were obtained at timed intervals during and following discontinuation of infusion. Pharmacodynamic variables evaluated included sedation scores, supplemental sedation and analgesia medication administration, time to tracheal extubation, respiratory function, and hemodynamic parameters. Infants achieved a deeper sedation measured by the University of Michigan Sedation Scale score (2.6 vs 1) despite requiring minimal supplemental sedation (0 unit doses/hr) and fewer analgesic medications (0.07 vs 0.15 unit doses/hr) while receiving dexmedetomidine compared with the 12-hour follow-up period. Thirty-one patients were successfully extubated while receiving the dexmedetomidine infusion. Only one patient remained intubated due to oversedation during the infusion. While receiving dexmedetomidine, there was a decrease in heart rate compared with baseline, 132 versus 161 bpm, but there was an increase in heart rate compared with postinfusion values, 132 versus 128 bpm. There was no statistically or clinically significant change in mean arterial blood pressure. Conclusions: Dexmedetomidine administration in infants following open heart surgery can provide improved sedation with reduction in supplemental medication requirements, leading to successful extubation while receiving a continuous infusion. The postoperative hemodynamic changes that occur in infants postoperative from open heart surgery are multifactorial. Although dexmedetomidine may play a role in decreasing heart rate immediately postoperative, the changes were not clinically significant and did not fall below postinfusion heart rates.

Dexmedetomidine Pharmacology in Neonates and Infants After Open Heart Surgery.

BACKGROUND:Dexmedetomidine is a highly selective &agr;2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day–1 month) and 36 evaluable infants (age, 1 month–24 months) after open heart surgery. METHODS:Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 &mgr;g/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 &mgr;g/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 &mgr;g/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 &mgr;g/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. RESULTS:Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated a plasma drug clearance of 657 × (weight/70)0.75 mL/min, intercompartmental clearance of 6780 × (weight/70)0.75 mL/min, central volume of distribution of 88 × (weight/70) L and peripheral volume of distribution of 112 × (weight/70) L for a typical subject with age >1 month with a cardiopulmonary bypass time of 60 minutes and without right-to-left intracardiac shunt. Dexmedetomidine pharmacokinetics may be influenced by age during the neonatal period, weight, total bypass time, and presence of intracardiac shunt. CONCLUSIONS:Dexmedetomidine clearance is significantly diminished in full-term newborns and increases rapidly in the first few weeks of life. The dependence of clearance on age during the first few weeks of life reflects the relative immaturity of metabolic processes during the newborn period. Continuous infusions of up to 0.3 &mgr;g/kg/h in neonates and 0.75 &mgr;g/kg/h in infants were well tolerated after open heart surgery.

Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia

Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, 2‐center clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight, 1.82–5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine‐3‐glucuronide and morphine‐6‐gluronide) were measured via a validated dried blood spot liquid chromatography–tandem mass spectrometry assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed‐effects modeling. The clearance of morphine and glucuronide metabolites was best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5‐kg neonate, morphine clearance was 0.77 L/h (CV, 48%), and the steady‐state volume of distribution was 8.0 L (CV, 49%). Compared with previous studies in full‐term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10 and 40 ng/mL. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweights.

Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease

Etomidate is a rapid‐onset, short‐acting hypnotic medication administered for the induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants are lacking.

Subglottic Stenosis Following Cardiac Surgery With Cardiopulmonary Bypass in Infants and Children

Objectives: To determine the 1) incidence of subglottic stenosis in infants and children following cardiac surgery with cardiopulmonary bypass and 2) risk factors associated with its development. Design: Retrospective cohort study. Setting: Tertiary children’s hospital in California. Patients: Infants and children who underwent cardiac surgery with cardiopulmonary bypass. Interventions: Diagnosis of subglottic stenosis by tracheoscopy. Measurements and Main Results: The incidence of subglottic stenosis at our institution during the study period was 0.7%. Young age (p = 0.014), prolonged cardiopulmonary bypass (p = 0.03), and prolonged mechanical ventilation (p < 0.01) were associated with the development of subglottic stenosis. Gender, chromosomal anomaly, presence of a cuffed endotracheal tube, and lowest core temperature during cardiopulmonary bypass were not associated with the development of subglottic stenosis. Conclusions: The incidence of subglottic stenosis was less than that previously reported in this population. Although the incidence is relatively low, subglottic stenosis is a serious complication of tracheal intubation and all measures to prevent subglottic stenosis should be undertaken.

Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass

Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population‐based pharmacokinetic model was developed using nonlinear mixed‐effects modeling (NONMEM) from 71 children (median age 5 months; 90% range 1 week to 10 years) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A 1‐compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in noncardiac children, theophylline clearance was markedly reduced across age. In the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50% to 75% lower than those recommended in noncardiac children were needed to achieve target serum concentrations of 5 to 10 mg/L.

333: QUANTITATIVE DIFFUSION-WEIGHTED MRI PREDICTS OUTCOMES IN SURVIVORS OF PEDIATRIC CARDIAC ARREST

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: The prognostic value of quantitative diffusion-weighted MRI (DWI MRI) in predicting neurologic outcomes after pediatric cardiopulmonary arrest (CPA) has not been determined. The aim of this study was to identify an optimal DWI MRI threshold for predicting neurologic outcomes in patients with neurologic deficits after return of spontaneous circulation from in-hospital or out-of-hospital CPA. Methods: This single-center retrospective study analyzed DWI MRIs of pediatric patients following CPA. Any MRI obtained within 2 weeks after CPA was analyzed. Poor neurologic outcome was defined as death during hospitalization or Pediatric Cerebral Performance Category (PCPC) score of 3–5 at 3–6 months after CPA. The mean apparent diffusion coefficient (ADC) value of brain voxels was determined. Brain volumes below each ADC threshold between 3001200 x10-6 mm2/sec with a step of 50 were studied for their correlation with outcome. ROC analysis was used to assess the performance of each ADC threshold and mean ADC of brain volumes to predict poor outcome. Results: Nineteen patients were included in this study. The median age was 9 years (range 3–15). Seven (37%) were females. Four (21%) experiences in-hospital CPA. Twelve survived and 11 had favorable outcomes. The median time from CPA to MRI was 3 days (range 2–6). An ADC threshold of less than 650 × 10−6 mm2/s in ≥11% of brain volume demonstrated a sensitivity of 0.75 (95% CI 0.36–0.96) and specificity of 1.0 (95% CI 0.68–1) for predicting poor outcome, with a negative predictive value of 0.85 (95% CI 0.54–0.97). Conclusions: In pediatric patients with neurologic deficits after CPA, quantitative DWI MRI correlates with functional neurologic outcome. A threshold of 650 × 10−6 mm2/s in ≥11% of brain volume may be used to predict poor outcome.