Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children.

Pharmacokinetic pharmacodynamic modeling is an important tool which uses statistical methodology to provide a better understanding of the relationship between concentration and effect of drugs such as analgesics and sedatives. Pharmacokinetic pharmacodynamic models also describe between-subject variability that allows identification of subgroups and dose adjustment for optimal pain management in individual patients. This approach is particularly useful in the pediatric population, where most drugs have received limited evaluation and dosing is extrapolated from adult practice. In children, the covariates of weight and age are used to describe size- and maturation-related changes in pharmacokinetics. It is important to consider both size and maturation in order to develop an accurate model and determine the optimal dose for different age groups. An adequate assessment of analgesic and sedative effect using pain scales or brain activity measures is essential to build reliable pharmacokinetic pharmacodynamic models. This is often challenging in children due to the multidimensional nature of pain and the limited sensitivity and specificity of some measurement tools. This review provides a summary of the pharmacokinetic and pharmacodynamic methodology used to describe the dose-concentration-effect relationship of analgesics and sedation in children, with a focus on the different pharmacodynamic endpoints and the challenges of pharmacodynamic modeling.

Oral morphine dosing predictions based on single dose in healthy children undergoing surgery.

BACKGROUND: Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose. AIMS: The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens. METHODS: Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg-1 , 200 mcg·kg-1 , 300 mcg·kg-1 ). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (TLAG ), and absorption half-time (TABS ). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg-1 ) at different dosing intervals (3, 4, 5, 6, 8, 12 h). RESULTS: The oral morphine formulation had F 0.298 (CV 36.5%), TLAG 0.45 (CV 63.6%) h and TABS 0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg-1 achieved a mean CMAX 10 mcg·l-1 . Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg·l-1 ; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l-1 at steady state. CONCLUSIONS: Oral morphine 200 mcg·kg-1 then 100 mcg·kg-1 4 h or 150 mcg·kg-1 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses.

Changes in QTc associated with a rapid bolus dose of dexmedetomidine in patients receiving TIVA: a retrospective study.

BACKGROUND: Clinical indications for the perioperative use of dexmedetomidine in pediatric anesthesia are accumulating. However, in 2013, dexmedetomidine was added to the list of medications with possible risk of prolonging the QT interval and/or inducing Torsades de Pointes. Unfortunately, current evidence for dexmedetomidine-induced QT prolongation is sparse and somewhat contradictory. OBJECTIVE: The purpose of this study was to evaluate temporal changes in corrected QT interval (QTc) after a rapid bolus administration of dexmedetomidine under total intravenous anesthesia (TIVA) with a standardized propofol and remifentanil administration. METHODS: Electrocardiography (ECG) and corresponding trend data were extracted from automated electronic data capture of physiological monitoring. Ten-second epochs of ECG data were extracted in 1-min intervals for 12 min, starting 1 min before dexmedetomidine bolus administration, and ending 10 min after. QT intervals were extracted using an automated routine in MATLAB, and corrected for heart rate (HR) using Bazett's (QTcB) and Fridericia's formulas (QTcF). QTcB and QTcF were compared using Wilcoxon signed-rank test between baseline measurements and the subsequent four interval values. RESULTS: Data from 21 subjects (17 male) with median (range) age 7.1 (5.4-9.5) yr, weight 23.6 (16.2-36.7) kg, and height 121 (103-140) cm were analyzed. Bolus administration of dexmedetomidine reduced HR in all subjects (median 22%), and caused transient reduction of QT interval, with its peak at 1-min postbolus administration: QTcB (median reduction 30.7 ms, P < 0.001) or QTcF (median reduction 15.4 ms, P = 0.001); QT shortening became statistically insignificant 4 min following dexmedetomidine bolus administration for QTcB and 2 min for QTcF. CONCLUSION: In this study, a rapid bolus of dexmedetomidine transiently shortened corrected QT intervals. However, these effects are confounded by dexmedetomidine-induced bradycardia. These findings should be confirmed in pediatric studies without concomitant TIVA administration and with optimized correction of baseline HR.

A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose.

BACKGROUND AND OBJECTIVES: Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. METHODS: The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. RESULTS: A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. CONCLUSION: This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.

Identifying a rapid bolus dose of dexmedetomidine (ED50) with acceptable hemodynamic outcomes in children.

BACKGROUND: Dexmedetomidine is a highly sensitive, specific α2 adrenoceptor agonist with anxiolytic, sedative, and analgesic effects. Administration is recommended as a loading dose infused over 10 min. Clinical experience and a previous study suggested a shorter time frame might be used without causing adverse hemodynamic effects. OBJECTIVE: To determine the dexmedetomidine dose that can be given as a rapid 5 s bolus to healthy children during total intravenous anesthesia (TIVA) without causing significant hemodynamic effects. METHODS: ASA I-II children, aged 5-9 years, having elective surgery under TIVA were recruited. The up-and-down sequential study design was employed to determine the effective dose of dexmedetomidine, starting at 0.3 mcg·kg(-1) with 0.1 mcg·kg(-1) intervals, which caused no hemodynamic response in half the subjects (ED50). Positive responses were defined as mean blood pressure (MAP) and/or heart rate (HR) changes ≥30% from baseline. Three parametric estimators and one nonparametric estimator were used to determine the ED50. RESULTS: Twenty-one subjects with median age 7.1 (range 5.4-9.5) years and median weight 23.6 (range 16.2-36.7) kg were recruited. A maximum median HR decrease of 20 b·min(-1) occurred at 50 s and a maximum median MAP increase of 12.5 mmHg occurred at 100 s after bolus dose administration. Fifteen subjects (71%) had a HR <60 b·min(-1) while one subject had a HR <40 b·min(-1) (minimum 35 b·min(-1)) for 60 s following the dexmedetomidine bolus. Four estimators led to an ED50 estimate for dexmedetomidine of 0.49 mcg·kg(-1) [95% CI 0.26-0.80 mcg·kg(-1)]. CONCLUSION: The ED50 of dexmedetomidine administered over 5 s without significant hemodynamic compromise is 0.49 mcg·kg(-1). Further work is needed to determine the 'safe' (ED5 or less) and effective dose for desired perioperative clinical outcomes.