AIMSOne barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. METHODSWe measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. RESULTSFentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h -1 (2.2-9.2 l h -1 ), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. CONCLUSIONSWe show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.

Milrinone reduces the risk of low cardiac output syndrome for some pediatric patients following congenital heart surgery. Data from adults undergoing cardiac surgery suggest an association between milrinone and increased risk for postoperative arrhythmias. We tested the hypothesis that milrinone is an independent risk factor for tachyarrhythmias following congenital heart surgery. Subjects undergoing congenital heart surgery at our institution were consecutively enrolled for 38 months, through September 2010. Data was prospectively collected, including review of full-disclosure telemetry and the medical record. Over 38 months, 603 enrolled subjects underwent 724 operative procedures. The median age was 5.5 months (0.0–426), weight was 6.0 kg (0.7–108), and the cohort was 45% female. Overall arrhythmia incidence was 50%, most commonly monomorphic ventricular tachycardia (n=85, 12%), junctional ectopic tachycardia (n=69, 10%), accelerated junctional rhythm (n=58, 8%), and atrial tachyarrhythmias (including atrial fibrillation, atrial flutter, and ectopic or chaotic atrial tachycardia, n=58, 8%). Multivariate logistic regression analysis demonstrated that independent of age less than 1 month, use of cardiopulmonary bypass, duration of cardiopulmonary bypass, RACHS-1 score greater than 3, and the use of epinephrine or dopamine, milrinone use on admission to the cardiac intensive care unit remained independently associated with an increase in the odds of postoperative tachyarrhythmia resulting in an intervention (OR 2.8 [95%CI 1.3–6.0], p=0.007). In conclusion, milrinone use is an independent risk factor for clinically significant tachyarrhythmias in the early postoperative period following congenital heart surgery.

Background Dexmedetomidine is commonly used after congenital heart surgery and may be associated with a decreased incidence of post-operative tachyarrhythmias. Using a large cohort of patients undergoing congenital heart surgery, we examined for an association between dexmedetomidine use in the immediate post-operative period and subsequent arrhythmia development. Methods and Results A total of 1,593 surgical procedures for congenital heart disease were performed. Dexmedetomidine was administered in the immediate post-operative period after 468 (29%) surgical procedures. Compared to 1,125 controls, the group receiving dexmedetomidine demonstrated significantly fewer tachyarrhythmias (29% vs. 38%, p<0.001), tachyarrhythmias receiving intervention (14% vs. 23%, p<0.001), bradyarrhythmias (18% vs. 22%, p=0.03) and bradyarrhythmias receiving intervention (12% vs. 16%, p=0.04). After propensity score matching with 468 controls, the arrhythmia incidence between groups became similar: tachyarrhythmias (29% vs. 31%, p=0.66), tachyarrhythmias receiving intervention (14% vs. 17%, p=0.16), bradyarrhythmias (18% vs. 15%, p=0.44) and bradyarrhythmias receiving intervention (12% vs. 9%, p=0.17). After excluding controls exposed to dexmedetomidine at a later time in the hospitalization, dexmedetomidine was associated with increased odds of bradyarrhythmias receiving intervention (odds ratio [OR] 2.18, 95% confidence interval (CI) 1.02 – 4.65). Furthermore, there was a dose-dependent increase in the odds of bradyarrhythmias (OR 1.04, 95% CI 1.01 – 1.07) and bradyarrhythmias receiving intervention (OR 1.05, 95% CI 1.01 – 1.08). Conclusions While dexmedetomidine exposure in the immediate post-operative period is not associated with a clinically meaningful difference in the incidence of tachyarrhythmias after congenital heart surgery, it may be associated with increased odds of bradyarrhythmias.