Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children

Abstract

Introduction: The response to exogenous epinephrine (Ep) is difficult to predict given the multitude of factors involved such as broad pharmacokinetic and pharmacodynamic between-subject variabilities, which may be more pronounced in children. We investigated the pharmacokinetics and pharmacodynamics of Ep, co-administered with milrinone, in children who underwent open heart surgical repair for congenital defects following cardiopulmonary bypass, including associated variability factors.

Methods: Thirty-nine children with a high risk of low cardiac output syndrome were prospectively enrolled. Ep pharmacokinetics, hemodynamic and metabolic effects were analyzed using the non-linear mixed effects modeling software MONOLIX. According to the final model, an Ep dosing simulation was suggested.

Results: Ep dosing infusions ranged from 0.01 to 0.23 μg.kg-1.min-1 in children whose weight ranged from 2.5 to 58 kg. A one-compartment open model with linear elimination adequately described the Ep concentration-time courses. Bodyweight (BW) was the main covariate influencing clearance (CL) and endogenous Ep production rate (q0) via an allometric relationship: CL(BWi) = θCL x (BWi)3/4 and q0(BWi) = θq0 x (BWi )3/4. The increase in heart rate (HR) and mean arterial pressure (MAP) as a function of Ep concentration were well described using an Emax model. The effect of age was significant on HR and MAP basal level parameters. Assuming that Ep stimulated the production rate of plasma glucose, the increases in plasma glucose and lactate levels were well described by turnover models without any significant effect of age, BW or exogenous glucose supply.

Conclusions: According to this population analysis, the developmental effects of BW and age explained a part of the pharmacokinetic and pharmacodynamics between-subject variabilities of Ep administration in critically ill children. This approach ultimately leads to a valuable Ep dosing simulation which should help clinicians to determine an appropriate a priori dosing regimen.

Figure 1

Prediction corrected-visual predictive check (PC-VPC) for epinephrine concentrations versus time in minutes. The green lines depict the 5th, 50th and 95th percentiles of observed data; the areas represent the 95% confidence interval around the simulated percentiles. Blue color represent the 5th and the 95th percentile of the predicted concentration versus time and pink color represent the median predicted concentration versus time. Time 0 min represents the starting time of epinephrine infusion.

Figure 2

Box and whisker plots of hemodynamic and metabolic data before and during epinephrine infusion. Box and whisker plots of (i) heart rate, beats⋅min^-1(A) before epinephrine infusion (minimum = 70; maximum (max) = 180; median = 135) and during epinephrine infusion (minimum = 70; max = 212; median = 159) (variance (w) = 2,563; P = 2.10^-8); (ii) mean arterial pressure, mmHg (B) before epinephrine infusion (minimum = 25; max = 65; median = 51) and during epinephrine infusion (minimum = 30; max = 94; median = 66) (variance (w) =2613; P = 5.10^-11); (iii) plasma glucose, mmol⋅L^-1(C) before epinephrine infusion (minimum = 4; max = 10.1; median = 6.2) and during epinephrine infusion (minimum = 4.9; max = 23.3; median = 9.85) (variance (w) = 339; P = 6.10^-9) and (iv) lactate levels, mmol⋅L^-1(D) before epinephrine infusion (minimum = 0.5; max = 3; median = 1) and during epinephrine infusion (minimum = 0.9; max = 7.1; median = 2.1) (variance (w) = 218; P = 3.10^-10).

Figure 3

Prediction corrected-visual predictive check (PC-VPC) for heart rate (A) and mean arterial pressure (B) observations versus time in minutes. The green lines depict the 5th, 50th and 95th percentiles of observed data; the areas represent the 95% confidence interval around the simulated percentiles. Blue color represent the 5th and the 95th percentile of the predicted HR and MAP versus time and pink color represent the median predicted HR and MAP versus time. Time 0 min represents the starting time of epinephrine infusion.

Figure 4

Prediction corrected-visual predictive check (PC-VPC) for plasma glucose level (A) and plasma lactate level (B) observations versus time in minutes. The green lines depict the 5th, 50th and 95th percentiles of observed data; the areas represent the 95% confidence interval around the simulated percentiles. Blue color represent the 5th and the 95th percentile of the predicted plasma glucose level and lactate level versus time and pink color represent the median predicted plasma glucose level and lactate level versus time. Time 0 min represents the starting time of epinephrine infusion.

Figure 5

Dosing simulations depicting the increases in epinephrine concentration and hemodynamic responses as a function of administered infusion rate in children of different bodyweights and ages for patients with a risk adjustment for congenital heart surgery (RACHS)-1 category of 2.

Figure 6

Time-course simulations of epinephrine concentration, plasma glucose and lactate levels following 0.02 to 0.25 μg⋅min ^-1 ⋅kg ^-1 epinephrine infusions in a child weighing 5 kg.