A Clinical Trial Simulation Evaluating Epinephrine Pharmacokinetics at various Dosing Frequencies during Cardiopulmonary Resuscitation

Abstract

Objective: This article seeks to test the hypothesis that repeated 1mg intravenous epinephrine dosing intervals of 3-minutes and 5-minutes results in differences in the total drug exposure and the maximum epinephrine concentration using simulated cardiopulmonary resuscitation (CPR) dosing.

Methods: Published population pharmacokinetic parameters were identified in the literature and pharmacokinetic dosing simulations were conducted according to the 2015 American Heart Association guidelines for CPR in adults. The stochastic pharmacokinetic simulations were conducted in MATLAB and R for statistical programming.

Results: A total of 5000 simulations were conducted in MATLAB while 90,000 data points for the 3-minute dosing interval and 150,000 data points for the 5-minute epinephrine dosing interval resulted from pharmacokinetic simulations in R. The difference between the 3-minute and 5-minute dosing intervals for patients with a SAP score of 30, were found to be: Male ΔAUC=2416 and ΔCmax=71, Female ΔAUC=1422 and ΔCmax=41, and for a 70kg patient ΔAUC=2968 and ΔCmax=90. While in virtual healthy participants, the differences were calculated to be ΔAUC=2658 and ΔCmax=81 for 3-minute and 5-minute dosing frequencies.

Conclusions: Epinephrine plasma levels during a simulated CPR scenario in a virtual patient population are dependent upon intravenous dosing intervals of either 3-minutes or 5-minutes. Based on the results of this clinical trial simulation, implications may exist that may require clinical studies investigating the influence of the 1mg epinephrine dosing frequency on the return of spontaneous circulation.

Keywords: CPR; clinical trial simulation; epinephrine; pharmacokinetics.

Figure 1

The catecholamine synthesis pathway with cofactors resulting in the formation of epinephrine.

Figure 2

Results of the 5000 stochastic pharmacokinetic simulations, in Matlab, illustrating the epinephrine concentration during cardiopulmonary resuscitation. The shaded regions depict the 10^th to 90^th percentiles of epinephrine plasma levels while the solid line illustrates the population mean. The results are for the following populations: (a) a three-minute epinephrine dosing frequency in an average weight American male (89kg) with a Simplified Acute Physiology Score II (SAPS II) score of 30; (b) a five-minute epinephrine dosing frequency with an average weight (89kg) American male with a SAPS II score of 30; (c) three-minute epinephrine dosing frequency in a healthy patient; (d) and a five-minute epinephrine dosing frequency.

Figure 3

Results of the 5000 stochastic pharmacokinetic simulations, in Matlab, illustrating the epinephrine concentration during cardiopulmonary resuscitation. The shaded regions depict the 10^th to 90^th percentiles of epinephrine plasma levels while the solid line illustrates the population mean. The results are for the following populations: (a) a three-minute epinephrine dosing frequency in patients weighing 70kg and a Simplified Acute Physiology Score II (SAPS II) score of 30; (b) a five-minute epinephrine dosing frequency in patients weighing 70kg and a SAPS II score of 30; (c) three-minute epinephrine dosing frequency in an average weight (65.6kg) American female with a SAPS II score of 30; (d) and a five-minute epinephrine dosing frequency in an average weight (65.6kg) American female with a SAPS II score of 30.

Figure 4

Epinephrine plasma concentrations (ng/mL) at the 10-minute time point during the clinical trial simulation, in R, comparing the 3-minute and 5-minute epinephrine dosing frequencies during cardiopulmonary resuscitation among virtual patient groups. Epi: epinephrine, SAPS: Simplified Acute Physiology Score II.

Figure 5

Epinephrine plasma concentrations (ng/mL) at the 40-minute time point during the clinical trial simulation, in R, comparing the 3-minute and 5-minute epinephrine dosing frequencies during cardiopulmonary resuscitation among virtual patient groups. Epi: epinephrine, SAPS: Simplified Acute Physiology Score II.