Research

Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status

Imad Abboud¹ , Nicolas Lerolle¹ , Saik Urien² , Jean-Marc Tadié¹ , Françoise Leviel³ , Jean-Yves Fagon¹ and Christophe Faisy¹

¹  Medical Intensive Care Unit, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris – Descartes, Paris, France

²  E.A. 3620, CIC-0109 Cochin-Necker Paris Descartes, Unité de Recherche Clinique, Tarnier Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris – Descartes, Paris, France

³  Department of Physiology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris – Descartes, Paris, France

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Critical Care 2009, 13:R120doi:10.1186/cc7972

Published:	21 July 2009

See related commentary by Calzia et al., http://ccforum.com/content/13/4/177

Abstract

Introduction

In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock.

Methods

Thirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C₀) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C₁) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM.

Results

Plasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 μg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 × (BW/70)^0.60 × (SAPS II/50)^-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 – 56.7) at C₀ vs. 4.5 (0.3 – 38.9) nmol/L at C₁, P < 0.001).

Conclusions

Epinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients.