Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 4/2009

Open Access 01-08-2009 | Research

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

Authors: Imad Abboud, Nicolas Lerolle, Saik Urien, Jean-Marc Tadié, Françoise Leviel, Jean-Yves Fagon, Christophe Faisy

Published in: Critical Care | Issue 4/2009

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Vincent JL, de Backer D: The International Sepsis Forum's controversies in sepsis: my initial vasopressor agent in septic shock is dopamine rather than norepinephrine. Crit Care 2003, 7: 6-8. 10.1186/cc1851PubMedCentralCrossRefPubMed
2.
Vincent JL, De Backer D: Inotrope/vasopressor support in sepsis-induced organ hypoperfusion. Semin Respir Crit Care Med 2001, 22: 61-74. 10.1055/s-2001-13841CrossRefPubMed
3.
Sharma VK, Dellinger RP: The International Sepsis Forum's controversies in sepsis: my initial vasopressor agent in septic shock is norepinephrine rather than dopamine. Crit Care 2003, 7: 3-5. 10.1186/cc1835PubMedCentralCrossRefPubMed
4.
Trager K, DeBacker D, Radermacher P: Metabolic alterations in sepsis and vasoactive drug-related metabolic effects. Curr Opin Crit Care 2003, 9: 271-278. 10.1097/00075198-200308000-00004CrossRefPubMed
5.
Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troche G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E, CATS Study Group: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet 2007, 370: 676-684. 10.1016/S0140-6736(07)61344-0CrossRefPubMed
6.
Kolo LL, Westfall TC, Macarthur H: Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed. Am J Physiol Heart Circ Physiol 2004, 286: H296-303. 10.1152/ajpheart.00668.2003CrossRefPubMed
7.
Macarthur H, Westfall TC, Riley DP, Misko TP, Salvemini D: Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci USA 2000, 97: 9753-9758. 10.1073/pnas.97.17.9753PubMedCentralCrossRefPubMed
8.
Eisenhofer G: The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 2001, 91: 35-62. 10.1016/S0163-7258(01)00144-9CrossRefPubMed
9.
Eisenhofer G, Kopin IJ, Goldstein DS: Catecholamine metabolis: a contemporary view with implication for physiology and medicine. Pharmacol Rev 2004, 56: 331-349. 10.1124/pr.56.3.1CrossRefPubMed
10.
Annane D, Bellissant E, Sebille V, Lesieur O, Mathieu B, Raphael JC, Gajdos P: Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Br J Clin Pharmacol 1998, 46: 589-597. 10.1046/j.1365-2125.1998.00833.xPubMedCentralCrossRefPubMed
11.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003, 29: 530-538.CrossRefPubMed
12.
Cameron OG, Gunsher S, Hariharan M: Venous plasma epinephrine levels and the symptoms of stress. Psychosom Med 1990, 52: 411-424.CrossRefPubMed
13.
Guillemin A, Troupel S, Galli A: Determination of catecholamines in plasma by high-performance liquid chromatography. Clin Chem 1988, 34: 1913-1914.PubMed
14.
Wang Y, Fice DS, Yeung PK: A simple high-performance liquid chromatography assay for simultaneous determination of plasma norepinephrine, epinephrine, dopamine and 3,4-dihydroxyphenyl acetic acid. J Pharm Biomed Anal 1999, 21: 519-525. 10.1016/S0731-7085(99)00117-XCrossRefPubMed
15.
Auriant I, Vinatier I, Thaler F, Tourneur M, Loirat P: Simplified acute physiology score II for measuring severity of illness in intermediate care units. Crit Care Med 1998, 26: 1368-1371. 10.1097/00003246-199808000-00023CrossRefPubMed
16.
Beal SL, Sheiner LB: NONMEM user's guide. NONMEM project group, San Francisco, University of california, USA. 1998.
17.
Comets E, Brendel K, Mentre F: Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed 2008, 90: 154-166. 10.1016/j.cmpb.2007.12.002CrossRefPubMed
18.
19.
Ihaka R, Gentleman RR: A language for data analysis and graphics. J Comput Graphic 1996, 5: 299-314. 10.2307/1390807
20.
Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, Wu Y, Peixoto A, Crowley S, Desir GV: Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest 2005, 115: 1275-1280.PubMedCentralCrossRefPubMed
21.
Clutter WE, Bier DM, Shah SD, Cryer PE: Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest 1980, 66: 94-101. 10.1172/JCI109840PubMedCentralCrossRefPubMed
22.
Fisher DG, Schwartz PH, Davis AL: Pharmacokinetics of exogenous epinephrine in critically ill children. Crit Care Med 1993, 21: 111-117.CrossRefPubMed
23.
Banner W Jr, Vernon DD, Dean JM, Swenson E: Nonlinear dopamine pharmacokinetics in pediatric patients. J Pharmacol Exp Ther 1989, 249: 131-133.PubMed
24.
Schwartz PH, Eldadah MK, Newth CJ: The pharmacokinetics of dobutamine in pediatric intensive care unit patients. Drug Metab Dispos 1991, 19: 614-619.PubMed
25.
Beloeil H, Mazoit JX, Benhamou D, Duranteau J: Norepinephrine kinetics and dynamics in septic shock and trauma patients. Br J Anaesth 2005, 95: 782-788. 10.1093/bja/aei259CrossRefPubMed
26.
Wilkie FL, Halter JB, Prinz PN, Benedetti C, Eisdorfer C, Atwood B, Yamasaki D: Age-related changes in venous catecholamines basally and during epinephrine infusion in man. J Gerontol 1985, 40: 133-140.CrossRefPubMed
27.
Cabal LA, Siassi B, Artal R, Gonzalez F, Hodgman J, Plajstek C: Cardiovascular and catecholamine changes after administration of pancuronium in distressed neonates. Pediatrics 1985, 75: 284-287.PubMed
28.
Cryer PE, Rizza RA, Haymond MW, Gerich JE: Epinephrine and norepinephrine are cleared through beta-adrenergic, but not alpha-adrenergic, mechanisms in man. Metabolism 1980, 29: 1114-1118. 10.1016/0026-0495(80)90019-0CrossRefPubMed
29.
Hjemdahl P: Catecholamine measurements by high-performance liquid chromatography. Am J Physiol 1984, 247: E13-20.PubMed
30.
Benedict CR, Grahame-Smith DG: Plasma noradrenaline and adrenaline concentrations and dopamine-beta-hydroxylase activity in patients with shock due to septicaemia, trauma and haemorrhage. Q J Med 1978, 47: 1-20.PubMed
31.
Mannelli M, Lazzeri C, Ianni L, La Villa G, Pupilli C, Bellini F, Serio M, Franchi F: Dopamine and sympathoadrenal activity in man. Clin Exp Hypertens 1997, 19: 163-179. 10.3109/10641969709080813CrossRefPubMed
32.
Parker DA, Hennian E, Marino V, de la Lande IS: Inhibitory effects of adrenaline on the release of noradrenaline from sympathetic nerves in human dental pulp. Arch Oral Biol 1999, 44: 391-394. 10.1016/S0003-9969(99)00015-1CrossRefPubMed
33.
Brede M, Nagy G, Philipp M, Sorensen JB, Lohse MJ, Hein L: Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol Endocrinol 2003, 17: 1640-1646. 10.1210/me.2003-0035CrossRefPubMed
34.
Maze M, Spiss CK, Tsujimoto G, Hoffman BB: Epinephrine infusion induces hyporesponsiveness of vascular smooth muscle. Life Sci 1985, 37: 1571-1578. 10.1016/0024-3205(85)90475-8CrossRefPubMed
35.
Bernard C, Szekely B, Philip I, Wollman E, Payen D, Tedgui A: Activated macrophages depress the contractility of rabbit carotids via an L-arginine/nitric oxide-dependent effector mechanism. Connection with amplified cytokine release. J Clin Invest 1992, 89: 851-860. 10.1172/JCI115664PubMedCentralCrossRefPubMed
36.
Rudiger A, Singer M: Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 2007, 35: 1599-1608. 10.1097/01.CCM.0000266683.64081.02CrossRefPubMed
Metadata
Title
Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status
Authors
Imad Abboud
Nicolas Lerolle
Saik Urien
Jean-Marc Tadié
Françoise Leviel
Jean-Yves Fagon
Christophe Faisy
Publication date
01-08-2009
Publisher
BioMed Central
Published in
Critical Care / Issue 4/2009
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc7972

Other articles of this Issue 4/2009

Critical Care 4/2009 Go to the issue

Letter

10% Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage

Research

Short-term outcomes of cadaveric lung transplantation in ventilator-dependent patients

Research

Non-invasive stroke volume measurement and passive leg raising predict volume responsiveness in medical ICU patients: an observational cohort study

Commentary

Acoustic monitoring – super sonics?

Research

Critical illness-related corticosteroid insufficiency in patients with severe acute biliary pancreatitis: a prospective cohort study

Commentary

Challenging the rationale of routine vasopressor therapy for management of hypotension