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Dexamethasone and Recombinant Human Activated Protein C Improve Myocardial Function and Efficiency During Experimental Septic Shock

Lemarié, Jérémie*†; Blet, Alice*‡§∥; Bouazza, Youcef*; Boisramé-Helms, Julie¶**; Meziani, Ferhat¶**; Levy, Bruno*††

doi: 10.1097/SHK.0000000000000148
Basic Science Aspects

ABSTRACT Corticosteroids have been shown to reduce short-term mortality during septic shock and therefore recommended in the most severe patients as adjuvant therapy. Until recently, recombinant human activated protein C (APC) was also considered in the management of more severe cases. As myocardial depression has long been recognized as a manifestation of organ dysfunction during septic shock, we examined whether corticosteroids (dexamethasone, 150 µg/kg per hour) and/or APC (33 µg/kg per hour) treatments improve sepsis-induced cardiac dysfunction during cecal ligature and puncture–induced septic shock in Wistar rats. All rats received intravenous saline resuscitation (10 mL/kg per hour) and antibiotics. Eighteen hours after surgery, anesthesia was performed (isoflurane), and myocardial function was assessed using a conductance catheter introduced into the left ventricle. Rats were then killed; blood and heart were harvested for biological analysis, including radical oxygen species determination. Cecal ligature and puncture induced hypotension, depression of myocardial systolic performance (demonstrated by significant decreases in dP/dtmax [first derivative of maximal developed pressure during isovolumetric contraction], end-systolic pressure-volume relationship, and preload recruitable stroke work) and alteration of diastolic function (dP/dtmin [first derivative of minimal developed pressure during isovolumetric relaxation]), whereas dexamethasone, APC, and their combination thereof allowed correction of hemodynamic disorders and improved myocardial mechanical efficiency. Cecal ligature and puncture was associated with higher levels of nitric oxide and superoxide anion (O2 ) in heart (electron paramagnetic resonance studies) and consequently peroxynitrite. Dexamethasone and APC also improved cardiac dysfunction by downregulating the inducible nitric oxide synthase pathway and reducing myocardial oxidative stress.

*Groupe CHOC, INSERM U1116, Faculté de Médecine de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy; Service de réanimation médicale, Hôpital Central, Nancy; Département d’Anesthésie-Réanimation, Centre de Traitement des Brûlés, Groupe Hospitalier Lariboisière Saint-Louis, Assistance publique–Hôpitaux de Paris; §Université Paris-VII–Denis-Diderot; and Inserm UMR 942, Paris; Service de réanimation médicale, Nouvel Hôpital Civil, Hôpitaux universitaires de Strasbourg, 1 place de l’Hôpital; and **EA 3072, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de médecine, Université de Strasbourg, Strasbourg; ††Service de réanimation Médicale, Institut Lorrain du Cœur et des Vaisseaux, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-lès-Nancy, France

Received 17 Dec 2013; first review completed 2 Jan 2014; accepted in final form 27 Jan 2014

Address reprint requests to Bruno Levy, MD PhD, Service de Réanimation médicale, Institute Lorrain de Cœur et des Vaisseaux, Centre Hospitalier Universitaire de Nancy, 5 rue du Morvan, 54511 Vœanduvre-lés-Nancy. E-mail: b.levy@chu-nancy.fr.

No conflicts of interest, financial or otherwise, are declared by the authors.

Author contributions: J.L., Y.B., and B.L.: conception and design of research; J.L. and A.B.: performed surgery and hemodynamic measurements; J.B.-H. and F.M.: performed electronic paramagnetic resonance studies; J.L. and B.L.: analyzed data and interpreted results of experiments; J.L.: prepared figures and drafted manuscript; J.L. and B.L.: edited and revised manuscript; all authors approved final version of the manuscript.

© 2014 by the Shock Society