Cumulative dose of epinephrine and mode of death after non-shockable out-of-hospital cardiac arrest: a registry-based study
Authors: Javaudin François , Bougouin Wulfran , Fanet Lucie , Diehl Jean-Luc , Jost Daniel , Beganton Frankie , Empana Jean-Philippe , Jouven Xavier , Adnet Frédéric , Lamhaut Lionel , Lascarrou Jean-Baptiste , Cariou Alain , Dumas Florence ,   the Sudden Death Expertise Center investigators, Adnet F. , Agostinucci J. M. , Aissaoui-Balanant N. , Algalarrondo V. , Alla F. , Alonso C. , Amara W. , Annane D. , Antoine C. , Aubry P. , Azoulay E. , Beganton F. , Billon C. , Bougouin W. , Boutet J. , Bruel C. , Bruneval P. , Cariou A. , Carli P. , Casalino E. , Cerf C. , Chaib A. , Cholley B. , Cohen Y. , Combes A. , Coulaud J. M. , Crahes M. , Da Silva D. , Das V. , Demoule A. , Denjoy I. , Deye N. , Diehl J. L. , Dinanian S. , Domanski L. , Dreyfuss D. , Duboc D. , Dubois-Rande J. L. , Dumas F. , Duranteau J. , Empana J. P. , Extramiana F. , Fagon J. Y. , Fartoukh M. , Fieux F. , Gabbas M. , Gandjbakhch E. , Geri G. , Guidet B. , Halimi F. , Henry P. , Lucet F. Hidden , Jabre P. , Joseph L. , Jost D. , Jouven X. , Karam N. , Kassim H. , Lacotte J. , Lahlou-Laforet K. , Lamhaut L. , Lanceleur A. , Langeron O. , Lavergne T. , Lecarpentier E. , Leenhardt A. , Lellouche N. , Lemiale V. , Lemoine F. , Linval F. , Loeb T. , Ludes B. , Luyt C. E. , Maltret A. , Mansencal N. , Mansouri N. , Marijon E. , Marty J. , Maury E. , Maxime V. , Megarbane B. , Mekontso-Dessap A. , Mentec H. , Mira J. P. , Monnet X. , Narayanan K. , Ngoyi N. , Perier M. C. , Piot O. , Pirracchio R. , Plaisance P. , Plaud B. , Plu I. , Raphalen J. H. , Raux M. , Revaux F. , Ricard J. D. , Richard C. , Riou B. , Roussin F. , Santoli F. , Schortgen F. , Sharifzadehgan A. , Sharshar T. , Sideris G. , Similowski T. , Spaulding C. , Teboul J. L. , Timsit J. F. , Tourtier J. P. , Tuppin P. , Ursat C. , Varenne O. , Vieillard-Baron A. , Voicu S. , Wahbi K. , Waldmann V. 
Published: December 2023

Abstract
Background
Epinephrine increases the chances of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA), especially when the initial rhythm is non-shockable. However, this drug could also worsen the post-resuscitation syndrome (PRS). We assessed the association between epinephrine use during cardiopulmonary resuscitation (CPR) and subsequent intensive care unit (ICU) mortality in patients with ROSC after non-shockable OHCA.

Methods
We used data prospectively collected in the Sudden Death Expertise Center (SDEC) registry (capturing OHCA data located in the Greater Paris area, France) between May 2011 and December 2021. All adults with ROSC after medical, cardiac and non-cardiac causes, non-shockable OHCA admitted to an ICU were included. The mode of death in the ICU was categorized as cardiocirculatory, neurological, or other.

Results
Of the 2,792 patients analyzed, there were 242 (8.7%) survivors at hospital discharge, 1,004 (35.9%) deaths from cardiocirculatory causes, 1,233 (44.2%) deaths from neurological causes, and 313 (11.2%) deaths from other etiologies. The cardiocirculatory death group received more epinephrine (4.6 ± 3.8 mg versus 1.7 ± 2.8 mg, 3.2 ± 2.6 mg, and 3.5 ± 3.6 mg for survivors, neurological deaths, and other deaths, respectively; p < 0.001). The proportion of cardiocirculatory death increased linearly (R2 = 0.92, p < 0.001) with cumulative epinephrine doses during CPR (17.7% in subjects who did not receive epinephrine and 62.5% in those who received > 10 mg). In multivariable analysis, a cumulative dose of epinephrine was strongly associated with cardiocirculatory death (adjusted odds ratio of 3.45, 95% CI [2.01–5.92] for 1 mg of epinephrine; 12.28, 95% CI [7.52–20.06] for 2–5 mg; and 23.71, 95% CI [11.02–50.97] for > 5 mg; reference 0 mg; population reference: alive at hospital discharge), even after adjustment on duration of resuscitation. The other modes of death (neurological and other causes) were also associated with epinephrine use, but to a lesser extent.

Conclusions
In non-shockable OHCA with ROSC, the dose of epinephrine used during CPR is strongly associated with early cardiocirculatory death. Further clinical studies aimed at limiting the dose of epinephrine during CPR seem warranted. Moreover, strategies for the prevention and management of PRS should take this dose of epinephrine into consideration for future trials.