title: Dantrolene improves survival after ventricular fibrillation by mitigating impaired calcium handling in animal models.
abstract: BACKGROUND
  Resistant ventricular fibrillation, refibrillation. and diminished myocardial contractility are important factors leading to poor survival after cardiac arrest. We hypothesized that dantrolene improves survival after ventricular fibrillation (VF) by rectifying the calcium dysregulation caused by VF.
  
  
  RESULTS
  VF was induced in 26 Yorkshire pigs for 4 minutes. Cardiopulmonary resuscitation was then commenced for 3 minutes, and dantrolene or isotonic saline was infused at the onset of cardiopulmonary resuscitation. Animals were defibrillated and observed for 30 minutes. To study the effect of VF on calcium handling and its modulation by dantrolene, hearts from 14 New Zealand rabbits were Langendorff-perfused. The inducibility of VF after dantrolene administration was documented. Optical mapping was performed to evaluate diastolic spontaneous calcium elevations as a measure of cytosolic calcium leak. The sustained return of spontaneous circulation (systolic blood pressure ≥60 mm Hg) was achieved in 85% of the dantrolene group in comparison with 39% of controls (P=0.02). return of spontaneous circulation was achieved earlier in dantrolene-treated pigs after successful defibrillation (21 ± 6 s versus 181 ± 57 s in controls, P=0.005). The median number of refibrillation episodes was lower in the dantrolene group (0 versus 1, P=0.04). In isolated rabbit hearts, the successful induction of VF was achieved in 83% of attempts in controls versus 41% in dantrolene-treated hearts (P=0.007). VF caused diastolic calcium leaks in the form of spontaneous calcium elevations. Administration of 20 μmol/L dantrolene significantly decreased spontaneous calcium elevation amplitude versus controls. (0.024 ± 0.013 versus 0.12 ± 0.02 arbitrary unit [200-ms cycle length], P=0.001).
  
  
  CONCLUSIONS
  Dantrolene infusion during cardiopulmonary resuscitation facilitates successful defibrillation, improves hemodynamics postdefibrillation, decreases refibrillation, and thus improves survival after cardiac arrest. The effects are mediated through normalizing VF-induced dysfunctional calcium cycling.
authors.affiliation: From The Hull Family Cardiac Fibrillation Management Laboratory, University Health Network, University of Toronto, Toronto, ON, Canada (A.M., N.Z., S.M., M.K., M.A.A, P.F.H.L., M.B.W., K.N.); Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada (A.R., X.H., A.A.-H., P.D.); Institute of Medical Science, University of Toronto, Toronto, ON, Canada (N.Z.); Department of Physiology, University of Toronto, Toronto, ON, Canada (J.L., P.B.); Institute LIRYC, Université Bordeaux 1, Bordeaux, France (E.J.V.); Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD (P.M.B.); and Department of Electrical Engineering, University of Calgary, Calgary, AB, Canada (E.B.).
authors.forename: Nima
authors.initials: N
authors.lastname: Zamiri
authors.forename: Stéphane
authors.initials: S
authors.lastname: Massé
authors.forename: Andrew
authors.initials: A
authors.lastname: Ramadeen
authors.forename: Marjan
authors.initials: M
authors.lastname: Kusha
authors.forename: Xudong
authors.initials: X
authors.lastname: Hu
authors.forename: Mohammed Ali
authors.initials: MA
authors.lastname: Azam
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Patrick F H
authors.initials: PF
authors.lastname: Lai
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Vigmond
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Boyle
authors.forename: Elham
authors.initials: E
authors.lastname: Behradfar
authors.forename: Abdul
authors.initials: A
authors.lastname: Al-Hesayen
authors.forename: Menashe B
authors.initials: MB
authors.lastname: Waxman
authors.forename: Peter
authors.initials: P
authors.lastname: Backx
authors.forename: Paul
authors.initials: P
authors.lastname: Dorian
authors.forename: Kumaraswamy
authors.initials: K
authors.lastname: Nanthakumar
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016887:Cardiopulmonary Resuscitation; D003620:Dantrolene / Q000494:pharmacology*; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004195:Disease Models, Animal; D004554:Electric Countershock; D006439:Hemodynamics / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008955:Models, Cardiovascular; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D034421:Sus scrofa; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality
chemical_list: D009125:Muscle Relaxants, Central; D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene; D002118:Calcium
keywords: cardiopulmonary resuscitation; death, sudden, cardiac; ryanodine receptor calcium release channel; ventricular fibrillation