Dantrolene Improves Survival Following Ventricular Fibrillation by Mitigating Impaired Calcium Handling in Animal Models
Background—Resistant ventricular fibrillation, re-fibrillation and diminished myocardial contractility are important factors leading to poor survival following cardiac arrest. We hypothesized dantrolene improves survival following VF by rectifying calcium dysregulation caused by VF.
Methods and Results—VF was induced in 26 Yorkshire pigs for 4 min. CPR was then commenced for 3 min and dantrolene or isotonic saline was infused at the onset of CPR. Animals were defibrillated and observed for 30 min. To study the effect of VF on calcium handling and its modulation by dantrolene, hearts from 14 New-Zealand rabbits were Langendorff-perfused. Inducibility of VF following dantrolene administration was documented. Optical mapping was performed to evaluate diastolic spontaneous calcium elevations (SCaE) as a measure of cytosolic calcium leak. Sustained Return of Spontaneous Circulation (ROSC) (sBP≥60mmHg) was achieved in 85% of dantrolene group compared to 39% of controls. (P=0.02) ROSC was achieved earlier in dantrolene-treated pigs after successful defibrillation. (21±6 sec vs. 181±57 sec in controls, P=0.005) Median number of re-fibrillation episodes was lower in dantrolene group (0 vs. 1, P= 0.04). In isolated rabbit hearts, 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 leak in the form of SCaEs. Administration of 20µM dantrolene significantly decreased SCaE amplitude vs. controls. (0.024±0.013 vs. 0.12±0.02 AU (200 msec CL), P=0.001)
Conclusions—Dantrolene infusion during CPR facilitates successful defibrillation, improves hemodynamics post-defibrillation, decreases re-fibrillation and thus improves survival following cardiac arrest. The effects are mediated through normalizing VF-induced dysfunctional calcium cycling.
- Received August 5, 2013.
- Revision received November 18, 2013.
- Accepted November 21, 2013.