Article

Cariporide given during resuscitation promotes return of electrically stable and mechanically competent cardiac activity

Resuscitation Institute at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Resuscitation (Impact Factor: 3.96). 10/2009; 81(1):106-10. DOI: 10.1016/j.resuscitation.2009.09.013
Source: PubMed

ABSTRACT Episodes of ventricular fibrillation (VF) and myocardial dysfunction commonly occur after cardiac resuscitation compromising the return of stable circulation. We investigated in a pig model of VF whether limiting Na(+)-induced cytosolic Ca(2+) overload using the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) inhibitor cariporide promotes resuscitation with stable circulation.
VF was electrically induced in 20 male pigs and left untreated for 6 min after which CPR was initiated and continued for 8 min before attempting defibrillation. Pigs were randomized to receive 3-mg/kg cariporide (n=10) or 0.9%-NaCl (n=10) before chest compression.
Seven of 10 pigs in each group were successfully resuscitated and survived 2h. Cariporide ameliorated post-resuscitation ventricular ectopic activity such that fewer singlets (5+/-5 vs. 26+/-21; p<0.05) and fewer bigemini (1+/-3 vs. 33+/-25; p<0.05) were observed during the initial 5 min post-resuscitation. Additionally, cariporide-treated pigs did not require additional post-resuscitation shocks for ventricular tachycardia or recurrent VF (0.0+/-0.0 vs. 5.3+/-7.8 shocks; p=0.073). During the initial 60 min cariporide-treated pigs had higher, cardiac index (6.1+/-0.7 vs. 4.4+/-1.1L/min/m(2); p<0.01), left ventricular stroke work index (45+/-9 vs. 36+/-10 gmm/beat/m(2); p<0.05), and numerically higher mean aortic pressure (104+/-11 vs. 91+/-12 mmHg; p=0.054).
Cariporide administered at the start of chest compression may help restore electrically and mechanically stable circulation after resuscitation from cardiac arrest.

Full-text

Available from: Raúl Gazmuri, Apr 30, 2015
0 Followers
 · 
110 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND During ischemia, enhancement of the "late Na+ current" (I-NaL) contributes to intracellular Ca2+ overload. Dysregulation of intracellular Ca2+ homeostasis plays a critical role in the pathophysiology of cardiac arrest and cardiopulmonary resuscitation (CPR), leading to ventricular arrhythmias and left ventricle (LV) dysfunction. OBJECTIVE The purpose of this study was to investigate the effects of the INaL Mocker ranolazine on outcome of CPR in a rat model. We hypothesized that ranotazine might reduce postresuscitation arrhythmias and improve survival and recovery. METHODS Eighteen rats were assigned to receive intravenous ranolazine 10 mg/kg or vehicle. Ventricular fibrillation was induced and untreated for 8 minutes. CPR then was performed for 8 minutes. ECG and arterial and right atrial pressures were monitored up to 3 hours after CPR. After resuscitation, LV function was monitored by echocardiography, and 72-hour survival with neurologic recovery was evaluated. Plasma was obtained for biomarkers of heart and brain injury. RESULTS All animals in the ranolazine group were resuscitated and survived up to 72 hours, whereas 72% in the vehicle group were resuscitated but 54% survived. The period of postresuscitation arrhythmia with hemodynamic instability was shorter in the ranolazine group compared to vehicle group (P < .02). Seventy-two hours after resuscitation, LV systolic and diastolic functions were better in the ranolazine group compared to vehicle (P <.05). Full neurologic recovery was observed in all ranotazine animals, whereas neurologic impairment persisted in the vehicle group (P < .02). CONCLUSION In this model, ranolazine pretreatment reduced postresuscitation electrical and hemodynamic instability and improved 72-hour postresuscitation LV function and survival with good neurologic recovery.
    Heart rhythm: the official journal of the Heart Rhythm Society 05/2014; 11(9). DOI:10.1016/j.hrthm.2014.05.023 · 4.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite decades of advances in prehospital and in-hospital medical care, patients with out-of-hospital cardiac arrest continue to have poor neurologic and cardiac function following otherwise successful resuscitation. This review examines the mechanisms and therapeutic strategies currently under development to activate the post-conditioning pathways and thereby improve survival and function. Post-conditioning utilizes the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways as common avenues to promote cell survival and function. Ischemic post-conditioning and multiple medications activate these pathways resulting in improved cardiac and neurological function in animal models of cardiac arrest. Detailed knowledge of the RISK and SAFE pathways can be used for further drug development. Human studies are now underway to test some of these strategies, but further clinical trials are necessary to translate these therapies to clinical practice.
    Current opinion in critical care 04/2014; DOI:10.1097/MCC.0000000000000087 · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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.
    Circulation 01/2014; 129(8). DOI:10.1161/CIRCULATIONAHA.113.005443 · 14.95 Impact Factor