Iyad M. Ayoub

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation Beneficial Effects on Ischemic Contracture, Action Potential Duration, Reperfusion Arrhythmias, Myocardial Function, and Resuscitability

Background—Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation. Methods and Results—Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0±0.2 to 1.5±0.3 cm with NaCl, P <0.001 versus 0.9±0.1 to 1.1±0.3 cm with cariporide, P =NS), maintained the coronary perfusion pressure above resuscitability thresholds (10±8 versus 19±3 mm Hg before attempting defibrillation, P <0.05), and increased resuscitability (2 of 8 versus 8 of 8, P <0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD60 at 2 minutes after resuscitation; 75±29 versus 226±16 ms, P <0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction. Conclusions—NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

Successful Ventricular Defibrillation by the Selective Sodium-Hydrogen Exchanger Isoform-1 Inhibitor Cariporide

Background—Sodium-hydrogen exchanger isoform-1 (NHE-1) activation worsens functional myocardial abnormalities associated with ischemia and reperfusion. We hypothesize that these abnormalities may limit cardiac resuscitation from ventricular fibrillation (VF) and investigated whether NHE-1 inhibition with the benzoylguanidine derivative cariporide could improve resuscitability, postresuscitation myocardial function, and short-term survival in isolated heart and intact rat models of VF. Methods and Results—In the isolated rat heart, VF was induced for 25 minutes. Perfusion was interrupted for the initial 10 minutes and restarted at 10% of baseline flow for the remaining 15 minutes (simulating chest compression). Cariporide ameliorated ischemic contracture, prevented postresuscitation diastolic dysfunction, and favored earlier return of contractile function. In the intact rat, cariporide, injected into the right atrium before chest compression was started (after 6 minutes of untreated VF), prompted spontaneous defibrillation between minutes 7 and 9 of chest compression in 6 of 8 rats. In contrast, electrical defibrillation was required in each of 8 control rats after completion of a predetermined 16-minute interval of VF. After resuscitation, cariporide-treated rats had less ventricular ectopic activity and normalized their hemodynamic function faster. Electrical defibrillation was then timed in control rats to match the time when spontaneous defibrillation occurred in cariporide-treated rats. With comparable VF duration, postresuscitation hemodynamic dysfunction was ameliorated by cariporide, but only when more severe ischemia was modeled by prolongation of the interval of untreated VF from 6 to 10 minutes. Conclusion—NHE-1 inhibition may represent a novel and remarkably effective intervention for resuscitation from VF.

Optimal timing for electrical defibrillation after prolonged untreated ventricular fibrillation.

ObjectiveIt currently is recommended that electrical shocks be delivered immediately on recognition of ventricular fibrillation. However, decreased effectiveness of this approach has been reported after prolonged intervals of untreated ventricular fibrillation. We investigated the optimal strategy for successful defibrillation after prolonged untreated ventricular fibrillation by using a rat model of ventricular fibrillation and closed-chest resuscitation. DesignControlled, randomized, laboratory study. SettingResearch laboratory at a VA hospital. SubjectsSeventy pentobarbital anesthetized Sprague-Dawley rats. InterventionsAfter 10 mins of untreated ventricular fibrillation, four groups of rats were randomized to receive electrical shocks (which we designated as “experimental shocks”) immediately before or at 2, 4, or 6 mins of chest compression. Unsuccessfully defibrillated rats received additional shocks (which we designated as “rescue shocks”) after 8 mins of chest compression. Measurements and Main ResultsThe number of rats that restored spontaneous circulation after the experimental shocks increased with increasing duration of the predefibrillatory interval of chest compression (0 of 8, 0 of 8, 2 of 8, and 7 of 8, respectively, p < .005). Two additional groups then were randomized to receive repetitive experimental shocks at 2, 4, and 6 mins or a single attempt at 6 mins of chest compression. Although a comparable number of rats restored spontaneous circulation in each group, rats subjected to repetitive defibrillation attempts had more intense postresuscitation ectopic activity and worse survival. Two final groups were used to investigate whether inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) could facilitate return of spontaneous circulation during repetitive defibrillation attempts. Although spontaneous circulation was restored earlier in more rats subjected to NHE-1 inhibition, the differences were statistically insignificant. NHE-1 inhibition, however, replicated previously reported resuscitation and postresuscitation benefits. The optimal predefibrillation interval of chest compression was ≈6 mins, and this coincided with partial return of the amplitude and frequency characteristics of the ventricular fibrillation waveform to those present immediately after induction of ventricular fibrillation. ConclusionsImproved outcome after prolonged untreated ventricular fibrillation may result from strategies that provide chest compression before attempting defibrillation and avoid early and repetitive defibrillation attempts. The amplitude and frequency characteristics of the ventricular fibrillation waveform could help identify the optimal timing for attempting electrical defibrillation.

Clinically plausible hyperventilation does not exert adverse hemodynamic effects during CPR but markedly reduces end-tidal PCO2

AIMS Ventilation at high respiratory rates is considered detrimental during CPR because it may increase intrathoracic pressure limiting venous return and forward blood flow generation. We examined whether ventilation at high, yet clinically plausible, tidal volumes could also be detrimental, and further examined effects on end-tidal pCO(2) (P(ET)CO(2)). METHODS Sixteen domestic pigs were randomized to one of four ventilatory patterns representing two levels of respiratory rate (min(-1)) and two levels of tidal volume (ml/kg); i.e., 10/6, 10/18, 33/6, and 33/18 during chest compression after 8 min of untreated VF. RESULTS Data (mmHg, mean ± SD) are presented in the order listed above. Ventilation at 33/18 prompted higher airway pressures (p<0.05) and persistent expiratory airway flow (p<0.05) before breath delivery demonstrating air trapping. The right atrial pressure during chest decompression showed a statistically insignificant increase with increasing minute-volume (7 ± 4, 10±3, 12 ± 1, and 13 ± 3; p=0.055); however, neither the coronary perfusion pressure (23 ± 1, 17 ± 6, 18 ± 6, and 21 ± 2; NS) nor the cerebral perfusion pressure (32 ± 3, 23 ± 8, 30 ± 12, and 31 ± 3; NS) was statistically different. Yet, increasing minute-volume reduced the P(ET)CO(2) demonstrating a high dependency on tidal volumes delivered at currently recommended respiratory rates. CONCLUSIONS Increasing respiratory rate and tidal volume up to a minute-volume 10-fold higher than currently recommended had no adverse hemodynamic effects during CPR but reduced P(ET)CO(2) suggesting that ventilation at controlled rate and volume could enhance the precision with which P(ET)CO(2) reflects CPR quality, predicts return of circulation, and serve to guide optimization of resuscitation interventions.

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

UNLABELLED 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. METHODS 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. RESULTS 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). CONCLUSION Cariporide administered at the start of chest compression may help restore electrically and mechanically stable circulation after resuscitation from cardiac arrest.

Myocardial protection by erythropoietin during resuscitation from ventricular fibrillation.

Human recombinant erythropoietin (rhEPO) can protect the myocardium during ischemia and reperfusion. We investigated whether rhEPO could ameliorate previously identified functional myocardial abnormalities that develop during resuscitation from cardiac arrest, using a rat model of ventricular fibrillation (VF) and closed-chest resuscitation. VF was electrically induced and maintained, untreated, for 10 minutes. Chest compression and ventilation were then started and electrical defibrillation was attempted 8 minutes later. Rats were randomized to receive rhEPO (5000 U/kg) in the right atrium at baseline, 15 minutes before induction of VF (rhEPOBL -15-min), or at 10 minutes of VF, immediately before the start of chest compression (rhEPOVF 10-min), or to receive 0.9% NaCl solution instead (control). rhEPO given at the time of resuscitation (rhEPOVF 10-min group)-but not at baseline-prompted more effective chest compression, yielding higher coronary perfusion pressures for a given compression depth (1.95 ± 0.27 mm Hg/mm; P < 0.05 in comparison with rhEPOBL -15-min [1.63 ± 0.23 mm Hg/mm] and control [1.62 ± 0.26 mm Hg/mm], by Dunnetts multicomparison method). Post-resuscitation, rats in the rhEPOVF 10-min group displayed higher mean aortic pressure associated with numerically higher cardiac index, stroke work index, and systemic vascular resistance index. rhEPO may rapidly induce myocardial protection during resuscitation from cardiac arrest.

Myocardial protection during ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1.

Activation of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) in response to the intense intracellular acidosis that develops during ischemia has been identified as an important mechanism of myocardial cell injury. NHE-1 inhibition in the quiescent (nonfibrillating) heart ameliorates functional manifestation of ischemia and reperfusion injury. We investigated in isolated heart and intact rat models of ventricular fibrillation whether NHE-1 inhibition, by using the selective inhibitor cariporide, could ameliorate myocardial abnormalities that develop during ventricular fibrillation and limit resuscitability and survival. In the isolated rat heart, cariporide significantly reduced the magnitude of ischemic contracture during ventricular fibrillation and the accompanying increases in coronary vascular resistance. Hearts that had received cariporide during ventricular fibrillation had no diastolic dysfunction after resuscitation and recovered their systolic function earlier. In intact rats, cariporide given immediately before starting chest compression allowed generation of a coronary perfusion pressure and end-tidal Pco2 comparable with control rats but with significantly less depth of compression. Cariporide had an unprecedented effect in this rat model, prompting spontaneous defibrillation after approximately 8 mins of chest compression. After resuscitation, rats treated with cariporide had significantly less ventricular ectopic activity, better hemodynamic function, and higher survival rates (22 of 24 [94%] vs. 15 of 24 [63%] in control rats, p <.05). We conclude that NHE-1 inhibition may represent a novel and highly effective form of treatment for resuscitation from ventricular fibrillation.

Cariporide minimizes adverse myocardial effects of epinephrine during resuscitation from ventricular fibrillation

Objective:Epinephrine given during closed-chest resuscitation increases blood flow across the coronary and cerebral circuits. However, epinephrine worsens reperfusion arrhythmias and intensifies postresuscitation myocardial dysfunction. We investigated whether cariporide—a selective sodium-hydrogen exchanger isoform-1 inhibitor—could ameliorate such adverse effects without diminishing its vasopressor actions. Design:Randomized animal study. Setting:University-based animal laboratory. Subjects:Twenty-four anesthetized male domestic pigs (29–43 kg). Interventions:Ventricular fibrillation was electrically induced and left untreated for 8 mins. Pigs were randomized to receive after 2 mins of chest compression a 3 mg/kg bolus of cariporide (n = 8), a 0.02 mg/kg bolus of epinephrine (n = 8), or a combination of cariporide and epinephrine (n = 8). Additional doses of epinephrine were given if the coronary perfusion pressure decreased below 15 mm Hg. Successfully resuscitated pigs were observed for 72 hrs. Measurements and Main Results:The averaged coronary perfusion pressure was higher in the epinephrine (34 ± 11 mm Hg, p = .001) and cariporide/epinephrine (35 ± 10 mm Hg, p < .001) groups compared with the cariporide group (15 ± 6 mm Hg). All pigs in the epinephrine and cariporide/epinephrine groups but only six in the cariporide group were successfully resuscitated and survived 72 hrs. During the immediate postresuscitation period, four of eight pigs in the epinephrine group had episodes of recurrent ventricular fibrillation or pulseless ventricular tachycardia requiring additional electrical shocks (7.0 ± 6.4) but none in the cariporide and cariporide/epinephrine groups (chi-square, p = .008). Myocardial dysfunction occurred early after return of spontaneous circulation but only in the epinephrine group. Conclusions:The combined administration of cariporide and epinephrine prompted adequate pressor effects during chest compression and facilitated reestablishment of cardiac activity without episodes of recurrent ventricular fibrillation or transient myocardial dysfunction as with epinephrine alone.

Cariporide Potentiates the Effects of Epinephrine and Vasopressin by Nonvascular Mechanisms During Closed-Chest Resuscitation

BACKGROUND The efficacy of vasopressor therapy during closed-chest resuscitation is limited and decreases over time. We previously reported that sodium-hydrogen exchanger isoform-1 inhibition during ventricular fibrillation (VF) using cariporide ameliorates ischemic contracture and enhances the efficacy of chest compression. We currently investigated whether cariporide could potentiate pressor responses to epinephrine and vasopressin. METHODS VF was induced and left untreated for 12 min in two series of 16 rats each. Chest compression was then started and the depth adjusted within the initial 2 min to attain an aortic diastolic pressure between 26 and 28 mm Hg. In one series, rats received boluses of epinephrine (150 microg/kg); in the other series, rats received boluses of vasopressin (0.8 U/kg) to maintain the aortic diastolic pressure > 25 mm Hg. Within each series, rats were randomized to receive a 3 mg/kg bolus of cariporide or 0.9% NaCl immediately before starting chest compression. Defibrillation was attempted at 20 min of VF (8 min of chest compression). RESULTS Cariporide prompted higher and more sustained coronary perfusion pressures in both the epinephrine group (37 +/- 5 mm Hg vs 29 +/- 7 mm Hg, p < 0.05) and the vasopressin group (36 +/- 5 mm Hg vs 28 +/- 6 mm Hg +/- SD, p < 0.02) even though fewer additional vasopressor doses were required. After resuscitation, cariporide-treated rats had less ventricular ectopic activity, better hemodynamic function, and improved survival scores. In separate experiments, in situ perfusion of the aorta excluded a vascular-mediated effect of cariporide. CONCLUSION Cariporide enhanced the hemodynamic efficacy of vasopressor agents and improved resuscitation outcomes probably as a result of enhanced forward blood flow without effect on the peripheral vasculature.

AVE4454B—a novel sodium-hydrogen exchanger isoform-1 inhibitor—compared less effective than cariporide for resuscitation from cardiac arrest

We compared the efficacy of the novel sodium-hydrogen exchanger (NHE-1) inhibitor AVE4454B with cariporide for resuscitation from ventricular fibrillation (VF) assessing the effects on left ventricular myocardial distensibility during chest compression, myocardial function after the return of spontaneous circulation, and survival. Three groups of 10 rats each were subjected to 10 min of untreated VF and resuscitation attempted by providing chest compression for up to 8 min with the depth of compression adjusted to attain an aortic diastolic pressure between 26 and 28 mmHg (to secure a coronary perfusion pressure above 20 mmHg) followed by electrical shocks. Rats received AVE4454B (1 mg/kg), cariporide (1 mg/kg), or vehicle control immediately before chest compression. We observed that NHE-1 inhibition (NHEI) preserved left ventricular myocardial distensibility during chest compression evidenced by less depth of compression required to attain the target aortic diastolic pressure corresponding to (mean ± standard deviation) 14.1 ± 1.1 mm in the AVE4454B group (P < 0.001 versus control), 15.0 ± 1.4 mm in the cariporide group (P < 0.01 versus control), and 17.0 ± 1.2 mm in controls. When the depth of compression was related to the coronary perfusion pressure generated-an index of left ventricular distensibility-only the cariporide group attained statistical significance. Postresuscitation, both compounds ameliorated myocardial dysfunction evidenced by lesser reductions in mean aortic pressure and the maximal rate of left ventricular pressure increase as well as earlier normalization of left ventricular end-diastolic pressure increases. This effect was associated with improved survival corresponding to 55% in the AVE4454B group (not significant) and 70% in the cariporide group (P < 0.01 versus control by Gehan-Breslow analysis) at 240 min postresuscitation. An inverse correlation was found between plasma cytochrome c and indices of left ventricular function at 240 min postresuscitation suggesting that NHEI exerts beneficial effects in part by attenuating mitochondrial injury. We conclude that cariporide is more effective than AVE4454B for resuscitation from cardiac arrest given its more prominent effect on preserving left ventricular myocardial distensibility and promoting survival.