Postresuscitation Myocardial Function Research Articles

Levosimendan improves postresuscitation myocardial dysfunction after β-adrenergic blockade

In earlier studies, we found that a nonselective beta-adrenergic blocking agent, propranolol, facilitated cardiac resuscitation, reduced postresuscitation myocardial ectopy, and improved postresuscitation survival. However, the potential adverse effects and specifically the negative inotropic actions of propranolol prompted our further investigation of the potential value of a non-beta-adrenergic inotropic drug, levosimendan, in conjunction with propranolol, for minimizing postresuscitation myocardial dysfunction after successful resuscitation from cardiac arrest. Ventricular fibrillation was induced and untreated for 7 minutes in 15 domestic pigs, which were divided into propranolol, propranolol plus levosimendan, and control groups. Propranolol was administered as a bolus dose of 0.1 mg/kg during cardiac arrest. Electrical defibrillation was attempted after 12 minutes of cardiac arrest including 5 minutes of precordial compression. Levosimendan was administered at 10 minutes after successful resuscitation in a dose of 20 microg/kg and followed by infusion of 0.4 microg/kg/min over the ensuing 220 minutes. Propranolol reduced energies or numbers of defibrillatory shocks and postresuscitation myocardial ectopy, and it improved postresuscitation myocardial dysfunction. When levosimendan was added, postresuscitation myocardial contractile function was improved even more.

Carvedilol Mitigates Adverse Effects of Epinephrine During Cardiopulmonary Resuscitation

Earlier studies have implicated the adverse effects of beta- and alpha(1)-adrenergic receptors during cardiopulmonary resuscitation (CPR). Because carvedilol is both a nonselective beta- and alpha1-selective adrenergic receptor-blocking agent, we hypothesized that pretreatment with carvedilol would convert the actions of epinephrine to that of a selective alpha2-agonist. Ventricular fibrillation (VF) was induced in Sprague-Dawley rats weighing approximately 500 g. Animals were randomized to 4 groups of 5 animals each: (1) placebo pretreatment and epinephrine treatment, (2) carvedilol pretreatment and placebo treatment, (3) carvedilol pretreatment and epinephrine treatment, and (4) placebo pretreatment and placebo treatment. Carvedilol (50 microg/kg) was injected as a bolus into the right atrium 15 minutes before VF was induced. VF was untreated for 8 minutes, after which CPR (chest compression and mechanical ventilation) was begun. Epinephrine (30 microg/kg) was injected into the right atrium 2 minutes after the start of CPR. Electrical defibrillation was attempted after 14 minutes of VF. All but 2 animals were successfully resuscitated. Approximately equivalent increases in coronary perfusion pressure from 23 +/- 1 mm Hg to 30 +/- 3 mm Hg were observed after the injection of epinephrine independently of carvedilol pretreatment. Carvedilol pretreatment followed by epinephrine treatment reduced early postresuscitation ventricular ectopy (116 +/- 147 vs 834 +/- 380, P < .01) and minimized increases in arterial blood lactate at 5 minutes after resuscitation (10.9 +/- 2.1 mmol/L vs 17.4 +/- 3.5 mmol/L, P < .01). The postresuscitation cardiac index measured 4 hours later was increased (307 +/- 43 mL x min(-1) x kg(-1) vs 210 +/- 6 mL x min(-1) x kg(-1), P < .05). Left ventricular diastolic pressures were decreased (6 +/- 1 vs 14 +/- 1 mm Hg, P < .05). Animals pretreated with carvedilol survived longer (71 +/- 1 vs 45 +/- 22 hours, P < .05) and with less postresuscitation neurologic deficit. After beta- and alpha1-adrenergic blockade with carvedilol before inducing cardiac arrest, epinephrine administered during CPR yielded better postresuscitation myocardial and neurologic functions and significantly increased postresuscitation survival.

Comparison between dobutamine and levosimendan for management of postresuscitation myocardial dysfunction*

To investigate the effects of levosimendan, a nonadrenergic inotropic calcium sensitizer, in comparison with adrenergic dobutamine for the management of postresuscitation myocardial dysfunction following resuscitation from prolonged cardiac arrest. Randomized prospective animal study. Animal research laboratory. Male Yorkshire-cross domestic pigs Ventricular fibrillation was induced in male domestic pigs weighing between 35 and 40 kg. Cardiopulmonary resuscitation, including precordial compression and mechanical ventilation, was started after 7 mins of untreated cardiac arrest. Electrical defibrillation was attempted after 5 mins of cardiopulmonary resuscitation. Each animal was successfully resuscitated without pharmacologic intervention. Resuscitated animals were randomized to treatment with levosimendan, dobutamine, or saline placebo. The inotropic agents or an equivalent volume of placebo diluents was administered 10 mins after restoration of spontaneous circulation. Levosimendan was administered in a loading dose of 20 microg.kg over 10 mins followed by a 220-min infusion of 0.4 microg.kg.min. Dobutamine was infused into the right atrium in an amount of 5 microg.kg.min. Treatment was continued for a total of 230 mins. Levosimendan and dobutamine produced comparable increases in cardiac output. However, levosimendan produced significantly greater left ventricular ejection fraction and fractional area changes compared with dobutamine and saline placebo. Levosimendan has the potential of improving postresuscitation myocardial function. It is likely to serve as an alternative to dobutamine as an inotropic agent for management of postresuscitation myocardial dysfunction.

The effects of biphasic waveform design on post-resuscitation myocardial function

ObjectivesThis study examined the effects of biphasic truncated exponential waveform design on survival and post-resuscitation myocardial function after prolonged ventricular fibrillation (VF). BackgroundBiphasic waveforms are more effective than monophasic waveforms for successful defibrillation, but optimization of energy and current levels to minimize post-resuscitation myocardial dysfunction has been largely unexplored. We examined a low-capacitance waveform typical of low-energy application (low-energy biphasic truncated exponential [BTEL]; 100 μF, ≤200 J) and a high-capacitance waveform typical of high-energy application (high-energy biphasic truncated exponential [BTEH]; 200 μF, ≥200 J). MethodsFour groups of anesthetized 40- to 45-kg pigs were investigated. After 7 min of electrically induced VF, a 15-min resuscitation attempt was made using sequences of up to three defibrillation shocks followed by 1 min of cardiopulmonary resuscitation. Animals were randomized to BTEL at 150 J or 200 J or to BTEH at 200 J or 360 J. ResultsResuscitation was unsuccessful in three of the five animals treated with BTEH at 200 J. All other attempts were successful. Significant therapy effects were observed for survival (p = 0.035), left ventricular ejection fraction (p < 0.001), stroke volume (p < 0.001), fractional area change (p < 0.001), cardiac output (p = 0.044), and mean aortic pressure (p < 0.001). Hemodynamic outcomes were negatively associated with energy and average current but positively associated with peak current. Peak current was the only significant predictor of survival (p < 0.001). ConclusionsMaximum survival and minimum myocardial dysfunction were observed with the low-capacitance 150-J waveform, which delivered higher peak current while minimizing energy and average current.

Evidence favoring the use of an alpha2-selective vasopressor agent for cardiopulmonary resuscitation.

Both alpha1- and beta-adrenergic agonists increase the severity of global myocardial ischemic injury. We hypothesized that combined beta- and alpha1-adrenergic blockade would improve initial resuscitation and postresuscitation myocardial and neurological functions. We further hypothesized that the resulting alpha2-actions of relatively brief duration would favor improved functions compared with the more prolonged effect of nonadrenergic vasopressin. Three groups of 5 male domestic pigs weighing 37+/-3 kg were investigated. Ventricular fibrillation was untreated for 7 minutes before the start of precordial compression, mechanical ventilation, and attempted defibrillation. Animals were randomized to receive central venous injections of equipressor doses of (1) epinephrine, (2) epinephrine in which both alpha1- and beta-adrenergic effects were blocked by previous administration of prazosin and propranolol, and (3) vasopressin during CPR. All but 1 animal were successfully resuscitated. After injection of epinephrine, significantly better cardiac output and fractional area change, together with lesser increases in troponin I, were observed after alpha1- and beta-adrenergic blockade. Postresuscitation neurological function was also improved after alpha1- and beta-block in comparison with unblocked epinephrine and after vasopressin. Equipressor doses of epinephrine, epinephrine after alpha1- and beta-adrenergic blockade, and vasopressin were equally effective in restoring spontaneous circulation after prolonged ventricular fibrillation. However, combined alpha1- and beta-adrenergic blockade, which represented a predominantly selective alpha2-vasopressor effect, resulted in improved postresuscitation cardiac and neurological recovery.

Vasopressor agents for cardiopulmonary resuscitation.

The primary goal of cardiopulmonary resuscitation is to reestablish blood flow to vital organs until spontaneous circulation is restored. Adrenergic vasopressor agents produce systemic vasoconstriction. This increases aortic diastolic pressure, and consequently, coronary and cerebral perfusion pressures. The pharmacologic responses to the adrenergic agents are mediated by a group of receptors that are classified as alpha (alpha), including alpha1 and alpha2, and beta (beta), including beta1 and beta2. Epinephrine, which has each of these adrenergic actions, has been the preferred adrenergic agent for the management of cardiac arrest for almost 40 years. Its primary efficacy is due to its alpha-adrenergic vasopressor effects. This contrasts with its beta-adrenergic actions, which are inotropic, chronotropic, and vasodilator. Accordingly, beta-adrenergic actions prompt increases in myocardial oxygen consumption, ectopic ventricular arrhythmias, and transient hypoxemia due to pulmonary arteriovenous shunting. This may account for the failure to demonstrate that epinephrine improves ultimate outcomes in human victims of cardiac arrest. Major interest has more recently been focused on selective alpha-adrenergic agonists. Both alpha1-agonists and alpha2-agonists are peripheral vasopressors. However, rapid desensitization of alpha1-adrenergic receptors occurs during cardiopulmonary resuscitation. Moreover, alpha1-adrenergic receptors are present in the myocardium, and beta1-agonists, like beta-adrenergic agonists, increase myocardial oxygen consumption. If they cross the blood-brain barrier, alpha2-adrenoceptor agonists also have centrally acting vasodilator effects. In the absence of central nervous system access, alpha2-adrenergic agonists have selective peripheral vasoconstrictor effects. Under experimental conditions of cardiopulmonary resuscitation, selective alpha2-agonists, which do not gain entrance into the brain, produce only systemic vasoconstriction. Experimentally, these selective alpha2-agonists are as effective as epinephrine for initial cardiac resuscitation and have the additional advantage of minimizing myocardial oxygen consumption during the global myocardial ischemia of cardiac arrest. Accordingly, myocardial ischemic injury during cardiopulmonary resuscitation is minimized, and postresuscitation myocardial function is preserved with improved survival.

A comparison of α-methylnorepinephrine, vasopressin and epinephrine for cardiac resuscitation

The objective of this research was to compare the effects of an α- and β-adrenergic agonist, epinephrine, a selective α 2-adrenergic agonist, α-methylnorepinephrine (α-MNE), and a non-adrenergic vasopressin on post-resuscitation myocardial function and duration of survival. Epinephrine continues to be the primary adrenergic agent for advanced cardiac life support. However, its major inotropic actions and especially its β-adrenergic and, to a lesser extent, its α 1-actions increase the severity of global ischemia during cardiac arrest and adversely affect post-resuscitation myocardial function and survival. We had previously observed significantly better outcomes with a selective α 2-adrenergic agonist when compared with epinephrine. Non-adrenergic vasopressin also has promise of more favorable actions. The present study was, therefore, undertaken to compare a selective α 2-adrenergic vasopressor drug with vasopressin, epinephrine, and saline placebo. Ventricular fibrillation (VF) was induced in 20 Sprague–Dawley rats. Mechanical ventilation and precordial compression were initiated after 8 min of untreated VF. About 2 min later, α-MNE in a dose of 100 μg/kg, vasopressin in a dose of 0.4 U/kg, epinephrine in a dose of 30 μg/kg, or saline control was administered. Defibrillation was attempted after 6 min of CPR. Left ventricular pressure, dP/dt 40, −dP/dt, and cardiac index were measured for an interval of 240 min after resuscitation. Except for saline controls, comparable increases in coronary perfusion pressure (CPP) were observed after each drug intervention. All animals were successfully resuscitated. Post-resuscitation myocardial function and survival were significantly better in animals treated with α-MNE. Both post-resuscitation myocardial function and survival were most improved after administration of the selective α 2-adrenergic agonist, intermediate after vasopressin and least after epinephrine and saline placebo.

A selective α2-adrenergic agonist for cardiac resuscitation

The effects of selective α2-adrenergic agonist α-methylnorepinephrine on the initial success of resuscitation and postresuscitation myocardial function were compared with nonselective α- and β-adrenergic epinephrine in a swine model of cardiac arrest. Epinephrine, the primary pharmacological intervention in the treatment of cardiac arrest, improves immediate outcome. However, epinephrine increases the severity of myocardial dysfunction after cardiac resuscitation. Both inotropic and chronotropic actions provoke disproportionate increases in myocardial oxygen consumption by the ischemic heart, prompting this study, in which we hypothesized that a selective α2-adrenergic agonist, α-methylnorepinephrine (α-MNE), would moderate these adverse effects of epinephrine and minimize postresuscitation myocardial dysfunction. After 7 minutes of untreated ventricular fibrillation (VF) in 14 anesthetized male domestic pigs, precordial compression at a fixed rate of 80 compressions/min was begun, along with mechanical ventilation. Either α-MNE (100 μg/kg) or epinephrine (20 μg/kg) was administered as a bolus after 2 minutes of precordial compression. After an additional 4 minutes of precordial compression, defibrillation was attempted. Left ventricular systolic and diastolic function was quantitated with the use of transesophageal echo-Doppler imaging. Comparable increases in coronary perfusion pressure to 15 mm Hg were observed after the administration of both drugs. All animals were successfully resuscitated; epinephrine and α-MNE were equally quick in restoring spontaneous circulation after 7 minutes of untreated VF. Ejection fraction was reduced by 35% and 14% by epinephrine and α-MNE, respectively, after resuscitation. Epinephrine and α-MNE increased postresuscitation heart rate by 38% and 15%, respectively. Accordingly, significantly less postresuscitation impairment followed the administration of α-MNE. α-MNE, a selective α-adrenergic agonist, was as effective as epinephrine in restoring spontaneous circulation after 7 minutes of untreated VF in a porcine model for CPR and demonstrated lesser postresuscitation myocardial injury. (J Lab Clin Med 2002;140:27-34)

A Comparison of Biphasic and Monophasic Waveform Defibrillation After Prolonged Ventricular Fibrillation

Study objectiveTo compare the effects of biphasic defibrillation waveforms and conventional monophasic defibrillation waveforms on the success of initial defibrillation, postresuscitation myocardial function, and duration of survival after prolonged duration of untreated ventricular fibrillation (VF), including the effects of epinephrine. DesignProspective, randomized, animal study. SettingAnimal laboratory and university-affiliated research and educational institute. ParticipantsDomestic pigs. InterventionsVF was induced in 20 anesthetized domestic pigs receiving mechanical ventilation. After 10 min of untreated VF, the animals were randomized. Defibrillation was attempted with up to three 150-J biphasic waveform shocks or a conventional sequence of 200-J, 300-J, and 360-J monophasic waveform shocks. When reversal of VF was unsuccessful, precordial compression was performed for 1 min, with or without administration of epinephrine. The protocol was repeated until spontaneous circulation was restored or for a maximum of 15 min. Measurements and resultsNo significant differences in the success of initial resuscitation or in the duration of survival were observed. However, significantly less impairment of myocardial function followed biphasic shocks. Administration of epinephrine reduced the total electrical energy required for successful resuscitation with both biphasic and monophasic waveform shocks. ConclusionsLower-energy biphasic waveform shocks were as effective as conventional higher-energy monophasic waveform shocks for restoration of spontaneous circulation after 10 min of untreated VF. Significantly better postresuscitation myocardial function was observed after biphasic waveform defibrillation. Administration of epinephrine after prolonged cardiac arrest decreased the total energy required for successful resuscitation.

Successful ventricular defibrillation by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide.

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. NHE-1 inhibition may represent a novel and remarkably effective intervention for resuscitation from VF.

Alpha-methylnorepinephrine, a selective alpha2-adrenergic agonist for cardiac resuscitation

OBJECTIVESThe purpose of this study was to investigate the effects of a selective alpha2-adrenergic agonist, alpha-methylnorepinephrine (alphaMNE) as an alternative vasopressor agent during cardiopulmonary resuscitation (CPR).BACKGROUNDFor more than 40 years, epinephrine has been the vasopressor agent of choice for CPR. Its beta- and alpha1-adrenergic effects increase myocardial oxygen consumption, magnify global myocardial ischemia and increase the severity of postresuscitation myocardial dysfunction.METHODSVentricular fibrillation (VF) was induced in 20 Sprague-Dawley rats. After 8 min of untreated VF, mechanical ventilation and precordial compression began. AlphaMNE, epinephrine or saline placebo was injected into the right atrium 2 min after the start of precordial compression. As an additional control, one group of animals was pretreated with alpha2-receptor blocker, yohimbine, before injection of alphaMNE. Defibrillation was attempted 4 min later. Left ventricular pressure, dP/dt40, negative dP/dt and cardiac index were measured for an interval of 240 min after resuscitation.RESULTSExcept for saline placebo and yohimbine-treated animals, comparable increases in coronary perfusion pressure were observed after each drug intervention. All animals were successfully resuscitated. Left ventricular diastolic pressure, cardiac index, dP/dt40and negative dP/dt were more optimal after alphaMNE; this was associated with significantly better postresuscitation survival. Pretreatment with yohimbine abolished the beneficial effects of alphaMNE.CONCLUSIONSThe selective alpha2-adrenergic agonist, alphaMNE, was as effective as epinephrine for initial cardiac resuscitation but provided strikingly better postresuscitation myocardial function and survival.

KATP channel activation reduces the severity of postresuscitation myocardial dysfunction

Postresuscitation myocardial dysfunction has been recognized as a leading cause of the high postresuscitation mortality rate. We investigated the effects of ischemic preconditioning and activation of ATP-sensitive K(+) (K(ATP)) channels on postresuscitation myocardial function. Ventricular fibrillation (VF) was induced in 25 Sprague-Dawley rats. Cardiopulmonary resuscitation (CPR), including mechanical ventilation and precordial compression, was initiated after 4 min of untreated VF. Defibrillation was attempted after 6 min of CPR. The animals were randomized to five groups treated with 1) ischemic preconditioning, 2) K(ATP) channel opener, 3) ischemic preconditioning with K(ATP) channel blocker administered 1 min after VF, 4) K(ATP) channel blocker administered 45 min before induction of ischemic preconditioning, and 5) placebo. Postresuscitation myocardial function, as measured by the rate of left ventricular pressure increase at 40 mmHg, the rate of left ventricular decline, cardiac index, and duration of survival, was significantly improved in both preconditioned and K(ATP) channel opener-treated animals. K(ATP) channel blocker administered 45 min before induction of ischemic preconditioning completely abolished the myocardial protective effects of preconditioning. We conclude that ischemic preconditioning significantly improved post-CPR myocardial function and survival. These results also provide evidence that the myocardial protective effects of ischemic preconditioning are mediated by K(ATP) channel activation.

The effects of biphasic and conventional monophasic defibrillation on postresuscitation myocardial function

OBJECTIVESThe purpose of this study was to compare the effects of biphasic defibrillation waveforms and conventional monophasic defibrillation waveforms on the success of initial defibrillation, postresuscitation myocardial function and duration of survival after prolonged ventricular fibrillation (VF).BACKGROUNDWe have recently demonstrated that the severity of postresuscitation myocardial dysfunction was closely related to the magnitude of the electrical energy of the delivered defibrillation shock. In the present study, the effects of fixed 150-J low-energy biphasic waveform shocks were compared with conventional monophasic waveform shocks after prolonged VF.METHODSTwenty anesthetized, mechanically ventilated domestic pigs were investigated. VF was induced with an AC current delivered to the right ventricular endocardium. After either 4 or 7 min of untreated ventricular fibrillation (VF), the animals were randomized for attempted defibrillation with up to three 150-J biphasic waveform shocks or conventional sequence of 200-, 300- or 360-J monophasic waveform shocks. If VF was not reversed, a 1-min interval of precordial compression preceded a second sequence of up to three shocks. The protocol was repeated until spontaneous circulation was restored or for a total of 15 min.RESULTSMonophasic waveform defibrillation after 4 or 7 min of untreated VF resuscitated eight of 10 pigs. All 10 pigs treated with biphasic waveform defibrillation were successfully resuscitated. Transesophageal echo-Doppler, arterial pressure and heart rate measurements demonstrated significantly less impairment of cardiovascular function after biphasic defibrillation.CONCLUSIONSLower-energy biphasic waveform shocks were as effective as conventional higher energy monophasic waveform shocks for restoration of spontaneous circulation after 4 and 7 min of untreated VF. Significantly better postresuscitation myocardial function was observed after biphasic waveform defibrillation.

Effects of buffer agents on postresuscitation myocardial dysfunction.

Earlier studies demonstrated that hypertonic buffer agents administered during cardiopulmonary resuscitation (CPR) altered neither myocardial pH nor cardiac resuscitability. The rationale for the routine use of buffer agents for CPR has therefore been challenged. However, when these buffer agents are administered during CPR, they may have favorable effects on the postresuscitation course. Postresuscitation myocardial dysfunction has more recently emerged as a potentially fatal complication after successful cardiac resuscitation. Options for prevention and management of this complication have prompted the present studies, in which the effects of buffer agents administered during CPR are evaluated as to their effects on postresuscitation myocardial function and survival. Prospective, randomized, controlled animal study. University animal laboratory. Forty male Sprague-Dawley rats (450 to 570 g). Ventricular fibrillation was induced electrically. Mechanical Ventilation and percordial compression were initiated after either a 4- or an 8-min interval of untreated cardiac arrest. Sodium bicarbonate as a CO2-generating buffer, Carbicarb and tromethamine as CO2-consuming buffers, or hypertonic saline placebo were injected as a bolus into the right atrium during CPR. Defibrillation after 10 mins of cardiac arrest and CPR was successful in each instance. No differences in the electric power required for successful resuscitation were documented. Left ventricular pressure, rate of left ventricular pressure increase measured at a left ventricular pressure of 40 mm Hg (dP/dt40), rate of left ventricular pressure decline (-dP/dt), and end-tidal PCO2 were continuously measured for 240 mins after successful resuscitation. Decreases in coronary perfusion pressure were observed after each buffer or placebo injection. As anticipated, end-tidal PCO2 increased after bicarbonate and decreased after Carbicarb or tromethamine. Postresuscitation left ventricular function was significantly decreased in all animals. However, there was significantly less depression in rate of left ventricular pressure increase measured at a left ventricular pressure of 40 mm Hg (dP/dt40), rate of left ventricular pressure decline (-dP/dt), and a lower left ventricular diastolic pressure with both Carbicarb and tromethamine in association with significant increases in postresuscitation survival rate. When the duration of untreated cardiac arrest was increased to 8 mins, the severity of postresuscitation left ventricular dysfunction was magnified and postresuscitation myocardial function and survival were significantly improved with both CO2-generating and CO2-consuming buffer agents. Although buffer agents may not improve the success of resuscitation when administered during CPR, they may ameliorate postresuscitation myocardial dysfunction and thereby improve postresuscitation survival.