Myocardial effects of repeated electrical defibrillations in the isolated fibrillating rat heart

OBJECTIVE: Although substantial myocardial cell injury has been reported after high-energy electrical defibrillation, only minimal injury with transient functional defects seems to develop at energy levels not exceeding those required to reverse ventricular fibrillation. Because multiple electrical shocks are often delivered in clinical settings during attempts to reverse ventricular fibrillation, we investigated the effects of repetitive shocks on postresuscitation myocardial dysfunction by using an isolated rat heart model of ventricular fibrillation. DESIGN: Prospective and randomized. SETTING: Cardiopulmonary resuscitation research laboratory. SUBJECTS: Twenty-seven Sprague-Dawley rats. INTERVENTIONS: Hearts were harvested and perfused at a constant flow of 10 mL/min by using a modified Krebs-Henseleit solution equilibrated with 95% oxygen and 5% CO2. Ventricular fibrillation (VF) was induced by a 0.05-mA current delivered to the right ventricular endocardium and the perfusate flow was stopped. After 10 mins, the perfusate flow was resumed at 20% of baseline flow and maintained for 15 additional minutes before returning to baseline flow after 25 mins of VF (VF25 mins). Twenty-seven hearts were randomized to receive from VF22 mins to VF25 mins either 0 epicardial shocks, 6 epicardial shocks, or 12 epicardial shocks. MEASUREMENTS AND MAIN RESULTS: Isovolumic indices of left ventricular function were obtained by using a latex balloon advanced through the mitral valve into the ventricular cavity. After defibrillation, indices of contractile function rapidly returned to baseline without differences among groups. The isovolumic end-diastolic pressure, however, remained elevated throughout the postresuscitation interval. A left shift of the diastolic pressure-volume curves without changes in their slope was observed at 10 mins after resuscitation with partial return to baseline by 30 mins postresuscitation. The shifts were significantly greater in hearts that received 12 shocks. CONCLUSIONS: These findings indicate that repetitive low-energy electrical shocks do not accentuate postischemic systolic dysfunction in the isolated fibrillating rat heart but adversely affect postischemic diastolic dysfunction by reducing the unstressed left ventricular end-diastolic volume.     

A selective alpha(2)-adrenergic agonist for cardiac resuscitation

The effects of selective alpha(2)-adrenergic agonist alpha-methylnorepinephrine on the initial success of resuscitation and postresuscitation myocardial function were compared with nonselective alpha- and beta-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 alpha(2)-adrenergic agonist, alpha-methylnorepinephrine (alpha-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 alpha-MNE (100 microg/kg) or epinephrine (20 microg/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 alpha-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 alpha-MNE, respectively, after resuscitation. Epinephrine and alpha-MNE increased postresuscitation heart rate by 38% and 15%, respectively. Accordingly, significantly less postresuscitation impairment followed the administration of alpha-MNE. alpha-MNE, a selective alpha-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.     

Effects of the specific bradycardic agent zatebradine on hemodynamic variables and myocardial blood flow during the early postresuscitation phase in pigs

Cardiopulmonary resuscitation (CPR) leads to an excessive stimulation of the sympathetic nervous system that may result in tachycardia and malignant arrhythmias in the postresuscitation phase. The attenuation of this reaction by a specific bradycardic agent has not been compared to beta-blockade and placebo. After 4 min of ventricular fibrillation, and 3 min of CPR, 21 pigs were randomized to receive 45 microg/kg epinephrine in combination with either a specific bradycardic agent (0.5 mg/kg zatebradine; n = 7), or a beta-blocker (1 mg/kg esmolol; n = 7), or placebo (normal saline; n = 7). Two minutes after drug administration, defibrillation was performed to restore spontaneous circulation (ROSC). Hemodynamic variables, left ventricular contractility, right ventricular function, and myocardial blood flow were studied at prearrest, and for 3 h after ROSC. In comparison with esmolol and placebo, zatebradine resulted in a significant reduction in heart rate during the postresuscitation period, and reduced the number of premature ventricular contractions in the first 5 min after ROSC. This reduction in heart rate was associated with a significantly higher right ventricular ejection fraction, stroke volume, and endocardial/epicardial perfusion ratio at 5 min after ROSC. In comparison with placebo, esmolol administration decreased heart rate only moderately, but significantly reduced right ventricular stroke volume and cardiac output at 5 min after ROSC. Although only one dose and only one administration pattern of zatebradine has been investigated, we conclude that zatebradine administration during CPR effectively reduced heart rate without compromising myocardial contractility during the postresuscitation phase in pigs.     

The Proinflammatory Cytokine Response following Resuscitation in the Swine Model Depends on the Method of Ventricular Fibrillation Induction

Objectives: A systemic inflammatory response has been reported following resuscitation from cardiac arrest. The purpose of this study was to compare the magnitude of the tumor necrosis factor‐α (TNF‐α) response in two different swine models of ventricular fibrillation (VF) arrest. Methods: This was a randomized comparative trial conducted with domestic swine (N = 28, mean weight 40 kg, range 34–49 kg) of both genders. Anesthetized and instrumented swine were randomized to electrically induced VF (n = 14) or spontaneous VF induced by occlusion of a coronary artery (n = 14). After 8 minutes of VF, countershocks were given and standard advanced cardiac life support was initiated. Resuscitated animals were observed for 3 hours, and hemodynamics, base excess, and TNF‐α concentrations were measured at intervals. Results: TNF‐α concentrations were significantly greater in the ischemic VF group throughout the postresuscitation period. Multivariate modeling demonstrated that the TNF‐α level was dependent on the method of VF induction and correlated with ischemia time (untreated VF period plus time to restoration of circulation) and the degree of postresuscitation hypoperfusion as reflected in base excess measurements. Conclusions: This study demonstrates that TNF‐α concentrations increase after resuscitation from cardiac arrest and that the TNF‐α response is more profound in animals subjected to ischemic, spontaneous VF. The observed differences may be due to a longer resuscitation time and persistent postresuscitation hypoperfusion in the ischemic VF group. These differences need to be considered in studies evaluating mechanisms of postresuscitation organ dysfunction and defining mortality markers.     

Tumor necrosis factor-alpha is associated with early postresuscitation myocardial dysfunction

OBJECTIVE: Left ventricular dysfunction after successful cardiopulmonary resuscitation contributes to early death following resuscitation. The stress-induced proinflammatory cytokines, particularly tumor necrosis factor-alpha and interleukin-1beta, are known to depress myocardial function. We hypothesized that tumor necrosis factor-alpha and interleukin-1beta, synthesized and released in response to the stress of global ischemia accompanying cardiac arrest, play a role in development of postresuscitation left ventricular dysfunction. METHODS: Hemodynamic variables, tumor necrosis factor-alpha , interleukin-1beta, interleukin-6 (enzyme-linked immunosorbent assay method), and ionized calcium were measured in ten anesthetized swine before and after 7 mins of cardiac arrest and during the early postresuscitation period (60-90 mins). RESULTS: Tumor necrosis factor-alpha increased three-fold within 15 mins of restoration of circulation and remained elevated throughout the observation period. A significant negative correlation was observed between tumor necrosis factor-alpha and left ventricular systolic change in pressure over time (r = -.54, p <.001). Interleukin-1beta was undetectable before and after resuscitation, and interleukin-6 was detectable in only two animals after resuscitation. Although a significant decline in ionized calcium was observed and correlated with left ventricular systolic change in pressure over time, an independent role for ionized calcium in postresuscitation left ventricular dysfunction was not demonstrated. CONCLUSION: Tumor necrosis factor-alpha increases during the early postresuscitation period and may play a role in postresuscitation myocardial dysfunction.     

Effect of acute fatal blood loss on the functional metabolic disturbances of the heart in the postresuscitation period

The investigation has been performed on the isolated isovolumically contracting hearts of rats resuscitated after a 4-min clinical death caused by acute blood loss. It has been established that myocardial contractility disturbances, minimum during clinical death, become far more marked 30-60 min after recirculation and progress in the first 3 days, especially in unfavourable course of the postresuscitation period. Disturbed myocardial contractility closely correlates with enzyme release into the coronary flow and the efficacy of glucose utilization per unit of myocardial function. By day 7 contractility disturbances attenuate, mounting again two weeks later. Relative normalization of myocardial contractility is observed by the end of the first postresuscitation month, however, the release of enzymes from various cardiomyocyte ultrastructures into the coronary flow remains still high.     

Effects of vasopressin and epinephrine on splanchnic blood flow and renal function during and after cardiopulmonary resuscitation in pigs

OBJECTIVE: To compare the effects of vasopressin versus epinephrine on splanchnic blood flow during and after cardiopulmonary resuscitation (CPR), and to evaluate the effects of these vasopressors on renal function in the postresuscitation phase. DESIGN: Prospective, randomized laboratory investigation using an established porcine CPR model with instrumentation for continuous measurement of splanchnic and renal blood flow. SETTING: University hospital experimental laboratory. SUBJECTS: A total of 12 anesthetized, 12- to 16-wk-old domestic pigs weighing 30-35 kg. INTERVENTIONS: After 4 mins of cardiac arrest, and 3 mins of CPR, 12 pigs were randomly assigned to receive either 0.4 units/kg vasopressin (n = 6) or 45 microg/kg epinephrine (n = 6). Defibrillation was performed 5 mins after drug administration; all animals were observed for 6 hrs after return of spontaneous circulation (ROSC). MEASUREMENTS AND MAIN RESULTS: Mean +/- SEM superior mesenteric artery blood flow was significantly (p < .05) lower after vasopressin compared with epinephrine at 90 secs after drug administration (13+/-3 vs. 129+/-33 mL/min); at 5 mins after drug administration (31+/-18 vs. 155+/-39 mL/min); at 5 mins after ROSC (332+/-47 vs. 1087+/-166 mL/min); and at 15 mins after ROSC (450+/-106 vs. 1130+/-222 mL/min); respectively. Mean +/- SEM left renal and hepatic artery blood flow after ROSC was comparable in both groups ranging between 120-290 mL/min (renal blood flow), and 150-360 mL/min (hepatic blood flow), respectively. Median urine output after ROSC showed no difference between groups, and highest values (180-220 mL/hr) were observed in the first 60 mins after ROSC. Median calculated glomerular filtration rate showed no difference between groups with values ranging between 30 and 80 mL/min in the postresuscitation phase. Calculated fractional sodium excretion and osmolar relationship between urea and plasma indicated no evidence for renal tubular dysfunction. CONCLUSIONS: In the early postresuscitation phase, superior mesenteric blood flow was temporarily impaired by vasopressin in comparison with epinephrine. With respect to renal blood flow and renal function after ROSC, there was no difference between either vasopressor given during CPR. Vasopressin given during CPR did not result in an antidiuretic state in the postresuscitation phase.     

Levosimendan improves postresuscitation outcomes in a rat model of CPR

In this study we sought to determine whether a calcium sensitizer, levosimendan, would have a more favorable effect on postresuscitation myocardial function and, consequently, postresuscitation survival than beta-adrenergic dobutamine. The extreme decrease in survival before hospital discharge of resuscitated victims is attributed, in part, to postresuscitation myocardial failure, and dobutamine has been recommended for the management of postresuscitation myocardial failure. We studied a total of 15 animals. Ventricular fibrillation was induced in Sprague-Dawley rats weighing 450 to 550 g. Cardiopulmonary resuscitation (CPR), including chest compressions and mechanical ventilation, was begun after 8 minutes of untreated cardiac arrest. Electrical defibrillation was attempted after 6 minutes of CPR. Each animal was resuscitated. Animals were randomized to undergo treatment with levosimendan, dobutamine, or saline-solution placebo. These agents were administered 10 minutes after the return of spontaneous circulation. Levosimendan was administered in a loading dose of 12 microg kg(-1) over a 10-minute period, followed by infusion of 0.3 microg kg(-1) min(-1) over the next 230 minutes. Dobutamine was continuously infused at a dosage of 3 microg kg(-1) min(-1). Saline-solution placebo was administered in the same volume and over the same amount of time as levosimendan. Levosimendan and dobutamine produced comparable increases in cardiac output and rate of left-ventricular pressure increase. However, administration of levosimendan resulted in lower heart rates and lesser increases in left ventricular diastolic pressure compared with both dobutamine and placebo. The duration of postresuscitation survival was significantly greater with levosimendan (16 +/- 2 hours), intermediate with dobutamine (11 +/- 2 hours) and least with saline-solution placebo (8 +/- 1 hour). Levosimendan and dobutamine both improved postresuscitation myocardial function. However, levosimendan produced more favorable postresuscitation myocardial function and increased the duration of postresuscitation survival.     

Mechanism by which activation of delta-opioid receptor reduces the severity of postresuscitation myocardial dysfunction

OBJECTIVE: Postresuscitation myocardial dysfunction has been recognized as a leading cause of early death after initially successful cardiopulmonary resuscitation. We have previously demonstrated that opening adenosine triphosphate (ATP)-sensitive K (KATP) channels or activation of delta-opioid receptors minimized the severity of postresuscitation myocardial dysfunction and increased the duration of postresuscitation survival. In the present study, we investigated the potential mechanism of myocardial protection following delta-opioid receptor activation in a rat model of cardiac arrest and cardiopulmonary resuscitation. DESIGN: Randomized prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Ventricular fibrillation was induced in 24 Sprague-Dawley rats. Mechanical ventilation and precordial compression were initiated after 8 mins of untreated ventricular fibrillation. Defibrillation was attempted after 6 mins of cardiopulmonary resuscitation. The animals were randomized to four groups: a) pentazocine (0.3 mg/kg), a delta-opioid receptor agonist; b) pentazocine pretreated with KATP channel blocker, glibenclamide (0.3 mg/kg), administered 45 mins before induction of ventricular fibrillation; c) glibenclamide pretreated alone 45 mins before induction of ventricular fibrillation; and d) placebo. Pentazocine or saline placebo was injected into the right atrium after 5 mins of untreated ventricular fibrillation. MEASUREMENTS AND MAIN RESULTS: Postresuscitation myocardial function, as measured by the rate of left ventricular pressure increase at 40 mm Hg, left ventricular end-diastolic pressure, and cardiac index, was significantly improved in pentazocine-treated animals. This was associated with significantly prolonged duration of survival. Except for ease of defibrillation, the beneficial effects of pentazocine were abolished by pretreatment with the KATP channel blocker glibenclamide. CONCLUSIONS: The postresuscitation myocardial protective effects provided by activation of delta-opioid receptor may be mediated via opening KATP channels.     

Pulmonary gas exchange after cardiopulmonary resuscitation with either vasopressin or epinephrine

OBJECTIVE: It is well established that epinephrine administered during cardiopulmonary resuscitation results in pulmonary gas exchange disturbances. It is uncertain how vasopressin affects gas exchange after cardiopulmonary resuscitation. DESIGN: Prospective, randomized experimental study. SETTING: Animal research laboratory. SUBJECTS: Twenty domestic pigs. INTERVENTIONS: Animals were subjected to ventricular fibrillation and cardiopulmonary resuscitation by using either vasopressin or epinephrine. Hemodynamic and pulmonary gas exchange (multiple inert gas elimination technique) variables were recorded before cardiopulmonary resuscitation and 10, 30, 60, and 120 mins after return of spontaneous circulation when either epinephrine (control) or vasopressin was used. MEASUREMENTS AND MAIN RESULTS: At 10 mins after return of spontaneous circulation, blood flow to low V /Q lung units was increased in animals treated with epinephrine (17.8 +/- 6 vs. 2.6 +/- 3%, mean +/- sd, p<.01). Resulting carbon dioxide elimination was impaired in animals treated with epinephrine but not in animals treated with vasopressin (PaCO2, 55 +/- 2 vs. 46 +/- 4 torr, p<.05). Thirty minutes after return of spontaneous circulation, blood flow to lung units with a normal VA /Q ratio was reduced in animals treated with epinephrine (79 +/- 1 vs. 84 +/- 12%, p<.05), resulting in a depressed PaO2 (147 +/- 4 vs. 127 +/- 10 torr, p<.05). CONCLUSION: Vasopressin compared with epinephrine for cardiopulmonary resuscitation resulted in better gas exchange variables in the early postresuscitation phase.     

The effect of preliminary administration of the beta-blocker inderal on the course of the postresuscitation period

The results of the effect of acute fetal blood loss and a beta-blocker inderal preinjection on the functional metabolic damage of vital organs in the early postresuscitation period are presented. It has been established that the drug preinjection restricts the lipolysis and considerably decreases the intensity of lipid peroxidation in the brain, heart and liver both due to prevention of antioxidant enzyme inhibition and to preservation of antioxidant lipid activity at a high level. It has been shown that inderal, retaining phospholipid content of cardiomyocyte membranes, reduces the electrical heart instability and completely prevents ventricular fibrillation in the early postresuscitation period. Inderal decreases considerably adenyl nucleotide brain and heart catabolism.     

Left Ventricular Function after Monophasic and Biphasic Waveform Defibrillation: The Impact of Cardiopulmonary Resuscitation Time on Contractile Indices

Previous work has suggested that low-energy biphasic waveform defibrillation (BWD) is followed by less post-resuscitation left ventricular (LV) dysfunction when compared with higher-energy monophasic waveform defibrillation (MWD). To the best of the authors' knowledge, the effect of cardiopulmonary resuscitation (CPR) duration and total ischemia time on LV function after countershock, controlling for waveform type, has not been evaluated. OBJECTIVE: To determine the effect of CPR duration on LV function after MWD and BWD. METHODS: VF was electrically induced in anesthetized and instrumented swine. After 5 minutes of VF, the animals were randomized to MWD (n = 22) or one of two BWDs (n = 46). If countershock terminated VF but was followed by a nonperfusing rhythm, conventional manual CPR without drug therapy was performed until restoration of spontaneous circulation (ROSC), defined as a systolic arterial pressure >60 mm Hg for 10 minutes without vasopressor support. Systolic LV pressure (LVP), LV dP/dt (first derivative of pressure measured over time), and cardiac output (CO) were measured at intervals for 60 minutes postresuscitation. CPR times (times to ROSC) and hemodynamic variables for the three groups were compared. Multivariable linear regression was performed to assess the contribution of defibrillation waveform, total joules, and CPR time on LVP, LV dP/dt, and CO at 15, 30, and 60 minutes postresuscitation. RESULTS: When analyzed as groups, significant differences in median number of shocks to terminate VF, total joules, or CPR time were not observed between waveform groups. Regression analysis demonstrated that increasing CPR time was associated with a significant effect on indices of LV function at 15 and 30 minutes postresuscitation. Global LV function was not influenced by waveform type or total joules. CONCLUSIONS: Adjustment for CPR time, a determinant of total myocardial ischemia time, is necessary when defibrillation waveforms are compared for their effect on postresuscitation cardiac function and short-term outcome.     

Alterations in tissue oxygen consumption and extraction after trauma and hemorrhagic shock

OBJECTIVES: Although trauma and hemorrhage are associated with tissue hypoperfusion and hypoxemia, changes in oxygen delivery (DO2), oxygen consumption VO2), and oxygen extraction at the organ level in a small animal (such as the rat) model of trauma and hemorrhage have not been examined. Therefore, the objectives of this study were to determine whether blood flow, DO2, VO2, and oxygen extraction ratio in various organs are differentially altered after trauma-hemorrhagic shock and acute resuscitation in the rat. DESIGN: Prospective, randomized animal study. SETTING: A university research laboratory. SUBJECTS: Male Sprague-Dawley rats (n = 6-7 animals/group) weighing 275-325 g. INTERVENTIONS: Male rats underwent laparotomy (i.e., soft tissue trauma) and were bled to and maintained at a blood pressure of 40 mm Hg until 40% of shed blood volume was returned in the form of lactated Ringer's solution. They were then resuscitated with four times the volume of shed blood with lactated Ringer's solution for 60 mins. At 1.5 hrs postresuscitation, cardiac output and blood flow were determined by using strontium-85 microspheres. Blood samples (0.15 mL each) were collected from the femoral artery and vein and the hepatic, portal, and renal veins to determine total hemoglobin and oxygen content. Systemic and regional DO2, VO2, and oxygen extraction ratio were then calculated. MEASUREMENTS AND MAIN RESULTS: Both the systemic hemoglobin and systemic arterial oxygen content in hemorrhaged animals at 1.5 hrs postresuscitation were >50% lower as compared with sham-operated controls. Cardiac output and blood flow in the liver, small intestine, and kidneys decreased significantly, but blood flow in the brain and heart remained unaltered after hemorrhage and resuscitation. Systemic DO2 and VO2 were 73% and 54% lower, respectively, than controls at 1.5 hrs after resuscitation. Similarly, regional DO2 and VO2 in the liver, small intestine, and kidneys decreased significantly under such conditions. In addition, the liver had the most severe reduction in VO2 (76%) among the tested organs. However, the oxygen extraction ratio in the liver of sham animals was the highest (72%) and remained unchanged after hemorrhage and resuscitation. CONCLUSION: Because the liver experienced the most severe reduction in VO2 associated with an unchanged oxygen extraction capacity, this organ appears to be more vulnerable to hypoxic insult after hemorrhagic shock.     

Effects of pretreatment with propranolol on potassium, calcium, and magnesium shifts after ventricular fibrillation in dogs

Hypokalemia and other electrolyte changes have been observed after resuscitation from ventricular fibrillation. We studied the effect of propranolol on postresuscitation electrolytes in a canine model of ventricular fibrillation and cardiac resuscitation by randomizing 40 anesthetized dogs to four groups: ventricular fibrillation--no drug (VF), ventricular fibrillation--propranolol pretreatment (VF-prop), control-no drug (NoVF), control--propranolol (NoVF-prop). We measured serum electrolytes at baseline and periodically for 3 hours. In VF dogs, serum potassium decreased from 3.9 +/- 0.4 to 3.2 +/- 0.2 mEq/L 60 minutes after resuscitation (p less than 0.001). The decrease in potassium was prevented (p less than 0.001) by propranolol. Serum calcium decreased from 10.6 +/- 0.8 to 10.2 +/- 0.8 mg/dl in VF dogs 15 minutes after resuscitation (p less than 0.05); this decrease was not blocked by propranolol (p = NS). Serum magnesium increased from 1.5 +/- 0.2 to 1.8 +/- 0.1 mEq/L in VF dogs 7 minutes after resuscitation (p less than 0.001); this rise was partially blocked by propranolol (p less than 0.01). Serum glucose increased from 105 +/- 6 to 183 +/- 27 mg/dl in VF dogs 7 minutes after resuscitation (p less than 0.001); this increase was diminished by propranolol (p less than 0.001). Thus propranolol prevents the decrease in serum potassium after ventricular fibrillation in this canine model, providing evidence that postresuscitation hypokalemia is caused by the beta-adrenergic effects of catecholamines secreted in response to cardiac arrest. Propranolol blocks the rise in magnesium and glucose but does not block the decrease in calcium after resuscitation.     

Levosimendan improves postresuscitation myocardial dysfunction after beta-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.     

The effect of normal saline resuscitation on vital organ blood flow in septic sheep

Objective To study the effect of resuscitation with normal saline on vital organ blood flow and renal function in sepsis.Design and setting Randomized controlled cross-over animal study in the animal laboratory of university physiology institute.Subjects Six merino cross-ewes.Interventions Chronic implantation of flow probes around aorta, coronary, renal and mesenteric arteries. Intravenous administration of live Escherichia coli. Random allocation to normal saline resuscitation (20 ml/kg over 15 min) or observation (control) for 210 min. Continuous measurement of central haemodynamics, organ blood flow and renal function.Results Live E. coli induced hyperdynamic sepsis with oliguria (28.3 ± 12.6 to 16.7 ± 11.9 ml/30min) and reduced creatinine clearance (87.9 ± 24.5 to 44.3 ± 34.5 ml/min). During this septic state mesenteric, coronary and renal blood flow increased. During the first hour (early effect) after saline resuscitation, central venous pressure, cardiac output, stroke volume, coronary blood flow, mesenteric blood flow, urine output and creatinine clearance increased, but there was no change in renal blood flow. In the following 2 h these increments were significantly attenuated, but urine output and creatinine clearance remained greater than controls; renal blood flow decreased slightly and the fractional excretion of sodium increased significantly.Conclusion In hyperdynamic sepsis resuscitation with normal saline increases central venous pressure, cardiac output, mesenteric blood flow, urine output, creatinine clearance, and fractional excretion of sodium despite a lack of effect on renal blood flow. These effects, however, are transient.     

Ultrastructural evidence of mitochondrial abnormalities in postresuscitation myocardial dysfunction

Objectives

Though there is evidence to implicate that the mitochondrion may play an important role in the development of postresuscitation myocardial dysfunction, limited data are available regarding the ultrastructural alterations of the mitochondria, mitochondrial energy-producing ability, and their relationship to postresuscitation myocardial dysfunction. This study was designed to determine whether mitochondrial abnormalities contribute to the development of postresuscitation myocardial dysfunction.

Methods

Fifteen anesthetized male Sprague-Dawley rats were randomized to: (1) global myocardial ischemia/reperfusion, in which 8 min of ventricular fibrillation was induced and successful defibrillation was achieved after 6 min of cardiopulmonary resuscitation (CPR); (2) global myocardial ischemia, in which ventricular fibrillation and CPR were performed without defibrillation attempt; and (3) sham control.

Results

Myocardial function was significantly impaired after resuscitation. Mitochondria were massively swollen in global ischemic hearts and mildly swollen in the resuscitated hearts. Concomitantly, ATP levels abruptly declined during global ischemia and partially recovered after resuscitation. Furthermore, mitochondrial abnormalities were supported by the incapability of utilizing energy substrates manifested by the accumulations of intramyocellular lipid droplets and glycogen deposits.

Conclusions

In this model of cardiac arrest and CPR, the presence of ultrastructural mitochondrial abnormalities, further evidenced by the incapability of utilizing energy substrates and impairment of energy-production, might, in part, contribute to the development of postresuscitation myocardial dysfunction.     

Comparison between dobutamine and levosimendan for management of postresuscitation myocardial dysfunction

OBJECTIVE: 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. DESIGN: Randomized prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Male Yorkshire-cross domestic pigs INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.     

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.     

Optimizing timing of ventricular defibrillation.

OBJECTIVE: Our intent was to evolve a prognosticator that would predict the likelihood that an electrical shock would restore a perfusing rhythm. Such a prognosticator was to be based on conventional electrocardiographic signals but without constraints caused by artifacts resulting from precordial compression. The adverse effects of "hands off" intervals for rhythm analyses would therefore be minimized. Such a prognosticator was further intended to reduce the number of electrical shocks and the total energy delivered and thereby minimize postresuscitation myocardial dysfunction. DESIGN: Observational study. SUBJECTS: Medical research laboratory of a university-affiliated research and educational institute. SUBJECTS: Domestic pigs. INTERVENTIONS: Ventricular fibrillation was induced in an established porcine model of cardiac arrest. Recordings of scalar lead 2 over the frequency range of 4-48 Hz were utilized. The area under the curve representing the amplitude and frequency was defined as the amplitude spectrum area (AMSA). MEASUREMENTS AND MAIN RESULTS: A derivation group of 55 animals yielded a threshold value of AMSA that uniformly predicted successful resuscitation. A separate group of 10 animals, a validation group, confirmed that an AMSA value of 21 mV.Hz predicted restoration of perfusing rhythm after 7 of 8 electrical shocks and failure of electrical conversion in 21 of 23 electrical shocks, yielding sensitivity and specificity of about 90%. The negative predictive value of AMSA was 95% and statistically equivalent to that of coronary perfusion pressure, mean amplitude, and median frequency. The positive predictive value that would prompt continuation of cardiopulmonary resuscitation without interruption for an unsuccessful defibrillation attempt was greatly improved with AMSA (78%) as compared with coronary perfusion pressure (42%), mean amplitude (32%), and median frequency (29%). CONCLUSION: AMSA has the potential for guiding more optimal timing of defibrillation without adverse interruption of cardiopulmonary resuscitation or the delivery of unsuccessful high energy electrical shocks that contribute to postresuscitation myocardial injury.