High-dose Epinephrine Research Articles

Staged High Dose Epinephrine Clysis in Pediatric Burn Excision

Staged High Dose Epinephrine Clysis in Pediatric Burn Excision

Antiemetic Inhibits Conditioned Taste Aversion, But Not the Hypophagia Induced by Epinephrine

It has been shown that relatively high doses of epinephrine (E) injected intraperitoneally (IP) produce hypophagia and conditioned taste aversion (CTA) in rats. We examined the possibility that E effects involve malaise. For this purpose, changes in saccharin preference induced by E injected IP (100 μg/kg) were determined after a previous administration of trimethobenzamide (TMB, 5 mg/kg), an antiemetic agent. E alone decreased saccharin preference by 54% ( p < 0.01), but only by 16% (not significant) in the presence of TMB. In contrast, the injection of 75 or 100 μg/kg E reduced food intake by 50 and 85%, respectively ( p < 0.01), regardless of previous injection of TMB. In conclusion, the results suggest that E-induced malaise is not the direct cause of the hypophagia it elicits.

Epinephrine enhances glycogen turnover and depresses glucose uptake in vivo in rat heart.

In vivo effects of epinephrine on glucose uptake and glycogen turnover in rat heart were studied and compared to liver and skeletal muscle. Fasted ketamine-anesthetized rats were intravenously infused with saline or epinephrine. Both the low and high doses of epinephrine resulted in hyperglycemia (40-50%) and hyperlactemia (threefold) at the end of infusion. Glucose uptake, determined by the phosphorylation of the intravenously injected [14C]2-deoxyglucose, was found to decrease in the heart and skeletal muscle of epinephrine-infused rats. Glycogen in livers, skeletal muscles, and hearts of the epinephrine-infused rats decreased to varying degrees relative to the saline-infused rats, indicating enhanced glycogenolysis in all three organs. Glycogen synthesis, determined by the incorporation of the co-infused [3-(3)H]glucose into glycogen, was found to decrease in liver and skeletal muscle. However, glycogen synthesis in the heart was found to increase 50% in Epi-1 and 280% in Epi-2 compared to the saline-infused rats. We conclude that glucose utilization in the in vivo heart may be preferentially channeled through glycogen turnover in the presence of epinephrine. That both synthesis and degradation of glycogen can be simultaneously activated appears to be unique to the heart and is protective against a loss of glycogen at a time of enhanced glucose utilization.

Acute lethal toxicity following passive immunization for treatment of murine cryptococcosis

Passive immunization with monoclonal antibodies (MAbs) specific for the major capsular polysaccharide of Cryptococcus neoformans alters the course of murine cryptococcosis. During studies of passive immunization for treatment of murine cryptococcosis, we noted the occurrence of an acute, lethal toxicity. Toxicity was characterized by scratching, lethargy, respiratory distress, collapse, and death within 20 to 60 min after injection of antibody. The toxic effect was observed only in mice with a cryptococcal infection and was reduced or absent in the early and late stages of disease. The clinical course and histopathology were consistent with those for shock. There was considerable variation between mouse strains in susceptibility to toxicity. Swiss Webster mice from the Charles River colony were most susceptible, followed by C3H/He, BALB/c, and C57BL/6 mice. DBA/2 mice and Swiss Webster mice from the Simonsen colony were resistant. Acute toxicity was mimicked by injection of preformed complexes of MAb and purified polysaccharide. The toxic effect was also produced by injection of MAbs into mice that were preloaded with polysaccharide. The toxic effect was not blocked by treatment of mice with chloropheniramine or anti-tumor necrosis factor alpha antibodies or by depletion of complement components via pretreatment with cobra venom factor. Toxicity was reduced by treatment of mice with high doses of epinephrine, dexamethasone, or chlorpromazine. Finally, the toxic effect was completely blocked by treatment of mice with the platelet-activating factor antagonist WEB 2170 BS or by pretreatment of mice with the liposome-encapsulated drug dichloromethylene diphosphonate, a procedure which depletes macrophages from the spleen and liver.

High-dose epinephrine: no added benefit in paediatric cardiac arrest

High-dose epinephrine: no added benefit in paediatric cardiac arrest

PHARMACOLOGY OF PEDIATRIC RESUSCITATION

The resuscitation of children from cardiac arrest and shock remains a challenging goal. The pharmacologic principles underlying current recommendations for intervention in pediatric cardiac arrest have been reviewed. Current research efforts, points of controversy, and accepted practices that may not be most efficacious have been described. Epinephrine remains the most effective resuscitation adjunct. High-dose epinephrine is tolerated better in children than in adults, but its efficacy has not received full analysis. The preponderance of data continues to point toward the ineffectiveness and possible deleterious effects of overzealous sodium bicarbonate use. Calcium chloride is useful in the treatment of ionized hypocalcemia but may harm cells that have experienced asphyxial damage. Atropine is an effective agent for alleviating bradycardia induced by increased vagal tone, but because most bradycardia in children is caused by hypoxia, improved oxygenation is the intervention of choice. Adenosine is an effective and generally well-tolerated agent for the treatment of supraventricular tachycardia. Lidocaine is the drug of choice for ventricular dysrhythmias, and bretylium, still relatively unexplored, is in reserve. Many pediatricians use dopamine for shock in the postresuscitative period, but epinephrine is superior. Most animal research on cardiac arrest is based on models with ventricular fibrillation that probably are not reflective of cardiac arrest situations most often seen in pediatrics.

Glucoprivation Attenuates the Hypophagia Induced by Epinephrine in Mice

It is well known that relatively high doses of epinephrine (E) injected intraperitoneally (IP) produce hypophagia, possibly by an action on liver metabolism. The purpose of the present experiment was to find out if lipoprivation with 2-mercaptoacetate (MA, 800 μmol/kg, IP) or glucoprivation with either 2-deoxy-D-glucose (2DG, 500 mg/kg, IP) or 2,5-anhydro-D-mannitol (2,5-AM, 400 mg/kg, IP) were able to modify the anorectic effect of E (300 μg/kg). At the onset of the dark period, mice received a first injection of saline (S) or one of the metabolic blockers mentioned above and, 30 min later, a second injection of S or E; then 30-min food intake was measured. E alone decreased feeding by 80% (p < 0.05); this effect was nearly the same when MA was previously injected. In contrast, in the presence of 2DG or 2,5-AM, E reduced food intake only by 22% and 24%, respectively (not significant). Attenuation of E-induced hypophagia by these blockers suggests the participation of glucose utilization pathways. Because it has been shown that 2,5-AM acts specifically on the liver, we could additionally suggest that E reduces feeding by an action on glucose hepatic metabolism.

Utstein-style guidelines for uniform reporting of laboratory CPR research.: A Statement for Healthcare Professionals from a Task Force of the American Heart Association, the American College of Emergency Physicians, the American College of Cardiology, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Institute of Critical Care Medicine, the Safar Center for Resuscitation Research, and the Society

Both laboratory and clinical investigators contribute to the multidisciplinary knowledge base of resuscitation science. While diversity can be a strength, it can also be a hindrance because of the lack of a common language and poor communication among investigators. Modern cardiopulmonary resuscitation (CPR) research depends on the use of animal models that are designed to simulate cardiac arrest in humans.1 2 Such models are used to explore important new treatments and to refine protocols used in standard interventions, including doses of drugs, chest compression techniques, defibrillation energies, and cerebral resuscitation, before they are applied to humans.3 When favorable results are reported in animal models, the new or refined techniques are often implemented soon afterward in human victims of cardiac arrest. Unfortunately, the results obtained in one laboratory may not be reproducible in another laboratory or in human trials. For example, high-dose epinephrine therapy significantly improves survival in most animal models of cardiac arrest but does not improve survival in humans.4 5 6 7 In addition, some animal studies have documented the efficacy of administering bicarbonate during cardiac arrest, while others have shown it to be ineffective or deleterious.8 Some of these differences are to be expected because an animal simulation is not a perfect model of cardiac arrest in humans. However, it is likely that some of these conflicting results are due to differences in experimental methods and laboratory model design. Variations in study design, such as the quality of chest compressions and ventilation, definitions of variables, or time intervals between an event and the beginning of therapy, are probably responsible for many of the inconsistencies and contradictions reported. The lack of standardization and the use of nonuniform terminology in reports of studies of cardiac arrest in humans have been described as a “Tower of Babel.” …

Utstein-Style Guidelines for Uniform Reporting of Laboratory CPR Research: A Statement for Health Care Professionals From a Task Force of the American Heart Association, the American College of Emergency Physicians, the American College of Cardiology, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Institute of Critical Care Medicine, the Safar Center for Resuscitation Research, and the

Utstein-Style Guidelines for Uniform Reporting of Laboratory CPR Research: A Statement for Health Care Professionals From a Task Force of the American Heart Association, the American College of Emergency Physicians, the American College of Cardiology, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Institute of Critical Care Medicine, the Safar Center for Resuscitation Research, and the

Adrenaline, cardiac arrest, and evidence based medicine.

In this article we review the evidence supporting the clinical application of adrenaline in cardiopulmonary arrest, and summarize the receptor effects of catecholamines and the basic principles producing perfusion during CPR. Animal and human studies show that in cardiac arrest, adrenaline has positive haemodynamic effects, increasing systemic pressures, myocardial perfusion, and cerebrally directed flow. The problems extrapolating from animal to human data are highlighted. Studies showing improvements in short term survival outcomes with high dose regimens have not been confirmed by other large prospective randomised trials. There is no evidence that high doses of adrenaline improve survival to hospital discharge. Most studies comparing adrenaline with placebo have been non-randomised and uncontrolled, with major methodological problems. Conclusions are difficult, but if anything adrenaline is associated with poorer outcomes.

Combined use of amrinone and high-dose epinephrine for postoperative low output syndrome (LOS) in pediatric patients

Low output syndrome (LOS) is one of the serious consequences following open-heart surgery, and high-dose catecholamines and/or mechanical assist devices are required to support failed myocardial function. As one of the pharmacological options to counteract this complication, epinephrine remains the most potent drug to treat LOS, especially in pediatric cases. Since the inotropic effect of epinephrine is dose-dependent, highdose epinephrine is sometimes necessary in patients with severe pump failure. However, the administration of high-dose epinephrine can interfere with peripheral circulation because of its strong vasoconstricting effects, resulting in severe acidosis and oliguria. Amrinone has become available as an inotrope and vasodilator with a suggested main mechanism of selective phosphodiesterase III inhibition. Its unique properties include inotropic support combined with pulmonary and systemic vasodilation [1], and this effect is maintained in the presence of exogenous catecholamines including dopamine (DOA), epinephrine and norepinephrine (NE) [2-4]. Therefore, the benefit of using amrinone and other inotropes in combination is the vasodilating action of amrinone to counteract the vasoconstricting effects of the strong inotropes, in addition to its inotropic support. We report on two pediatric patients who successfully recovered from life-threatening heart failure by the combined use of high-dose epinephrine and amrinone.

Epinephrine and high-flow reperfusion after cardiac arrest in a canine model: Ann Emerg Med 1995; 26/2: 208–215

Abstract Study objectives: Epinephrine has been used in cardiac arrest to increase the low blood flow generated by standard CPR methods. Reperfusion with high flow such as that obtained with cardiopulmonary bypass (CPB) may obviate the need for or alter the dose of epinephrine after cardiac arrest. The objective of this study was to evaluate the effect of high-flow reperfusion after cardiac arrest with and without epinephrine on coronary perfusion pressure, defibrillation energy, restoration of spontaneous circulation (ROSC), and 2-hour survival after prolonged cardiac arrest. Design: Prospective, randomized, double-blind, placebo-controlled study using a canine model. Interventions: Thirty mongrel dogs were randomized to receive, after ventricular fibrillation cardiac arrest of 12 minutes' duration without CPR, placebo (n=10), standard-dose epinephrine (.02 mg/kg) (n=10), or high-dose epinephrine (.2 mg/kg) (n=10) during reperfusion with CPB. Epinephrine or placebo was given with the start of CPB and then every 5 minutes, followed by countershock until ROSC or crossover at the fourth dose to high-dose epinephrine. Results: ROSC was achieved in the first 15 minutes of bypass in 10 of 10 dogs given high-dose epinephrine, in 9 of 10 given standard-dose epinephrine, and in 1 of 10 given placebo. After the crossover to high-dose epinephrine, ROSC was achieved in 8 of 10 dogs originally given placebo and the remaining animal given the standard dose of epinephrine. During early reperfusion, the high-dose group had a higher mean coronary perfusion pressure (high dose, 153+62 mm Hg; standard dose, 81±18 mm Hg; placebo, 51±15 mm Hg; P P Conclusion: Restoration of high blood flow alone is insufficient to restore spontaneous circulation after prolonged cardiac arrest. Epinephrine, when administered early under high-flow conditions, increases coronary perfusion pressure, decreases defibrillation energy, and decreases time elapsed before ROSC. Higher doses of epinephrine under conditions of high-flow reperfusion do not improve 2-hour survival compared with standard-dose epinephrine. [Angelos MG, DeBehnke DJ: Epinephrine and high-flow reperfusion after cardiac arrest in a canine model. Ann Emerg Med August 1995;26:208-215.]

Combined use of amrinone and high-dose epinephrine for postoperative low output syndrome (LOS) in pediatric patients

Combined use of amrinone and high-dose epinephrine for postoperative low output syndrome (LOS) in pediatric patients

Resuscitation from cardiac arrest in cats: influence of epinephrine dosage on brain recovery

The quality of brain recovery after cardiac arrest depends crucially on the speed of cardiac resuscitation because the low cerebral perfusion pressure during the resuscitation procedure facilitates the development of no-reflow. To accelerate return of spontaneous circulation, high dose epinephrine has been recommended but the effect on the dynamics of early brain recovery is still unknown. We, therefore, studied the dynamics of brain resuscitation after cardiopulmonary resuscitation (CPR) with standard and high dose epinephrine using non-invasive NMR techniques. Fifteen min cardiac arrest was induced in normothermic cats by ventricular fibrillation. CPR was performed using an inflatable pneumatic vest for cyclic chest compression. With the beginning of CPR the standard dose group received 0.02 mg/kg epinephrine ( n = 6) and the high dose group received 0.2 mg/kg ( n = 8). Brain recovery was monitored by magnetic resonance imaging of the apparent diffusion coefficient (ADC) of water for 3 h. Although high dose epinephrine treatment led to a significantly higher blood pressure during early reperfusion, rapidly changing heterogeneities of early brain recovery were observed in both groups. High dose epinephrine thus does not improve the quality of post-cardiac arrest brain recovery during the first 3 h of reperfusion.

Epinephrine and High-Flow Reperfusion After Cardiac Arrest in a Canine Model

Study objectives: Epinephrine has been used in cardiac arrest to increase the low blood flow generated by standard CPR methods. Reperfusion with high flow such as that obtained with cardiopulmonary bypass (CPB) may obviate the need for or alter the dose of epinephrine after cardiac arrest. The objective of this study was to evaluate the effect of high-flow reperfusion after cardiac arrest with and without epinephrine on coronary perfusion pressure, defibrillation energy, restoration of spontaneous circulation (ROSC), and 2-hour survival after prolonged cardiac arrest. Design: Prospective, randomized, double-blind, placebo-controlled study using a canine model. Interventions: Thirty mongrel dogs were randomized to receive, after ventricular fibrillation cardiac arrest of 12 minutes' duration without CPR, placebo (n=10), standard-dose epinephrine (.02 mg/kg) (n=10), or high-dose epinephrine (.2 mg/kg) (n=10) during reperfusion with CPB. Epinephrine or placebo was given with the start of CPB and then every 5 minutes, followed by countershock until ROSC or crossover at the fourth dose to high-dose epinephrine. Results: ROSC was achieved in the first 15 minutes of bypass in 10 of 10 dogs given high-dose epinephrine, in 9 of 10 given standard-dose epinephrine, and in 1 of 10 given placebo. After the crossover to high-dose epinephrine, ROSC was achieved in 8 of 10 dogs originally given placebo and the remaining animal given the standard dose of epinephrine. During early reperfusion, the high-dose group had a higher mean coronary perfusion pressure (high dose, 153+62 mm Hg; standard dose, 81±18 mm Hg; placebo, 51±15 mm Hg; P<.002) and a shorter mean ROSC time (high dose, 16.2±.8 minutes; standard dose, 20.3±3.6 minutes; placebo, 27.9±3.2; P<.02) and required less defibrillation energy. CPB flow during ventricular fibrillation was 63% of baseline cardiac output in all three groups. Two-hour survival was 5 of 10 in the high-dose group, 8 of 10 in the standard-dose group, and 5 of 10 in the placebo group. Conclusion: Restoration of high blood flow alone is insufficient to restore spontaneous circulation after prolonged cardiac arrest. Epinephrine, when administered early under high-flow conditions, increases coronary perfusion pressure, decreases defibrillation energy, and decreases time elapsed before ROSC. Higher doses of epinephrine under conditions of high-flow reperfusion do not improve 2-hour survival compared with standard-dose epinephrine. [Angelos MG, DeBehnke DJ: Epinephrine and high-flow reperfusion after cardiac arrest in a canine model. Ann Emerg Med August 1995;26:208-215.]

Regulation of outflow rate and resistance in the perfused anterior segment of the bovine eye

Contractile properties of isolated trabecular meshwork strips have recently been described. In the present paper we characterize the regulation of the outflow pathway in the isolated perfused anterior segment of the bovine eye. Anterior segments of bovine eyes with detached iris, ciliary body and ciliary muscle were perfused at constant pressure of 8.8 mmHg. A constant outflow of approximately 6-8 microliters min-1 could be obtained for at least 3 hr. The calculated outflow resistance was in the range 1.1-1.4 mmHg min microliter-1. The relative outflow was significantly reduced after application of carbachol, reaching a maximal inhibition of 30%. EC50 for carbachol was 3 x 10(-8) mol l-1. Atropin completely blocked the effect of carbachol on outflow. Morphological examination of perfused anterior segments which were perfused with carbachol revealed an intact fine structure of the meshwork cells. Pilocarpine at 10(-5) mol l-1 reduced outflow by 15%. Epinephrine at 10(-5) mol l-1 reduced outflow, while epinephrine at 10(-6) mol l-1 slightly increased the outflow rate. This effect could be blocked by metipranolol. Endothelin-1 in concentrations of 2 x 10(-9) and 2 x 10(-8) mol l-1 inhibited relative outflow by > 30%. Carbachol, pilocarpine, endothelin and a high dose of epinephrine, which have been shown to induce contractions in isolated bovine trabecular meshwork and ciliary muscle strips, induced a reduction of outflow rate and an increase of outflow resistance of the anterior segment. Thus, at least in the bovine eye, the trabecular meshwork per se is directly involved in the regulation of aqueous humor outflow.

High-Dose Epinephrine in Pediatric Out-of-Hospital Cardiopulmonary Arrest

To compare the efficacy of high-dose epinephrine (HDE) and standard-dose epinephrine (SDE) for out-of-hospital treatment of pediatric cardiopulmonary arrest (CPA). Forty-eight-month retrospective cohort study. Prehospital emergency medical services (EMS) system of a large metropolitan region. All children younger than 18 years of age, who suffered nontraumatic CPA, did not meet local EMS criteria for death in the field, and were treated by paramedics according to EMS pediatric CPA protocols. Paramedics administered HDE (> 0.1 mg/kg), SDE (< 0.1 mg/kg), or no epinephrine (NE), based on base hospital physician order and availability of access for drug delivery. Protocols permitted either HDE or SDE. The drug was given through an endotracheal tube, intraosseous line, or intravenous line. Return of spontaneous circulation (ROSC) and return of an organized electrical rhythm (ROER) in the ambulance and emergency department, hospital admission, hospital discharge, and short- and long-term neurologic outcome by pediatric cerebral performance category (PCPC) score. During the study period, 65 children met inclusion criteria and underwent attempted out-of-hospital resuscitation. Forty patients (62%) received HDE (mean dose +/- SD, 0.19 +/- 0.06 mg/kg); 13 patients (20%) received SDE (mean dose +/- SD, 0.02 +/- 0.02 mg/kg); and 12 patients (18%) received NE. The HDE and SDE groups were statistically different only in epinephrine dose but not in age, gender, proportion of asystolic presenting rhythms, success of endotracheal tube intubation or intraosseous line insertion, rate of ROSC, rate of ROER, survival, or proportion of sudden infant death syndrome final diagnoses. Fifty-four children (83%) presented in asystole, 5 (8%) had pulseless electrical activity (PEA), and 6 (9%) had ventricular fibrillation (VF). None presented with either supraventricular tachycardia or ventricular tachycardia. Thirty-nine patients receiving HDE had asystole or VF as presenting rhythms, 4 (10%) had ROER, and 1 had ROSC. The single child receiving HDE presenting with PEA did not have ROSC. Ten patients receiving SDE had asystole or VF, 2 (20%) had ROER, and none had ROSC. There were 3 children receiving SDE who had PEA, and 1 had ROSC. Eleven patients receiving NE had asystole or VF, and none had ROER. One child receiving NE had PEA and ROSC. Altogether, 1 patient receiving HDE, 1 receiving SDE, and 1 receiving NE had ROSC in the field, which continued in the emergency department; all 3 were admitted to the hospital. Two children (3%), 1 receiving HDE and 1 receiving SDE, survived to hospital discharge. The survivor receiving HDE had spastic quadriplegia and profound neurologic handicaps at discharge, with a PCPC score of 4 (severe disability with daily living milestones below the 10th percentile and excessive dependence on others for provision of activities of daily living); at a 1-year follow-up, she had a PCPC score of 4. The survivor receiving SDE was neurologically healthy at discharge; at discharge and at follow-up at age 1 year, she had a PCPC score of 1 (age-appropriate level of functioning and developmentally appropriate). HDE does not seem to improve the rates of ROER and ROSC, hospital admission, survival, or neurologic outcome when compared with SDE for treatment of out-of-hospital pediatric CPA. A large, blinded prospective clinical trial testing different epinephrine doses is necessary to determine drug efficacy and safety. Future pediatric CPA studies must standardize reporting of core data elements, using the adult Utstein criteria modified for pediatrics, to allow valid treatment comparisons. Overall, survival in out-of-hospital pediatric CPA is dismal.(ABSTRACT TRUNCATED)

Reversal of vagal tone in conjunction with high-dose epinephrine in a canine asphyxial pulseless electrical activity model: Crit. Care Med. 1994; 22/12: 1981–1986

OBJECTIVE To investigate the effects of surgical vagotomy in conjunction with high-dose epinephrine (0.2 mg/kg) on return of spontaneous circulation rates in a canine model of asphyxial pulseless electrical activity. DESIGN Prospective, controlled laboratory investigation, using an asphyxial canine cardiac arrest model randomized to receive bilateral cervical vagotomy or no vagotomy. SETTING Emergency medicine animal research laboratory. SUBJECTS Sixteen mongrel dogs weighing 15 to 25 kg. INTERVENTIONS Pulseless electrical activity arrest was induced by clamping the endotracheal tube. All animals remained in untreated pulseless electrical activity for 10 mins and then were randomized to receive bilateral cervical vagotomy (n = 8) or no vagotomy (n = 8). All animals received standard external cardiopulmonary resuscitation and high-dose epinephrine (0.2 mg/kg every 5 mins) throughout resuscitation. MEASUREMENTS AND MAIN RESULTS The electrocardiogram complex rate, arterial blood gases, and coronary perfusion pressure during resuscitation were not statistically different between groups. Return of spontaneous circulation was achieved in 88% (7/8) of the no vagotomy vs. 63% (5/8) of the vagotomy animals (p = NS). All animals that achieved return of spontaneous circulation survived 1 hr. CONCLUSIONS In conjunction with high-dose epinephrine, vagotomy did not improve the return of spontaneous circulation rate in this pulseless electrical activity arrest model. Additionally, the hemodynamic effects of high-dose epinephrine overshadowed the effects of vagotomy.

Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats

Although high-dose epinephrine during CPR improves coronary perfusion pressure (CoPP) and rate of return of spontaneous circulation (ROSC) in some models, its impact on long term outcome (≥ 72 h) has not been evaluated. Previous studies of sodium bicarbonate (NaHCO 3) therapy during CPR indicate that beneficial effects may be dependent on epinephrine (EPI) dose. We hypothesized that EPI and NaHCO 3 given during CPR have a significant impact on long term outcome. One hundred male Sprague-Dawley rats were prospectively studied in a block randomized placebo controlled trial. Rats were anesthetized, paralyzed, mechanically ventilated, instrumented, and each underwent 10 min of asphyxia, resulting in 6.8 ± 0.4 min of circulatory arrest. Resuscitation was performed by mechanical ventilation and manual external chest compressions. EPI 0.0 (placebo), 0.01, 0.1, or 1.0 mg/kg IV was given at the onset of CPR, followed by NaHCO 3 0.0 (placebo) or 1.0 mEq/kg IV. Successfully resuscitated rats were monitored and ventilated for l h without hemodynamic support. Neurologic deficit scores (NDS), cerebral histopathologic damage scores (CHDS) and myocardial histopathologic damage scores (MHDS) were determined in rats that survived 72 h, EPI improved CoPP and ROSC in a dose-dependent manner up to 0.1 mg/kg. Rats receiving EPI 0.1 and 1.0 mg/kg during CPR exhibited prolonged post-ROSC hypertension and metabolic acidemia, increased A-a O 2 gradient, and an increased incidence of post-ROSC ventricular tachycardia or fibrillation. Overall survival was lower with EPI 0.1 and 1.0 mg/kg compared to 0.01 mg/kg. Although NDS was significantly less with EPI 0.1 mg/kg compared to placebo, there was no difference in CHDS between groups. In contrast, MDS was significantly higher with EPI 0.1 mg/kg compared to placebo or EPI 0.01 mg/kg. There was an overall trend toward improved survival at 72 h in rats that received NaHCO 3 which was most evident in the EPI 0.1 mg/kg group. We conclude that (1) EPI during CPR has a biphasic dose/response curve in terms of survival, when post-resuscitation effects are left untreated and (2) NaHCO 3 doses greater than 1.0 mEq/kg may be necessary to treat the side-effects of high-dose EPI. Further work is needed to determine if treating the immediate post-resuscitation effects of high-dose EPI can prevent detrimental effects on long-term outcome.

Epinephrine-mediated changes in carbon dioxide tension during reperfusion of ventricular fibrillation in a canine model

Previous studies suggest that epinephrine may alter the correlation of perfusion with measures of PCO2 during cardiopulmonary resuscitation. This study investigated the effects of epinephrine on PaCO2 and mixed venous PCO2 in a high-flow reperfusion model of cardiac arrest. Prospective, block randomized, blinded, placebo-controlled, laboratory study. Thirty mixed breed canines. After a 12-min ventricular fibrillation cardiac arrest, 30 mixed breed canines were reperfused with standardized (3200 revolutions/min) cardiopulmonary bypass and were given placebo (n = 10), standard dose epinephrine (0.02 mg/kg; n = 10), or high-dose epinephrine (0.2 mg/kg; n = 10). Arterial and mixed venous blood gases, coronary perfusion pressure, pump flow and peripheral vascular resistance were compared between groups during the early reperfusion period using analysis of variance with a post hoc Tukey's multiple comparison test. Baseline variables were similar between groups. With reperfusion, the high-dose epinephrine group had higher coronary perfusion pressures (p < .002), lower systemic pump flow (p < .01), and higher peripheral vascular resistance (p < .001). In the high-dose epinephrine group, both PaCO2 (high-dose epinephrine, 40 +/- 6 torr [5.3 +/- 0.8 kPa]; standard dose epinephrine, 45 +/- 7 torr [6.0 +/- 0.9 kPa]; placebo, 54 +/- 4 torr [7.2 +/- 0.5 kPa]; p < .01) and mixed venous PCO2 (high-dose epinephrine, 55 +/- 10 torr [7.3 +/- 1.3 kPa]; standard dose epinephrine, 57 +/- 9 torr [7.6 +/- 1.2 kPa]; placebo, 67 +/- 4 torr [8.9 +/- 0.5 kPa]; p < .05) were significantly decreased, and arterial pH, PaO2, and mixed venous PO2 were significantly increased compared with the placebo group. In this model, when ventilation and CO2 production are constant, the decrease in PaCO2 with epinephrine is due to decreased pulmonary blood flow (flow to membrane oxygenator) and peripheral shunting.