Comparison of Different Doses of Epinephrine on Myocardial Perfusion and Resuscitation Success During Cardiopulmonary Resuscitation in a Pig Model KARL H. LINDNER, MD, FRIEDRICH W. AHNEFELD, MD, INGRID M. BOWDLER, MD Published results of dose-response effects of adrenergic drugs (eplnephrine [E]) vary so much between studies because of differences in animal models and duration of ischemia before drug administration. In this investlgatlon the effects of different doses of E on coronary perfusion pressure (CPP), left ventricular myecardial blood flow (MBF) and resuscitation success were compared during closed-chest cardiopulmonary resuscitation (CPR) after a 4-minute period of ventricular fibrillation in 28 pigs. M8F was measured during normal sinus rhythm using tracer microspheres. After 4 minutes of ventricular fibriilatlon CPR was performed with the use of a pneumatic piston compressor. After 4 minutes of mechanical measures only, the anlmais were randomly allocated into four groups of seven, receiving 0.015, 0.030, 0.045, and 0.090 mg/kg E intravenously respectively. MBF measurements were started 45 seconds after E administration; hemodynamic measurements after 90 seconds. Four minutes after the first administration, the same E dose was given before defibrillation. The CPP of animals given 0.015, 0.030, 0.045 and 0.090 mg/kg E were as follows: 18.3 + 6.1, 25.6 f 5.8, 33.2 f 8.4 and 30.4 f 6.3 mm Hp. The left ventricular M8F values were: 14 + 9, 27 f 11, 43 f 6, 46 f IO mUmin/lOO g. The differences between the groups receiving 0.015 and 0.045 mu/kg and beiween the gmups receiving 0.015 mg/kg and 0.090 mu/kg were statistlcally significant (P < .05). Resuscitation success was 14.3%, 42.g%, 100% and 88.7% respectively. A significant difference in resuscitation success was found only between 0.015 mg/kg and 0.045 mg/kg E. Our results suggest that after a 4-minute period of arrest and 4 minutes of CPR, CPP, M8F and resuscitation success are Increased when E is given at a dosage of up to 0.045 mglkg; however, the increase to 0.090 mu/kg does not lead to any further improvement. (Am J Emerg Med 1991;9:27-31. Copyright 0 1991 by W.8. Saunders Company)
According to the current recommendation of the American Heart Association, epinephrine in a dosage of 0.015 mg/ kg is the drug of choice during cardiopulmonary resuscitation (CPR) in all forms of cardiac arrest.’ The resulting vasoconstriction via cw-adrenergic stimulation is necessary for the improvement of myocardial and cerebral perfusion and hence resuscitation success.2’3 Our study design for evaluation of different epinephrine doses was orientated on an out-of-hospital cardiac arrest sitFrom the Universitatsklinik fiir Anhthesiologie, Klinikum der Universitlt Ulm, Ulm, Germany. Manuscript received January 22, 1990; revision accepted August 1, 1990. Address reprint requests to Dr Lindner: Universittitsklinik ftir Antisthesiologie, Klinikum der Universitlt, Ulm Steinhdvelstrasse 9 D-7900 Ulm (Donau). Key Words: Cardiopulmonary resuscitation, epinephrine dosage, coronary perfusion pressure, myocardial blood flow. Copyright 0 1991 by W.B. Saunders Company 0735-6757191 I0901 -0007$5.00/O
uation with bystanders starting basic life support at 4 minutes of collapse, and paramedics or physicians applying advanced cardiac life support at 8 minutes. We therefore determined the effect of higher epinephrine doses on coronary perfusion pressure, myocardial blood flow, and resuscitation success after a 4-minute period of ventricular fibrillation followed by a 4-minute period of closed-chest CPR in a pig model. METHODS Animal
Preparation
Anesthesia was induced in 28 pigs weighing between 20 and 24 kg by injecting 10 mg/kg metomidate into an ear vein. The animals were intubated endotracheally during spontaneous respiration, and then placed in a dorsal recumbent position on a specially designed board. Muscular relaxation was carried out with 0.25 mg/kg alcuronium. The animals were subsequently ventilated with a Servo ventilator 900 (Siemens, Germany) using 02/N2 = 35/65%. To maintain anesthesia, a bolus of 0.03 mg/kg buprenorphine was injected followed by a continuous infusion of 0.5 mg/kg/h metomidate using an infusion pump (Braun, Germany). The animals were hemodynamically stable during the preparation phase. Metomidate infusion was stopped at the end of the preparation phase 10 minutes before induction of cardiac arrest. Stable heart rate and blood pressure values during this period of time indicated that the animals were still sufficiently anesthetized. A lead II electrocardiogram (ECG) was monitored. A double-lumen 7F catheter was advanced via femoral cutdown into the descending aorta to monitor blood pressure. Reference blood samples for the measurement of myocardial blood flow were withdrawn from this catheter. A 5F catheter was placed via femoral cutdown into the right atrium (pressure monitoring). A pigtail catheter was placed into the left ventricle for injection of radionuclide microspheres for the measurement of myocardial blood flow. Pressure transducers were aligned at the level of the right atrium, and zero established at atmospheric pressure and calibrated using a mercury sphygmomanometer. Correct placement of the catheters was confirmed at autopsy. All pressures were recorded on a 4-channel recorder (LRS 4, Penless, Linseis, Germany). Experimental
Oesign
During normal sinus rhythm before induction of cardiac arrest, measurements were made of aortic and right atrial 27
AMERICAN
28
JOURNAL OF EMERGENCY
pressures and myocardial blood flow. Ventricular fibrillation was induced by applying an alternating current of 50 Hz and 60 V via two subcutaneously placed needle electrodes for 2.5 seconds. Ventilation was stopped at the same point in time at which the electric shock was applied. After a 4-minute period of circulatory arrest closed-chest CPR with a pneumatically driven chest compressor (Thumper Model 1004, Michigan Instruments, Grand Rapids, MI) and ventilation (Servo Ventilator 900, Siemens, Germany) were begun (Figure 1). The rate of compression was 80 per minute, and the duration of compression was 50% of the cycle time. The chest compression force, 80 to 100 pounds, was selected to produce 25% sternal displacement (expressed as a percentage of anterior-posterior diameter). The Thumper was readjusted as necessary to ensure standardized displacement. The animals’ lungs were ventilated with 100% oxygen at a respiratory rate of 20 per minute independent of chest compression, the tidal volume that, before induction of cardiac arrest, had been shown to result in normal Pace, values. Myocardial blood flow measurements were started 30 seconds after the onset of CPR. Intravascular pressure measurements were made one minute after initiating CPR. Four minutes after beginning closed-chest CPR, 7 pigs received CPR plus either 0.015 mg/kg (group I), 0.030 mglkg (group II), 0.045 mg/kg (group III) or 0.090 mg/kg (group IV) epinephrine diluted to 10 mL with physiological saline via the right atrial line. The animals were randomly assigned to the groups during the period of arrest. Myocardial blood flow measurements were begun 45 seconds after drug administration. Aortic and right atria1 pressure measurements were performed at 90 seconds after epinephrine. The average of six readings during each phase was used for calculations. Coronary perfusion pressure was calculated as the difference between end-diastolic aortic and end-diastolic right atria1 pressure. Four minutes following the first epinephrine dose a repeat injection of the same amount was given. Sixty seconds after drug administration, the animals received external DC shocks of 4 J/kg (Life-Pak 4, Physio-Control, Redmond, WA). When the initial DC shock failed to convert the ventricular fibrillation, the animals received another DC shock of 4 J/kg 30 seconds later. When this second DC shock was also unsuccessful, further DC shocks were administered at 90 second intervals using 8 J/kg. After the sixth DC shock the energy level was increased to 16 J/kg. Ventilation and chest compressions were continued during and between attempts at defibrillation, which was considered successful when ventricular fibrillation was replaced by a sinus rhythm, electromechanical dissociation or asystole. Successful resuscitation was defined at the presence of coordinated elec-
Epinephrine
Epinephrine DC-shocks
Ventricular Fibrillation ~
Clos!?chest
f
MEDICINE
n Volume 9, Number 1 n January 1991
trical activity, a systolic blood pressure over 90 mm Hg and a diastolic blood pressure over 40 mm Hg for the duration of at least 5 minutes, during which no further resuscitative measures were applied. Blood Analysis Immediately before administering the second epinephrine dose during CPR, arterial blood samples were obtained for analysis of blood gases and pH using a blood gas analyser (IL 1302, Instrumentation Laboratories, Lexington, MA) corrected for body temperature. Plasma lactate concentration was measured using a lactate analyzer (Roche, Germany). Myocardial Blood Flow Myocardial blood flow was measured with radionuclide microspheres according to the technique of Heymann et a1.4 Microspheres with a mean diameter of 15 ? 1.5 pm were used. They were labeled to “niobium, ‘03ruthenium and “‘cerium. Before injection, the microsphere vial was placed for one minute in an ultrasonically vibrated water bath. For each myocardial blood flow determination approximately 6.0 x 10’ microspheres diluted to 10 mL with saline were forcibly injected. Blood was continuously withdrawn from the catheter in the descending aorta at a rate of 9.91 mL/min using a calibrated pump (Braun, Germany) from 10 seconds before microsphere injection and continuing for a total of 160 seconds. The amount of blood used as a surrogate organ was replaced with an equal volume of the same animal’s blood. This had been withdrawn (80 mL) after giving a slow intravenous infusion of the same volume of 4.5% dextran 60 at the beginning of the experiment and was anticoagulated with heparin. By this means hematocrit and blood volume were not cumulatively changed during the experiment as a consequence of blood sampling. The radioactivity of the blood collected, which served as reference organ, was measured with a scintillation counter, (Berthold, Germany) as was the radioactivity in the left ventricular free wall. Validation of Microsphere Technique Several sources of error must be considered when using this technique. We have evaluated this method during CPR in a pilot study (6 animals). A residual count of 1.9% (range 0.4% to 6.2%) of the total activity injected was measured in the blood of the left atrium and ventricle at 160 seconds after microsphere injection. This was considered to be good evidence for microsphere ejection from the heart. Adequate microsphere mixing was determined by comparison of right and left cerebral cortex and right and left renal blood flow, which showed no significant difference by Wilcoxon signedrank test during normal sinus rhythm, during CPR before and after 0.090 m&g epinephrine (Table 1). This nonparametric test was used to compare paired blood flows, because the data was not normally distributed. A comparison of total lung flow to cardiac output demonstrates how many microspheres bypassed the peripheral tissues. The mean calculated shunt was 3.4% (range 0.9% to 6.8%) without and 3.7% (range 1.2% to 5.7%) with 0.090 mg/kg epinephrine. Statistical Analysis
4 min
4 min FIGURE
1.
4 min
Experimental study design.
Myocardial blood flow and intravascular pressure data during normal sinus rhythm and CPR before and after epi-
LINDNER, AHNEFELD, AND BOWDLER n DIFFERENT DOSES OF EPINEPHRINE DURING CPR
TABLE1. Validation Datafor MicrosphereMixing
29
mmtig 100
Regional Blood Flow (mL/min/lOO g) L&t
Cerebral cortex (NSR) Cerebral cortex (CPR) Cerebral cortex (CPR + E) Kidney (NSR) Kidney (CPR) Kidney (CPR + E)
44.9 * 10.7 4.2 * 2.5 18.9 ? 190.6 * 13.9 f 8.5 f
P Value
Right
45.0 f 8.5 5.0 f 2.4
9.6 76.9 12.7 7.7
19.5 f 177.5 2 14.5 2 6.8 *
9.5 53.8 12.7 4.5
0.75 0.60 0.35 0.35 0.75 0.92
NOTE.Values are mean f SD. ABBREVIATIONS: NSR, normal sinus rhythm; CPR, cardiopulmonary resuscitation; CPR + E, cardiopulmonary resuscitation and 0.090 mg/kg epinephrine.
RESULTS
Baseline pressures did not differ significantly between the four groups. The mean aortic diastolic pressure during CPR before epinephrine administration ranged from 15.0 to 18.3 mm Hg in the four groups, and coronary perfusion pressure mmtlg 100
T
0.090
0
0.046mglkg
E
-
0.090
E
mg/kg E
mglkg
n” aaulin*
CPR prl0r to
CPR lollowln~ E ldmlnlrtretlon
FIGURE 3. Coronary perfusion pressure during normal sinus rhythm, during CPR before and after administration of the four epinephrine doses. *Statistically significant difference (P < .05) between 0.015 mg/kg epinephrine and 0.045 mgikg epinephrine and between 0.015 mgikg epinephrine and 0.090 mg/kg epinephrine.
was only between 8.6 and 12.4 mm Hg (Figures 2 and 3). Following drug administration, there was a significant increase in aortic diastolic and coronary perfusion pressure in those animals receiving epinephrine at doses of 0.045 mg/kg and 0.090 mg/kg compared with those animals that had been given 0.015 mg/kg. There was no significant difference in aortic diastolic and coronary perfusion pressure between doses of 0.045 mg/kg and 0.090 mg/kg. In the four groups, right atrial diastolic pressure was not significantly different after epinephrine (Figure 4). Lett Ventricular Blood Flow
Aortic and Right Atrial Pressures
h
0.016 mglkg E
m
50
E admln,str.,lon
nephrine administration and arterial blood gas analysis were assessed by analysis of variance. If necessary, a square root transformation was performed on the data before calculation to satisfy the assumption of approximate normality of the sampling distribution. Blood flows and pressures after epinephrine administration were adjusted for baseline differences during CPR using an analysis of covariance. Significant comparisons were then differentiated using multiple comparison testing (Student’s_Newman-Keuls). One-way analyses of variance were performed to compare resuscitation rates for the different epinephrine doses with a correction factor for small numbers. Significant differences were evaluated further with Bonferroni t-testing. A P-value of
According to the current recommendation of the American Heart Association, epinephrine in a dosage of 0.015 mg/ kg is the drug of choice during cardiopulmonary resuscitation (CPR) in all forms of cardiac arrest.’ The resulting vasoconstriction via cw-adrenergic stimulation is necessary for the improvement of myocardial and cerebral perfusion and hence resuscitation success.2’3 Our study design for evaluation of different epinephrine doses was orientated on an out-of-hospital cardiac arrest sitFrom the Universitatsklinik fiir Anhthesiologie, Klinikum der Universitlt Ulm, Ulm, Germany. Manuscript received January 22, 1990; revision accepted August 1, 1990. Address reprint requests to Dr Lindner: Universittitsklinik ftir Antisthesiologie, Klinikum der Universitlt, Ulm Steinhdvelstrasse 9 D-7900 Ulm (Donau). Key Words: Cardiopulmonary resuscitation, epinephrine dosage, coronary perfusion pressure, myocardial blood flow. Copyright 0 1991 by W.B. Saunders Company 0735-6757191 I0901 -0007$5.00/O
uation with bystanders starting basic life support at 4 minutes of collapse, and paramedics or physicians applying advanced cardiac life support at 8 minutes. We therefore determined the effect of higher epinephrine doses on coronary perfusion pressure, myocardial blood flow, and resuscitation success after a 4-minute period of ventricular fibrillation followed by a 4-minute period of closed-chest CPR in a pig model. METHODS Animal
Preparation
Anesthesia was induced in 28 pigs weighing between 20 and 24 kg by injecting 10 mg/kg metomidate into an ear vein. The animals were intubated endotracheally during spontaneous respiration, and then placed in a dorsal recumbent position on a specially designed board. Muscular relaxation was carried out with 0.25 mg/kg alcuronium. The animals were subsequently ventilated with a Servo ventilator 900 (Siemens, Germany) using 02/N2 = 35/65%. To maintain anesthesia, a bolus of 0.03 mg/kg buprenorphine was injected followed by a continuous infusion of 0.5 mg/kg/h metomidate using an infusion pump (Braun, Germany). The animals were hemodynamically stable during the preparation phase. Metomidate infusion was stopped at the end of the preparation phase 10 minutes before induction of cardiac arrest. Stable heart rate and blood pressure values during this period of time indicated that the animals were still sufficiently anesthetized. A lead II electrocardiogram (ECG) was monitored. A double-lumen 7F catheter was advanced via femoral cutdown into the descending aorta to monitor blood pressure. Reference blood samples for the measurement of myocardial blood flow were withdrawn from this catheter. A 5F catheter was placed via femoral cutdown into the right atrium (pressure monitoring). A pigtail catheter was placed into the left ventricle for injection of radionuclide microspheres for the measurement of myocardial blood flow. Pressure transducers were aligned at the level of the right atrium, and zero established at atmospheric pressure and calibrated using a mercury sphygmomanometer. Correct placement of the catheters was confirmed at autopsy. All pressures were recorded on a 4-channel recorder (LRS 4, Penless, Linseis, Germany). Experimental
Oesign
During normal sinus rhythm before induction of cardiac arrest, measurements were made of aortic and right atrial 27
AMERICAN
28
JOURNAL OF EMERGENCY
pressures and myocardial blood flow. Ventricular fibrillation was induced by applying an alternating current of 50 Hz and 60 V via two subcutaneously placed needle electrodes for 2.5 seconds. Ventilation was stopped at the same point in time at which the electric shock was applied. After a 4-minute period of circulatory arrest closed-chest CPR with a pneumatically driven chest compressor (Thumper Model 1004, Michigan Instruments, Grand Rapids, MI) and ventilation (Servo Ventilator 900, Siemens, Germany) were begun (Figure 1). The rate of compression was 80 per minute, and the duration of compression was 50% of the cycle time. The chest compression force, 80 to 100 pounds, was selected to produce 25% sternal displacement (expressed as a percentage of anterior-posterior diameter). The Thumper was readjusted as necessary to ensure standardized displacement. The animals’ lungs were ventilated with 100% oxygen at a respiratory rate of 20 per minute independent of chest compression, the tidal volume that, before induction of cardiac arrest, had been shown to result in normal Pace, values. Myocardial blood flow measurements were started 30 seconds after the onset of CPR. Intravascular pressure measurements were made one minute after initiating CPR. Four minutes after beginning closed-chest CPR, 7 pigs received CPR plus either 0.015 mg/kg (group I), 0.030 mglkg (group II), 0.045 mg/kg (group III) or 0.090 mg/kg (group IV) epinephrine diluted to 10 mL with physiological saline via the right atrial line. The animals were randomly assigned to the groups during the period of arrest. Myocardial blood flow measurements were begun 45 seconds after drug administration. Aortic and right atria1 pressure measurements were performed at 90 seconds after epinephrine. The average of six readings during each phase was used for calculations. Coronary perfusion pressure was calculated as the difference between end-diastolic aortic and end-diastolic right atria1 pressure. Four minutes following the first epinephrine dose a repeat injection of the same amount was given. Sixty seconds after drug administration, the animals received external DC shocks of 4 J/kg (Life-Pak 4, Physio-Control, Redmond, WA). When the initial DC shock failed to convert the ventricular fibrillation, the animals received another DC shock of 4 J/kg 30 seconds later. When this second DC shock was also unsuccessful, further DC shocks were administered at 90 second intervals using 8 J/kg. After the sixth DC shock the energy level was increased to 16 J/kg. Ventilation and chest compressions were continued during and between attempts at defibrillation, which was considered successful when ventricular fibrillation was replaced by a sinus rhythm, electromechanical dissociation or asystole. Successful resuscitation was defined at the presence of coordinated elec-
Epinephrine
Epinephrine DC-shocks
Ventricular Fibrillation ~
Clos!?chest
f
MEDICINE
n Volume 9, Number 1 n January 1991
trical activity, a systolic blood pressure over 90 mm Hg and a diastolic blood pressure over 40 mm Hg for the duration of at least 5 minutes, during which no further resuscitative measures were applied. Blood Analysis Immediately before administering the second epinephrine dose during CPR, arterial blood samples were obtained for analysis of blood gases and pH using a blood gas analyser (IL 1302, Instrumentation Laboratories, Lexington, MA) corrected for body temperature. Plasma lactate concentration was measured using a lactate analyzer (Roche, Germany). Myocardial Blood Flow Myocardial blood flow was measured with radionuclide microspheres according to the technique of Heymann et a1.4 Microspheres with a mean diameter of 15 ? 1.5 pm were used. They were labeled to “niobium, ‘03ruthenium and “‘cerium. Before injection, the microsphere vial was placed for one minute in an ultrasonically vibrated water bath. For each myocardial blood flow determination approximately 6.0 x 10’ microspheres diluted to 10 mL with saline were forcibly injected. Blood was continuously withdrawn from the catheter in the descending aorta at a rate of 9.91 mL/min using a calibrated pump (Braun, Germany) from 10 seconds before microsphere injection and continuing for a total of 160 seconds. The amount of blood used as a surrogate organ was replaced with an equal volume of the same animal’s blood. This had been withdrawn (80 mL) after giving a slow intravenous infusion of the same volume of 4.5% dextran 60 at the beginning of the experiment and was anticoagulated with heparin. By this means hematocrit and blood volume were not cumulatively changed during the experiment as a consequence of blood sampling. The radioactivity of the blood collected, which served as reference organ, was measured with a scintillation counter, (Berthold, Germany) as was the radioactivity in the left ventricular free wall. Validation of Microsphere Technique Several sources of error must be considered when using this technique. We have evaluated this method during CPR in a pilot study (6 animals). A residual count of 1.9% (range 0.4% to 6.2%) of the total activity injected was measured in the blood of the left atrium and ventricle at 160 seconds after microsphere injection. This was considered to be good evidence for microsphere ejection from the heart. Adequate microsphere mixing was determined by comparison of right and left cerebral cortex and right and left renal blood flow, which showed no significant difference by Wilcoxon signedrank test during normal sinus rhythm, during CPR before and after 0.090 m&g epinephrine (Table 1). This nonparametric test was used to compare paired blood flows, because the data was not normally distributed. A comparison of total lung flow to cardiac output demonstrates how many microspheres bypassed the peripheral tissues. The mean calculated shunt was 3.4% (range 0.9% to 6.8%) without and 3.7% (range 1.2% to 5.7%) with 0.090 mg/kg epinephrine. Statistical Analysis
4 min
4 min FIGURE
1.
4 min
Experimental study design.
Myocardial blood flow and intravascular pressure data during normal sinus rhythm and CPR before and after epi-
LINDNER, AHNEFELD, AND BOWDLER n DIFFERENT DOSES OF EPINEPHRINE DURING CPR
TABLE1. Validation Datafor MicrosphereMixing
29
mmtig 100
Regional Blood Flow (mL/min/lOO g) L&t
Cerebral cortex (NSR) Cerebral cortex (CPR) Cerebral cortex (CPR + E) Kidney (NSR) Kidney (CPR) Kidney (CPR + E)
44.9 * 10.7 4.2 * 2.5 18.9 ? 190.6 * 13.9 f 8.5 f
P Value
Right
45.0 f 8.5 5.0 f 2.4
9.6 76.9 12.7 7.7
19.5 f 177.5 2 14.5 2 6.8 *
9.5 53.8 12.7 4.5
0.75 0.60 0.35 0.35 0.75 0.92
NOTE.Values are mean f SD. ABBREVIATIONS: NSR, normal sinus rhythm; CPR, cardiopulmonary resuscitation; CPR + E, cardiopulmonary resuscitation and 0.090 mg/kg epinephrine.
RESULTS
Baseline pressures did not differ significantly between the four groups. The mean aortic diastolic pressure during CPR before epinephrine administration ranged from 15.0 to 18.3 mm Hg in the four groups, and coronary perfusion pressure mmtlg 100
T
0.090
0
0.046mglkg
E
-
0.090
E
mg/kg E
mglkg
n” aaulin*
CPR prl0r to
CPR lollowln~ E ldmlnlrtretlon
FIGURE 3. Coronary perfusion pressure during normal sinus rhythm, during CPR before and after administration of the four epinephrine doses. *Statistically significant difference (P < .05) between 0.015 mg/kg epinephrine and 0.045 mgikg epinephrine and between 0.015 mgikg epinephrine and 0.090 mg/kg epinephrine.
was only between 8.6 and 12.4 mm Hg (Figures 2 and 3). Following drug administration, there was a significant increase in aortic diastolic and coronary perfusion pressure in those animals receiving epinephrine at doses of 0.045 mg/kg and 0.090 mg/kg compared with those animals that had been given 0.015 mg/kg. There was no significant difference in aortic diastolic and coronary perfusion pressure between doses of 0.045 mg/kg and 0.090 mg/kg. In the four groups, right atrial diastolic pressure was not significantly different after epinephrine (Figure 4). Lett Ventricular Blood Flow
Aortic and Right Atrial Pressures
h
0.016 mglkg E
m
50
E admln,str.,lon
nephrine administration and arterial blood gas analysis were assessed by analysis of variance. If necessary, a square root transformation was performed on the data before calculation to satisfy the assumption of approximate normality of the sampling distribution. Blood flows and pressures after epinephrine administration were adjusted for baseline differences during CPR using an analysis of covariance. Significant comparisons were then differentiated using multiple comparison testing (Student’s_Newman-Keuls). One-way analyses of variance were performed to compare resuscitation rates for the different epinephrine doses with a correction factor for small numbers. Significant differences were evaluated further with Bonferroni t-testing. A P-value of
