Feature Articles
Comparison of epinephrine and vasopressin in a pediatric porcine model of asphyxial cardiac arrest Wolfgang G. Voelckel, MD; Keith G. Lurie, MD; Scott McKnite, BS; Todd Zielinski, MS; Paul Lindstrom, BS; Colleen Peterson, RN; Anette C. Krismer, MD; Karl H. Lindner, MD; Volker Wenzel, MD
Objective: This study was designed to compare the effects of vasopressin vs. epinephrine vs. the combination of epinephrine with vasopressin on vital organ blood flow and return of spontaneous circulation in a pediatric porcine model of asphyxial arrest. Design: Prospective, randomized laboratory investigation using an established porcine model for measurement of hemodynamic variables, organ blood flow, blood gases, and return of spontaneous circulation. Setting: University hospital laboratory. Subjects: Eighteen piglets weighing 8 –11 kg. Interventions: Asphyxial cardiac arrest was induced by clamping the endotracheal tube. After 8 mins of cardiac arrest and 8 mins of cardiopulmonary resuscitation, a bolus dose of either 0.8 units/kg vasopressin (n ⴝ 6), 200 g/kg epinephrine (n ⴝ 6), or a combination of 45 g/kg epinephrine with 0.8 units/kg vasopressin (n ⴝ 6) was administered in a randomized manner. Defibrillation was attempted 6 mins after drug administration. Measurements and Main Results: Mean ⴞ SEM coronary perfusion pressure, before and 2 mins after drug administration, was 13 ⴞ 2 and 23 ⴞ 6 mm Hg in the vasopressin group; 14 ⴞ 2 and 31 ⴞ 4 mm Hg in the epinephrine group; and 13 ⴞ 1 and 33 ⴞ 6 mm Hg in the epinephrine-vasopressin group, respectively (p ⴝ NS). At the same time points, mean ⴞ SEM left ventricular myo-
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cardial blood flow was 44 ⴞ 31 and 44 ⴞ 25 mL䡠minⴚ1䡠100 gⴚ1 in the vasopressin group; 30 ⴞ 18 and 233 ⴞ 61 mL䡠minⴚ1䡠100 gⴚ1 in the epinephrine group; and 36 ⴞ 10 and 142 ⴞ 57 mL䡠minⴚ1䡠100 gⴚ1 in the epinephrine-vasopressin group (p < .01 epinephrine vs. vasopressin; p < .02 epinephrine-vasopressin vs. vasopressin). Total cerebral blood flow trended toward higher values after epinephrine-vasopressin (60 ⴞ 19 mL䡠minⴚ1䡠100 gⴚ1) than after vasopressin (36 ⴞ 17 mL䡠minⴚ1䡠100 gⴚ1) or epinephrine alone (31 ⴞ 7 mL䡠minⴚ1䡠100 gⴚ1; p ⴝ .07, respectively). One of six vasopressin, six of six epinephrine, and four of six epinephrine-vasopressin-treated animals had return of spontaneous circulation (p < .01, vasopressin vs. epinephrine). Conclusions: Administration of epinephrine, either alone or in combination with vasopressin, significantly improved left ventricular myocardial blood flow during cardiopulmonary resuscitation. Return of spontaneous circulation was significantly more likely in epinephrine-treated pigs than in animals resuscitated with vasopressin alone. (Crit Care Med 2000; 28:3777–3783) KEY WORDS: asphyxia; pediatrics; cardiac arrest; cardiopulmonary resuscitation; coronary perfusion pressure; vasopressin; epinephrine; regional blood flow; return of spontaneous circulation; postresuscitation phase
ediatric cardiopulmonary arrest has a very poor prognosis. Moreover, survivors often remain neurologically disabled (1). Deterioration in respiratory function or prolonged shock, the main causes of cardiac arrest in children, contributes to survival rates in the range of only 2% to 17% (1–3). Once cardiac arrest has occurred, correction of inadequate oxygen delivery is critical. Furthermore, advanced life support techniques and use of
pharmacologic agents are essential to restart the arrested heart and to preserve brain function (4). Epinephrine is recommended in both the American and European Pediatric Advanced Cardiac Life Support guidelines for all pediatric cardiac arrest settings (i.e., bradyarrhythmia, asystole, pulseless electrical activity, and ventricular fibrillation) (5, 6). In asphyxiation, the most common cause of cardiac arrest in infants, the benefits of epinephrine in re-
From the Cardiac Arrhythmia Center, Cardiovascular Division, Department of Medicine (Drs. Voelckel and Lurie, Mr. McKnite, Zielinski, and Lindstrom, and Ms. Peterson), the University of Minnesota, MN; and the Departments of Anesthesiology and Critical Care Medicine (Drs. Voelckel, Krismer, Lindner, and Wenzel), Leopold-Franzens-University of Innsbruck, Austria. Supported, in part, by the Cardiac Arrhythmia Center, University of Minnesota, MN, and the Department of Anesthesiology and Critical Care Medicine, Leopold-
Franzens-University of Innsbruck, Austria. Presented, in part, as an abstract to the 72nd Scientific Sessions of the American Heart Association, Atlanta, GA, November 1999. Address requests for reprints to: Keith G. Lurie, MD, Department of Medicine, Cardiac Arrhythmia Center, Cardiovascular Division, University of Minnesota, Box 508, Mayo 420 Delaware Street SE, Minneapolis, MN 55455. E-mail:
[email protected] Copyright © 2000 by Lippincott Williams & Wilkins
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storing spontaneous circulation are likely attributable to ␣-receptor stimulation (7), but the “optimal” dose is still unknown (4, 8). Based on experimental and limited clinical data (9 –11), epinephrine doses as high as 200 g/kg are considered as probably helpful and are recommended if the initial standard dose of 10 g/kg appears to be ineffective (5, 6, 12). However, recent clinical studies have failed to show any benefit of high-dose epinephrine in terms of survival (1, 13), thus encouraging the evaluation of alternative vasopressor drugs. In this regard, vasopressin has been found to be a promising nonadrenergic vasoconstrictor in adults. In studies in mature animals, vasopressin results in superior vital organ perfusion (14) and better resuscitation results than epinephrine (15). In addition, the combined use of vasopressin and epinephrine has been 3777
shown to result in a more rapid rise in coronary artery perfusion pressure compared with vasopressin alone and a more sustained elevation than observed with epinephrine alone (16). Moreover, vasopressin is effective after prolonged cardiopulmonary resuscitation (CPR). In small clinical studies, vasopressin improved rates of return of spontaneous circulation, even after prolonged, unsuccessful advanced cardiac life support with epinephrine (17), and improved 24-hr survival rate (18). Although vasopressin has been identified as an important endogenous stress hormone in newborn infants with congestive heart failure contributing to circulatory homeostasis (19), the effects of vasopressin in pediatric cardiac arrest are unknown. Accordingly, the purpose of this study was to evaluate the effects of vasopressin vs. epinephrine on vital organ blood flow and return of spontaneous circulation in a pediatric porcine model. Moreover, given different mechanisms of action, we also investigated the potential synergistic effects of the combination of these two potent vasopressors. Our hypothesis was that study endpoints would not differ between groups.
MATERIALS AND METHODS Surgical Preparation. This project was approved by the Committee on Animal Experimentation at the University of Minnesota, and the animals were managed in accordance with the American Physiologic Society, institutional guidelines, and Position of the American Heart Association on Research Animal Use, as adopted on November 11, 1984. Animal care and use was performed by qualified individuals and supervised by veterinarians, and all facilities and transportation comply with current legal requirements and guidelines. Anesthesia was used in all surgical interventions. All unnecessary suffering was avoided, and research was terminated if unnecessary pain or fear resulted. Our animal facilities meet the standards of the American Association for Accreditation of Laboratory Animal Care. The study was performed according to Utstein-style guidelines (20) on 18 healthy, 4to 6-wk-old female domestic farm pigs weighing 8 –11 kg. The piglets were anesthetized with a single bolus dose of ketamine (30 mg/kg im), pentobarbital (15 mg/kg iv bolus, followed by 15 mg/kg per hour iv infusion), and morphine (1-mg bolus) given via an ear vein. The piglets were intubated during spontaneous respiration with a 5-mm cuffed endotracheal tube (Mallinckrodt Critical Care, Glens Falls, NY) and mechanically ventilated (model 607, Harvard Apparatus, Dover, MA) at
3778
a volume-controlled, pressure-limited setting of 20 mL/kg with room air. During the experiment, respiratory frequency was adjusted at 18 –20 breaths/min according to end-tidal and arterial carbon dioxide partial pressure values to maintain the mean arterial carbon dioxide partial pressure at 35 torr. Dextrose 5% solution and normal saline (10 mL䡠kg⫺1䡠hr⫺1) was administered continuously throughout the preparation and postresuscitation phase with an infusion pump (Flo-Gard 6201, Baxter Healthcare, Dearfield, IL). Blood samples during the experiment were replaced by a threefold higher volume of normal saline. Left ventricular and ascending aortic arch blood pressures were monitored using a single high-fidelity micromanometer-tipped catheter (Millar Instruments, Houston, TX). This lumenal aorto-left ventricular micromanometer catheter was positioned under fluoroscopic guidance by femoral cutdown and used for injection of radiolabeled microspheres. To monitor right atrial pressures and to administer the study drugs, another micromanometer catheter was inserted through a right jugular vein sheath. Reference blood samples for measurement of organ blood flow were withdrawn from a 5-Fr catheter placed in the descending aorta by femoral cutdown. For the measurement of body temperature, a thermistor probe (Yellow Springs Instrument, Friendswood, TX) was placed in the rectum. Body temperature was maintained with a heating blanket (Bair Hugger, Augustine Medical, Eden Prairie, MN) between 38° and 39°C. Measurements. Pressure tracings obtained from the high-fidelity micromanometer catheters were continuously monitored with a data acquisition and recording system (Superscope II v1.295, GW Instruments, Somerville, MA on Power Macintosh 7100/66 computer, Cupertino, CA). Digitized data were analyzed electronically to provide hemodynamic measurements. Heart rate was determined from a simultaneously recorded electrocardiogram signal. Coronary perfusion pressure calculated during diastole (relaxation) was defined as the arteriovenous pressure difference (timecoincident difference between aortic and right atrial pressure). Arterial blood gases were analyzed (IL 1301, Instrumentation Laboratory, Lexington, MA) every 30 mins to ensure adequate acid base status and oxygenation. Organ blood flow was measured by use of radiolabeled microspheres before cardiac arrest, 4 mins after the start of CPR but before drug administration, and 2 mins after drug administration. If spontaneous circulation was restored, blood flow was further assessed 5 mins after successful resuscitation. Microspheres radioactively labeled with 141Ce, 95Nb, 51 Cr, and 113Sr (New England Nuclear, Dupont, Boston, MA) had a mean diameter of 15 ⫾ 1.5 m and a specific activity of 10 mCi/g. Each microsphere vial was placed in a water bath and subjected to ultrasonic vibration for 1 min before injection. Approximately 5 ⫻ 106 microspheres were then immediately
injected into the left ventricle through the lumen of the Millar catheter. The syringe and catheter were flushed with 10 mL of heparinized saline. With an automatic pump (Masterflex, Barnant, Barrington, IL), arterial blood was continuously withdrawn from the descending aorta at a rate of 6 mL/min just before the microsphere injection to 4 mins thereafter. At the end of the experiment, the entire heart, cerebrum, adrenal glands, both kidneys, and pancreas were removed. The left ventricular free wall was sectioned into three layers. Aliquots of each tissue were weighed and placed into vials. Radioactivities from tissues and blood were measured with a gamma scintillation spectrometer, and blood flow values were subsequently calculated according to the method described by Heyman et al (21). Experimental Protocol. After measurement of prearrest hemodynamic variables and organ blood flow with radiolabeled microspheres, animals were paralyzed with 1 mg/kg rocuronium (Organon, West Orange, NJ) to avoid gasping, and 2000 units iv of sodium heparin was administered. Cardiorespiratory arrest was induced by apnea (disconnection from the ventilator and clamping of the endotracheal tube until immediately before CPR). Cardiac arrest was determined by loss of aortic pulsations, defined as an aortic pulse pressure ⬍2 mm Hg (22). After 8 mins of loss of aortic pulsations without intervention, CPR was initiated at 100 compressions/min with a pneumatically driven automatic piston device for CPR (ACD Controller, Ambu, Glostrup, Denmark). Compression excursion was measured visually with a ruler attached to the piston housing and continuously recorded with the data acquisition system; depth of compression (⬃3 cm) was 25% of the transthoracic diameter. All pigs received pressure-controlled 100% oxygen ventilation every five compressions. After 8 mins of CPR, animals were randomly assigned to receive either 0.8 unit/kg vasopressin, 200 g/kg epinephrine, or a combination of 45 g/kg epinephrine with 0.8 unit/kg vasopressin (Fujisawa USA, Deerfield, IL) given via the right atrial catheter, which was followed up by 10 mL of saline flush. The investigators were blinded as to the drugs. Vital organ blood flow measurement was performed 4 mins after the start of CPR, 2 mins after drug administration, as well as at 5 mins after the return of spontaneous circulation. Immediately after acquiring the last blood sample during CPR (i.e., after a total of 22 mins of arrest, including 16 mins of CPR), we attempted to restore spontaneous circulation with direct current shocks (Lifepak 7, Physiocontrol, Redmont, WA) at increasing levels of 3, 5, and 10 J/kg, respectively (Table 1). If ventricular fibrillation, pulseless electrical activity, or asystole was observed, CPR was resumed, and an additional dose of either 0.8 unit/kg vasopressin, 200 g/kg epinephrine, or a combination of 45 g/kg epinephrine with 0.8 unit/kg vasopressin was given; defi-
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Table 1. Blood gas variables before asphyxiation, at cardiac arrest (indicated by loss of aortic pulsations during asphyxiation), during cardiopulmonary resuscitation, and during the postresuscitation phase in piglets CPR
PO2, torr (arterial) Vasopressin Epinephrine Epinephrine ⫹ vasopressin PO2, torr (mixed venous) Vasopressin Epinephrine Epinephrine ⫹ vasopressin PCO2, torr (arterial) Vasopressin Epinephrine Epinephrine ⫹ vasopressin PCO2, torr (mixed venous) Vasopressin Epinephrine Epinephrine ⫹ vasopressin pH units (arterial) Vasopressin Epinephrine Epinephrine ⫹ vasopressin pH units (mixed venous) Vasopressin Epinephrine Epinephrine ⫹ vasopressin
Postresuscitation Phase
Prearrest
Cardiac Arrest
Before DA
6 Mins After DA
5a
15a
77 ⫾ 4 68 ⫾ 3 75 ⫾ 2
10 ⫾ 2 8⫾1 12 ⫾ 5
320 ⫾ 45 220 ⫾ 45 254 ⫾ 60
350 ⫾ 50 270 ⫾ 45 310 ⫾ 60
90 ⫾ 0 100 ⫾ 20 100 ⫾ 10
105 ⫾ 0 115 ⫾ 15 130 ⫾ 20
44 ⫾ 2 45 ⫾ 2 45 ⫾ 2
11 ⫾ 1 11 ⫾ 3 11 ⫾ 2
32 ⫾ 4 25 ⫾ 2 25 ⫾ 3
33 ⫾ 3 40 ⫾ 4 40 ⫾ 3
56 ⫾ 0 45 ⫾ 3 53 ⫾ 4
51 ⫾ 0 45 ⫾ 5 40 ⫾ 4
37 ⫾ 1 35 ⫾ 1 37 ⫾ 2
93 ⫾ 4 95 ⫾ 10 98 ⫾ 9
26 ⫾ 3 35 ⫾ 4 32 ⫾ 6
22 ⫾ 4 25 ⫾ 5 24 ⫾ 5
60 ⫾ 0 52 ⫾ 3 50 ⫾ 4
44 ⫾ 0 45 ⫾ 3 36 ⫾ 5
40 ⫾ 1 41 ⫾ 2 40 ⫾ 2
90 ⫾ 5 77 ⫾ 5 93 ⫾ 9
77 ⫾ 9 79 ⫾ 6 75 ⫾ 9
60 ⫾ 7 48 ⫾ 6 59 ⫾ 7
54 ⫾ 0 67 ⫾ 7 64 ⫾ 5
49 ⫾ 0 68 ⫾ 5 66 ⫾ 2
7.45 ⫾ .01 7.45 ⫾ .02 7.46 ⫾ .01
6.97 ⫾ .04 7.01 ⫾ .06 7.02 ⫾ .05
7.31 ⫾ .06 7.18 ⫾ .05 7.24 ⫾ .05
7.27 ⫾ .07 7.14 ⫾ .05 7.17 ⫾ .04
6.94 ⫾ .0 6.88 ⫾ .04 6.99 ⫾ .04
7.01 ⫾ .0 6.95 ⫾ .03 7.11 ⫾ .06
7.40 ⫾ .01 7.37 ⫾ .02 7.39 ⫾ .02
6.98 ⫾ .03 7.02 ⫾ .05 7.03 ⫾ .05
7.02 ⫾ .04 6.96 ⫾ .03 7.01 ⫾ .03
7.00 ⫾ .05 6.94 ⫾ .04 6.95 ⫾ .05
6.91 ⫾ .0 6.86 ⫾ .04 6.93 ⫾ .04
6.94 ⫾ .0 6.87 ⫾ .04 6.98 ⫾ .03
Prearrest, measurements before induction of cardiac arrest; CPR, cardiopulmonary resuscitation; DA, drug administration. a n ⫽ 1 for vasopressin; n ⫽ 6 for epinephrine; n ⫽ 4 for epinephrine ⫹ vasopressin. All variables are given as mean ⫾ SEM. To convert torr to kPa, multiply the value by 0.1333.
brillation was performed again at 2 mins after drug administration if ventricular fibrillation was observed. Return of spontaneous circulation was defined as an unassisted pulse, with a systolic blood pressure of at least 50 mm Hg. The dextrose-saline infusion was started again at a rate of 10 mL䡠kg⫺1䡠hr⫺1 to replace further fluid loss and maintained during the postresuscitation period. If spontaneous ventricular fibrillation occurred during the postresuscitation period, additional countershocks were applied as needed. Hemodynamic variables were observed for 15 mins (Fig. 1). After finishing the experimental protocol, the animals were euthanized with an overdose of pentobarbital and potassium chloride; all pigs were then necropsied to check correct positioning of the catheters and damage to the rib cage and internal organs. Statistical Analysis. All values are expressed as mean ⫾ SEM. All data were stored on a computer system (Power Macintosh 7100/ 66, Cupertino, CA). The comparability of weight and baseline data was tested with the Student’s t-test for continuous variables. One way analysis of variance was used to determine statistical significance between groups. If the data were unevenly distributed, the KruskalWallis test was used to determine differences between the three groups. For these variables, the Mann-Whitney U test (two-tailed) was further applied to determine a significant difference between each group, and the P value was subsequently adjusted with the Bonferroni
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method. Using the Wilcoxon’s test for equality of survival and subsequent pairwise Breslow comparisons between the groups, we tested the null hypothesis that the number of surviving animals is independent of treatment. Statistical significance was considered to be at p ⬍ .05.
RESULTS Before induction of asphyxial cardiac arrest and before drug administration during CPR, there were no statistically significant differences in weight, temperature, hemodynamic variables, organ blood flow, and blood gases between groups (Tables 1 and 2; Figs. 2 and 3). The interval between clamping the tube and loss of aortic pulsations was 9.5 ⫾ 1.5 mins in the vasopressin group, 9.5 ⫾ 2 mins in the epinephrine pigs, and 7.5 ⫾ 1 mins in the epinephrine-vasopressin swine (NS between groups). During the consecutive 8 mins of nonintervention interval, spontaneous ventricular fibrillation occurred temporarily in 4/18 animals, and in 14/18 animals, bradyarrhythmia (heart rate, ⬍40 beats/min) was observed (NS). All cardiac rhythms subsequently resulted in asystole. Left ventricular blood flow was significantly
higher after both epinephrine alone and epinephrine-vasopressin compared with vasopressin alone (p ⬍ .01 and p ⬍ .02, respectively) (Fig. 3). Total cerebral blood flow trended toward higher values after epinephrine-vasopressin during CPR compared with epinephrine alone (p ⫽ .07) (Fig. 4). Left ventricular and total cerebral blood flow at 5 mins after return of spontaneous circulation was 640 and 170 mL䡠min⫺1䡠100 g⫺1 after vasopressin (n ⫽ 1); 950 ⫾ 150 and 110 ⫾ 25 mL䡠min ⫺1 䡠100 g ⫺1 after epinephrine (n ⫽ 6); and 600 ⫾ 150 and 135 ⫾ 35 mL䡠min⫺1䡠100 g⫺1 after epinephrinevasopressin (n ⫽ 4), respectively. Kidney blood flow at 2 mins after drug administration was significantly higher after vasopressin (p ⬍ .05 vs. epinephrine and epinephrine-vasopressin, respectively). Adrenal glands and pancreas blood flow did not differ significantly between groups (Table 2). After 22 mins of cardiac arrest, including 14 mins of CPR, all animals had ventricular fibrillation, and defibrillation was attempted in all animals; one of six animals in the vasopressin group, six of six swine in the epinephrine group, and four of six pigs in the epinephrine-vasopressin 3779
Table 2. Kidney, adrenal glands, and pancreas blood flow before asphyxiation, during cardiopulmonary resuscitation before and after drug administration, and during the postresuscitation phase Cardiopulmonary Resuscitation
Right kidney (mL䡠min⫺1䡠100 g⫺1) Vasopressin Epinephrine Epinephrine ⫹ vasopressin Left kidney (mL䡠min⫺1䡠100 g⫺1) Vasopressin Epinephrine Epinephrine ⫹ vasopressin Right adrenal gland (mL䡠min⫺1䡠100 g⫺1) Vasopressin Epinephrine Epinephrine ⫹ vasopressin Left adrenal gland (mL䡠min⫺1䡠100 g⫺1) Vasopressin Epinephrine Epinephrine ⫹ vasopressin Pancreas (mL䡠min⫺1䡠100 g⫺1) Vasopressin Epinephrine Epinephrine ⫹ vasopressin
Postresuscitation Phase
Prearrest
Before DA
2 Mins After DA
5 Minsa
470 ⫾ 15 525 ⫾ 40 445 ⫾ 30
0.5 ⫾ 0.1 0.6 ⫾ 0.2 0.5 ⫾ 0.1
6.4 ⫾ 1.9 0.0 ⫾ 0.0b 0.2 ⫾ 0.1b
26 ⫾ 0.0 23 ⫾ 4.5 66 ⫾ 15
460 ⫾ 15 510 ⫾ 35 460 ⫾ 30
1.3 ⫾ 0.3 1.1 ⫾ 0.3 0.5 ⫾ 0.1
5.9 ⫾ 1.5 1.2 ⫾ 1.2b 0.5 ⫾ 0.2b
20 ⫾ 0.0 26 ⫾ 5.0 60 ⫾ 13
395 ⫾ 75 465 ⫾ 130 420 ⫾ 105
65 ⫾ 25 45 ⫾ 15 45 ⫾ 10
170 ⫾ 85 260 ⫾ 65 260 ⫾ 65
890 ⫾ 0.0 590 ⫾ 110 600 ⫾ 250
360 ⫾ 70 455 ⫾ 95 395 ⫾ 95
85 ⫾ 45 55 ⫾ 15 45 ⫾ 10
195 ⫾ 120 290 ⫾ 75 230 ⫾ 90
850 ⫾ 0.0 660 ⫾ 115 545 ⫾ 160
45 ⫾ 5 50 ⫾ 15 40 ⫾ 5
5.6 ⫾ 2.3 6.9 ⫾ 3.2 3.0 ⫾ 1.2
1.8 ⫾ 1.2 0.3 ⫾ 0.1 0.2 ⫾ 0.1
6.3 ⫾ 0.0 18.3 ⫾ 5.5 13.1 ⫾ 5.0
Prearrest, measurements before induction of cardiac arrest; DA, drug administration. a n ⫽ 1 for vasopressin; n ⫽ 6 for epinephrine, n ⫽ 4 for epinephrine plus vasopressin; bp ⬍ .05 vs. vasopressin. No statistical analysis was performed regarding the postresuscitation phase because of lower sample size. All variables are given as mean ⫾ SEM.
Table 3. Regional left ventricular blood flow before asphyxiation, during cardiopulmonary resuscitation before and after drug administration, and during the postresuscitation phase Cardiopulmonary Resuscitation
Epicardial blood flow (mL䡠min⫺1䡠100 g⫺1) Vasopressin Epinephrine Epinephrine ⫹ vasopressin Endocardial blood flow (mL䡠min⫺1䡠100 g⫺1) Vasopressin Epinephrine Epinephrine ⫹ vasopressin Endo/epi ratio Vasopressin Epinephrine Epinephrine ⫹ vasopressin
Postresuscitation Phase
Prearrest
Before DA
2 Mins After DA
5 Minsa
170 ⫾ 20 205 ⫾ 35 180 ⫾ 15
51 ⫾ 26 38 ⫾ 19 39 ⫾ 8
49 ⫾ 20 219 ⫾ 43b 127 ⫾ 38b
485 ⫾ 0.0 835 ⫾ 130 580 ⫾ 175
220 ⫾ 25 225 ⫾ 35 205 ⫾ 15
31 ⫾ 29 20 ⫾ 17 32 ⫾ 12
39 ⫾ 32 220 ⫾ 79b 150 ⫾ 77
810 ⫾ 0.0 1050 ⫾ 205 600 ⫾ 145
1.32 ⫾ 0.07 1.26 ⫾ 0.07 1.21 ⫾ 0.18
0.23 ⫾ 0.16 0.32 ⫾ 0.12 0.25 ⫾ 0.13
0.36 ⫾ 0.21 0.87 ⫾ 0.21 1.01 ⫾ 0.47
1.66 ⫾ 0.0 1.24 ⫾ 0.1 1.98 ⫾ 0.8
Prearrest, measurements before induction of cardiac arrest; DA, drug administration. n ⫽ 1 for vasopressin; n ⫽ 6 for epinephrine; n ⫽ 4 for epinephrine plus vasopressin; bp ⬍ .05 vs. vasopressin. No statistical analysis was performed regarding the postresuscitation phase because of lower sample size. All variables are given as mean ⫾ SEM. a
group had return of spontaneous circulation (p ⬍ .01, vasopressin vs. epinephrine). In surviving animals, the number of countershocks administered was 2.3 ⫾ 0.4 after epinephrine (n ⫽ 6), 1.8 ⫾ 0.5 after epinephrine-vasopressin (n ⫽ 4), and one after vasopressin (n ⫽ 1). During the postresuscitation phase, recurrent ventricular fibrillation occurred in four of six epinephrine-treated animals, requiring up to three additional countershocks of 10 J/kg. None of the animals treated with epinephrine-vasopressin had recur3780
rent ventricular fibrillation. Necropsy confirmed appropriate catheter positions and revealed no injuries of the rib cage or intrathoracic organs in any animals.
DISCUSSION In this pediatric model of prolonged asphyxial cardiac arrest, administration of high-dose epinephrine, either alone or in combination with vasopressin, significantly improved left ventricular myocardial blood flow in comparison with vaso-
pressin alone. Furthermore, return of spontaneous circulation was significantly more likely after epinephrine compared with vasopressin alone. Results from this study indicate that asphyxiation in a pediatric population may require a fundamentally different treatment from adults in ventricular fibrillation and cardiac arrest. It is well recognized that immediate restoration of ventilation is the most important therapy in asphyxial cardiac arrest in pediatric patients, thus eliminating the underlying Crit Care Med 2000 Vol. 28, No. 12
A
dministration of epinephrine, either alone or in
combination with vasopresFigure 1. Flow chart of the experimental protocol. Cardiac arrest is indicated by loss of aortic pulsation during airway occlusion; drug administration indicates central venous injection of 0.8 unit/kg vasopressin vs. 200 g/kg epinephrine vs. 45 g/kg epinephrine combined with 0.8 unit/kg vasopressin; defibrillation was with 3, 5, or 10 J/kg as needed; BLS, basic life support; ACLS, advanced cardiac life support; *sampling of arterial and mixed venous blood gases; †measurement of vital organ blood flow. Time is given in minutes.
sin, significantly improved left ventricular myocardial blood flow during cardiopulmonary resuscitation in this pediatric porcine model of asphyxial cardiac arrest.
Figure 2. Mean ⫾ SEM coronary perfusion pressure during cardiopulmonary resuscitation after drug administration (DA). BLS CPR, basic life support cardiopulmonary resuscitation.
Figure 3. Mean ⫾ SEM left ventricular myocardial blood flow before induction of cardiac arrest and during cardiopulmonary resuscitation before and 2 mins after drug administration (DA). Prearrest, baseline blood flow before asphyxiation; *p ⬍ .01 vasopressin vs. epinephrine; †p ⬍ .02 vasopressin vs. epinephrine combined with vasopressin.
cause of cardiocirculatory failure (4 – 6, 12). In this regard, when cardiac arrest occurred during asphyxiation after ⬃8 –10 mins, we choose an additional 8-min interval without treatment before initiating CPR. Interestingly, pilot studies showed that this period was absolutely necessary to avoid successful resuscitaCrit Care Med 2000 Vol. 28, No. 12
tion with ventilation and chest compressions alone. Although we had to use anesthesia in our animal model, we suggest that our study protocol may reflect a clinically realistic setting of asphyxia in children; and furthermore, our protocol was similar to other models of asphyxial cardiac arrest (7, 22, 23).
After asphyxiation, if restoration of oxygenation and chest compressions fail to restart the arrested heart, epinephrine is recommended in all cardiac arrest settings (4 – 6, 12). The efficacy of epinephrine in aiding resumption of spontaneous circulation from asphyxial arrest is attributable to ␣-adrenergic receptor stimulation (7). Although experimental (9, 10, 24) and limited clinical data (11) suggest that higher doses of epinephrine may more effectively increase myocardial and cerebral blood flow and the rate of restoration of spontaneous circulation in pediatric patients, the “optimal” dose of epinephrine is still controversial (4). At present, pediatric advanced life support guidelines consider a second or subsequent dose of 100 g/kg epinephrine as probably helpful (Class IIa) for victims with unresponsive asystolic and pulseless arrest (5). The epinephrine doses administered in our experiment are based on dose-response investigations indicating an optimal hemodynamic effect in pigs (25). In this regard, the 200 g/kg epinephrine dose reflects an escalating dose that is needed to restart a heart subjected to severe acidosis and hypoxia during prolonged resuscitation efforts (9). Results from our study confirmed the effects of epinephrine on myocardial blood flow (26) and subsequent restoration of spontaneous circulation; all epinephrinetreated animals could be successfully defibrillated. Nevertheless, the epinephrine dose used in our study seemed to lower the fibrillation threshold in the postresuscitation phase, when four of six epinephrine-treated animals needed additional countershocks because of sponta3781
Figure 4. Mean ⫾ SEM left total cerebral blood flow before induction of cardiac arrest and during cardiopulmonary resuscitation before and 2 mins after drug administration (DA). Prearrest, baseline blood flow before asphyxiation; §p ⫽ .07 epinephrine combined with vasopressin vs. epinephrine.
neous fibrillation after return of spontaneous circulation. Interestingly, this electrical instability did not occur when a lower dose of epinephrine was administered in combination with vasopressin. Vasopressin has been reported to be an effective alternative vasopressor during CPR (14, 15, 27), which appears to work during CPR by acutely increasing systemic vascular resistance (28) via the V1receptor. When administered during CPR, vasopressin mediated a pronounced blood flow shift from muscle, skin, and gut toward vital organs, which resulted in increased myocardial perfusion (14) and cerebral oxygen delivery in an animal model (27). Accordingly, vasopressin improved return of spontaneous circulation after prolonged, unsuccessful advanced cardiac life support in adult patients (17) and the 24-hr survival rate in a small out-of hospital trial compared with epinephrine (18). Vasopressin has been further identified as an acute stress hormone in children suffering from thermal injury (29) and is considered to contribute to circulatory homeostasis in neonates with congestive heart failure (19). Given the hypothesis that the effectiveness of a pharmacologic intervention during CPR in asphyxial cardiac arrest models is entirely the result of peripheral vasoconstriction (7), we speculated that the effects of vasopressin would be comparable with those of epinephrine. Surprisingly, we found myocardial blood flow not improved by 0.8 unit/kg vasopressin during CPR, which is in contrast to our extensive experience. In fact, this is the first cardiac arrest setting in which CPR effects with vasopressin alone were clearly inferior to those achieved with epinephrine alone. Although coronary perfusion pressure increased after vasopressin from ⬃13 to ⬃23 mm Hg, 3782
myocardial blood flow remained unchanged at ⬃45 mL䡠min⫺1䡠100 g⫺1 (Fig. 2). By contrast, however, coronary perfusion pressure increased in the epinephrine pigs only slightly more from ⬃15 to ⬃32 mm Hg, but left ventricular myocardial blood flow increased from ⬃35 to ⬃230 mL䡠min⫺1䡠100 g⫺1. Thus, because changes in myocardial blood flow were markedly different from what could be predicted and/or extrapolated from coronary perfusion pressure levels, it is likely that different levels of flow resistance were present in the cardiac vasculature. These findings suggest that above a certain threshold, small increases in coronary perfusion pressure may induce significant changes in blood flow, which may reflect a nonlinear, almost exponential relationship between pressure and flow during external chest compressions in this pediatric model. In this regard, Berkowitz et al. (26) reported a three-fold increase in coronary blood flow when the coronary perfusion pressure was doubled in an infant swine model of CPR with different doses of epinephrine. At the present time, we are unable to determine the underlying mechanisms of these new observations. One possible reason may be that vasopressin receptors were not fully developed in the piglets used in our study, which is suggested by the insufficient blood pressure response to vasopressin alone to levels of only ⬃50% as expected from previous studies in adult pigs (14). However, when used in combination with epinephrine, we speculate that vasopressin may act synergistically in this pediatric porcine model. In this regard, total cerebral blood flow trended toward higher values after epinephrinevasopressin compared with epinephrine alone. This is in contrast to an earlier study in adult pigs in ventricular fibrilla-
tion, when epinephrine-vasopressin vs. vasopressin alone resulted in comparable left ventricular myocardial blood flows, but vasopressin alone increased cerebral blood flow to levels that were about double that with epinephrine-vasopressin (30). Both drug dose and pig age may be responsible for these observations, namely the vasopressor dosage (0.8 unit/kg vasopressin plus 200 g/kg epinephrine in our earlier study (30) in mature pigs (12–16 wks) vs. 0.8 unit/kg vasopressin plus 45 g/kg epinephrine in this piglet study (4 – 6 wks). Hence, combining vasopressin and a lower dose of epinephrine may be beneficial by ensuring both excellent vital organ blood flow during CPR and minimizing adverse epinephrine-associated effects such as cardiac arrhythmias after return of spontaneous circulation. If these results can be extrapolated to the clinical setting, this study suggests that epinephrine alone or in combination with vasopressin is best for the treatment of asphyxial cardiac arrest in pediatric patients. Furthermore, vasopressin may be beneficial in preserving blood flow to other vital organ systems, such as the kidneys (28). According to the specific distribution of V1-receptors, kidney blood flow is not directly affected by vasopressin (31); as such, we found renal perfusion significantly higher 2 mins after vasopressin administration compared with the epinephrine or epinephrine-vasopressin group. However, the decrease in renal blood flow during CPR with epinephrine has been previously reported and appears to be dose related (26). Some limitations of the present study should be noted, including different vasopressin receptors in pigs (lysine vasopressin) and humans (arginine vasopressin), which may result in a different hemodynamic response to exogenously administered arginine vasopressin. In addition, this study lacks dose-response data; therefore, we are not able to report on the “optimal” dose of either vasopressor for CPR in infants. Furthermore, results from this study may be influenced by the need for general anesthesia in animal studies, which may subsequently impair endogenous hormone and catecholamine response. As such, we speculate that in the clinical setting, lower doses of epinephrine may be sufficient to improve vital organ blood flow during CPR. Moreover, this experiment simulates pediatric patients and is not able to reflect an infant or even neonatal model Crit Care Med 2000 Vol. 28, No. 12
as well. Finally, we did not evaluate longterm survival after resuscitation from asphyxial cardiac arrest. In conclusion, administration of epinephrine, either alone or in combination with vasopressin, significantly improved left ventricular myocardial blood flow during CPR in this pediatric porcine model of asphyxial cardiac arrest. Furthermore, return of spontaneous circulation was more likely in epinephrinetreated pigs than in animals resuscitated with vasopressin.
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