Download and Werner Lingnau Volker Wenzel, Karl H. Lindner

Repeated Administration of Vasopressin but Not Epinephrine Maintains Coronary
Perfusion Pressure After Early and Late Administration During Prolonged
Cardiopulmonary Resuscitation in Pigs
Volker Wenzel, Karl H. Lindner, Anette C. Krismer, Egfried A. Miller, Wolfgang G. Voelckel
and Werner Lingnau
Circulation. 1999;99:1379-1384
doi: 10.1161/01.CIR.99.10.1379
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1999 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/99/10/1379
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ by guest on March 5, 2014
Repeated Administration of Vasopressin but Not
Epinephrine Maintains Coronary Perfusion Pressure After
Early and Late Administration During Prolonged
Cardiopulmonary Resuscitation in Pigs
Volker Wenzel, MD; Karl H. Lindner, MD; Anette C. Krismer, MD; Egfried A. Miller, BS;
Wolfgang G. Voelckel, MD; Werner Lingnau, MD
Background—It is unknown whether repeated dosages of vasopressin or epinephrine given early or late during basic life
support cardiopulmonary resuscitation (CPR) may be able to increase coronary perfusion pressure above a threshold
between 20 and 30 mm Hg that renders defibrillation successful.
Methods and Results—After 4 minutes of cardiac arrest, followed by 3 minutes of basic life support CPR, 12 animals were
randomly assigned to receive, every 5 minutes, either vasopressin (early vasopressin: 0.4, 0.4, and 0.8 U/kg,
respectively; n56) or epinephrine (early epinephrine: 45, 45, and 200 mg/kg, respectively; n56). Another 12 animals
were randomly allocated after 4 minutes of cardiac arrest, followed by 8 minutes of basic life support CPR, to receive,
every 5 minutes, either vasopressin (late vasopressin: 0.4 and 0.8 U/kg, respectively; n56), or epinephrine (late
epinephrine: 45 and 200 mg/kg, respectively; n56). Defibrillation was attempted after 22 minutes of cardiac arrest.
Mean6SEM coronary perfusion pressure was significantly higher 90 seconds after early vasopressin compared with
early epinephrine (5064 versus 3463 mm Hg, P,0.02; 4265 versus 1563 mm Hg, P,0.0008; and 3765 versus
1163 mm Hg, P,0.002, respectively). Mean6SEM coronary perfusion pressure was significantly higher 90 seconds
after late vasopressin compared with late epinephrine (4063 versus 2264 mm Hg, P,0.004, and 3264 versus
1564 mm Hg, P,0.01, respectively). All vasopressin animals survived 60 minutes, whereas no epinephrine pig had
return of spontaneous circulation (P,0.05).
Conclusions—Repeated administration of vasopressin but only the first epinephrine dose given early and late during basic
life support CPR maintained coronary perfusion pressure above the threshold that is needed for successful defibrillation.
(Circulation. 1999;99:1379-1384.)
Key Words: cardiopulmonary resuscitation n vasopressin n epinephrine n perfusion n drugs
T
he role of epinephrine during cardiopulmonary resuscitation (CPR) is currently controversial. In laboratory
studies, epinephrine during CPR has been associated with an
increase of myocardial oxygen consumption,1 ventricular
arrhythmias,2 ventilation-perfusion defect,3 and more severe
postresuscitation myocardial dysfunction.4 In clinical trials,
epinephrine did not result in better outcome than did saline
placebo.5 Furthermore, high-dose epinephrine was not able to
improve hospital discharge rates.6 – 8
In laboratory investigations of cardiac arrest from either
ventricular fibrillation9 or pulseless electrical activity,10 vasopressin provided more effective vital organ blood flow9,10
and cerebral oxygen delivery11 than did epinephrine. In
preliminary clinical trials, vasopressin resulted in return of
spontaneous circulation after unsuccessful prolonged advanced cardiac life support with epinephrine.12 Compared
with epinephrine, vasopressin significantly improved 24-hour
survival rate in a small (n540) study of patients with
ventricular fibrillation.13
Although the American Heart Association14 and the European Resuscitation Council15 recommend repeated administration of epinephrine during advanced cardiac life support, it
is unknown whether epinephrine given repeatedly during
CPR may be effective or whether this strategy may even
result in inadvertent catecholamine toxicity. Moreover, it is
unknown whether repeated administration of vasopressin
Received July 29, 1998; revision received October 21, 1998; accepted November 3, 1998.
From the Department of Anesthesia and Intensive Care Medicine, Leopold-Franzens-University of Innsbruck, Austria.
This article was submitted as an abstract to the 28th Educational and Scientific Symposium of the Society of Critical Care Medicine, San Francisco,
Calif, January 23–27, 1999.
Correspondence to Dr Volker Wenzel, The Leopold-Franzens-University of Innsbruck, Department of Anesthesia and Intensive Care Medicine,
Anichstrasse 35, 6020 Innsbruck, Austria. E-mail [email protected]
Reprint requests to Dr Karl H. Lindner, The Leopold-Franzens-University of Innsbruck, Department of Anesthesia and Intensive Care Medicine,
Anichstrasse 35, 6020 Innsbruck, Austria.
© 1999 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
1379
Downloaded from http://circ.ahajournals.org/
by guest on March 5, 2014
1380
Repeated Vasopressin vs Epinephrine During CPR
TABLE 1.
Flow Chart of the Experimental Protocol
Preparation,
min
0
120*†
VF, min
0
Cardiopulmonary Resuscitation, min
4
0
3†
4.5†
Early vasopressin vs early epinephrine:
1
DA1
Late vasopressin vs late epinephrine:
8†
Postresuscitation Phase, min
9.5†
13†
14.5†
1
DA2
1
DA3
1
DA1
1
18†
5†
15†
30†
60†
DA2
Defibrillation
1
VF indicates ventricular fibrillation; DA, drug administration. Early vasopressin vs early epinephrine: DA1, 0.4 U/kg vasopressin vs 45 mg/kg epinephrine; DA2, 0.4
U/kg vasopressin vs 45 mg/kg epinephrine; DA3, 0.8 U/kg vasopressin vs 200 mg/kg epinephrine. Late vasopressin vs late epinephrine: DA1, 0.4 U/kg vasopressin
vs 45 mg/kg epinephrine; DA2, 0.8 U/kg vasopressin vs 200 mg/kg epinephrine.
*Sampling of blood gases; †measurement of hemodynamic variables.
during CPR is effective and whether such a treatment
regimen may result in prolonged elevated systemic vascular
resistance, which may induce cardiac failure in the postresuscitation phase. Furthermore, the effects of vasopressin versus
epinephrine may vary significantly when given early or late
during basic life support (BLS) CPR. Accordingly, the
purpose of the present investigation was to evaluate the
effects of repeated administration of optimal (0.4 U/kg) and
high (0.8 U/kg) dosages of vasopressin versus optimal (45
mg/kg) and high (200 mg/kg) dosages of epinephrine in a
porcine cardiac arrest model simulating a short (3 minutes)
and prolonged (8 minutes) duration of BLS with subsequent
advanced cardiac life support.
Methods
Surgical Preparation and Measurements
This project was approved by the Austrian Federal Animal Investigational Committee, and the animals were managed in accordance
with American Physiological Society and institutional guidelines.
This study was performed according to Utstein-style guidelines16 on
24 healthy, 12- to 16-week-old swine (Tyrolean domestic pigs) of
either sex weighing 30 to 40 kg. The animals were fasted overnight
but had free access to water. The pigs were premedicated with
azaperone (neuroleptic agent; 4 mg/kg IM) and atropine (0.1 mg/kg
IM) 1 hour before surgery, and anesthesia was induced with
thiopental (7 to 15 mg/kg IV). After intubation during spontaneous
respiration, the pigs were ventilated with a volume-controlled ventilator (Draeger EV-A) with 100% O2 at 20 breaths per minute and
with a tidal volume adjusted to maintain normocapnia. Anesthesia
was maintained with propofol (6 to 8 mg z kg21 z h21) and a single
dose of piritramide (30 mg). We achieved muscle paralysis with 8
mg pancuronium after intubation and subsequently with repeated
doses of 8 mg pancuronium as needed. Ringer’s solution (6 mL z
kg21 z h21) and a 3% gelatin solution (4 mL z kg21 z h21) were
administered in the preparation phase before induction of cardiac
arrest and in the postresuscitation phase. A standard lead II ECG was
used to monitor cardiac rhythm; depth of anesthesia was judged
according to blood pressure, heart rate, and electroencephalography
(Neurotrac, Engström). If cardiovascular variables or electroencephalography indicated a reduced depth of anesthesia, we increased
the propofol dose, and additional piritramide was given. Body
temperature was maintained with a heating blanket between 38.0°C
and 39.0°C.
A 7F catheter was advanced into the descending aorta via femoral
cutdown for withdrawal of arterial blood samples and measurement
of arterial blood pressure. A 5F pulmonary artery catheter was placed
in the pulmonary artery via cutdown in the neck to measure cardiac
output and to sample mixed venous blood. Cardiac output was
measured with the thermodilution technique, and cardiac index was
calculated by dividing cardiac output by body weight. Another 7F
catheter was placed into the right atrium via femoral cutdown to
measure right atrial pressure and for drug administration. Aortic,
right atrial, and pulmonary artery pressures were measured with
saline-filled catheters attached to pressure transducers (model
1290A, Hewlett Packard) that were calibrated to atmospheric pressure at the level of the right atrium; pressure tracings were recorded
with a data acquisition system (Dewetron port 2000). Coronary
perfusion pressure (CPP) was defined as the difference between
aortic and right atrial diastolic pressures. Blood gases were measured
with a blood gas analyzer (Chiron Diagnostics), and end-tidal carbon
dioxide was measured with an infrared absorption analyzer (Sirecust
960, Siemens).
Experimental Protocol
Fifteen minutes before cardiac arrest, 5000 U heparin IV was
administered to prevent intracardiac clot formation, a single dose of
15 mg piritramide and 8 mg pancuronium was given, and hemodynamic parameters as well as blood gases were measured. A 50-Hz,
60-V alternating current was then applied via 2 subcutaneous needle
electrodes to induce ventricular fibrillation. Cardiopulmonary arrest
was defined as the point at which the aortic pressure decreased
profoundly to hydrostatic pressure, and the ECG showed ventricular
fibrillation; ventilation was stopped at that point. After 4 minutes of
untreated ventricular fibrillation, closed-chest CPR was performed
manually, and mechanical ventilation was resumed at the same
setting as before induction of cardiac arrest. Chest compression,
guided by acoustical audiotones, was always performed by the same
investigator at a rate of 80 compressions per minute. This investigator was blinded to hemodynamic and end-tidal carbon dioxide
monitor tracings.
The first part of the study was designed to simulate administration
of vasopressors after a short period of BLS CPR. Accordingly, after
4 minutes of ventricular fibrillation followed by 3 minutes of BLS
CPR, 12 animals were randomly assigned to receive either vasopressin (early vasopressin group: 0.4, 0.4, and 0.8 U/kg; n56) or
epinephrine (early epinephrine group: 45, 45, and 200 mg/kg; n56)
after 3, 8, and 13 minutes of CPR, respectively (Table 1). The second
part of the study was designed to simulate administration of
vasopressors after a prolonged period of BLS CPR. Thus, 12 animals
were randomly allocated after 4 minutes of ventricular fibrillation
and 8 minutes of BLS CPR to receive either vasopressin (late
vasopressin group: 0.4 and 0.8 U/kg; n56) or epinephrine (late
epinephrine group: 45 and 200 mg/kg; n56) after 8 and 13 minutes
of CPR, respectively (Table 1).
All drugs were diluted to 10 mL with normal saline and subsequently injected into the right atrium, followed by 20 mL saline flush
(investigators were blinded to the drugs). Hemodynamic parameters
were measured before induction of cardiac arrest, after 3 minutes of
CPR, and 90 seconds and 5 minutes after each drug administration,
respectively. After 22 minutes of cardiac arrest, including 18 minutes
of CPR, up to 5 countershocks were administered with an energy of
3, 4, and 6 J/kg. If asystole or pulseless electrical activity was present
after defibrillation, the experiment was terminated. Return of spontaneous circulation was defined as an unassisted pulse with a systolic
arterial pressure of $80 mm Hg and pulse pressure of $40 mm Hg
lasting for at least 5 minutes. In the postresuscitation period,
Downloaded from http://circ.ahajournals.org/ by guest on March 5, 2014
Wenzel et al
March 16, 1999
1381
TABLE 2. Hemodynamic Variables at Prearrest and After Return of Spontaneous
Circulation (Postresuscitation Phase)
Postresuscitation Phase, min
Prearrest
5
15
30
60
Early vasopressin
9065
133616
129617
148612
155616
Early epinephrine
10061
Late vasopressin
9563
zzz
13269
zzz
126612
zzz
13069
zzz
13868
Late epinephrine
9766
zzz
zzz
zzz
zzz
10667
10264
6364
7062
6864
HR, bpm
MAP, mm Hg
Early vasopressin
Early epinephrine
9964
Late vasopressin
10666
zzz
95612
zzz
6768
zzz
6264
zzz
6463
Late epinephrine
11168
zzz
zzz
zzz
zzz
MPAP, mm Hg
Early vasopressin
1862
2062
1962
2262
2162
Early epinephrine
1861
Late vasopressin
1861
zzz
2064
zzz
1963
zzz
2363
zzz
2364
1662
zzz
zzz
zzz
zzz
Early vasopressin
14762
7566
5966
7766
10468
Early epinephrine
14869
Late vasopressin
14467
zzz
94621
zzz
58615
zzz
87613
zzz
123610
Late epinephrine
14668
zzz
zzz
zzz
zzz
Early vasopressin
1604685
31546249
22636159
19886178
13616122
Early epinephrine
14796180
Late vasopressin
16016181
zzz
24046299
zzz
18316181
zzz
15376191
zzz
11156169
Late epinephrine
CI, mL z kg
21
z min
21
SVR, dyne z s z cm25
Late epinephrine
17176182
zzz
zzz
zzz
zzz
Prearrest indicates measurements before induction of cardiac arrest; postresuscitation phase, after
return of spontaneous circulation; HR, heart rate; MAP, mean arterial pressure; MPAP, mean
pulmonary artery pressure; CI, cardiac index; SVR, systemic vascular resistance; . . ., not applicable—no return of spontaneous circulation; early vs late, first drug administration after 3 vs 8 minutes
of basic life support CPR, respectively. Values are mean6SEM.
hemodynamic parameters were measured at 5, 15, 30, and 60
minutes after return of spontaneous circulation. After the experimental protocol was finished, the animals were killed and necropsied to
verify correct positioning of the catheters and injuries to the rib cage.
Statistical Analysis
The comparability of weight and baseline data were tested with the
t test for continuous variables. One-way ANOVA was used to
determine statistical significance between groups and was corrected
for multiple comparisons by the Bonferroni method. Using Fisher’s
exact test, we tested the null hypothesis that the number of surviving
animals is independent of treatment. We considered a 2-tailed value
of P,0.05 statistically significant.
Results
Before induction of ventricular fibrillation and before drug
administration during CPR, there were no differences in
weight, hemodynamic variables, or blood gases between
groups (Table 2). When drugs were given early during
BLS CPR (after 3 minutes of chest compressions), there
was a strong trend toward significantly higher CPP 90
seconds after vasopressin compared with epinephrine. This
trend became statistically significant between groups 5
minutes after the first vasopressin or epinephrine administration and remained significantly different for the remainder of the experiment (Figure 1).
When drugs were given late during BLS CPR (after 8
minutes of chest compressions), CPP was significantly
higher after vasopressin compared with epinephrine at both
90 seconds and 5 minutes after each of 2 drug administrations (Figure 2). After 22 minutes of cardiac arrest,
including 18 minutes of CPR, all pigs in the early and late
vasopressin group had return of spontaneous circulation
(early vasopressin group, 1.360.2 countershocks; late
vasopressin group, 4.260.9 countershocks) and survived
the 60-minute postresuscitation phase. In the early epinephrine group, 2 animals were defibrillated into pulseless
electrical activity, and 4 animals had asystole. In the late
epinephrine group, all animals had asystole. Necropsy
confirmed appropriate catheter positions and revealed no
injuries to the rib cage or intrathoracic organs in any
animals.
Downloaded from http://circ.ahajournals.org/ by guest on March 5, 2014
1382
Repeated Vasopressin vs Epinephrine During CPR
Figure 1. Administration of repeated doses of vasopressin (f)
but not epinephrine (l) given early during BLS CPR maintained
mean6SEM CPP above the threshold of '20 to 30 mm Hg
(dashed lines) that is needed for successful defibrillation with
return of spontaneous circulation. DA 1 indicates drug administration of 0.4 U/kg vasopressin vs 45 mg/kg epinephrine; DA 2,
0.4 U/kg vasopressin vs 45 mg/kg epinephrine; DA 3, 0.8 U/kg
vasopressin vs 200 mg/kg epinephrine; *P,0.05 vs epinephrine;
ROSC, return of spontaneous circulation; VF, ventricular fibrillation; and ACLS, advanced cardiac life support. Time is given in
minutes (9) and seconds (0).
Discussion
Repeated administration of vasopressin but only the first dose
of epinephrine given early and late during BLS CPR were
able to maintain CPP above the threshold between 20 and
30 mm Hg that is needed for successful defibrillation.22
Furthermore, these effects lasted longer after vasopressin than
epinephrine, and significantly more vasopressin than epinephrine animals had return of spontaneous circulation (6 of
6 versus 0 of 6, respectively; P,0.05).
The present model closely simulates a short and prolonged
duration of BLS followed by advanced cardiac life support.
Although the 45-mg/kg dose of epinephrine used in our
porcine study is higher than the 15-mg/kg dose recommended
for clinical use,14,15 the first dosages of both vasopressin and
epinephrine reflect an established optimal dose in this pig
model.9,17 Furthermore, the high doses of 0.8 U/kg vasopres-
Figure 2. Administration of repeated doses of vasopressin (f)
but not epinephrine (l) given late during BLS CPR maintained
mean6SEM CPP above the threshold of '20 to 30 mm Hg
(dashed lines) that is needed for successful defibrillation with
return of spontaneous circulation. Abbreviations and values as
in Figure 1.
sin and 200 mg/kg epinephrine are the maximum effective
doses in swine.9,18 Interestingly, the effects of vasopressin
versus epinephrine on CPP varied depending on the time of
drug administration during advanced life support CPR. For
example, the first vasopressin administration in the late model
achieved an '66% increase in CPP over the first vasopressin
injection in the early model ('20 mm Hg versus 30 mm Hg).
Conversely, the first epinephrine dose in the late model
achieved only an '35% increase in CPP over the first
epinephrine dose in the early model ('6 mm Hg versus
'17 mm Hg). This indicates that the effects of epinephrine
given late seemed to be more attenuated compared with late
administration of vasopressin during BLS CPR. In fact,
arteries from rats with metabolic acidosis or uremia showed
selective blunting of biochemical and contractile responses to
norepinephrine but not to vasopressin.19 This may suggest
that after prolonged cardiac arrest and therefore fundamental
global hypoxia and hypercarbic acidosis, the pressor sensitivity to vasopressin may be normal and the effects of
catecholamines may be blunted.10 The underlying mechanism
for a rapid and profound tachyphylaxis of epinephrine may be
desensitized myocardial and peripheral adrenergic receptors.20 Accordingly, substantially elevated plasma levels of
epinephrine that are endogenously released immediately after
cardiac arrest before initiation of CPR may be a possible
explanation for limited effectiveness of epinephrine. This
may explain that in addition to endogenous epinephrine,
exogenous epinephrine is necessary to increase vital organ
blood flow during CPR.21
A CPP between 20 and 30 mm Hg during CPR is one of the
best predictors of return of spontaneous circulation in both
animals and humans.22 The epinephrine animals reached this
level only transiently 90 seconds after the first drug administration given early and late during BLS CPR, whereas CPP
in the vasopressin animals was at or above this level for the
entire experiment. Accordingly, all vasopressin animals in
our study were successfully defibrillated after 22 minutes of
cardiac arrest and survived the 60-minute postresuscitation
phase, whereas all pigs resuscitated with epinephrine died.
The duration of BLS and therefore of suboptimal vital organ
blood flow during CPR may have a fundamental impact on
resuscitability. For example, the early vasopressin pigs were
successfully defibrillated with 1.360.2 countershocks,
whereas the late vasopressin pigs needed 4.260.9 defibrillation attempts to achieve return of spontaneous circulation,
indicating more severe cardiac ischemia.
Only the first of repeated doses of epinephrine in our
animals were able to increase CPP above a threshold that
renders successful defibrillation likely. Subsequent doses,
including a high dosage, were not able to increase CPP above
a level that usually correlates with return of spontaneous
circulation. This is in good agreement with a preliminary
canine study showing that the first dose of epinephrine
determined whether the critical CPP needed for return of
spontaneous circulation was reached and the animals survived.23 In fact, with the exception of 2 animals in the early
epinephrine group that we defibrillated into pulseless electrical activity, all pigs treated with epinephrine had asystole,
indicating fundamental depletion of myocardial energy. This
Downloaded from http://circ.ahajournals.org/ by guest on March 5, 2014
Wenzel et al
may confirm previous results from laboratory investigations
demonstrating that epinephrine fueled cardiac oxygen consumption, which subsequently resulted in a severe mismatch
of cardiac oxygen delivery versus oxygen consumption during CPR.24 This mechanism may have been an important
component in a clinical study, when a total cumulative dose
of 15 mg epinephrine was found to best predict 24-hour
mortality in patients with out-of-hospital cardiac arrest.25 In
fact, the weight-adjusted total epinephrine dose given to our
early epinephrine animals was almost identical to this lethal
dose ('285 mg/kg versus '215 mg/kg). Subsequently, no
epinephrine pig had return of spontaneous circulation despite
the absence of underlying disease, such as severe coronary
atherosclerotic disease. Thus, if our results can be extrapolated to clinical management of cardiac arrest, they are in
strong disagreement with the current guidelines of both the
American Heart Association14 and the European Resuscitation Council,15 which recommend “looping” an algorithm of
defibrillation– epinephrine– defibrillation while performing
CPR if return of spontaneous circulation cannot be achieved.
If our explanation of the observed effects in the present
experiment is correct, humans with coronary artery disease
might have a greater benefit when being resuscitated with
vasopressin than with epinephrine. For example, when a 33%
stenosis in the mid left anterior descending coronary artery
was induced in a porcine model, myocardial perfusion was
not diminished during normal physiological conditions, but
endocardial blood flow was significantly decreased during
CPR.26 Given the fact that irreversible injury of ischemic
myocardium was shown to develop as a transmural wave
front that started in the subendocardial myocardium and
moved progressively toward the subepicardial myocardium in
a canine model,27 this mechanism may result in significant
complications in the postresuscitation phase, such as fatal
arrhythmias. Thus, this may indicate that during CPR in the
presence of coronary artery disease, which is very common in
humans suffering cardiac arrest, a relatively high CPP may be
beneficial to supply appropriate perfusion to the entire myocardium. Accordingly, a vasopressin-mediated CPP that is
significantly above the threshold that is actually needed to
achieve return of spontaneous circulation in patients with
coronary artery disease may represent an additional advantage with regard to resuscitability compared with epinephrine.
Effects of CPR management that are beneficial during the
resuscitation attempt may result in potentially deleterious
effects in the postresuscitation phase, which is a critical time
interval between return of spontaneous circulation and longterm survival. For example, a vasopressin-mediated increased
systemic vascular resistance has been shown to be an important mechanism to increase vital organ blood flow during
CPR,9 but persisting elevated systemic vascular resistance
after return of spontaneous circulation may result in cardiac
failure. In fact, a reversible depressant effect on myocardial
function of pigs resuscitated with vasopressin was observed
compared with epinephrine; however, overall cardiovascular
function was not critically or irreversibly impaired after the
administration of vasopressin.28 Although we did not measure
left ventricular pressure pattern velocity in our pigs to
determine cardiac contractility after return of spontaneous
March 16, 1999
1383
circulation, cardiocirculatory parameters were stable in all
animals in the postresuscitation phase. Furthermore, despite
repeated administration of vasopressin during CPR, systemic
vascular resistance was elevated only for '15 minutes after
return of spontaneous circulation. Accordingly, we suggest
that vasopressin may be superior to epinephrine to achieve
return of spontaneous circulation, whereas catecholamines
may be saved for careful titration of hemodynamic variables
after successful defibrillation.
Some limitations of this 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. However, the circulatory effects
of arginine vasopressin, as administered in the present investigation, may be even greater in humans than in pigs. In
addition, we did not evaluate vasopressin plasma levels
throughout the study. Furthermore, we were not able to assess
whether higher return of spontaneous circulation rates as
observed in the early and late vasopressin animals might have
had a beneficial effect on long-term survival and neurological
outcome after return of spontaneous circulation. Also, usage
of potent anesthetics may have impaired cardiovascular
function and autonomic control. We also used young, healthy
pigs that were free of atherosclerotic disease. Furthermore,
this study lacks dose-response data; therefore, we are not able
to report the minimally effective vasopressin dose. Finally,
we purposely omitted defibrillation attempts on starting CPR
and immediately after vasopressor administration to study the
hemodynamic effects of the study drugs during the resuscitation attempt.
In conclusion, repeated administration of vasopressin but
only the first epinephrine dose given early and late during
BLS CPR maintained CPP above a threshold that is needed
for successful defibrillation.
Acknowledgments
This study was supported in part by science project No. 7280 of the
Austrian National Bank; a Dean’s grant for medical school graduates
of the Leopold-Franzens-University of Innsbruck, Austria; and the
Department of Anesthesia and Intensive Care Medicine, LeopoldFranzens-University of Innsbruck, Austria. We would like to thank
Martin Stoffaneller, BS, and Ulrich Achleitner, MS, for skillful
assistance in data acquisition and technical expertise.
References
1. Ditchey RV, Lindenfeld JA. Failure of epinephrine to improve the
balance between myocardial oxygen supply and demand during
closed-chest resuscitation in dogs. Circulation. 1988;78:382–389.
2. Nieman JT, Haynes KS, Garner D, Renie CJ, Jagels G, Storm O. Postcountershock pulseless rhythms: response to CPR, artificial cardiac
pacing, and adrenergic agonists. Ann Emerg Med. 1986;15:112–120.
3. Tang W, Weil MH, Gazmuri R, Sun S, Duggal C, Bisera J. Pulmonary
ventilation/perfusion defects induced by epinephrine during cardiopulmonary resuscitation. Circulation. 1991;84:2101–2107.
4. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri R. Epinephrine
increases the severity of postresuscitation myocardial dysfunction. Circulation. 1995;92:3089 –3093.
5. Woodhouse SP, Cox S, Boyd P, Case C, Weber M. High dose and
standard dose adrenaline do not alter survival, compared with placebo, in
cardiac arrest. Resuscitation. 1995;30:243–249.
6. Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J. A randomized clinical trial of high-dose epinephrine and norepinephrine vs
Downloaded from http://circ.ahajournals.org/ by guest on March 5, 2014
1384
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Repeated Vasopressin vs Epinephrine During CPR
standard-dose epinephrine in prehospital cardiac arrest. JAMA. 1992;268:
2667–2672.
Stiell IG, Hebert PC, Weitzmann BN, Wells GA, Ramann S, Stark RM,
Higginson LA, Ahuja J, Dickinson GE. High-dose epinephrine in adult
cardiac arrest. N Engl J Med. 1992;327:1045–1050.
Lindner KH, Ahnefeld FW, Prengel AW. A comparison of standard and
high-dose adrenaline in the resuscitation of asystole and electromechanical dissociation. Acta Anaesthesiol Scand. 1991;35:253–256.
Lindner KH, Prengel AW, Pfenninger EG, Lindner IM, Strohmenger HU,
Georgieff M, Lurie KG. Vasopressin improves vital organ blood flow
during closed-chest cardiopulmonary resuscitation in pigs. Circulation.
1995;91:215–221.
Wenzel V, Lindner KH, Prengel AW, Maier C, Voelckel W, Lurie KG,
Strohmenger HU. Vasopressin improves vital organ blood flow after
prolonged cardiac arrest with post-countershock pulseless electrical
activity in pigs. Crit Care Med. In press.
Prengel AW, Lindner KH, Keller A. Cerebral oxygenation during cardiopulmonary resuscitation with epinephrine and vasopressin in pigs.
Stroke. 1996;27:1241–1248.
Lindner KH, Prengel AW, Brinkmann A, Strohmenger HU, Lindner IM,
Lurie KG. Vasopressin administration in refractory cardiac arrest. Ann
Intern Med. 1996;124:1061–1064.
Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie
KG. A randomized comparison of epinephrine and vasopressin in patients
with out-of-hospital ventricular fibrillation. Lancet. 1997;349:535–537.
Emergency Cardiac Care Committee and Subcommittees, American
Heart Association. Guidelines for cardiopulmonary resuscitation, III:
adult advanced cardiac life support. JAMA. 1992;268:2199 –2241.
Robertson C, Stehen P, Adgey J, Bossaert L, Carli P, Chamberlain D,
Dick W, Ekstrom L, Hapnes SA, Holmberg S, Juchems R, Kette F, Koster
R, de Latorre FJ, Lindner K, Perales N. The European Resuscitation
Council guidelines for adult advanced life support: a statement from the
working group on advanced life support, and approved by the executive
committee of the European Resuscitation Council. Resuscitation. 1998;
1998:37:81–90.
Idris AH, Becker LB, Ornato JP, Hedges JR, Bircher NG, Chandra NC,
Cummins RO, Dick WF, Ebmeyer U, Halperin HR, Hazinski MF, Kerber
RE, Kern KB, Safar P, Steen PA, Swindle MM, Tsitlik JE, von Planta I,
von Planta M, Wears RL, Weil MH. Utstein-style guidelines for uniform
reporting of laboratory CPR research. Circulation. 1996;94:2324 –2336.
17. Lindner KH, Ahnefeld FW, Bowdler IM. Comparison of different doses
of epinephrine on myocardial perfusion and resuscitation success during
cardiopulmonary resuscitation in a pig model. Am J Emerg Med. 1991;
9:27–31.
18. Brown CG, Werman HA, Davis EA, Hobson J, Hamlin RL. The effects
of graded doses of epinephrine on regional myocardial blood flow during
cardiopulmonary resuscitation in swine. Circulation. 1987;75:491– 497.
19. Fox AW, May RE, Mitch WE. Comparison of peptide and nonpeptide
receptor-mediated responses in rat tail artery. J Cardiovasc Pharmacol.
1992;20:282–289.
20. Insel PA. Adrenergic receptors: evolving concepts and clinical implications. N Engl J Med. 1996;334:580 –585.
21. Paradis NA, Martin GB, Rosenberg J, Rivers EP, Goetting MG, Appleton
TJ, Feingold M, Cryer PE, Wortsman J, Nowak RM. The effect of
standard- and high-dose epinephrine on coronary perfusion pressure
during prolonged cardiopulmonary resuscitation. JAMA. 1991;265:
1139 –1144.
22. Kern KB, Niemann JT. Coronary perfusion pressure during cardiopulmonary resuscitation. In: Paradis NA, Halperin HR, Nowak RM, eds.
Cardiac Arrest: The Science and Practice of Resuscitation Medicine.
Baltimore, Md: Williams & Wilkins; 1996:270 –285.
23. Cairns CB, Niemann JT. Hemodynamic effects of repeated doses of
epinephrine after prolonged cardiac arrest and CPR: preliminary observations in an animal model. Resuscitation. 1998;36:181–185.
24. Ditchey RV. The choice of vasopressor agents in cardiopulmonary resuscitation. Curr Opin Crit Care. 1996;2:170 –175.
25. Rivers EP, Wortsman J, Rady MY, Blake HC, McGeorge FT, Buderer
NM. The effect of the total cumulative epinephrine dose administered
during human CPR on hemodynamic, oxygen transport, and utilization
variables in the postresuscitation period. Chest. 1994;106:1499 –1507.
26. Kern KB, Ewy GA. Minimal coronary stenoses and left ventricular blood
flow during CPR. Ann Emerg Med. 1992;21:1066 –1072.
27. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront
phenomenon of ischemic cell death, I: myocardial infarct size vs duration
of coronary occlusion in dogs. Circulation. 1977;56:786 –794.
28. Prengel AW, Lindner KH, Keller A, Lurie KG. Cardiovascular function
during the postresuscitation phase after cardiac arrest in pigs: a comparison of epinephrine versus vasopressin. Crit Care Med. 1996;24:
2014 –2019.
Downloaded from http://circ.ahajournals.org/ by guest on March 5, 2014