SCIENTIFIC REVIEWS
Vasopressin and endothelin during cardiopulmonary resuscitation
Volker Wenzel MD 1
Gordon A. Ewy MD 2
Karl H. Lindner MD 1
From the Department of Anesthesiology and Critical Care Medicine (Drs. Wenzel and
Lindner), Leopold Franzens University, Innsbruck, Austria;
2 and Department of Cardiology (Dr. Ewy), University of Arizona College of Medicine,
Tucson, Arizona.
1
Supported, in part, by the Laerdal Foundation for Acute Medicine, Austrian National Bank Science
Project 7280, a Founder's Grant for Critical Care Medicine Research of the Society of Critical Care
Medicine, the Department of Anesthesiology and Critical Care Medicine, Leopold Franzens University,
and the Austrian Science Foundation grant P-14169-Med, Vienna, Austria (all to Drs. Wenzel and
Lindner); and by a Grant-in-aid from the American Heart Association, Arizona Affiliate (to Dr. Ewy).
Presented, in part, at the Wolf Creek V Conference, September 1999, Rancho Mirage, CA.
Address requests for reprints to: Karl H. Lindner, MD, Department of Anesthesiology
and Critical Care Medicine, Leopold Franzens University, Anichstrasse 35, 6020
Innsbruck, Austria (E-mail: karl.lindner@uibk.ac.at) or Gordon A. Ewy, MD, Department
of Cardiology, University of Arizona College of Medicine, 1501 North Campbell Avenue,
Tucson, AZ 85724 (E-mail: gaewy@aol.com).
Copyright © 2000 by Lippincott Williams & Wilkins
Vital
organ
blood
flow
during
Innsbruck,
Austria,
are
currently
cardiopulmonary resuscitation (CPR) and
coordinating a multicenter, randomized
neurologic
clinical
recovery
after
CPR
were
trial
under
the
aegis
of
the
significantly better in pigs treated with
European Resuscitation Council to study
vasopressin compared with epinephrine.
the effects of vasopressin vs. epinephrine
Furthermore,
in out-of-hospital cardiac arrest patients.
evaluating
two
both
clinical
studies
out-of-hospital
and
Results
of
anticipated
1,500
enrolled
inhospital cardiac arrest patients found
patients may be available in 2001 and
higher 24-hr survival rates in patients
may
who were resuscitated with vasopressin
vasopressin during CPR. Another new,
compared with epinephrine. Scientists at
recently studied vasopressor for CPR is
the
endothelin-1. To date, this vasopressor
Leopold
Franzens
University
in
help
to
determine
the
role
of
has only been studied as an intervention
there was no difference in endothelin
in animal CPR models, although plasma
concentrations between resuscitated and
levels have been investigated in cardiac
nonresuscitated
arrest
found
parallel increases in plasma vasopressin
pressure
and endothelin during CPR were found
epinephrine.
only in surviving patients. Similar to this
patients.
improved
when
Initial
coronary
combined
reports
perfusion
with
patients.
However, the CPR research group of the
study,
multiple
University
stress
hormones
of
Arizona
Sarver
Heart
Center found excessive vasoconstriction
patients
and worse survival than with epinephrine
significant
alone.
plasma
(Crit
Care
Med
2000;
However,
regression
revealed
analysis
in
cardiac
that
there
association
endothelin
of
arrest
was
between
a
higher
concentration
and
28[Suppl.]:N233-N235)
survival
K EY W ORDS: heart arrest therapy;
vasopressin
vasopressors;
life
potent nonadrenergic vasopressors that
vasopressin;
may act in addition to catecholamines as
support;
advanced
cardiac
endothelin;
cardiopulmonary
resuscitation;
chest
compressions; drugs, experimental
[6]
. Accordingly, both endogenous
and
and
CPR
mechanism
[1]
and
Council
of
the
European
Resuscitation
recommend the administration
[2]
epinephrine
resuscitation
during
cardiopulmonary
(CPR),
this
drug
may
be
"back-up" vasoconstrictors during cardiac
arrest
Although the American Heart Association
endothelin
advanced
may
As
be
cardiac
administering
.
[7]
such,
utilized
life
this
during
support
additional
by
exogenous
vasopressin and/or endothelin during CPR
[8]
.
is
currently controversial because its use
results
in
increased
consumption,
myocardial
ventricular
oxygen
arrhythmias,
CPR
with
Vasopressin
in
Laboratory
Investigations
ventilation-perfusion defects, contributes
After a short duration of ventricular
to
fibrillation,
postresuscitation
myocardial
vasopressin
during
CPR
dysfunction, and unfavorable neurologic
increased coronary perfusion pressure
recovery.
vital organ blood flow
Furthermore,
epinephrine
discharge
did
not
rates
improve
in
multicenter clinical trials
Endogenous
successfully
high-dose
several
[3]
vasopressin
resuscitated
hospital
large
cerebral oxygen delivery
levels
in
patients
were
[12]
,
, ventricular
fibrillation median frequency
with epinephrine
.
[10]
[9]
[11]
, and
in comparison
. Similar results
were found with prolonged cardiac arrest
and
pulseless
electrical
activity;
significantly higher than in patients who
furthermore,
died
vasopressin animals could be resuscitated,
;
[4]
epinephrine
interestingly,
and
plasma
norepinephrine
and
significantly
vasopressin
did
not
more
result
in
concentrations were significantly higher in
bradycardia after return of spontaneous
patients who died when compared with
circulation
surviving
.
vasopressin during CPR may be explained
Although plasma endothelin was higher in
by both a vasopressin-induced increased
resuscitated patients than in controls,
systemic
cardiac
arrest
victims
[5]
[13]
.
vascular
Beneficial
resistance
effects
[14]
of
and
vasopressin-mediated
dilation
of
the
of
low-dose
dopamine
improved
gut
cerebral vasculature, which shifts blood
perfusion in the postresuscitation phase
toward the myocardium and brain
[28]
Interestingly,
a
vasopressin
and
[15]
.
combination
of
epinephrine
vs.
. Although epinephrine was superior
to vasopressin in a pediatric model
vasopressin
was
[29]
beneficial
,
over
vasopressin only resulted in comparable
epinephrine in other preparations such as
left ventricular myocardial blood flow,
epidural anesthesia
but
, and hypovolemic shock
in
significantly
perfusion
extracellular
identical
CPR
receptors,
intracellular
pathways.
cerebral
; this may be the result of
[16]
different
decreased
Although
decreased
levels in swine
research
but
underlying
transduction
necessary.
vasopressin
in
, hypothermia
special
, rendering
[32]
cardiac
[31]
arrest
with
pathophysiology
during
catecholamine
plasma
and humans
[17]
more
[30]
[18]
, it
CPR
with
Vasopressin
in
Clinical
remains to be determined whether this
Investigations
decreases myocardial oxygen consumption
In
as
of
arrest, intravenous vasopressin induced an
vasopressin may include that the same
increase in blood pressure, and in some
dose
cases, return of spontaneous circulation,
well.
Additional
can
be
advantages
effectively
administered
intravenously, endobronchially
intraosseously
[19]
, and
, rendering usage of
[20]
patients
where
with
standard
compressions,
refractory
therapy
cardiac
with
ventilation,
chest
defibrillation,
this vasopressor during CPR simple and
and epinephrine had failed
. After
rapid. In addition,
approximately 40 mins of unsuccessful
[33]
advanced cardiac life support, four of ten
patients had a mean increase in coronary
234
perfusion pressure of 28 mm Hg
repeated administration of vasopressin,
a
but
to
randomized investigation of patients with
perfusion
out-of-hospital ventricular fibrillation, a
pressure and ventricular fibrillation mean
significantly larger proportion of patients
frequency
treated with vasopressin were successfully
not
epinephrine,
maintain
both
[21]
coronary
pathology
phase,
[22]
recovery
[23]
able
during prolonged advanced
cardiac life support
neurologic
was
small
(n
, and ensured full
resuscitated,
with
compared
no
brain
. In the postresuscitation
vasopressin-mediated
=
and
with
epinephrine
[34]
40)
. In
prospective,
survived
patients
[14]
24
hrs
treated
with
. Scientists at Leopold
increased
Franzens University in Innsbruck, Austria
systemic vascular resistance resulted into
are currently coordinating a multicenter
a transient reversible depressant effect
randomized clinical trial in Europe under
on cardiac output
the aegis of the European Resuscitation
[24]
. Although renal
and splanchnic perfusion may be impaired
Council
during
vasopressin
[25]
and
after
[26]
CPR
with
to
study
vs.
the
epinephrine
in
out-of-
hospital
renal function after CPR was influenced
Efficiency of a CPR intervention is judged
by vasopressin
in regard to its effects on long-term
; continuous infusion
patients
of
vasopressin, neither renal blood flow nor
[27]
cardiac arrest
effects
[35]
.
survival
and
dilemma
is
neurologic
that,
outcome.
because
of
a
The
large
pressure in a canine model of CPR. The
question
is, does the
combination
of
variety of confounding variables, such a
endothelin-1 and epinephrine improve 24-
study requires ~15,000 patients, several
hr survival from cardiac arrest? To study
years, and millions of U.S. dollars--items
this possibility, the University of Arizona
that are hard to come by, as healthcare
CPR Research Group placed swine into
and
ventricular
research
throughout
funding
the
is
world;
decreasing
furthermore,
fibrillation
and
untreated for 2 mins
left
them
. Basic CPR
[36]
commercial manufacturers of vasopressin
was then begun and continued for the
have no interest in this drug inasmuch as
next 6 mins. At 8 mins, the animals
the patent is expired. As such, the
were administered epinephrine (1 mg)
primary
intravenously
either
vasopressor study (anticipated number of
endothelin-1
(0.1
patients,
compressions
end
point
of
1,500)
the
are
European
effects
of
and
vasopressin vs. epinephrine on short-term
were
continued
survival--not
mins.
Both
the
optimum,
but
a
alone
or
plus
mg).
assisted
for
an
groups
Chest
ventilation
additional
received
10
additional
realistic solution.
doses of epinephrine at 5-min intervals;
The monitoring committee of the study
at 18 mins of cardiac arrest including 16
met in June
mins
2000 to conduct the
of
CPR,
defibrillation
preliminary analysis. It was determined
attempted.
that the study is safe; randomization
greater return of spontaneous circulation
works out as planned; no adverse effects
in
or
combination
complications
were
reported;
and
the
Although
animals
there
was
who
of
was
received
a
the
endothelin-1
plus
there is a good chance of successfully
epinephrine, the 1-hr and 24-hr survival
completing
were both less. This was the result of a
the
trial
as
planned
on
randomizing 1,500 patients. By October
marked
2000, we had randomized 450 patients,
combination
indicating
of
endothelin-1 in the doses used. There
randomization--currently, 36 ground and
was a marked increase in the coronary
5 rotor-winged emergency medical service
perfusion
vehicles
are
employed
narrowing of the pulse pressure, and a
patients
in
Germany,
an
increased
speed
to
randomize
Austria,
and
Switzerland.
marked
vasoconstricting
of
in
of
epinephrine
pressure,
drop
effect
the
but
a
the
and
dramatic
end-tidal
carbon
dioxide level indicating a marked decrease
in forward blood flow. Results from a
canine study suggested that endothelin-1
CPR
with
Endothelin-1
in
Laboratory
Investigations
circulation after cardiac arrest
Endothelin-1
is
vasoconstrictor.
DeBehnke
reported
may contribute to the failure of cerebral
that,
a
powerful
et
[7]
. In
summary, it had been axiomatic that
increased
vasoconstriction
during
CPR
with
improves coronary perfusion pressure, and
endothelin-1 or epinephrine by itself, the
thereby immediate resuscitation success;
combination
however,
of
compared
al.
[37]
endothelin-1
plus
epinephrine improved coronary perfusion
our
data
vasoconstriction
can
indicate
be
that
excessive.
Postresuscitation
left
ventricular
2. Robertson C, Steen P, Adgey J, et
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