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(Circulation. 1997;96:2709-2714.)
© 1997 American Heart Association, Inc.
Articles |
Is Epinephrine Contraindicated During Cardiopulmonary Resuscitation?
From the Department of Anesthesiology, University of South Florida College of Medicine, Tampa.
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Abstract |
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Background Why pulmonary gas exchange deteriorates after administration of epinephrine during cardiopulmonary resuscitation (CPR) is unclear.
Methods and Results Forty-four anesthetized swine
received an infusion of six inert gases. Animals underwent
ventricular fibrillation with CPR and
intravenous administration of saline (control),
epinephrine (15 µg/kg), or methoxamine (150 µg/kg).
Cardiac output, aortic blood pressure, pH, and arterial
oxygen saturation were recorded. Distributions of
A and 
were determined by the multiple inert
gas elimination technique. Ventricular fibrillation and CPR
caused significant decreases in cardiac output, aortic blood pressure,
and arterial pH. With epinephrine (versus saline),
diastolic blood pressure was significantly higher (23±7
versus 8±4 mm Hg), but the increase in shunt (from 7±4% to
29±17%) and the reduction in SaO2 (from
99.7% to 76.8%) were significantly larger. Also, the increase in dead
space was greater and elimination of CO2 less. There were
no differences between animals given methoxamine or saline,
except for increased diastolic blood pressure.
Conclusions During experimental ventricular
fibrillation and CPR, epinephrine increased
intrapulmonary shunt 
300% more than saline or
methoxamine and significantly reduced arterial
oxygen saturation. We suspect that the ß-adrenergic receptor activity
of epinephrine attenuated hypoxic pulmonary
vasoconstriction. Methoxamine is as effective a pressor as
epinephrine for CPR and devoid of ß-adrenergic activity. We
recommend that such an agent be considered, instead of
epinephrine, for CPR.
Key Words: methoxamine • cardiopulmonary resuscitation • epinephrine • fibrillation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Studies have shown that during cardiopulmonary resuscitation (CPR), pulmonary gas exchange becomes less efficient after administration of epinephrine.1 2 Unfortunately, these investigations have used only determinations of the difference between the alveolar and arterial partial pressures of oxygen and measurements of the partial pressure of end-tidal carbon dioxide. Such calculations do not allow one to differentiate and quantify the various abnormalities that cause mismatching of alveolar ventilation (the volume of alveolar gas in the tidal volume per minute,
A) and perfusion (the volume of blood passing
through the lungs per minute, ).
For example, use of indices derived from oxygen tension would not
reveal whether the cause of impaired gas exchange was right-to-left
intrapulmonary shunting of blood, perfusion of lung units
having a low value for the ventilation-to-perfusion ratio (), a
defect in oxygen diffusion, or venous admixture from the thebesian
(cardiac) and bronchial circulations. Likewise, use of indices derived
from carbon dioxide tension would not reveal whether the cause was true
dead space ventilation or ventilation of lung units having a high but
finite value for A. Moreover, these indices of gas
exchange do not permit determination of whether impairment of the
process resulted from a change in the distribution of alveolar
ventilation or blood flow or both.
Cardiac output and pulmonary blood flow decrease significantly during ventricular fibrillation and CPR. The marked reduction in cardiac output in turn causes a much greater distribution of blood flow to gravity-dependent lung units than to nondependent lung units.3 Positive-pressure breathing, as occurs during CPR, asymmetrically distributes alveolar ventilation to nondependent versus dependent lung units.4 Therefore, significant mismatching of ventilation and perfusion will probably occur during CPR.
Theoretically, the ß-adrenergic effects of epinephrine would
produce bronchodilation that could affect the distribution of
ventilation. However, because epinephrine activates
both 
-and ß-receptors, both pulmonary vasoconstriction
() and vasodilation (ß) are possible. Therefore, to determine the
mechanism of epinephrine-induced deterioration of
pulmonary gas exchange, we examined the distribution of
ventilation and perfusion, relative to regional ratios, that
were determined by the multiple inert gas elimination
technique5 during ventricular fibrillation and
CPR in swine.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Preparation
After approval of the Institutional Animal Care and Use Committee was obtained, swine of either sex were given an injection of ketamine hydrochloride (25 mg/kg IM) followed by sodium pentobarbital (25 mg/kg and 8 mg · kg-1 · h-1 IV). Subcutaneous needle electrodes were placed for monitoring of the ECG. We positioned the animals in the supine position and intubated the trachea (internal diameter of tube, 7.5 mm) through a tracheostomy. For airway sampling of respired gas, a pneumotachograph (Bicore) was attached to the tracheal tube and was connected to a pulmonary mechanics computer (Bicore). Between the pneumotachograph and breathing circuit, we positioned a gas analyzer (Ultima, Datex) calibrated with room air and a gas mixture of 95% O2 and 5% CO2 (Air Products) and the aspiration port of the sample tubing.
Animals were ventilated by means of an oxygen-powered mechanical ventilator/precordial compressor (Thumper, Michigan Instruments) at the rate of 12 breaths per minute and with a tidal volume adjusted to keep the arterial partial pressure of carbon dioxide (PaCO2) between 35 and 45 mm Hg.
A 7F thermistor-tipped catheter was inserted into the right internal jugular vein and was advanced into a main pulmonary artery. A polyethylene catheter was inserted into the right carotid artery and was advanced into the descending aorta. Each of these two catheters was hydraulically linked to a pressure transducer, and each had its final position confirmed by pressure tracing. A third catheter was inserted percutaneously into an ear vein. A solution of six inert gases representing a wide range of solubilities in blood (sulfur hexafluoride, ethane, cyclopropane, enflurane, diethyl ether, and acetone) was prepared as described elsewhere5 and was infused at the rate of 2.0 mL/min into the ear vein.
Measurements and Calculations
We used a timed recording of the ECG to determine
heart rate and a trace of aortic blood pressure on a calibrated chart
to determine systolic and diastolic blood
pressures. Pulmonary blood flow was derived by the mass balance
method (Fick's principle) using values for the retention and excretion
of sulfur hexafluoride, ethane, cyclopropane, and enflurane and
the minute ventilation.5 Core body temperature was
measured by means of the thermistor-tipped catheter in the
pulmonary artery. The differential pressure produced by the
pneumotachograph was processed by the computer to calculate tidal
volume (VT), respiratory rate, and expired minute volume
(E). We verified the accuracy of these three
computations by simulating tidal ventilation with a giant syringe
(Hamilton Medical), using injection-aspiration cycles of 300 mL at the
rate of 12 per minute. Gas volume was converted to BTPS. We also
measured the fraction of oxygen and carbon dioxide in respired gas.
Following the methods of Wagner et al,5 we obtained 10-mL samples of aortic and pulmonary artery blood simultaneously and in duplicate and used a gas chromatograph (HP 5890, Hewlett-Packard) to assay the samples immediately for their concentrations of inert gases. The blood-gas partition coefficient for each inert gas was determined for each pig as previously described.5 6 We also obtained separate 5-mL samples of aortic and pulmonary artery blood simultaneously and in duplicate and used the appropriate electrodes (IL 1301, Instrumentation Laboratories) to assay the samples immediately for respiratory gas tensions and pH. The hemoglobin content and oxyhemoglobin saturation of these samples were assayed spectrophotometrically (Co-oximeter IL 282, Instrumentation Laboratories). We then used a computer program developed by Ruiz et al7 to convert oxyhemoglobin saturation values to reflect the oxygen-combining characteristics of adult pig hemoglobin.6
Expired gas was collected with a heated corrugated hose and a 9-L box heated to 40°C to 42°C and was vented to the ambient atmosphere through a calibrated Wright respirometer (British Oxygen Co) for collaborative measurement of minute ventilation. We sampled mixed expired gas in duplicate from the collection box for assay of inert gas tensions (gas chromatography) and respiratory gas tensions (gas analyzer). Airway sampling of respired gas was suspended during the collection of expired gas and the determination of lung mechanics.
We determined arterial (CaO2) and
mixed venous (C¯vO2) oxygen content,
respectively, from arterial and mixed venous oxygen tension
and arterial and mixed venous oxyhemoglobin saturation from
the following equation: oxygen content= (oxyhemoglobin
saturationxhemoglobin contentx1.32)+(partial pressure of
oxygenx0.0031). Systemic oxygen delivery was computed as the
product of arterial blood oxygen content and cardiac
output. We calculated the uptake of oxygen and the elimination of
carbon dioxide as the product of minute ventilation and the
difference between the percentages of inspired and mixed expired oxygen
or carbon dioxide, respectively. Intrapulmonary shunting of
blood was estimated from the equation
ps/t=(C
O2-CaO2)/(CO2-C¯vO2),
where ps is physiological shunt, t is
cardiac output, and CO2 is the oxygen
content of alveolar capillary blood, as determined by assuming a
capillary oxygen tension calculated according to the alveolar air
equation.8 Extrapulmonary venous admixture was
assessed by comparing the shunt value derived from the classic equation
with the value derived by the inert gas technique. We assessed the
presence of an oxygen diffusion defect by comparing the measured
partial pressure of oxygen in arterial blood
(PaO2) and the PaO2
predicted by the multiple inert gas elimination
technique.9
Inert Gas Analysis
The details for determining the distribution of blood flow and
ventilation as a function of the A/ ratio
appear elsewhere.5 6 Briefly, for each inert gas, the
retention ratio (the ratio of the partial pressure of the gas in
arterial blood to that in mixed venous blood) and the
excretion ratio (the ratio of the partial pressure of the gas in mixed
expired gas to that in mixed venous blood) were plotted against
solubility of the gas. Then, by use of a computer program written in
FORTRAN that incorporates the mathematical approach of Evans and
Wagner,10 values for retention and excretion were
transformed into a plot of the percentage of total ventilation and
blood flow as a function of A/ by a linear
least-squares regression method with enforced smoothing (smoothing
coefficient, Z=40).
We classified the distributions of A and
relative to the value for A/ as follows: (1)
perfusion of unventilated lung regions (right-to-left
intrapulmonary shunting of venous blood), ie, areas having a
value of almost zero (
0.005) for A/; (2)
perfusion of poorly ventilated lung units, ie, lung regions having a
low value (>0.005 through 0.1) for A/; (3)
perfusion of lung regions having a normal value (>0.1 through 10) for
A/; (4) ventilation of poorly perfused lung
regions, ie, those having a high value (>10 through 100) for
A/; and (5) ventilation of unperfused lung
regions (dead space), ie, those having a very high value (>100) for
A/. Perfusion and ventilation as functions of
A/ are expressed as percentages of
pulmonary blood flow and minute ventilation, respectively. The
SD of the ventilation distribution (LSD|$$&MIDDOT;)
was computed and reflects changes in ventilation
heterogeneity.
Investigative Procedures
We collected baseline data at least 60 minutes after initiating
infusion of inert gases and when animals were stable: that is, when
minute ventilation, end-tidal carbon dioxide
(PETCO2), heart rate, and mean
arterial blood pressure had not changed more than 10% over
three consecutive observation periods, each period being 5 minutes.
Then, ventricular fibrillation was induced with
transthoracic electrocution (400 W/s), and animals
underwent CPR by means of mechanical precordial compression (60
compressions per minute). Ventilation (12 breaths per minute) was
provided at a compression-to-ventilation ratio of 5:1 and a
compression-to-relaxation ratio of 1:1. Compression force was adjusted
to produce sternal displacement of 25% of the anteroposterior thoracic
diameter.11
After the start of CPR, animals were randomly assigned to receive an injection of 5.0 mL IV of physiological saline alone or with epinephrine (15 µg/kg) or methoxamine (150 µg/kg) immediately and every 5 minutes for 15 minutes. After 15 minutes of CPR, we again collected data. Animals were euthanized without attempting defibrillation.
Data Management
Data are summarized as mean±SD. We used the Levine median test
to assess the variance for response variables. When the variance of
response variables during intragroup or intergroup comparisons was
equal (P>.05) or not equal (P<.05), statistical
analysis was performed with, respectively, a parametric
or nonparametric statistic. Intragroup statistical
comparisons were performed with Student's t test for paired
observations when variance was equal or the Mann-Whitney rank sum test
when variance was not equal. When the variance of the data was equal,
intergroup comparisons were performed with an ANOVA for repeated
measures; when P<.05, differences were distinguished with
Tukey's test. Intergroup data with unequal variance were compared by
the Kruskal-Wallis ANOVA on ranks; when P<.05, differences
were distinguished with Dunnett's method. Statistical analyses
were performed with SigmaStat computer software (version 2.0, Jandel
Scientific).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Forty-four swine (23±2 kg) underwent positive-pressure ventilation with comparable minute ventilation (5.4±1.2 L/min) and inspired concentrations of oxygen (0.95±0.03) throughout the study, and those data were pooled for summary. Data are summarized in the Tables and Figs 1
and 2. There were no between-group
differences in cardiopulmonary function before induction of
ventricular fibrillation and initiation of CPR. The results
of ventricular fibrillation and CPR by themselves and with
epinephrine or methoxamine are as follows.
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P<.008 vs "after" columns for saline or
methoxamine.
With Saline (Control Animals, n=14)
By themselves, ventricular fibrillation and CPR
decreased pulmonary blood flow and blood pressure;
arterial blood pH, oxygenation, and
PCO2; oxygen uptake and delivery; and
elimination of carbon dioxide. Dead space and shunting of inert gases
increased. Data are summarized in the Tables and Figs 1
and 2.
With Epinephrine (n=15)
Although the consequences of CPR with epinephrine versus
saline were similar, diastolic blood pressure was higher
with epinephrine. Intrapulmonary shunting and dead
space ventilation also were greater, conditions that significantly
decreased PaO2 and arterial blood
oxygen saturation (SaO2) and increased
PaCO2, respectively. The latter caused
arterial pH to be significantly lower with
epinephrine than saline or methoxamine. Dead space
ventilation was increased by epinephrine compared with saline
and methoxamine. Data are summarized in the Tables and Figs 1 and 2.
With Methoxamine (n=14)
The consequences of CPR with methoxamine versus saline
were similar, except that diastolic blood pressure was
higher with methoxamine. Data are summarized in the Tables and
Figs 1 and 2.
Intergroup Comparisons
When right-to-left intrapulmonary shunting of blood
(percentage of cardiac output), as determined by the classic
two-compartment model, was compared with shunting of inert gases,
similar values resulted for the saline (10.3±5.8% versus 9.8±5.9%),
epinephrine (30.8±23.9% versus 29.3±16.9%), and
methoxamine (17.9±11.4% versus 16.5±10.7%) groups. This
similarity indicated that a comparable small degree of
extrapulmonary venous admixture occurred in the animals of all
three groups. There was no evidence of an oxygen diffusion defect,
because no significant difference existed between the measured
PaO2 and the predicted
PaO2 after administration of saline (265±142
versus 283±167 mm Hg), epinephrine (143±120 versus
159±137 mm Hg), or methoxamine (216±185 versus
231±176 mm Hg).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We were able to define the mechanism by which epinephrine impaired gas exchange during ventricular fibrillation and CPR in swine. Animals given epinephrine had more right-to-left intrapulmonary shunting of blood and more ventilation of dead space during CPR than those given saline or methoxamine. We found no evidence of increased extrapulmonary venous admixture, and we believe that epinephrine increased blood flow to unventilated alveoli, probably by attenuating hypoxic pulmonary vasoconstriction that most likely results from activation of ß-adrenergic receptors.
Martin and colleagues1 observed a decrease in PETCO2 after administration of epinephrine in dogs, despite constant minute ventilation during ventricular fibrillation and CPR. The authors speculated that the pulmonary vasoconstrictive effects of epinephrine may have increased shunting and thus impaired elimination of carbon dioxide. As an alternative mechanism, they also suggested that epinephrine may have increased right ventricular afterload, thereby reducing pulmonary blood flow and elimination of carbon dioxide. In view of our findings, it is likely that their observation was secondary to an increase in alveolar dead space.
Tang and associates2 reported a decrease in
PaO2 and PETCO2 after
administration of epinephrine but not methoxamine or
saline during ventricular fibrillation and CPR in rats.
Also, PaCO2 was higher and pH lower with
epinephrine than with saline or methoxamine. Rats
treated with epinephrine needed significantly more electrical
countershocks for conversion of cardiac rhythm from
ventricular fibrillation to a functional rhythm and for
restoration of spontaneous circulation. The authors speculated that the
adverse effect of epinephrine on pulmonary gas exchange
might have been caused by diversion of blood from well-ventilated to
poorly ventilated alveoli (via -adrenergic–mediated
vasoconstriction) and release of hypoxic vasoconstriction (via
ß-adrenergic–mediated vasodilation).
Previous investigations have not quantified pulmonary blood flow and have used measurements unsuitable to distinguish and quantify the elements contributing to inefficient elimination of carbon dioxide1 2 and deficient oxygenation2 induced by epinephrine during CPR. Moreover, results of these studies do not permit assessment of the presence of anatomic arteriovenous shunting within the lung12 or pulmonary edema,13 both of which have been observed after administration of epinephrine in dogs.
Impaired oxygenation during CPR frequently is
attributed to pulmonary edema,14 15 16 the mechanism
of which is unclear. Intracardiac and intrathoracic vascular pressures
generated during effective cardiac compression are nearly equal to and
often exceed 60 mm Hg.17 The combination of low
cardiac output and high pulmonary venous pressure may increase
permeability of the endothelium, thereby increasing
extravascular lung water. In turn, pulmonary edema may impair
gas exchange by compressing airways and alveoli (resulting in shunting
and/or A/ mismatch) and may limit oxygen
diffusion. During CPR, an elevated concentration of inspired oxygen
will mask the effects of a mismatch of ventilation and perfusion and a
defect in oxygen diffusion but will not mask the effects of atelectasis
or arteriovenous shunting. Therefore, we used the multiple inert gas
elimination technique to quantify the contribution of each mechanism to
the defect in gas exchange during CPR and to compare the effects of
epinephrine and methoxamine.
Despite having similar mechanical ventilatory and cardiac support,
inspired concentrations of oxygen, pulmonary blood flow, and
mixed venous oxygen tensions, animals given epinephrine had
more right-to-left shunting of blood and ventilation of dead space than
those given either saline or the pure -adrenergic agent
methoxamine (these two groups were similar in results).
Distribution of blood flow and ventilation is normally such that gas
exchange in alveolar blood is optimized. However, when alveolar
hypoxemia occurs, compensatory pulmonary vasoconstriction
diverts blood to better-ventilated alveoli. Hypoxic vasoconstriction is
enhanced when the oxygen tension of mixed venous blood is lower than
normal.18 Thus, pulmonary vasoregulation limits
the effect of poor ventilation of the alveoli on arterial
oxygenation. Hypoxic pulmonary vasoconstriction
is particularly important during hypercapnia, acidemia, and extremely
low oxygen tension in mixed venous blood. The increase in blood flow to
poorly ventilated alveoli and the concomitant reduction in blood flow
to well-ventilated alveoli with epinephrine suggest that the
drug attenuates hypoxic pulmonary vasoconstriction. The
epinephrine-induced increase in inert gas shunt was reflected
by significant arterial oxyhemoglobin desaturation (see Fig 1).
Shunting and dead space ventilation induced by epinephrine was responsible for significant arterial oxyhemoglobin desaturation, increased PaCO2, and acidemia. Arterial oxyhemoglobin saturation decreased more with epinephrine than with saline or methoxamine. Arterial blood oxygen content did not decrease significantly, only because the concentration of hemoglobin increased in animals who received epinephrine. The reported mobilization of blood from the spleen and liver of dogs and cats19 20 may account for the increase in hemoglobin content seen in our animals. Alternatively, animals who received epinephrine may have had greater extravasation of intravascular fluid, causing a relative concentration of the hemoglobin. Such increases in hemoglobin content have not been reported to occur in humans undergoing CPR. Therefore, a comparable reduction in oxyhemoglobin saturation would markedly reduce oxygen content and delivery. Oxygen delivery is already critically low during CPR, and further decreases in oxygen saturation and content are undesirable. Animals who received epinephrine had elevation of PaCO2. Animals given saline or methoxamine had lower PaCO2 values, despite equivalent minute ventilation. These differences were of physiological significance. The increase in dead space and shunt was associated with a reduction in carbon dioxide elimination and respiratory acidosis. This would necessitate an increase in ventilation, which would decrease venous return and oxygen delivery further. This also might explain why PaCO2 increases after the administration of sodium bicarbonate during cardiopulmonary resuscitation, ie, increased production of carbon dioxide coincident with decreased carbon dioxide elimination. Thus, methoxamine may render sodium bicarbonate more efficacious than previously appreciated. Moreover, although cardiac output produced with methoxamine and epinephrine is similar, because blood flow to unventilated alveoli is not oxygenated and CO2 is not removed, the cardiac output produced by epinephrine is functionally 20% less effective than that produced by methoxamine.
The goal of CPR is to restore cardiopulmonary function and
perfusion of vital organs so that disruption of vital organ function is
minimal. The success of resuscitation depends on the
maintenance of adequate systemic blood flow and
oxygenation of arterial blood and on the
minimization of the detrimental effects of CPR. Epinephrine has
been the preferred adrenergic agent for the management of cardiac
arrest for more than three decades. Animal studies and anecdotal
reports involving patients have provided the rationale for its
use.21 22 23 24 In contrast, some authors argue that
ß-adrenergic stimulation might be deleterious during and after
resuscitation because of the increase in myocardial oxygen
demand.25 The ability of epinephrine to restore
spontaneous circulation from ventricular fibrillation and
asystole has been shown to be a result of its
1-adrenergic effect. Although other agents having
selective 1-adrenergic effects (such as
phenylephrine and methoxamine) have been as
effective as epinephrine in restoring spontaneous circulation
after cardiac arrest,12 13 15 26 27 they are not currently
recommended for CPR. We did not attempt defibrillation in the
present study.
Our data indicate that the epinephrine-induced
deterioration in pulmonary gas exchange during CPR results from
a diversion of blood flow from relatively well ventilated to
unventilated alveoli. Distribution of blood flow to unventilated
alveoli was similar in swine given saline or the selective
1-adrenergic receptor agonist methoxamine,
suggesting that the ß-agonistic activity of epinephrine
blunts or prevents hypoxic pulmonary vasoconstriction. Such an
event would increase blood flow to unventilated alveoli and the
shunting of blood. Because shunt and dead space were increased by
epinephrine, blood flow to ventilated alveoli was decreased.
ß-Adrenergic control of anatomic shunts has also been studied by
Shirai et al.28 In cats, the internal diameter of small
pulmonary arteries and veins (100 to 600 µm) was
measured during global alveolar hypoxia. The reduction in
arterial lumen diameter was greater if cats had received
propranolol before experiencing alveolar hypoxia.
The authors concluded that hypoxic pulmonary vasoconstriction
was attenuated by a ß-adrenergic receptor–mediated vasodilation
caused by reflex release of catecholamine from the adrenal
gland and sympathetic nerves. In our study, the only difference was
that the catecholamine (epinephrine) was
administered exogenously.
We conclude that epinephrine but not methoxamine
exacerbates hypoxemia and acidosis and therefore may not be the drug of
choice for CPR. Use of a selective -adrenergic receptor agonist such
as methoxamine would increase diastolic blood
pressure without adversely affecting pulmonary gas exchange.
Because such an agent would be as effective in resuscitation from
experimental ventricular fibrillation, it may be a more
appropriate agent for CPR than epinephrine.
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Footnotes |
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Reprint requests to Editorial Office, Department of Anesthesiology, MDC 59, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612.
Received November 25, 1996; revision received May 15, 1997; accepted May 28, 1997.
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 K. Naganobu, Y. Hasebe, Y. Uchiyama, M. Hagio, and H. Ogawa A Comparison of Distilled Water and Normal Saline as Diluents for Endobronchial Administration of Epinephrine in the Dog Anesth. Analg., August 1, 2000; 91(2): 317 - 321. [Abstract] [Full Text] [PDF]
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