(Circulation. 1997;95:2610-2613.)
© 1997 American Heart Association, Inc.
Articles |
Postresuscitation Left Ventricular Systolic and Diastolic Dysfunction
Treatment With Dobutamine
From the University Heart Center and the Department of Medicine (K.B.K., R.W.H., G.A.E.), the Department of Pediatrics (R.A.B., K.H.R.), the Department of Surgery (A.B.S.), and the Department of Anesthesiology (C.W.O.), University of Arizona College of Medicine, Tucson.
Correspondence to Karl B. Kern, MD, Department of Medicine, Section of Cardiology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724. E-mail kernk{at}u.arizona.edu
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Global left ventricular dysfunction after successful resuscitation is well documented and appears to be a major contributing factor in limiting long-term survival after initial recovery from out-of-hospital sudden cardiac death. Treatment of such postresuscitation myocardial dysfunction has not been examined previously.
Methods and Results Systolic and
diastolic parameters of left
ventricular function were measured in 27 swine before and
after successful resuscitation from prolonged ventricular
fibrillation cardiac arrest. Dobutamine infusions (10
µg·kg-1·min-1
in 14 animals or 5
µg·kg-1·min-1
in 5 animals) begun 15 minutes after resuscitation were compared with
controls receiving no treatment (8 animals). The marked deterioration
in systolic and diastolic left
ventricular function seen in the control group after
resuscitation was ameliorated in the dobutamine-treated
animals. Left ventricular ejection fraction fell from a
prearrest 58±3% to 25±3% at 5 hours after resuscitation in the
control group but remained unchanged in the dobutamine (10
µg·kg-1·min-1)
group (52±1% prearrest and 55±3% at 5 hours after resuscitation).
Measurement of the constant of isovolumic relaxation of the left
ventricle (
) demonstrated a similar benefit of the
dobutamine infusion for overcoming postresuscitation
diastolic dysfunction. The rose in the controls from
28±1 milliseconds (ms) prearrest to 41±3 ms at 5 hours after
resuscitation whereas it remained constant in the
dobutamine-treated animals (31±1 ms prearrest and 31±5 ms
at 5 hours after resuscitation).
Conclusions Dobutamine begun within 15 minutes of successful resuscitation can successfully overcome the global systolic and diastolic left ventricular dysfunction resulting from prolonged cardiac arrest and cardiopulmonary resuscitation.
Key Words: cardiopulmonary resuscitation • cardiac arrest • fibrillation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Significant left ventricular dysfunction, including both systolic and diastolic dysfunction, has been documented after successful resuscitation from prolonged cardiac arrest.1 2 3 4 This dysfunction peaks in an experimental model at 2 to 5 hours after resuscitation.1
Postresuscitation systolic left ventricular dysfunction is manifested by a decreased ejection fraction, a decrease in fractional shortening, a decrease in dP/dt-40, a decreased peak systolic left ventricular pressure/end-systolic volume ratio, and a rightward shift in the pressure-volume relationship.1 2 3 4 The global nature of this systolic dysfunction has been shown with contrast ventriculograms as well as with transthoracic echocardiography.1
A compromise in left ventricular diastolic
function has also been demonstrated after resuscitation from prolonged
cardiac arrest.1 2 3 A rise in left ventricular
end-diastolic pressure and a decrease in -dP/dt occur, whereas the
hemodynamically determined time constant of pressure
decline during isovolumic relaxation () demonstrates abnormal left
ventricular relaxation. Transthoracic
echocardiographic examinations after resuscitation
reveal diastolic left ventricular dysfunction
as manifested by a decrease in mitral valve deceleration time and an
increase in left ventricular isovolumic relaxation
time.1
The present study was designed to investigate the use of dobutamine as a treatment for global left ventricular dysfunction after resuscitation from prolonged cardiac arrest.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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All animal experiments were done in accordance with the American Physiological Society's policy for research animal use and with the approval of the University of Arizona Institutional Animal Care and Use Committee.
Animal Preparation
The methodology has been published previously.1 In
brief, 27 domestic swine (weight, 29±1 kg) were anesthetized
with isoflurane. Eight of the 27 animals were included from a previous
and similar protocol1 but were not given any form of
postresuscitation treatment and served as historical controls. Fourteen
animals were studied for the effect of dobutamine (10
µg·kg-1·min-1)
on postresuscitation left ventricular dysfunction. Five
additional animals were studied for the effect of
dobutamine at 5
µg·kg-1·min-1.
Each animal was endotracheally intubated and then instrumented with
monitoring ECG leads and micromanometer-tipped
pressure transducer catheters in the left ventricle, aorta, and right
atrium. A pulmonary artery catheter and a right
ventricular pacing catheter (for electrical induction of
ventricular fibrillation) were inserted.
Systolic Parameters of Left Ventricular
Function
Contrast ventriculograms were performed for the
calculation of ejection fraction, end-diastolic volume,
end-systolic volume, stroke volume, and regional wall motion.
Left ventricular pressure was measured with high-fidelity,
micromanometer-tipped catheters (Millar). Peak left
ventricular systolic pressure/end-systolic
volume ratios were calculated as a load-independent measure of
systolic function.5 Pulmonary artery
pressures were measured with a fluid-filled pulmonary artery
catheter (Baxter).
Diastolic Parameters of Left
Ventricular Function
Diastolic function was measured
hemodynamically and
echocardiographically. The time constant of isovolumic
left ventricular relaxation () was calculated by use of
high-fidelity, micromanometer-tipped catheter
pressure measurements and a custom-designed computer
program.1 6 Doppler echocardiographic
measures of diastolic function, including mitral valve
deceleration time and left ventricular isovolumic
relaxation time, were performed at baseline and at 5 hours after
resuscitation.
Experimental Protocol
Pre–cardiac arrest baseline data evaluating left
ventricular systolic and diastolic
function were obtained, and electrical stimulation of
ventricular fibrillation was then performed. Untreated
ventricular fibrillation cardiac arrest was allowed to
continue for 15 minutes. At that time, aggressive
cardiopulmonary resuscitation, including advanced cardiac life
support with the administration of 1 mg of intravenous
epinephrine and defibrillation, was performed. The eight
control animals received no therapy after resuscitation. Fourteen
animals were treated with dobutamine (10
µg·kg-1·min-1)
begun within 15 minutes of successful resuscitation. Five animals were
studied in a post hoc fashion with the use of 5
µg·kg-1·min-1
of dobutamine. Postresuscitation data were obtained at 30
minutes, 2 hours, and 5 hours after successful resuscitation.
Statistical Analysis
Comparisons between control and treatment groups were made at
four different time intervals (baseline, 30 minutes, 2 hours, and 5
hours) by use of Student's t test for unpaired values with
a Newman-Keuls multiple comparison correction factor. Repeated measures
ANOVA was used to compare the mean values of all left
ventricular function variables within each group over
time from a prearrest baseline and at 30 minutes, 2 hours, and 5 hours
after resuscitation. A Newman-Keuls multiple comparison procedure was
performed to further identify specific differences between the
different time intervals. A significant difference was assumed when a
value of P=.05 was reached. All data are presented
as mean±SEM. Data analysis was performed with the use of the
commercially available software program True Epi-Stat, version 5.2.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Left Ventricular Systolic Function and Dobutamine
Ejection fraction was found to progressively decline in the control group from baseline to 5 hours after resuscitation (P<.05). However, the dobutamine-treated (10 µg·kg-1·min-1) group showed no such decline over the same period. There were significant differences in ejection fraction between the control and dobutamine-treated groups at 30 minutes, 2 hours, and 5 hours after resuscitation (Figure
). Heart rate was
significantly higher in the dobutamine-treated group at 30
minutes, 2 hours, and 5 hours after resuscitation (P<.05).
Pulmonary capillary wedge pressure was significantly decreased
at 30 minutes and at 2 hours in the dobutamine-treated
group (P<.05). No change was seen in
end-diastolic volume, but end-systolic volume was
significantly less at 5 hours in the treatment group, and stroke volume
was subsequently increased significantly at 5 hours in the
dobutamine-treated group (P<.05). Peak
systolic left ventricular
pressure/end-systolic left ventricular volume
ratios were also greater with dobutamine at 5 hours after
resuscitation (P<.05). Table 1 summarizes
these hemodynamic and volume
parameters.
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Left Ventricular Diastolic Dysfunction
and Dobutamine
Left ventricular end-diastolic pressure
showed a marked rise in the control group at all time points after
resuscitation but was unchanged in the dobutamine group
(P<.05). The , though slightly different at baseline,
was markedly prolonged at 5 hours after resuscitation in control
animals but was unchanged from baseline levels in
dobutamine-treated animals.
Doppler echocardiographic examinations demonstrated a decline in left ventricular diastolic function in both the control group and the dobutamine group at 5 hours after resuscitation. Mitral valve deceleration time decreased from 88±2 to 64±8 milliseconds (ms) (P<.05) in the control group and from 98±5 to 64±4 ms (P<.001) in the dobutamine-treated group. Left ventricular isovolumic relaxation time also worsened, showing a significant increase in both the control group (58±6 to 82±5 ms; P<.02) and the dobutamine group (70±3 to 88±3 ms; P<.01).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This is the first report of successful treatment of postresuscitation left ventricular systolic and diastolic dysfunction. The ß-adrenergic agonist dobutamine was used at the clinically relevant dose of 10 µg·kg-1·min-1 previously shown to enhance left ventricular function in chronic heart failure.7 Left ventricular ejection fraction, peak systolic pressure, end-systolic volume ratios, end-systolic volume, and stroke volume normalized with dobutamine therapy. Wedge pressure also improved with dobutamine in this model of global left ventricular dysfunction.
Limited data are available on the effect of dobutamine on left ventricular diastolic function,8 9 10 and no data exist concerning the treatment of diastolic dysfunction after prolonged cardiac arrest. It is postulated that dobutamine improves diastolic relaxation of the left ventricle through the same mechanism by which it improves systolic function, mainly by increasing cAMP levels in the cardiac myocytes. cAMP increases calcium flux across the sarcolemma during the action potential but also enhances the rate of calcium uptake by the sarcoplasmic reticulum, whereas the calcium sensitivity of the individual myofibril is decreased. The cumulative effect of ß-adrenergic stimulation is an increase in myocardial contractile strength and a shortening of ventricular relaxation time.9
Carroll et al10 reported an improvement in ventricular relaxation in 12 patients with diffuse congestive cardiomyopathy treated with dobutamine (10 µg·kg-1·min-1), but the data herein reported are the first to show improved diastolic relaxation in the immediate postresuscitation setting.
The echocardiographic parameters of
diastolic left ventricular function continued
to be abnormal at 5 hours after resuscitation in the
dobutamine group. This was distinctly opposite from the
improvement in hemodynamic parameters of
diastolic function (). Secondary to the difficulty in
obtaining good echocardiographic data (because of the
dobutamine-induced tachycardia), the
dobutamine was temporarily stopped for 10 minutes before
the fifth-hour echocardiograms. The half-life of
intravenous dobutamine is only 2 to 3 minutes.
Therefore, no dobutamine effect was present 10 minutes
after its cessation. The abnormal left ventricular
diastolic function reappeared and was documented by
Doppler echocardiography demonstrating
shortened mitral valve deceleration times and prolonged isovolumic
relaxation times. In contrast, was measured during the ongoing
dobutamine infusion. This apparent discrepancy confirms the
effectiveness of dobutamine for the immediate treatment of
left ventricular dysfunction after resuscitation but also
reconfirms that such dysfunction may last for up to 48
hours.1
Limitations
Although this is the first report of successful treatment of
postresuscitation global left ventricular dysfunction, the
increased heart rate with dobutamine treatment could
potentially create an increased ischemic burden in those with
underlying coronary artery disease or previous left
ventricular dysfunction.
Due to the excessive increase in heart rate with 10
µg·kg-1·min-1
dobutamine, five additional animals were studied post hoc
using the same protocol except for a lower dose of
dobutamine (5
µg·kg-1·min-1).
Heart rate response was significantly less with 5
µg·kg-1·min-1
and was not different from the control group except early at 30 minutes
after resuscitation (Table 2). Left
ventricular function was better than in the untreated
controls at 2 and 5 hours after resuscitation, but 5
µg·kg-1·min-1
was not as effective as 10
µg·kg-1·min-1
for improving myocardial dysfunction early at 30 minutes after
resuscitation (Table 2). Additional study is planned to investigate the
treatment of postresuscitation left ventricular
dysfunction, including the optimal dosing of dobutamine, in
a porcine model with coronary artery lesions.
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Conclusions
Dobutamine, an intravenous, predominantly
ß1-adrenergic agonist, given in standard clinical doses
of 10
µg·kg-1·min-1
can overcome the global left ventricular systolic
and diastolic dysfunction seen after successful
resuscitation from prolonged cardiac arrest. A dose of 5
µg·kg-1·min-1
produced less tachycardia but was less effective than 10
µg·kg-1·min-1
in improving left ventricular dysfunction, especially at 30
minutes after resuscitation. Optimal dosing of dobutamine
for treating postresuscitation myocardial dysfunction appears to be
between 5 and 10
µg·kg-1·min-1
in this experimental model but needs to be individualized by monitoring
heart rate and left ventricular function. Increased
attention to treatment of postresuscitation left
ventricular dysfunction is warranted.
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Acknowledgments |
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This study was supported in part by a grant from the Arizona Disease Control Research Commission, Phoenix.
Received February 10, 1997; revision received April 15, 1997; accepted April 16, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Raya TE, Gay RG, Lancaster LD, Aquirre M, Moffett C,
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Leier CV, Webel J, Bush CA. The
cardiovascular effects of dobutamine in
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8. Klewer SE, Goldberg SJ, Donnerstein RL, Berg RA, Hutter JJ. Dobutamine stress echocardiography: a sensitive indicator of diminished myocardial function in asymptomatic doxorubicin-treated long-term survivors of childhood cancer. J Am Coll Cardiol. 1992;19:394-401.[Abstract]
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