Postresuscitation Left Ventricular Systolic and Diastolic Dysfunction
Treatment With Dobutamine
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 (τ) demonstrated a similar benefit of the dobutamine infusion for overcoming postresuscitation diastolic dysfunction. The τ 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.
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 (τ) 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.
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.
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 (τ) 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.
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.
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.
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.
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 τ, 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).
This is the first report of successful treatment of postresuscitation left ventricular systolic and diastolic dysfunction. The β-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 β-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 (τ). 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, τ 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
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.
Dobutamine, an intravenous, predominantly β1-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.
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.
- Copyright © 1997 by American Heart Association
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