Anesth Analg 2003;96:1369-1373
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Hemodynamic Interactions of Propofol and Dantrolene in Chronically Instrumented Dogs
Sungsam Cho, MD,
Shiping Zhang, MD,
Hiroyuki Ureshino,
Tetsuya Hara, MD,
Shiro Tomiyasu, MD, and
Koji Sumikawa, MD
Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki, Japan
Address correspondence and reprint requests to Sungsam Cho, MD, Department of Anesthesiology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Address e-mail to chos{at}net.nagasaki-u.ac.jp
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Abstract
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The hemodynamic interaction of dantrolene, a specific drug for malignant hyperthermia, and propofol which appears to be safe in malignant hyperthermia-susceptible patients, has not been investigated. We performed this study to examine the hemodynamic actions of dantrolene at a therapeutic dose during propofol anesthesia. Ten dogs were chronically instrumented for the measurements of systemic and coronary hemodynamics. The dogs were assigned to receive propofol with vehicle or dantrolene in a random manner on separate experimental days. Propofol significantly decreased mean arterial blood pressure, left ventricular systolic and end-diastolic pressure, the maximal rate of increase in left ventricular pressure, and left ventricular regional segment shortening. Coronary blood flow (CBF) was unchanged but coronary vascular resistance (CVR) decreased. Dantrolene reversed the decrease in mean arterial blood pressure and left ventricular systolic pressure caused by propofol, and significantly increased heart rate. However, left ventricular end-diastolic pressure, cardiac output, maximal rate of increase in left ventricular pressure, and segment shortening were unchanged. CBF was significantly increased with a decrease in CVR. These results suggest that dantrolene reverses the hypotensive action produced by propofol and causes an increase in CBF with a decrease in CVR, but does not significantly change the negative inotropic effects. Thus, dantrolene exerts favorable hemodynamic effects during propofol anesthesia.
IMPLICATIONS: Our study suggests that dantrolene reverses the hypotensive action produced by propofol and causes an increase in coronary blood flow with a decrease in coronary vascular resistance, but does not significantly change the negative inotropic effects.
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Introduction
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Malignant hyperthermia (MH) is a potentially fatal hypermetabolic disorder of skeletal muscle triggered in susceptible patients by the administration of volatile anesthetics and depolarizing muscle relaxants during anesthesia (1). MH episodes can be avoided by using nontriggering anesthetics for MH-susceptible patients. However, it is difficult to identify an MH-susceptible patient if neither the patient nor his or her family has previous anesthesia experience. When MH occurs during anesthesia, all triggering drugs should be immediately discontinued and dantrolene, a specific drug for the treatment of MH (2), should be administered. When surgery cannot be stopped, anesthesia should be continued with an alternative anesthetic that is not a known trigger for MH.
Propofol appears to be a safe anesthetic for MH-susceptible patients (3–6). Several studies have shown that propofol produced a negative inotropic effect (7–9), and that dantrolene also has a mild negative inotropic effect in isolated myocardial tissues (10–12). The negative inotropic effects of propofol and dantrolene may be partly attributed to inhibition of transsarcolemmal Ca2+ influx (7,12). Propofol was shown to have a direct vasodilatory effect mediated by the release of nitric oxide (NO) from vascular endothelial cells (13,14). The hemodynamic interaction of dantrolene and propofol has not been fully investigated. Thus, the present study was designed to investigate their combined effects on the systemic and coronary hemodynamics in chronically instrumented dogs.
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Materials and Methods
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Surgical Preparation
All experimental procedures and protocols used in this study were reviewed and approved by the Animal Care and Use Committee of Nagasaki University School of Medicine. Ten healthy mongrel dogs of either sex, weighing 10–15 kg, were fasted overnight and then anesthetized with pentobarbital sodium (20 mg/kg IV) and fentanyl citrate (15 µg/kg IV). After intubation of the trachea, anesthesia was maintained with isoflurane (1.0%–1.2% end-tidal) in 100% oxygen via positive-pressure ventilation. Under sterile conditions, a thoracotomy was performed in the left fifth intercostal space. Heparin-filled catheters (Argyle; UNITIKA Co., Hyogo, Japan) were inserted into the descending thoracic aorta and the right atrium for measurement of arterial blood pressure (AoP) and fluid or drug administration, respectively. A similar catheter was introduced into the left ventricle at the apex for measurement of continuous left ventricular pressure (LVP). The maximal rate of increase in LVP (LV dP/dtmax) was obtained by electronic differentiation of the LVP waveform. A 10-MHz ultrasonic flowprobe (Crystal Biotech, Hopkinton, MA) was positioned around the ascending aorta for measurement of cardiac output (CO). A 1.5- to 2-cm segment of the proximal left circumflex coronary artery was isolated, and a 20-MHz ultrasonic flowprobe (Crystal Biotech) was placed around this vessel for measurement of coronary blood flow (CBF). A pair of miniature ultrasonic segment-length crystals (5 MHz) for measurement of changes in regional contractile function (segment shortening [%SS]) were implanted within the LV subendocardium (10–15 mm apart and 5–7 mm deep) in the area perfused by the left circumflex artery.
After chest closure, the pneumothorax was evacuated and the chest drain removed on the first postoperative day. The instrumentation wires and catheters were exteriorized into a specially designed pouch, which was sewn to the posterior cervical region and protected by a specially designed animal jacket. The dogs were nursed carefully through the first 24 h with IV fluids and were treated with an IV antibiotic, cefodizim sodium (Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) 0.5 g intraoperatively, and 0.5 g a day postoperatively for 1 wk.
The dogs were allowed to recover from the surgery for at least 10 days before subsequent experimentation and were trained to lie quietly in the right lateral position in the laboratory.
Experimental Measurements
AoP and LV systolic pressure (LVSP) were measured with pressure transducers (P10EZ; Nihon Kohden, Tokyo, Japan) positioned at midchest level. The LV end-diastolic pressure (LVEDP) was measured at the time of maximal negative LV dP/dtmax. Heart rate (HR) was calculated by a cardiotachometer triggered by the AoP pulse. CO, CBF, and %SS were driven and monitored continuously by a Cardiovascular Hemodynamics Measurement Total System (Crystal Biotech). Total peripheral vascular resistance (SVR) was calculated as the quotient of mean arterial blood pressure (MAP) and CO. Mean coronary vascular resistance (CVR) was calculated as the quotient of MAP and mean CBF. AoP, LVSP, LVEDP, and LV dP/dtmax were recorded continuously on a seven-channel ink-writing polygraph (ZG66; Nihon Kohden), and CO, CBF, and %SS were recorded continuously digitized by a Compaq computer interfaced with an analog-to-digital converter (Physio-Tech HEM, Tokyo, Japan).
Experimental Protocols
The dogs were assigned to receive propofol (Diprivan®; Zeneca, Osaka, Japan) with vehicle or propofol with dantrolene (Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan) in a random manner on separate experimental days. After the animals were fasted overnight, fluid replacement was accomplished with 500-mL normal saline, and fluid maintenance was continued at 3 mL · kg-1 · h-1 for the duration of each experiment. Instrumentation was calibrated and baseline hemodynamic data were recorded in the conscious state after a 30-min equilibration. Thereafter, anesthesia was induced with propofol 5 mg/kg IV bolus, and maintained with propofol administered continuously at 30 mg · kg-1 · h-1. During anesthesia, the lungs were mechanically ventilated with an air and oxygen mixture adjusted to maintain normal arterial blood gases (PaO2: 100–150 mm Hg, PaCO2: 30–40 mm Hg). After a 30-min equilibration, the dogs received vehicle or dantrolene 2.5 mg/kg IV bolus, and the systemic and coronary hemodynamics were continuously recorded for 60 min.
Drug Preparation
Dantrolene was prepared by adding 15 mL of sterile water to a vial containing dantrolene 20 mg and mannitol 3 g, and sufficient sodium hydroxide to yield a pH of approximately 9.5. Mannitol 20% solution (Nik-ken Co. Ltd., Tokyo, Japan) was used for vehicle. The solution was prepared on the day of the experiment.
All values were presented as mean ± SEM. The data were analyzed with repeated-measurement analysis of variance, followed by application of two-tailed Student’s t-test with Duncan’s adjustment for multiple comparisons, using StatView® (version 5; SAS Institute, Cary, NC). A probability value of <0.05 was regarded as significant.
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Results
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The systemic and coronary hemodynamic variables in conscious dogs and in dogs given propofol are shown in Table 1. There was no difference between the vehicle and dantrolene administration groups. Propofol significantly decreased MAP, LVSP, LVEDP, LV dP/dtmax, and %SS. CBF was unchanged but CVR decreased. No change in HR, CO, or SVR occurred. The time courses of hemodynamic responses after vehicle or dantrolene administration are shown in Figures 1 and 2. The infusion of vehicle did not cause significant alteration in systemic and coronary hemodynamics compared with propofol alone. The administration of dantrolene significantly increased HR, MAP, and LVSP compared with propofol alone, whereas it caused no change in LVEDP, CO, SVR, LV dP/dtmax, or %SS. CBF was significantly increased (14.7 ± 2.2 in the conscious state to 25.1 ± 2.5 mL/min) and CVR was significantly decreased (384 ± 55 in the conscious state to 286 ± 43 kdynes · s · cm-5) by dantrolene. The peak effects on HR and MAP occurred 30 and 50 min after starting the administration of dantrolene (Fig. 1), and the peak effects on CBF and CVR occurred after 10 min (Fig. 2), respectively.
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Figure 1. Time course of (A) heart rate (HR), mean arterial blood pressure (MAP), left ventricular systolic pressure (LVSP), and left ventricular end-diastolic pressure (LVEDP), and (B) cardiac output (CO), systemic vascular resistance (SVR), maximal rate of increase in left ventricular pressure (LV dP/dtmax), and segment shortening (%SS) after vehicle or dantrolene administration. *Significantly (P < 0.05) different from propofol alone.  Significantly (P < 0.05) different from conscious.
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Figure 2. Time course of coronary blood flow (CBF) and coronary vascular resistance (CVR) after vehicle or dantrolene administration. *Significantly (P < 0.05) different from propofol alone. Significantly (P < 0.05) different from conscious.
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Discussion
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This study demonstrates that dantrolene at a therapeutic dose changes hemodynamic cardiovascular function, causing marked increases in HR, MAP, LVSP, and CBF with a marked decrease in CVR, and with no alteration of LVEDP, CO, SVR, LV dP/dtmax, or %SS during propofol anesthesia in chronically instrumented dogs.
The myocardial disorder caused by MH is clinically characterized by tachycardia and arrhythmias followed by hypotension, impaired systolic function, and eventual cardiac arrest (15). Adequate therapy is urgently needed for survival because the myocardial function is severely altered and CO decreases rapidly in human MH. Drugs that suppress myocardial function should be avoided in treating MH-susceptible patients.
The present results show that propofol decreases MAP, LVSP, LVEDP, LV dP/dtmax, %SS, and CVR without altering CO, CBF, or SVR. These data are consistent with those reported by Pagel and Warltier (16) except for an unchanged HR in our study. The present results also show that the administration of dantrolene does not cause a depression of myocardial contractility during propofol anesthesia, and that dantrolene reverses the hypotensive effects caused by propofol. In vitro studies reported that dantrolene exerted a direct negative inotropic effect on isolated ventricular muscles in rat and guinea pigs (10–12). However, Fratea et al. (12) found that dantrolene induced a moderate, concentration-dependent negative inotropic effect only at a small calcium concentration in rat LV papillary muscles in vitro. Craft et al. (17) and Lynch et al. (18) reported that dantrolene increased MAP. Divergent from our findings, however, Craft et al. (17) found an increase in CO but not a change in HR. Lynch et al. (18) observed a significant change in HR and a decrease in cardiac index and an increase in SVR. These conflicting results might be partially ascribed to differences between species and study models including the difference of background anesthetics.
The changes of HR and MAP observed in this study do not depend on myocardial contractility. Thus, the increases in HR and MAP in response to dantrolene might represent direct or indirect circulatory effects rather than a direct enhancement of sympathetic nervous system activity. Previous studies have shown that dantrolene may inhibit both the activity and formation of NO elicited by lipopolysaccharide in rat and mouse alveolar macrophages (19–21). Endogenous NO has an important physiologic role in the regulation of smooth muscle vascular tone. Propofol was suggested to stimulate the production and release of NO from endothelial cells (13,14), which would contribute to hypotension. One explanation for the phenomenon observed in our study could be that dantrolene inhibited the release of NO by propofol. In addition, dantrolene was shown to decrease basal intracellular Ca2+ concentrations, resulting in a decrease in NO production, in mouse macrophage (19).
In the present study, the administration of dantrolene caused a transient increase in CBF during propofol anesthesia. The increase in CBF appears not to be in parallel with the changes in HR and MAP. Dantrolene caused a peak increase in CBF 10 minutes after dosage. In contrast, the maximal effects of dantrolene on HR and MAP occurred 30 and 50 minutes after the administration of the drug. Propofol was demonstrated to cause vasorelaxation through blockade of Ca2+-channel-dependent mechanisms that were evident in both endothelium-intact and endothelium-denuded preparations (22). It was suggested that propofol may possess direct vasodilator effects on coronary artery smooth muscle besides the effects on endothelium-derived relaxing factor. However, the inhibition of Ca2+ release from the sarcoplasmic reticulum might be responsible for the coronary vasomotor responses to dantrolene. Thus, the combined effects of dantrolene, which inhibit the release of Ca2+ from the sarcoplasmic reticulum, and propofol, which decreases influx of Ca2+ into vascular smooth muscle, might contribute to a marked decrease in the CVR in the present study.
In conclusion, a bolus injection of dantrolene 2.5 mg/kg IV at a therapeutic dose reverses the decreases in HR and MAP caused by propofol. The combination of dantrolene and propofol causes an increase in CBF with a decrease in CVR but does not enhance the negative inotropic effect.
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Acknowledgments
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This study was supported by Grant-in-Aid B 10470319 for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, Tokyo, Japan.
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References
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Accepted for publication December 26, 2002.
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Abstract
Introduction
