Although opioids have few hemodynamic side effects, during the induction of anesthesia sufentanil decreases systolic function significantly more than fentanyl and alfentanil, and alfentanil produces the greatest decrease in mean arterial pressure associated with a decrease in diastolic compliance and production of myocardial lactate (1). Remifentanil induces a similar decrease in heart rate and blood pressure as alfentanil in healthy, unpremedicated patients (2), but it induces severe cardiovascular depression during the induction of anesthesia (3). These results suggest that opioids used in the clinical practice of anesthesia may have different and deleterious hemodynamic effects that remain incompletely examined. Specifically, the direct myocardial effect of opioids remains poorly studied, even though this effect may contribute to the deleterious hemodynamic effects reported. In vivo, opioids may alter hemodynamic variables via histamine release, inhibitory actions on autonomic and central nervous systems, and direct myocardial and vascular effects. In addition, in in vivo studies, hemodynamic effects of opioids have been measured even though other IV anesthetics or surgery may have been confounding factors. It is important to note that in vivo studies do not permit precise assessment of the direct myocardial effects of opioids. Because knowledge of myocardial effects of opioids is important for anesthesiologists to better understand the opioid-induced hemodynamic effects previously reported (1–3), we conducted an experimental study to examine and compare the direct myocardial effects of several opioids used in the clinical practice of anesthesia.
The results of in vitro studies dealing with the direct myocardial effects of opioids remain controversial, and the direct myocardial effects of sufentanil and remifentanil have never been examined. Alfentanil induces either no significant inotropic effect (4) or a positive effect (5). In isolated rat ventricular myocytes, fentanyl depressed myocardial contractility by decreasing both the intracellular Ca2+ transient and myofilament Ca2+ sensitivity (6). These discrepancies could be related to species differences that also preclude extrapolation to clinical practice. Because the clinical relevance of experimental studies is an important issue, we studied the direct inotropic and lusitropic effects of a wide range of concentrations of remifentanil, sufentanil, fentanyl, and alfentanil on isolated human myocardium.
Methods
After the approval of the local medical ethics committee, 48 human right atrial trabeculae were obtained from 48 patients scheduled for routine coronary artery bypass surgery (n = 26) or aortic valve replacement (n = 22) without atrial disease. Patient demographic data, preoperative drug treatment, and preoperative left ventricular ejection fraction are reported in Table 1. All patients received midazolam, sufentanil, and etomidate, except 13 who received propofol, pancuronium, and isoflurane. The right atrial appendage was removed during surgery for the purpose of cannulation before cardiopulmonary bypass was initiated and immediately placed in a hermetic bottle containing 100 mL of cold (4°C), preoxygenated (95% oxygen and 5% CO2) Tyrode’s modified solution containing (mM) 120 NaCl, 3.5 KCl, 1.1 MgCl2, 1.8 NaH2PO4, 25.7 NaHCO3, 2.0 CaCl2, and 11 glucose.
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Table 1: Patient Demographic Data, Preoperative Drug Treatment, Preoperative Left Ventricular Ejection Fraction, and Anesthetics Used
A long, thin, and rectilinear trabecula was carefully dissected in oxygenated Tyrode’s modified solution. During this dissection, great care was taken not to damage the tissue by stretching or clamping it with forceps or scissors. The trabecula was suspended vertically between stainless steel clips in a 200-mL jacketed reservoir containing the Tyrode’s modified solution as described previously. The average time between removal by the surgeon and immersion in the jacketed reservoir was 10 min. The jacketed reservoir was maintained at 37°C by a thermostatic water circulator (Polystat micropros; Bioblock, Illkirch, France). The bathing solution was bubbled with 95% oxygen/5% CO2, resulting in a pH of 7.40 and a partial pressure of oxygen of 600 mm Hg. Isolated muscles were field-stimulated at 1 Hz by two platinum electrodes with rectangular wave pulses of 5 ms duration and 20% above threshold (CMS 95107; Bionic Instrument, Paris, France).
After each experiment, the length and the weight of the muscle were measured. The muscle cross-sectional area (CSA) was calculated from its weight and length, assuming a cylindric shape and a density of 1. To avoid core hypoxia, trabeculae should have a CSA <1.0 mm2, an active isometric force normalized per CSA (AF) >5.0 mN/mm2, and a ratio of resting force/total force (RF/TF) <0.45.
Right atrial trabeculae were mounted between an isometric force transducer (UC3; Gould, Cleveland, OH) and a stationary clip in the jacketed reservoir. After a 60-min stabilization period at the initial muscle length at the apex of the length-active isometric tension curve (Lmax), atrial trabeculae recovered their optimal mechanical performance. The force developed by the muscle and its positive derivative were measured continuously, digitized at a sampling frequency of 200 Hz, and stored on the hard disk of a microcomputer for analysis (MacLab; AD Instrument, Sydney, Australia).
For the contraction phase, TF and RF were measured. The inotropic state in isometric conditions was tested by AF, the peak of the positive force derivative normalized per CSA (+dF/dt), and the time to peak force (TPF) measured.
The relaxation phase of the isometric twitch was tested by the time to half-relaxation (t1/2), which is a good index of isometric relaxation in mammalian myocardium (7). This variable is insensitive to increase in contractility induced by increasing extracellular calcium concentration. Conversely, isoproterenol as little as 10−10 M significantly decreased t1/2(7). Because changes in the contraction phase induce coordinated changes in the relaxation phase (8,9), the peak of the negative force derivative normalized per CSA (−dF/dt) could not assess isometric relaxation independently of the contraction phase. Therefore, indexes of contraction-relaxation coupling have been developed to take simultaneous variations in contraction and relaxation into account and to quantify drug-induced changes in myocardial lusitropy (9,10).
The coefficient R2 = (+dF/dt)/(−dF/dt) tests the coupling between contraction and relaxation under high load and, thus, the lusitropic state under high load in a manner that is less dependent on inotropic changes. When the muscle contracts isometrically, sarcomeres shorten very little (11). Because of an increased sensitivity of myofilament for calcium (12), the relaxation time course is mainly determined by calcium unbinding from troponin C rather than by Ca2+ sequestration by the sarcoplasmic reticulum or Ca2+ extrusion via Na+/Ca2+ exchange. Thus, R2 (contraction-relaxation coupling under high load) indirectly reflects myofilament calcium sensitivity (9,10,13). The contraction-relaxation coupling variable R2 has been used and validated as an index of myocardial lusitropy (14).
In a Control group (n = 10), we measured the mechanical variables of isolated human atrial trabeculae every 10 min for 60 min. We then studied the effects of cumulative concentrations (10−11, 10−10, 10−9, 10−8, 10−7, and 10−6 M) of alfentanil (n = 8), fentanyl (n = 8), sufentanil (n = 8), and remifentanil (n = 8) on mechanical variables of human right atrial trabeculae. A 10-min period of equilibration was allowed between each concentration. This wide range of concentrations was chosen on the basis of the opioids’ respective protein-binding and plasma concentrations measured in clinical practice. Remifentanil was purchased from Glaxo-Wellcome (GlaxoWellcome, Marly-le-Roi, France), sufentanil and alfentanil from Janssen-Cilag (Janssen-Cilag, Berchem, Belgium), and fentanyl from Distriphar (Distriphar, Uxbridge, UK).
In an additional group of six trabeculae, we measured the inotropic effect of alfentanil 10−6 M after increasing [Ca2+]o from 2.0 to 4.0 mM. Because increasing [Ca2+]o increases Ca2+ inward transients (ICa) (15), we tested the hypothesis that an alfentanil-induced negative inotropic effect could be related, at least in part, to a decrease in ICa.
Data are expressed as mean ± sd. Control values between groups were compared by analysis of variance. Comparison of several means was performed with a repeated-measures analysis of variance and Newman-Keuls test. All P values were two-tailed, and a P value of <0.05 was required to reject the null hypothesis. Statistical analysis was performed on a computer by using Statview 5 software (Deltasoft, Meylan, France).
Results
Forty-eight human right atrial trabeculae were studied. There were no differences in values for Lmax, CSA, RF/TF, and main mechanical variables among all groups (Table 2).
Table 2: Control Values of Main Mechanical Variables of Human Right Atrial Trabeculae
In the Control group, RF, t1/2, R2, and TPF remained stable for 60 min. AF normalized per CSA slightly decreased with time. This decrease became significant at 50 min (AF, 95% ± 4% of baseline) and 60 min (AF, 94% ± 4% of baseline). The peak of the positive force derivative slightly decreased with time and became significant at 60 min (+dF/dt, 94% ± 5% of baseline).
Whatever the concentration, sufentanil and remifentanil did not modify AF and +dF/dt from baseline values. The moderate decrease in AF and +dF/dt induced by fentanyl became significant at 10−7 M (AF, 95% ± 3% of baseline; +dF/dt, 93% ± 5% of baseline) and 10−6 M (AF, 94% ± 2% of baseline; +dF/dt, 91% ± 4% of baseline). The decrease in AF and +dF/dt induced by alfentanil became significant at 10−7 M (AF, 83% ± 10% of baseline; +dF/dt, 84% ± 6% of baseline) and 10−6 M (AF, 75% ± 12% of baseline; +dF/dt, 75% ± 10% of baseline).
Figure 1 shows that the effects of cumulative concentrations of fentanyl, sufentanil, and remifentanil on AF and +dF/dt did not differ from the Time Control group. An alfentanil-induced negative inotropic effect was significantly different from the Time Control group and from the effects of fentanyl, sufentanil, and remifentanil.
Figure 1: Concentration-dependent effects of alfentanil, fentanyl, sufentanil, and remifentanil on maximum isometric active force normalized per cross-sectional area (left panel) and the peak of the positive force derivative (right panel) expressed as percentage of baseline. In the Control group, AF and +dF/dt were measured every 10 min. AF = maximum isometric active force normalized per cross-sectional area; +dF/dt = peak of the positive force derivative normalized per cross-sectional area; NS = not significant. Data are mean ± sd. *P < 0.05 versus baseline value. Brackets indicate between-group comparisons.
At all study concentrations, fentanyl, sufentanil, remifentanil, and alfentanil did not modify TPF.
Increasing [Ca2+]o from 2.0 to 4.0 mM induced a positive inotropic effect (AF, 130% ± 6% of baseline; +dF/dt, 136% ± 5% of baseline). In the presence of a [Ca2+]o of 4.0 mM, alfentanil 10−6 M did not modify inotropic variables of atrial trabeculae (AF, 98% ± 8% of the value measured at [Ca2+]o of 4.0 mM; +dF/dt, 97% ± 10% of the value measured at [Ca2+]o of 4.0 mM; not significant).
Alfentanil, fentanyl, sufentanil, and remifentanil did not modify R2 as compared with the Control group (Fig. 2). Fentanyl, sufentanil, and remifentanil did not modify t1/2, whereas alfentanil significantly decreased it (Fig. 2).
Figure 2: Concentration-dependent effects of alfentanil, fentanyl, sufentanil, and remifentanil on the contraction-relaxation coupling variable under high load (left panel) and time to half-relaxation (right panel) expressed as percentage of baseline. In the time Control group, R2 and t1/2 were measured every 10 min. R2 = contraction-relaxation coupling variable under high load; t1/2 = time to half-relaxation; NS = not significant. Data are mean ± sd. *P < 0.05 versus baseline value. Brackets indicate between-group comparisons.
Discussion
This is the first study comparing the direct myocardial effects of a wide range of concentrations of remifentanil, sufentanil, fentanyl, and alfentanil on human atrial myocardium in vitro. We showed that 1) remifentanil, sufentanil, and fentanyl did not modify the inotropic state of isolated human atrial myocardium; 2) alfentanil induced a significant concentration-dependent negative inotropic effect that was abolished by increasing [Ca2+]o; and 3) remifentanil, sufentanil, fentanyl, and alfentanil did not modify the contraction-relaxation coupling variables under high load.
The myocardial effects of IV anesthetics and volatile anesthetics have been widely studied, but those induced by opioids have been poorly examined. However, such information is important for anesthesiologists to better understand hemodynamic effects observed in clinical practice. Moreover, comparative myocardial effects of anesthetic drugs may help anesthesiologists make more appropriate choices when considering the patient’s medical status, surgery, and clinical situation. Opioids have few myocardial effects, on the basis of clinical studies (16,17) and controversial experimental data (4–6,18,19). Nevertheless, during the induction of anesthesia in patients scheduled for coronary artery bypass surgery, alfentanil produced the greatest decrease in mean arterial pressure and diastolic compliance, and the greatest incidence of myocardial lactate production compared with fentanyl and sufentanil (1). Moreover, sufentanil significantly reduced systolic function (1). The hemodynamic effects induced by alfentanil are comparable to those induced by remifentanil (2), which induces severe cardiovascular depression (3). However, hemodynamic data obtained during anesthesia for various surgical procedures cannot be used to assess the myocardial effects of opioids because preload, afterload, heart rate, and sympathetic tone cannot be controlled. In addition, concomitant anesthetic drugs and a pathologic state could influence these results. Thus, experimental studies are the only way to precisely assess the myocardial effects of opioids independently of confounding factors.
Our study clearly showed that remifentanil and sufentanil did not modify inotropic nor lusitropic variables of human right atrial myocardium in vitro. Although James et al. (20) showed, in barbiturate-anesthetized dogs, that remifentanil decreased +dP/dt and cardiac output more than alfentanil, this study could not assess the direct effect of remifentanil on myocardial contractility, because preload, afterload, and heart rate were not controlled. Moreover, the effect of continuous barbiturate anesthesia could not be eliminated. Lack of an inotropic effect of sufentanil reported in our study is in accordance with experimental studies showing that sufentanil modified neither left ventricular end-systolic pressure nor regional left ventricular systolic shortening in chronically instrumented dogs (18). Our results showed that fentanyl did not modify the inotropic variables of isolated human myocardium as compared with the Time Control group. In rat and cat isolated papillary muscles, concentrations of fentanyl from 10−9 to 10−6 M induced no inotropic effect (19,21). In contrast, Kanaya et al. (6) showed that fentanyl (10−8 to 10−6 M) decreased cell shortening in isolated rat cardiomyocytes. However, it has been suggested that isolated cardiomyocyte shortening is not a reliable index of contractility because 1) isolated myocytes contract at varying lengths shorter than in intact muscles and against internal restoring forces such as the cytoskeletal microtubular system; 2) measurements of force and load are not available; and 3) sarcolemmal proteins, such as channels, could have been altered by biochemical isolation procedures (22). It is important to note that Kanaya et al. (6) showed that fentanyl did not modify either the stores or the Ca2+ uptake/release activity or the sarcoplasmic reticulum function, which is the main regulator mechanism of contraction and relaxation in rat cardiomyocytes. We showed that alfentanil induced a concentration-dependent negative inotropic effect in isolated human atrial myocardium. Previous studies have shown that alfentanil (10−6 to 10−4 M) induced a positive inotropic effect in rabbit atrial tissue, but no inotropic effect in ventricular papillary muscles (5), and that it did not modify contractility of isolated rat heart (6). However, controversial myocardial effects reported in these studies could be related to the concomitant negative chronotropic effect of alfentanil and to species differences. As shown in Table 3, the negative inotropic effect of alfentanil observed in our study was in the range of plasma concentrations of alfentanil measured in clinical practice. Clinical plasma concentrations of remifentanil, sufentanil, and fentanyl range between 10−10 and 10−8 M, suggesting that our results explain the lack of myocardial effects of these opioids in clinical practice.
Table 3: Plasma Concentrations Measured During Minor and Major Surgery and Protein Binding of Remifentanil, Sufentanil, Fentanyl, and Alfentanil
The main mechanism by which opioids may modify the inotropic state of the myocardium is through modification of the cellular components involved in intracellular calcium homeostasis (i.e., ICa, sarcoplasmic reticulum, and myofilaments). Kanaya et al. (6) showed that morphine did not modify the peak of ICa, whereas fentanyl decreased it. Our results indirectly suggest that the negative inotropic effect of alfentanil may be related to a decrease in ICa, because the alfentanil-induced negative inotropic effect was abolished if [Ca2+]o (and thus ICa) was increased. In isolated rat myocytes and sarcoplasmic reticulum vesicles, morphine and fentanyl did not modify Ca2+ content, uptake, or release but decreased myofilament Ca2+ responsiveness (6). Further studies are needed to precisely understand the effects of new opioids on ICa, sarcoplasmic reticulum function, myofilament Ca2+ sensitivity, and actin-myosin cross-bridges mechanics.
The following points must be considered in the assessing the clinical relevance of our results. First, because this study was conducted in vitro, it dealt only with intrinsic myocardial contractility and did not consider the vasodilatory effects of opioids or their influence on sympathetic nervous system tone in vivo. Observed changes in cardiac function after anesthetic administration also depend on modifications in heart rate, venous return, afterload, sympathetic nervous system activity, and compensatory mechanisms. Second, we studied only isometric conditions, but in vivo, the myocardium contracts against various levels of afterload in auxotonic conditions. Third, this study was performed at a high temperature (37°C) and high frequency of stimulation (1 Hz), approximating physiologic conditions that have been suggested to induce core hypoxia of isolated muscles. However, the diameter and the control values of mechanical variables of our preparations (reported in Table 2) strongly suggested that our muscles did not experience core hypoxia. Moreover, these experimental conditions are widely used in in vitro human myocardium studies (23,24). It is important to note that we compared all groups of experiments with a control group. Finally, the decrease in AF observed in the Control group occurred without increased resting tension as observed in hypoxic muscles. Fourth, the experiment was performed on atrial myocardium, which differs from ventricular myocardium with regard to Ca2+ homeostasis (25). Fifth, because there is no protein in Tyrode’s solution, the concentrations of opioids tested in our study were free concentrations. However, as shown in Table 3, the range of concentrations tested in our study included the free plasma concentrations measured in clinical practice that take protein binding into account (26). Sixth, although experiments performed in human myocardium have the benefit of more relevant clinical extrapolations, the effects of anesthetic drugs, diseases, or treatments received by the patients cannot be eliminated. However, the patients included in this study were representative of patients who may receive opioids. In clinical situations, the preoperative disease or treatments would be present.
In conclusion, in isolated human right atrial trabeculae, remifentanil, sufentanil, and fentanyl did not induce any significant inotropic effect. In contrast, alfentanil induced a negative inotropic effect. Furthermore, we showed that remifentanil, sufentanil, fentanyl, and alfentanil did not modify the lusitropic state of isolated human myocardium.
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