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CARDIOVASCULAR ANESTHESIA

The Coronary and Myocardial Effects of Remifentanil and Sufentanil in the Erythrocyte-Perfused Isolated Rabbit Heart

From the Laboratory of Anesthesiology, Department of Anesthesia and Critical Care and Department of Emergency Medicine and Surgery, Centre Hospitalier Universitaire Pitié-Salpêtrière, Assistance-Publique-Hôpitaux de Paris, Université Pierre et Marie Curie (Paris 6), Paris, France.

Address correspondence and reprint requests to Alexandre Ouattara, MD, Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Address e-mail to alexandre.ouattara{at}psl.aphp.fr.

	Abstract

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Remifentanil-induced hypotension may be associated with adverse ischemic myocardial events. Although these events can be easily attributed to a decrease in coronary pressure perfusion, we tested the hypothesis that remifentanil could directly affect coronary vasomotor tone. Therefore, we assessed intrinsic coronary and myocardial in vitro effects of remifentanil on a Langendorff’s rabbit model and compared these effects with those provoked by similar intracoronary concentrations of sufentanil. Under general anesthesia, hearts from New Zealand rabbits were rapidly excised and mounted on an erythrocyte-perfused and isolated heart preparation. The hearts were then exposed to increasing concentrations (10-1000 nM) of either remifentanil (n = 10) or sufentanil (n = 8). Between each concentration, hearts were allowed to return to baseline status. The maximal coronary and myocardial effects of each concentration of both drugs were noted. Baseline values of coronary blood flow and myocardial performances were comparable between groups. Neither remifentanil nor sufentanil induced significant coronary and myocardial effects. These results suggest that myocardial ischemia, which may occur during remifentanil-induced hemodynamic disturbances, especially in cardiac patients, is only related to a decrease in coronary perfusion pressure provoked by peripheral hemodynamic changes.

	Introduction

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Remifentanil is a potent µ-opioid receptor agonist with unique pharmacokinetic properties as a result of its rapid metabolism by nonspecific plasma and tissue esterases (1,2). For this reason it has been suggested by several authors as a suitable opioid for patients undergoing fast-track cardiac surgery (3–5). Although remifentanil has been safely used in clinical practice for more than 10 yr, it is not devoid of cardiovascular adverse events. These hemodynamic changes include a decrease in arterial blood pressure, heart rate, cardiac output, and systemic vascular resistances (6–8). Some studies have demonstrated that the remifentanil-induced hypotension could be explained by a direct arterial vasodilator effect (8,9). In coronary patients, this decrease in arterial blood pressure may even induce adverse ischemic myocardial effects, generally attributed to coronary hypoperfusion (7). However, the hypothesis that the remifentanil-induced changes in coronary vasomotor changes could be involved in those adverse coronary events remains to be tested.

Therefore, we studied the intrinsic coronary and myocardial effects of remifentanil in an intact coronary circulation of an erythrocyte-perfused isolated heart model in comparison with sufentanil.

	METHODS

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Eighteen New Zealand rabbits (weight, 2.8–3.0 kg) aged 14 wk were used. Care of the animals conformed to the recommendations of the Helsinki Declaration and the study was performed in accordance with the regulations of the official edict of the French Ministry of Agriculture.

The perfusion medium was reconstituted by mixing human erythrocytes and a modified Krebs-Henseleit bicarbonate buffer containing 118 mM NaCl, 5.9 mM K⁺, 2.5 mM free Ca²⁺, 0.5 mM MgSO₄, 1.17 mM NaH₂PO₄, 28 mM NaHCO₃, 11 mM glucose, 0.9 mM lactate, and 0.5% bovine serum albumin. The human erythrocytes were stored at 4°C in our laboratory for no longer than 1 wk. They were centrifuged and washed with saline (Cell-Saver 4; Hemonetics, Braintree, MA). The mixture allowed us to obtain a hemoglobin value of approximately 8 g/dL. The reconstituted blood was filtered, then continuously oxygenated with a gas mixture comprising 20% O₂, 5% CO₂, and 75% N₂ using a membrane oxygenator (Medtronic, Boulogne-Billancourt, France). After rewarming to 37°C, electrolyte concentrations were adjusted to achieve physiologic concentrations and sodium bicarbonate was added to obtain a pH between 7.35 and 7.45.

After the rabbits were anesthetized with sodium thiopental (25–35 mg/kg IV), the heart and aorta arch were excised and rapidly placed in cold (4°C) isotonic saline solution. Under immersion, the pericardium was quickly removed and the aorta was prepared for the cannulation. The heart was mounted on an aortic cannula and retrograde perfusion was begun according to the Langendorff technique with a constant hydrostatic perfusion pressure of 80 mm Hg. As previously described (10–13), the apparatus was modified to enable the continuous recording of coronary blood flow (CBF). Briefly, the column used to set the perfusion pressure was replaced by a syringe with a plunger containing mercury and attached to a displacement transducer that controlled the speed of the peristaltic coronary pump reflecting the CBF. Coronary driving pressure was computed from the signal pressure obtained from a small catheter that was positioned above the aortic valves and connected to a pressure transducer. The heart rate was maintained constant between 110 and 130 bpm during each experiment by atrial pacing. The coronary sinus was drained by a small catheter inserted into the pulmonary artery. A cannulated fluid-filled balloon connected to a pressure transducer by a rigid catheter was inserted into the left ventricle through a left atrial incision. A 2-mL graduated syringe was connected on this pressure transducer and allowed to increase the intraventricular volume, which was noted for each experiment. Left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP), and heart rate were recorded and the maximal positive (dP/dt_max) and negative (dP/dt_min) left ventricular pressure derivatives were electronically derived from the left ventricular pressure signal. Because intraventricular volume and heart rate were held constant, dP/dt_max and dP/dt_min reflected inotropic and lusitropic properties, respectively. The entire apparatus was enclosed in a thermostatic chamber at 37.5°C.

Arterial (Pao₂), venous (Pvo₂), and coronary oxygen tension and pH were measured with standard electrodes at 37°C (GEM Premier 3000; Instrumentation Laboratory, Saint-Mandé, France) and the arterial hemoglobin concentration and arterial (Sao₂) and venous (Svo₂) coronary oxygen saturation were measured with a hemoximeter (Co-Oximeter IL682; Instrumentation Laboratory, Saint-Mandé, France). Venous (Cvo₂) coronary oxygen content, oxygen extraction (O₂ extraction), and myocardial oxygen consumption (MvO₂) were derived from standard formulas. At the onset of each experiment, a sample of the reconstituted blood was withdrawn to determine the concentration of main electrolytes (Na⁺, K⁺, Cl^–, HCO₃^– and Ca²⁺).

The left ventricular volume was adjusted to obtain an LVEDP of approximately 10 mm Hg, as previously reported (12). A 10-min recovery period was allowed for stabilization of myocardial performances and CBF. After baseline measurements, increased concentrations (10, 30, 100, 300, 1000 nM) of remifentanil (Ultiva®; Glaxo-Smith-Kline, Nanterre, France) (n = 10) or sufentanil (Sufenta®; Janssen-Cilag, Issy-Les-Moulineaux, France) (n = 8) were infused above the aortic cannula. Both opioids, freshly prepared and dissolved in sterile water, were infused using an automatic pump (Kd Scientific Inc, Holliston, MA). The rate of the pump was calculated by considering the dilution of the freshly prepared solution and the resting CBF. Moreover, the dilution of opioids was adapted so that the volume of intracoronary infusion never exceeded 5% of the resting CBF rate. Preliminary experiments revealed that steady-state of cardiac effects of remifentanil as well as sufentanil was obtained within 5 min. Consequently, the infusion of each concentration of opioid was maintained for 5 min. After the end of each opioid infusion a recovery period was allowed to return to baseline status. Before and after each opioid infusion, arterial and coronary sinus samples were collected for blood gas analysis. The tested concentrations were chosen to encompass the therapeutic range of concentrations of remifentanil (3). Because we chose to compare equimolar concentrations of opioids, the concentrations of sufentanil tested in the present work do not encompass the therapeutic range. However, the smallest tested sufentanil concentration (10 nM = 3.77 ng/mL) could be observed in cardiac patients in whom a large effect-site concentration of sufentanil may be required (14).

Data are expressed as mean ± sd. Comparison of several means was performed using analysis of variance for repeated measurements. Post hoc test analysis was performed using Newman-Keuls test. All P values were two-tailed and a P value <0.05 was required to reject the null hypothesis.

	RESULTS

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pH and electrolyte composition of the reconstituted perfusate were: pH: 7.41 ± 0.08; Na⁺: 134 ± 5 mM; Cl^–: 100 ± 4 mM; K⁺: 5.5 ± 0.9 mM; NaHCO₃ : 23.9 ± 2.8 mM; Ca²⁺: 2,31 ± 0.36 mM). Left ventricular weight (5.5 ± 0.9 g) was similar between groups. The mean volume of saline solution instilled in the intraventricular balloon before infusion of increased concentrations was 2.14 ± 0.20 mL and was not significantly different in both groups.

Before administration of subsequent increasing doses of remifentanil or sufentanil, CBF and myocardial performances were allowed to return to baseline status (Table 1). After the recovery period, baseline values of CBF were comparable between groups (2.8 ± 1.2 versus 2.6 ± 1.2 mL ·min^–1 ·g^–1; not significant). Neither remifentanil nor sufentanil had significant intrinsic coronary effects (Fig. 1). The heart rate was not significantly different between groups and remained stable throughout the entire experiment (Table 2). Remifentanil and sufentanil were devoid of significant effects on left ventricular diastolic pressure (Table 2). Similarly, both drugs had no significant effect on inotropic (LVESP and dP/dt_max) and lusitropic (dP/dt_min) variables (Table 2).

View larger version (19K): [in this window] [in a new window]   Figure 1. Comparison of vascular coronary effects of remifentanil (n = 10) and sufentanil (n = 8). CBF = coronary blood flow; BL = baseline value. CBF was expressed in percentages of baseline values. Data are mean ± sd. There was no significant difference versus baseline value in each group. NS = not significant between groups.

The mean hemoglobin level was similar in both groups (7.7 ± 0.6 versus 7.3 ± 0.5 g/dL; not significant). As shown in Table 3, Pao₂, Pvo₂, Cvo₂, and O₂ extraction were unaffected by the infusion of increasing concentrations of remifentanil or sufentanil.

Because neither drug had any significant effect on the isolated heart model, we tested our experimental setting. We therefore performed, at the end of each experiment, an intracoronary infusion of propofol (100 µM), which induces a significant coronary vasodilation on our model (13). As expected, propofol induced significant coronary vasodilation up to 150% of baseline values (data not shown).

	DISCUSSION

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In an erythrocyte-perfused isolated rabbit heart model, we demonstrated that remifentanil is devoid of significant coronary and myocardial effects and has no significant direct myocardial metabolic effects in vitro.

Because of its potency and ultra-short pharmacokinetic profile, remifentanil has been proposed by several authors as a drug of choice for patients undergoing fast-track cardiac anesthesia (3–5). Although remifentanil is now safely used worldwide in both cardiac and noncardiac surgical patients, this opioid has been associated with significant hemodynamic changes. These hemodynamic disturbances are characterized by decreases in heart rate, cardiac output, arterial blood pressure, and systemic vascular resistance (6–9). We have reported that remifentanil provokes a systemic arterial vasodilation without significant effect on the capacitance vessels in critically ill patients with a total artificial heart (9). However, the underlying mechanism of the remifentanil-induced vasodilation remains unclear. Unlügenc et al. (15) reported a direct in vitro vasodilator effect of remifentanil involving both endothelium-dependent and endothelium-independent mechanisms. The fact that remifentanil-induced vasodilation is produced by a direct mechanism has been confirmed by other studies in which the involvement of sympathetic outflow or histamine liberation has been clearly excluded (8,16). In human myocardial trabeculae, Hanouz et al. (17) clearly demonstrated that remifentanil is devoid of significant intrinsic effects on myocardial properties. However, in patients with coronary artery disease, Elliott et al. (7) have reported myocardial ischemia associated with remifentanil-induced hypotension. These adverse myocardial events are very likely related to a marked decrease in coronary perfusion pressure. Nevertheless, the hypothesis that remifentanil could exert a direct vascular effect on coronary circulation remained to be elucidated.

The present study is the first to assess in vitro intrinsic coronary effects of remifentanil on intact coronary arteries. In vivo, the assessment of the effects of remifentanil on coronary intrinsic properties remains difficult because of concomitant changes in preload and afterload, systemic vascular resistances, and sympathetic activity. An isolated and erythrocyte-perfused heart allows a precise assessment of intrinsic coronary circulation. The ventricular volume and heart rate are maintained constant and influences of the autonomic nervous system are abolished. Thus, dP/dt_max and dP/dt_min are reliable estimates of the inotropic and lusitropic properties, respectively. The clear advantage of our model is the presence of erythrocytes in the perfusate medium, which allows us to perform experiments with relative physiological levels of O₂ tension. Indeed, O₂ tension interferes with coronary vasculature (13,18).

Our results clearly demonstrate that remifentanil is devoid of any intrinsic coronary effects. These findings suggest that remifentanil-induced adverse ischemic myocardial events that may be observed during its clinical use are only related to the decrease in coronary perfusion pressure. From our data we can also conclude that remifentanil does not directly modify either inotropic or lusitropic properties of the myocardium. These findings are consistent with those published by other authors on isolated human right atria (17,19). On other hand, the absence of any intrinsic coronary effect of remifentanil contradicts the findings of Kazmaier et al. (6) obtained in patients suffering from coronary artery disease. These authors observed a significant decrease in coronary perfusion and myocardial blood flow after anesthetic induction based on remifentanil (6). Nevertheless, these coronary effects could be easily explained by a decrease in myocardial O₂ uptake related to a decrease in stroke volume index and heart rate. As mentioned above, their findings illustrate that in vivo assessment of the intrinsic coronary effects of a drug is difficult because of coexisting and uncontrolled variables influencing the coronary vascular tone. We found that sufentanil is devoid of significant direct coronary effects on a blood-perfused and isolated heart model. These findings are consistent with those obtained on isolated porcine artery segments (20).

In our study, the main myocardial O₂ variables were not altered by remifentanil (Table 3). This not only indicates the absence of interaction of both opioids with myocardial function but also excludes any possible time-related change within the model. The return to the baseline value of coronary and myocardial variables between infusion of opioids (Table 1) confirms and demonstrates the stability of this model, as described in previous work from our laboratory (12,13). We also observed that the coronary O₂ extraction ratio was well below physiologic levels we usually find. The reason for this rather low extraction ratio is that the isolated and instrumented heart only performs an isovolumetric contraction without any presence of afterload. Therefore, myocardial O₂ consumption is considerably less, yet stable within the model.

The following limitations must be considered in the assessment of the clinical relevance of our study. First, to study direct coronary and myocardial effects of remifentanil on an isolated and erythrocyte-perfused heart model, concepts of preload and afterload are eliminated. In vivo, the cardiovascular depression is a result of both myocardial and systemic vascular effects. Second, the current study was performed in rabbit hearts and thus species differences cannot be completely eliminated. Moreover, human red blood cells are antigen-bearing cells, which could induce immunoregulatory reactions on the rabbit heart. However, this model has been validated and published in numerous studies, so this reaction may be considered trivial (12,13,18). Third, the concentrations of tested drugs were only calculated and not measured. Finally, a nonrandomization of the sequence of drug administration could be considered a potential limitation of the study.

In conclusion, our study demonstrates that remifentanil is devoid of any significant intrinsic coronary effects. These results suggest that the myocardial ischemia that may occur during remifentanil-induced hemodynamic disturbances, especially in coronary patients, does not involve direct changes in vasomotor coronary tone. Because remifentanil-induced hypotension seems mainly to involve direct peripheral arterial vasodilation (9), its rapid treatment should include vasopressor drugs to avoid harmful myocardial hypoperfusion and, thus, ischemia.

	Footnotes

 
Accepted for publication March 16, 2006.

Presented, in part, at the annual meeting of the European Society of Anaesthesiology 2003 at Glasgow, United Kingdom. Support was provided solely from departmental sources. There is no conflict of interest from any author.

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