Anesth Analg 2006;102:118-123
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000184826.02943.70
ANESTHETIC PHARMACOLOGY
An Analysis of Remifentanil in the Pulmonary Vascular Bed of the Cat
Alan D. Kaye, MD, PhD*
,
Amir Baluch, BS
,
James Phelps, MPT,
Syed R. Baber, BS
,
Ikhlass N. Ibrahim, DVM*,
Jason M. Hoover, BS,
Cuihua Zhang, MD, PhD*, and
Aaron Fields, MD||
Departments of *Anesthesiology and Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana; Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas and El Paso, Texas; Tulane University, New Orleans, Louisiana; and ||Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Alan D. Kaye, MD, PhD, DABPM, Professor and Chairman, Department of Anesthesiology, Professor, Department of Pharmacology, Louisiana State University School of Medicine, 1542 Tulane Ave. T6M5, New Orleans, LA 70112. Address e-mail to akaye{at}lsuhsc.edu.
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Abstract
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In this investigation we sought to identify the role of remifentanil in the feline pulmonary vascular bed. Using adult mongrel cats in separate experiments, the effects of glibenclamide (adenosine triphosphate-sensitive K+ channel blocker), diphenhydramine (histamine H1-receptor antagonist), L-N5-(1-Iminoethyl) ornithine hydrochloride (nitric oxide synthase inhibitor), and naloxone (opioid receptor antagonist) were investigated in pulmonary arterial responses to remifentanil (opioid agonist), pinacidil (adenosine triphosphate-sensitive K+ channel activator), and bradykinin (nitric oxide synthase inducer). Under increased tone conditions in the isolated left lower lobe vascular bed of the cat, remifentanil induced a dose-dependent vasodepressor response that was not significantly altered after administration of glibenclamide and L-N5-(1-Iminoethyl) ornithine hydrochloride. Responses to remifentanil were significantly attenuated after administration of diphenhydramine and naloxone. The results suggest that remifentanil has potent vasodepressor activity in the feline pulmonary vascular bed and that these responses are mediated by histamine and opioid receptor sensitive pathways.
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Introduction
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One of the more recently developed opioid analgesics is remifentanil. This drug is a synthetic opioid that acts as an agonist at the µ-opioid receptor and that has a more rapid onset and predictable termination of opioid-induced effects (1–4). For example, the analgesic effects occur within 1–1.5 min and remifentanil blood concentration decreases 50% in 3–6 min after a 1-min infusion or after prolonged continuous infusion as a result of rapid distribution and elimination processes and is independent of duration of drug administration (5,6). Another benefit of remifentanil is its unique metabolism by plasma esterases (7,8). As a result, its elimination is independent of hepatic metabolism or renal excretion (8). After 3 to 5 h of constant infusion, the respiratory recovery may be seen in 3 to 5 min and a full recovery from all effects may be observed within 15 min.
Although the clinical application and pharmacokinetics of remifentanil have been examined, little, if anything, is known of the direct effects of remifentanil in the lung vascular bed. We believe it is incumbent to document the putative effects of remifentanil on the lung vasculature because of the presence of µ-opioid receptors in the pulmonary circuit (9,10). Therefore, the present study was undertaken to investigate the pulmonary vascular response to remifentanil in the pulmonary vascular bed of the intact chest cat under constant flow conditions.
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Methods
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After approval by the IRB for the care of animal subjects and while maintaining standards of care and handling of the animals in accordance with National Institutes of Health guidelines, 36 adult mongrel cats of either sex weighing 3.0–4.7 kg were sedated with IM ketamine hydrochloride (10–15 mg/kg) and anesthetized with IV pentobarbital sodium (30 mg/kg). The animals were restrained in the supine position on a fluoroscopic table, and supplemental doses of anesthetic were administered as necessary to maintain a uniform level of anesthesia. The trachea was intubated with a cuffed pediatric endotracheal tube, and the animals spontaneously breathed room air enriched with 100% O2 at a 6-L flow rate. Therefore, the oxygen concentration was approximately 40%. Systemic arterial blood pressure was measured from a catheter inserted into the aorta from a femoral artery. IV injections were given into a catheter in the inferior vena cava from a femoral vein and intraarterial (IA) injections were given into the perfused lobar artery.
For perfusion of the left lower lung lobe, a triple lumen 6F balloon perfusion catheter was passed under fluoroscopic guidance from an external jugular vein into the artery to the left lower lung lobe. After the animal had been heparinized (1000 U/kg IV), the lobar artery was vascularly isolated by distension of the balloon cuff on the perfusion catheter. The lobe was perfused with a Harvard model 1210 perfusion pump (Harvard Apparatus, South Natick, MA) by way of the catheter lumen beyond the balloon cuff with blood withdrawn from a femoral artery. The perfusion rate (25–40 mL/min) was adjusted so that lobar arterial perfusion pressure approximated the mean pressure in the main pulmonary artery and was not changed thereafter for the remainder of the experiment. The flow rate ranged from 30 to 41 mL/min, and in some experiments, left atrial pressure was measured with a radio-opaque 6F single-lumen or 6F double-lumen catheter passed transseptally into the left atrium from an external jugular vein. All vascular pressures were measured with SpectroMed DTX Plus (Viggo-Spectromed, Oxnard, CA) transducers zeroed at the right atrial level and were recorded on a Grass model 7D recorder (Grass Instruments, Quincy, MA).
Agonists were injected directly into the lobar arterial perfusion circuit in small volumes and in random sequence. Sufficient time was permitted between injections for pressure to return to baseline values. Because lobar arterial perfusion flow is constant, alterations in lobar pressure would represent changes in pulmonary arterial vascular resistance.
The antagonists, glibenclamide, an adenosine triphosphate (ATP)-sensitive K+ channel blocker, diphenhydramine, a histamine H1-receptor blocker, L-N5-(1-Iminoethyl) ornithine hydrochloride (L-NIO) an inhibitor of nitric oxide synthase, and naloxone, an opioid receptor antagonist, were dissolved in normal saline immediately before use. The agonists, remifentanil (4.0–40.0 µg), an opioid receptor agonist, pinacidil (10.0–100.0 µg), an ATP-sensitive K+ channel activator, and bradykinin (0.2–0.5 µg), an inducer of nitric oxide synthase, were also dissolved in normal saline immediately before use. Preliminary pilot studies with each drug determined a dose range for drug used in the experiments. Stock solutions of the thromboxane A2 mimic, U46619, (Upjohn, Kalamazoo, MI) were prepared in 100% ethanol at concentrations of 5–10 mg/mL and were stored in a freezer at –20°C. None of the vehicle solutions (agonist and antagonist) used had a significant effect on lobar arterial pressure. Working solutions were prepared just before use, stored in brown-stoppered bottles, and kept on crushed ice during the experiments.
The pulmonary vascular bed of the intact chest cat has little, if any, vasopressor tone response under resting conditions when the Fio2 is 0.21. Therefore, pulmonary arterial pressure in the bed must be actively increased so that vasodilator responses can be measured. In all experiments, tone was increased in the control period to an average value of 35 ± 2 mm Hg with an intralobar infusion of U46619. Under conditions of increased tone in the control period, pulmonary vascular responses to remifentanil, pinacidil, and bradykinin were obtained. The agonists were injected in small volumes (0.1–0.3 mL) directly into the perfusion circuit distal to the pump in a random sequence during the control period.
The experiments were divided into five groups. In the first set of experiments, responses to intralobar agonists were studied under increased tone conditions before and after each antagonist drug. Before glibenclamide infusion, U46619 was stopped because of the potential for glibenclamide to increase tone and lobar arterial pressure was permitted to return to near control values. After the peak increase in lobar arterial pressure in response to glibenclamide (5 mg/kg IA, n = 5), the U46619 infusion was resumed, if necessary, to increase pulmonary vascular tone to a level similar to that attained during the control period (Table 1). In some experiments, glibenclamide administration alone was sufficient to increase lobar vascular tone to a level equal to the control level. In these experiments, U46619 infusion was resumed when lobar arterial pressure had decreased to <30 mm Hg. Responses were compared before and beginning 20–30 min after administration of glibenclamide given IA.
In the second through fifth sets of experiments, the responses to intralobar agonists were measured after administration of diphenhydramine (1.0 mg/kg IV, n = 5), L-NIO (1.0 mg/kg IV, n = 5), and naloxone (0.1 mg/kg IV, n = 5). Responses were compared before and beginning 20–30 min after administration of diphenhydramine, L-NIO, and naloxone given IV.
All vascular pressures are expressed in mm Hg as mean ± sd. The data were analyzed with a paired and unpaired Student's t-test and Scheffé's F-test (Excel 2002; Microsoft, Redmond, WA). A value of P < 0.05 was considered the criterion for statistical significance.
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Results
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The effects of glibenclamide on the response to remifentanil are illustrated in Figure 1. The vasodepressor effects of remifentanil were not significantly altered after administration of glibenclamide (5.0 mg/kg IA).
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Figure 1. Influence of glibenclamide on responses to remifentanil (n = 5). Data are expressed as mean ± sd.
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The effects of diphenhydramine on the responses to remifentanil and pinacidil are illustrated in Figure 2. At a dose that significantly attenuated the vasodilatory effects of remifentanil, the vasodepressor effects of pinacidil were not significantly altered after administration of diphenhydramine (1.0 mg/kg IV).
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Figure 2. Influence of diphenhydramine on responses to remifentanil (n = 5) and pinacidil (n = 5). *P < 0.05 indicates significance. Data are expressed as mean ± sd.
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The effects of L-NIO on responses to remifentanil and bradykinin are illustrated in Figure 3. At a dose that significantly altered the dilatory effects of bradykinin, the vasodepressor responses of remifentanil were not significantly attenuated by the administration of L-NIO (1.0 mg/kg IV).
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Figure 3. Influence of L-N5-(1-Iminoethyl) ornithine hydrochloride on responses to remifentanil (n = 5) and bradykinin (n = 5). *P < 0.05 indicates significance. Data are expressed as mean ± sd.
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The effects of naloxone on responses to remifentanil and pinacidil are illustrated in Figure 4. At a dose that significantly attenuated the depressor effects of remifentanil, the vasodilatory responses of pinacidil were not significantly altered by the administration of naloxone (0.1 mg/kg IV).
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Figure 4. Influence of naloxone on responses to remifentanil (n = 5) and pinacidil (n = 5). *P < 0.05 indicates significance. Data are expressed as mean ± sd.
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Discussion
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Results of the present investigation indicate that remifentanil decreases lobar arterial pressure when tone in the pulmonary vascular bed was increased to a high steady-state level with U46619. When remifentanil was administered under constant-flow conditions, decreases in lobar arterial pressure were dose-dependent and were significantly attenuated by diphenhydramine and naloxone but not by glibenclamide and L-NIO. These results suggest that decreases in pulmonary vascular resistance in response to remifentanil are, in part, mediated or modulated by both a histamine receptor and opioid receptor-sensitive pathway.
Remifentanil-induced vasodepression was not significantly attenuated by glibenclamide, which indicates these effects are attributable to a mechanism other than the opening of ATP-sensitive potassium channels. The data also suggest that remifentanil induces vasodepression independent of de novo formation of nitric oxide, as such vascular responses were not significantly decreased by L-NIO.
Regarding the effects of opioids as a class on the vasculature, when vasodilation occurs with other anesthetics in the perioperative period, concomitant administration of opioids is likely to result in vasoconstriction of cerebral blood vessels (11). In the peripheral vasculature, opioids such as morphine, fentanyl, and sufentanil may cause direct smooth muscle relaxation in the canine model (11). The effects of other opioids on the peripheral vasculature of the human warrants further investigation.
Research regarding the effects of remifentanil specifically on vascular structures has been a topic of great interest. Recently, analysis of remifentanil and renal perfusion in the rat model demonstrated vasodilatory effects (12). In this study, the rat kidney was perfused and artificially vasoconstricted with phenylephrine before infusion with remifentanil. Vasodilation resulted after the remifentanil administration and was attenuated when tetraethyl ammonium, a calcium-dependent potassium channel blocker, was introduced, suggesting a mechanism that may involve calcium-dependent potassium channel activation (13).
Other studies have used human models to elucidate the effects of remifentanil on vascular tone, as well as other variables. Noseir et al. (14) conducted a human study which examined sympathetic and vascular responses to remifentanil. Electrocardiogram, heart rate, arterial blood pressure, muscle sympathetic nerve activity, and forearm blood flow (FBF) were monitored. Respiratory rate decreased and end-tidal carbon dioxide increased in a dose-responsive manner (14). All other variables did not show a significant change, except for FBF, which increased. The direct effect of remifentanil on vascular tone was determined by infusing 1 to 100 µg/hour of the opioid progressively into the tissue. Results demonstrated a significant increase in FBF from 3.5 to 4.3 mL/minute per 100 mL of tissue, which translates into approximately a 13%–18% increase (14). Thus, remifentanil may directly vasodilate the forearm arterial vasculature, resulting in the increased blood flow.
In summary, the present data indicate that remifentanil has potent vasodepressor activity in the feline pulmonary vascular bed when tone is increased experimentally by U46619. The data suggest that remifentanil-induced vasodilation may, in part, be mediated by both a histamine receptor and opioid receptor sensitive pathway. Future research is needed to better interpret the role of opioid receptors in the pulmonary vascular bed and their function in pathological conditions involving the lung vasculature.
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Footnotes
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Accepted for publication August 16, 2005.
Supported, in part, by the Department of Anesthesiology, Texas Tech, University Health Sciences Center School of Medicine.
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Abstract
Introduction
