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Cardiovascular Effects of Tramadol in Dogs Anesthetized with Sevoflurane

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Cardiovascular Effects of Tramadol in Dogs Anesthetized with Sevoflurane FULL PAPER Surgery Cardiovascular Effects of Tramadol in Dogs Anesthetized with Sevoflurane Takaharu ITAMI1), Naomichi TAMARU1), Kodai KAWASE1), Tomohito ISHIZUKA1), Jun TAMURA1), Kenjirou MIYOSHI1), Mohammed A. UMAR1), Hiroki INOUE2) and Kazuto YAMASHITA1)* 1)Department of Small Animal Clinical Sciences, School of Veterinary Medicine and 2)Department of Biosphere and Environmental Sciences, Faculty of Environment Systems, Rakuno Gakuen University, Ebetsu, Hokkaido 069–8501, Japan (Received 11 May 2011/Accepted 28 July 2011/Published online in J-STAGE 11 August 2011) ABSTRACT. Cardiovascular effects of tramadol were evaluated in dogs anesthetized with sevoflurane. Six beagle dogs were anesthetized twice at 7 days interval. The minimum alveolar concentration (MAC) of sevoflurane was earlier determined in each dog. The dogs were then anesthetized with sevoflurane at 1.3 times of predetermined individual MAC and cardiovascular parameters were evaluated before (baseline) and after an intravenous injection of tramadol (4 mg/kg). The administration of tramadol produced a transient and mild increase in arterial blood pressure (ABP) (P=0.004) with prolonged increase in systemic vascular resistance (SVR) (P<0.0001). Com- pared with baseline value, mean ABP increased significantly at 5 min (119% of baseline value, P=0.003), 10 min (113%, P=0.027), and 15 min (111%, P=0.022). SVR also increased significantly at 5 min (128%, P<0.0001), 10 min (121%, P=0.026), 30 min (114%, P=0.025), 45 min (113%, P=0.025) and 60 min (112%, P=0.048). Plasma concentrations of tramadol were weakly correlated with the percentage changes in mean ABP (r=0.642, P<0.0001) and SVR (r=0.646, P<0.0001). There was no significant change in heart rate, cardiac output, cardiac index, stroke volume, pulmonary arterial pressure, right atrial pressure and pulmonary capillary wedge pressure. In conclusion, the administration of tramadol produces a prolonged peripheral vascular constriction in dogs anesthetized with sevoflurane, which is accompanied with a transient and mild increase in arterial blood pressure. It also indicated that the degree of vasoconstriction might depend on the plasma concentration of tramadol. KEY WORDS: canine, cardiovascular effects, sevoflurane, tramadol. J. Vet. Med. Sci. 73(12): 1603–1609, 2011 Treatment with analgesic drugs reduces the amount of to μ-opioid receptor [2, 9]. M1 has a 200 times higher μ- anesthetics required to produce surgical anesthesia, helps to opioid receptor binding activity than tramadol [8, 25] and its stabilize anesthesia, and decreases overall patient morbidity formation is important for the anti-nociceptive effects of tra- associated with surgery and anesthesia [17]. Opioid admin- madol [24]. In dogs, M1 production from the parent com- istration decreases the amount of volatile anesthetics pound has been also demonstrated [11, 33]. Therefore, M1 required to produce general anesthesia, as evidenced by probably contributes to anti-nociceptive effects of tramadol decreases in the minimum alveolar concentration (MAC) of in dogs. volatile anesthetics [10, 19]. Sevoflurane is a volatile anesthetic drug with a relatively Tramadol is a centrally acting ‘atypical’ opioid analgesic low blood/gas solubility coefficient resulting in rapid induc- and widely used in humans for control of acute and chronic tion and recovery from anesthesia [29]. Because of these pain [6, 25]. Tramadol is less likely to induce tolerance in strong points, sevoflurane has become a popular inhalation animals and humans compared with morphine because of its anesthetic in veterinary practice. Sevoflurane is minimally non-opioid mechanism of action [15]. Use of tramadol in metabolized and easily cleared in animals; however, it dogs has gained popularity among veterinarians because the should be remembered that sevoflurane causes dose-depen- drug is perceived to be an effective analgesic, in easily dent hypotension, hypoventilation, impaired cardiac con- administered, and has a longer duration of action and fewer tractility and hypothermia [20]. Therefore, a sparing effect adverse effects than most other opioids. It was demon- on anesthetic requirement provided by the preoperative strated that tramadol administration decreased in the MAC administration of tramadol is expected to convey the advan- of volatile anesthetics [28] and its preoperative administra- tage of preserving cardiovascular function in patients anes- tion provided an early pain control after ovariohysterectomy thetized with sevoflurane. On the other hand, it has been in dogs [13]. Tramadol produces a synergistic analgesic suggested that tramadol is a mild myocardial depressant in effect provided by a μ-opioid receptor affinity coupled with dogs [23]. Therefore, it is important for veterinary practitio- inhibitions of synaptic reuptake of monoamine neurotrans- ners to confirm interactions between sevoflurane and trama- mitters such as 5-hydroxytryptamine (5-HT) and norepi- dol on the cardiovascular function in dogs. To our nephrine [8, 25]. In addition, one of its active metabolites, knowledge, however, there is no published report evaluating O-desmethyltramadol (M1), also has a weak agonistic effect the cardiovascular effect of tramadol in dogs during anes- thesia. *CORRESPONDENCE TO: YAMASHITA, K., Department of Small Ani- mal Clinical Sciences, School of Veterinary Medicine, Rakuno The purpose of the present study was to evaluate the car- Gakuen University, Ebetsu, Hokkaido 069–8501, Japan. diovascular effects of tramadol in dogs anesthetized with e-mail: [email protected] sevoflurane. We also evaluated plasma concentrations of 1604 T. ITAMI ET AL. tramadol and M1 to confirm relationship with the cardiovas- tilator (Nuffield Anesthesia Ventilator Series 200, Penlon, cular function in dogs. Abingdon Oxon, U.K.) to maintain end-tidal partial pressure of carbon dioxide (PETCO2) between 35 and 40 mmHg. All MATERIALS AND METHODS dogs received lactated Ringer’s solution at a rate of 10 ml/ kg/hr intravenously through a 22-gauge catheter placed in Experimental animals: Six beagle dogs aged from 8 to 10 the right cephalic vein. Esophageal temperature was main- years (9.7 ± 0.8 years of mean ± SD, 3 males and 3 females) tained between 37.5 and 38.5C, using a heating pad and a and weighing from 9.4 to 15.4 kg (11.6 ± 2.3 kg) were used warm air blanket. Esophageal temperature, PETCO2, and for this study. The dogs were judged to be in good to excel- ETSEV were monitored using a veterinary patient monitor- lent health based upon the results of a physical examination, ing system (BP-508V, Omron Colin Co., Tokyo, Japan). complete blood cell count and serum biochemical analysis. Esophageal temperature was measured using an electric The dogs were owned by the university and cared for thermometer probe placed orally into the thoracic esopha- according to the principles of the “Guide for the Care and gus. A side-stream capnometer and anesthetic agent moni- Use of Laboratory Animals” prepared by Rakuno Gakuen tor was used to determine respiratory rate, PETCO2, and University. The Animal Care and Use Committee of ETSEV. The anesthetic agent monitor was calibrated Rakuno Gakuen University approved the study. Food and immediately prior to each sevoflurane MAC determination. water were withheld from dogs for 12 hr before experiment. Evaluation of cardiovascular effects of tramadol: Seven All dogs were anesthetized twice at 7 days interval. The days later since the MAC determination, all dogs were MAC of sevoflurane was earlier determined in each dog. orotracheally intubated following a mask induction with The dogs were then anesthetized with 1.3 times concentra- sevoflurane and connected to an anesthetic machine with a tion of individual predetermined sevoflurane MAC and car- built-in ventilator (ACOMA BLANDA-STD, Acoma Med- diovascular effects of tramadol were evaluated. ical Industry Co., Tokyo, Japan). Then, the dogs were anes- Determination of sevoflurane MAC: The MAC of sevof- thetized with 1.3 times of individual sevoflurane MAC in lurane was determined by the tail clamp method [29]. Anes- right lateral recumbency. During anesthesia, the dogs were thesia was induced by mask induction using sevoflurane mechanically ventilated to maintain arterial partial pressure (Sevoflo, Dainippon-Sumitomo Pharma. Osaka, Japan) in of carbon dioxide (PaCO2) between 40 and 45 mmHg and oxygen. All dogs were orotracheally intubated after the administered lactated Ringer’s solution at a rate of 10 ml/kg/ induction of anesthesia and positioned in left lateral recum- hr intravenously through a 22-gauge catheter placed in the bency. Anesthesia was maintained with sevoflurane in oxy- left cephalic vein. gen (2 l/min) delivered via a circle rebreathing system and Left neck and right interior femoral region were clipped anesthetic machine (Beaver 20, Kimura Medical Instrument and aseptically prepared. Then, approximately 0.5 ml of 2% Co., Tokyo, Japan) with an out-of-circuit vaporizer (Sevo- lidocaine (Xylocaine, Astra-Zeneca, Osaka, Japan) was tech III, Ohmeda, Datex-Ohmeda, Tokyo, Japan). After the injected subcutaneously at each catheter site. A 6-Fr cathe- dogs were allowed to equilibrate for 30 min at 2.4% of end- ter introducer (Catheter Introducer, Medikit Co., Tokyo, tidal concentration of sevoflurane (ETSEV), a 13-cm stan- Japan) was transcutaneously placed in the left jugular vein. dard Backhaus towel clamp (Backhaus Towel Clamp, A 5-Fr thermodilution catheter (TC-504, Nihon Koden Co., Mizuho, Tokyo, Japan) was
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