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Hyperalgesia During Sedation: Effects of Barbiturates and Propofol in The

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Hyperalgesia During Sedation: Effects of Barbiturates and Propofol in The 532 Laboratory Investigations Hyperalgesia during sedation: effects of barbiturates and Alastair Ewen MBChB FRCA FRCPC,* David P. Archer BSc MDCMMSe FRCPC,* propofol in the rat Naaznin Samanani Bsc,* Sheldon H. Roth PhD*'f Subhypnotic doses of thiopentone are considered to possess On considbre que les doses sous-hypotiques de thiopentone pos- antianalgesic or hyperalgesic properties. In this study, we have s~dent des propridtds antianalgdsiques ou hyperalgdsiques. Cette tested the hypothesis that the coincidence of sedation and hy- dtude vdrifie 17~ypothb.seselon laquelle la cogncidence de la sdda- peralgesia is a property of both barbiturate and non-barbiturate tion avec lhyperalgie constitue d la fois une propridtd des agents anaesthetic agents. In a randomized, prospective, blinded study, anesthdsiques barbituriques et des non barbituriques. Au cours the effects of slow (20 rain) iv infusions of thiopentone, pen- d'une dtude randomisde, prospective et ?l l'aveugle, les rdper- tobarbitone, methohexitone or propofol on nociceptive thresh- cussions sur le seuil nociceptif d'une perfusion lente (20 min) old were measured in rats by tail pressure analgesimetry and de thiopentone, pentobarbitone, mdthohexitone et de propofol compared with saline-infused control animals. Nociceptive sont mesurdes par analgdsiomdtrie de compression sur la queue thresholds were correlated with measurements of plasma drug du rat et compardes avec des animaux de contrtle sous per- concentrations and behavioural assessments. Comparison of fusion au solutd physiologique. Les seuils nociceptifs sont cor- pre-infusion nociceptive threshold with the lowest threshold ob- relds avec les mesures de concentration plasmatique des drogues tained during drug infusion revealed decreases in all four treat- et par l~valuation du comportement. La comparaison du seuil ment groups. As a percentage of the pre-infusion values, the nociceptif avant la perfusion avec le seuil le plus bas obtenu decreases were: thiopentone: 42.5% (P < 0.001), pentobarbi- pendant la perfusion rdv~le des diminutions dans tousles tone: 27.8% (P = 0.014), methohexitone: 24.9% (P = 0.013), groupes de traitement. En pourcentage des valeurs de pr~- propofok 21.6% (P = 0.006). There were no changes in no- infusion, les diminutions sont les suivantes: thiopentone: 42,5% ciceptive threshold in the control groups. The relationship be- (P < 0.001), pentobarbitone: 27,8% (P = 0,014), mdthohexi- tween nociceptive threshold and plasma drug concentration was tone: 24.9% (P = 0,013), propofol: 21,6% (P = 0,006). I1 n'y usually characterized by an initial decline followed by a rise a pas de changement dans les groupes contrtle au regard du in nociceptive threshold as the plasma concentration and degree seuil nociceptif. La relation entre le seuil nociceptif et la concen- of sedation increased. The results support the hypothesis that tration plasmatique des drogues est ordinairement caractdrisde hyperalgesia is a property of different anaesthetic agents when par une baisse initiale suivie par une augmentation du seuil administered at sub-hynotic concentrations. nociceptif h mesure que la concentration plasmatique et le ni- veau de sddation augmentent. Ces rdsultats supportent lT~y- poth~se selon laquelle l~yperalgie serait une propri~td de plu- Key words sieurs anesthdsiques quand ils sont administrds d des ANAESTHETICS, INTRAVENOUS: methohexitone, concentrations sous-hypnotiques. pentobarbitone, propofol, thiopentone; MEASUREMENT" nociceptive threshold, sedation; PAIN: hyperalgesia, nociception. The belief that sub-hypnotic doses of barbiturate agents From the Department of Anaesthesia,* and Department of enhance pain, perception has been a tenet of anaesthetic Pharmacology and Therapeutics,t Universityof Calgary. practice for >30 yr. In 1960, Dundee ~used tibial pressure Address correspondence to: Dr. Alastair Ewen, Department analgesimetry to demonstrate a reduction in nociceptive of Anaesthesia, Foothills Hospial, 1403 29th Street NW, threshold (NT) in humans following low doses of thio- Calgary, Alberta, Canada T2N 2T9. pentone or pentobarbitone. Since then, similar actions of Accepted for publication lOth February, 1995. barbiturates have been demonstrated in both human 2 and CAN J ANAESTH 1995 / 42:6 / pp 532-40 Ewen et al.: HYPERALGESIADURING SEDATION 533 animal 3 studies. Contradictory evidence, however, has clusion in the study, the physiological status of each an- come from other studies which suggest that barbiturates imal was evaluated. Mean arterial pressure was measured (and other/v anaesthetic agents) possess only antinoci- by an electromanometer (model 33-260, Baxter Health- ceptive properties.4.5 care Corp., Irvine, CA., U.S.A.). A sample of arterial The methodological differences among the preceding blood was withdrawn for measurement of arterial oxy- studies are considerable. A recent editorial by Kitahata gen tension, carbon dioxide tension, pH and haematocrit. and Saberski 6 cautioned against extrapolating the con- We sought to conftrm, for each animal, that these meas- clusions of in vitro studies to support observations in urements lay within the normal limits for our laboratory the intact animal. Qualitative differences among such (PaO2 > 65 mmHg, PaCO2 30-45 mmHg, pH 7.30-7.45 things as the method of restraint or the type of nociceptive and haematocrit 35-55 vol%). Rectal temperature was stimuli militate against comparisons of different studies. 7 maintained between 36~ and 38~ with a warming Investigations of non-barbiturate anaesthetic agents, no- lamp. This was confua'ned, at the beginning and end of tably propofol,4 have generally failed to demonstrate hy- the experiments, with a thermistor probe thermometer peralgesia. In spite of the recent interest in the subject, (model 43 TD, Yellow Springs Instruments, Yellow the question of barbiturate or non-barbiturate induced Springs, OH., U.S.A.). Each sample of blood withdrawn hyperalgesia remains conjectural. during the experiment was replaced immediately with an Recently, using tail pressure analgesimetry in rats, we equivalent volume of normal saline: demonstrated that sub-hypnotic doses of thiopentone were associated with a reduction in NT which we believe re- Measurement of nociceptive threshold flected a hyperalgesic action of this drug. 8 We speculated The thresholds for responses to noxious mechanical stim- that both barbiturate and non-barbiturate anaesthetic uli were measured by tail pressure analgesimetry, a mod- agents would cause hyperalgesia at plasma concentrations ification of the Randall and Selitto paw pressure test. s0 which caused sedation. To test the hypothesis, we per- Nociceptive threshold was defined as the weight (in formed this prospective, blinded study in two parts. In grams), applied to the tail, which caused a brisk with- the first part of the investigation, we used the technique drawal response. The stimulus was applied by an of tail pressure analgesimetry in rats to study the effects Analgesy-Meter (Ugo-Basile, Milan, Italy). H Using this of slowly increasing plasma concentrations of thiopen- device, the tail was supported on a plinth while pressure tone, methohexitone or pentobarbitone on NT, and to was exerted by means of one or two weights via a cone- correlate these effects with assessments of the animals' shaped pusher at a rate which increased linearly by 32 behaviour. g. sec -~ from zero to 250 g when one weight was used, In the second part of the study, we used the same or by 64 g. sec -~ from zero to 500 g when two weights measure of nociception, in a similar study design, to com- were used. We stimulated the distal 4 cm of the tail, pare the effects on NT of sedative concentrations of pro- avoiding, as much as possible, repetitive use of the same pofol and thiopentone. pressure point. The measurement scale on the Analgesy- Meter was hidden from the observer by a screen; an as- Methods sistant recorded each end point. The NT was calculated The study protocols were approved by the University of as the mean of three consecutive measurements. Prior Calgary Animal Care Committee. A total of 55 male to each infusion, baseline measurements of NT were per- Sprague-Dawley rats, each weighing between 250-325 g, formed in the manner described above. In both parts were studied. of the study, NT measurements were repeated at 4, 8, 12, 16, and 20 min after the start of the infusion. In Animal model part 1 of the study, additional measurements were made The investigations were performed with animals re- at two and six minutes. strained in a manner similar to that previously described Arterial blood samples (250 ~1) were withdrawn at the for autoradiographic studies in the rat. 9 After weighing, corresponding times for analyses of plasma barbiturate each animal was anaesthetized with 2% halothane in oxy- or propofol concentrations. gen. Femoral arterial and venous catheters were inserted under direct vision. The animal was partially restrained Infusion strategy by wrapping it from ankles to rnidthorax in a plaster The infusion rates for the different barbiturates were cho- cast which prevented escape whilst permitting free move- sen with the knowledge of their respective potencies and ment of the head and forelimbs. It was then taped to on the basis of our previous observations of the animals' a wooden block and placed under a warming lamp for behaviours during thiopentone infusions. Over the course two hours to allow elimination of halothane. Before in- of a 20 min infusion, we attempted to produce a spectrum 534 CANADIAN JOURNAL OF ANAESTHESIA of behaviour proceeding from an awake animal to one brissae. A sedation score was assigned as follows: that was unresponsive to non-noxious stimuli. After the 0 Awake: actively exploring, brisk head response. two-hour recovery period, and following confu-mation of 1 Slightly drowsy: not actively exploring, easily stimu- acceptable physiological variables, each animal was ran- lated by manipulating head or vibrissae. domly allocated to receive an intraveous infusion of one 2 Drowsy: responds only to vigorous manipulation of of the following solutions: head or vibrissae. 1 Thiopentone (STP group) 650 ~g. kg -I. min -t 3 Unresponsive to head manipulation.
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