Effects of Volatile Anesthetics on the Activity of Laryngeal ‘Drive’ Receptors in Anesthetized Dogs

Tatsushi MUTOH*, Arata KANAMARU1), Kentaro KOJIMA, Ryohei NISHIMURA, Nobuo SASAKI and Hirokazu TSUBONE1)** Departments of Veterinary Surgery and of 1)Comparative Pathophysiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113Ð8657, Japan

(Received 20 January 1999/Accepted 6 May 1999)

ABSTRACT. Effects of halothane, isoflurane and sevoflurane on laryngeal drive receptor activity were studied in the afferent activity of the superior laryngeal nerve in anesthetized spontaneously breathing dogs. Of 40 single units recorded, most of them (65%) responded to the volatile anesthetics applied to the isolated larynx at a concentration of 5%. The exposure to the anesthetics resulted in either an inspiratory increase (15%), both inspiratory and expiratory decrease (54%), or both inspiratory increase and expiratory decrease (31%) responses. The average discharge frequency of the receptors tended to be decreased on inhalation of the anesthetics, where significant decreases were observed in both respiratory phases for halothane and at expiration for isoflurane, but in neither respiratory phase for sevoflurane. These results support an advantage of sevoflurane over halothane and isoflurane for induction of anesthesia to minimize the influence of the activity of laryngeal drive receptors on the breathing pattern and airway stability.—KEY WORDS: canine, control of breathing, laryngeal afferent, laryngeal muscle, volatile anesthetic. J. Vet. Med. Sci. 61(9): 1033Ð1038, 1999

The larynx is a potent reflexogenic region of the upper not show responsiveness to volatile anesthetics [12]. airway which is rich in sensory receptors. In a recent study Moreover, the ventilatory depressive effect is pronounced we suggested the activation of these receptors by application by cooling of the larynx in newborns, presumably through of volatile anesthetics into the larynx of dogs [10]. The the stimulus of laryngeal cold receptors, but often induction of anesthesia in this manner promotes the exertion completely absent in adult animals [21]. Nishino et al. [12] of upper airway reflexes such as inhibited breathing (apnea), reported that some of the laryngeal cold receptors were breath-holding, coughing and laryngospasm [1, 4, 5, 6, 16]. stimulated by inhalation of halothane, but not by isoflurane The responses may not delay the induction but induce it in and enflurane. patients at risk for hypoxemia. The sensory innervation of In the larynx, laryngeal muscle contraction and/or tracheal the larynx is mainly supplied by the internal branch of the tug with respiration activates sensory receptors known as superior laryngeal nerve (SLN) [21, 23, 24]. It is well laryngeal ‘drive’ receptors [21, 23, 24]. Recent studies have known that the initiation of the upper airway respiratory clarified important roles of laryngeal drive receptors in reflexes is under the control of non-respiratory-modulated maintaining upper airway patency and the breathing pattern: laryngeal irritant and capsaicin-sensitive C-fibers. Besides Curran et al. [3] suggested that respiratory frequency is these fibers, the SLN contains a substantial number of other increased after section of the SLN in dogs breathing through receptors showing signs of strong respiratory modulation a tracheostomy, and the reflex prolongation of expiration [21, 23, 24]. Three types of laryngeal respiration-modulated time induced by upper airway collapse was greatly reduced. receptors which are affected by changes in transmural It is probable that feedback from the laryngeal ‘drive’ pressure, temperature, and laryngeal motion have been receptors acts as a kind of ‘sensor’ of larynx distortion which identified from single unit recordings of SLN afferents [21, regulates the breathing pattern and airway patency. 23, 24]. Among them, a prevalent effect of laryngeal Laryngeal drive receptors have been recognized as naked ‘negative pressure’ receptors on the breathing pattern and nerve endings in the airway muscle, acting like spindles [7]. upper airway patency during collapsing pressure has been In previous studies, slowly adapting pulmonary stretch reported in several studies [17, 18], but these receptors did receptors which are sensitive to stretching of the airway smooth muscle were greatly influenced by volatile anesthetics [11, 13]. It is possible that volatile anesthetics *PRESENT ADDRESS: Division of Cardiovascular Medicine, can also affect the laryngeal drive receptors, and thus affect Department of Internal Medicine, University of California, ventilation and airway condition during the induction of Davis, CA95616, USA. anesthesia with volatile anesthetics, but the ** CORRESPONDENCE TO: PROF. TSUBONE, H., Dept. of Comparative Pathophysiology, Graduate School of Agricultural and Life electrophysiologial data on the endings are limited. The Sciences, The University of Tokyo, 1Ð1Ð1 Yayoi, Bunkyo- purpose of the present study is to evaluate the effects of ku, Tokyo 113Ð8657, Japan. recently available volatile anesthetics on the activity of laryngeal drive receptors in dogs. 1034 T. MUTOH ET AL.

MATERIALS AND METHODS

Animals and basal anesthesia: Fifteen healthy beagle dogs (8 males and 7 females) were used in this study. Their mean age was 13.6-months (ranging from 10 to 18 months) and mean body weight was 9.7 kg (ranging from 7.6 to 14.0 kg). Anesthesia was induced with thiopental sodium (25 mg/kg), then maintained with a mixture of urethane (500 mg/kg) and α-chloralose (50 mg/kg) injected intravenously. A supplemental dose of urethane (200 mg/kg) and α- Fig. 1. Diagrammatic representation of the experimental set-up. chloralose (20 mg/kg) was injected hourly through an The tracheal cannula with two side arms allowed the diversion intravenous catheter placed into the cephalic or saphenous of breathing from the upper airway (A open; B1 and B2 closed) vein. All the dogs were euthanized after the experiment by to the tracheostomy (B2 open; closed at C), as well as the an intravenous injection of pentobarbital sodium (50 mg/ occlusion of the airway at the level of either the upper airway kg). (B1 and B2 closed; occluded at A ) or the trachea (closed at C; Animal preparation: The dogs were placed on an occluded at B2), by inflating the cuff of Foley catheters. operating table in the supine position, and a laryngeal mask Anesthetic gases were passed through the isolated upper airway ¨ in the expiratory direction (arrows) while the subject breathed (LMA Size-3, Intervent, UK) was introduced to cover the through the tracheostomy (B open; closed at C). larynx, including the epiglottis (Fig. 1). Arterial blood 2 pressure was monitored with a pressure transducer (DX- 300, Nihon Kohden, Japan) connected to a catheter inserted characterized. Briefly, the identification was performed on into the femoral artery. A thermal probe was inserted just the basis of recordings under four respiratory conditions: below the epiglottis through the laryngeal mask to record (1) upper airway breathing (U.A.B.), in which the dogs were laryngeal temperature. The cervical trachea was exposed in allowed to breath via the oral cannula, with the two sidearms its entire length and cut longitudinally to insert a tracheal of the tracheal cannula occluded (Fig. 1, A open; B1 and B2 cannula with two side arms. A pressure transducer (PD closed); (2) tracheostomy breathing (T.B.) in which the dogs 104, Toyoda Machine Works, Japan) was attached to the breathed via the most cranial sidearm of the tracheal cannula most cranial sidearm of the cannula to measure upper airway (Fig. 1, B2 open; closed at C); (3) upper airway occlusion pressure. A saline-filled polyethylene catheter (O.D. = 3 (U.A.O.), in which the dogs were subjected to occlusion of mm) was placed in the middle portion of the esophagus and both the oral and tracheal cannula at either end-inspiration connected to a pressure transducer (DX-300, Nihon Kohden, or end-expiration (Fig. 1, B1 and B2 closed; occluded at A); Japan) for recording esophageal pressure. and (4) tracheal occlusion (T.O.), in which the caudal side The internal branch of the SLN was transected bilaterally of the trachea was occluded (Fig. 1, closed at C, occluded at at the junction with the external branch, and the peripheral B2). cut end on the left side was split into fine filaments in The diversion of the breathing route and the occlusions preparation for recording its electrical activity. The during 3 consecutive breaths were made by inflating Foley recurrent nerve was also cut bilaterally to avoid secondary catheters. In this study the type of receptor which had respiratory-modulated reflexes mediated by the nerves. spontaneous discharges during T.B. and augmented activity Recordings of laryngeal afferent activity: Afferent activity during T.O. was categorized as a ‘drive’ receptor. The of the nerve filament was recorded with a pair of platinum location of each receptive field was established by touching electrodes. The nerve trunk was dissected into several thin the laryngeal mucosa with the Foley catheter or the external filaments until a single unit activity was clearly surface of the larynx with a cotton stick. In addition, the discriminated. These nerve preparations were produced larynx was manually displaced in both caudal and cranial within a pool of paraffin oil by using fine forceps with the directions. aid of a binocular microscope (SZ 60, OLYMPUS, Japan). Experimental protocol: The upper airway was The signal was amplified by a low noise DC-amplifier (DPA functionally isolated by inflating the cuff of a Foley catheter 201, DIA Medical, Japan) and a biophysical amplifier (DPA at the middle position of the tracheal cannula, which allowed

200, DIA Medical, Japan), and displayed on an oscilloscope tracheostomy breathing (Fig. 1, B2 open; closed at C). After (SS 5762, IWATSU, Japan) in parallel with a loudspeaker a control period of more than 1 min with 100% oxygen at a (Model 7747, NEC san-ei, Japan). All the signals were flow rate of 6 L/min through the isolated upper airway in displayed on a thermal-array recorder (RT 3100N, NEC san- the expiratory direction, all fibers were exposed to a 5% ei, Japan) and copied by a magnetic tape recorder (PC 204A, concentration of each of three anesthetics for 1 min: SONY, Japan). Once an acceptable single unit was found, sevoflurane, halothane and isoflurane. The order of the sensory mode of that particular ending was identified by administration was random. If any response of the receptor the conventional method [19], from which respiration- was observed, 1 and 3% of each anesthetic were tried. The modulated ‘pressure’, ‘drive’, and ‘cold’ receptors were anesthetic vaporizer was the usual type for each anesthetic VOLATILE ANESTHETICS AND DRIVE RECEPTORS 1035

(FLUOTEC Mark 3 for halothane, Cyprane; FORAWIC for were stimulated by cranial (6/30, 20%) or caudal (24/30, isoflurane, Muraco Medical; S-3 for sevoflurane, Kimura 80%) tracheal displacement. Medical) and was precalibrated for the intended anesthetic Effects of volatile anesthetics on the laryngeal drive concentration (5% = dial vol.5, full dial setting; 3% = dial receptors: Twenty-six drive receptors (26/40, 65%) showed vol.3; 1% = dial vol. 1). The intralaryngeal anesthetic an excitatory (Fig. 3, type ‘a’) or inhibitory (Fig. 3, type concentration was monitored with an infrared gas monitor ‘b’) response to volatile anesthetics at a concentration of (AGM-103 Capnomac, Datex, Finland) which was attached 5%. The exposure to the anesthetics, irrespective of their by means of a sampling tube connected to the uppermost type, resulted in either an increased response (4/26, 15%) sidearm of the tracheal cannula. which was observed predominantly during the inspiratory Data analysis: The discharge frequencies of single unit phase, or a decreased response (14/26, 54%, Fig. 3 type activity during each inspiratory and expiratory phase were ‘b’), observed in both inspiratory and expiratory phases. counted with a spike height discriminator (DSE 425, DIA Abrupt and transient inhibition of the drive receptor Medical, Japan). The mean discharge frequency was activities (e.g., Fig. 3, type ‘b’) was observed for 5 receptors counted breath by breath to 3 breaths during the control and by halothane, 3 by isoflurane, and none by sevoflurane. In test periods at the maximum response after the onset of addition, 8 (31%) drive receptors with tonic activity had inhalation. In addition, the time when the receptor was both an inspiratory increase and expiratory decrease (Fig. 3, stimulated or inhibited by the anesthetic was measured. type ‘a’). All of them (26/26, 100%) were sensitive to both Wilcoxon’s signed rank sum test or the Mann-Whitney U- intra- and extra-luminal probings at a level between the test was employed for comparison of the data. To compare cricoid cartilage and epiglottis. the differences among anesthetic groups, a one-way Significant decreases in receptor discharges were ANOVA test was run, followed, when necessary, by Tukey’s observed for both inspiratory and expiratory phases for multiple comparison test. To determine concentration- halothane, but a significant decrease was recognized only at related changes in the receptors, the correlation of peak expiration in isoflurane and there were no significant values of individual receptor response to each anesthetic at changes in sevoflurane during either respiratory phase (Fig. different concentrations (1, 3 and 5%) were calculated by 4). As a whole, the net discharge frequency from all three using simple linear regression analysis. All data were anesthetics at 5% decreased during inspiratory and expressed as the mean ± SE. P<0.05 was considered expiratory phases. The effect of sevoflurane was statistically significant. significantly less at expiration than with the other two anesthetics, whereas no significant differences were found RESULTS at inspiration. The onset of inhibition or excitation of the receptor Laryngeal ‘Drive’ receptors: Single unit activities were activity after administration of 5% volatile anesthetics was recorded from a total of 40 ‘drive’ receptors, which were 30.1 ± 3.7 sec in halothane, 37.0 ± 4.5 sec in isoflurane, and stimulated by T.O. at either end-expiration [Fig. 2, T.O.(E)] 48.6 ± 6.4 sec in sevoflurane. No statistically significant or inspiration [Fig. 2, T.O.(I)]. Twenty-nine (29/40, 73%) differences were found in the duration of responses among of the inspiration-modulated receptors showed signs of tonic anesthetics. The excitatory or inhibitory response tended to activity (Fig.3 types ‘a’ and type ‘b’), and the rest (11/40, be prolonged if the inhalation of anesthetics was sustained 27%) had phasic activity during U.A.B. and T.B. (Fig. 2). (data not shown). Some receptors, 7 in halothane (e.g., Fig. Thirty-two (32/40, 80%) of the ‘drive’ receptors responded 5), 3 in isoflurane, and 1 in sevoflurane, showed increased to both intra- and extra-luminal probings at a level between or decreased discharges in a concentration-dependent the cricoid cartilage and epiglottis. Thirty drive receptors manner after the inhalation of each anesthetic at three different concentrations.

Fig. 2. Activities of a laryngeal drive receptor during upper airway breathing (U. A. B.), tracheal breathing (T. B.), and tracheal

occlusions (T. O.) during both expiration (E) and inspiration (I). ENG = electroneurogram, PES = esophageal pressure, PUA = upper airway pressure, Temp. = laryngeal temperature. 1036 T. MUTOH ET AL.

Fig. 3. Examples of recordings from two laryngeal drive receptors when 5% halothane was inhaled. Type ‘a’ increased and type ‘b’ decreased inspiratory discharges after the onset of inhalation, while both types equally decreased expiratory discharges. The horizontal lines show the inhalation time of each volatile anesthetic. Abbreviations as in Fig. 1.

DISCUSSION

Afferent activity of laryngeal ‘drive’ receptors is mostly related to the contraction of intrinsic laryngeal muscles such as the posterior cricoarytenoid muscle (PCA) or passive movements of the larynx [21, 23, 24], and its response can be sustained in the absence of airflow and transmural pressure change across the larynx (e.g., Fig. 2). The results of this study suggest that volatile anesthetics affect the drive receptor activity of the larynx. It is important to note that a total of 65% of the drive receptors responded to volatile anesthetics applied to the larynx. Most of the drive receptors seem to be located relatively deep in the larynx because they required longer duration than other superficial endings Fig. 4. Responses of laryngeal drive receptors (n = 26) to 5% to block their activities by application of local anesthesia to volatile anesthetics. Each value (mean ± SE) was obtained from recordings of 3 consecutive breaths during each of the the internal surface of the larynx [20]. In this study, the control and test (approximately 1 min after the onset of effect of volatile anesthesia was observed 30.1 to 48.6 sec inhalation) periods. The data were expressed as percent after the beginning of applications, indicating some delay in change from the control period (before inhalation). * P<0.05 inducing functional changes in the nerve endings. In a vs control, ** P<0.01 vs control, † P<0.05 vs sevoflurane. previous study [20], 15% of the drive receptors were not Hal = halothane, Iso = isoflurane, Sevo = sevoflurane. Inspi. blocked, but the remaining 85% were blocked by lidocaine = inspiratory phase, Expi. = expiratory phase. applied to the laryngeal mucosa with a delay of 9 sec - 14 min. The drive receptors which were blocked by lidocaine or influenced by volatile anesthetics in this study were likely to be located at joints or ligaments close to the internal VOLATILE ANESTHETICS AND DRIVE RECEPTORS 1037

Fig. 5. Time-course changes in discharge frequency in a laryngeal drive receptor to 1, 3 and 5% of halothane. The abscissa and ordinate represent the time (sec) and discharge frequency (imp./sec). The thick line represents the intralaryngeal application of each volatile anesthetic. surface of the larynx. In fact, in the present study most of elicited by brief inhalation of halothane and isoflurane in the drive receptors which were influenced by volatile humans, as represented by an increase in respiratory anesthetics could be stimulated by inflation of a balloon frequency and a decrease in tidal volume, may be a catheter inside the larynx, as well as by external probings. reflection of such responses [4]. In this study two types of response - sensitization and Overall quality of the induction of anesthesia is generally depression (Fig. 3, types ‘a’ and ‘b’) - were exhibited by higher for sevoflurane than for other anesthetics [25Ð27]. inhalation of volatile anesthetics. It is noteworthy that the The breathing pattern during induction is less frequently responses of the laryngeal drive receptors to volatile changed by sevoflurane than by halothane or isoflurane [4]. anesthetics were mostly consistent with those of slowly In the present study the volatile anesthetics tended to adapting tracheobronchial stretch receptors [11, 13]. The decrease drive receptor activities, most remarkably for net inhibitory effect of halothane on the laryngeal halothane, less for isoflurane, and least for sevoflurane at respiration-modulated mechanoreceptors was reported in a the full vaporizer dial setting (5%). Although the minimum previous study [12], which agrees with our results. Abrupt alveolar concentration (MAC) of each anesthetic [9] might and transient inhibition of drive receptor activities (Fig. 3, be considered for the quantitative comparison of anesthetics, type ‘b’) might be caused by the blocking effect of volatile the vaporizer percent concentrations were employed for the anesthetics on the nerve endings. It is possible that the comparison of the drive receptor activities in this study, sensitization of drive receptor activity during inhalation of since a higher concentration such as 3Ð5% is generally halothane and isoflurane is due to increased PCA contraction required in any anesthetic for accelerating the induction and/or a direct effect on the sensory endings. Curran et al. period in humans [1, 25Ð27] and dogs [8, 14]. [3] pointed out that the removal of drive receptor activity In view of the above, the results of the present study increases the compliance of the upper airway, as with the support an advantage of a high concentration of sevoflurane effect of upper airway collapse on genioglossus for the induction of anesthesia over halothane and isoflurane electromyogram activation in tracheostomy-breathing dogs. to minimize the effect of the activity of laryngeal drive On the other hand, several reports suggest that primary receptors on the breathing pattern and airway stability. muscle spindle endings or arterial baroreceptors are sensitized by halothane [2, 15, 22]. ACKNOWLEDGMENTS. The authors are grateful to The removal of feedback from the laryngeal drive Jeanine McElwain for editorial assistance with this receptors is a source of the alteration in the breathing pattern manuscript. This study was supported by a Research and stabilization of the upper airway [3]. Although the Fellowship of the Japan Society for the Promotion of elicitation of the powerful airway defensive or protective Science for Young Scientists. reflexes such as coughing or laryngospasm by acute inhalation of volatile anesthetics is related to the stimulation REFERENCES of non-respiration modulated laryngeal irritant receptors [10, 12] and capsaicin-sensitive C-fibers [10], the inhibition of 1. Anonymous. 1986. Editorial: Inhalational induction of anaes- laryngeal drive receptors would also affect the regulation of thesia-New inspiration? Lancet ii: 84. breathing [3]. In fact changes in the breathing pattern, 2. Biscoe, T.J. and Millar, R.A. 1964. The effect of halothane 1038 T. MUTOH ET AL.

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