An Evaluation of the Influence of Medetomidine Hydrochlorideand Atipamezole Hydrochloride on the Arrhythmogenic Dose

of Epinephrine in Dogs during Halothane Anesthesia

Glenn R. Pettifer, Doris H. Dyson, and Wayne N. McDonell

ABSTRACT

Alterations in the arrhythmo-genic dose of epinephrine (ADE)were determined following adminis-tration of medetomidine hydrochlo-ride (750 [ug/M2) and a salineplacebo, or medetomidine hydro-chloride (750 pug/M2), followed byspecific medetomidine reversalagent, atipamezole hydrochloride(50 pug/kg) 20 min later, inhalothane-anesthetized dogs (n = 6).ADE determinations were madeprior to the administration of eithertreatment, 20 min and 4 h followingmedetomidine/saline or medetomi-dine/atipamezole administration.Epinephrine was infused for 3 minat increasing dose rates (2.5 and5.0 pug/kg/min) until the arrhythmiacriterion (4 or more intermittent orcontinuous premature ventricularcontractions) was reached. Theinterinfusion interval was 20 min.There were no significant differ-ences in the amount of epinephrinerequired to reach the arrhythmiacriterion following the administra-tion of either treatment. In addi-tion, the ADE at each determinationwas not different between treatmentgroups. In this study, the administra-tion of medetomidine to halothane-anesthetized dogs did not alter theirarrhythmogenic response to infusedepinephrine.

RESUME

Les changements de la dose aryth-mogenique d'epinephrine (DAE) ontete determines apres l'administra-tion d'hydrochlorure de metedomi-dine (750 pug/M2) et un placebo de

saline ou d'hydrochlorure de mete-domidine (750 pug/M2) suivi del'antagoniste speciflque de mete'do-midine, l'hydrochlorure d'atipame-zole (50 ,ug/kg) chez des chiensanesthesies avec l'halothane (n = 6).Les determinations de la DAE ontete faites avant l'administration del'un ou l'autre traitement, 20 minu-tes et 4 heures apres l'administra-tion dudit traitement. L'epinephrinea t administree en infusion con-tinue pendant trois minutes a deuxdoses croissantes (2,5 et 5,0 pugIkgImin) jusqu'a ce que le critiered'arythmie soit atteint (quatre ouplus de quatre contractions ventric-ulaires prematurees continues ouintermittentes). L'intervalle detemps entre les deux infusions etaitde 20 minutes. II n'y avait pas dedifference dans la quantite d'epine-phrine necessaire pour atteindre lecritiere d'arythmie apries l'admini-stration de l'un ou l'autre traite-ment. De plus, la DAE de chaquedetermination n'etait pas differenteentre les deux traitements. Dans lecontexte de cette etude, I'admini-stration de mete'domidine a deschiens anesthesies avec de l'halo-thane ne modifie pas leur reponsearythmogenique a une infusiond'epinephrine.

(Traduit par docteure Sophie Cuvelliez)

INTRODUCTION

Medetomidine is a relatively newa2-adrenoceptor agonist that is cur-rently undergoing licensing in NorthAmerica. Presently, it is used in smallanimal veterinary practices in bothEurope and Great Britain (1,2). As an

ao2-adrenoceptor agonist, medetomi-dine demonstrates a much greateraffinity for c,-adrenoceptors than doother drugs in its class (3,4). It hasbeen employed as the sole agent forthe production of sedation, analgesia,and muscle relaxation (5), in combina-tion with other injectable agents forthe production of general anesthesia indogs and cats (6,7), and as an adjunctto inhalation anesthesia in dogs (8).

Atipamezole hydrochloride, a spe-cific reversal agent for medetomidine,demonstrates a high a2/0t, selectivityratio of 8500:1 (9). The sedation pro-duced by medetomidine can bereversed by IM administration of ati-pamezole at 4 to 6 times the adminis-tered medetomidine dose ( 1, 10).One of the cardiovascular conse-

quences of medetomidine administra-tion is a relatively rapid and immediatedrop in heart rate to levels approx-imating 50% of baseline rates (5,1 1).In addition to this effect on heart rate,medetomidine can affect cardiac rhyth-mic. The most frequently reportedrhythm disturbances include an exag-geration of sinus arrhythmias, sinuspauses and 2nd degree atrioventricularblocks (1,5,11,12). Second degreeatrioventricular blocks are most likelyto occur within 30 min of medetomi-dine administration (11), with an inci-dence of 15% (5). Some authorshave reported changes in T wave mor-phology following medetomidineadministration (5), occasional prema-ture ventricular contractions (PVC)and premature supraventricular con-tractions have been recorded (12,13).These observations, in conjunctionwith previous reports concerning theproarrhythmic nature of the medeto-midine congener xylazine (14-16),

Can J Vet Res 1996; 60: 1-6

Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario N I G 2W 1.

This work was sponsored by Farmos Group Ltd., Turku, Finland.

Submitted January 2, 1995.

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have identified the need to furtherinvestigate the proarrhythmic natureof medetomidine.The determination of the arrhyth-

mogenic dose of epinephrine (ADE) isa technique which has been employedin a variety of investigations to quan-tify the pro- or antiarrhythmic natureof anesthetics and other drugs in vari-ous species (17-19). Using this tech-nique, Hayashi et al (20), have demon-strated that an intravenous infusionof dexmedetomidine, the d-isomer,increases the arrhythmogenic doseof epinephrine (ADE) in halothane-anesthetized dogs and that levome-detomidine, the i-isomer, is devoid ofthis effect. The existence of a similarprotective effect 10 min following theintramuscular administration of a sin-gle dose (15 ,ug/kg) of d/L medetomi-dine to either halothane (21) or isoflu-rane (22) anesthetized dogs was notconfirmed. These results may indicatea dose-dependent or temporal effect,or they may represent the inability ofthe model used in these investigationsto determine any alterations in theADE. The model employed did notconfirm the marked difference in theADE during halothane and isofluraneanesthesia that has been identified andconfirmed by a number of laboratoriesnot necessarily employing similarmethodologies (23-26).The objectives of the present inves-

tigation were to determine if a singledose of medetomidine, given at a dosecomparable to that employed in rou-tine clinical practice, would alter theresponse of dogs to infused cate-cholamines during halothane ane-sthesia and to determine if any medeto-midine-related effect could be reversedwith atipamezole. In addition, we wereinterested in determining if anyobserved effects on catecholamine-induced arrhythmias persisted beyondthe period in which the clinical effectsof sedation and analgesia had waned.This objective was established in lightof the previous results of Wright et al(16), that demonstrated a protractedeffect of xylazine on catecholamine-induced arrhythmias.

MATERIALS AND METHODS

ANIMALS AND INSTRUMENTATION

Six healthy mixed-breed dogs(3 males, 3 females), weighing

19.0-23.0 kg, were used in this inves-tigation. Health status was establishedon the basis of a thorough physicalexamination and complete bloodcounts, biochemistry profiles, urinaly-sis, thoracic radiographs, and electro-cardiograms using standard methods.All animals were handled accordingto the guidelines established by theCanadian Council on Animal Careand the experimental protocol wasapproved by the University of GuelphAnimal Care Committee.The animals were fasted for 12 h

prior to the commencement of eachtrial. Anesthesia was induced withhalothane (Fluothane, Ayerst Labora-tories, Montreal, Que.) in 100% oxy-gen delivered by face mask. Follow-ing endotracheal intubation andplacement in left lateral recumbency,intermittent positive pressure ventila-tion (Fraser Harlake 701, FraserSweatman Inc., 5490 Broadway,Lancaster, N.Y., USA) was institutedto maintain normocapnea. Halothaneadministration was adjusted to main-tain an end-expired concentration of1.2% (1.3 minimum alveolar concen-tration [MAC] for the dog) (27).A balanced electrolyte solution(Plasma-Lyte 148, Baxter Corpora-tion, Toronto, Ont.) was administeredat a rate of 10 mL/kg/h through a20 gauge catheter (Cathlon IV,Critikon Canada Inc., Markham, Ont.)placed in a cephalic vein. Tempera-ture was monitored electronicallywith a rectal probe (Tele-thermome-ter, Yellow Springs Instrument Cor-poration, Yellow Springs, OH, USA)and maintained between 37.5 and38.5°C with a hot water blanket. End-expired anesthetic concentration andend-tidal carbon dioxide were moni-tored continuously with an infraredgas analyzer (Datex 254 Capnomac,Datex Instrumentation Corporation,Helsinki, Finland) which was cali-brated with a manufacturer-suppliedcalibration gas. This calibration wasverified before each trial using a pre-cision gas mixture of halothane innitrogen (1.75 ± 0.03%) (MathesonGas Products Canada, Whitby, Ont.).A 20 gauge, 20 cm catheter

(L-Cath, Luther Medical ProductsIncorporated, Santa Ana, CA, USA)was placed in the right jugular vein tofacilitate central venous administra-tion of the epinephrine solution.Direct arterial blood pressure was

monitored using a transducer (DTXPressure Transducer System, Viggo-Spectramed, Oxnard, CA, USA)attached to a 20 gauge catheter(Cathlon IV, Critikon Canada Inc.,Markham, Ont.) which was placedpercutaneously in a dorsal metatarsalartery. Lead I and Lead II electrocar-diograms (ECG) were monitored con-tinuously using percutaneously placedstainless steel wires. Blood pressureand ECG measurements were dis-played and recorded on an 8 channelphysiograph (Gould TA 2000, GouldInc., Cleveland, OH, USA). Systolicpressure (SBP), diastolic pressure(DBP), mean arterial pressure (MBP),and heart rate (HR) were obtainedfrom the blood pressure and ECGtracings. The mean blood pressurewas calculated as MBP = DBP +1/3(SBP - DBP). The value of eachcardiovascular parameter at the sam-pling point was the average value forthat parameter in the 60 s period pre-ceding the sampling point.

Blood gas and acid-base status wereassessed before the beginning of eachADE determination (ABL 3, Acid-BaseAnalyzer, Radiometer, Copenhagen,Denmark). Samples for blood gasanalysis were withdrawn from the dor-sal metatarsal arterial catheter into3.0 mL, heparinized plastic syringes(Smooth-E, Radiometer, Westlake,OH, USA) and were processed imme-diately. All samples were temperaturecorrected.

EXPERIMENTAL PROTOCOL

Each dog was studied twice, with atleast a 1 wk recovery period betweeneach trial. The order of treatment wasrandom and consisted of eithermedetomidine/saline (Group A) ormedetomidine/atipamezole (Group B).For both treatment groups, a baselineADE determination (halothane anes-thesia alone) was initiated approxi-mately 60 min following the inductionof anesthesia. Determinations of theADE were made following a previ-ously described method (16,26).Epinephrine (Adrenalin, Parke-Davis,Canada, Inc., Scarborough, Ont.),diluted to 100 ,ug/mL in 0.9% sodiumchloride, was infused through the jugu-lar venous access with a volumetricinfusion pump (I-MED 928, I-MED,Milton Trading Estate, Abingdon,England) which was calibrated at thebeginning of each trial. The infusion

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chamber was filled prior to the initia-tion of each epinephrine infusion inorder to avoid any interruption duringthe ADE determination.The arrhythmia criterion was

defined as the occurrence of a mini-mum of 4 continuous or intermittentpremature ventricular contractions(PVC) within 15 s during a 3 mininfusion period, or during the 1 minperiod immediately following the ter-mination of the infusion, according topreviously documented techniques(16,28,29). Expanded ECG recordings(10 mm/s) were taken during the3 min infusion period and for 1 minafterwards. Both lead tracings werecarefully evaluated to determine if thearrhythmia criterion had been reachedduring this infusion. The ADE wasthe total dose (Qig/kg) of epinephrineinfused during the period prior to theoccurence of the 1st PVC which leadto the establishment of the arrhythmiacriterion.

Infusion rates were 2.5 and 5.0 ,uzg/kg/min and all ADE determinationsbegan with the lowest infusion rate. Ifthe arrhythmia criterion was not metafter 3 min, the infusion was termi-nated and the next level of infusionwas administered following a recov-ery period of 20 min.

Following determination of the base-line ADE, a 1 mg/mL solution ofmedetomidine hydrochloride (Domitor,Farmos Group, Turku, Finland) wasadministered at a dose rate of750 pug/M2 via the cephalic catheter.This dose was chosen on the basis ofmanufacturer's recommendations andas a dose which is used to produceadequate sedation for the performanceof routine clinical procedures (5,13).Body surface area (M2) was calculatedaccording to the following formula:BSA (M2) = [K X W213 ]/104, whereK = 10.1 and W = body weight (kg)(13). Fifteen minutes following theadministration of medetomidine,either saline (Group A) or atipame-zole hydrochloride (Group B) wasadministered intravenously. The doseof atipamezole (50 ,ug/kg) (Antisedan,Norden Laboratories, Herts, England)was chosen on the basis of the manu-facturers' recommendations and cur-rent reports that identify the reversalof medetomidine-induced sedation,analgesia and recumbency with thisdose (1,10). Group A animals receiveda similar volume of normal saline. The

cephalic catheter was flushed with2 mL normal saline following theadministration of any test substances.The second ADE determination was

made 5 min after the administration ofeither atipamezole or saline, is 20 minfollowing medetomidine administra-tion. The final ADE determinationwas made 4 h after the administrationof medetomidine. In the intervalsbetween ADE determinations, all ani-mals were maintained at 1.3 MAClevels of halothane. Following thefinal (4 h) ADE determination, allinstrumentation and catheters wereremoved and the animals were recov-ered from anesthesia.

Individual physiograph recordingswere examined, and SBP, DBP, MBP,and HR were measured 1 min prior tothe administration of the medetomi-dine, 1 min following medetomidineadministration and 1 min prior to theadministration of the saline placebo oratipamezole. Measurements were alsoobtained just prior to the beginning ofeach epinephrine infusion for ADEdetermination.

STATISTICAL ANALYSIS

Main effects of treatment or timewere evaluated using analysis of vari-ance for repeated measures. In analy-ses that demonstrated a significantmain effect, pairwise comparisons ofthe appropriate means were madeusing Tukey's method for pairwisecomparisons. In all tests, significancewas assigned to P values < 0.05.

RESULTS

The ADE was not significantly dif-ferent from the baseline value (halo-thane alone) 20 min or 4 h followingthe administration of medetomidine/saline (Group A) or medetomidine/atipamezole (Group B). No significantdifferences were found in the ADEbetween treatment groups (Table I).There were no significant differencesin blood gas parameters between the2 treatment groups at baseline, 20 min,or 4 h following treatment initiation.Neither was there any significantchange in any measured blood gasparameter over time within treatmentgroups.

In both treatment groups, significantincreases in SBP, DBP, and MBP wereproduced following medetomidineadministration (Table II). In dogs that

Table I. The arrhythmogenic dose of epine-phrine (ADE) (p,g/kg) in halothane-anesthetized dogs following the administra-tion of medetomidine/saline or medetomidine/atipamezole (mean ± SE; n = 6)

Treatment group;Sampling period Treatment A Treatment BBaseline

(Halothane alone) 7.03 ± 0.60 5.79 ± 0.48+ 20 min PTIb 6.59 ± 0.64 5.79 ± 0.46+ 4 h PTI 6.37 ± 0.61 5.28 ± 1.02Medetomidine administered at 750 pg/M2 (IV)following baseline ADE determination. Saline(treatment A) or atipamezole (50 pg/kg IV),(treatment B) administered 15 min followingmedetomidine administrationPosttreatment initiation

did not receive atipamezole, thisincrease remained significant until theADE determination at 20 min. Ati-pamezole administration produced asignificant decrease in SBP, DBP, andMBP. Mean heart rates were signifi-cantly decreased following the admin-istration of medetomidine. Heart ratesin both treatment groups had returnedto baseline values by 14 min post-medetomidine administration. Theadministration of atipamezole did notaffect the mean heart rate for treat-ment group B.

Prior to both infusions (2.5 and5 pug/kg/min) at the baseline ADEdetermination, and at 4 hr; SBP, DBP,MBP, and HR were not significantlydifferent between the treatmentgroups (Table III). Dogs that hadreceived atipamezole following mede-tomidine administration had signifi-cantly lower SBP, DBP, and MBPprior to the first epinephrine infusionat the 20 min ADE determination,compared to dogs that had notreceived atipamezole (Table III).Each treatment group experienced asignificant increase in SBP, DBP, andMBP prior to the first epinephrineinfusion (2.5 ,ug/kg/min) at 20 min,compared to values determined priorto infusion, at the baseline ADE deter-mination. This increase was observedin both treatment groups. In dogs thatdid not receive atipamezole, the DBPand MBP prior to the 2nd infusion at20 min remained significantly higherthan comparable measures at the base-line ADE determination. In this treat-ment group, as well, the mean HRprior to the 2.5 ,ug/kg/min infusion at20 min was significantly higher thanthe HR prior to the same infusion at

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Table II. The effect of medetomidine (750 p.g/M2 IV) and atipamezole (50 Lg/kg IV) on bloodpressure and heart rates in halothane-anesthetized dogs (mean ± SE; n = 6)

Systolic blood Diastolic blood Mean blood Heart rateTime pressure (mm Hg) pressure (mm Hg) pressure (mm Hg) (bpm)

Medetomidine/Saline (A)b

Baseline 108.3A ± 5.6 60.OA ± 4.7 76.3A ± 4.9 89 OA,B ± 6 31 min pre-MDT 103.3A ± 6.2 57.5A ± 5.0 73.OA ± 5.3 89 OA.B + 9 2I min post-MDT 170.OB ± 9.3 124.2B ± 4.2 145.OB ± 8.3 65.5A + 9.414 min post-MDT 164.2B ± 10.0 120.0B ± 5.8 134.7B ± 6.4 97.2B ± 5.15 min post-saline 159.2B ± 8.9 1 16.7B ± 5.1 130.8B ± 5.6 100.OB ± 4.8

Medetomidine/Atipamezole (B)b

Baseline 108.3A ± 5.3 59.2A ± 5.9 75.6A ± 3.9 79.OA ± 5.91 min pre-MDT 116.7A ± 6.0 65.8A ± 5.8 83.1A ± 5.7 85 OAB + 5 7I min post-MDT 175.8B 12.7 129.2B 11.4 144.8B ± 11.7 64.OB ± 10.014 min post-MDT 160.OBc + 7.0 1 17.5B + 6.5 131.7B ± 6.4 104.OA ± 5.35 min post-ATP 130.8AC + 4.7 79.2A ± 3.3 96.4A ± 2.7 78 OA B + 9 4A.B.C Within a treatment group and within a column, different superscripts indicate values that are

significantly different from one another by Tukey's method (P < 0.05)

Table III. Cardiovascular parameters prior to each epinephrine infusion during ADEdeterminations in halothane-anesthetized dogs (mean ± SE; n = 6)

Systolic bloodC Diastolic blood Mean bloodInfusion pressure pressure pressure Heart rate

Time rate(pLg/kg/min) (mmHg) (mmHg) (mmHg) (bpm) N

Medetomidine (750 Rg/M2 IV)/ Saline (A)

Baseline 2.50 108.3 ± 5.6 60.OA ± 4.7 76.3 ± 4.9 89.OAB ± 6.3 6.005.00 106.7 ± 8.8 60.0 ± 0.0 75.6 ± 2.9 84.0 ± 9.2 3.00

20 min 2.50 159.2B± 8.9 116.7B +5.1 130.8B± 5.6 100.OA.B+B4.8 6.005.00 143.3AB + 19.7 88.3C ± 1.7 106.7c ± 7.6 92.OAB ± 2.0 3.00

4 h 2.50 135.OA B ± 7.3 79.2A. + 7 3 97 8A.C + 6.9 75OB ± 4.6 6.005.00 125.0AB +54 63.7A 5.5 84.2AC+ 5.4 84.OAB± 6.5 4.00

Medetomidine (750 tg/M2 IV)/Atipamezole (50 ,ug/kg IV) (B)

Baseline 2.50 108.3A ± 5.3 59.2A ± 5.9 75.6A ± 3.9 790A ± 5.9 6.005.00 11OA 65A 80A 96A 1.00

20 min 2.50 130.8A-D + 4.7 79.2AD + 3.3 96.4A.D + 2.7 78.OA + 9.4 6.005.00 117.5 ± 24.7 80.OA 14.1 92.5 17.7 93.O + 12.7 2.00

4 h 2.50 120.8AB + 3.0 69.2AB + 2.3 86.5AB + 2.3 73.OA + 10.4 6.005.00 125.OA 7.1 67.5A± 3.5 86.7A 4.7 78.OA 33.9 2.00

A.B.C Within a treatment group and within a column, different superscripts indicate values that aresignificantly different by Tukey's method (P < 0.05)

D Significantly different from the corresponding value in treatment Group A by Tukey's method(P. 0.05)

Table IV. Blood pressures and heart rates at the time that the arrhythmia criterion was reachedin halothane-anesthetized dogs treated with either medetomidine/saline or medetomidine/atipamezolea

SBPc DBP MBP HRTime (mmHg) (mmHg) (mmHg) (bpm)

Medetomidine/Saline (A)b

Baseline 302.5 ± 17.6 154.4 ± 3.7 203.8 ± 6.4 54.7 ± 9.5+ 20 min 328.9 + 13.7 172.8 ± 4.2 224.8 ± 6.6 82.0 ± 2.5+ 4 h 314.5 ± 13.8 160.5 ± 4.9 204.5 ± 10.5 74.2 ± 5.6

Medetomidine/Atipamezole (B)

Baseline 298.6 ± 12.9 152.9 ± 5.9 201.4 ± 8.6 64.3 ± 6.2+ 20 min 295.0 ± 15.6 155.0 ± 10.2 201.7 ± 11.6 74.2 ± 5.5+ 4 h 286.3 ± 20.3 146.9 ± 13.5 193.4 ± 15.3 75.7 ± 7.4

a Results represent mean ± SE; N = 6Medetomidine administered at 750 pg/M2 IV; atipamezole administered at 50 pg/kg IVSystolic (SBP), diastolic (DBP) and mean (MBP) blood pressures and heart rate (HR)

4 h. There were no significant differ-ences, between treatment groups inthe SBP, DBP, MBP and HR at thetime the arrhythmia criterion wasreached (Table IV).

DISCUSSION

The results of this investigationindicate that a single dose of medeto-midine given intravenously at a doserate of 750 p,g/M2 to halothane-anesthetized dogs does not alter thearrhythmogenic dose of epinephrine.In addition, administration of ati-pamezole (50 ,ug/kg IV) to dogs thatreceived medetomidine during halo-thane anesthesia did not alter theirarrhythmogenic response to exoge-nously administered epinephrine.The findings concerning the effect

of medetomidine on the ADE are inagreement with those previously pub-lished (21,22). Hayashi et al (20),however, identified a protective effectof d-medetomidine on epinephrine-induced arrhythmias in halothaneanesthetized dogs. They were unableto identify a similar effect forl-medetomidine. The medetomidineadministered in the present investiga-tion, as well as that employed byLemke et al (21,22) was the racemicmixture that contains equal concentra-tions of both stereoisomers. Thus, theabsence of an effect seen with theracemic mixture may be due toan inadequate concentration of thed-isomer. Hayashi et al (20) observeda protective effect of dexmedetomi-dine but with a higher (0.5 ,ug/kg/min) dose, thus supporting a dose-dependent effect. In addition, theydetermined the ADE in the presenceof an infusion of dexmedetomidinerather than after a single dose. Thus,differences in observations betweenthe present work and those obtainedduring an infusion of dexmedetomi-dine may be due to differences in thetotal dose of d-medetomidine admin-istered. While the results of Hayashiet al (20) have served to further eluci-date the mechanisms underlying theprotective effect of at2-adrenoceptorstimulation against catecholamine-halothane-induced arrhythmias, thestudy was designed to more closelymimic the pharmacological milieuwhich may occur in routine veterinaryanesthetic practice.

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While the results of the presentinvestigation appear to concur withthose of Lemke et al (21), there arecertain methodological differencesbetween the 2 investigations that mayprevent an interpretation of equiva-lency of the results. Lemke et al (21)chose the appearance of 4 or moreectopic ventricular depolarizations asthe arrhythmia endpoint. This end-point includes arrhythmias that wereused as the arrhythmia criterion in thepresent investigation (occurence of4 or more premature ventricular con-tractions), as well as early ventriculardepolarizations (EVD) that occur dur-ing periods of an accelerated sinusescape rhythm. In comparison toPVC's, EVD's occur early in theepinephrine infusion, are uni-focal inorigin and are not associated withpulse deficits (21,22). In our work,EVD's were usually noted within the1st minute of the 3 min infusion. Weoverlooked the EVD as an endpoint infavour of the multi-focal PVC associ-ated with pulse deficits, as theoccurence of this arrhythmia type mayhave more severe clinical importancethan the EVD. While the resultsobtained using the EVD as thearrhythmia endpoint are similar tothose obtained in the present investi-gation, this endpoint does not detect adifference in the ADE obtained duringeither halothane or isoflurane anesthe-sia (21,22). This difference has beenrepeatedly identified by previousinvestigators employing an arrhyth-mia criterion similar to that employedin this investigation (23-25). Thus, itappears that methodologies whichdefine a broader arrhythmia criterionmay lose the ability to identify differ-ences that have been previouslythought to exist. In this respect, thecriterion employed in the presentinvestigation appear to be more likelyto detect a difference in ADE determi-nations if one does, in fact, exist.The administration of atipamezole

15 min following medetomidineadministration did not alter the ADEcompared to that obtained in dogs thatreceived a saline injection. Theadministration of atipamezole wasincluded in this investigation in orderto determine if it would alter anyeffect that may have been producedby medetomidine administrationalone. Previous work has demon-strated that atipamezole administered

as a single bolus (10 ,ug/kg IV) atten-uates the protective effect of dexme-detomidine (0.5 p,g/kg/min) (19).Unlike the absence of a medetomidineeffect, the absence of an atipamezoleeffect was unlikely to have beenrelated to inadequate dosing, since adose just 20% of that employed in thepresent investigation has been shownto completely block the anti arrhyth-mic effect of dexmedetomidine (20).Alternatively, the absence of an effectof atipamezole in the present investi-gation is likely related to the absenceof an initial effect of medetomidine,as discussed above.The increases in SBP, DBP, and

MBP following medetomidine admin-istration, and the return of theseparameters to baseline values follow-ing atipamezole administration, paral-lel previously reported cardiovascularresponses to medetomidine and ati-pamezole administration during inha-lation anesthesia (8). We did not,however, observe the period of pro-tracted bradycardia and hypotensionfollowing the initial hypertensivephase subsequent to medetomidineadministration that has been reportedin isoflurane-anesthetized dogs (8)and in dogs sedated with medetomi-dine alone (1 1). Differences in cardio-vascular responses to medetomidineadministration in halothane- andisoflurane-anesthetized dogs havebeen noted by others. In separateinvestigations, Lemke et al observed ashort period (<10 min) of bradycardiafollowing medetomidine administra-tion to halothane-anesthetized dogs(21) that was more protracted inisoflurane-anesthetized dogs (22).Thus, there may be a significant inter-action between the various cardiovas-cular effects of different inhaled anes-thetics and the cardiovascular effectsof medetomidine.

Particularly germaine to the presentinvestigation was the observation thatmedetomidine did not produce aperiod of protracted bradycardia intreatment group A dogs. Lemke et al(21) also noted a relatively rapidreturn to normal heart rates followingmedetomidine administration. In thepresent investigation, medetomidineproduced a reduction in heart rateimmediately following administration,but these values returned to normal (orslightly higher) prior to the first ADEdetermination at 20 min postmedeto-

midine administration. One may spec-ulate that, if there were any residualeffect of epinephrine from the baselineADE determination, this may haveprovided sympathetic input sufficientto offset the medetomidine-mediatedbradycardia.As determined by the return of

MBP to baseline values prior to the 4 hADE determination in treatmentgroup A, the absence of a protractedperiod of hypotension subsequent tothe initial hypertension may similarlybe due to residual epinephrine effectswhich offset the ot,-adrenoceptor-mediated reduction in sympatheticoutflow. The results of a separateinvestigation carried out in our labo-ratory (30) suggest that there may bemechanisms at work that can affectcardiovascular function beyond theperiod of a single ADE determination.In this investigation, we did notobserve an increase in baseline hemo-dynamic variables over time duringrepeat ADE determinations; however,an absolute change need not necessar-ily exist in order to produce a signifi-cant interaction between the cardio-vascular effects of a2-adrenoceptorstimulation and any residual effects dueto repeated exposure to epinephrine.The administration of medetomi-

dine precluded equivalency of mea-sured and derived blood pressureparameters prior to the initiation of the1st and 2nd infusions at 20 minpostmedetomidine administration intreatment Group A, and prior to theinitiation of the 1st infusion at 20 minpostmedetomidine administration intreatment Group B. The extent towhich this nonequivalency of hemo-dynamic functioning can effect ADEdeterminations is not known. Woehlcket al (28) have demonstrated thatnonequivalency of hemodynamic sta-tus prior to epinephrine infusions canalter the measured ADE while main-taining equal plasma concentrations ofepinephrine at the time of arrhythmia.They observed a significant increasein the amount of epinephrine requiredto achieve equivalent plasma concen-trations in animals that demonstratedhigher cardiac outputs, central venouspressures, heart rates, and reducedsystemic vascular resistances. Theydid not observe any difference in SBP,DBP, or MBP between animals thatdemonstrated this elevation in cardiacfunction and those that did not. In

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their paradigm, this nonequivalency ofhemodynamic status was purportedlyproduced by residual epinephrine fromprevious infusions. They suggest thatthe elevation in hemodynamic func-tioning may have accelerated themetabolism of infused epinephrine,thereby requiring greater infusedquantities to obtain plasma concentra-tions equivalent to those in animalsnot demonstrating the effects of resid-ual tissue epinephrine. While the stim-ulus for nonequivalency of hemody-namic status observed in the presentinvestigation is not the same as thatsuggested by Woehlck et al (28), wedid not measure cardiac output prior toeach epinephrine infusion and, there-fore, cannot rule out the influence ofsimilar alterations in hemodynamicfunctioning on the ADE determina-tions made in our investigation.The increase in baseline SBP, DBP,

and MBP prior to the 20 min ADEdetermination did not affect the maxi-mum blood pressures obtained duringthe infusion of epinephrine. This is animportant observation since someinvestigators have suggested a criticalrole for blood pressure and heart rateelevations in the development ofcatecholamine-induced arrhythmiasduring inhalant anesthesia (31). Thiseffect is equivocal, Maze and Smith(32) have observed that the afterloadreduction that accompanies theadministration of prazosin (anct,-adrenoceptor antagonist), can beproduced by sodium nitroprussidewithout the concomitant reduction inthe arrhythmogenic response toinfused catecholamines observed withprazosin administration.The results of this investigation indi-

cate that medetomidine does not alterthe ADE in halothane-anesthetizeddogs. Thus, given our present knowl-edge, it appears that medetomidine canplay a role as an adjunct to inhalationalanesthesia without the threat of anincrease in morbidity related to theoccurence of ventricular arrhythmiasin response to elevations in circulatingcatecholamines.

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