The Cardiovascular Sparing Effect of Fentanyl and Atropine,Administered to Enflurane Anesthetized Dogs

Jan E. Ilkiw, Peter J. Pascoe, Steve C. Haskins, John D. Patz and Rory Jaffe

ABSTRACT

Cardiovascular effects of high doseopioid together with low dose inhalantwere compared with inhalant alone todetermine whether opioid/inhalanttechniques were less depressant onthe cardiovascular system. The effectsof positive pressure ventilation andincreasing heart rate to a more phys-iological level were also studied.Cardiovascular measurements recordedduring administration of enfluraneat 1.3 minimum alveolar concen-tration (MAC; 2.89 ± 0.02%) to spon-taneously breathing dogs (time 1)and during controlled ventilation[arterial carbon dioxide tension at40 ± 3 mmHg (time 2)] were simi-lar. At time 2, mixed venous oxygentension and arterial and mixed venouscarbon dioxide tensions were signifi-cantly decreased, while arterial andmixed venous pH were significantlyincreased compared to measurementsat time 1. After administration of fen-tanyl to achieve plasma fentanyl con-centration of 71.7 ± 14.4 ng/mL andreduction of enflurane concentrationto yield 1.3 MAC multiple (0.99 ±0.01%), heart rate significantlydecreased, while mean arterial pres-sure, central venous pressure, strokeindex, and systemic vascular resis-tance index increased compared tomeasurements taken at times 1 and 2.Pulmonary arterial occlusion pres-sure was significantly increased com-pared to measurements taken at time 2.After administration of atropine untilheart rate was 93 ± 5 beats/min(plasma fentanyl concentration 64.5 ±13.5 ng/mL) heart rate, mean arte-rial pressure, cardiac index, oxygen

delivery index, and venous admix-ture increased significantly and oxy-gen utilization ratio decreasedsignificantly compared to valuesobtained at all other times. Centralvenous and pulmonary arterial occlu-sion pressures and systemic vascularresistance index were significantlydecreased compared with measure-ments taken prior to atropine admin-istration, but were not significantlydifferent to those recorded at times 1and 2. We conclude that, in healthydogs, an anesthetic technique utilizingfentanyl/enflurane offers consider-able cardiovascular sparing comparedto enflurane alone, provided an anti-cholinergic is administered to pre-vent bradycardia.

RESUME

Les effets cardio-vasculaires d'unehaute dose d'opioide combinee 'a unefaible dose de gaz anesthesique ontete compares a ceux du gaz anes-thesique utilise seul, afin de deter-miner si les techniques anesthesiquesopioide/gaz avaient moins d'effetsdeleteres sur le systeme cardio-vasculaire. Les effets de la ventila-tion 'a pression positive et ceux del'augmentation de la frequence car-diaque 'a un niveau plus physiologiqueont egalement ete etudie's. Les mesurescardio-vasculaires enregistrees surdes chiens recevant de l'enflurane 'a1.3 fois la concentration alveolaireminimale (CAM; 2.89 ± 0.02%)etaient similaires pendant la respi-ration spontanee (temps 1) et pen-dant la ventilation controlee (pres-sion partielle de dioxyde de carbone

dans le sang arteriel maintenue ia 40 ±3 mmHg) (temps 2). Au temps 2, lespressions partielles d'oxygene et dedioxyde de carbone dans le sangveineux me'lange et la pression par-tielle de dioxyde de carbone dans lesang arteriel e'taient diminuees defaqon significative alors que le pH dusang arteriel et veineux melange aug-mentait significativement par rap-port aux mesures du temps 1. Apresavoir administre' du fentanyl de facona obtenir une concentration plasma-tique de fentanyl de 71.7 ± 14.4 ng/mLet diminue la concentration d'enflu-rane (0.99 + 0.01%), la frequencecardiaque diminuait significative-ment alors que la pression arteriellemoyenne, la pression veineuse cen-trale, l'index d'ejection et l'index deresistance vasculaire systemique aug-mentaient par rapport aux mesureseffectuees aux temps 1 et 2. La pres-sion arterielle pulmonaire bloqueeetait significativement augmentee parrapports aux mesures prises au temps2. Apres l'administration d'atropinejusqu'a ce que la frequence cardiaquesoit de 93 ± 5 battements/min (con-centration plasmatique de fentanyl64.5 ± 13.5 ng/mL), la frequence car-diaque, la pression arterielle moyenne,l'index cardiaque, l'index de distri-bution d'oxygene et l'effet de shuntaugmentaient significativement et leratio d'utilisation d'oxygene dimi-nuait significativement compares auxvaleurs obtenues a tous les autrestemps. Les mesures de la pressionveineuse centrale, de la pressionarterielle pulmonaire bloquee et del'index de resistance vasculaire sys-temique etaient significativementdiminuees par rapport aux mesures

Department of Surgical and Radiological Sciences, School of Veterinary Medicine (Ilkiw, Pascoe, Haskins, Patz) and Department of Anesthesiology, Schoolof Medicine (Jaffe), University of California, Davis, California 95616.

This project was supported in part by a Companion Animal Laboratory Research Grant, School of Veterinary Medicine, University of California,Davis.

Submitted August 31, 1993.

Can J Vet Res 1993; 57: 248-253248

prises avant I'administration d'atro-pine mais elles n'etaient pas signi-ficativement differentes de cellesenregistrees aux temps 1 et 2. Nousconcluons qu'une technique anesthe-sique utilisant fentanyVenflurane pro-tege beaucoup mieux la fonctioncardio-vasculaire que 1'enflurane seul,a condition qu'un agent anticholi-nergique soit administre pourprevenir la bradycardie. (Traduit parDr Phillipe Pibarot)

INTRODUCTION

In veterinary practice, anesthesia isusually maintained by administrationof the potent inhalant anesthetic agents,methoxyflurane, halothane, or isoflu-rane. These agents, as well as induc-ing progressive depression of the centralnervous system, induce cardiovascularand respiratory depression in dose-dependent fashion (1,2). While opioidsinduce minimal changes in cardiovas-cular dynamics (3,4), their ability toproduce anesthesia is debated (5,6). Inhuman beings, opioids and sedativehypnotics are often administered withlow concentrations of inhalant anes-thetics and muscle relaxants as a tech-nique called "balanced anesthesia."Opioids are known to reduce the con-centration of inhalant anestheticsrequired for anesthesia (7,8), and opioid/inhalant anesthetic techniques arethought to cause less depression of car-diovascular and other organ systems(9,10). Opioids and inhalant anestheticsinteract synergistically to produce ven-tilatory depression (11,12) and after

administration of these drugs, ventilationis usually controlled. Positive pressureventilation may induce greater cardio-vascular depression and outweigh thebenefits of reduced inhalant concentra-tion (2,13).The study reported here was under-

taken to determine whether adminis-tration of an opioid under inhalant anes-thesia induced less cardiovasculardepression than an equivalent level ofinhalant anesthesia alone. The effects onhemodynamics of positive pressure ven-tilation and increasing the heart ratewere also studied. All studies wereundertaken in healthy dogs with car-diovascular and respiratory systemsdeemed normal on physical examination.

MATERIALS AND METHODS

INSTRUMENTATION

The experimental protocol wasapproved by the campus animal careand use committee. Ten nonconditioned,mixed-breed dogs of either sex, weigh-ing 18.5 to 27.9 kg, were used in thisstudy. The dogs were vaccinated againstdistemper, hepatitis, leptospirosis, par-vovirus and rabies, held for two weeksand only included in the study if theywere considered healthy by thoroughphysical examination. Food was with-held for 12 hours and anesthesia inducedwith enflurane (Ethrane, Anaquest,Madison, Wisconsin) and oxygen deliv-ered via a face mask. Anesthesia wasmaintained with enflurane and oxygenadministered through an orotrachealtube placed in the trachea. A catheterwas passed down the lumen of the oro-

tracheal tube so that its distal tip laylevel with the tip of the orotrachealtube. This catheter was used to mea-sure inspiratory pressure and to collectgas samples for determination of end-tidal enflurane concentration by infraredabsorption (Beckman Medical GasAnalyzer LB-2, Beckman InstrumentsInc., Anaheim, California). Prior to andat the completion of each experiment,the gas analyzer was calibrated withgases containing known concentrationsof enflurane (1.00% and 2.89%). ATeflon catheter (2-inch, 20-gauge,Insyte, Deseret Medical Inc., BectonDickinson & Co., Sandy, Utah) wasplaced percutaneously in the dorsalmetatarsal artery for continuous mea-surement of arterial blood pressure andrepeated collection of arterial bloodsamples for pH, blood gas, PCV andTP measurements. Another Tefloncatheter was placed percutaneously inthe cephalic vein for administration offentanyl (Fentanyl citrate injection USP,Elkins-Sinn Inc., Cherry Hill, NewJersey). A balloon-tipped catheter(7.5-F, Swan Ganz thermodilutioncatheter, Baxter Healthcare Corp.,Edwards Critical-Care Division, Irvine,California) was inserted percutaneouslyvia the jugular vein so that the tip lay inthe pulmonary artery. Correct posi-tioning was confirmed by observation ofa characteristic pulmonary arterial pres-sure waveform prior to balloon inflationand observation of a characteristic pul-monary arterial occlusion pressure wave-form after inflation of the balloon. Thiscatheter was used for continuous mea-surement of pulmonary arterial and cen-tral venous pressures, intermittent mea-

TABLE I. Cardiovascular effects of enflurane (1.3 MAC') during spontaneous and controlled ventilation and of subsequent administration of fentanylto enflurane to yield 1.3 MAC multiple in dogs (n = 10)

Time 1 Time 2 Time 3 Time 4Enflurane 1.3 Enflurane 1.3 Fentanyl and Fentanyl and enflurane at 1.3 MAC

MAC, spontaneous MAC, controlled enflurane at 1.3 multiple and atropine administrationVariable ventilation ventilation MAC multiple (heart rate 80 to 100 beats/min)Heart rate (beats/min) 114 + 9Cd 112 + 9Cd 54 ± 8"" 93 ± 5abcMean arterial pressure (mmHg) 59 ± 6c' 64 + 7cd 82 + 20abd I1 + 0IabcMean pulmonary arterial pressure (mmHg) 9.3 ± 1.5 8.5 ± 1.9 9.6 ± 2.3 10.6 + 4.4Central venous pressure (mmHg) 1.3 ± 1.4- 1.8 ± 1.3c 3.9 ±- 1.7abd 1.0 + 1.4cPulmonary arterial occlusion pressure (mmHg) 5.7 ± 1.0* 4.4 1I.7-+ 6.9 t 2.Obd* 4.4 ± 1.2c*Stroke index (ml/beat/m2) 24 ± 5cd 23 + 5cd 42 ± 10ab 48 I labCardiac index (L/min/m2) 2.71 ± 0.48d 2.55 + 0.57d 2.24 + 0.64d 4.44 + 0.96abcSystemic vascular resistance index (dyne-sec/cm5/m2) 1738 ± 397- 2010 + 446C 2851 + 626abd 2059 ± 494cPulmonary vascular resistance index (dyne-sec/cm5/m2) 100 + 32* 103 + 58+ 94 ± 33* 105 ± 92*' Minimum alveolar concentration; * n = 9; + n = 8a Significantly different from value under enflurane 1.3 MAC, spontaneous ventilation (p < 0.05)b Significantly different from value under enflurane 1.3 MAC, controlled ventilation (p < 0.05)c Significantly different from value under fentanyl and enflurane at 1.3 MAC multiple (p < 0.05)d Significantly different from value under fentanyl and enflurane at 1.3 MAC multiple, with heart rate 80 to 100 beats/min (p < 0.05)Data are expressed as mean ± SD

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TABLE II. Oxygenation effects of enflurane (1.3 MAC') during spontaneous and controlled ventilation and of subsequent administration of fentanylto enflurane to yield 1.3 MAC multiple in dogs (n = 10)

Time 1 Time 2 Time 3 Time 4Enflurane 1.3 Enflurane 1.3 Fentanyl and Fentanyl and enflurane at 1.3 MAC

MAC, spontaneous MAC,controlled enflurane at 1.3 multiple and atropine administrationVariable ventilation ventilation MAC multiple (heart rate 80 to 100 beats/min)Partial pressure of oxygen in arterial blood (mmHg) 532.0 + 30.7 548.6 + 25.0 545.9 + 17.3 528.1 + 35.7Hemoglobin (g/L) 141 16 142 14 140 + 13 140 + 14Oxygen delivery index (ml/min/m2) 513 129d 485 + 129d 423 + 146d 833 + 238abcOxygen consumption index (ml/min/m2) 115 + 31 d 95 + 18+ 100 16* 84 + 18a+Oxygen utilization ratio 0.23 + 0.05d 0.20 + 0.07d+ 0.26 + O.09d* 0.11 + 0.05abc+Partial pressure of oxygen in mixed venous blood(mmHg) 70.3 + 9.9bx 59.5 + 7oa 54.5 88ad* 73.4+ 1l.lIVenous admixture (%) 1.1 + 0.5d 1.1 + 0.5d+ 0.9 + 0.2d* 2.5 0.8a+'Minimum alveolar concentration; * n = 9; + n = 8Significantly different from value under enflurane 1.3 MAC, spontaneous ventilation (p < 0.05)Significantly different from value under enflurane 1.3 MAC, controlled ventilation (p < 0.05)

c Significantly different from value under fentanyl and enflurane at 1.3 MAC multiple (p < 0.05)dSignificantly different from value under fentanyl and enflurane at 1.3 MAC multiple, with heart rate 80 to 100 beats/min (p < 0.05)Data are expressed as mean + SD

surement of pulmonary arterial occlusionpressure and cardiac output, and forrepeated collection of blood samplesfor mixed venous pH and blood gasmeasurements. Limb leads were attachedfor recording the ECG (Amplifier 134615 55, Gould Inc., Cleveland, Ohio).Core temperature was measured from thethermistor of the balloon-tipped catheter.All measurements were recorded on aphysiograph (ES 1000 recorder, GouldInc., Cleveland, Ohio). Throughout thestudy, a 100 volt single twitch stimulus(Grass S48 stimulator, Grass InstrumentsCo., Quincy, Massachusetts) was deliv-ered every 12 seconds to the lip.

Arterial and mixed venous oxygen(PaO2, PV-02) and carbon dioxide(PaC02,P_VC02) tensions and arterial andmixed venous pH (pHa, pWv) were mea-sured, using a blood-gas analyzer(IL system 1306, InstrumentationLaboratory Inc., Lexington,Massachusetts). All measurements werecorrected for patient temperature (14).Bicarbonate concentration (mmol/L)and base deficit (mmol/L) were calcu-lated (14,15). Hemoglobin concentration(g/L) was measured by use of the cyan-methemoglobin method and a spec-trophotometer(Beckman DB, BeckmanInstruments Inc.).Mean arterial, mean pulmonary arte-

rial, pulmonary arterial occlusion, airwayand central venous pressures (all,mmHg) were measured, using pressuretransducers (Gould disposable trans-ducer, T4812AD-R, Oxnard, California).Prior to each study, all pressure trans-ducers were calibrated against a mercurymanometer, with zero level set at the

thoracic inlet in laterally recumbentdogs.

Cardiac output was measured by ther-modilution (Cardiac output computerCOM-1, American EdwardsLaboratories, Irvine, California). Fivemilliliters of a 0.9% sodium chloridesolution at room temperature wereinjected under pressure via the rightatrium (Thermal dilution injector,Lexington, Massachusetts). This pro-cedure was repeated five times, andvalues obtained were averaged anddivided by body surface area [(bodyweight, kg)0667/10] to obtain cardiacindex (L/min/m2).

Systemic vascular resistance index(dyne-sec/cm5/m2), pulmonary vascu-lar resistance index (dyne-sec/cm5/m2),arterial and mixed venous blood oxygencontent (CaO2 and C-v02, mL/L), venousadmixture (%), oxygen consumptionindex (mL/min/m2), oxygen deliveryindex (mL/min/m2), and oxygen uti-lization ratio were calculated from mea-sured values (14,16,17).

EXPERIMENTAL PROTOCOL

After instrumentation and with thedogs breathing spontaneously, the end-tidal enflurane concentration was main-tained between 2.84 and 2.92% [1.3minimum alveolar concentration (MAC)]for 20 minutes and measurements weretaken (time 1-enflurane, spontaneouslybreathing). Throughout the study, allpressure measurements, except pul-monary arterial occlusion pressure, werecontinuously recorded. Mechanical ven-tilation was then instituted and contin-ued for the remainder of the study to

maintain the PaC02 at 40 + 3 mmHgwith an inspiratory pressure < 8 mmHg.End-tidal enflurane concentration wasmaintained at 1.3 MAC for a further20 minutes and measurements weretaken (time 2-enflurane,controlled ven-tilation). Fentanyl was then adminis-tered intravenously, using a loading(15.9 ,ug/kg/min for 20 minutes) andinfusion dose (1.065 ,ug/kg/min), tomaintain the arterial plasma fentanylconcentration at > 30 ng/mL for 60 min-utes. At the same time, the enfluraneend-tidal concentration was decreased by65% (0.99-1.02%, 1.3 MAC multiple)and held constant for 60 minutes. Athird set of measurements was thentaken (time 3-fentanyl and enflurane).Atropine sulfate (Atropine sulfate injec-tion USP, Elkins-Sinn Inc., 0.01 to 0.02mg/kg) was then administered intra-venously until the heart rate was 80 to100 beats/min, while continuing thefentanyl infusion and maintaining theend-tidal enflurane concentration at0.99 to 1.02%. Once heart rate was 80 to100 beats/min, a fourth set of measure-ments was taken (time 4-fentanyl, enflu-rane and atropine). Arterial blood sam-ples for determination of plasma fentanyllevels using radioimmunoassay (18)were collected prior to measurement 3and after measurement 4.

STATISTICAL ANALYSIS

Data were analyzed, using ANOVAfor repeated measures to determine ven-tilation and drug effects. When a sig-nificant effect was detected, pairwisecomparisons of means were made, usinga two-tailed t-test. All results are

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TABLE III. Acid-base effects of enflurane (1.3 MAC') during spontaneous and controlled ventilation and of subsequent administration of fentanylto enflurane to yield 1.3 MAC multiple in dogs (n = 10)

Time IEnflurane 1.3

MAC, spontaneous

Time 2Enflurane 1.3

MAC,controlled

Time 3Fentanyl and

enflurane at 1.3

Time 4Fentanyl and enflurane at 1.3 MACmultiple and atropine administration

Variable ventilation ventilation MAC multiple (heart rate 80 topHa (U) 7.250 0.069 7.358 + 0.03 la 7.341 + 0.045a 7.357 *Partial pressure of carbon dioxide in arterialblood (mmHg) 53.9 + 8.6bcd 40.7 + Ila 41.4 + 1.7a 40.9 +Bicarbonate concentration (mmol/L) 22.4 + 1.6 21.9 + 1.7 21.4 + 2.1 21.9 +Base deficit (mmol/L) -4.2 + 2.3 -1.9 + 1.9 -2.6 2.6 - 1.8pHv(U) 7.213 + 0.064hd 7.299 + 0.021 a 7.294 + 0.047a' 7.316 +Partial pressure of carbon dioxide in mixed venousblood (mmHg) 62.4 + 8.2bcd 49.0 2.6a+ 50.2 + 3.0a* 46.3 +' Minimum alveolar concentration; * n = 9; + n = 8aSignificantly different from value under enflurane 1.3 MAC, spontaneous ventilation (p < 0.05)b Significantly different from value under enflurane 1.3 MAC, controlled ventilation (p < 0.05)c Significantly different from value under fentanyl and enflurane at 1.3 MAC multiple (p < 0.05)dSignificantly different from value under fentanyl and enflurane at 1.3 MAC multiple, with heart rate 80 to 100 beats/min (p < 0.05)Data are expressed as mean + SD

100 beats/min)F 0.0383

F 2.0aF 2.1F 2.50.04 la+

1.4a+

expressed as mean ± SD, and differ-ences were considered significant if p <0.05.

RESULTS

Throughout the study, model condi-tions were preserved with no signifi-cant changes in temperature, packedcell volume or total protein betweenmeasurement times. There was no sig-nificant difference in end-tidal enflu-rane concentration between spontaneousventilation (2.89 ± 0.02%) and con-trolled ventilation (2.89 ± 0.02%). Boththese values were significantly differentcompared to the end-tidal enfluraneconcentrations at both measurementtimes during infusion of fentanyl. Therewas no significant difference in the end-tidal enflurane concentration duringinfusion of fentanyl with enflurane (0.99± 0.01%) and similar conditions withheart rate increased to 80 to 100beats/min (0.99 ± 0.01%). Plasma fen-tanyl concentration at time 3 (71.7 ±14.4 ng/mL) was not significantly dif-ferent from that at time 4 (after atropineadministration; 64.5 ± 13.5 ng/mL).

Institution of positive pressure ven-tilation (time 2) did not significantlychange any of the cardiovascular mea-surements compared to measurementstaken during spontaneous ventilation(time 1; Table I). The mixed venousoxygen tension and the arterial andmixed venous carbon dioxide tensionswere significantly decreased, while thearterial and mixed venous pH were sig-nificantly increased at time 2 comparedto time 1 (Tables II and III).

Administration of fentanyl and reduc-tion of enflurane to yield 1.3 MAC mul-tiple (time 3) induced a significantdecrease in heart rate, while mean arte-rial pressure, central venous pressure,stroke index, and systemic vascularresistance index increased compared tomeasurements taken at times 1 and 2.Mixed venous oxygen and carbon diox-ide tensions and arterial carbon dioxidetension were significantly decreased,while arterial and mixed venous pHwere significantly increased at time 3compared to values recorded at time 1(Tables II and III). Pulmonary arterialocclusion pressure was significantlyincreased at time 3 compared to time 2(Table I).

After atropine administration, heartrate increased significantly from 54 ± 8to 93 ± 5 beats/min (Table I). Meanarterial pressure, cardiac index, oxy-gen delivery index, and venous admix-ture were increased significantly andoxygen utilization ratio decreased sig-nificantly compared to values obtainedat times 1, 2 and 3 (Tables I and II).Central venous and pulmonary arterialocclusion pressures and systemic vas-cular resistance index were significantlydecreased compared to measurementstaken at time 3, but not different tothose at times 1 and 2 (Table I). Oxygenconsumption index at time 4 was sig-nificantly less than that measured attime 1, while stroke index was signifi-cantly greater than that measured attimes I and 2, but not different fromthat measured at time 3. Mixed venousoxygen tension measured at time 4 wassignificantly increased compared to thevalues measured at times 2 and 3, but

not different from the value obtainedat time 1.

DISCUSSION

This study was designed to investigatewhether opioidlinhalant anesthetic tech-niques, using high dose fentanyl infusionwith low concentration of enflurane,were less depressant on cardiovascularfunction than standard inhalant tech-niques. Hypoventilation and a decreasein heart rate usually occur when highdose opioid infusions are administeredduring inhalant anesthesia in dogs. Toprevent hypoventilation, respiration isusually controlled to maintain arterialcarbon dioxide at about 40 mmHg, butthe decrease in heart rate may not betreated if arterial blood pressure is wellmaintained. Thus, the effects of positivepressure ventilation and of increasingheart rate to a higher level were alsostudied.The study was undertaken in dogs,

since in veterinary practice opioid/inhalant anesthetic techniques are morecommonly administered to that speciesthan other domestic species. Fentanylwas selected for study, as it is frequentlyused in opioid/inhalant anesthetic tech-niques in dogs (19,20), its pharmacoki-netic profile and MAC reduction poten-tial have been reported in dogs underenflurane anesthesia (7,21), plasma con-centrations of the drug can be easilyassayed (18), the pharmacodynamic/pharmacokinetic profile indicates a rela-tionship between effect and plasma con-centration (22) and this profile suitsadministration as an infusion. A loading

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dose, as well as a 60 minute infusion offentanyl, were administered to ensure asteady state had been reached. Althoughenflurane is rarely administered to vet-erinary patients, it is commonly admin-istered to human beings. In the presentstudy, enflurane was selected for studybecause the maximal anesthetic MACreduction for fentanyl in dogs had beenreported for enflurane but not for otherinhalants (7). We think that these resultscan be extrapolated to other inhalants,although the degree of cardiovascularsparing may be less with agents such asisoflurane which induce less myocardialdepression. The end-tidal anestheticconcentration prior to fentanyl admin-istration was maintained at 2.89 ±0.02%, a value equal to 1.3 X MAC.This value was selected as one whichwould provide surgical anesthetic levels.Throughout the study, a supramaximalsingle twitch stimulus was applied to thelip of the dogs every 12 seconds to act asa noxious stimulus and simulate surgi-cal conditions and to negate some ofthe depressant effects of the inhalants(23,24). Maximal reduction in enflu-rane concentration of 65% has beenreported at plasma fentanyl concentra-tions of 30 ng/mL, with no further sig-nificant reduction at 97.0 ng/mL (7).In our study, the 65% reduction wasapplied to 1.3 X MAC so that the end-tidal enflurane concentration wasdecreased to 0.99 ± 0.01% and held atthat level during infusion of fentanyl.Loading and infusion doses of fentanylwere calculated from pharmacokineticdata (21) to achieve plasma concentra-tions of - 30 ng/mL (25). Plasma fen-tanyl levels measured in this study wereapproximately twice as high as thosedesired. This was not considered toaffect the experimental results, as higherlevels do not produce a greater reductionin enflurane MAC (7). It appeared thatthe loading dose was responsible forthe high plasma levels, as plasma fen-tanyl levels from samples collected at thecompletion of administration of theloading dose in four dogs, indicatedthat the high plasma level had alreadybeen reached. The entire study, includ-ing instrumentation, took approximatelythree hours to complete, and as we didnot measure the cardiovascular changesunder enflurane alone for this durationwe are unable to comment on time-related changes in cardiovascular func-tion. Hemodynamic adaptation to pro-longed inhalant anesthesia has been

reported in dogs (26) but is unlikely tohave influenced our results as nochanges in cardiac index were foundbetween times 1 and 3. The significantdifference occurred between times 3and 4, measurement times which wereseparated by less than 15 minutes.The cardiovascular and respiratory

effects of enflurane during both spon-taneous and controlled ventilation aresimilar to those published previously(27). No differences in cardiovascularmeasurements were found betweenspontaneous and controlled respirationat 1.5 MAC (27), a similar result to thatfound in the present study at 1.3 MAC.Mixed venous oxygen tension decreasedsignificantly during controlled ventila-tion in our study; the importance of thisis unknown as oxygen delivery indexand oxygen utilization ratio wereunchanged. Although not found in thisstudy, greater cardiovascular depres-sion during positive pressure ventila-tion has been reported previously due inpart to the effects of ventilation onvenous return (13), as well as to themaintenance of a normal arterial car-bon dioxide tension and therefore lack ofsympathetic stimulation (2). In ourstudy, respiratory depression inducedby enflurane alone was significant(Paco2 53.9 ± 8.6 mmHg), and sinceapnea, has been reported when fentanylwas administered to dogs already underinhalant anesthesia (28), controlled ven-tilation is necessary with opioid/inhalanttechniques.When fentanyl was administered and

enflurane reduced to 1.3 MAC multiple,heart rate decreased significantly com-pared with administration of enfluranealone. Mu-receptor agonist opioidsinduce bradycardia, which is reportedlymore marked in anesthetized than con-scious human beings (29). In the studyreported here, the plasma fentanyl con-centration attained was 71.7 ± 14.4ng/mL rather than the desired concen-tration of 30 ng/mL. Although it is pos-sible that a lower plasma fentanyl con-centration might not have induced sucha decrease in heart rate, the maximalanalgesic action appears to coincidewith maximal changes in respiratoryand cardiovascular systems at a plasmafentanyl level of approximately 30 ng/mL(30). The mechanism of fentanyl-induced bradycardia, while not com-pletely understood, is most likely due tostimulation of the vagal nucleus in themedulla (31). Blockade of sympathetic

chronotropic action may also play aminor role (31). In our study, there wasa significant increase in mean arterialpressure due to an increase in peripheralvascular resistance. In dogs, peripheralvascular resistance does not changeunder enflurane (27,32), and perhapsthis increase is a compensatory responsefor the decrease in heart rate and cardiacoutput. Stroke index increased signifi-cantly, but cardiac index did not changedue to the decrease in heart rate. Despitethe increase in stroke index, both centralvenous and pulmonary arterial occlusionpressures increased significantly, pos-sibly because the heart was incapable ofpumping the increased volume. Sincefentanyl alone appears to have mini-mal effects on myocardial contractil-ity (3,30,33), while enflurane inducesdose-dependent myocardial depression,we expected the hemodynamics toimprove as the level of enfluranedecreased.

In the present study, administration ofatropine to increase heart rate to 93 ± 5beats/min during administration of fen-tanyl and enflurane, increased cardiacindex causing an increase in mean arte-rial pressure, oxygen delivery indexand a decrease in oxygen utilizationratio. From this response, it wouldappear that the cardiovascular sparingeffects of administering fentanyl anddecreasing enflurane concentration werepresent only when heart rate wasincreased. In a previous study in dogs,fentanyl alone was found not to depressmyocardial contractility and thus cardiacoutput was maintained because of acompensatory increase in stroke vol-ume (34). With other potent opioidshowever, significant decreases in cardiacoutput, which were attenuated byatropine, have been reported (35,36,37).In normal hearts, not under the influenceof drugs,cardiac output appeared to beindependent of heart rate, except at thevery extremes (38,39), whereas, inabnormal hearts with impairment ofventricular function, stroke volumeappeared to be fixed and cardiac outputbecame dependent on heart rate (40).In our study, it appeared that ventricularimpairment limited the increase in strokevolume in response to the fentanyl-induced bradycardia so that cardiac out-put was maintained at levels similar tothose with enflurane alone. The signif-icant increase in central venous andpulmonary arterial occlusion pressure arefurther evidence for impairment of ven-

252

tricular function. The most likely reasonfor ventricular impairment in our studyis depression of myocardial contractil-ity by the inhalant anesthetic. Enfluraneis reported to induce potent, direct,dose-dependent depression of myocar-dial contractility (41,42). Thus, althougha lower concentration of enflurane wasadministered with the opioid infusiontechnique, cardiac output was not sparedbecause ventricular impairment wasstill sufficient, in the face of a decreasein heart rate, to limit stroke volume.When atropine was administered andheart rate increased to more physiolog-ical levels, the cardiovascular sparingeffect became evident, with a significantincrease in cardiac index, mean arte-rial pressure, mixed venous oxygen ten-sion, oxygen delivery index and adecrease in oxygen utilization ratio.The cardiac index at this time was sim-ilar to the value reported for normal,nonpremedicated, conscious dogs (43)and, when compared with the value forenflurane alone, attests to the cardio-vascular sparing effect. Thus, the car-diovascular sparing effect of this opi-oid/inhalant technique is only present ifan anticholinergic is administered toprevent the drug-induced decrease inheart rate.

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