AJVR, Vol 63, No. 7, July 2002 969

The perioperative stress response is a physiologicreaction to various events associated with anesthe-

sia and surgery that can be characterized by changes incardiovascular function and hormonal secretion.1,2 Instressful situations, hypothalamic activation leads toincreased sympathetic outflow and release of epineph-rine from the adrenal medulla and norepinephrine fromprimarily peripheral sympathetic nerve terminals. Inaddition, secretion of pituitary (eg, β-endorphin) andadrenocortical (eg, cortisol) hormones is increased. Inmany cases, these neurohumoral changes can be bene-ficial to an individual; however, in the perioperativeperiod, they may also be 1 of the factors contributing topatient morbidity.2,a Thus, attempts to attenuate theperioperative stress response have become a focus ofmuch interest among anesthesiologists.2,3

Preanesthetic medications play an important rolein the field of anesthetic management. Because of theirability to influence events during the preoperative,intraoperative, and postoperative periods, preanesthet-ic medications may also affect the development andmagnitude of the perioperative stress response. The α2-adrenoceptor agonists (also called α2-agonists)have been used in humans to decrease cardiovascularas well as hormonal responses in the perioperativeperiod.4 Reportedly, medetomidine, a highly potent α2-agonist, attenuates the hormonal responses to ovario-hysterectomy in dogs, compared with preanestheticadministration of saline (0.9% NaCl) solution.5,6 Indogs and cats, acepromazine, a phenothiazine tranquil-izer, is another agent that is widely used to providerestraint and sedation. In contrast to medetomidine,this antidopaminergic drug does not possess profoundsedative effects and also lacks analgesic properties.However, when combined with an opioid, its sedativeand analgesic effects can be greatly enhanced. Whereasmedetomidine induces vasoconstriction and bradycar-dia, acepromazine possesses vasodilatative properties.Cardiovascular actions of these 2 preanesthetic med-icants have been compared in dogs.7,b

The study reported here was designed to investi-gate the development and magnitude of the periopera-tive stress response in healthy dogs when they wereadministered medetomidine or acepromazine as part ofthe preanesthetic medication. To characterize hormon-al responses, plasma concentrations of catecholamines(epinephrine and norepinephrine), cortisol, and β-endorphin were measured at various points duringthe perioperative period. In addition, a number of car-diovascular and clinical variables were monitored. Ourhypothesis was that each of the preanesthetic med-icants would differentially influence development of

Received Nov 13, 2001.Accepted Feb 11, 2002.From the Department of Clinical Sciences, Faculty of Veterinary

Medicine, University of Helsinki, 00014 Helsinki, Finland(Väisänen, Raekallio, Kuusela, Kirves, Vainio); and theDepartments of Forensic Medicine (Huttunen) and Physiology(Leppäluoto), University of Oulu, 90014 Oulu, Finland.

Supported by the Finnish Foundation of Veterinary Sciences, HelviKnuuttila Foundation, and Orion Pharma Corporation.

The authors thank Satu Sankari, Anu Lappalainen, Sari Mölsä, andAnu-Leena Hongell for technical assistance and Hanna Oksanenfor statistical assistance.

Address correspondence to Dr. Väisänen.

Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanestheticmedication

Misse Väisänen, DVM; Marja Raekallio, DVM, PhD; Erja Kuusela, DVM; Pirkko Huttunen, PhD;Juhani Leppäluoto, MD, PhD; Petra Kirves, DVM; Outi Vainio DVM, PhD

Objective—To compare the perioperative stressresponse in dogs administered medetomidine or ace-promazine as part of the preanesthetic medication.Animals—42 client-owned dogs that underwentelective ovariohysterectomy. Procedure—Each dog was randomly allocated toreceive medetomidine and butorphanol tartrate (20 µg/kg and 0.2 mg/kg, respectively, IM) or acepro-mazine maleate and butorphanol (0.05 and 0.2 mg/kg,respectively, IM) for preanesthetic medication.Approximately 80 minutes later, anesthesia wasinduced by administration of propofol and maintainedby use of isoflurane in oxygen. Each dog was alsogiven carprofen before surgery and buprenorphineafter surgery. Plasma concentrations of epinephrine,norepinephrine, cortisol, and β-endorphin were mea-sured at various stages during the perioperative peri-od. In addition, cardiovascular and clinical variableswere monitored. Results—Concentrations of epinephrine, norepineph-rine, and cortisol were significantly lower for dogsadministered medetomidine. Concentrations of β-endorphin did not differ between the 2 groups.Heart rate was significantly lower and mean arterialblood pressure significantly higher in dogs adminis-tered medetomidine, compared with values for dogsadministered acepromazine. Conclusions and Clinical Relevance—Results indi-cate that for preanesthetic medications, medetomi-dine may offer some advantages over acepromazinewith respect to the ability to decrease perioperativeconcentrations of stress-related hormones. In particu-lar, the ability to provide stable plasma catecholamineconcentrations may help to attenuate perioperativeactivation of the sympathetic nervous system. (Am J Vet Res 2002;63:969–975)

01-11-0323R.qxd 6/14/2002 2:20 PM Page 969

the stress response and that medetomidine administra-tion before anesthesia would produce lower periopera-tive concentrations of stress-related hormones.

Materials and MethodsAnimals—Forty-four bitches that underwent elective

ovariohysterectomy at Helsinki University VeterinaryTeaching Hospital between January and August 2000 wereused in the study. Inclusion criteria were that a dog had goodbody condition, weighed between 15 and 40 kg, was 2 to 7years old, and was not receiving concurrent medications.Brachycephalic and Greyhound-type breeds were excluded.Dogs were determined to be in good health on the basis ofresults of a complete physical examination, CBC count, andserum biochemical analysis. Written consent was obtainedfrom each owner, and the study protocol was approved by thelocal Ethical Committee.

Study design—Each dog was assigned a number inaccordance with the sequence of enrollment in the study.Sealed envelopes were used to randomly allocate dogs to 2treatment groups. One group (group MED) was administeredmedetomidinec and butorphanol tartrated (20 µg/kg and 0.2mg/kg, respectively, IM), whereas the other group (groupACE) was administered acepromazine maleatee and butor-phanol (0.05 and 0.2 mg/kg, respectively, IM). Because oftechnical difficulties, 2 dogs were omitted from the study;thus, there were 21 dogs in each group. The preanestheticmedication was provided in covered syringes that containedequal volumes. All medications were injected into the bicepsfemoris muscle by the same trained investigator (MV). Thisinvestigator, who was unaware of the treatment administeredto each dog but was aware of the 2 medication possibilities,was responsible for monitoring anesthesia as well as moni-toring dogs during the recovery and postoperative periods.

Study protocol and anesthetic management—On theday of surgery, all dogs arrived at the clinic at or before noon;dogs remained at the clinic for 24 hours. After arrival, eachdog was placed in a separate cage. Areas around the cages andthe operating theater were kept quiet, and the dogs were han-dled only by members of the investigative team. After eachdog had spent approximately 1 hour in a cage, the preanes-thetic medication was administered IM. The dog then wasleft undisturbed for 15 to 20 minutes before preparation forsurgery began, which included placement of catheters into ajugular veinf and femoral arteryg (for collection of venousblood samples and continuous direct measurement of bloodpressure, respectively). Local anesthetic was infiltrated forplacement of the catheters. Cephalothin (30 mg/kg, IV) andcarprofen (4 mg/kg, IV) were administered before inductionof anesthesia. An infusion of lactated Ringer’s solution (10 ml/kg/h, IV) was initiated, and the infusion was contin-ued until the end of surgery.

Anesthesia was induced by administration of an amountof propofol sufficient to enable orotracheal intubation.Propofol was administered IV in small increments through-out a 90-second period until the desired effect was achieved.Anticipated propofol dose requirements were 1 to 2 and 3 to6 mg/kg for MED and ACE groups, respectively; the actualamount of propofol injected for each dog was recorded.Anesthesia was maintained by use of isoflurane in oxygen(flow rate, 1 L/min) through a semiclosed circle.h At least 10minutes were allowed to elapse from induction of anesthesiauntil the beginning of surgery. Ovariohysterectomy was per-formed by 1 of 3 experienced surgeons by use of a standardmanner through a ventral approach.

During anesthesia, heart rate, direct arterial blood pres-sure,i end-tidal CO2, and end-tidal isoflurane concentrations,respiratory rate,j and arterial hemoglobin saturation (SpO2;

measuredk by use of a probe placed on the dog’s tongue) wereobserved continuously. Arterial blood samples were obtainedjust before induction and at the end of surgery for measure-ment of PaO2, PaCO2, and pH.l Dogs were allowed to breathespontaneously, but respiration was assisted manually whennecessary to maintain end-tidalCO2 < 60 mm Hg. Additionalboluses of fluids (5 to 10 ml/kg, IV) were administered toprevent hypotension (mean arterial blood pressure [MAP] <60 mm Hg). Heating blankets were used to maintain rectaltemperature at ≥ 37 C. Buprenorphine (0.010 mg/kg) wasadministered IV at the completion of surgery, after which thedogs were maintained in a light plane of anesthesia for 15minutes while the catheter was removed from the femoralartery. The vaporizer was then turned off, and the dogs wereallowed to breathe pure oxygen for 5 minutes. Duration ofpreoperative sedation, anesthesia, and surgery was recorded.

Dogs were allowed to recover from anesthesia in theircages, and interval until extubation was recorded. Dogs thatbecame excited during recovery were administered propofol(2 to 4 mg/kg, IV) and buprenorphine (0.005 mg/kg, IV).Physical examinations were performed at predeterminedtime points, and additional warming was provided, whenneeded, to maintain rectal temperature ≥ 37 C.Buprenorphine (0.010 mg/kg, IV) was used for additionalpostoperative analgesia, and the amount administered wasrecorded. Throughout the study, each dog wore an ambula-tory electrocardiographic monitor (ie, Holter monitor), andthe behavior was videotaped. Results of Holter monitoringand behavioral analysis were not evaluated in this study.

Measurement of hormone concentrations—Blood sam-ples (7 ml) were obtained from a jugular vein into chilledtubes that contained EDTA. Plasma was separated by use ofrefrigerated centrifugation, divided into 3 aliquots, andfrozen (–80 C) within 30 minutes after collection.Concentrations of epinephrine, norepinephrine, cortisol, andβ-endorphin were measured. Plasma used for catecholamineassays was treated with an antioxidant (ie, Na2S2O5).

Blood samples were collected at time of arrival (within 2minutes after the dog’s owner had departed), immediatelybefore induction, within 2 minutes after removal of the sec-ond ovary, at the end of surgery, 1, 3, and 6 hours aftersurgery, and 24 hours after the initial sample was collected(approx 20 hours after surgery). The first sample was col-lected by use of a needle to puncture the vein, and each dogwas muzzled during the collection. Subsequent samples werecollected via the indwelling catheter; 1.5 ml was discarded aswaste prior to collection of each of these samples. Blood vol-ume was replaced by giving a bolus of 20 ml of lactatedRinger’s solution. Heparinized saline solution was used toprevent clotting of the catheter between samples. Blood sam-ples were collected before any other procedures were per-formed that might have disturbed the dog. In addition, bloodsamples (3 ml) were collected for immunologic analysis.Results of immunologic analysis were not evaluated in thisstudy.

Hormonal analyses were performed in duplicate andwithin 14 months after collection of samples. Cate-cholamines were extracted from plasma into Al2O3 and elut-ed into a solution of acetic acid. Catecholamines from eluateswere analyzed by use of high-performance liquid chromatog-raphy, using a multichannel electrochemical detector.8,m Limitof detection was 0.05 nmol/L, and the interassay coefficientof variation (CV) was 6%. For measurement of β-endorphinconcentrations, 1 ml of plasma was extracted by use of car-tridges,n using an automatic sample preparation system.o

Eluates were dried in a vacuum dryer,p reconstituted withradioimmunoassay buffer, and measured by use of a radioim-munoassay method.9 Limit of detection of the assay was 0.5 fmol/tube, and interassay CV was < 15%. Cortisol con-

970 AJVR, Vol 63, No. 7, July 2002

01-11-0323R.qxd 6/14/2002 2:20 PM Page 970

centrations were measured by use of a commercial radioim-munoassay kit.q Limit of detection was 5.5 nmol/L, and intra-assay CV was < 10% as calculated from results of duplicateanalyses of the samples. Samples that had catecholamineconcentrations less than the limit of detection were assigneda value equal to the limit of detection.

Measurement of heart rate and blood pressure—Heartrate was measured by palpation of the pulse immediatelybefore administration of preanesthetic medication and 1, 3,and 6 hours after surgery. Additionally, intraoperative heartrate and MAP (directly measured) were recordedi immediate-ly before induction, 10 minutes after induction, at the time ofthe abdominal incision, at time of removal of each ovary, dur-ing closure of the incision, and at the end of surgery.

Evaluation of sedation and pain-distress—Response ofeach dog to handling was recorded during the entire perioper-ative period. In addition, sedation and pain-distress wereassessed (Appendix). Sedation and pain-distress scores weredetermined immediately before administration of preanesthet-ic medication and after surgery at the same times as collectionof blood samples for hormonal analysis. Assessments were per-formed for each dog after other measurements and collectionof samples were completed. Sedation was assessed initially by

monitoring each dog’s response to opening of the door to thecage, hand clapping, and speaking to the dog. For pain-distressevaluation, vocalization, restlessness, freedom of movement,and finally, response to firm pressure applied to the region ofthe incision were observed. The protocol used was a modifica-tion of scoring systems described elsewhere.10,11

Statistical analysis—Data for hormone concentrationswere analyzed as logarithmic interventions because of theskewed distribution of the original data. Hormone concen-trations, heart rates, and blood pressures were analyzed byuse of repeated-measures ANOVA. Linear mixed-effects mod-elsr were used to study the similarity of the response curvesover the entire observation period. Values of the later mea-surement points were contrasted to values for the first andsecond measurements. Confidence intervals were calculatedon the basis of data obtained for each time point. Differencesin pain-distress and sedation scores were tested by use of a χ2 test and by logistic regression. Significance was designatedat values of P < 0.05.

ResultsDogs—Mean ± SD age of the MED group (4.5 ±

1.6 years) did not differ significantly from that of the

AJVR, Vol 63, No. 7, July 2002 971

Figure 1—Plasma hormone concentrations in 2 groups of dogs (21 dogs/group) administered medetomidine and butorphanol tartrate(20 µg/kg and 0.2 mg/kg, respectively, IM; open circle) or acepromazine maleate and butorphanol (0.05 and 0.2 mg/kg, respectively;solid circle) as part of the preanesthetic medication prior to ovariohysterectomy. Anesthesia was induced with propofol and maintainedwith isoflurane in oxygen. Blood samples were collected at time of arrival at our facility (Arr), immediately preceding induction of anes-thesia (Ind), after removal of the second ovary (Ov2), at the end of surgery (End), 1, 3, and 6 hours after surgery, and 24 hours aftercollection of the initial sample (approx 20 hours after the end of surgery). Data are expressed as geometric means and 95% confi-dence intervals (95% CI). Overall, epinephrine, norepinephrine, and cortisol values differed significantly (P < 0.05) between groups.

01-11-0323R.qxd 6/14/2002 2:20 PM Page 971

ACE group (5.2 ± 1.5 years). Similarly, body weightdid not differ significantly between the groups of dogs(MED, 25.2 ± 5.8 kg; ACE, 29.1 ± 6.0 kg).

Anesthetic variables—Duration of preoperativesedation, anesthesia, and surgery was similar betweenthe 2 groups. Mean duration of preoperative sedationfor the MED and ACE groups was 84.0 ± 15.8 and 86.9± 14.7 minutes, respectively. Mean duration of anes-thesia, mean duration of surgery, and mean intervalfrom the end of surgery until extubation were 73.1 ±11.1, 38.9 ± 10.2, and 13.1 ± 5.7 minutes, respective-ly, for the MED group and 74.0 ± 10.6, 38.8 ± 6.8, and11.8 ± 4.6 minutes, respectively, for the ACE group.

The ACE group required significantly more propo-fol for induction of anesthesia (mean, 3.6 ± 0.7mg/kg), compared with the MED group (1.3 ± 0.2mg/kg). Mean end-tidal isoflurane concentration(ETISO) was significantly higher during anesthesia forthe ACE group (1.6 ± 0.2%), compared with the MEDgroup (1.4 ± 0.3%). During surgery, isoflurane admin-istration was increased in both groups on the basis ofchanges detected in response to surgical stimuli (sud-den changes in heart rate, respiratory rate, or bloodpressure). Before the initial incision was made, meanETISO was 1.4 ± 0.2 and 1.2 ± 0.2% for the ACE andMED groups, respectively. However, after removal ofthe second ovary, mean ETISO increased to 1.8 ± 0.2and 1.7 ± 0.2% for the ACE and MED groups, respec-tively.

In all dogs, pH and SpO2 remained between 7.20and 7.40 and 99 and 100%, respectively. Arterial bloodgas values (ie, PaO2 and PaCO2) were within clinicallyacceptable limits.12 Eleven dogs of the ACE group weregiven additional fluids (range, 5 to 10 ml/kg; mean, 6ml/kg) at the beginning of anesthesia; none of the dogsin the MED group received additional fluids. One dogin the ACE group became excited during recovery (19minutes after extubation) but was successfully treatedby administration of propofol (3.5 mg/kg, IV) andbuprenorphine (0.005 mg/kg, IV).

Hormone concentrations—Plasma concentrationsof epinephrine and norepinephrine were significantlylower in the MED group, compared with concentra-tions for the ACE group. Values for the MED groupdecreased to a lower concentration and increased at alater time point (Fig 1). Concentration of cortisol wassignificantly lower for the MED group, compared withthe ACE group; however, the cortisol concentrationincreased during surgery in both groups and remainedat or above the concentration of the initial sample untilcollection of the sample at 24 hours. Concentration ofβ-endorphin was not significantly different betweenthe 2 groups, with the values peaking during surgery inboth groups. However, after the peak concentrationwas reached, the concentration in the MED groupdecreased more rapidly, compared with the ACE group.

Heart rate and MAP—Heart rate was signifi-cantly lower (Fig 2) and MAP significantly higher(Fig 3) in the MED group, compared with values forthe ACE group. In both groups, heart rate increasedduring anesthesia. The MAP decreased significantly

after induction of anesthesia in both groups, but val-ues did not differ between groups during surgery.

Assessment of sedation and pain-distress—In gen-eral, the dogs were easy to handle; however, there was 1dog in the MED group that appeared extremely nervouswhen approached and touched while it was in its cage.Another dog in the MED group had a brief period ofaggressive behavior immediately before administrationof preanesthetic medication. During the preoperativesedation period, all dogs could be maintained in lateralrecumbency with light or no restraint. However, dogs inthe MED group were considered more sedated, andthese dogs were easier to manage. One dog in the ACEgroup whimpered when a cannula was inserted in ajugular vein, but we did not detect any other reactionsto potentially painful stimuli. In 4 dogs in the ACEgroup, we could not insert a catheter into the femoral

972 AJVR, Vol 63, No. 7, July 2002

Figure 2—Heart rates in dogs administered medetomidine andbutorphanol (open circle) or acepromazine and butorphanol(solid circle) as part of the preanesthetic medication prior toovariohysterectomy. Anesthesia was induced with propofol andmaintained with isoflurane in oxygen. Heart rate was recordedimmediately before administration of preanesthetic medication(Bef), immediately preceding induction of anesthesia (Ind), 10minutes after induction (Afi), at the time of the abdominal inci-sion (Inc), at the time of removal of the first and second ovaries(Ov1 and Ov2, respectively), at the time of closure of theabdominal incision (Sut), at the end of surgery (End), and 1, 3,and 6 hours after the end of surgery. Data are expressed asmeans and 95% CI. Overall, values differed significantly (P < 0.05) between groups.

Figure 3—Mean (± 95% CI) arterial blood pressures in dogsadministered medetomidine and butorphanol (open circle) oracepromazine and butorphanol (solid circle) as part of the pre-anesthetic medication prior to ovariohysterectomy. Anesthesiawas induced with propofol and maintained with isoflurane inoxygen. Arterial blood pressure was directly measured at vari-ous time points. Overall, values differed significantly (P < 0.05)between groups. See Figure 2 for key.

01-11-0323R.qxd 6/14/2002 2:20 PM Page 972

artery in the sedated dogs because of their resistance tobeing positioned in dorsal recumbency. In these dogs,the catheter was inserted after induction of anesthesia.

One hour after surgery, most of the dogs wereclearly sedated (32 dogs did not stand up in responseto stimulation) and had minimal signs of pain-distress(no or only intermittent vocalization or restlessnessand no or only mild reactions to palpation of the inci-sion) without significant differences detected betweenthe 2 groups. Signs of sedation were evident for alonger period in the ACE group, with the sedationscores being significantly higher for the ACE groupthan for the MED group 3 (range [median], 1 to 3 [2]and 1 to 2 [1] hours for ACE and MED, respectively)and 6 (range [median], 0 to 3 [1] and 0 to 1 [0] hoursfor ACE and MED, respectively) hours after comple-tion of surgery. The MED group had higher pain-dis-tress scores throughout the entire assessment period,compared with the ACE group, but the values wereonly significantly different 6 hours after surgery (range[median], 0 to 3 [1] and 0 to 3 [0] for MED and ACEgroups, respectively). At that time, 9 dogs in the MEDgroup and 2 dogs in the ACE group had a score of 2 or3. Five dogs in the MED group and 2 dogs in the ACEgroup were administered additional buprenorphine 6hours after surgery.

DiscussionIn the study reported here, perioperative concentra-

tions of catecholamines and cortisol were lower in dogsadministered medetomidine prior to induction, comparedwith dogs administered acepromazine as a preanestheticmedication. In addition, these 2 medications had differingeffects on the cardiovascular variables measured.

Low plasma concentrations of epinephrine and nor-epinephrine have been found in association with α2-agonist administration in relation to sedative effects13 aswell as during the perioperative period,14 including dur-ing ovariohysterectomy in dogs.5 The sympatholyticeffect produced by α2-agonists is believed to be attribut-able to central α2-adrenoreceptor activation leading to astate of profound sedation, anxiolysis, and decreasedsympathetic outflow.4 One of the target sites of thesedrugs is the locus ceruleus, the brain region criticallyinvolved in control of vigilance.4 In addition, α2-agonistsmay also directly inhibit the release of norepinephrinefrom peripheral sympathetic nerve terminals by activat-ing presynaptic α2-adrenoreceptors at that location.15

Tranquilizing effects of acepromazine, on the otherhand, are related to antidopaminergic actions.16

Although antidopaminergic agents are able to produce astate of behavioral quiet and CNS depression, the abilityof those agents to attenuate perioperative sympathoad-renal activation may be less efficient. Indeed, it has beenclaimed that dopamine antagonists may actuallyenhance sympathetic activity, at least in some stressfulsituations.17 Such an effect may be related to antagonistactions at presynaptic inhibitory dopamine receptors.15

This lower potency with regard to ability to attenuatesympathoadrenal activity may have been reflected in thestudy reported here, especially in the early recoveryphase when the dogs encountered physiologic and psy-chologic stress.

Although the cortisol responses differed betweenthe 2 groups, the response generally was similar to thatreported for dogs undergoing ovariohysterectomy.5,18

Reportedly, α2-agonists decrease plasma cortisol con-centrations in addition to their sedative actions,19 andthey may attenuate the effects of ACTH on adrenal cor-tex activity in dogs.20 However, the ability of an α2-ago-nist to decrease the perioperative cortisol response hasvaried.5,6,14 This property may be dose dependent,14 butit is also possible that in the perioperative period theeffects of tissue injury, pain, or hypotension may atleast partially override the actions of many drugs.Accordingly, because acepromazine caused lowerblood pressure and may also have resulted in minoranalgesia, the effects of such stressors could have led togreater enhancement of adrenocortical activity in thatgroup. In addition, plasma cortisol concentrations mayincrease in dogs after administration of a dopamineantagonist21; thus, it is possible that administration ofacepromazine may have increased the plasma cortisolconcentration in the study reported here.

However, higher preoperative cortisol concentra-tions in the ACE group may merely have been relatedto the minor sedative actions produced by use of thisneuroleptic combination. Indeed, during the preopera-tive period, dogs in the ACE group were considered tobe in a lighter state of sedation, although gross reac-tions to external stimuli were not detected. Such simi-larities between hormonal concentrations and clinicalevaluation of the dogs were not so obvious during theearly recovery phase. One hour after surgery, most ofthe dogs were clearly sedated; nonetheless, a distinctdifference in plasma hormone concentrations wasdetected between the 2 groups. By contrast, dogs in theMED group were less sedated and had higher pain-dis-tress scores 6 hours after surgery; it was the only timeat which epinephrine concentrations were significant-ly higher in that group. This was probably attributableto waning of the pharmacologic actions of medetomi-dine. However, it is difficult to determine whether painperception increased in dogs of the MED group at thattime or whether those dogs merely were better able toexpress discomfort. It is possible that in addition to thediffering amounts of sedation, the somewhat subjectiveand momentary assessment protocol used here furtherconfounded evaluation of the degree of pain-distress.

The similar pattern of β-endorphin concentra-tions in both groups was in contrast to other results ofour study. In humans, intraoperative increases in plas-ma β-endorphin concentrations have been reportedwith and without prior administration of α2-agonists.14

The fact that values peaked at the time of the greatestsurgical intervention may reflect the inability of thiskind of anesthetic management to prevent hypothala-mopituitary activation during surgical stimuli, an effectthat also was evident during the intraoperative increas-es in cortisol concentrations in both groups. It is diffi-cult to conclude whether such an effect was trulyattributable to the anesthetic protocol used, the phar-macologic actions of the drugs, or an inadequate pro-vision of anesthesia. In dogs, plasma β-endorphin con-centrations can increase after administration of adopamine antagonist.22 However, opioids23 and non

AJVR, Vol 63, No. 7, July 2002 973

01-11-0323R.qxd 6/14/2002 2:20 PM Page 973

steroidal anti-inflammatory agents24 may also modulateperioperative β-endorphin responses; thus, suchactions may partly explain the results for both groupsin our study.

A greater hypotensive effect for acepromazine wasalready evident during the sedation period, with a fur-ther decrease detected after induction of anesthesia.Lower blood pressures of dogs in the ACE group mayhave been attributable to the differing amounts of anes-thetics used as well as the differing actions of the 2medicants. Possibly, the vasoconstrictive effects ofmedetomidine may play a role in attenuating anesthe-sia-induced hypotension,25 compared with the vasodi-latative properties of the α1-antagonist acepromazine.Minor increases in intraoperative blood pressure fordogs in the MED group may have been related to theexistence of a deeper plane of anesthesia. However, ithas also been speculated that α2-agonists may modu-late hemodynamic responses to nociceptive stimuli asa result of their direct pharmacologic actions.4,26 Thus,stable cardiovascular variables in relation to surgicalstimuli may not necessarily indicate an adequatedegree of anesthesia when α2-agonist agents are used.Higher6,7,b and more stable6 blood pressures have beenreported when preanesthetic administration ofmedetomidine is compared with preanesthetic admin-istration of saline solution6 and acepromazine.7,b Higherblood pressures related to medetomidine administra-tion may make it easier to manage anesthesia in surgi-cal patients; however, the relationship of this phenom-enon with other physiologic variables (eg, tissue perfu-sion) should be investigated further.

Lower heart rates measured in the MED group arerelated to the powerful bradycardic effects of medeto-midine,27 although opioids may have contributed to theeffect. In addition, greater hypotensive actions of theACE group with concurrent milder sympathetic atten-uation may result in higher heart rates. In contrast tothe difference in blood pressures, the intraoperativepattern of heart rates was similar in both groups, withthe values also clearly increasing in the MED group. Asimilar dissociation between perioperative blood pres-sure and heart rate responses with medetomidine pre-anesthetic medication was also apparent in data report-ed by Ko et al.6 Possibly, peripheral and central actionsof the α2-agonists may have varying ability to modulatecardiovascular responses during the perioperative peri-od. It is difficult to determine whether the effects seenare related to changes in central sympathetic tone. Inthe study reported here, plasma catecholamine con-centrations did not clearly reflect the cardiovascularchanges. Such a result may be related to the samplecollection interval, because the increases in plasma cat-echolamine concentrations can be easily missed as aresult of the short-lived response of these hormones.28,29

However, it is also possible that the true sympatheticactivity may not always be readily assessed by mea-surement of plasma catecholamine concentrations,because the circulating concentrations can be modulat-ed by many peripheral factors.28

In the study reported here, despite the use of multi-ple-drug protocols, responses were recorded for bothanesthetic regimens. This may reflect, in part, the exis-

tence of incomplete analgesic or sedative effects, or it maymerely underline the difficulties encountered whenattempting to control perioperative events.Responsiveness has its role in the perioperative period,and to totally abolish the neuroendocrine responses (orthe physiologic functions responsible for them) may neg-atively affect outcome. Indeed, adequate adrenocorticalfunction is vital for the survival of patients undergoingsurgery,30 and perioperative sympathoadrenal activationmay, in turn, prove important when enhancement of car-diovascular function is needed. However, becauseincreased cortisol concentrations are known for theiradverse effects, and excessive sympathetic tone has apotential for producing deleterious events, modificationof the perioperative stress response is considered benefi-cial for the welfare of patients.2,3 Methods to achieve sucha goal must be decided on a case-by-case basis. Analysis ofresults of the study reported here indicated that medeto-midine may offer some advantages over acepromazinewhen used as part of preanesthetic medications in respectto medetomidine’s more potent effect for decreasing peri-operative concentrations of stress-related hormones. Inparticular, the ability to provide stable plasma cate-cholamine concentrations may help attenuate periopera-tive activation of the sympathetic nervous system.

aRoizen MF, Lampe GH, Benefiel DJ, et al. Is increased operativestress associated with worse outcome (abstr)? Anesthesiology1987;67(suppl):A1.

bÄngeby E, Benson GJ, Jerre S. A comparison of anesthesia in dogspremedicated with medetomidine or acetylpromazine (abstr), inProceedings. Assoc Vet Anaesth Spring Conf 2001;49.

cDomitor, Orion Pharma Corp, Turku, Finland.dTorbugesic vet, Fort Dodge Laboratories, Fort Dodge, Iowa.ePlegisil vet, Pharmacia & Upjohn, Helsingborg, Sweden.fV-PPC-5.OU-20-PE5.0, Cook Veterinary Products, Brisbane,

Australia. gLeaderCath 115.12 18G, Vygon, Ecouen, France. hCDS 2000 small animal anesthesia unit, Anesco, Georgetown, Ky.iLife Scope 6, model OEC-6102J/K/L, Nihon, Kohden, Japan.jCapnomac Ultima, Datex Engström, Helsinki, Finland.kModel 8500V, Nonin Medical Inc, Plymouth, Minn.lABL 555 acid-base laboratory, Radiometer, Copenhagen, Denmark.mESA, CoulArray, Model 5600, ESA Inc, Chemsford, Mass.nSep-Pak C18, Waters Corp, Milford, Mass.oGilson ASPEC automatic sample preparation system, Gilson Inc,

Middleton, Wis.pSpeed-Vac, Savant, Hicksville, NY.qCoat-a-Count cortisol, Diagnostic Products Corp, Los Angeles,

Calif.rS-plus 2000, MathSoft Inc, Seattle, Wash.

References1. Derbyshire DR, Smith G. Sympathoadrenal responses to

anaesthesia and surgery. Br J Anaesth 1984;56:725–739. 2. Desborough JP. The stress response to trauma and surgery.

Br J Anaesth 2000;85:109–117. 3. Roizen MF. Should we all have a sympathectomy at birth?

Or at least preoperatively? Anesthesiology 1988;68:482–484. 4. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazole

receptor agonists. Their pharmacology and therapeutic role.Anaesthesia 1999;54:146–165.

5. Benson GJ, Grubb TL, Neff-Davis C, et al. Perioperativestress response in the dog: effect of pre-emptive administration ofmedetomide. Vet Surg 2000;29:85–91.

6. Ko JCH, Mandsager RE, Lange DN, et al. Cardiorespiratoryresponses and plasma cortisol concentrations in dogs treated withmedetomidine before undergoing ovariohysterectomy. J Am Vet MedAssoc 2000;217:509–513.

974 AJVR, Vol 63, No. 7, July 2002

01-11-0323R.qxd 6/14/2002 2:20 PM Page 974

7. Räihä MP, Räihä JE, Short CE. A comparison of xylazine,acepromazine, meperidine and medetomidine as preanesthetics tohalothane anesthesia in dogs. Acta Vet Scand 1989;85:97–102.

8. Arjamaa O, Mäkinen T, Turunen L, et al. Are the blood pres-sure and endocrine responses of healthy subjects exposed to coldstress altered by an acutely increased sodium intake? Eur J ApplPhysiol 2001;84:48–53.

9. Vuolteenaho O, Leppäluoto J, Vakkuri O, et al.Development and validation of a radioimmunoassay for beta-endor-phin-related peptides. Acta Physiol Scand 1981;112:313–321.

10. Stobie D, Caywood DD, Rozanski EA, et al. Evaluation ofpulmonary function and analgesia in dogs after intercostal thoraco-tomy and use of morphine administered intramuscularly orintrapleurally and bupivacaine administered intrapleurally. Am J VetRes 1995;56:1098–1109.

11. Lascelles BDX, Cripps PJ, Jones A, et al. Post-operative cen-tral hypersensitivity and pain: the pre-emptive value of pethidine forovariohysterectomy. Pain 1997;73:461–471.

12. Haskins SC. Monitoring the anesthetized patient. In:Thurmon JC, Tranquilli WJ, Benson GJ, eds. Veterinary anesthesia.3rd ed. Baltimore: The Williams & Wilkins Co, 1996;409–423.

13. Kuusela E, Vainio O, Kaistinen A, et al. Sedative, analgesicand cardiovascular effects of levomedetomidine alone and in combi-nation with dexmedetomidine in dogs. Am J Vet Res2001;62:616–621.

14. Aho M, Scheinin M, Lehtinen A-M, et al. Intramuscularlyadministered dexmedetomidine attenuates hemodynamic and stresshormone responses to gynecologic laparoscopy. Anesth Analg 1992;75:932–939.

15. Langer SZ. Presynaptic regulation of the release of cate-cholamines. Pharmacol Rev 1981;32:337–362.

16. Plumb DC. Veterinary drug handbook. 3rd ed. Ames, Iowa:Iowa State University Press, 1999;1–4.

17. Mannelli M, Ianni L, Lazzeri C, et al. In vivo evidence thatendogenous dopamine modulates sympathetic activity in man.Hypertension 1999;34:398–402.

18. Fox SM, Mellor DJ, Lawoko CRO, et al. Changes in plasmacortisol concentrations in bitches in response to different combina-tions of halothane and butorphanol, with or without ovariohysterec-tomy. Res Vet Sci 1998;65:125–133.

19. Kallio A, Koulu M, Scheinin H, et al. Acute effects ofmedetomidine, a selective α2-adrenoceptor agonist, on anterior pitu-itary hormone and cortisol secretion in man. Acta Endocrinol(Copenh) 1988;119:11–15.

20. Maze M, Virtanen R, Daunt D, et al. Effects of dexmedetomi-dine, a novel imidazole sedative-anesthetic agent, on adrenal steroido-genesis: in vivo and in vitro studies. Anesth Analg 1991;73:204–208.

21. Kemppainen RJ, Sartin JL. Differential secretion of pro-opi-omelanocortin peptides by the pars distalis and pars intermedia ofbeagle dogs. J Endocrinol 1988;117:91–96.

22. Sharp B, Ross R, Levin E, et al. Dopamine regulates canineplasma β-endorphin-immunoreactivity levels. Endocrinology1982;110:1828–1830.

23. Hargreaves KM, Dionne RA, Mueller GP, et al. Naloxone,

fentanyl and diazepam modify plasma beta-endorphin levels duringsurgery. Clin Pharmacol Ther 1986;40:165–171.

24. Troullos E, Hargreaves KM, Dionne RA. Ibuprofen elevatesimmunoreactive beta-endorphin levels in humans during surgicalstress. Clin Pharmacol Ther 1997;62:74–81.

25. Keegan RD, Greene SA, Bagley RS, et al. Effects of medetomi-dine administration on intracranial pressure and cardiovascular vari-ables of isoflurane-anesthetized dogs. Am J Vet Res 1995;56:193–198.

26. Aantaa R, Kanto J. Is clonidine an anesthetic in man?Anaesthesia 1992;47:533.

27. Pypendop BH, Verstegen JP. Hemodynamic effects of medeto-midine in the dog: a dose-titration study. Vet Surg 1998;27:612–622.

28. Hjemdahl P. Physiological aspects on catecholamine sam-pling. Life Sci 1987;41:841–844.

29. Engeland WC, Miller P, Gann DS. Pituitary-adrenal andadrenomedullary responses to noise in awake dogs. Am J Physiol1990;258:R672–R677.

30. Salem M, Tainsh RE Jr, Bromberg J, et al. Perioperative glu-cocorticoid coverage. Ann Surg 1994;219:416–425.

AJVR, Vol 63, No. 7, July 2002 975

Appendix Scoring of sedation and pain-distress (PD) in dogs

Evaluation of sedation Score

Responsive, able to walk without ataxia 0Responsive, able to walk but ataxic 1Recumbent, attempts to rise but will not stand 2Recumbent and does not respond by moving 3

EEvvaalluuaattiioonn ooff PPDD** SSccoorreeVocalization

None 0Intermittent, responds to talking and stroking 1Persistent 2

Restlessness None 0Intermittent, responds to talking and stroking 1Persistent 2

MovementMoves freely 0Slight stiffness at beginning of movement 1Clear signs of discomfort during movement, may refuse to move 2

Response to palpation of surgical siteNo response 0Tensing of abdominal muscles, may turn head 1Tensing of abdominal muscles, may turn head, brief movement

or vocalization 2Tensing of abdominal muscles, may turn head, stronger

movement or vocalization, may be aggressive 3

*Values for each category were added to provide final scores that wereclassified as follows: total score of 0 or 1, P-D 0; total score of 2 or 3, P-D 1;total score of 4 or 5, P-D 2; total score of � 6, P-D 3.

Dogs with a score of 3 for response to palpation of surgical site and ascore of 1 or 2 for movement were classified as P-D 3.

01-11-0323R.qxd 6/14/2002 2:20 PM Page 975