Effects of a peripheral α2 adrenergic-receptor antagonist on the hemodynamic changes induced by medetomidine administration in conscious dogs

Saad S. Enouri Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1H 2W1, Canada

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 BVSc, MSc
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Carolyn L. Kerr Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1H 2W1, Canada

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 DVM, DVSc, PhD
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Wayne N. McDonell Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1H 2W1, Canada

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M. Lynne O'Sullivan Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1H 2W1, Canada

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Francisco J. Teixeira Neto Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1H 2W1, Canada

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 MV, PhD
DOI:
https://doi.org/10.2460/ajvr.69.6.728
Volume/Issue:
Volume 69: Issue 6
Online Publication Date:
01 Jun 2008
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Abstract

Objective—To evaluate the effects of administration of a peripheral α2-adrenergic receptor antagonist (L-659,066), with and without concurrent administration of glycopyrrolate, on cardiopulmonary effects of medetomidine administration in dogs.

Animals—6 healthy adult dogs.

Procedures—Dogs received saline (0.9% NaCl) solution (saline group), L-659,066 (group L), or L-659,066 with glycopyrrolate (group LG). These pretreatments were followed 10 minutes later by administration of medetomidine in a randomized crossover study. Hemodynamic measurements and arterial and mixed-venous blood samples for blood gas analysis were obtained prior to pretreatment, 5 minutes after pretreatment, and after medetomidine administration at intervals up to 60 minutes.

Results—After pretreatment in the L and LG groups, heart rate, cardiac index, and partial pressure of oxygen in mixed-venous blood (PvO2) values were higher than those in the saline group. After medetomidine administration, heart rate, cardiac index, and PvO2 were higher and systemic vascular resistance, mean arterial blood pressure, and central venous pressure were lower in the L and LG groups than in the saline group. When the L and LG groups were compared, heart rate was greater at 5 minutes after medetomidine administration, mean arterial blood pressure was greater at 5 and 15 minutes after medetomidine administration, and central venous pressure was lower during the 60-minute period after medetomidine administration in the LG group.

Conclusions and Clinical Relevance—Administration of L-659,066 prior to administration of medetomidine reduced medetomidine-induced cardiovascular changes in healthy dogs. No advantage was detected with concurrent administration of L-659,066 and glycopyrrolate.

Abstract

Objective—To evaluate the effects of administration of a peripheral α2-adrenergic receptor antagonist (L-659,066), with and without concurrent administration of glycopyrrolate, on cardiopulmonary effects of medetomidine administration in dogs.

Animals—6 healthy adult dogs.

Procedures—Dogs received saline (0.9% NaCl) solution (saline group), L-659,066 (group L), or L-659,066 with glycopyrrolate (group LG). These pretreatments were followed 10 minutes later by administration of medetomidine in a randomized crossover study. Hemodynamic measurements and arterial and mixed-venous blood samples for blood gas analysis were obtained prior to pretreatment, 5 minutes after pretreatment, and after medetomidine administration at intervals up to 60 minutes.

Results—After pretreatment in the L and LG groups, heart rate, cardiac index, and partial pressure of oxygen in mixed-venous blood (PvO2) values were higher than those in the saline group. After medetomidine administration, heart rate, cardiac index, and PvO2 were higher and systemic vascular resistance, mean arterial blood pressure, and central venous pressure were lower in the L and LG groups than in the saline group. When the L and LG groups were compared, heart rate was greater at 5 minutes after medetomidine administration, mean arterial blood pressure was greater at 5 and 15 minutes after medetomidine administration, and central venous pressure was lower during the 60-minute period after medetomidine administration in the LG group.

Conclusions and Clinical Relevance—Administration of L-659,066 prior to administration of medetomidine reduced medetomidine-induced cardiovascular changes in healthy dogs. No advantage was detected with concurrent administration of L-659,066 and glycopyrrolate.

Medetomidine, an α2-adrenergic receptor agonist, is a popular sedative and preanesthetic drug used in small animal practice in North America and Europe because of its ability to induce reliable and predictable sedation.1,2,3,4 However, medetomidine administration is associated with profound alterations in cardiovascular function. Dramatic increases in arterial blood pressure, systemic and pulmonary vascular resistance, and myocardial workload are evident after administration, and reductions in heart rate and CO decrease global DO2 by at least 50%.3,5,6,7,8,9,10,11,12,a A decrease in PO2 following administration of an α2-adrenergic receptor agonist has been reported in several studies8,13,14,15,a and could imply that oxygen supply to at least some peripheral tissues may be inadequate. In fact, deficiency in myocardial DO2 may be 1 mechanism responsible for the increase in perioperative morbidity and mortality rates associated with α2-receptor agonist administration reported16,17 in small animals. The primary mechanism responsible for the adverse cardiovascular effects of the α2-receptor agonists is mediated via peripheral α2-adrenergic receptors. Activation of these receptors results in marked peripheral vasoconstriction and an increase in arterial blood pressure that, in turn, cause vagally induced decreases in heart rate, CO, and DO2.3,6,9,11,18,19,20 Additionally, activation of central α2-adrenergic receptors by α2-receptor agonists results in a decrease in sympathetic tone and a relative increase in vagal tone that lead to decreases in heart rate, CO, and DO2.5,7,18 Because α2-receptor agonists have no apparent direct depressant effect on the myocardium,21,22,23,24 targeting treatments that block their peripheral vascular effects may prove beneficial.25

Several approaches have been investigated to minimize the deleterious effects of the α2-receptor agonists, including evaluating the dose dependency of the cardiovascular alterations and the effects of coadministration of anticholinergic agents. Although the duration of cardiovascular depression induced by medetomidine administration is dose dependent, the magnitude of change in many of the measured cardiovascular variables, such as CI, is relatively dose independent.3 Therefore, in contrast to many other agents, the clinical safety of this drug may not be improved by administration of low doses. Use of anticholinergic agents (atropine or glycopyrrolate) to prevent or treat the decrease in heart rate and subsequent decrease in CO attributable to α2-receptor agonists has been reported by several investigators.6,20,26,27,28,a Although anticholinergics are effective in preventing bradycardia and somewhat effective in increasing CO after α2-receptor agonist administration, they do not ensure improvement in overall cardiac performance. When administered with α2-receptor agonists, anticholinergics increase SVR and cause dramatic increases in blood pressure; cardiac workload; and, presumably, myocardial O2. Therefore, many investigators do not recommend treatment with anticholinergic drugs to prevent or treat bradycardia induced by α2-receptor adrenergic agonists.20,26,a

Another potential approach to minimize cardiovascular effects mediated by α2-adrenergic receptor agonists would be to block the effects of these agents on the cardiovascular system. Although α2-receptor antagonists exist, the commercial agents currently available act both centrally and peripherally and therefore reverse both the sedative and cardiovascular effects of the agonists. Antagonists that preferentially act peripherally may prevent peripheral cardiovascular effects (vasoconstriction) without antagonizing central effects (sedation and analgesia) of the agonist drugs. An experimental compound, L-659,066, has been used to attenuate the peripheral vascular effects of the α2-receptor agonists.25,29,b This agent is an α2-adrenergic receptor antagonist with a reported α2/α1 selectivity of 105.30 It acts only on peripheral α2-adrenergic receptors as a result of its low lipophilic property, which limits penetration across the blood-brain barrier.30 To our knowledge, there are no published studies in which use of L-659,066 was evaluated, whether given alone or concurrently with an anticholinergic drug, to reduce adverse hemodynamic effects associated with use of medetomidine administered clinically in dogs. We hypothesized that α2-receptor–mediated peripheral vasoconstriction would be prevented by administration of a peripheral α2-receptor antagonist and that this would minimize the undesirable cardiovascular effects caused by medetomidine. We further hypothesized that combining the peripheral antagonist L-659,066 with an anticholinergic drug would block the vagally mediated decrease in heart rate and that heart rate and CO would therefore remain higher than when the antagonist alone was administered. The objective of the study reported here was to evaluate the effects of the peripheral α2-adrenergic receptor antagonist L-659,066 alone or with glycopyrrolate on the cardiopulmonary effects of medetomidine.

Materials and Methods

Animals—Six healthy male mixed-breed dogs with a mean ± SD weight of 26.3 ± 1.8 kg and an age of 29 ± 2.4 months were used. Dogs were considered healthy on the basis of physical examination, a CBC, and serum biochemical analyses.c Dogs were allowed free access to water until the beginning of the experimental period, but food was withheld beginning 12 hours prior to the study. The experimental protocol was reviewed and approved by the Animal Care Committee of the University of Guelph.

Treatment groups—Dogs were randomly allocated to groups by use of a modified Latin square to receive 1 of 3 pretreatments in a randomized crossover design. Treatments were separated by a minimum of 1 week. Pretreatment 1 was administration of 2 mL of saline (0.9% NaCl) solution (saline group); pretreatment 2 (antagonist; L group) was administration of 0.2 mg of L-659,066d/kg; and pretreatment 3 (antagonist-anticholinergic; LG group) was administration of 0.2 mg of L-659,066/kg and 5 μg of glycopyrrolatee/kg. Ten minutes after administration of pretreatments, dogs received a 10 μg/kg dose of medetomidine.f All drugs were administered IV.

Instrumentation—At the start of the experimental period, anesthesia was induced in all dogs by IV administration of 1% propofol solution.g Dogs were orotracheally intubated with an appropriately sized, cuffed endotracheal tube that was immediately connected to a universal F-circuit attached to an anesthetic machine. Isofluraneh delivered in oxygen was used to maintain anesthesia, with an oxygen flow rate of 60 to 100 mL/kg/min and with the vaporizer adjusted to maintain a light surgical plane of anesthesia. Each dog was positioned in lateral recumbency, and two 20-gauge, 4.8-cm catheters were inserted (one in a cephalic vein and the other in a dorsal pedal artery). The cephalic venous catheter was used for drug administration, and the dorsal pedal arterial catheter was used for direct measurement of systolic, diastolic, and mean arterial blood pressure and for blood sampling of gas analysis. An 8.5-F introduceri was placed in the jugular vein after infiltration of subcutaneous tissues with 0.5 mL of 2% lidocaine hydrochloride,j and a 7-F thermodilution catheterk was advanced into the pulmonary artery under fluoroscopic guidance. The distal port of the thermodilution catheter was used for mixed-venous blood sampling and measurement of core body temperature; measurement of pulmonary artery occluded pressure; and measurement of systolic, diastolic, and mean pulmonary arterial blood pressures, whereas the proximal port was used for measurement of central venous pressure and injection of cold injectate (5% dextrose solution) to measure CO. All pressure transducersl were calibrated before each study by use of a mercury manometer. A lead II ECG was monitored throughout the study period to record heart rate and detect arrhythmias.m

Study protocol—After instrumentation and bandaging of the catheters, isoflurane administration was discontinued and dogs recovered from anesthesia and were permitted to walk around the study room. A minimum of 30 minutes after extubation when preanesthetic activity had returned (defined as the dog being able to respond to its name and walk without ataxia), dogs were gently restrained in the standing position and baseline measurements of cardiopulmonary variables (respiratory rate, heart rate, systemic arterial blood pressure, diastolic arterial blood pressure, mean arterial blood pressure, mean pulmonary arterial pressure, pulmonary artery occluded pressure, central venous pressure, and CO) and body temperature were recorded and blood samples were collected. Throughout the study, both arterial and mixed-venous blood samples were stored on ice for a maximum of 2 hours prior to measurement of blood gas partial pressures, pH, bicarbonate concentration, and base excess with a blood gas analyzer.n Hemoglobin concentration and hemoglobin oxygen saturation were measured by use of a co-oximeter.o Packed cell volume and total protein concentration were determined by centrifugationp and refractometry, respectively. The point of the shoulder or the manubrium was used as the zero reference point for pressure measurements when dogs were standing, and the midpoint of the trachea was used when dogs were positioned in lateral recumbency. Cardiac output was measured by use of a CO computerq via the thermodilution technique in accordance with a method described elsewhere,31 with an injectate volume of 5 mL. At each time point, CO was the mean of at least triplicate values that did not exceed 10% in variation.

After recording of baseline measurements and CO measurement and collection of blood samples, 1 of 3 pretreatments (saline solution, L-659,066, or L-659,066 and glycopyrrolate) was administered IV. Five minutes after administration of the assigned pretreatment, hemodynamic variables were measured and blood samples were obtained. Ten minutes after pretreatment drug administration, medetomidine was administered IV and dogs were placed in right lateral recumbency.

Measurements were repeated 5, 15, 30, 45, and 60 minutes after medetomidine administration. The CI, stroke volume, stroke index, SVR, CaO2, CO2, DO2, O2, and oxygen extraction ratio were calculated by use of standard equations.32,33 At the end of each experiment, meloxicamr (0.1 mg/kg) was administered IV to all dogs for analgesia.

Statistical analysis—Statistical analyses were performed with commercially available software.s Data were reported as mean ± SD. The Shapiro-Wilk test was used to evaluate normality of the data distribution. Data were analyzed via ANOVA for repeated measures (F test), and treatment, time, and treatment-time interactions were included in the test. When significant differences were detected or there was an overall effect of time, a post hoc Dunnett test was used to compare treatment values with baseline values. Group means were compared by use of the Tukey test. Values of P < 0.05 were considered significant.

Results

Cardiopulmonary results were summarized (Tables 1–3; Figures 1 and 2). No differences in baseline measurements were detected among the groups for any study variable. Five minutes after administration of saline solution in the saline group, none of the variables other than arterial pH were altered, whereas after administration of L-659,066 in group L, there was an increase in heart rate, CI, mean pulmonary arterial pressure, o2, and Do2 values and a decrease in SVR values, compared with baseline values. Five minutes after L-659,066 and glycopyrrolate were administered (group LG), there was an increase in heart rate, CI, mean pulmonary arterial pressure, o2, and Do2 values and a decrease in SI and SVR values over baseline measurements. In the saline group, after medetomidine administration, there was a decrease in heart rate, respiratory rate, CI, SI, O2, DO2, PO2, CO2, SO2, and base excess values and an increase in SVR, mean arterial blood pressure, central venous pressure, mean pulmonary arterial pressure, pulmonary arterial–occluded pressure, and oxygen extraction ratio values from 5 to 60 minutes, compared with baseline values. After medetomidine administration in group L, there was a decrease in heart rate, CI, O2, DO2, and base excess values and an increase in SVR, central venous pressure, pulmonary artery occluded pressure, from 5 to 60 minutes; and an increase in oxygen extraction ratio values at 5, 15 and 45 minutes, compared with baseline values. After medetomidine administration in group LG, there was a decrease in heart rate, CI, SI, O2, and DO2 at 5 to 60 minutes and an increase in extraction ratio values at 5 and 15 minutes. There was an increase in SVR values at 5 to 60 minutes after medetomidine administration and in systolic arterial blood pressure, diastolic arterial blood pressure, and mean arterial blood pressure values at 5 minutes after medetomidine administration, compared with baseline values.

Table 1—

Mean ± SD values for cardiopulmonary variables in 6 healthy dogs after pretreatment with saline (0.9% NaCl) solution (group saline), a peripheral a2-adrenergic receptor antagonist (group L), or a combination of the receptor antagonist and an anticholinergic drug (group LG), followed by administration of medetomidine.
VariableGroupBaselinePretreatmentTime after medetomidine administration (min)
515304560
COSaline4.2 ± 0.74.2 ± 0.61.4 ± 0.2a1.3 ± 0.1a1.4 ± 0.2a1.4 ± 0.1a1.5 ± 0.2a
(L/min)L4.0 ± 0.75.0 ± 0.7a,b2.4 ± 0.5a,b2.5 ± 0.3a,b2.5 ± 0.3a,b2.4 ± 0.4a,b2.5 ± 0.6a,b
LG4.1 ± 0.35.4 ± 0.8a,b2.9 ± 0.7a,b2.6 ± 0.6a,b2.3 ± 0.4a,b2.1 ± 0.4a,b2.1 ± 0.3a,b
SISaline1.83 ± 0.381.82 ± 0.331.52 ± 0.27a1.39 ± 0.30a1.45 ± 0.38a1.32 ± 0.34a1.58 ± 0.37a
(mL/beat/kg)L1.69 ± 0.301.88 ± 0.361.66 ± 0.34b1.49 ± 0.291.63 ± 0.46b1.63 ± 0.46b1.63 ± 0.37
LG1.82 ± 0.461.48 ± 0.27a,b,c1.49 ± 0.36a1.44 ± 0.32a1.44 ± 0.27a1.36 ± 0.20a1.56 ± 0.24a
SABPSaline159 ± 18153 ± 17214 ± 35a155 ± 23142 ± 11142 ± 10150 ± 27
(mm Hg)L162 ± 10173 ± 14b150 ± 23b143 ± 17146 ± 13a148 ± 14150 ± 11
LG157 ± 16164 ± 18194 ± 34a,c148 ± 24147 ± 19147 ± 19143 ± 21
DABPSaline77 ± 373 ± 8128 ± 7a110 ± 5a102 ± 6a96 ± 3a94 ± 7a
(mm Hg)L77 ± 474 ± 1089 ± 6a,b77 ± 5b75 ± 5b73 ± 7b74 + 10b
LG79 ± 875 ± 10122 ± 29a,c89 ± 12b,c76 ± 8 b72 ± 7b69 ± 7a,b
MPAPSaline13 ± 314 ± 423 ± 2a20 ± 3a18 ± 3a17 ± 2a16 ± 3a
(mm Hg)L13 ± 215 ± 3a14 ± 3b14 ± 2b14 ± 1b13 ± 1b13 ± 2b
LG13 ± 216 ± 2a15 ± 2a,b13 ± 1b12 ± 1b12 ± 1b12 ± 1b
o2		Saline6.9 ± 2.29.4 ± 3.35.2 ± 1.2a4.2 ± 0.2a4.2 ± 0.3a4.1 ± 0.4a4.1 ± 0.5a
(mL/min/kg)L6.5 ± 2.58.3 ± 2.8a5.1 ± 0.4a5.0 ± 0.9a4.4 ± 0.6a4.1 ± 1.4a3.4 ± 1.7a
LG6.9 ± 1.39.5 ± 3.1a5.4 ± 0.6a4.5 ± 0.8a4.0 ± 0.5a3.6 ± 0.3a3.9 ± 0.8a

Variables were measured at baseline; 5 minutes after pretreatment with saline solution, L-659,066, or L-659,066 and glycopyrrolate; and 5, 15, 30, 45, and 60 minutes after administration of medetomidine.

Within a row, value differs significantly (P < 0.05) from the baseline value.

Within a time point within a variable, value differs significantly (P < 0.05) from the value for group saline.

Within a time point within a variable, value differs significantly (P < 0.05) from the value for group L.

SABP = Systolic arterial blood pressure. DABP = Diastolic arterial blood pressure. MPAP = Mean pulmonary artery pressure.

Table 2—

Mean ± SD values for respiratory rate, blood gas analyses, hematologic variables, and body temperature in 6 healthy dogs after pretreatment with saline solution (group saline), a peripheral α2-adrenergic receptor antagonist (group L), or a combination of the receptor antagonist and an anticholinergic drug (group LG), followed by administration of medetomidine.
VariableGroupBaselinePretreatmentTime after medetomidine administration (min)
515304560
Respiratory rate (breaths/min)Saline37 ± 2043 ± 1812 ± 3a10 ± 2a9 ± 2a10 ± 2a9 ± 2a
L29 ± 2520 ± 5b11 ± 3a10 ± 2a12 ± 2a13 ± 2a12 ± 3a
LG25 ± 623 ± 9b11 ± 3a10 ± 2a9 ± 2a9 ± 2a9 ± 3a
Pao2 (mm Hg)Saline94.5 ± 4.395.4 ± 7.991.2 ± 7.9a92.1 ± 6.2a92.0 ± 3.8a93.3 ± 4.793.5 ± 9.0
L100.1 ± 2.499.9 ± 3.594.3 ± 5.2a97.8 ± 11.1a98.2 ± 6.4a96.5 ± 7.898.1 ± 5.4
LG96.8 ± 5.897.9 ± 3.593.0 ± 6.2a92.3 ± 6.8a92.2 ± 6.9a93.4 ± 5.194.7 ± 5.0
P
O2 (mm Hg)		Saline44.2 ± 2.942.0 ± 4.035.8 ± 2.9a38.8 ± 2.7a38.0 ± 1.7a38.8 ± 1.9a39.4 ± 1.0a
L45.9 ± 1.648.0 ± 5.0b44.8 ± 3.6b45.9 ± 2.9b46.2 ± 2.6b44.2 ± 3.7b45.1 ± 2.3b
LG45.3 ± 2.846.4 ± 3.2b46.2 ± 5.5b46.4 ± 3.0b44.7 ± 2.6b42.8 ± 2.6b42.3 ± 3.2b
Paco2 (mm Hg)Saline35.9 ± 5.135.4 ± 5.434.4 ± 6.036.2 ± 5.636.9 ± 4.936.6 ± 4.037.5 ± 3.4
L39.5 ± 2.439.1 ± 1.040.2 ± 2.039.7 ± 5.241.4 ± 2.540.3 ± 1.738.8 ± 2.3
LG39.8 ± 2.539.7 ± 2.738.9 ± 1.540.6 ± 1.641.5 ± 2.041.0 ± 2.040.9 ± 2.3
Arterial pHSaline7.397 ± 0.047.400 ± 0.04a7.376 ± 0.04a7.364 ± 0.04a7.365 ± 0.04a7.367 ± 0.03a7.365 ± 0.03a
L7.372 ± 0.027.364 ± 0.02b7.345 ± 0.02a7.358 ± 0.03a7.346 ± 0.02a7.356 ± 0.027.367 ± 0.03
LG7.369 ± 0.017.361 ± 0.01b7.365 ± 0.017.358 ± 0.017.354 ± 0.017.356 ± 0.017.354 ± 0.01
Base excess (mmol/L)Saline−2.3 ± 1.4−2.1 ± 0.6−4.0 ± 1.1a−3.9 ± 0.9a−3.6 ± 0.7a−3.6 ± 0.9a−3.3 ± 1.1a
L−1.9 ± 1.7−2.6 ± 1.5−3.1 ± 1.4a−2.3 ± 1.3a,b−2.8 ± 1.7a−2.5 ± 1.6a−2.1 ± 1.4a
LG−2.0 ± 0.4−2.6 ± 0.9−2.6 ± 0.9a,b−2.5 ± 0.8b−2.3 ± 0.8b−2.4 ± 0.7−2.6 ± 0.6
PCV (%)Saline40 ± 242 ± 347 ± 3a47 ± 4a45 ± 4a45 ± 5a42 ± 3
L43 ± 343 ± 243 ± 3b41 ± 4b42 ± 3b41 ± 4b41 ± 1
LG42 ± 343 ± 344 ± 342 ± 4b42 ± 4b41 ± 4b40 ± 4
Total protein (g/dL)Saline6.2 ± 0.36.1 ± 0.26.0 ± 0.25.8 ± 0.3a5.8 ± 0.2a5.7 ± 0.2a5.7 ± 0.2a
L6.2 ± 0.56.0 ± 0.65.8 ± 0.35.8 ± 0.5a5.8 ± 0.5a5.6 ± 0.5a5.7 ± 0.5a
L/G6.0 ± 0.36.1 ± 0.46.1 ± 0.36.0 ± 0.3a5.9 ± 0.4a5.8 ± 0.3a5.8 ± 0.3a
Temperature (°C)Saline37.9 ± 0.537.9 ± 0.538.2 ± 0.438.1 ± 0.437.8 ± 0.437.6 ± 0.437.4 ± 0.5a
L38.1 ± 0.438.1 ± 0.437.8 ± 0.4a37.6 ± 0.5a37.5 ± 0.5a37.4 ± 0.6a37.3 ± 0.6a
L/G38.1 ± 0.537.9 ± 0.537.6 ± 0.7a,b37.4 ± 0.6a,b37.2 ± 0.6a,b36.8 ± 0.7a,b,c36.7 ± 0.6a,b,c

See Table 1 for key

Table 3—

Mean ± SD values for oxygenation analysis in 6 healthy dogs after pretreatment with saline solution (group saline), a peripheral α2-adrenergic receptor antagonist (group L), or a combination of the receptor antagonist and an anticholinergic drug (group LG), followed by administration of medetomidine.
VariableGroupBaselinePretreatmentTime after medetomidine administration (min)
515304560
Cao2 (mL/100mL)Saline19.6 ± 2.220.1 ± 1.422.1 ± 1.5a21.5 ± 1.5a20.3 ± 1.820.3 ± 1.819.8 ± 2.0
L19.4 ± 1.319.1 ± 1.720.0 ± 1.6b19.4 ± 2.1b19.3 ± 1.819.2 ± 2.519.2 ± 2.1
LG20.3 ± 1.920.8 ± 2.1c21.2 ± 1.920.2 ± 2.419.7 ± 2.318.9 ± 2.3a,b18.8 ± 1.7a,b
C
O2 (mL/100mL)		Saline15.0 ± 1.714.4 ± 1.912.7 ± 1.3a13.5 ± 1.2a12.8 ± 1.7a13.1 ± 1.8a13.3 ± 1.8a
L15.3 ± 0.815.3 ± 0.814.6 ± 1.5b13.6 ± 0.7b14.8 ± 1.4b13.3 ± 1.0a14.6 ± 1.4b
LG15.4 ± 1.215.5 ± 0.916.1 ± 1.4b,c15.1 ± 1.3b15.1 ± 1.5b14.3 ± 1.5b13.8 ± 1.6a
Sao2 (%)Saline100 ± 2.999.8 ± 3.699.6 ± 2.899.2 ± 3.299.1 ± 1.9100.6 ± 2.8100.0 ± 3.2
L98.7 ± 0.5100 ± 2.299.3 ± 1.999.6 ± 1.899.6 ± 2.499.7 ± 2.298.5 ± 0.8
LG99.6 ± 3.5100.3 ± 3.1100.1 ± 3.199.6 ± 3.799.7 ± 3.3100.2 ± 3.499.2 ± 3.2
S
O2 (%)		Saline75.1 ± 5.672.3 ± 3.454.6 ± 2.6a58.9 ± 3.2a60.5 ± 3.2a62.4 ± 4.7a64.1 ± 3.2a
L73.7 ± 1.274.4 ± 5.271.5 ± 3.3b74.3 ± 3.2b74.7 ± 3.3b74.3 ± 5.5b74.8 ± 2.2b
LG73.2 ± 4.977.8 ± 4.3b75.7 ± 4.5b76.3 ± 1.4b75.2 ± 2.2b73.6 ± 2.0b72.6 ± 3.8b

See Table 1 for key.

Figure 1—
Figure 1—

Mean ± SD values for the cardiovascular variables heart rate (HR; A), CI (B) DO2 (C), and oxygen extraction ratio (ER; D) in 6 healthy adult dogs after pretreatment with saline (0.9% NaCl) solution (group saline; black circles), a peripheral α2-adrenergic receptor antagonist (group L; white circles), or a combination of the receptor antagonist and an anticholinergic drug (group LG; inverted black triangles), followed by administration of medetomidine. Variables were measured at baseline (BL); 5 minutes after pretreatment with saline solution, L-659,066, or L-659,066 and glycopyrrolate (Pre); and 5, 15, 30, 45, and 60 minutes after administration of medetomidine. aWithin a group within a time point, value differs significantly (P < 0.05) from the baseline value. bWithin a time point, value differs significantly (P < 0.05) from the value for group saline. cWithin a time point, value differs significantly (P < 0.05) from the value for group L.

Citation: American Journal of Veterinary Research 69, 6; 10.2460/ajvr.69.6.728

Figure 2—
Figure 2—

Mean ± SD values for mean arterial blood pressure (MABP; A), SVR (B), central venous pressure (CVP; C), and pulmonary artery occlusion pressure (PAOP; D) in 6 healthy adult dogs after pretreatment with saline solution (black circles), a peripheral α2-adrenergic receptor antagonist (white circles), or a combination of the receptor antagonist and an anticholinergic drug (inverted black triangles), followed by administration of medetomidine. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 69, 6; 10.2460/ajvr.69.6.728

Comparison of the 3 treatment groups revealed that heart rate, CI, DO2, and PO2 were significantly higher 5 minutes after pretreatment in the L and LG groups than in the saline group. From 5 to 60 minutes after medetomidine administration, heart rate, CI, DO2, and PO2 were significantly greater and SVR, mean arterial blood pressure, mean pulmonary arterial pressure, central venous pressure, pulmonary artery occluded pressure, and oxygen extraction ratio were significantly lower in the L and LG groups than in the saline group. Comparison of the LG and L groups revealed that heart rate was significantly higher at 5 minutes after pretreatment and at 5 minutes after medetomidine administration, whereas mean arterial blood pressure was significantly higher at 5 and 15 minutes after medetomidine administration in the LG group. Values for SI were significantly lower in the LG group 5 minutes after pretreatment, whereas central venous pressure values were significantly higher with pretreatment L than with pretreatment LG from 5 to 60 minutes after medetomidine administration. Minor differences were detected in certain variables at specific time periods (Tables 1–3; Figures 1 and 2).

Sinus arrhythmia (4 dogs in the saline group, 3 dogs in group L, and 1 dog in group LG) and second-degree atrioventricular blocks (1 dog in the saline group and 5 dogs in group LG) were detected. Premature ventricular contractions were detected in 1 dog when it was assigned to the saline group and in another dog assigned to the LG group. All arrhythmias were detected immediately after administration of medetomidine and were not detected 30 minutes after medetomidine administration.

Discussion

In the study reported here, the peripheral α2-adrenergic receptor antagonist L-659,066 reduced negative cardiovascular alterations induced by medetomidine administration. The magnitude of decrease in heart rate, CI, and DO2 and increase in systemic and vascular pressures was minimized by prior administration of the peripheral receptor antagonist. Although the reduction in the degree of change in these variables may not be sufficient reason to warrant intervention, the prevention of a decrease in PO2, reduction of a decrease in base excess, and increase in oxygen extraction ratio associated with medetomidine administration implied that a debt in DO2 to tissues was reduced by prior administration of a peripheral α2-receptor antagonist. At the dose of receptor antagonist evaluated, concurrent administration of glycopyrrolate did not yield an advantage.

Our results are consistent with those from other investigations.25,34,35,b In the study reported here, IV administration of L-659,066 alone was associated with mild increases in heart rate and CI but no change in vascular pressures. The increases in heart rate and CI with L-650,066 administration are proposed to be sympathetically mediated, secondary to a reduction in peripheral vascular tone as a result of α2-adrenergic receptor blockade.25,34 In the present study, similar to other investigations, the compensatory response in heart rate and CO prevented a reduction in systemic pressures. At the dose used in our study, L-659,066 administration prevented significant increases in systemic and pulmonary arterial blood pressures when given before medetomidine, although increases in SVR were detected, which implied that there was at least partial blockade of the peripheral vascular effects of medetomidine. These findings are consistent with results of other investigations,25,b in which the effects of this peripheral α2-adrenergic receptor antagonist were evaluated in several species and with the known mechanism of α2-adrenergic receptor agonist–mediated increase in vascular tone.

The increase in vascular pressures is a result of a direct effect of α2-adrenergic agonists on the peripheral vasculature.3,9,11,18,19,20,21,36,a Blocking of these receptors leads to prevention of the effects of α2-adrenergic receptor agonists on systemic and pulmonary blood pressures. Despite the lack of an increase in arterial blood pressure in the study reported here after administration of L-659,066 alone, heart rate decreased from baseline values after medetomidine administration. This bradycardic effect was partially prevented when glycopyrrolate was given concurrently. This finding also implied that the vascular effects of medetomidine may not have been completely blocked by the antagonist at the dose used. Because dogs in both the L and LG groups had decreases in heart rate after medetomidine administration, compared with baseline values, it appears that there is a centrally mediated component to the reduction in heart rate detected after medetomidine administration. The heart rates detected after medetomidine administration in the L and LG groups are similar to those obtained in quiet resting dogs and were significantly higher than rates in dogs that did not receive the antagonist.

In addition to preventing the increase in systemic and pulmonary artery pressures, pretreatment with the receptor antagonist minimized the increase in pulmonary artery occluded pressure and central venous pressure associated with medetomidine administration. Central venous pressure and pulmonary artery occluded pressure are indirect indices of right and left ventricular preload, respectively, and are influenced by venous return and myocardial performance. Regarding pulmonary artery occluded pressure increases after administration of an α2-adrenergic receptor agonist, there is considerable evidence that an increase in afterload (ie, increase in SVR) is an important factor contributing to reduction in myocardial performance.3 Similar to the effects on arterial pressures, prevention of the increase in these variables caused by medetomidine administration in association with administration of a peripheral antagonist is likely a result of blockade of α2-adrenergic receptor–mediated venous and arterial vasoconstriction and a resulting increase in venous capacitance. In addition, the increase in CI in the groups receiving the antagonist may have contributed to the reduction in increase in right and left ventricular afterload. Interestingly, although there were no differences in pulmonary artery occluded pressure between the 2 groups that received the antagonist, central venous pressure was significantly lower in the group that received glycopyrrolate in addition to the antagonist than in the group that received the antagonist alone. This may reflect differences in the degree of peripheral α2-adrenergic receptor blockade on the systemic versus the pulmonary vasculature or differences in CO between the right and left sides of the heart.

Despite the significant reduction in PaO2 values detected in all groups, PaO2 and SaO2 values remained > 90 mm Hg and > 95%, respectively; therefore, the reductions were not considered clinically relevant. These findings are consistent with results of other studies.9,13,37,38,39,40 Similarly, despite the decrease in respiratory rate detected in the study reported here, there were no dramatic changes in PaCO2 after medetomidine administration, with values for this variable remaining within reference limits throughout the study. Of greater interest, however, was the prevention of medetomidine-induced decreases in PO2, CO2, and SO2 and the increase in oxygen extraction ratio in both the L and LG groups, compared with values after administration of medetomidine alone. A decreased PO2 indicates that DO2 is reduced relative to tissue needs. This may be evident when O2 exceeds the amount delivered (ie, an increase in extraction ratio).33 Although O2 was similar among groups and did not change dramatically over time, DO2 decreased in all groups, compared with baseline values. This decrease in DO2 was greater in the group that did not receive the antagonist. As a consequence, the oxygen extraction ratio remained fairly constant after medetomidine administration in the groups that received the antagonist, whereas the remaining group had a dramatic increase in oxygen extraction ratio. This finding, along with prevention of the decrease in PO2 when the antagonist was administered, provides a strong rationale for concluding that the peripheral vascular effects induced by medetomidine at the doses used were reduced by administration of the antagonist.

The effects of administering an anticholinergic drug concurrently with an α2-adrenergic agonist in an attempt to improve heart rate and CO have been investigated.6,20,26,27,28,a Administration of these drugs does not result in an overall improvement in hemodynamic variables, and currently, they are not recommended for use in combination with α2-adrenergic receptor agonists in most circumstances. Although bradycardia is reduced or prevented, there is no effect on SVR and little effect on CI or oxygen extraction ratio, but the potential does exist for a marked and undesirable increase in systolic and mean arterial blood pressure and myocardial oxygen requirements.20,a In the present study, we chose to evaluate administration of an anticholinergic drug concurrently with a peripheral receptor antagonist to verify complete blockade of any peripheral vascular–mediated reduction in heart rate. Our objective was to select a dose of glycopyrrolate that would induce minimal effects when administered alone but would prevent vagally mediated reduction in heart rate. Five minutes after administration of glycopyrrolate, a moderate increase in heart rate and CI was detected; however, arterial blood pressures were not influenced. Because heart rate and CI were higher in the LG group after medetomidine was administered, systemic arterial pressures were significantly greater in that group than in the group receiving the antagonist alone. Effects of the anticholinergic drug on heart rate and CI were evident for approximately 20 to 30 minutes after its administration or approximately 15 to 20 minutes after medetomidine sedation, after which the effects appeared to wane.

The dose of L-659,066 (0.2 mg/kg) used in the study reported here was chosen on the basis of results of other studies in which a range of doses of L-659,066 was used in various species.25,34,35 Results of all studies indicated that administration of L-659,066 alone at a dose of 0.1 mg/kg did not cause significant changes in heart rate and blood pressure and was ineffective in reducing vasoconstriction induced by administration of dexmedetomidine in dogs.25 Doses of 0.2, 0.3, or 0.4 mg of L-659,066/kg alone increased heart rate25,34 and CO25 in a dose-dependent manner. When administered after dexmedetomidine, doses of 0.2 and 0.4 mg of antagonist/kg were both effective in reducing peripheral vasoconstriction. In humans, adverse effects, such as nausea, vomiting, discomfort and cramping in the lower portion of the abdomen, and increases in heart rate and blood pressure, developed after administration of higher doses of L-659,066 (> 0.14 mg/kg; range, 0.14 to 0.30 mg/kg).35

In conclusion, premedication with L-659,066 prior to sedation with medetomidine in dogs was associated with a reduction in the degree of peripheral vasoconstriction; attenuation of the reduction in heart rate, CI, and DO2 and the increase in oxygen extraction ratio and central venous pressure; and maintenance of the mean arterial blood pressure, mean pulmonary arterial pressure, and pulmonary artery occluded pressure. Changes in acid-base and blood gas values were minimal in dogs that received L-659,066 alone and in those that received L-659,066 with glycopyrrolate. No further hemodynamic improvement was evident in association with anticholinergic drug administration. Additional studies are needed to investigate the cardiopulmonary effects of concurrent administration of L-659,066 and IM administration of medetomidine, given that the IM route is the most common route for administration of medetomidine in dogs.

ABBREVIATIONS

CaO2

Arterial oxygen content

CI

Cardiac index

CO

Cardiac output

CO2

Mixed-venous oxygen content

DO2

Oxygen delivery

PO2

Partial pressure of oxygen in mixed venous blood

SaO2

Arterial oxygen saturation

SI

Stroke index

SO2

Mixed-venous oxygen saturation

SVR

Systemic vascular resistance

O2

Oxygen consumption
a.

Moraes AN, Mirakhur K, McDonell W, et al. Modification of the cardiopulmonary response to medetomidine in isoflurane anesthetized dogs following treatment with glycopyrrolate (abstr), in Proceedings. 2003 Am Coll Vet Anesthesiol Annu Meet. Available at: www.acva.org/professional/abstract/abstracts_detail.asp?inews=325&itype=22. Accessed Mar 19, 2008.

b.

Honkavaara JM, Raekallio RM, Vainio OM. The peripheral alpha-2 adrenergic antagonist L659,066 prevents the early dexmedetomidine-induced cardiopulmonary effects in sheep (abstr), in Proceedings. 9th World Cong Vet Anaesth 2006;158.

c.

Animal Health Laboratory, Ontario Veterinary College, Guelph, ON, Canada.

d.

Generously provided by Merck & Co Inc, Rahway, NJ.

e.

Sandoz Canada Inc, Boucherville, QC, Canada.

f.

Domitor, Novartis Animal Health Canada Inc, Mississauga, ON, Canada.

g.

Novopharm Ltd, Toronto, ON, Canada.

h.

Aerrane, Baxter Corp, Mississauga, ON, Canada.

i.

IntroFlex percutaneous sheath introducer kit, Edwards Lifesciences LLC, Irvine, Calif.

j.

Xylocaine, AstraZeneca Canada Inc, Mississauga, ON, Canada.

k.

Edwards Swan-Ganz, Edwards Lifesciences LLC, Irvine, Calif.

l.

DTX Plus pressure transducer systems, Ohmeda Medical Devices, Madison, Wis.

m.

Criticare Model 1100, Criticare System Inc, Waukesha, Wis.

n.

ABL 700 Series analyzer, Radiometer, Copenhagen, Denmark.

o.

OSM3 hemoximeter, Radiometer, Copenhagen, Denmark.

p.

Haemofuge, Baxter Canlab, Mississauga, ON, Canada.

q.

COM-2, cardiac output computer, Baxter Healthcare Corp, Santa Ana, Calif.

r.

Boehringer Ingelheim Ltd, Burlington, ON, Canada.

s.

SAS Online Doc, version 8, SAS Institute Inc, Cary, NC.

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Contributor Notes

Supported by the Pet Trust Foundation and by Merck & Co.

Presented in part at the 2007 Annual Meeting of the American College of Veterinary Anesthesiologists, New Orleans, September 2007.

The authors thank Gabrielle Monteith for assistance with data analysis.

Address correspondence to Dr. Enouri.
Cover American Journal of Veterinary Research
American Journal of Veterinary Research
Publication Date:
01 Jun 2008
  • Figure 1—
    View in gallery
    Figure 1—

    Mean ± SD values for the cardiovascular variables heart rate (HR; A), CI (B) DO2 (C), and oxygen extraction ratio (ER; D) in 6 healthy adult dogs after pretreatment with saline (0.9% NaCl) solution (group saline; black circles), a peripheral α2-adrenergic receptor antagonist (group L; white circles), or a combination of the receptor antagonist and an anticholinergic drug (group LG; inverted black triangles), followed by administration of medetomidine. Variables were measured at baseline (BL); 5 minutes after pretreatment with saline solution, L-659,066, or L-659,066 and glycopyrrolate (Pre); and 5, 15, 30, 45, and 60 minutes after administration of medetomidine. aWithin a group within a time point, value differs significantly (P < 0.05) from the baseline value. bWithin a time point, value differs significantly (P < 0.05) from the value for group saline. cWithin a time point, value differs significantly (P < 0.05) from the value for group L.

  • Figure 2—
    View in gallery
    Figure 2—

    Mean ± SD values for mean arterial blood pressure (MABP; A), SVR (B), central venous pressure (CVP; C), and pulmonary artery occlusion pressure (PAOP; D) in 6 healthy adult dogs after pretreatment with saline solution (black circles), a peripheral α2-adrenergic receptor antagonist (white circles), or a combination of the receptor antagonist and an anticholinergic drug (inverted black triangles), followed by administration of medetomidine. See Figure 1 for remainder of key.

Figure 1—

Mean ± SD values for the cardiovascular variables heart rate (HR; A), CI (B) DO2 (C), and oxygen extraction ratio (ER; D) in 6 healthy adult dogs after pretreatment with saline (0.9% NaCl) solution (group saline; black circles), a peripheral α2-adrenergic receptor antagonist (group L; white circles), or a combination of the receptor antagonist and an anticholinergic drug (group LG; inverted black triangles), followed by administration of medetomidine. Variables were measured at baseline (BL); 5 minutes after pretreatment with saline solution, L-659,066, or L-659,066 and glycopyrrolate (Pre); and 5, 15, 30, 45, and 60 minutes after administration of medetomidine. aWithin a group within a time point, value differs significantly (P < 0.05) from the baseline value. bWithin a time point, value differs significantly (P < 0.05) from the value for group saline. cWithin a time point, value differs significantly (P < 0.05) from the value for group L.
Figure 2—

Mean ± SD values for mean arterial blood pressure (MABP; A), SVR (B), central venous pressure (CVP; C), and pulmonary artery occlusion pressure (PAOP; D) in 6 healthy adult dogs after pretreatment with saline solution (black circles), a peripheral α2-adrenergic receptor antagonist (white circles), or a combination of the receptor antagonist and an anticholinergic drug (inverted black triangles), followed by administration of medetomidine. See Figure 1 for remainder of key.
  • 1.

    Vaha-Vahe T. Clinical evaluation of medetomidine, a novel sedative and analgesic drug for dogs and cats. Acta Vet Scand 1989;30:267–273.

  • 2.

    Vainio O, Vaha-Vahe T, Palmu L. Sedative and analgesic effects of medetomidine in dogs. J Vet Pharmacol Ther 1989;12:225–231.

  • 3.

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

  • 4.

    Clarke KW, England GCW. Medetomidine, a new sedative-analgesic for use in the dog and its reversal with atipamezole. J Small Anim Pract 1989;30:343–348.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Savola JM. Cardiovascular actions of medetomidine and their reversal by atipamezole. Acta Vet Scand Suppl 1989;85:39–47.

  • 6.

    Vainio O, Palmu L. Cardiovascular and respiratory effects of medetomidine in dogs and influence of anticholinergics. Acta Vet Scand 1989;30:401–408.

  • 7.

    Vickery RG, Maze M. Action of the stereoisomers of medetomidine, in halothane-anesthetized dogs. Acta Vet Scand Suppl 1989;85:71–76.

  • 8.

    Pypendop B, Verstegen J. Cardiorespiratory effects of a combination of medetomidine, midazolam, and butorphanol in dogs. Am J Vet Res 1999;60:1148–1154.

    • Search Google Scholar
    • Export Citation
  • 9.

    Kuo WC, Keegan RD. Comparative cardiovascular, analgesic, and sedative effects of medetomidine, medetomidine-hydromorphone, and medetomidine-butorphanol in dogs. Am J Vet Res 2004;65:931–937.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Kuusela E, Raekallio M, Anttila M, et al. Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Ther 2000;23:15–20.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Hayashi K, Nishimura R, Yamaki A, et al. Cardiopulmonary effects of medetomidine, medetomidine-midazolam and medetomidine-midazolam-atipamezole in dogs. J Vet Med Sci 1995;57:99–104.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Dodam JR, Cohn LA, Durham HE, et al. Cardiopulmonary effects of medetomidine, oxymorphone, or butorphanol in selegiline-treated dogs. Vet Anaesth Analg 2004;31:129–137.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    England GC, Clarke KW. The use of medetomidine/fentanyl combinations in dogs. Acta Vet Scand Suppl 1989;85:179–186.

  • 14.

    Ko JC, Weil AB, Kitao T, et al. Oxygenation in medetomidine-sedated dogs with and without 100% oxygen insufflation. Vet Ther 2007;8:51–60.

    • Search Google Scholar
    • Export Citation
  • 15.

    Pypendop B, Serteyn D, Verstegen J. Hemodynamic effects of medetomidine-midazolam-butorphanol and medetomidine-midazolam-buprenorphine combinations and reversibility by atipamezole in dogs. Am J Vet Res 1996;57:724–730.

    • Search Google Scholar
    • Export Citation
  • 16.

    Dyson DH, Maxie MG, Schnurr D. Morbidity and mortality associated with anesthetic management in small animal veterinary practice in Ontario. J Am Anim Hosp Assoc 1998;34:325–335.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Clarke KW, Hall LW. A survey of anaesthesia in small animal practice: AVA/BSAVA report. J Assoc Vet Anaesth 1990;17:4–10.

  • 18.

    Scheinin H, Virtanen R, MacDonald E, et al. Medetomidine—a novel alpha 2-adrenoceptor agonist: a review of its pharmacodynamic effects. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:635–651.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Bloor BC, Frankland M, Alper G, et al. Hemodynamic and sedative effects of dexmedetomidine in dog. J Pharmacol Exp Ther 1992;263:690–697.

    • Search Google Scholar
    • Export Citation
  • 20.

    Sinclair MD, McDonell WN, O'Grady M, et al. The cardiopulmonary effects of romifidine in dogs with and without prior or concurrent administration of glycopyrrolate. Vet Anaesth Analg 2002;29:1–13.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Housmans PR. Effects of dexmedetomidine on contractility, relaxation, and intracellular calcium transients of isolated ventricular myocardium. Anesthesiology 1990;73:919–922.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Flacke WE, Flacke JW, Blow KD, et al. Effect of dexmedetomidine, an alpha 2-adrenergic agonist, in the isolated heart. J Cardiothorac Vasc Anesth 1992;6:418–423.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Day TK, Muir WW III. Alpha 2-adrenergic receptor agonist effects on supraventricular and ventricular automaticity in dogs with complete atrioventricular block. Am J Vet Res 1993;54:136–141.

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