Cardiopulmonary effects of intravenous fentanyl infusion in dogs during isoflurane anesthesia and with concurrent acepromazine or dexmedetomidine administration during anesthetic recovery

Stephanie C. J. Keating Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Carolyn L. Kerr Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Alexander Valverde Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Ron J. Johnson Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Wayne N. McDonell Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Abstract

Objective—To evaluate the cardiopulmonary effects of IV fentanyl administration in dogs during isoflurane anesthesia and during anesthetic recovery with or without dexmedetomidine or acepromazine.

Animals—7 sexually intact male purpose-bred hound-type dogs aged 11 to 12 months.

Procedures—Dogs received a loading dose of fentanyl (5 μg/kg, IV) followed by an IV infusion (5 μg/kg/h) for 120 minutes while anesthetized with isoflurane and for an additional 60 minutes after anesthesia was discontinued. Dogs were randomly assigned in a crossover design to receive dexmedetomidine (2.5 μg/kg), acepromazine (0.05 mg/kg), or saline (0.9% NaCl) solution (1 mL) IV after anesthesia ceased. Cardiopulmonary data were obtained during anesthesia and for 90 minutes after treatment administration during anesthetic recovery.

Results—Concurrent administration of fentanyl and isoflurane resulted in significant decreases in mean arterial blood pressure, heart rate, and cardiac index and a significant increase in Paco2. All but Paco2 returned to pretreatment values before isoflurane anesthesia was discontinued. During recovery, dexmedetomidine administration resulted in significant decreases in heart rate, cardiac index, and mixed venous oxygen tension and a significant increase in arterial blood pressure, compared with values for saline solution and acepromazine treatments. Acepromazine administration resulted in significantly lower blood pressure and higher cardiac index and Po2 in mixed venous blood than did the other treatments. Dexmedetomidine treatment resulted in significantly lower values for Pao2 and arterial pH and higher Paco2 values than both other treatments.

Conclusions and Clinical Relevance—Fentanyl resulted in transient pronounced cardiorespiratory effects when administered during isoflurane anesthesia. During anesthetic recovery, when administered concurrently with an IV fentanyl infusion, dexmedetomidine resulted in evidence of cardiopulmonary compromise and acepromazine transiently improved cardiopulmonary performance.

Abstract

Objective—To evaluate the cardiopulmonary effects of IV fentanyl administration in dogs during isoflurane anesthesia and during anesthetic recovery with or without dexmedetomidine or acepromazine.

Animals—7 sexually intact male purpose-bred hound-type dogs aged 11 to 12 months.

Procedures—Dogs received a loading dose of fentanyl (5 μg/kg, IV) followed by an IV infusion (5 μg/kg/h) for 120 minutes while anesthetized with isoflurane and for an additional 60 minutes after anesthesia was discontinued. Dogs were randomly assigned in a crossover design to receive dexmedetomidine (2.5 μg/kg), acepromazine (0.05 mg/kg), or saline (0.9% NaCl) solution (1 mL) IV after anesthesia ceased. Cardiopulmonary data were obtained during anesthesia and for 90 minutes after treatment administration during anesthetic recovery.

Results—Concurrent administration of fentanyl and isoflurane resulted in significant decreases in mean arterial blood pressure, heart rate, and cardiac index and a significant increase in Paco2. All but Paco2 returned to pretreatment values before isoflurane anesthesia was discontinued. During recovery, dexmedetomidine administration resulted in significant decreases in heart rate, cardiac index, and mixed venous oxygen tension and a significant increase in arterial blood pressure, compared with values for saline solution and acepromazine treatments. Acepromazine administration resulted in significantly lower blood pressure and higher cardiac index and Po2 in mixed venous blood than did the other treatments. Dexmedetomidine treatment resulted in significantly lower values for Pao2 and arterial pH and higher Paco2 values than both other treatments.

Conclusions and Clinical Relevance—Fentanyl resulted in transient pronounced cardiorespiratory effects when administered during isoflurane anesthesia. During anesthetic recovery, when administered concurrently with an IV fentanyl infusion, dexmedetomidine resulted in evidence of cardiopulmonary compromise and acepromazine transiently improved cardiopulmonary performance.

The recovery phase of anesthesia in veterinary patients is one of the most challenging anesthetic periods to manage effectively because of the need to control postoperative pain and the physiologic and behavioral changes that occur as patients recover from the effects of general anesthetics. It is also a time of high risk; as many as 47% of anesthetic deaths occur within 48 hours after recovery, with 21% happening within the first 3 hours.1

The most commonly reported causes of death in the postoperative period are respiratory compromise and cardiac arrest, although the inciting cause often remains unknown.2,3 Contributing factors may be the presence of residual or combined drug effects causing cardiopulmonary depression, the transition from a high concentration of inspired oxygen to room air, and a decrease in the monitoring of physiologic variables, all at a time of considerable cardiopulmonary change.

Opioids are some of the most effective analgesics, and their use for pain control in the postoperative period is considered the gold standard in care.4 Fentanyl, a synthetic μ-opioid receptor agonist, is routinely administered as an IV infusion following an initial bolus dose because of its pharmacokinetic properties, which include a rapid onset and short duration of action.5 Intraoperative use of fentanyl has been advocated as a means of reducing the minimum alveolar concentration of inhalation anesthetics and providing analgesia, and IV infusions are often continued into the postoperative period for continued pain management.6,7 When used alone, fentanyl is associated with moderate bradycardia that results from enhanced parasympathetic tone; however, other cardiac and respiratory variables remain within reference limits.8 Therefore, fentanyl administration is generally considered safe at clinically recommended doses in most animals.

In addition to opioids, sedatives such as acepromazine or dexmedetomidine are often administered at the time of anesthetic recovery to control the excitement caused by emergence delirium or dysphoria. Although these drugs provide sedation and muscle relaxation, their use also yields major cardiovascular effects. When administered alone, dexmedetomidine causes profound bradycardia, a decrease in cardiac output, and first- and second-degree heart blocks as well as an increase in systemic vascular resistance, which is a response typical of other α2-adrenergic receptor agonists at clinically recommended doses in dogs.9 In contrast, acepromazine administered IV at a dose of 0.1 mg/kg in dogs can cause a decrease in systemic vascular resistance, with subsequent decreases in blood pressure, cardiac output, and stroke volume.10 The combined use of these sedatives with opioids further alters cardiopulmonary performance because their physiologic effects are additive or even synergistic.11–13 These combined effects, plus any residual effects of volatile anesthetics, may ultimately contribute to disease and death during recovery from anesthesia when appropriate patient management is not performed.

Despite the common use of sedatives in combination with opioid analgesics during anesthetic recovery, no literature exists regarding their physiologic effects at clinically relevant doses during that period. The objectives of the study reported here were to evaluate the cardiopulmonary effects of fentanyl, administered IV as a bolus followed by a CRI during isoflurane anesthesia and with the concurrent administration of acepromazine or dexmedetomidine during recovery from isoflurane anesthesia in dogs. An additional objective was to characterize the cardiopulmonary changes that occur during anesthetic recovery in dogs receiving only an opioid analgesic. We hypothesized that fentanyl administration would cause moderate bradycardia, a decrease in arterial blood pressure, and respiratory depression in isoflurane-anesthetized dogs. We also hypothesized that IV dexmedetomidine and acepromazine administration would both result in clinically important cardiopulmonary alterations during the recovery period when administered concurrently with fentanyl, with dexmedetomidine having the greatest negative impact.

Materials and Methods

Animals—Seven sexually intact male purpose-bred hound-type dogs were used in the study. Dogs were 11 to 12 months of age with a mean ± SD body weight of 22.3 ± 1.2 kg and were considered healthy on the basis of findings from the medical history, physical examination, CBC, and serum biochemical analysis. Food but not water was withheld for 12 hours prior to the experimental period. The study was performed in accordance with the guidelines of the Canadian Council on Animal Care, and the protocol was approved by the Institutional Animal Care Committee at the University of Guelph.

Treatment groups—Dogs were assigned through a modified Latin square approach to receive 1 of 3 postanesthetic treatments in a randomized crossover design, with treatments separated by a minimum of 7 days. The 3 treatments were acepromazinea (0.05 mg/kg, IV), dexmedetomidineb (2.5 μg/kg, IV), or saline (0.9% NaCl) solution (1 mL, IV). Acepromazine and dexmedetomidine doses were prepared to a final volume of 1 mL, with saline solution as the diluent.

Instrumentation—For each treatment trial, a 20-gauge, 4.78-cm catheterc was inserted into a cephalic vein. This catheter was used for propofol, fentanyl, and fluid administration throughout each trial. Anesthesia was induced with propofol.d After placement of an appropriately sized endotracheal tube, anesthesia was maintained with isofluranee (1.5% to 2%) delivered in 100% oxygen via an F-circuit, with the oxygen flow rate set at 60 to 100 mL/kg/min. An 8.5F introducerf was placed in a jugular vein after infiltration of subcutaneous tissues with 0.5 mL of 2% lidocaine hydrochloride solution,g and a 7F thermodilution catheterh was advanced through the introducer into the pulmonary artery. Correct catheter placement was verified via fluoroscopy and identification of a pulmonary artery pressure trace. The distal port of the thermodilution catheter was used for mixed venous blood sample collection and measurement of core body temperature, PAOP, and MPAP. The proximal port was used for measurement of CVP, injection of 5% dextrose solution for measurement of cardiac output, and blood sample collection for a separate investigation evaluating the pharmacokinetics of fentanyl. A second 20-gauge, 4.78-cm catheter was placed in the cephalic vein in the opposite limb for subsequent administration of the treatment drug on recovery, and a third 20-gauge, 4.78-cm catheter was inserted in a dorsal pedal artery for direct arterial blood pressure measurements and collection of arterial blood samples for gas analysis. All cardiovascular variables were recorded with a multiparameter monitor.i

Study protocol—Following instrumentation, dogs were positioned in lateral recumbency, and the concentration of isoflurane was adjusted to achieve a stable end-tidal concentration of 1. 2%, with dogs breathing spontaneously. End-tidal CO2 and isoflurane concentrations were measured with a sidestream gas analyzer positioned between the endotracheal tube and the anesthetic circuit, at a sampling rate of 200 mL/min. Core body temperature as measured through the thermodilution catheter was maintained between 37° and 39° C with external heat support provided when needed. A bolus dose of fentanylj (5 μg/kg) was administered IV over 15 seconds, followed immediately by a CRI of fentanyl at 5 μg/kg/h. Dogs remained anesthetized for 120 minutes, at which point isoflurane administration was discontinued. They were extubated when the end-tidal isoflurane concentration reached 0. 8%, and the assigned treatment was subsequently administered. The fentanyl infusion was continued for 60 minutes after treatment administration, and measurements were made for 90 minutes after treatment administration. An isotonic balanced solutionk was administered IV at a rate of 3 mL/kg/h from the start of anesthesia to 90 minutes afterward. Following the final data collection point, cefazolinl (22 mg/kg) and meloxicamm (0. 1 mg/kg) were administered IV and all catheters were removed.

Cardiopulmonary measurements—Values of cardiopulmonary variables were recorded, cardiac output measured, and blood samples collected for gas analysis after instrumentation and before fentanyl administration (baseline) as well as 5, 10, 15, 30, 60, 90, and 120 minutes after fentanyl administration during isoflurane anesthesia and at 5, 10, 15, 30, 60, 75, and 90 minutes after treatment administration during anesthetic recovery. At each data collection point throughout the study, cardiopulmonary variables recorded included CVP, MPAP, PAOP, SAP, DAP, and MAP. The zero reference for all pressure measurements was the manubrium.

Cardiac output was measured with the thermodilution technique. Briefly, 10 mL of injectate (solution of 5% dextrose in water) chilled to 1° to 2°C was used in each of 3 consecutive measurements. The mean of values within 15% of each other was then calculated to provide the value for that time point. Blood samples obtained from the dorsal pedal artery and pulmonary artery were analyzed immediately after collection with an automated blood gas analyzer,n with values corrected for core body temperature. Heart rate was calculated by counting the arterial pressure trace for 30 seconds, and respiratory rate was obtained from capnograph measurements or counted for 30 seconds after extubation. Cardiac index, SI, SVRI, PVRI, oxygen delivery, and oxygen extraction ratio were calculated by use of standard equations.14

Statistical analysis—Statistical analysis was performed with standard statistical software.o Normal distribution of the data was assessed graphically, through residual analysis, and with the Shapiro-Wilk test. When necessary, data were logarithmically transformed to achieve a normal distribution and allow the use of parametric tests. For anesthetic maintenance and recovery data, 3-way ANOVA for repeated measures was used to determine the interaction of treatment, time, treatment by time, and carryover effect from the previous treatment, controlling for the random effects of dog and test period. This analysis was followed by Dunnett or Tukey post hoc analysis, with values of P < 0.05 considered significant.

Results

Instrumentation and anesthetic maintenance phase—No differences were evident among the 3 postanesthetic treatments (acepromazine, dexmedetomidine, or saline solution) nor was there any carryover effect from previous treatments for propofol dose, interval from anesthetic induction to collection of baseline data, or any cardiopulmonary variable during the maintenance phase of anesthesia. The means and SDs reported for these values were obtained from the mean values of the 3 replicate measurements for each dog. The mean ± SD dose of propofol to induce anesthesia was 5.7 ± 0.3 mg/kg, and the mean interval from anesthetic induction to the collection of baseline data was 72 ± 26 minutes.

All reported cardiopulmonary variables significantly changed after administration of the fentanyl bolus and initiation of the infusion, with the exception of SAP and PVRI, which did not differ significantly from baseline values at any point throughout the trials (Tables 1 and 2). A significant decrease in heart rate was evident 5 minutes after IV fentanyl administration, which gradually returned to values that were not significantly different from baseline by the 60-minute measurement point. A corresponding decrease in cardiac index and oxygen delivery was identified at 5 and 10 minutes, and SI was significantly higher than baseline from 5 to 120 minutes. The oxygen extraction ratio was significantly higher than baseline at the 5-minute measurement point only. Systemic vascular resistance index initially increased to values significantly greater than baseline at 5 minutes but was significantly lower than baseline at many points from 10 to 120 minutes. Both DAP and MAP decreased to values significantly lower than baseline at 5 minutes and remained lower than baseline for the duration of the maintenance phase or until the 30-minute measurement point, respectively. Central venous pressure, PAOP, and MPAP were all significantly higher than baseline between 5 and 10 minutes and remained significantly increased for the duration of the anesthetic maintenance phase.

Table 1—

Mean ± SD cardiovascular values in 7 healthy dogs during isoflurane anesthesia (baseline) and at various points following IV administration of a fentanyl bolus (5 μg/kg), immediately followed by a fentanyl CRI (5 μg/kg/h).

  Time after fentanyl bolus (min)
VariableBaseline51015306090120
Heart rate (beats/min)93 ± 1156* ± 1463* ± 1574* ± 2085* ± 2186 ± 1988 ± 2388 ± 22
SAP (mm Hg)93 ± 989 ± 1496 ± 2487 ± 1291 ± 791 ± 991 ± 1093 ± 10
DAP (mm Hg)50 ± 541* ± 941* ± 738* ± 541* ± 242* ± 442* ± 442* ± 4
MAP (mm Hg)60 ± 552* ± 1153* ± 851* ± 654 ± 354 ± 555 ± 555 ± 5
CVP (mm Hg)3 ± 16* ± 17* ± 16* ± 15* ± 15* ± 15* ± 15* ± 1
MPAP (mm Hg)11 ± 211 ± 114* ± 214* ± 114* ± 213* ± 214* ± 214* ± 3
PAOP (mm Hg)5 ± 17* ± 18* ± 18* ± 17* ± 17* ± 17* ± 17* ± 1
Cardiac index (mL/min/kg)115 ± 1281* ± 1699* ± 27119 ± 48127 ± 57129 ± 61130 ± 60138 ± 59
SI (mL/beat/kg)1.24 ± 0.151.46* ± 0.211.60* ± 0.311.60* ± 0.321.46* ± 0.311.48* ± 0.411.46* ± 0.321.53* ± 0.35
SVRI (dyne•s/cm5/kg)80.4 ± 11.894.0* ± 26.177.3 ± 15.165.1* ± 15.467.3* ± 17.169.7 ± 21.471.2 ± 21.767.4* ± 24.3
PVRI (dyne•s/cm5/kg)8.9 ± 1.87.9 ± 2.28.4 ± 1.88.8 ± 1.68.6 ± 1.68.5 ± 1.28.9 ± 1.28.3 ± 0.8

Value is significantly (P < 0.05) different from baseline.

Table 2—

Mean ± SD cardiopulmonary values in the dogs in Table 1.

  Time after fentanyl bolus (min)
VariableBaseline51015306090120
Respiratory rate (breaths/min)16 ± 72* ± 37* ± 59 ± 216 ± 617 ± 818 ± 923 ± 19
Paco2 (mm Hg)528.9 ± 13.9513.5 ± 10.3511.7* ± 10.0516.3 ± 12.4522.6 ± 15.2520.9 ± 8.3530.6 ± 19.5531.9 ± 16.7
Paco2 (mm Hg)45.4 ± 2.962.4* ± 4.465.5* ± 9.759.0* ± 6.754.8* ± 4.954.9* ± 4.955.4* ± 5.655.9* ± 5.6
Arterial pH7.338 ± 0.0167.235* ± 0.0177.218* ± 0.0447.244* ± 0.0367.266* ± 0.0297.282* ± 0.0277.284* ± 0.0267.284* ± 0.025
Po2 (mm Hg)72.2 ± 4.063.2* ± 4.972.4 ± 7.479.9 ± 13.682.4* ± 21.981.6 ± 17.186.5* ± 23.182.9* ± 16.6
Oxygen extraction ratio0.14 ± 0.020.22* ± 0.050.17 ± 0.060.15 ± 0.070.15 ± 0.060.14 ± 0.050.13 ± 0.060.14 ± 0.06
Oxygen delivery (mL/kg/min)22.7 ± 2.515.6* ± 2.718.9* ± 5.822.4 ± 10.524.3 ± 13.225.0 ± 14.226.4 ± 14.527.8 ± 14.2

See Table 1 for key.

Respiratory variables also significantly changed during the maintenance phase of anesthesia following fentanyl administration. The most profound change was the respiratory depression that occurred immediately after the bolus dose of fentanyl was administered; however, by 15 minutes after fentanyl administration, the mean respiratory rate was not significantly different from baseline. Values for Paco2 were significantly higher than baseline at 5 minutes and remained high for the duration of the maintenance phase; however, Pao2 was only significantly lower than baseline at the 10-minute measurement point. In contrast, the Po2 initially decreased at 5 minutes to values significantly lower than baseline before increasing to higher than baseline at multiple points up to 120 minutes.

Recovery phase—Physiologic variables were successfully recorded throughout the recovery period for all dogs while they were gently restrained. Some dogs developed signs of excitement, including vocalization, paddling, and thrashing in the first 10 minutes following treatment administration. These behaviors were noticed in 3 of 7 dogs when the dexmedetomidine and acepromazine treatments were administered and in 5 of 7 dogs following administration of saline solution.

No significant differences were evident among treatments for any of the measured or calculated physiologic variables before treatment administration in dogs anesthetized for 120 minutes. A treatment-by-time effect was detected for all variables in the recovery period except MPAP and respiratory rate.

Throughout the 90-minute posttreatment recovery period, significant differences were detected among the treatment groups (Tables 3 and 4; Figures 1 and 2). Heart rate, cardiac index, SI, Po2, and oxygen delivery were significantly lower and oxygen extraction ratio significantly higher with dexmedetomidine treatment, compared with values after acepromazine and saline solution treatment throughout most of the posttreatment period. Although acepromazine administration generally resulted in higher heart rates than when the dogs received saline solution, values did not differ significantly between these treatment groups at most measurement points.

Figure 1—
Figure 1—

Mean ± SD heart rate (HR; A), cardiac index (CI; B), MAP (C), and SVRI (D) in 7 healthy dogs recovering from isoflurane anesthesia and receiving a fentanyl CRI (5 μg/kg/h, IV) at various points after IV administration of dexmedetomidine (2.5 μg/kg; triangles), acepromazine (0.05 mg/kg; squares), or saline (0.9% NaCl) solution (circles). *Value is significantly (P < 0.05) different from that for dexmedetomidine. †Value is significantly (P < 0.05) different from that for acepromazine.

Citation: American Journal of Veterinary Research 74, 5; 10.2460/ajvr.74.5.672

Figure 2—
Figure 2—

Mean ±SD oxygen delivery (DO2; A), Paco2 (B), Po2 (C), and oxygen extraction ratio (ER; D) in the dogs in Figure 1. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 74, 5; 10.2460/ajvr.74.5.672

Table 3—

Mean ± SD cardiovascular values in 7 healthy dogs recovering from isoflurane anesthesia and receiving a fentanyl CRI (5 μg/kg/h, IV) at various points after IV administration of dexmedetomidine (2.5 μg/kg), acepromazine (0.05 mg/kg), or saline (0.9% NaCl) solution.

  Time after treatment administration (min)
VariableBefore treatment5101530607590
SAP (mm Hg)
 Dexmedetomidine100 ± 15165 ± 13151 ± 13138 ± 12130 ± 12127 ± 15134 ± 15139 ± 18
 Acepromazine92 ± 1493 ± 27*105 ± 25*106 ± 21*111 ± 23*110 ± 21110 ± 19*116 ± 20*
 Saline solution85 ± 10121 ± 18*144 ± 33139 ± 27138 ± 13134 ± 14147 ± 24130 ±13
DAP (mm Hg)
 Dexmedetomidine43 ± 497 ± 1089 ± 1380 ± 1070 ± 1265 ± 1267 ± 1373 ± 15
 Acepromazine42 ± 348 ± 13*54 ± 11*52 ± 9*56 ± 10*51 ± 8*50 ± 6*52 ± 7*
 Saline solution40 ± 661 ± 17*72 ± 21*72 ± 1567 ± 861 ± 863 ± 761 ± 6
CVP (mm Hg)
 Dexmedetomidine5 ± 112 ± 111 ± 110 ± 19 ± 18 ± 18 ± 28 ± 2
 Acepromazine5 ± 25 ± 3*4 ± 2*5 ± 2*3 ± 1*3 ± 2*3 ± 2*3 ± 2*
 Saline solution5 ± 111 ± 610 ± 510 ± 46 ± 3*6 ± 46 ± 46 ± 4
MPAP (mm Hg)
 Dexmedetomidine15 ± 420 ± 320 ± 219 ± 217 ± 318 ± 217 ± 217 ± 3
 Acepromazine14 ± 318 ± 518 ± 519 ± 417 ± 414 ± 315 ± 315 ± 3
 Saline solution14 ± 225 ± 823 ± 623 ± 620 ± 318 ± 417 ± 416 ± 3
PAOP (mm Hg)
 Dexmedetomidine8 ± 117 ± 215 ± 114 ± 212 ± 210 ± 210 ± 210 ± 3
 Acepromazine7 ± 16 ± 2*7 ± 2*9 ± 3*7 ± 2*5 ± 3*6 ± 3*7 ± 3
 Saline solution7 ± 114 ± 815 ± 515 ± 513 ± 411 ± 410 ± 310 ± 4
SI (mL/beat/kg)
 Dexmedetomidine1.64 ± 0.421.22 ± 0.351.43 ± 0.291.34 ± 0.181.41 ± 0.231.62 ± 0.211.72 ± 0.342.12 ± 0.32
 Acepromazine1.56 ± 0.462.13 ± 0.40*1.93 ± 0.25*2.01 ± 0.35*2.02 ± 0.34*1.99 ± 0.26*2.10 ± 0.282.04 ± 0.29
 Saline solution1.35 ± 0.191.85 ± 0.27*1.69 ± 0.371.84 ± 0.47*2.29 ± 0.37*1.92 ± 0.44*1.91 ± 0.232.06 ± 0.35
PVRI (dyne•s/cm5/kg)
 Dexmedetomidine7.9 ± 1.214.1 ± 8.113.3 ± 5.613.6 ± 6.813.1 ± 4.414.4 ± 5.110.2 ± 4.58.7 ± 4.7
 Acepromazine8.2 ± 1.85.8 ± 1.3*6.9 ± 2.2*5.8 ± 1.4*6.3 ± 0.6*7.1 ± 1.2*6.9 ± 2.06.2 ± 1.4
 Saline solution8.8 ± 0.99.0 ± 5.07.5 ± 4.1*6.6 ± 2.2*6.0 ± 2.8*7.6 ± 4.3*7.7 ± 3.76.6 ± 2.2

Value is significantly (P < 0.05) different from that for dexmedetomidine.

Value is significantly (P < 0.05) different from that for acepromazine.

Table 4—

Mean ± SD cardiopulmonary values in the dogs in Table 3.

  Time after treatment administration (min)
VariableBefore treatment5101530607590
Respiratory rate (breaths/min)
 Dexmedetomidine29 ± 3117 ± 415 ± 316 ± 117 ± 424 ± 1824 ± 1127 ± 16
 Acepromazine21 ± 1821 ± 730 ± 1424 ± 930 ± 652 ± 3751 ± 2750 ± 36
 Saline solution17 ± 1018 ± 222 ± 630 ± 1230 ± 1153 ± 3248 ± 3338 ± 12
Pao2 (mm Hg)
 Dexmedetomidine537.5 ± 20.290.6 ± 5.686.3 ± 5.889.4 ± 6.289.0 ± 6.998.0 ± 11.2102.8 ± 6.7108.3 ± 7.4
 Acepromazine544.6 ± 17.6120.9* ± 9.4117.5* ± 11.0121.0* ± 13.6111.3* ± 7.2103.7 ± 5.6106.5 ± 8.2112.6 ± 8.4
 Saline solution510.4 ± 30.5114.8* ± 9.5110.0* ± 5.5108.9* ± 7.2101.8* ± 5.8102.3 ± 5.0101.5 ± 7.4102.8 ± 6.8
Arterial pH
 Dexmedetomidine7.282 ± 0.0237.299 ± 0.0297.291 ± 0.0257.294 ± 0.0237.305 ± 0.0387.343 ± 0.0337.370 ± 0.0207.380 ± 0.012
 Acepromazine7.284 ± 0.0347.360* ± 0.0307.374* ± 0.0157.378* ± 0.0147.370* ± 0.0167.366 ± 0.0177.386 ± 0.0137.405 ± 0.018
 Saline solution7.287 ± 0.0267.374* ± 0.0407.366* ± 0.0367.354* ± 0.0287.348* ± 0.0297.366 ± 0.0247.384 ± 0.0207.389 ± 0.018

See Table 3 for key.

The cardiac index following acepromazine treatment was significantly higher than that for saline solution at 5 minutes, although differences in oxygen delivery were not significant. The oxygen extraction ratio was significantly higher 5 and 10 minutes following the saline solution treatment than after the acepromazine treatment.

With respect to systemic arterial blood pressures, acepromazine treatment resulted in values significantly lower than for dexmedetomidine and saline solution from the 5- through 90-minute measurement points. Treatment with dexmedetomidine resulted in a higher SAP, DAP, and MAP shortly after administration than did treatment with saline solution; however, there were no differences between these treatments by the 15-minute measurement point.

Central venous pressure and PAOP were significantly higher at 5 minutes when dogs received dexmedetomidine or saline solution than when they received acepromazine. The differences among treatments were evident at various points from 5 to between 60 and 90 minutes. Although dexmedetomidine treatment appeared to yield the highest CVP values of all treatments, these values were not significantly different from those for saline solution, except at 30 minutes.

Dexmedetomidine administration was associated with a peak in blood pressures and a concurrent marked increase in SVRI at the 5-minute measurement point. Although SVRI steadily decreased, values remained significantly higher than those for both saline solution and acepromazine from 5 to between 75 and 90 minutes. With acepromazine and saline solution administration, SVRI values did not differ except for higher values for saline solution at 10 and 15 minutes. Changes in PVRI were not pronounced; however, values for dexmedetomidine were higher than those for acepromazine at 5 minutes and saline solution at 10 minutes, up to 60 minutes. Despite this, changes in MPAP were not significant.

Dexmedetomidine caused significant changes in values of the measured respiratory variables during the recovery phase of the treatment trial. Compared with acepromazine and saline solution treatments, dexmedetomidine treatment resulted in a significantly lower Pao2 from 5 to 30 minutes and significantly higher Paco2 from 5 to 60 minutes.

Discussion

Fentanyl is commonly administered during inhalation anesthesia to provide analgesia and reduce inhalation anesthetic requirements.6,15 In the present study, a dose of fentanyl recommended for intraoperative and postoperative analgesia was administered as a bolus followed by an infusion in dogs concurrently receiving isoflurane. This protocol resulted in significant decreases in heart rate, MAP, and cardiac index. In a previous study8 of awake dogs, only minor changes in cardiovascular function were identified despite a dose of fentanyl administered IV as a bolus that was 3-fold greater than that used in our study. The difference in findings between the studies was not unexpected, considering that inhalation anesthesia results in a magnification of the decrease in heart rate, blood pressure, and cardiac output associated with opioid administration.16 The cardiovascular effects of fentanyl administration are dose dependent,17 and it is likely that a lower dose would have resulted in less cardiovascular depression.

The bolus and infusion doses of fentanyl in our study were selected on the basis of reported plasma concentrations that result in analgesia and clinically relevant decreases in inhalation anesthetic requirement.11,18 Following the initial changes associated with administration of the fentanyl bolus, heart rate, MAP, and cardiac index gradually returned toward baseline values during the fentanyl CRI. This observation was likely attributable to a decrease in fentanyl plasma concentrations but may also have been a result of sympathetic stimulation from the increase in Paco2.19 Although the cardiovascular effects of fentanyl eventually stabilized, the rapid administration of a fentanyl bolus in anesthetized animals should be done with monitoring of heart rate and arterial blood pressure. In a clinical setting, a slower administration rate for the initial loading dose or a lower dose could also be considered to decrease the cardiopulmonary impact of fentanyl administration. Atropine administration can minimize the bradycardia and decrease in cardiac output associated with fentanyl administration15; however, an anticholinergic was not administered prior to, or concurrently with, fentanyl in the present study to evaluate the effects of the study drugs alone.

To improve cardiopulmonary performance in a patient when an opioid is added to an anesthetic regimen, the concentration of inhalation anesthetic delivered could be decreased, assuming a constant degree of stimulation. In the present study, isoflurane anesthesia was maintained in the dogs at a concentration of 1.2% prior to and during the period of fentanyl administration. As would happen in a clinical setting, our goal was to provide an adequate depth of anesthesia and minimize the cardiopulmonary adverse effects of the inhalation anesthetic. Our preliminary work in healthy dogs showed that delivery of an end-tidal isoflurane concentration of 1.2% was necessary to permit cardiopulmonary measurements without any dogs responding. To minimize potential variability in end-tidal isoflurane concentrations, we elected to maintain the isoflurane at the same concentration when fentanyl was added to the anesthetic regimen. The increase in anesthetic depth due to fentanyl administration likely played a role in the observed change in heart rate, MAP, and cardiac index.

In the present study, baseline blood pressure values were lower than in other studies20,21 in which isoflurane was administered via a mask to induce anesthesia prior to instrumentation. Potential contributors to this difference in study findings include the lack of noxious stimulation and differences in study protocols. Specifically, in the present study, propofol was used for anesthetic induction, which prevented the excitatory phase typically associated with mask anesthetic inductions that have commonly been used to evaluate cardiopulmonary effects of inhalation anesthetics. Although it is possible that a low degree of hypovolemia may have existed in the study dogs, we do not believe it contributed to the low blood pressure observed. Instrumentation of the dogs was minimal, and hydration status was considered unremarkable prior to each treatment trial as assessed via physical examination and Hct and blood total protein measurement.

The respiratory effects of fentanyl differ markedly in conscious dogs, compared with in anesthetized dogs. Following IV administration of a 15 μg/kg IV bolus of fentanyl in another study,8 dogs had no significant changes in Pao2 or Paco2, compared with baseline values. Furthermore, doses far exceeding the clinical dose range are required before changes in blood gases values typically develop.17 In contrast, respiratory depression is common following fentanyl administration in anesthetized dogs.22 Despite anticipating a respiratory depressant effect of fentanyl administration in dogs receiving isoflurane, we chose not to provide ventilatory support for the study dogs to avoid changes in cardiopulmonary function during the transition from manual to spontaneous ventilation. The period of apnea that occurred resulted in a maximum mean increase in Paco2 to 65.5 mm Hg; however, hypoxemia did not develop because the dogs were inspiring a high oxygen fraction. In a clinical setting, where a dog may have underlying disease or be subjected to positioning that further impairs spontaneous ventilation, one should be prepared to support ventilation when fentanyl is administered as a bolus, decrease the dose, or decrease the rate of administration, particularly when an increase in Paco2 is contraindicated.

The anesthetic recovery period is characterized by the emergence through progressively lighter planes of anesthesia to the full return of consciousness. In the present study, dogs were extubated at an end-tidal isoflurane concentration of 0.8%. This target was selected instead of conventional extubation criteria, such as swallowing, to optimize the consistency at the time of sedative administration relative to the effects of residual isoflurane within dogs. In addition, preliminary work performed by our research group determined that extubating the dogs at an end-tidal isoflurane concentration of 0.8% was best for lessening the excitatory behavior seen when extubation is delayed until swallowing or signs of resistance to the endotracheal tube are present. Signs of the dogs’ resistance to the endotracheal tube were evident at an endtidal isoflurane concentration of approximately 0.4%. In dogs with underlying disease or surgical trauma, transitioning to room air at an end-tidal isoflurane concentration of 0.8% or earlier may have more profound effects on blood oxygenation, and supplemental oxygen administration is recommended.

Sedatives are often administered to dogs recovering from inhalation anesthesia to minimize the excitement caused by dysphoria or emergence delirium.23 Acepromazine and dexmedetomidine are the most commonly used sedatives for this purpose in our veterinary teaching hospital. Because of the different characteristics of sedation associated with these sedatives, determining equivalent sedative doses is difficult. Doses recommended for sedation range from 5 to 50 μg/kg for medetomidine (corresponding to approx 2.5 to 25 g of dexmedetomidine/kg) and 0.025 to 0.2 mg/kg for acepromazine.24 Controlled studies evaluating doses specifically used for postoperative sedation have not yet been performed; however, doses generally recommended for this purpose begin at 0.01 mg/kg for acepromazine and range from 2 to 5 μg/kg for medetomidine.23 Ultimately, doses of these sedative agents for use during anesthetic recovery in the present study were selected on the basis of the high end of clinically used doses that are effective in young, healthy dogs in our clinic as well as results of preliminary investigations in our laboratory. A comprehensive recovery scoring evaluation was not used because of the amount of intervention required to ensure collection of cardiopulmonary data. However, dexmedetomidine and acepromazine administration resulted in a similar frequency of excitatory behavior, which was less common than in dogs that received saline solution. The lack of preanesthetic sedation and the fairly high dose of fentanyl administered in the absence of substantial postoperative pain may have contributed to the high incidence of excitatory behavior observed, despite efforts to lessen rapid emergence with prompt extubation. Additionally, the delay in the onset of the sedating effects from the sedatives may also have contributed to the brief period of mild disorientation observed in some dogs when they received acepromazine or dexmedetomidine. Additional studies are needed to evaluate the impact of sedatives on the characteristics of anesthetic recovery in dogs.

Administration of acepromazine and dexmedetomidine at the doses used resulted in marked cardiopulmonary changes in dogs receiving fentanyl following isoflurane-based anesthesia. Overall, dexmedetomidine administration was characterized by greater cardiovascular alterations than acepromazine. The cardiovascular effects of dexmedetomidine administration, including bradycardia, decreased cardiac output, and increased systemic vascular resistance, are consistent with the effects of dexmedetomidine and other α2-adrenergic receptor agonists in dogs.25 The commonly described increase in blood pressure response was also evident: blood pressure initially increased to exceed that with both other treatments, then was followed by a decrease to baseline in 15 to 30 minutes. Despite similar blood pressures among treatments 15 minutes after administration, other drug effects persisted because heart rate remained lower and SVRI was significantly higher with dexmedetomidine treatment for at least 75 minutes and likely contributed to the lower SI for the drug. Potentially of greatest clinical relevance, in combination with the decrease in heart rate and cardiac index, dexmedetomidine administration was associated with the lowest global oxygen delivery and tissue perfusion relative to tissue requirements, as indicated by lower Po2 and higher oxygen extraction ratio than with other treatments.

The cardiovascular effects of α2-adrenergic receptor agonists are only somewhat dose dependent.26 A dose-titration study26 in conscious dogs demonstrated that medetomidine administered IV at doses as low as 1 and 2 μg/kg reduces heart rate by approximately 50% and cardiac index by > 60%. The corresponding reductions are only slightly greater and are maximal at doses ≥ 5 μg/kg, with higher doses resulting in a longer duration of effect.26 Thus, the dexmedetomidine dose of 2.5 μg/kg used in the present study (equivalent to approx 5 μg of medetomidine/kg27) may result in maximal cardiovascular depression. Lower doses may provide effective sedation in other samples of dogs and result in cardiovascular changes of shorter duration; however, the magnitude of these effects would be expected to be only slightly less or similar to the ones we observed.

The administration of anticholinergics with α2-adrenergic receptor agonists has been explored in dogs and is not recommended because of additional decreases in cardiovascular performance, as demonstrated by a decrease in systolic cardiac function and increase in cardiac wall stress.28 Prevention of the cardiovascular changes associated with the α2-adrenergic receptor agonists is difficult, so the cardiovascular effects of dexmedetomidine administration should be carefully considered on an individual patient basis and its use avoided during anesthetic recovery in dogs in which its cardiopulmonary effects would be deleterious.

Interestingly, acepromazine and fentanyl administration transiently enhanced hemodynamic function, compared with function when only fentanyl was administered during recovery. Stroke index and heart rate were not often statistically different between acepromazine and saline solution; however, the observed higher heart rates with acepromazine resulted in a statistically greater value for cardiac index 5 minutes after administration. This observation in acepromazine-treated dogs may be explained by the baroreflex responding to lower MAP caused by peripheral α-adrenergic receptor antagonism and enhancing sympathetic outflow.29 A high cardiac index coupled with a low SVRI likely resulted in enhanced tissue perfusion, given that increases in Po2 were observed that directly reflected those of cardiac index, indicating less oxygen extraction and more efficient circulation. A decrease in cardiac index from conscious baseline values has been reported following acepromazine administration at 0.1 mg/kg IV,10 although values remained within reference limits.30 This finding was attributed to a decrease in stroke volume secondary to a decrease in left ventricular contractility and preload, given that heart rate remained unchanged. The changes were considered to be a result of a decrease in sympathetic tone and may have been less significant in the present study because a lower dose of acepromazine was used. Despite the larger dose of acepromazine and subsequent buprenorphine administration in the other study,10 systemic arterial blood pressure was still lower in dogs of the present study, suggesting additional decreases in blood pressure were due to the use of fentanyl and potentially the effects of any residual isoflurane in the immediate recovery period.

In addition to causing the greatest oxygen extraction ratio, dexmedetomidine was also the only treatment that resulted in significant ventilatory depression. When administered alone, medetomidine decreases respiratory rate and inspiratory occlusion pressure, whereas tidal volume, Paco2, and Pao2 remain within clinically acceptable limits.31,32 However, administration of opioid-medetomidine combinations results in more remarkable respiratory depression. The Paco2 in the present study was greater than previously described for opioid-medetomidine combinations,8,31,33,34 which may have been attributable to dose or route of administration. Another contributing factor may have been additional short-lived respiratory depression from residual isoflurane, although studies32,35 have not shown clinically meaningful differences in respiratory rate or tidal volume in dogs treated with medetomidine, compared with dogs treated with medetomidine and isoflurane.

Although Paco2 was higher than the upper reference limit, dogs did not become hypoxemic during the anesthetic recovery phase. This might have been because of previous administration of supplemental oxygen, which was continued until the time of extubation. Transitioning dogs to room air at an earlier point may have more profound effects on blood oxygenation, and supplemental oxygen administration is recommended when dexmedetomidine is used with opioids during anesthetic recovery.

Acepromazine administration had little effect on any of the measured respiratory variables. A previous study36 showed that treatment with acepromazine alone causes a decrease in respiratory rate but maintenance of minute volume, and therefore the effect on Pao2 and Paco2 is minimal. When acepromazine was administered with opioids in other studies,10,12,37 variable decreases in respiratory rate, minute volume, and Pao2 and increases in Paco2 were observed, although the same was not found in our study. The discrepancy may be attributable to lower doses of acepromazine or opioid used or differences in the method of drug administration. Specifically, in the other studies, the opioid and acepromazine were administered as rapid IV boluses, whereas the fentanyl was delivered as a CRI in the present study and sedatives were administered when fentanyl plasma concentrations had likely decreased from initial peak values following the initial bolus.

The onset and duration of cardiovascular effects with dexmedetomidine or acepromazine administration at the doses used had many similarities. Most variables reached maximum or minimum values 10 minutes after either sedative was given; however, the duration of effect differed among variables and between drugs. The greatest effect on MAP was evident 5 minutes after administration with both sedatives; however, the duration of this effect differed between treatments. Following dexmedetomidine administration, values returned to baseline within 10 minutes and remained stable between the 30- and 90-minute measurement points. This finding is in contrast to the effects of acepromazine administration, after which blood pressure remained persistently low for the duration of the experimental period, indicating a longer lasting influence on blood pressure. The effect on heart rate was greatest for both drugs 10 minutes after administration; however, the increase following acepromazine administration decreased steadily toward baseline over the course of 90 minutes, whereas the decrease following dexmedetomidine administration changed gradually and remained low for 90 minutes, suggesting that postanesthetic treatment with dexmedetomidine may result in longer lasting changes in heart rate than with acepromazine.

Despite these differences between drugs, their duration appeared to be similar with respect to their influence on cardiac index. Cardiac index reached its greatest values with acepromazine and lowest values with dexmedetomidine 5 minutes after administration and gradually returned toward baseline, remaining slightly higher and lower than normal reported values at 90 minutes for acepromazine and dexmedetomidine, respectively. The respiratory depression resulting from concurrent dexmedetomidine and fentanyl administration was slightly slower in onset, compared with its cardiovascular effects. Values for Pao2 were lowest 10 minutes following administration, and elevations in Paco2 were maximal between 15 to 30 minutes. Both variables gradually returned to the normal physiologic range at 60 minutes and normalized further following the discontinuation of fentanyl administration. The discontinuation of fentanyl administration 60 minutes after sedative administration made it difficult to discern between cardiovascular changes due to the waning of drug effects versus a reduction in drug interactions; however, the findings in our study suggested that cardiovascular and respiratory changes will be compromised for at least 60 minutes with dexmedetomidine and fentanyl at the doses administered, and dogs should be monitored more closely during this period. Although acepromazine and fentanyl administration on recovery did not result in circulatory or respiratory compromise, it can be expected that blood pressure would be reduced for at least 90 minutes.

A control group given fentanyl alone was included in this study to determine the physiologic changes occurring during recovery from general anesthesia in dogs receiving a clinically relevant dose of an opioid and to determine the effects of the sedatives administered. The cardiopulmonary outcome of anesthetic recovery in the dogs that received fentanyl alone was a return of respiratory and most cardiovascular variables to normal conscious values. However, CVP, MPAP, and PAOP increased and remained higher than typical for most of the recovery period.30

The cardiopulmonary consequences of opioid-induced excitement have not been formally characterized in dogs, but increases in heart rate, MAP, cardiac index, and sympathetic stimulation have been reported to accompany signs of excitement following opioid administration in species more prone to their excitatory effects.38–41 Such a response is not consistent, and a human study42 demonstrated no change in blood pressure or heart rate in patients with opioid-induced dysphoria, despite an increase in plasma noradrenaline concentration. It is unclear whether the dogs in the present study had any cardiovascular stimulation beyond their conscious resting values because preanesthetic baseline measurements were not obtained. High CVP, MPAP, and PAOP might be attributed to increases in right and left ventricular preload from a return of vascular tone following discontinuation of isoflurane anesthesia and possibly fluid retention. Although a balanced electrolyte solution was administered at a daily maintenance rate, additional fluids were administered during cardiac output measurements, and both fentanyl and inhalation anesthesia have been shown to decrease urine production43–45 and may have contributed to the high blood pressures observed in the present study by increasing circulating blood volume.

Our findings suggest that postanesthetic treatment with dexmedetomidine causes significantly greater cardiovascular and respiratory compromise than treatment with fentanyl alone or acepromazine with concurrent fentanyl administration in dogs recovering from isoflurane anesthesia. In particular, acepromazine administration resulted in an increase in cardiac index and other measures of perfusion without respiratory compromise, providing a hemodynamic benefit in anesthetic recovery. Use of fentanyl alone during anesthetic recovery was associated with minimal adverse cardiopulmonary effects. When interpreting these findings, one should consider that young, healthy dogs were used in the present study. In addition, dogs received supplemental oxygen until the point of extubation (0.8% end-tidal isoflurane concentration) and the effects of either sedative or fentanyl alone may be more extreme in sick or debilitated dogs with low concentrations of circulating catecholamines or poor cardiopulmonary function. Ongoing oxygen supplementation and monitoring of physiologic variables as well as administration of the lowest effective drug doses are recommended during the anesthetic recovery period to minimize the risk of adverse anesthetic events. Additional, clinically based studies will help clarify the cardiopulmonary impact of these sedatives in different populations.

ABBREVIATIONS

CRI

Constant rate infusion

CVP

Central venous pressure

DAP

Diastolic arterial blood pressure

MAP

Mean arterial blood pressure

MPAP

Mean pulmonary artery pressure

PAOP

Pulmonary artery occlusion pressure

Po2

Partial pressure of oxygen in mixed venous blood

PVRI

Pulmonary vascular resistance index

SAP

Systolic arterial blood pressure

SI

Stroke index

SVRI

Systemic vascular resistance index

a.

Atravet, Wyeth Animal Health, Guelph, ON, Canada.

b.

Dexdomitor, Pfizer Animal Health, Kirkland, QC, Canada.

c.

Insyte-W, Becton Dickinson Infusion Therapy Systems, Sandy, Utah.

d.

Diprivan 1%, AstraZeneca, Mississauga, ON, Canada.

e.

IsoFlo, Abbott Animal Health, Abbott Park, Ill.

f.

Intro-Flex-Percutaneous sheath introducer kit, Edwards Lifescience LLC, Irvine, Calif.

g.

2% lidocaine hydrochloride injection, Alveda Pharma, Toronto, ON, Canada.

h.

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

i.

S/5 Anesthesia Monitor, Datex-Ohmeda, GE Healthcare, Helsinki, Finland.

j.

Fentanyl citrate, Sandoz Canada Inc, Boucherville, QC, Canada.

k.

Plasma-Lyte A, Baxter Corp, Mississauga, ON, Canada.

l.

Cefazolin, Apotex Inc, Toronto, ON, Canada.

m.

Metacam, Boehringer Ingelheim, Burlington, ON, Canada.

n.

Critical Care Xpress, Nova Biomedical Corp, Waltham, Mass.

o.

SAS OnlineDoc, version 9.2, SAS Institute Inc, Cary, NC.

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  • Figure 1—

    Mean ± SD heart rate (HR; A), cardiac index (CI; B), MAP (C), and SVRI (D) in 7 healthy dogs recovering from isoflurane anesthesia and receiving a fentanyl CRI (5 μg/kg/h, IV) at various points after IV administration of dexmedetomidine (2.5 μg/kg; triangles), acepromazine (0.05 mg/kg; squares), or saline (0.9% NaCl) solution (circles). *Value is significantly (P < 0.05) different from that for dexmedetomidine. †Value is significantly (P < 0.05) different from that for acepromazine.

  • Figure 2—

    Mean ±SD oxygen delivery (DO2; A), Paco2 (B), Po2 (C), and oxygen extraction ratio (ER; D) in the dogs in Figure 1. See Figure 1 for remainder of key.

  • 1. Brodbelt DC, Blissitt KJ, Hammond RA, et al. The risk of death: the confidential enquiry into perioperative small animal fatalities. Vet Anaesth Analg 2008; 35:365373.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Clarke KW, Hall LW. A survey of anaesthesia in small animal practice: AVA/BSAVA report. Vet Anaesth Analg 1990; 17:410.

  • 3. 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; 34:325335.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Lipkowski A, Misicka A, Carr D, et al. Neuropeptide mimetics for pain management. Pure Appl Chem 2004; 76:941950.

  • 5. Ilkiw JE. Balanced anesthetic techniques in dogs and cats. Clin Tech Small Anim Pract 1999; 14:2737.

  • 6. Steagall PVM, Teixeira Neto FJ, Minto BW, et al. Evaluation of the isoflurane-sparing effects of lidocaine and fentanyl during surgery in dogs. J Am Vet Med Assoc 2006; 229:522527.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Aguado D, Benito J, Gomez De Segura IA. Reduction of the minimum alveolar concentration of isoflurane in dogs using a constant rate of infusion of lidocaine-ketamine in combination with either morphine or fentanyl. Vet J 2011; 189:6366.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Grimm KA, Tranquilli WJ, Gross DR, et al. Cardiopulmonary effects of fentanyl in conscious dogs and dogs sedated with a continuous rate infusion of medetomidine. Am J Vet Res 2005; 66:12221226.

    • Crossref
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