Materials and Methods

Animals—Six healthy mature mixedbreed male dogs were used in the study. Mean ± SD body weight was 25.6 ± 2.5 kg, and mean age was 24.6 ± 9.5 months. Dogs were considered healthy on the basis of results of a physical examination, CBC, and serum biochemical analysis.^b Dogs were housed separately in the central animal facility at the University of Guelph and were allowed unlimited access to water up until the time of each experimental period; however, food was withheld for 12 hours prior to each experimental period. The experimental protocol was reviewed and approved by the Animal Care Committee of the University of Guelph.

Induction regimens—Dogs were randomly allocated by use of a modified Latin square in a randomized crossover design to receive each of 3 induction regimens. Subsequent anesthetic episodes were separated by a minimum period of 1 week. On the basis of preliminary findings, low initial induction doses were used (1.25 mg of ketamine hydrochloride^c/kg [solution of 100 mg/mL] and 0.0625 mg of diazepam^d/kg [solution of 5 mg/mL] mixed in the same syringe [volume of the mixture administered was 0.025 mL/kg], 1 mg of 1% propofol^e/kg, and 2.5 mg of 2% thiopental^f/kg).

Instrumentation—On the day of each experiment, anesthesia was induced in dogs by administration of isoflurane^g in oxygen delivered via a face mask. Once the palpebral reflex and jaw tone disappeared, dogs were orotracheally intubated with an appropriately sized endotracheal tube that was immediately connected to a universal F-circuit attached to an anesthetic machine. Oxygen flow was between 60 and 100 mL/kg/min, and the vaporizer was adjusted to maintain a light surgical plane of anesthesia. Dogs were positioned in lateral recumbency, and 20-gauge, 4.8-cm catheters were inserted (one in a cephalic vein and another in a dorsal pedal artery). The cephalic vein catheter was used for drug administration, whereas the dorsal pedal artery catheter was used for direct measurement of SABP, MABP, and DABP and for collection of blood samples for analysis. Subcutaneous tissues over a jugular vein were infiltrated with 0.5 mL of 2% lidocaine hydrochloride.^h An 8.5-F introducerⁱ was then inserted into that jugular vein, and a 7-F thermodilution catheter^j was passed through the introducer. Verification of the position of the thermodilution catheter was determined fluoroscopically Specifically, the distal port of the thermodilution catheter was located in the pulmonary artery for measurement of core body temperature; collection of mixed-venous blood samples; and measurement of SPAP, MPAP, and DPAP, whereas the proximal port was located in the right atrium for measurement of CVP and injection of cold 5% dextrose solution to measure CO. All pressure transducers^k were calibrated before each experiment by use of a mercury manometer. Pulmonary pressure waveforms were then confirmed on the monitor.^l A lead II ECG^m was monitored throughout the experimental period to record HR and for detection of arrhythmias. End-tidal calibration was performed prior to each experiment by use of manufacturerre-commended gases containing isoflurane.ⁿ

Procedures—After instrumentation, dogs were allowed to recover from anesthesia. A minimum of 30 minutes after extubation, dogs were evaluated to determine that they had returned to preanesthetic activities (defined as a dog that would respond to its name and walk without ataxia). Then, baseline cardiopulmonary variables (HR, SABP, DABP, MABP, MPAP, and CVP) and body temperature were recorded, CO was measured, and blood samples were collected while the dogs were gently restrained in a standing position. Throughout the experiments, blood samples (arterial and mixed venous) were collected and then stored on ice for a maximum of 2 hours before measurement of blood gas partial pressures, pH, bicarbonate concentration, and base excess by use of a blood gas analyzer.^o Hemoglobin concentration and hemoglobin oxygen saturation were measured by use of a co-oximeter.^p The PCV and total protein concentration were determined by centrifugation^q and refractometry respectively. The point of the shoulder (or the manubrium) was used as the zero reference point for pressure measurements when the dogs were in the standing (or laterally recumbent) position. Cardiac output was measured by a CO computer^r by use of the thermodilution technique. Briefly, 5 mL of cold 5% dextrose solution was injected through the proximal port of the thermodilution catheter. At each time point, CO was measured in triplicate, and the mean was calculated (values could not exceed 10% variation).

After variables were recorded at baseline, CO was measured, and blood samples were collected, medetomidine^s (10 μg/kg) and hydromorphone^d (0.05 mg/kg) were administered IV during a 30-second period. Doses of the drugs for a dog were mixed in 1 syringe immediately prior to administration. Medetomidine and hydromorphone were administered IV to maximize consistency of the response and avoid potential variation attributable to differences in absorption. Dogs were subsequently positioned in right lateral recumbency. Ten minutes after administration of medetomidine and hydromorphone, hemodynamic measurements were recorded and blood samples were obtained. Twenty minutes after injection of medetomidine and hydromorphone, anesthesia was induced by administration of one of the assigned induction regimens (ketamine-diazepam, propofol, or thiopental). All induction agents were administered IV during a 15-second period. When administration of the initial induction dose did not result in sufficient depth of anesthesia to permit orotracheal intubation of the dog by an experienced veterinary anesthesiologist, another dose of the induction regimen was administered, and intubation was reattempted.

Ten minutes after administration of the induction dose, hemodynamic measurements and blood samples were obtained. Immediately thereafter, dogs were connected to the anesthesia machine (Fcircuit) with the oxygen flow rate set between 60 and 100 mL/kg/min and the isoflurane vaporizer set at 1%. A catheter^t was inserted in the lumen of the orotracheal tube. The proximal end of this catheter was connected to an infrared absorption spectrometer^l to measure end-tidal isoflurane concentration. End-tidal isoflurane concentration was recorded at all subsequent recording periods. Variables were recorded, CO was measured, and blood samples were obtained 5,15, and 25 minutes after initiation of isoflurane administration. The CI, stroke volume, SI, SVR, CaO₂, mixedvenous oxygen content, DO₂, O₂, and ER were calculated from the measured variables by use of standard equations.^31,32.

At the end of each anesthetic episode, meloxicam^u was administered IV to all dogs to provide postanesthetic analgesia. Dogs were then allowed to recover from anesthesia.

Statistical analysis—Statistical analyses were performed by use of commercially available software.^v All data were reported as mean ± SD. A Shapiro-Wilk test was performed to assess normality of the data. When required, data were logarithmically transformed to improve the distribution. Data were analyzed by an ANOVA for repeated measures. Treatment (ie, induction regimen), time, and the treatment-time interaction were included in the analysis. When significant differences (P < 0.05) were detected or there was an overall effect of time, a post hoc Dunnett test was used to compare data at each time point with baseline values within each induction regimen. Within each induction regimen, paired t tests were used to compare values 10 minutes after administration of the induction dose with values 10 minutes after administration of the preanesthetic medications and to compare values 5, 15, and 25 minutes after administration of isoflurane with values after administration of the preanesthetic medications and after administration of the induction dose. Tukey adjustment was used when there was an overall treatment-time interaction or treatment effect. A Tukey test was used to compare group means.

Results

Doses of the induction agents that enabled endotracheal intubation were 1.25 mg of ketamine/kg with 0.0625 mg of diazepam/kg (0.025 mL/kg of a 1:1 mixture), 1 mg of propofol/kg, and 2.5 mg of thiopental/kg. Induction of anesthesia was smooth and intubation was easily performed in all dogs at these doses. One dog receiving the propofol regimen and 1 dog receiving the thiopental regimen coughed once after placement of the orotracheal tube; however, depth of anesthesia was judged to be adequate in both dogs, and additional drugs were not administered. There were no significant differences in end-tidal concentrations of isoflurane within or among induction regimens. All dogs recovered from anesthesia without complications.

Cardiopulmonary results were analyzed (Tables 1 and 2; Figures 1 and 2). For all induction regimens, HR was significantly lower starting 10 minutes after administration of preanesthetic medication and continuing until the end of the experimental period, compared with the respective HR at baseline. For ketamine-diazepam and thiopental, HR was higher after administration of the induction agents than after administration of the preanesthetic medications. From 5 to 25 minutes after initiation of isoflurane administration (ketamine-diazepam) and from 15 to 25 minutes after initiation of isoflurane administration (all induction regimens), HR was significantly higher than the value obtained after administration of preanesthetic medications. Comparisons among induction regimens revealed that mean HR was lower after administration of the induction agents and 5 minutes after initiation of isoflurane administration when dogs were induced with propofol and after administration of the induction agent when induced with thiopental, compared with results for dogs induced with ketamine-diazepam. Heart rate was higher after administration of the induction agent when induced with thiopental, compared with results after induction with propofol.

Table 1—

Mean ± SD values for cardiorespiratory variables measured in 6 dogs before administration of preanesthetic medications (Baseline); 10 minutes after IV administration of preanesthetic medications (medetomidine at 10 μg/kg and hydromorphone at 0.05 mg/kg; After MH); 10 minutes after induction of anesthesia with ketamine-diazepam, propofol, or thiopental (After induce); and during maintenance of anesthesia with isofurane at 5, 15, and 25 minutes after initiation of isofurane administration (Iso5, Iso15, and Iso25, respectively).

Variable	Induction regimen	Baseline	After MH	After induce	Iso5	Iso15	Iso25
CO (L/min)	Ketamine-diazepam	4.6 ± 0.4	1.5 ± 0.3a	1.9 ± 0.3a,A,B	2.4 ± 0.2a,b,c,B	2.3 ± 0.3a,b,c	2.4 ± 0.4a,b,c
	Propofol	5.0 ± 0.5	1.5 ± 0.3a	1.5 ± 0.2a	2.1 ± 0.4a,b,c	2.4 ± 0.3a,b,c	2.4 ± 0.4a,b,c
	Thiopental	4.6 ± 0.4	1.5 ± 0.2a	1.6 ± 0.1a	1.9 ± 0.3a,b,c	2.4 ± 0.3a,b,c	2.3 ± 0.4a,b,c
SABP (mm Hg)	Ketamine-diazepam	147 ± 25	152 ± 14	169 ± 34a	148 ± 11c	131 ± 9a,c	127 ± 8a,b,c
	Propofol	150 ± 20	153 ± 22	163 ± 24a	152 ± 23c	147 ± 23a,c	136 ± 12a,b,c
	Thiopental	152 ± 25	158 ± 22	163 ± 16a	145 ± 20c	142 ± 16a,c	131 ± 21a,b,c
DABP (mm Hg)	Ketamine-diazepam	81 ± 16	110 ± 9a	114 ± 10a	88 ± 17b,c	82 ± 9b,c	76 ± 6b,c
	Propofol	84 ± 15	113 ± 11a	109 ± 26a	84 ± 10b,c	81 ± 8b,c	78 ± 9b,c
	Thiopental	81 ± 7	113 ± 20a	108 ± 23a	84 ± 12b,c	79 ± 10b,c	78 ± 7b,c
O2 (mL/min/m2)	Ketamine-diazepam	198.2 ± 64.9	150.3 ± 68.4a	129.8 ± 8.9a	110.6 ± 17.7a	97.2 ± 32.2a	81.1 ± 4.3a
	Propofol	187.8 ± 42.6	132.8 ± 12.1a	121.7 ± 21.2a	116.1 ± 8.0a	101.4 ± 7.7a	94.7 ± 8.7a
	Thiopental	196.5 ± 50.3	134.3 ± 14.0a	118.4 ± 6.8a	105.0 ± 27.4a	111.1 ± 13.8a	87.8 ± 15.4a
Do2 (mL/min/m2)	Ketamine-diazepam	929.2 ± 46.7	286.9 ± 35.3a	322.5 ± 36.6a	509.9 ± 28.2a,b,c	498.8 ± 73.8a,b,c	498.2 ± 30.4a,b,c
	Propofol	980.6 ± 88.0	291.9 ± 36.6a	313.5 ± 40.9a	498.2 ± 95.4a,b,c	545.4 ± 82.2a,b,c	535.2 ± 79.9a,b,c
	Thiopental	987.7 ± 125.2	288.3 ± 62.1a	305.0 ± 22.1a	423.6 ± 44.0a,b,c	508.9 ± 72.9a,b,c	510.4 ± 74.7a,b,c

^aWithin a row, value differs significantly (P < 0.05) from the value for baseline.

^bWithin a row, value differs significantly (P < 0.05) from the value for After MH.

^cWithin a row, value differs significantly (P < 0.05) from the value for After induce.

^AWithin a variable within a column, value differs significantly (P < 0.05) from the value for propofol.

^BWithin a variable within a column, value differs significantly (P < 0.05) from the value for thiopental.

Table 2—

Mean ± SD values for cardiorespiratory variables, total protein concentration, and core body temperature measured in 6 dogs at baseline; 10 minutes after IV administration of preanesthetic medications (After MH); 10 minutes after induction of anesthesia with ketamine-diazepam, propofol, or thiopental (After induce); and during maintenance of anesthesia (Iso5, Iso15, and Iso25, respectively.

Variable	Induction regimen	Baseline	After MH	After induce	Iso5	Iso15	Iso25
Respiratory rate (breaths/min)	Ketamine-diazepam	69 ± 51	11 ± 4a	11 ± 3a	9 ± 7a	10 ± 6a	9 ± 5a
	Propofol	50 ± 24	11 ± 4a	7 ± 4a	7 ± 4a	8 ± 4a
	Thiopental	51 ± 20	10 ± 4a	11 ± 5a	8 ± 5a	10 ± 6a	9 ± 5a
Pao2 (mm Hg)	Ketamine-diazepam	96 ± 4.5	80 ± 6a	61 ± 4a,b,a,B	519 ± 29a,b,c	536 ± 18a,b,c	546 ± 11a,b,c
	Propofol	101 ± 0	78 ± 5a	76 ± 6a	513 ± 32a,b,c	536 ± 14a,b,c	544 ± 19a,b,c
	Thiopental	103 ± 4	76 ± 10a	74 ± 7a	526 ± 11a,b,c	529 ± 22a,b,c	520 ± 40a,b,c
P O2 (mm Hg)	Ketamine-diazepam	48.9 ± 3.7	37.4 ± 3.6a	37.3 ± 1.6a	67.8 ± 3.3a,b,c	74.6 ± 4.0a,b,c	76.3 ± 4.5a,b,c
	Propofol	53.2 ± 7.2	37.7 ± 3.5a	40.6 ± 2.9a	61.7 ± 3.1a,b,c	70.6 ± 2.7a,b,c	73.9 ± 4.8a,b,c
	Thiopental	47.8 ± 3.7	38.6 ± 3.6a	39.1 ± 2.5a	59.9 ± 2.6a,b,c	73.3 ± 10.1a,b,c	71.7 ± 5.7a,b,c
Paco2 (mm Hg)	Ketamine-diazepam	38.1 ± 2.3	44.8 ± 2.0a	51.5 ± 1.8a,b	59.9 ± 2.6a,b,c	58.4 ± 2.6a,b,c	59.5 ± 3.4a,b,c
	Propofol	38.1 ± 3.1	42.9 ± 2.8a	48.2 ± 2.8a,b	60.5 ± 5.1a,b,c	58.5 ± 2.8a,b,c	59.4 ± 2.8a,b,c
	Thiopental	36.2 ± 1.3	44.6 ± 2.1a	49.8 ± 1.6a,b	57.4 ± 7.2a,b,c	61.8 ± 4.2a,b,c	59.3 ± 5.8a,b,c
Arterial pH	Ketamine-diazepam	7.35 ± 0.03	7.29 ± 0.02a	7.25 ± 0.01a,b	7.20 ± 0.03a,b,c	7.21 ± 0.03a,b,c	7.21 ± 0.03a,b,c
	Propofol	7.36 ± 0.05	7.29 ± 0.02a	7.27 ± 0.01a,b	7.20 ± 0.04a,b,c	7.21 ± 0.03a,b,c	7.22 ± 0.02a,b,c
	Thiopental	7.35 ± 0.03	7.29 ± 0.03a	7.27 ± 0.02a,b	7.22 ± 0.04a,b,c	7.20 ± 0.03a,b,c	7.21 ± 0.03a,b,c
Base excess (mmol/L)	Ketamine-diazepam	-4.3 ± 1.0	−5.7 ± 0.8a	−5.3 ± 1.0a	−6.3 ± 1.0a,b,c	−6.0 ± 1.0a,c	−5.7 ± 1.0a,c
	Propofol	−4.1 ± 0.7	−5.7 ± 1.0a	−5.4 ± 1.0a	−6.1 ± 2.0a,b,c	−5.9 ± 2.0a,c	−5.6 ± 1.0a,c
	Thiopental	−3.8 ± 0.8	−5.2 ± 2.0a	−4.9 ± 1.0a	−5.8 ± 1.0a,b,c	−5.6 ± 1.0a,c	−5.9 ± 2.0a,c
PCV (%)	Ketamine-diazepam	44 ± 4	46 ± 3a	46 ± 3a	44 ± 3b,c	43 ± 3b,c	43 ± 3b,c
	Propofol	43 ± 2	47 ± 3a	45 ± 3a	44 ± 4b,c	43 ± 3b,c	44 ± 3b,c
	Thiopental	43 ± 4	46 ± 3a	46 ± 2a	44 ± 4b,c	44 ± 3b,c	43 ± 3b,c
Total protein (g/dL)	Ketamine-diazepam	6.3 ± 0.5	5.8 ± 0.3a	5.9 ± 0.5a	5.9 ± 0.5a	5.8 ± 0.5a	5.9 ± 0.4a
	Propofol	6.2 ± 0.4	5.8 ± 0.2a	5.9 ± 0.3a	5.8 ± 0.3a	5.8 ± 0.4a	5.8 ± 0.3a
	Thiopental	6.2 ± 0.5	5.9 ± 0.4a	5.9 ± 0.4a	5.9 ± 0.4a	5.9 ± 0.4a	5.9 ± 0.4a
Body temperature (°C)	Ketamine-diazepam	38.3 ± 0.6	38.3 ± 0.4	38.2 ± 0.3b	38.1 ± 0.4b	37.9 ± 0.4a,b,c	37.8 ± 0.4a,b,c
	Propofol	38.3 ± 0.5	38.4 ± 0.6	38.2 ± 0.6b	38.1 ± 0.7b	38.0 ± 0.7a,b,c	37.8 ± 0.7a,b,c
	Thiopental	38.3 ± 0.6	38.6 ± 0.6	38.4 ± 0.6b	38.3 ± 0.5b	38.1 ± 0.6a,b,c	38.0 ± 0.5a,b,c

See ^{Table 1} for key.

Mean ± SD values for HR (A), CI (B), SI (C), and ER (D) measured in 6 dogs before administration of preanesthetic medications (Baseline); 10 minutes after IV administration of preanesthetic medications (medetomidine at 10 μg/kg and hydromorphone at 0.05 mg/kg; After MH); 10 minutes after induction of anesthesia (After induce); and during maintenance of anesthesia with isoflurane at 5, 15, and 25 minutes (lso5, lso15, and lso25, respectively). The induction regimens were ketamine-diazepam (black circles), propofol (white circles), or thiopental (inverted black triangles). ^aWithin an induction regimen, value differs significantly (P < 0.05) from the value for baseline. ^bWithin an induction regimen, value differs significantly (P < 0.05) from the value for After MH. ^cWithin an induction regimen, value differs significantly (P < 0.05) from the value for After induce. ^aWithin a time point, value differs significantly (P < 0.05) from the value for propofol. ^bWithin a time point, value differs significantly (P < 0.05) from the value for thiopental.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.586

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Mean ± SD values for HR (A), CI (B), SI (C), and ER (D) measured in 6 dogs before administration of preanesthetic medications (Baseline); 10 minutes after IV administration of preanesthetic medications (medetomidine at 10 μg/kg and hydromorphone at 0.05 mg/kg; After MH); 10 minutes after induction of anesthesia (After induce); and during maintenance of anesthesia with isoflurane at 5, 15, and 25 minutes (lso5, lso15, and lso25, respectively). The induction regimens were ketamine-diazepam (black circles), propofol (white circles), or thiopental (inverted black triangles). ^aWithin an induction regimen, value differs significantly (P < 0.05) from the value for baseline. ^bWithin an induction regimen, value differs significantly (P < 0.05) from the value for After MH. ^cWithin an induction regimen, value differs significantly (P < 0.05) from the value for After induce. ^aWithin a time point, value differs significantly (P < 0.05) from the value for propofol. ^bWithin a time point, value differs significantly (P < 0.05) from the value for thiopental.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.586

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Mean ± SD values for HR (A), CI (B), SI (C), and ER (D) measured in 6 dogs before administration of preanesthetic medications (Baseline); 10 minutes after IV administration of preanesthetic medications (medetomidine at 10 μg/kg and hydromorphone at 0.05 mg/kg; After MH); 10 minutes after induction of anesthesia (After induce); and during maintenance of anesthesia with isoflurane at 5, 15, and 25 minutes (lso5, lso15, and lso25, respectively). The induction regimens were ketamine-diazepam (black circles), propofol (white circles), or thiopental (inverted black triangles). ^aWithin an induction regimen, value differs significantly (P < 0.05) from the value for baseline. ^bWithin an induction regimen, value differs significantly (P < 0.05) from the value for After MH. ^cWithin an induction regimen, value differs significantly (P < 0.05) from the value for After induce. ^aWithin a time point, value differs significantly (P < 0.05) from the value for propofol. ^bWithin a time point, value differs significantly (P < 0.05) from the value for thiopental.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.586

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Mean ± SD values for MABP (A), SVR (B), CVP (C), and MPAP (D) measured in 6 dogs at baseline, 10 minutes after IV administration of preanesthetic medications (After MH), 10 minutes after induction of anesthesia (After induce), and during maintenance of anesthesia with isoflurane (lso5, lso15, and lso25, respectively). The induction regimens were ketamine-diazepam (black circles), propofol (white circles), or thiopental (inverted black triangles). See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.586

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Mean ± SD values for MABP (A), SVR (B), CVP (C), and MPAP (D) measured in 6 dogs at baseline, 10 minutes after IV administration of preanesthetic medications (After MH), 10 minutes after induction of anesthesia (After induce), and during maintenance of anesthesia with isoflurane (lso5, lso15, and lso25, respectively). The induction regimens were ketamine-diazepam (black circles), propofol (white circles), or thiopental (inverted black triangles). See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.586

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Mean ± SD values for MABP (A), SVR (B), CVP (C), and MPAP (D) measured in 6 dogs at baseline, 10 minutes after IV administration of preanesthetic medications (After MH), 10 minutes after induction of anesthesia (After induce), and during maintenance of anesthesia with isoflurane (lso5, lso15, and lso25, respectively). The induction regimens were ketamine-diazepam (black circles), propofol (white circles), or thiopental (inverted black triangles). See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 69, 5; 10.2460/ajvr.69.5.586

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The CO and CI values for all induction regimens were lower after administration of the preanesthetic medications until the end of the experimental period, compared with the values at baseline. There were no significant differences in CO and CI between values obtained after administration of the preanesthetic medications and after administration of the induction doses for any of the induction regimens. For all induction regimens, CO and CI were greater from 5 to 25 minutes after initiation of isoflurane administration, compared with values after administration of preanesthetic medications or after administration of induction doses. Comparisons among induction regimens revealed that the CO and CI values were greater when dogs were induced with ketamine-diazepam than when dogs were induced with thiopental or propofol after administration of induction doses and greater than when dogs were induced with thiopental at 5 minutes after initiation of isoflurane administration.

Stroke index values for all induction regimens were significantly lower after administration of preanesthetic medications and after administration of induction doses, compared with their respective values at baseline. For all induction regimens, SI values after administration of preanesthetic medications were significantly lower than values after administration of induction doses; the values remained significantly lower than values at baseline but higher than values after administration of induction doses from 5 to 25 minutes after initiation of isoflurane administration. Comparisons among induction regimens did not reveal significant differences in SI values throughout the experimental period.

For all induction regimens, SABP after administration of induction doses was significantly greater than the value at baseline but lower than the baseline value at 15 and 25 minutes after initiation of isoflurane administration. During isoflurane administration, SABP was lower than the value after administration of the induction doses, and SABP 25 minutes after initiation of isoflurane administration was lower than the value after administration of the preanesthetic medications. The MABP and DABP had similar patterns, with all induction regimens resulting in values after administration of preanesthetic medications and administration of induction doses greater than values at baseline, whereas values were lower from 5 to 25 minutes after inititation of isoflurane administration, compared with values after administration of preanesthetic medications and after administration of induction doses. When dogs were induced with ketamine-diazepam, the MABP after administration of the induction dose was greater than the value after administration of the preanesthetic medications. Comparisons among induction regimens revealed that the MABP was higher for ketamine-diazepam than for propofol at 10 minutes after administration of the induction doses.

For all induction regimens, MPAP was greater after administration of the preanesthetic medications and after administraiton of the induction doses, compared with values at baseline, whereas MPAP from 5 to 25 minutes after initiation of isoflurane administration was lower than values after administration of the preanesthetic medications or after administration of the induction doses. The only difference in MPAP among induction regimens was a lower value at 5 minutes after initiation of isoflurane administration when dogs were induced with propofol, compared with the corresponding value when dogs were induced with thiopental.

The CVP and SVR for all induction regimens were significantly greater from administration of the preanesthetic medications until the end of the experimental period, compared with values at baseline. No other differences in CVP were detected among the periods or induction regimens. During the period of isoflurane anesthesia (5 to 25 minutes), SVR was lower than values after administration of preanesthetic medications and after administration of induction doses.

For all induction regimens, DO₂ and O₂ values were lower than values at baseline from 10 minutes after administration of preanesthetic medications until the end of the experimental period; however, the DO₂ values were greater from 5 to 25 minutes after initiation of isoflurane administration, compared with the values 10 minutes after administration of the preanesthetic medications and 10 minutes after administration of the induction doses. The ER values for all induction regimens were higher at 10 minutes after administration of the preanesthetic medications and 10 minutes after administration of the induction doses, compared with the value at baseline, but ER values were lower from 5 to 25 minutes after initiation of isoflurane administration, compared with values at 10 minutes after administration of the preanesthetic medications and 10 minutes after administration of the induction doses. During maintenance of anesthesia, ER values were similar to the ER value at baseline.

For all induction regimens, PaO₂ and PO₂ were lower after administration of preanesthetic medications and after administration of induction doses, compared with values at baseline. From 5 to 25 minutes after initiation of isoflurane administration (ie, when dogs were receiving supplemental oxygen), mean PaO₂ and PO₂ were greater than values at baseline, after administration of preanesthetic medications, and after administration of induction doses. Dogs had a lower PaO₂ after administration of the induction dose when induced with ketamine-diazepam, compared with corresponding values when dogs were induced with propofol or thiopental and compared with PaO₂ after sedation.

For all induction regimens, respiratory rates were lower and PaCO₂ values higher after administration of preanesthetic medications and continuing through the end of the experimental period, compared with values at baseline. No other significant differences were detected in respiratory rates among periods or induction regimens; however, PaCO₂ was higher after administration of the induction doses and during the period of isoflurane administration, compared with PaCO₂ after administration of the preanesthetic medications. Mean pH values for all induction regimens were lower after administration of the preanesthetic medications and continuing until the end of the experimental period, compared with the pH value at baseline. The pH values for all induction regimens were lower after administration of the induction doses, compared with values after administration of the preanesthetic medications, and pH values from 5 to 25 minutes after initiation of isoflurane administration were lower than pH values after administration of the preanesthetic medications and after administration of the induction doses. Base excess for all induction regimens was lower after administration of the preanesthetic medications and 25 minutes after initiation of isoflurane administration, compared with the value at baseline. There was a reduction in base excess between the periods after administration of the preanesthetic medications and after administration of the induction doses; there was also a reduction in base excess during the period of isoflurane administration. Base excess at 5 minutes after initiation of isoflurane administration was lower than the values obtained after administration of the preanesthetic medications or after administration of the induction doses.

For all induction regimens, PCV was higher after administration of the preanesthetic medications and after administration of the induction doses, compared with the value at baseline, whereas PCV was lower during isoflurane administration than after administration of preanesthetic medications or after administration of induction doses. Mean total protein concentration for all induction regimens was lower after administration of the preanesthetic medications and continuing throughout the remainder of the experimental period, compared with the value at baseline. Body temperature decreased during the experimental period for all induction regimens, with the mean value being lower after anesthetic induction, compared with the values at baseline and after administration of the preanesthetic medications.

One dog had a sinus arrhythmia that was detected after administration of the preanesthetic medications and after administration of the induction dose when induced with thiopental, but the arrhythmia disappeared after initiation of isoflurane administration. One dog developed second-degree atrioventricular block each time it received medetomidine and hydromorphone, and the block persisted after induction of anesthesia with all 3 induction regimens but was not evident when the dog was receiving isoflurane. A third dog had premature ventricular contractions after medetomidine and hydromorphone administration that persisted after administration of thiopental, but the premature contractions were not detected from 5 to 25 minutes after initiation of isoflurane administration.

Discussion

In the study reported here, medetomidine and hydromorphone administration in dogs resulted in cardiovascular changes consistent with those reported for investigations with medetomidine alone or for medeotimidine administered in combination with an opioid, including decreases in HR, CO, and DO₂ and increases in systemic and pulmonary arterial blood pressures, CVP, SVR, and ER.^5,7,8,33 Induction of anesthesia with ketamine-diazepam, propofol, or thiopental after sedation with medetomidine-hydromorphone caused minimal additional changes in the measured hemodynamic variables. With the exception of HR and CI in dogs when receiving ketamine-diazepam, no differences in cardiovascular performance were detected after induction of anesthesia with the various regimens. However, induction of anesthesia had a clinically relevant impact on pulmonary function, with a decrease in PaO₂ and an increase in PaCO₂ for all induction regimens. The impairment in pulmonary gas exchange was more profound in dogs when receiving ketamine-diazepam, compared with results for the other induction regimens.

Medetomidine was probably responsible for the severe cardiovascular changes detected after administration of preanesthetic medications.^34–36 This agent can result in α₂-adrenergic receptor-mediated peripheral vasoconstriction, which leads to an increase in SVR as well an increase in blood pressure and bradycardia that is partially mediated vagally and partially mediated centrally. Hydromorphone may have contributed to the reduction in HR³⁷; however, its effects on the peripheral vasculature were probably minimal. The dose of hydromorphone used in the study reported here was relatively low, and higher doses may be used in clinical practice and could cause other undesirable changes in cardiopulmonary function from those reported in this study.

Although the cardiovascular effects of the premedication agents were profound, the results are consistent with those reported by other investigators.^{5,7,8,11,33,38,39} Furthermore, the findings were likely representative of changes detected in dogs at clinical practices because we chose doses of medetomidine and hydromorphone that are routinely recommended for use with dogs.⁴⁰ Although lower doses of medetomidine may have resulted in a shorter duration of effect,⁵ the magnitude of the cardiopulmonary alterations would have been similar for at least 30 minutes and therefore would not have been likely to impact the changes detected during the postinduction period. Similarly, IM administration of the same doses of medetomidine and hydromorphone used in this study may have resulted in a slower onset of cardiopulmonary effects; however, the degree of change in cardiopulmonary function would probably have been similar because the cardiopulmonary effects of medetomidine are not necessarily dose dependent.⁵ Although we are not aware of any in-depth cardiopulmonary studies, a higher dose of medetomidine (such as 40 μg/kg administered IM) can cause similar peak sedation and changes in HR and respiratory rate as is evident with doses of 20 μg/kg administered IV.⁴¹ Therefore, we speculate that a dose of 20 μg of medetomidine/kg would result in changes similar to those for the 10 μg of medetomidine/kg administered IV in the study reported here.

Veterinary clinicians generally select an anesthetic induction agent on the basis of preoperative evaluation of a patient (especially with respect to cardiovascular status), the anticipated duration and type of surgical procedure, personal familiarity with use of the agent, and cost. Commonly, ketamine or the combination of ketamine-diazepam is recommended over other anesthetic agents for use in hemodynamically compromised patients.⁴² In the study reported here, the differences in cardiovascular responses that were detected after induction were relatively minor and were consistent with the known cardiovascular effects of the agents. Specifically, increases in HR, CI, and blood pressure associated with ketamine-diazepam administration have also been reported in unpremedicated dogs,^23,43,44 although the magnitude of the change was reduced dramatically by the prior administration of medetomidine and hydromorphone in our study. Similarly, the trend toward an increase in HR after induction with propofol has also been detected in other investigations.⁴⁵.

Because of the low doses required to induce anesthesia for the various regimens, it was not surprising that the differences between the periods after administration of preanesthetic medications and after administration of induction doses as well as among induction regimens were minor. Although it was our intent to titrate the induction agents with a fraction of the recommended doses, the dogs may not have received the absolute lowest dose possible to achieve a depth of anesthesia sufficient to allow intubation, considering that the initial dose achieved the desired effect in all dogs, and therefore differences among induction regimens may have been minimized. Nevertheless, the doses used were consistently capable of achieving the target depth of anesthesia without further impairing the cardiovascular status of the dogs. Of additional clinical importance is the low dose of all of the induction agents that was needed to achieve an anesthetic depth suitable to achieve orotracheal intubation in dogs after administration of medetomidine and hydromorphone, compared with the doses reported^46–48 after sedation with other more traditionally used premedication regimens, such as acepromazine and butorphanol. Specifically, approximately a fourth of the recommended dose was used in all dogs. Had we adhered to the standard dosage recommendations, it is possible that there would have been additional cardiovascular changes with substantial risk to each dog. However, such dosages clearly were not needed for the induction of anesthesia and intubation after preanesthetic administration of medetomidine and hydromorphone, and they should be avoided unless the needs of a patient dictate otherwise.

Medetomidine administered alone in healthy dogs consistently results in minimal effects on PaCO₂.⁴⁹ Although the inclusion of an opioid analgesic with sedatives for the purposes of preanesthetic medications is routinely recommended, the combination of the α₂-adrenergic receptor agonist and an opioid caused a decrease in effective alveolar ventilation. Similarly, although PaO₂ values are generally > 80 mm Hg in dogs sedated with medetomidine alone,^7,8,50-53 sedation with the combination of medetomidine and hydromorphone in the study reported here resulted in a significant decrease in PaO₂. In addition to the decrease in PaO₂, a decrease in PO₂ and an increase in ER were detected. Combined with the decrease in CI, the calculated DO₂ was noticeably reduced. Although the PaO₂ values detected in the healthy dogs of this study were not critical and there was no evidence of a deficit in DO₂ as determined on the basis of the measured base excess, respiratory function should be closely monitored in dogs with preexisting respiratory dysfunction or an increase in the work of breathing after administration of medetomidine and hydromorphone.

Practitioners may not always elect to provide supplemental oxygen to dogs anesthetized for short-duration procedures, such as suturing of minor lacerations or removal of porcupine quills; thus, we chose to delay the administration of oxygen to the dogs in this study to evaluate the effects of anesthetic induction on respiratory gas exchange while the dogs were breathing room air. Despite the low doses of induction agents administered, dogs induced with ketamine-diazepam had a further reduction in oxygenation with an increase in PaCO₂ values. Similar results have been reported^7,44 when a combination of medetomidine and ketamine was used. The differences in partial pressures of arterial gas for dogs induced with ketamine-diazepam, relative to those for the other induction regimens, were probably attributable to the longer duration of effect of ketamine and diazepam relative to that for propofol and thiopental and therefore the greater depth of anesthesia at the time of collection of blood samples for blood gas analysis in these dogs (approx 10 minutes). It is possible that similar respiratory depression would have been evident had samples of arterial blood for blood gas analysis been collected 1 to 2 minutes after induction when dogs were induced with thiopental and propofol. Dogs sedated with medetomidine had a similar reduction in PaO₂ at 3 minutes after induction of anesthesia with propofol in another study⁵⁴ Irrespective of the induction regimen, supplemental oxygen is recommended after induction as determined on the basis of our findings.

In contrast to cardiovascular function during the postinduction period, there was a degree of improvement in cardiovascular function with an increase in CI and DO₂ during maintenance of anesthesia with isoflurane. These improvements may have been attributable to the direct effects of isoflurane or the reduction of the effects induced by medetomidine over time. Isoflurane is a potent vasodilator,⁵⁵ which could explain the return of arterial and pulmonary pressures to values similar to those measured at baseline. Interestingly, CVP did not return to the baseline value. Despite the vasodilation induced by isoflurane, SVR remained significantly higher than the baseline value. The decrease in venous capacitance and CO caused by medetomidine probably prevented the return of CVP to the value measured at baseline.¹⁸ Not surprisingly, oxygenation improved substantially during maintenance of anesthesia as a result of administration of supplemental oxygen. Alveolar ventilation was further impaired during isoflurane administration as a result of the respiratory depressive effects of isoflurane; however, PaCO₂ values were within acceptable ranges for spontaneously breathing dogs.

In dogs, preanesthetic medication with medetomidine and hydromorphone caused dramatic changes in cardiopulmonary variables and the induction of anesthesia by use of low doses (approx a fourth of the dose typically recommended for dogs) of ketamine-diazepam, propofol, or thiopental did not appear to further compromise cardiovascular function. However, respiratory gas exchange should be closely monitored after induction of anesthesia, and supplemental oxygen is recommended, particularly when ketamine-diazepam is used to induce anesthesia.