Sedation can be an alternative to general anesthesia for minor medical procedures and diagnostic imaging in dogs. Intramuscular drug administration can be quickly performed and is practical in most clinical scenarios, including those where the animal does not tolerate physical restraint. Drugs commonly administered IM for sedation in dogs include α2-adrenergic receptor agonists, acepromazine, a tiletamine-zolazepam combination, benzodiazepines, and ketamine, some of which have undesirable effects on cardiorespiratory variables.1–4
Alfaxalone is a neuroactive steroid anesthetic that enhances the effects of GABA at the GABAA receptor, thus potentiating the neurotransmitter's inhibitory effect.5 Activation of this GABA receptor results in the opening of chloride channels and hyperpolarization of the neuronal cell membrane, resulting in unconsciousness. Alfaxalone is licensed in the United States for use in dogs and cats as an IV anesthetic induction agent. Its IV use had been previously described.6,7 Alfaxalone has been administered IM for sedation in cats and has been shown to provide reliable sedation without negative effects on cardiorespiratory stability in this species8; however, when administered IM as a sole agent in dogs, it has been associated with poor recovery from sedation.9
Butorphanol is an opioid agonist-antagonist. It has antagonist activity at μ receptors and partial agonist activity at ĸ receptors. Butorphanol is rapidly absorbed after IM administration,10 producing sedation with an onset time of < 15 minutes.11 In addition, butorphanol is associated with minimal cardiorespiratory depression.12
Midazolam is a water-soluble benzodiazepine administered IV or IM in various species. Midazolam potentiates the actions of GABA by increasing the affinity of the neurotransmitter for the GABAA receptor, producing anxiolysis, sedation, muscle relaxation, and anticonvulsant activity. It acts synergistically with other sedative drugs.13 Midazolam administered by the IM route has a rapid onset of action and complete absorption, with peak plasma concentrations achieved ≤ 15 minutes after administration.13 These properties render it a suitable drug for IM administration when venous access is limited and a rapid onset of sedation is desired.
Acepromazine is a phenothiazine derivative, and its mechanism of action for sedation is through postsynaptic dopaminergic D2 receptor antagonism. The duration of sedation after acepromazine administration is dose dependent, and sedation is prolonged at higher doses.3 Acepromazine causes a decrease in arterial blood pressure by means of α1-adrenergic receptor antagonism. It also results in decreases in stroke volume and oxygen consumption14 and can lower circulating hemoblobin concentration, leading to decreased oxygen carrying capacity.15 Acepromazine is commonly used and effective as a premedicant administered IM in various anesthetic protocols for dogs.16,17
Dexmedetomidine is an α2-adrenergic receptor agonist that acts centrally on the α2-adrenergic receptors in the locus coeruleus (producing sedation) and in the dorsal horn of the spinal cord and brainstem (producing analgesia). Presynaptic binding of agonists to α2-adrenergic receptors in the CNS causes reduction in norepinephrine release, resulting in sedation.1 In addition, α2-adrenergic receptor agonists can cause dose-dependent cardiorespiratory depression.1 Dexmedetomidine has been used extensively IM for sedation in dogs with consistent results.18,19
Intramuscular administration of a drug combination that provides predictable and reliable sedation with minimal cardiorespiratory changes and smooth recovery in dogs would be of great value in clinical practice. As such, the purpose of the study reported here was to evaluate the degree of sedation and cardiorespiratory changes after administration of 3 different protocols involving the administration of alfaxalone and butorphanol IM, in combination with acepromazine (AB-ace), midazolam (AB-mid), or dexmedetomidine (AB-dex), in healthy dogs. We hypothesized that MAP, heart rate, and CO would decrease from baseline (time 0) measurements after drug administration in all protocols, that measures of alveolar ventilation would remain unchanged over time, and that sedation with AB-mid would be less profound and of shorter duration than sedation with AB-ace or AB-dex.
Materials and Methods
Dogs
All study protocols and procedures were approved by The Ohio State University Institutional Animal Care and Use Committee (protocol No. A201800000033). Six sexually intact purpose-bred hounds (3 males and 3 females; 11 to 15 months of age; mean ± SD body weight, 25.4 ± 2.2 kg) were used in the study. Dogs were housed in groups or individually, depending on their temperament and sex. Environmental enrichment was provided, water was available ad libitum, and dogs were fed a commercial laboratory dog food (dry kibble) twice daily. The dogs were confirmed to be healthy before the start of the study by a physical examination and evaluation of CBC and serum biochemical analysis results.
Study design and treatments
A prospective, blinded, randomized crossover design was used for the study. Randomization was performed with publicly accessible software.a Each dog underwent 3 sedation protocols with a 1-week washout period between treatments; food, but not water, was withheld overnight before each treatment. All drug doses were selected on the basis of doses commonly used for dogs in clinical practice and doses used in a similar study of cats.8
The AB-ace treatment included alfaxaloneb (2 mg/kg), butorphanolc (0.4 mg/kg), and acepromazine maleated (0.02 mg/kg). The AB-mid treatment included alfaxaloneb (2 mg/kg), butorphanolc (0.4 mg/kg), and midazolame (0.2 mg/kg). The AB-dex treatment included alfaxaloneb (2 mg/kg), butorphanolc (0.4 mg/kg), and dexmedetomidinef (0.005 mg/kg).
Preinstrumentation measurements and sedation scoring
On the day of each treatment, the dogs were allowed to acclimate to the room before preinstrumentation measurements were obtained. These included sedation score, rectal temperature, heart rate (beats counted over 15 seconds and multiplied by 4), respiratory rate (excursions counted over 15 seconds and multiplied by 4), and arterial blood pressure (MAP, SAP, and DAP) determined by use of a noninvasive oscillometric methodg with the cuff placed on the mid antebrachium. The width of the cuff measured approximately 40% of the circumference of the limb, and the mean of 3 consecutive readings was recorded as preinstrumentation arterial blood pressure. Dogs were placed in lateral recumbency and gently restrained during noninvasive measurement of blood pressure, which took place after the other preinstrumentation measurements were obtained.
Sedation scoring was performed by evaluation of spontaneous posture; palpebral reflexes; position of the eye globes; jaw tone, tongue relaxation, and gag reflex; response to a standardized noise (a concierge bell); resistance to being placed in lateral recumbency; and general appearance and attitude. The scoring system was previously described20,21 and adapted from another source21; each of the 7 variables was rated with a separate subscale, and the results were summed (Supplementary Appendix S1, available at: avmajournals.avma.org/doi/suppl/10.2460/ajvr.81.1.65). The sum of possible scores ranged from 0 to 21. Scores > 15 indicated deep sedation, 10 to 15 indicated moderate sedation, 5 to 9 was considered mild sedation, and < 5 was considered not very sedate. Peak sedation was taken as the time point of the highest median sedation score for a particular treatment. One investigator (MAM) performed all sedation scoring and remained blinded to the treatment administered (and to administration of reversal agents, if applicable) until the study was complete. Dogs were allowed to roam freely in the room for sedation scoring, except when the evaluation required lateral recumbency, for preinstrumentation and time 0 assessments.
Instrumentation
For instrumentation of dogs, general anesthesia was induced with 6% sevofluraneh in oxygen, delivered through a tight-fitting facemask until intubation could be achieved. After orotracheal intubation, anesthesia was maintained with sevoflurane in oxygen delivered via a circle rebreathing system.i Ventilationi was performed with the use of a volume control mode to achieve an end-tidal CO2 concentration of 35 to 45 mm Hg (a tidal volume of approx 10 mL/kg). Electrocardiography, pulse oximetry, and measurement of end-tidal CO2 concentration, heart rate, respiratory rate, and arterial blood pressures (obtained noninvasively) were performed with a commercially available patient monitorg and recorded during instrumentation.
Intravenous catheter placement sites were clipped of hair and prepared aseptically. Indwelling 20-gauge, 1.25-inch cathetersj were placed in a cephalic vein and a dorsal pedal artery. Arterial catheter placement was confirmed by observing pulsation and an arterial waveform once connected to a fluid-filled transducer.k Once the catheters were secured, volume-controlled ventilation and sevoflurane administration were discontinued; the dogs were allowed to breathe spontaneously and were monitored throughout recovery from anesthesia. Sedation score was recorded 1 hour after sevoflurane delivery was discontinued and every 10 minutes thereafter until it was equal to or less than the preinstrumentation score.
Drug administration and data collection
After recovery from anesthesia for instrumentation, dogs were gently placed in right lateral recumbency and baseline (time 0) measurements were recorded, immediately followed by IM administration of the assigned sedative drug combination. Unpreserved alfaxalone was combined with butorphanol and the designated sedative in a single syringe immediately before injection. Because of the large total volume, each injection was divided between 2 injection sites in the left and right lumbar epaxial muscles. Any reaction to injection (eg, vocalization, avoidance, or struggling) was noted. One investigator (CHRP) administered all injections, and another investigator who was blinded to the treatment assignment (MAM) performed data collection, sedation scoring, and recovery assessments.
Physiologic measurements were recorded in the following order at each time point: SAP, MAP, and DAP (by direct measurement); heart rate and respiratory rate (in the same manner described for preinstrumentation measurements); and CO as determined by lithium dilution22,l and arterial blood sampling for pH and blood gas measurements.m At time 0, the sedation score was determined immediately prior to placing the dogs in lateral recumbency for these assessments; at all other time points, sedation score and rectal temperature were recorded last.
Arterial blood for pH and blood gas determination was collected from the dorsal pedal arterial catheter into heparinized syringes; 3 mL of blood was collected into 1 syringe, and another 2 mL of blood was collected into a second syringe for the blood gas sample immediately afterward. The initial 3-mL sample was then returned via the catheter, and the catheter was flushed with 3 mL of saline (0.9% NaCl) solution. The samples were sealed and placed on ice until analyzed.
For measurement of CO, transducer accuracy was verified with a mercury column each morning of the study, and the transducer was zeroed to atmospheric pressure before data collection. The transducer was attached directly to the arterial catheter with an 18-gauge, 1-inch needle in the T-portn hub, and the T-port was connected to the pump of the hemodynamic monitoring device,l which was designed to draw blood out of the catheter at a controlled rate of 4 mL/min during lithium dilution CO determination.
Measurements for all described variables were completed 5, 10, 20, and 30 minutes after injection of the assigned treatment. Time was recorded when dogs first lost the gag reflex. To evaluate the gag reflex, the tongue was extruded and a wooden tongue depressor was applied to the base of the tongue, just rostral to the epiglottis but not touching the larynx, as part of the sedation scoring protocol. After the 30-minute time point, SAP, MAP, DAP, heart rate, respiratory rate, sedation score, and rectal temperature were recorded every 10 minutes up to 180 minutes or until the sedation score was equal to or less than the time 0 value. Dogs remained in right lateral recumbency on the examination table throughout this portion of the study and were allowed to assume sternal recumbency when they were able to do so independently. Dogs were placed on the floor for observation once they attempted to stand up. If the dog was not rousable after verbal stimulation at the 180-minute time point, a reversal drug was administered when one was appropriate. Selected reversal agents were as follows: atipamezoleo (0.05 mg/kg, IM) for reversal of dexmedetomidine in dogs that received AB-dex, flumazenilp (0.01 mg/kg, IM) for reversal of midazolam in dogs that received AB-mid, and naloxoneq (0.01 mg/kg, IM) for reversal of butorphanol effects in dogs that received AB-ace (as acepromazine has no reversal agent). All dogs breathed room air during data collection. Recovery from sedation was subjectively assessed as smooth (no evidence of vocalization, paddling, nystagmus, hypersalivation, pacing, or dysphoria), or poor (eg, showing signs of vocalization, paddling, nystagmus, hypersalivation, pacing, or dysphoria).
The measured variables included arterial blood pH, Paco2, Pao2, arterial oxygen saturation, Hct, and circulating hemoglobin, Na+, K+, Cl−, Ca2+, Mg2+, glucose, and lactate concentrations. The calculated variables included base excess in extracellular fluid, arterial blood HCO3− and total CO2 content, and Cao2. The Pao2, alveolar-arterial gradient in partial pressure of oxygen, Pao2-to-Pao2 ratio, Pao2-to-fraction of inspired oxygen ratio, stroke volume, Do2, and SVR were also calculated and included in the statistical analysis. All calculations were completed as described by Haskins et al.23
Statistical analysis
Probability plots were used to assess distribution of the data. Each variable was analyzed separately as an outcome. Normally distributed variables (heart rate; rectal temperature; SAP; MAP; DAP; CO; SVR; stroke volume; arterial blood pH; Paco2; Pao2; arterial oxygen saturation; Hct; total CO2 content; base excess; concentrations of hemoglobin, Na+, K+, Cl−, Ca2+, Mg2+, glucose, and lactate; Cao2; Pao2; Do2; alveolar-arterial gradient in partial pressure of oxygen; Pao2-to-Pao2 ratio; and Pao2-to-fraction of inspired oxygen ratio) were summarized as mean ± SD, and skewed variables (respiratory rate and sedation score) were summarized as median and range.
Effects of treatment and time on outcomes were assessed with a mixed-model ANOVA for normally distributed data or repeated-measures LGEE for skewed data. The linear models (mixed-model ANOVA or LGEE) specified the treatment, time, and interaction between treatment and time as fixed effects, with dog identification specified as the random effect (mixed-model ANOVA) or the subject for LGEE. To test for effects of treatment at each time point, slice-level P values were determined and adjusted for multiple testing across all variables and time points by means of the Benjamini-Hochberg false discovery rate method.24 When slice-level P values were significant, 2-way comparisons were performed with the Tukey procedure. To test for effects of time within each treatment, slice-level P values were determined and adjusted for multiple testing across all variables and across all treatments with the Benjamini-Hochberg false discovery rate method, and when significant slice-level P values were detected, 2-way comparisons were performed with the Tukey procedure. Variables were also compared between the preinstrumentation time point and time 0 with a mixed-model ANOVA or LGEE as described for the primary analysis. For all comparisons, values of P < 0.05 were considered significant. All analyses were performed with commercially available software.r
Results
There was no significant difference in sedation scores or cardiorespiratory variables between the preinstrumentation time point and time 0. The total volumes of injectate for the AB-mid, AB-ace, and the AB-dex treatments were 0.28, 0.24, and 0.25 mL/kg, respectively.
Sedation scores were tabulated (Table 1). Median sedation scores were significantly higher (indicating greater sedation) than the time 0 value at all time points from 5 to 180 minutes (P < 0.032 [for all comparisons]), 5 to 170 minutes (P < 0.001), and 5 to 170 minutes (P < 0.018) after administration of AB-ace, AB-dex, and AB-mid, respectively. Peak sedation times were 10, 10, and 20 minutes after injection for AB-ace, AB-dex, and AB-mid treatments, respectively. Sedation scores differed significantly among treatments, with lower scores after AB-ace administration than after AB-dex administration, at the 40-, 100-, 120-, and 160-minute time points (P < 0.044). Scores were lower (indicating less sedation) for dogs that received AB-mid than for dogs that received AB-dex from 70 to 140 minutes and at 160 minutes after injection (P < 0.043). After AB-ace administration, scores were higher (indicating more sedation) than those after AB-mid administration at the 90-, 100-, and 140-minute time points (P < 0.001).
Median (range) sedation scores in 6 healthy mixed-breed hounds in a blinded, randomized crossover-design study to evaluate the sedative and cardiorespiratory effects of single-dose IM administration of alfaxalone (2 mg/kg) and butorphanol (0.4 mg/kg) combined with acepromazine (0.02 mg/kg; AB-ace), midazolam (0.2 mg/kg; AB-mid), or dexmedetomidine (0.005 mg/kg; AB-dex) in dogs.
AB-ace | AB-dex | AB-mid | ||||
---|---|---|---|---|---|---|
Time (min) | No. of dogs | Score | No. of dogs | Score | No. of dogs | Score |
0 | 6 | 2 (1–3) | 6 | 3 (1–3) | 6 | 3 (1–4) |
5 | 6 | 15 (14–18)* | 6 | 17 (12–19)* | 6 | 16 (14–16)* |
10 | 6 | 17 (15–18)*† | 6 | 19 (11–20)*† | 6 | 17 (13–18)* |
20 | 6 | 16 (15–19)* | 6 | 18 (13–20)* | 6 | 17 (16–19)*† |
30 | 6 | 17 (15–20)* | 6 | 19 (15–20)* | 6 | 17 (16–19)* |
40 | 6 | 17 (12–20)*A | 6 | 19 (15–20)*B | 5 | 16 (12–19)*A,B |
50 | 6 | 16 (12–17)* | 6 | 18 (11–20)* | 5 | 17 (16–19)* |
60 | 6 | 16 (15–17)* | 6 | 17 (14–21)* | 5 | 16 (10–18)* |
70 | 6 | 14 (12–18)*A,B | 6 | 18 (14–19)*B | 6 | 11 (8–16)*‡A |
80 | 6 | 15 (7–17)*A,B | 6 | 18 (13–19)*B | 6 | 11 (8–15)*‡A |
90 | 6 | 14 (10–15)*A | 6 | 18 (12–19)*A | 6 | 11 (5–12)*‡B |
100 | 5 | 12 (9–14)*‡A | 6 | 17 (12–19)*B | 6 | 10 (3–12)*‡C |
110 | 6 | 11 (5–16)*A,B | 6 | 15 (10–19)*B | 6 | 10 (3–11)*‡A |
120 | 6 | 10 (6–16)*‡A | 6 | 17 (9–17)*‡B | 5 | 10 (7–11)*‡A |
130 | 6 | 11 (6–15)*‡A,B | 6 | 16 (9–17)*‡B | 5 | 10 (5–11)*‡A |
140 | 6 | 12 (5–14)*A | 6 | 14 (5–16)*‡A | 5 | 8 (3–11)*‡B |
150 | 6 | 11 (5–14)*‡ | 6 | 13 (4–17)*‡ | 5 | 8 (7–10)*‡ |
160 | 6 | 9 (3–13)*‡A | 6 | 13 (6–15)*‡B | 5 | 5 (4–7)*‡A |
170 | 5 | 6 (3–11)*‡ | 6 | 11 (4–15)*‡ | 3 | 6 (6–7)*‡ |
180 | 4 | 8 (5–12)*‡ | 6 | 9 (3–15)‡ | 3 | 9 (4–10)‡ |
Time 0 assessments were performed after dogs recovered from inhalation anesthesia for instrumentation and immediately prior to injection of the assigned sedative drug combination. Scores ranged from 0 (no sedation) to 21 (profound sedation).
Within a treatment, sedation score is significantly different from that at time 0.
Peak sedation score for the specified treatment, as determined by highest median sedation score.
Within a treatment, sedation score is significantly different from the peak sedation score.
Within a time point, scores with different superscript letters are significantly different among treatments.
Cardiovascular and respiratory variables up to 30 minutes after treatment were summarized in tabular form (Tables 2 and 3). Overall data for heart rate and MAP were represented graphically (Figures 1 and 2).
Mean ± SD cardiovascular values and arterial blood lactate and glucose concentrations before (time 0) and during the first 30 minutes after drug administration for the same 6 dogs in Table 1.
Time (min) | ||||||
---|---|---|---|---|---|---|
Variable | Treatment | 0 | 5 | 10 | 20 | 30 |
Heart rate (beats/min) | AB-ace | 70 ± 14 | 56 ± 7A,B | 61 ± 6A | 57 ± 7A,B | 59 ± 3A |
AB-dex | 72 ± 14a | 40 ± 7b,A | 42 ± 5b,B | 41 ± 5b,A | 40 ± 3b,B | |
AB-mid | 74 ± 13 | 69 ± 9B | 69 ± 6A | 60 ± 8B | 57 ± 5A,B | |
SAP (mm Hg) | AB-ace | 118 ± 22 | 104 ± 18A | 111 ± 19A | 104 ± 18A | 104 ± 19A |
AB-dex | 118 ± 7a | 148 ± 27b,B | 146 ± 27a,b,B | 138 ± 19a,b,B | 135 ± 13a,b,B | |
AB-mid | 122 ± 20 | 109 ± 13A | 115 ± 15A | 108 ± 15A | 108 ± 27A | |
MAP (mm Hg) | AB-ace | 81 ± 18 | 67 ± 12A | 70 ± 9A | 66 ± 9A | 65 ± 9A |
AB-dex | 86 ± 7 | 106 ± 24B | 106 ± 29B | 101 ± 19B | 94 ± 11B | |
AB-mid | 88 ± 10 | 71 ± 4A | 75 ± 6A | 70 ± 5A | 70 ± 12A | |
DAP (mm Hg) | AB-ace | 70 ± 14a | 49 ± 11b,A | 50 ± 4a,b,A | 47 ± 5b,A | 47 ± 4b,A |
AB-dex | 71 ± 5 | 86 ± 23B | 87 ± 30B | 82 ± 19B | 74 ± 11B | |
AB-mid | 70 ± 8 | 51 ± 5A | 55 ± 6A,B | 52 ± 5A | 51 ± 8A | |
CO (L/min) | AB-ace | 3.43 ± 0.98 | 3.02 ± 0.23A | 3.11 ± 0.27A | 3.07 ± 0.29A | 2.88 ± 0.38A |
AB-dex | 3.03 ± 0.90a | 1.95 ± 0.58a,b,B | 1.80 ± 0.42b,B | 1.76 ± 0.32b,B | 1.81 ± 0.34b,B | |
AB-mid | 3.68 ± 1.78 | 3.23 ± 0.67A | 3.33 ± 0.52A | 3.37 ± 0.92A | 2.97 ± 0.68A | |
Stroke volume (mL/beat) | AB-ace | 49 ± 14 | 55 ± 7 | 51 ± 4 | 54 ± 7 | 49 ± 6 |
AB-dex | 42 ± 10 | 40 ± 21 | 43 ± 9 | 44 ± 12 | 45 ± 11 | |
AB-mid | 48 ± 17 | 47 ± 10 | 49 ± 6 | 56 ± 15 | 52 ± 10 | |
SVR (dynes•sec•cm−5) | AB-ace | 2,000 ± 551 | 1,776 ± 274A | 1,815 ± 169A | 1,734 ± 291A | 1,838 ± 279A |
AB-dex | 2,446 ± 733a | 4,931 ± 2,396b,B | 4,971 ± 1,920b,B | 4,715 ± 1,118b,B | 4,397 ± 1,422b,B | |
AB-mid | 2,633 ± 2,145 | 1,829 ± 384A | 1,851 ± 366A | 1,787 ± 604A | 2,032 ± 916A | |
Hct (%) | AB-ace | 31.2 ± 2.2a | 27.5 ± 2.7b | 27.7 ± 3.4a,b,A | 27.8 ± 1.3a,b,A | 26.2 ± 3.5b,A |
AB-dex | 32.5 ± 2.0 | 30.0 ± 2.8 | 32.0 ± 2.4B | 32.8 ± 2.9B | 33.0 ± 2.3B | |
AB-mid | 31.8 ± 2.6a | 27.3 ± 3.3b | 26.3 ± 4.8b,A | 27.7 ± 2.0b,A | 27.0 ± 2.0b,A | |
Hemoglobin (g/dL) | AB-ace | 10.4 ± 0.8a | 9.2 ± 0.9b | 9.2 ± 1.2b,A | 9.3 ± 0.3a,b,A | 8.7 ± 1.1b,A |
AB-dex | 10.9 ± 0.6 | 10.1 ± 0.8 | 10.7 ± 0.9B | 10.0 ± 1.0B | 11.0 ± 0.8B | |
AB-mid | 10.6 ± 0.9a | 9.1 ± 1.0b | 8.8 ± 1.6b,A | 9.3 ± 0.6b,A | 9.0 ± 0.6b,A | |
Lactate (mmol/L) | AB-ace | 0.5 ± 0.1 | 0.5 ± 0.1 | 0.5 ± 0.0A | 0.6 ± 0.0A | 0.5 ± 0.0A |
AB-dex | 0.6 ± 0.1 | 0.6 ± 0.2 | 0.7 ± 0.2B | 0.7 ± 0.2B | 0.7 ± 0.2B | |
AB-mid | 0.5 ± 0.1 | 0.6 ± 0.0 | 0.6 ± 0.1A | 0.6 ± 0.1A | 0.6 ± 0.1A | |
Glucose (mg/dL) | AB-ace | 86 ± 5 | 87 ± 3A,B | 87 ± 3A | 85 ± 4A | 84 ±4A |
AB-dex | 87 ± 6a | 93 ± 8a,b,A | 98 ± 9b,B | 96 ± 8b,B | 96 ± 8b,B | |
AB-mid | 86 ± 8 | 85 ± 5B | 83 ± 6A | 82 ± 6A | 81 ± 5A |
Within a treatment, values with different lowercase superscript letters are significantly different among time points.
Within a time point for a given variable, values with different uppercase superscript letters are significantly different among treatments.
Respiratory rate and arterial blood gas values at time 0 and during the first 30 minutes after drug administration for the same 6 dogs as in Table 1.
Time (min) | ||||||
---|---|---|---|---|---|---|
Variable | Treatment | 0 | 5 | 10 | 20 | 30 |
Respiratory rate (breaths/min) | AB-ace | 16 (12–28)a | 12 (6–16)a,b,A | 12 (8–16)a,b,A | 12 (8–16)a,b | 8 (8–16)b |
AB-dex | 16 (12–20) | 10 (6–20)A | 12 (12–20)B | 12 (8–20) | 10 (8–20) | |
AB-mid | 18 (8–20) | 18 (12–24)B | 14 (12–24)B | 12 (8–24) | 12 (8–20) | |
Pao2 (mm Hg) | AB-ace | 96.1 ± 6.3 | 92.1 ± 10.0 | 86.5 ± 8.3 | 91.5 ± 3.6 | 93.4 ± 4.5 |
AB-dex | 95.9 ± 4.1 | 82.3 ± 8.6 | 97.5 ± 29.5 | 91.5 ± 7.5 | 86.3 ± 8.5 | |
AB-mid | 100.4 ± 9.6 | 85.3 ± 9.0 | 89.6 ± 11.9 | 94.6 ± 4.6 | 102.1 ± 28.1 | |
Paco2 (mm Hg) | AB-ace | 31.6 ± 2.5a | 35.3 ± 2.2b | 37.4 ± 2.5b,c | 39.1 ± 2.4c | 38.0 ± 1.6b,c |
AB-dex | 31.5 ± 1.8a | 34.7 ± 2.0b | 36.7 ± 2.0b,c | 37.6 ± 1.9b,c | 39.7 ± 1.4c | |
AB-mid | 29.9 ± 1.9a | 37.0 ± 2.1b | 35.8 ± 5.4b | 37 ± 2.5b | 37.9 ± 2.4b | |
Sao2 (%) | AB-ace | 97.1 ± 0.6a | 95.7 ± 1.1a,b | 94.3 ± 1.7b | 95.2 ± 0.5a,b | 95.2 ± 0.7a,b |
AB-dex | 97.3 ± 0.4a | 94.7 ± 1.3b | 95.5 ± 2.0a,b | 95.7 ± 1.0a,b | 94.6 ± 2.2b | |
AB-mid | 97.4 ± 0.5a | 94.7 ± 1.4b | 94.5 ± 1.7b | 95.4 ± 1.3a,b | 95.3 ± 2.4b | |
Pao2 (mm Hg) | AB-ace | 110.2 ± 3.1a | 105.6 ± 2.7b | 103.0 ± 3.1b,c | 100.9 ± 3.0c | 102.3 ± 2.0b,c |
AB-dex | 110.4 ± 2.2a | 106.4 ± 2.4b | 103.9 ± 2.4b,c | 103.7 ± 2.4b,c | 100.0 ± 1.7c | |
AB-mid | 112.3 ± 2.4a | 103.5 ± 2.6b | 104.9 ± 6.7b | 102.3 ± 3.1b | 102.3 ± 3.0b | |
Pao2 - Pao2 (mm Hg) | AB-ace | 14.2 ± 3.8 | 13.6 ± 10.2 | 16.5 ± 8.3 | 9.4 ± 6.2 | 8.9 ± 6.1 |
AB-dex | 14.5 ± 3.5 | 24.1 ± 8.7 | 6.3 ± 29.5 | 11.2 ± 6.7 | 13.8 ± 7.9 | |
AB-mid | 12.0 ± 10.2a,b | 18.2 ± 10.6a | 15.3 ± 10.2a,b | 7.7 ± 11.9a,b | 0.2 ± 27.6b | |
Pao2-to-Fio2 ratio | AB-ace | 457 ± 30 | 438 ± 48 | 412 ± 39 | 435 ± 17 | 445 ± 22 |
AB-dex | 457 ± 19 | 392 ± 41 | 464 ± 57 | 436 ± 36 | 411 ± 40 | |
AB-mid | 468 ± 46 | 386 ± 36 | 408 ± 62 | 437 ± 57 | 467 ± 140 | |
Pao2-to-Pao2 ratio | AB-ace | 0.91 ± 0.04 | 0.91 ± 0.10 | 0.88 ± 0.08 | 0.95 ± 0.06 | 0.95 ± 0.06 |
AB-dex | 0.90 ± 0.03 | 0.81 ± 0.08 | 0.98 ± 0.30 | 0.93 ± 0.07 | 0.90 ± 0.08 | |
AB-mid | 0.94 ± 0.09 | 0.86 ± 0.10 | 0.89 ± 0.10 | 0.97 ± 0.12 | 1.04 ± 0.28 | |
Cao2 (mL O2/dL) | AB-ace | 14.4 ± 1.0a | 12.5 ± 1.2b | 12.3 ± 1.6b,A | 12.6 ± 0.5b,A | 11.8 ± 1.6b,A |
AB-dex | 15.0 ± 0.9a | 13.5 ± 1.0b | 14.5 ± 1.2a,b,B | 14.8 ± 1.3a,b,B | 14.7 ± 1.3a,b,B | |
AB-mid | 14.7 ± 1.1a | 12.2 ± 1.4b | 11.8 ± 2.1b,A | 12.6 ± 1.0b,A | 12.3 ± 0.9b,A | |
Do2 (mL O2/min) | AB-ace | 490.23 ± 137.62 | 379.99 ± 54.63A | 383.43 ± 59.16 | 385.40 ± 13.14A,B | 336.58 ± 35.22 |
AB-dex | 457.43 ± 148.80a | 212.92 ± 117.16b,B | 261.12 ± 56.08b | 257.48 ± 31.79b,A | 263.33 ± 41.38b | |
AB-mid | 537.49 ± 271.47a | 395.62 ± 102.22a,b,A | 392.38 ± 90.33a,b | 422.28 ± 122.59a,b,B | 362.76 ± 76.86b | |
Tco2 (mmol/L) | AB-ace | 22.4 ± 1.7 | 22.9 ± 2.0A,B | 22.6 ± 1.3 | 23.4 ± 1.7 | 22.9 ± 0.8 |
AB-dex | 21.5 ± 1.1 | 20.9 ± 4.0A | 21.8 ± 0.8 | 22.0 ± 0.9 | 22.7 ± 0.6 | |
AB-mid | 20.8 ± 0.7a | 23.4 ± 1.5bB | 21.8 ± 2.5a,b | 22.5 ± 1.7a,b | 22.6 ± 1.6a,b |
Data are represented as median (range) or mean ± SD.
Fio2 = Fraction of inspired oxygen.
Pao2 - Pao2 = Alveolar-arterial gradient in partial pressure of oxygen.
Sao2 = Arterial oxygen saturation.
Tco2 = Total CO2 content.
See Table 2 for remainder of key.
Mean heart rate after AB-dex administration was significantly (P < 0.044) lower than the time 0 value at all time points after injection (Table 2; Figure 1); there was no significant difference from the time 0 value after AB-mid or AB-ace administration. Mean heart rate differed among treatments, with significantly (P < 0.044 and P < 0.035, respectively) higher values for AB-ace and AB-mid than for AB-dex treatment, at multiple time points. Mean heart rate differed significantly (P = 0.027) between the AB-ace and AB-mid treatments 90 minutes after injection, with a higher value after AB-mid administration.
Mean SAP did not differ significantly from the time 0 value after AB-ace or AB-mid administration but was increased significantly (P = 0.045) 5 minutes after AB-dex administration (Table 2). Mean SAP after AB-dex administration was significantly higher than that after AB-ace (P < 0.039) and AB-mid (P < 0.018) administration from 5 to 30 minutes after injection. Similar differences between mean SAP after AB-dex administration and that after AB-ace or AB-mid administration were observed at various time points up to 180 minutes (data not shown).
Mean MAP did not differ significantly from the time 0 value over time following AB-ace, AB-mid, or AB-dex administration (Table 2; Figure 2). Differences in mean MAP were observed between AB-ace and AB-dex (P < 0.015) and between AB-dex and AB-mid (P < 0.038) at multiple time points, whereas the measurement differed between AB-ace and AB-mid (P = 0.037) at 150 minutes only.
Mean DAP after AB-ace administration was significantly (P < 0.028) lower than the time 0 value at 5, 20, and 30 minutes after injection, but there was no significant change in DAP at these times relative to time 0 after AB-dex or AB-mid administration (Table 2). Mean DAP after AB-dex administration was significantly (P < 0.001) higher than after AB-ace administration from 5 to 30 minutes and significantly (P < 0.001) higher than after AB-mid administration at 5, 20, and 30 minutes after injection. Differences in mean DAP between AB-mid and AB-dex treatments and between AB-ace and AB-dex treatments persisted up to 40 and 60 minutes after injection, respectively; few differences were detected sporadically among treatments after 60 minutes (data not shown).
Administration of AB-ace or AB-mid was associated with no significant change in CO, compared with the time 0 value (Table 2). After AB-dex administration, CO was significantly (P < 0.021) decreased from the time 0 value at the 10- to 30-minute time points. The CO after AB-dex administration was also significantly lower than that after AB-ace (P < 0.033) or AB-mid (P < 0.011) administration at the 5- to 30-minute time points. Stroke volume was stable and did not differ significantly among time points or between treatments. There was no significant difference in SVR over time after AB-ace or AB-mid administration. The SVR was significantly (P < 0.004) increased, compared with the time 0 value, from 5 to 30 minutes after AB-dex administration, and was significantly lower after AB-ace (P < 0.001) and AB-mid (P < 0.001) treatments, compared with AB-dex treatment, at the same time points.
Mean circulating hemoglobin concentration decreased, compared with that at time 0, from 5 to 30 minutes after AB-mid (P < 0.012) and at 5, 10, and 30 minutes after AB-ace (P < 0.036) administration (Table 2). These measurements were significantly higher after AB-dex administration than after AB-ace (P < 0.002) or AB-mid (P < 0.001) administration from 10 to 30 minutes after injection. Mean arterial blood glucose concentration was significantly (P ≤ 0.035) increased from 10 to 30 minutes after AB-dex administration, compared with the time 0 concentration. Mean glucose concentration was significantly higher 10, 20, and 30 minutes after AB-dex administration than at the same time points after AB-ace administration (P ≤ 0.001). The result for this variable was significantly (P < 0.023) higher from 5 to 30 minutes after AB-dex administration than at the same time points after AB-mid administration. However, the highest recorded glucose concentration after AB-dex administration (result for 1 dog at the 10-minute time point) was 110 mg/dL (reference range, 78 to 126 mg/dL). Mean arterial blood lactate concentration from 10 to 30 minutes after AB-dex injection was significantly greater than after AB-ace (P < 0.023) and AB-mid (P = 0.046 for all comparisons) injection at the same time points. The highest lactate concentration found after AB-dex administration (recorded for 1 dog at the 10-minute time point) was 1 mmol/L (reference range, 0.5 to 3.5 mmol/L).
Median respiratory rate was significantly (P = 0.031) lower than the respective time 0 value 30 minutes after AB-ace administration, with significantly (P < 0.008) higher values after AB-mid injection than after AB-ace injection at 5 and 10 minutes and AB-mid injection at 5 minutes (Table 3). Respiratory rates varied within and among treatments at additional later time points (data not shown).
Mean Paco2 was significantly greater from 5 to 30 minutes after administration of AB-ace (P < 0.017), AB-dex (P < 0.048), and AB-mid (P < 0.001), compared with the respective time 0 values, with no differences among treatments over time (Table 3). However, the highest recorded Paco2 (result for 1 dog 20 minutes after AB-ace administration) was 42.1 mm Hg (reference range, 35 to 45 mm Hg). Mean Sao2 was lower than the time 0 value at the 10-minute (P = 0.002), 5- and 30-minute (P < 0.005), and 5-, 10- and 30-minute (P < 0.037) time points after AB-ace, AB-dex, and AB-mid treatment, respectively. Mean arterial blood pH varied over time but remained within an acceptable range (7.337 to 7.436; reference range, 7.350 to 7.450). Mean Pao2 was significantly lower, compared with the time 0 value, from 5 to 30 minutes after injection of AB-ace, AB-dex, and AB-mid (P < 0.017, P < 0.048, and P < 0.001, respectively), with no significant differences among groups for this variable. Compared with the time 0 value, Cao2 was significantly lower from 5 to 30 minutes after injection of AB-ace (P < 0.013) and AB-mid (P < 0.002). The Cao2 after AB-ace and AB-mid treatments was significantly (P < 0.001) lower than that after AB-dex treatment at the 10- to 30-minute time points. The Do2 was significantly decreased, compared with the time 0 value, from 5 to 30 minutes after AB-dex administration (P < 0.021) and 30 minutes after AB-mid administration (P = 0.049), with significant (P < 0.026) differences among treatments at various times. The Pao2-to-fraction of inspired oxygen ratio, Pao2-to-Pao2 ratio, and alveolar-arterial gradient in partial pressure of oxygen did not differ significantly from the baseline value within treatments and did not differ among treatments over time.
Mean ± SD rectal temperature steadily decreased from the time 0 measurement after all treatments (data not shown). The lowest temperature recorded for any dog after administration of AB-ace, AB-dex, and AB-mid was 36.2°, 35.6°, and 35.7°C, respectively.
Reaction to the IM injection was noted in 1, 3, and 3 of 6 dogs on administration of AB-mid, AB-ace, and AB-dex, respectively. Reactions included mild vocalizations and physical resistance to restraint during drug administration.
For the AB-mid treatment, loss of the gag reflex was noted in 3 of 6 dogs between 5 and 10 minutes after injection and in the remaining 3 dogs between 10 and 20 minutes after injection. For the AB-ace treatment, loss of gag reflex was detected in 1 of the 6 dogs within 5 minutes, 4 of 6 dogs between 5 and 10 minutes, and 1 of 6 dogs between 10 and 20 minutes after injection. For the AB-dex treatment, loss of gag reflex was noted in 2 of 6 dogs within 5 minutes, 3 of 6 dogs between 5 and 10 minutes, and 1 of 6 dogs between 20 and 30 minutes after injection. Mild to moderate jaw tone was still present despite loss of the gag reflex at the same time point in 3 of 6 dogs after AB-mid administration, and moderate jaw tone was observed at this time point in 1 of 6 dogs after AB-ace administration. Jaw tone in all 6 dogs was relaxed when the gag reflex was lost after AB-dex administration.
Four of 6 dogs were given atipamezole owing to lack of response to verbal stimulation 180 minutes after administration of AB-dex. All 4 dogs responded appropriately to atipamezole administration, with improved mental alertness and ability to ambulate around the room. No dogs required administration of a reversal agent after administration of AB-mid or AB-ace. Sedation score for dogs that received AB-dex treatment was higher than the time 0 value for all 6 dogs at all time points up to 180 minutes after drug administration. In contrast, sedation scores had returned to the time 0 value in 2 of the 6 dogs after AB-mid administration and 2 of the 6 dogs after AB-ace administration by the 180-minute time point.
Recoveries were smooth in all dogs after AB-dex and AB-ace treatments. Two of 6 dogs had poor recoveries with rapid nystagmus, paddling, head thrashing, and dysphoria that lasted between 20 and 30 minutes after AB-mid administration. One of these 2 dogs had paddling and nystagmus noted at the 40-minute time point, and the signs had resolved by the 60-minute time point; its sedation score returned to the time 0 value between the 100- and 110-minute time points. The other dog was vigorously paddling and vocalizing at the 40-minute time point; this dog became quiet and sedate by the 70-minute time point and remained moderately sedate until the 180-minute time point. One other dog appeared anxious 150 minutes after AB-mid administration, with restless pacing, vocalization, and hypersalivation; these signs resolved by the end of the study period, and the dog was observed acting normally when returned to its housing for the night.
On 2 occasions, the building fire alarm sounded unexpectedly (once 180 minutes after administration of AB-mid and once 100 minutes after administration of AB-ace), potentially affecting data for 2 dogs. The dog that had received AB-mid (not included among the 3 previously described dogs with poor recoveries) became very agitated and appeared anxious, with pacing and whining; the experiment was ended at that time because the dog appeared alert. The dog that had received AB-ace prior to this occurrence was less sedate during the alarm but otherwise showed no reaction to the noise and flashing lights. Once the alarm stopped, this dog's sedation score returned to that recorded prior to the alarm. All data from both dogs were included in the statistical analysis.
Respiratory sinus arrhythmia was noted at time 0 and was present but not annotated at subsequent time points for 2 of 6 dogs during the AB-mid experiment; an additional dog had ventricular escape beats at time 0 with a heart rate of 40 to 50 beats/min during this experiment, and the same dog had ventricular escape beats with a heart rate of 44 beats/min at 80 minutes after administration of AB-ace. Mean arterial blood pressure of this dog did not change during the periods of ventricular arrhythmia. The other 5 of 6 dogs had respiratory sinus arrhythmia at all time points after time 0 throughout the AB-ace experiment. Respiratory sinus arrhythmia was also noted in 4 of 6 dogs at time 0 during the AB-dex experiment. All 6 dogs had respiratory bradyarrhythmia after injection of AB-dex, with regularly irregular, normal QRS complexes. Heart rates ranged from 28 to 60 beats/min after AB-dex administration.
Discussion
The effects of IM administration of alfaxalone in combination with medetomidine and butorphanol at various doses25,26 or IV administration of alfaxalone administered sequentially after butorphanol and midazolam for anesthetic induction27 in dogs have been previously described, but to the authors’ knowledge, the present study was the first to evaluate cardiorespiratory variables after IM administration of AB-ace and to compare the results with those for dogs that received AB-mid and AB-dex IM. One disadvantage of IM injection of alfaxalone is the high total volume of injectate required to deliver an appropriate dose.9 Current guidelines28 recommend that ≤ 0.25 mL/kg be administered as a single IM injection in dogs. For this reason, the treatments administered in the present study (for which the maximum total volume was 0.28 mL/kg) were divided into 2 injections each.
There was no significant difference between preinstrumentation and time 0 sedation scores, which suggested that dogs were fully recovered from inhalation anesthesia with sevoflurane before the assigned drug combinations were administered IM for sedation. Relaxed jaw tone and loss of gag reflex in most dogs after IM drug administration suggested these protocols might be useful for tracheal intubation. We did not attempt intubation to prevent cardiorespiratory changes associated specifically with intubation.29,30 Although neither airway obstruction nor aspiration was observed during this study, the loss of gag reflex could predispose a dog to these types complications.
All 3 drug combinations resulted in a median sedation score ≥ 15 of 21 (indicating moderate to deep sedation) beginning 5 minutes after injection and lasting until ≥ 1 hour after injection. From 70 to 140 minutes after IM drug injection, median sedation scores for dogs that received AB-mid were consistently lower (indicating a lesser degree of sedation) than those for dogs that received AB-dex and sporadically lower than those for dogs that received AB-ace. Median sedation scores for dogs that received AB-ace were also sporadically lower than those for dogs that received AB-dex. Beginning 5 minutes after AB-dex administration, these scores reflected moderate (score, 10 to 15) to deep sedation until the end of the study at the 180-minute time point, and 4 of the 6 dogs required reversal of the effects of dexmedetomidine with atipamezole at that time.
Investigators of a previous study27 administered butorphanol (0.1 mg/kg), midazolam (0.2 mg/kg), and alfaxalone (2 mg/kg) sequentially to dogs by the IV route, and the mean ± SD duration of deep sedation or anesthesia was 29 ± 6 minutes. Overall, the AB-mid treatment in the present study was associated with deep sedation for approximately 1 hour after injection, possibly owing to more gradual uptake after IM administration, as the onset time of alfaxalone is later and its terminal half-life is longer after IM versus IV administration.31,32 In another study26 a combination of butorphanol (0.1 mg/kg), medetomidine (0.01 mg/kg), and alfaxalone (1.5 mg/kg) administered to dogs IM was associated with sedation for a mean ± SD duration of 89 ± 17 minutes. The difference between those results and the extended duration of sedation in dogs after AB-dex administration in the present study could have been attributable to the higher doses of alfaxalone and butorphanol used in our study, differences in sedation criteria and scoring as well as evaluation times, or a combination of these factors. Combined administration of alfaxalone (2.5 mg/kg), butorphanol (0.25 mg/kg), and medetomidine (0.025 mg/kg) IM to dogs in another study25 resulted in sedation for a mean ± SD duration of 100 ± 48 minutes. Although this duration was closer to the results for dogs that received AB-dex in the present study, the doses were not comparable. Previous studies6,7 have been performed to evaluate administration of alfaxalone IV for anesthetic induction or total intravenous anesthesia in dogs after premedication with acepromazine IM, but recovery properties were not described in those reports.
We observed undesirable recovery characteristics in 4 of 6 dogs after AB-mid administration. Undesirable recovery characteristics similar to those observed in these dogs of the present study (paddling, vocalization, hypersalivation, pacing, ataxia, agitation, and nystagmus) have been found in other investigations in which alfaxalone was administered to dogs alone9,32,33 or in combination with other sedative and analgesic drugs.25,27 Other responses observed in those studies9,25,27,32,33 included opisthotonos, tremors, myoclonus, auditory hyperesthesia, and vision disturbances. We considered it possible that the added degree of sedation from midazolam in affected dogs of the present study was not sufficient to eliminate the poor recovery characteristics often seen with alfaxalone administration. It was also possible that midazolam had an excitatory effect in some dogs, as benzodiazepines have been associated with unpredictable and variable sedation and can cause excitation instead of sedation in healthy dogs.34 Another possibility was that the duration of action of midazolam after IM administration was similar to that of alfaxalone and did not provide enough sedation to prevent the poor recovery characteristics we observed. The terminal half-life of midazolam was previously determined to be 27 ± 12 minutes,35 and that of alfaxalone was previously determined to be 29 ± 8 minutes32 after IM administration to dogs.
Recoveries of dogs after AB-ace or AB-dex administration were smooth. Given that the duration of sedation for dogs that received AB-dex exceeded the duration expected from alfaxalone32,33 or dexmedetomidine alone36 and, as previously mentioned, most dogs required administration of a reversal agent 180 minutes after the AB-dex treatment was administered, it was possible that the effects of one or more of these drugs were influenced by their concurrent administration. The profound effect on CO and local vasoconstriction (reflected by changes in SVR) after AB-dex administration could have affected absorption, distribution, and elimination of the drug combination.37,38 Bradycardia (heart rate < 50 beats/min) was also detected in dogs that received this treatment. Results of other studies25,26 that involved IM administration of alfaxalone with medetomidine and butorphanol revealed similar cardiovascular effects. Cardiac output as measured by echocardiography in dogs of the study by Lee et al26 was decreased from the time 0 value by 57% at 20 minutes and had a 67% maximum decrease at 40 minutes, whereas a maximum 42% reduction was found 20 minutes after AB-dex administration in the present study. The decrease in CO for affected dogs of the present study was likely the result of bradycardia, as stroke volume was not significantly different from the time 0 value at any subsequent time point. Despite the decrease in CO, the highest blood lactate concentration in any dog was 1 mmol/L, indicating that Do2 met global tissue requirements. Given that CO and circulating lactate concentration were not measured > 30 minutes after drug administration, it was unknown whether these changes remained present or other changes occurred at subsequent time points. Cardiovascular variables of dogs after injection with AB-ace or AB-mid were stable and within acceptable clinical ranges during the data collection period. Results of a previous study32 indicated that IM administration of alfaxalone does not cause a significant decrease in CO in healthy dogs, further supporting that the decrease in CO observed in dogs that received AB-dex in our study was attributable to the effects of dexmedetomidine or combined drug administration.
The mean Cao2 was lower than the time 0 value from 5 to 30 minutes after administration of AB-ace and AB-mid treatments and was lower after administration of either treatment than after AB-dex treatment between the 10- and 30-minute time points. For the latter 2 treatments, major components for the calculation of Cao2 (Hct and total hemoglobin concentration) had similar changes relative to time 0 measurements and similar differences relative to results after AB-dex administration at these time points. A dose-dependent decrease in Hct after acepromazine administration in dogs has been previously reported.39 Alfaxalone has also been found to decrease Hct in dogs,40 and this could have accounted for the decreases observed in the AB-ace and AB-mid experiments. In contrast, Hct was unchanged over time after AB-dex administration in the present study. The postsynaptic adrenergic receptors in the splenic vasculature are mostly α1-adrenergic receptors41; thus, the evidence of vasoconstriction observed after AB-dex administration could have contributed to splenic contraction as well as RBC recruitment from the peripheral vasculature and offset the effects of alfaxalone on Hct. The Do2 was decreased, compared with the time 0 value, after AB-dex but not after AB-ace administration and at only 1 time point after AB-mid administration (30 minutes after injection). The decrease in CO after AB-dex administration likely had a greater influence on Do2 than the decrease in Cao2 following AB-ace and AB-mid administration.
The median respiratory rate was significantly lower than the time 0 measurement 30 minutes after AB-ace administration, and differences were detected among groups at various time points. However, the overall range was variable, and this was not considered to be clinically important. Five minutes after injection, the respiratory rate was higher for dogs that received AB-mid than for those that received AB-ace or AB-dex, and at 10 minutes, the respiratory rate was lower for dogs that received AB-ace than for those that received the other treatments. This had no major effects on oxygenation or alveolar ventilation on the basis of results for arterial blood gas analysis at the same time points. Despite a significant increase in Paco2 from the time 0 value in all experiments, both Pao2 and Paco2 remained within clinically acceptable limits. This was consistent with the results of other studies25–27 that included alfaxalone in combination with other sedatives and opioids in dogs. Results of another study42 also revealed minimal respiratory changes in dogs that received alfaxalone as a sole agent at 2 mg/kg, IV; tidal volume, Pao2, and Paco2 remained within acceptable limits.
One limitation of the present study was the relatively small sample size. We attempted to maximize the information gathered by implementing a randomized crossover study design, but inclusion of only 6 dogs might not have resulted in sufficient power to detect some subtle differences in cardiorespiratory variables among treatments. In addition, the only external stimulus used to evaluate sedation was a concierge bell, so the use of these drug combinations for clinical procedures that involve other types of stimuli should include close monitoring and appropriate caution. Also, the study sample comprised young, healthy dogs that were accustomed to handling and considered to have even temperaments. This could have limited the clinical applicability of the results, considering the wide range of temperaments and health statuses of dogs that require sedation.
Taken together, the results of the present study suggested that AB-ace, AB-dex, or AB-mid at the described doses resulted in reliable sedation ≤ 5 minutes after IM administration, and this effect was observed for ≥ 1 hour in most dogs. However, the findings also indicated that in young, healthy dogs, the AB-mid protocol used in this study can result in undesirable recovery characteristics and that the described AB-dex protocol resulted in significant changes indicating cardiovascular depression and should be used with caution.
Acknowledgments
Funding was provided by the College of Veterinary Medicine, The Ohio State University. Alfaxalone was donated by Jurox Animal Health, Rutherford, NSW, Australia.
The authors declare that there were no conflicts of interest.
Presented in abstract form at the 13th World Congress of Veterinary Anesthesia, Venice, Italy, September 2018.
The authors thank Stephen Werre, Virginia-Maryland College of Veterinary Medicine, for assistance with statistical analysis.
ABBREVIATIONS
AB-ace | Alfaxalone-butorphanol-acepromazine |
AB-dex | Alfaxalone-butorphanol-dexmedetomidine |
AB-mid | Alfaxalone-butorphanol-midazolam |
Cao2 | Arterial oxygen content |
CO | Cardiac output |
DAP | Diastolic arterial blood pressure |
Do2 | Oxygen delivery |
GABA | γ-Aminobutyric acid |
LGEE | Linear generalized estimating equations |
MAP | Mean arterial blood pressure |
Pao2 | Alveolar partial pressure of oxygen |
SAP | Systolic arterial blood pressure |
SVR | Systemic vascular resistance |
Footnotes
Randomization plan generator. Available at: www.randomization.com. Accessed Mar 30, 2018.
Alfaxan, Jurox Animal Health, Rutherford, Australia.
Torbugesic, Zoetis, Parsippany, NJ.
VetOne, MWI Animal Health, Boise, Idaho.
Midazolam hydrochloride, AKORN Pharmaceuticals, Lakefront, Ill.
Dexdomitor, Zoetis, Parsippany, NJ.
Passport 12, Mindray, Mahwah, NJ.
Sevoflurane, AKORN Pharmaceuticals, Lakefront, Ill.
A5, Mindray, Mahwah, NJ.
Abbott Laboratories, North Chicago, Ill.
Utah Medical Products, Midvale, Utah.
LiDCO plus, LiDCO, London, England.
Stat profile, pHOx Ultra, Nova Biomedical, Waltham, Mass.
B Braun Medical Inc, Bethlehem, Pa.
Antisedan, Zoetis, Parsippany, NJ.
Novaplus, West-Ward Pharmaceutical Corp, Eatontown, NJ.
Naloxone hydrochloride, Novaplus, Hospira, Lake Forest, Ill.
SAS, version 9.4, Cary, NC.
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