Research in Veterinary Science 143 (2022) 4–12

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Research in Veterinary Science

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Intraoperative effect of low doses of ketamine or dexmedetomidine

continuous rate infusions in healthy dogs receiving propofol total
intravenous anaesthesia and epidural anaesthesia: A prospective,
randomised clinical study
Rocío Bustamante a, Susana Canfrán b, *, Ignacio A. Gómez de Segura b, Delia Aguado b
a
Anaesthesiology Service, Vetsia Veterinary Hospital, Calle Galileo 3, 28914, Leganés, Madrid, Spain
b
Anaesthesiology Service, Department of Animal Medicine and Surgery, Veterinary Teaching Hospital, Veterinary Faculty, Complutense University of Madrid, Avda.
Puerta de Hierro s/n, 28040 Madrid, Spain

A R T I C L E I N F O A B S T R A C T

Keywords: The present study aimed to determine the effect of either ketamine or dexmedetomidine constant rate infusion
Canine anaesthesia (CRI) on intraoperative propofol anaesthetic requirements during total intravenous anaesthesia (TIVA) in healthy
Constant rate infusion dogs undergoing hindlimbs orthopaedic procedures receiving epidural anaesthesia. In this randomised, blinded
Dexmedetomidine
clinical study, thirty-nine healthy client-owned dogs were premedicated intramuscularly (dexmedetomidine 4
Dog
Propofol
μg/kg and methadone 0.3 mg/kg). General anaesthesia was induced to effect with propofol administered as
TIVA intravenous bolus, and maintained with propofol TIVA (18 mg/kg/h), adjusted to meet the suitable clinical
anaesthetic depth (indicatively±20%) based on clinical judgement. Lumbosacral epidural anaesthesia was per­
formed using bupivacaine (1 mg/kg) and morphine preservative free (0.1 mg/kg). Dogs randomly received either
saline (SP; loading dose 1 mL/kg, CRI 1 mL/kg/h), or ketamine (KP; loading dose 1.5 mg/kg, CRI 1.5 mg/kg/h),
or dexmedetomidine (DP; loading dose 1 μg/kg/, CRI 1 μg/kg/h). Physiological variables were recorded intra­
operatively at 5-min intervals using standard-of-care monitoring. Recovery quality and duration were recorded.
Treatment groups were compared with parametric and non-parametric tests as appropriate, p < 0.05.
Propofol rates and recovery scores were similar between groups. Overall mean and diastolic blood pressures
were higher in group DP compared to group KP (12–14 mmHg, p = 0.016 and p = 0.015, respectively). More
dogs required mechanical ventilation in group KP (12 dogs) than in either group SP or DP (7 dogs per group, p =
0.037).
Ketamine or dexmedetomidine CRIs, at the studied rates, did not reduce propofol TIVA requirements in dogs
undergoing orthopaedic surgery with epidural anaesthesia.

1. Introduction
Total intravenous anaesthesia (TIVA) is considered the induction and
maintenance of anaesthesia achieved solely by intravenous (IV) drugs
(Morgan and Legge, 1989). This technique offers good haemodynamic
stability, smooth recovery and avoids exposure to inhalant anaesthetics
(Andreoni and Lynne Hughes, 2009). Propofol has favourable pharma­
cokinetic characteristics for use in TIVA, such as rapid onset, short
duration of action, and non-cumulative effects (Nolan and Reid, 1993).
However, relatively high propofol infusion rates are required to main­
tain anaesthesia when is used alone and it is associated with profound
respiratory depression (Aguiar et al., 2001). In order to reduce propofol
associated dose-dependent adverse effects and for provision of analgesia
in patients undergoing surgical procedures, the use of a balanced
anaesthesia technique during propofol TIVA is advisable. This technique
by combining different agents (anaesthetic, analgesics and/or sedatives)
and techniques (locoregional or neuraxial) allows the reduction of each
drug dose and its associated dose-dependent adverse effects providing

* Corresponding author at: Anaesthesiology Service, Department of Animal Medicine and Surgery, Veterinary Teaching Hospital, Veterinary Faculty, Complutense
University of Madrid, Avda. Puerta de Hierro s/n, 28040 Madrid, Spain.
E-mail addresses: robustam@ucm.es (R. Bustamante), scanfran@vet.ucm.es (S. Canfrán), ialvarez@ucm.es (I.A. Gómez de Segura), deliaaguado@vet.ucm.es
(D. Aguado).

https://doi.org/10.1016/j.rvsc.2021.12.017
Received 16 March 2021; Received in revised form 2 December 2021; Accepted 16 December 2021
Available online 18 December 2021
0034-5288/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
R. Bustamante et al.
also analgesia (Ilkiw, 1999).
A strategy for balanced anaesthesia involves the use of locoregional
and neuraxial analgesic techniques. Lumbosacral epidural anaesthesia
blocks nerve impulses coming from the caudal portion of the body
providing analgesia including the pelvic limbs during procedures such as
orthopaedic surgery (Jones, 2001). Additionally, this technique has
been shown to reduce anaesthetic requirements and improve muscle
relaxation in dogs (Kona-Boun et al., 2006). Locoregional or neuraxial
techniques may reduce propofol requirements, further decreasing pro­
pofol induced dose-dependent adverse effects (Boscan et al., 2005;
Tusell et al., 2005) while offering an additional analgesic modality.
The effects of a ketamine constant rate infusion (CRI) during pro­
pofol TIVA (Kennedy and Smith, 2015; Reed et al., 2015; Seliskar et al.,
2007) have been studied in dogs at dose rates ranging 1.5–3 mg/kg/h.
These studies found to reduce anaesthetic requirements and improve
haemodynamic stability and ventilation (Kennedy and Smith, 2015;
Seliskar et al., 2007). Low CRI dose rates of dexmedetomidine in the
range of 0.5–3 μg/kg/h also reduced propofol experimental re­
quirements (Smith et al., 2017) in dogs, and it has been suggested as a
reliable and effective adjunct to anaesthesia in healthy dogs subjected to
surgical procedures (Uilenreef et al., 2008).
To the best of the authors' knowledge, no published studies have
evaluated neither the intraoperative cardiorespiratory effects nor the
propofol sparing effects of ketamine or dexmedetomidine CRIs during
TIVA in healthy dogs combined with epidural anaesthesia. The purpose
of this study was to determine the effects of ketamine or dexmedeto­
midine CRIs on intraoperative propofol anaesthetic requirements during
TIVA in healthy premedicated dogs receiving epidural anaesthesia and
undergoing orthopaedic procedures. Our hypothesis was that dexme­
detomidine or ketamine CRIs, in combination with epidural anaesthesia,
would reduce intraoperative propofol requirements compared to pro­
pofol and epidural anaesthesia while maintaining an adequate anaes­
thetic plane in premedicated dogs undergoing hindlimb orthopaedic
procedures receiving epidural anaesthesia.
2. Material and methods
This clinical, prospective, randomised, blinded study was approved
by the Institutional Ethics Committee (****, reference number 16/2017)
and all owners gave their consent prior to the enrolment of their dogs in
the study. The CONSORT (Consolidated Standards of Reporting Trials)
guidelines have been followed.
2.1. Animals
Healthy dogs with an American Society of Anesthesiologists (ASA)
classification as I-II based on pre-surgical physical examination, hae­
matology, serum biochemistry analysis and electrocardiogram, older
than 4 months scheduled for orthopaedic surgery involving the pelvic
limbs, excluding amputation were included. Dogs with a body condition
score higher than 7/9 were excluded due to the potentially increased
difficulty of the epidural administration technique. Dogs requiring
treatment for bradycardia and/or hypotension after anaesthetic induc­
tion before starting the infusion treatment administration (CRIs) were
also excluded (see below Intraoperative interventions).
Dogs were randomly allocated to receive one of three treatments
using a computer-generated randomization table (RAND function,
Microsoft Excel 16.0). Treatments were assigned and prepared by a
member of anaesthesia team whom was not involved in the present
5
Research in Veterinary Science 143 (2022) 4–12
study. The investigator who performed all the anaesthetic procedures
(***) was blinded to the treatment.
2.2. Anaesthetic protocol
All dogs were sedated with dexmedetomidine 0.004 mg/kg (Dex­
domitor; Ecuphar) and methadone 0.3 mg/kg (Semfortán; Ecuphar)
mixed in the same syringe and injected intramuscularly into the cervical
epaxial muscles. Sedation was scored 15 min after premedication using a
sedation scale (Gurney et al., 2009) (Appendix A). Subsequently, both
cephalic veins were catheterized, to administer propofol TIVA and
treatment drug separately. Venous catheterization was performed using
appropriately sized over-the-needle catheters (Surflo IV Catheter; Ter­
umo). Before anaesthetic induction, dogs were preoxygenated via face­
mask with oxygen for 5 min. Then, general anaesthesia was induced by
administering propofol (Propofol Lipuro; BBraun) IV to effect as a bolus
of 0.5 mg/kg over 30 s and evaluating its effect after 30 s, until achieving
appropriate conditions for endotracheal intubation (ventral positioning
of the eyeball, absence of palpebral reflex, relaxed jaw tone and absent
swallowing reflex). Dogs were then endotracheally intubated using an
appropriately sized cuffed endotracheal tube that was connected to a
rebreathing circle system with 50% oxygen and 50% medical air gas
flow at 1 L/min. The total dose of propofol required for induction was
recorded. After induction, propofol TIVA was started with an initial dose
rate of 18 mg/kg/h administered through the left IV catheter using a
syringe pump (Perfusor fm; BBraun). This initial dose rate was used
according to a previous clinical report in premedicated dogs (Busta­
mante et al., 2018). The syringe and infusion pumps accuracy had been
checked prior to the study according to manufacturer's recommenda­
tion. Lumbosacral epidural technique (Torske and Dyson, 2000) was
performed in anaesthetised dogs once appropriate anaesthetic plane was
achieved. Patients were placed in sternal recumbency with hindlimbs
extended cranially. The lumbosacral area was clipped and aseptically
prepared. The correct position of the spinal needle in the epidural space
(Spinal Needle, BD) was confirmed by the hanging drop technique, lack
of resistance to injection of local anaesthetic plus morphine
preservative-free (Jones, 2001). Moreover, aspiration test was per­
formed to confirm that the tip of the needle was not in a vessel neither in
the subarachnoid space. All dogs received 1 mg/kg bupivacaine (Bupi­
vacaína 0.5%; BBraun), and 0.1 mg/kg morphine (Morfina 1%,
preservative-free.; BBraun) via lumbosacral epidural administration
over 1 min. Total bupivacaine volume was set to 0.2 mL/kg, although a
maximum of 6 mL was given to dogs weighing more than 30 kg (Torske
and Dyson, 2000).
Once patients were moved to theatre, infusion drug administration
was performed according to group allocation: propofol and saline (NaCl
0.9%; BBraun) (group SP), propofol and ketamine (Anesketin; Dechra)
(group KP) or propofol and dexmedetomidine (Dexdomitor; Ecuphar)
(group DP). Loading doses were administered at 1 mL/kg over a 5-min
period: saline (SP), ketamine (KP, 1.5 mg/kg) or dexmedetomidine
(DP, 1 μg/kg). Afterwards, CRIs were administered at 1 mL/kg/h as
follows: saline (SP), ketamine at 1.5 mg/kg/h (KP) and dexmedetomi­
dine at 1 μg/kg/h (DP) using an infusion pump (Infusomat fmS; BBraun)
through an IV catheter placed in the right forelimb. Infusion treatments
were added to the saline solution, with the equivalent volume of the
solution previously removed, and administered at the indicated rate.
Anaesthetic plane was evaluated every 5 min and adjusted to maintain
an adequate surgical anaesthetic plane, based on five clinical signs
(Table 1). After any dose rate change, the propofol TIVA was kept at the
R. Bustamante et al. Research in Veterinary Science 143 (2022) 4–12

Table 1
Algorithm based on clinical signs used to adjust the propofol TIVA in 39 dogs undergoing hindlimb orthopaedic procedures. All dogs were sedated with dexmede­
tomidine and methadone IM, general anaesthesia was induced with boluses of propofol (0,5 mg/kg IV) and maintained with either propofol TIVA (18 mg/kg/h at
initial dose) combined with saline (1 mL/kg/h; group SP, n = 13 dogs), with ketamine (1.5 mg/kg/h; group KP, n = 13 dogs), or with dexmedetomidine (1 μg/kg/h;
group DP, n = 13 dogs). Lumbosacral epidural anaesthesia was performed in all dogs (1 mg/kg 0.5% bupivacaine +0.1 mg/kg morphine p.f.).
Movement or swallowing Palpebral reflex Jaw tone Autonomic nervous system changes Eyeball position Action

Yes Indifferent Indifferent Indifferent Indifferent B1 ↑

No Brisk Strong Yes, sudden increase (≥20% of previous values over 1 min) Central B0.5 ↑
No Brisk Strong No Indifferent ↑
No Slight or absent Slight or absent Yes, gradual increase (<20% of previous values) Indifferent ↑
No Slight or absent Slight or absent No Medioventrally rotated –
No Slight or absent Slight or absent No Central ↓
No Slight or absent Slight or absent Yes, decrease (≥20% of previous values) Indifferent ↓

Each evaluation was performed every 5 min. Propofol boluses of 0.5 and 1 mg/kg IV on the top of the TIVA are indicated as (B0.5) and (B1) respectively. Increase by
20% (↑), decrease by 20% (↓), or not change (− ) the propofol TIVA.

same rate for 5 min before further adjustment. All patients received
Lactated Ringer's solution (Lactated Ringer's solution; BBraun) at 4 mL/
kg/h throughout surgery. Active heating systems were used when
required (oesophageal temperature < 37 ◦ C) including a circulating
warming water blanket (Gaymar T-pump; Invatech) and a warm air
blanket (Bair Hugger Model 505; 3 M Health Care).
Before administering the bolus loading dose (T0), 5 min afterwards
and before infusion starting (T1) and every 5 min later during the
anaesthetic procedure, the following physiologic parameters were
recorded using a multi-parametric monitor (B40 Patient Monitor; GE
Healthcare): heart rate (HR) in beats/min from electrocardiogram lead
II; respiratory rate (fR, in breaths/min) and end-tidal carbon dioxide
(PE'CO2, mmHg, kPa) using a sidestream capnograph; oscillometric non-
invasive systolic (SAP), diastolic (DAP) and mean (MAP) arterial blood
pressures (mmHg) with a cuff with width approximately 40% of limb
circumference, placed over the dorsal pedal artery; haemoglobin oxygen
saturation (SpO2, %), by pulse oximetry placing the probe on the tongue,
and oesophageal temperature (T, ◦ C). The propofol infusion rate was
also verified and recorded every 5 min. The number of dogs that
required additional boluses of propofol or presented myoclonus during
surgery were recorded.
infusion) were calculated.
2.4. Recovery
Once the surgical procedure had finished, all infusions were dis­
continued (end of anaesthesia) and dogs were allowed to recover un­
disturbed. Mechanical ventilation, if used, was discontinued providing
manually at least two breaths/min until spontaneous ventilation was
resumed. Supplementation of 100% oxygen was provided until the
endotracheal tube was removed. Dogs were extubated when they
regained the swallowing reflex. Time from end of anaesthesia to extu­
bation (TEX) and time from end of anaesthesia to sternal recumbency
(considered when dogs were able to support themselves on their flexed
elbows; TST) were both recorded. Quality of anaesthetic recovery was
determined by the same anaesthetist unaware of the treatment group
who monitored intraoperative anaesthesia, following extubation, using
a modified standardized scale (Sams et al., 2008), and classified as
acceptable or unacceptable (Appendix B). When recovery occurred with
vocalization and agitation, an IV dose of dexmedetomidine (1 μg/kg)
was administered. When dexmedetomidine was administered, the TST
value from that particular dog was excluded from the statistical analysis.

2.3. Intraoperative interventions 2.5. Statistical analysis

Mechanical ventilation was initiated if dogs presented hypo­
ventilation [PE'CO2 exceeding 55 mmHg (7.3 kPa)] or apnoea (defined
as a lack of respiratory movement for at least 30 s), with a tidal volume
10–15 mL/kg adjusting fR to normalize PE'CO2 (35–45 mmHg or 4.6–5.9
kPa) (Anaesthesia Workstation; Datex-Ohmeda 9100c; GE Healthcare).
Hypotension was defined as a MAP below 60 mmHg for more than 5
min, and treated as required in the following order: decreasing the
propofol infusion rate by 20%, administering atropine 0.02 mg/kg IV
(Atropina; Braun VetCare) if there was concurrent bradycardia (<60
beats/min), or administering a dopamine CRI to effect (5–10 μg/kg/min
IV; Dopamina; Grifols) otherwise. Bradycardia ranging 40–59 beats/min
due to loading dose of CRIs and/or without concurrent hypotension, it
was not treated. The number of dogs that required any intervention due
to hypoventilation, apnoea, hypotension or bradycardia, as previously
indicated, was recorded. All dogs that required intraoperative rescue
analgesia (fentanyl 0.002 mg/kg IV) were excluded from the study due
to epidural failure. Surgery duration (from the first skin incision to the
end of the surgical wound closure), anaesthesia duration (from start to
discontinuation of propofol TIVA), duration of infusion (Tinfusion), and
time from premedication to loading CRI bolus administration (Tpremed to
A prospective sample size calculation indicated that 13 dogs per
group would be required to confirm a reduction in the propofol infusion
rate (alpha error of 0.05; beta error of 0.20) of 5.4 mg/kg/h (effect size
= 30%) with a standard deviation (SD) of 4.8 mg/kg/h (pilot experi­
ences). A randomised block design was used to reassess sample size
during the study, considering three randomization blocks (15, 12 and 12
dogs per group in each block; Fig. 1).
Normality of data was assessed using the Shapiro-Wilk test. For
physiological variables, overall mean values were calculated as the
mean of all data from T1 to the end of the surgery and compared be­
tween groups. Parametric variables were compared with the analysis of
variance (ANOVA) test and the Bonferroni post hoc test, while non-
parametric data were analysed with the Kruskal-Wallis test. When this
test revealed statistical differences, the Mann-Whitney test was used for
group comparisons. Categorical data were analysed with the Chi-
squared or Fisher's exact tests. For paired measurements, the paired t-
test was used to compare physiological variables from T0 to T1 within
each group. A value of p < 0.05 was considered statistically significant.
The SPSS program was used (IBM SPSS Statistics vs.25). Data are
expressed as mean ± SD or median (minimum-maximum) as

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R. Bustamante et al. Research in Veterinary Science 143 (2022) 4–12

Fig. 1. Flow Diagram of the dogs undergoing hindlimb orthopaedic procedures and anaesthetised with eitherpropofol alone (group SP), propofol combined with
ketamine (group KP), or propofol combined withdexmedetomidine (group DP), and epidural anaesthesia. A sample size calculation was performed indicating 39 dogs
were initially necessary and a block design was used. Excluded dogs were replaced and allocated.

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R. Bustamante et al. Research in Veterinary Science 143 (2022) 4–12

Table 2
Demographic data of 39 dogs undergoing hindlimb orthopaedic procedures. All dogs were sedated with dexmedetomidine and methadone IM, general anaesthesia was
induced with boluses of propofol (0,5 mg/kg IV) and maintained with either propofol TIVA (18 mg/kg/h at initial dose) combined with saline (1 mL/kg/h; group SP, n
= 13 dogs), with ketamine (1.5 mg/kg/h; group KP, n = 13 dogs), or with dexmedetomidine (1 μg/kg/h; group DP, n = 13 dogs). Lumbosacral epidural anaesthesia was
performed in all dogs (1 mg/kg 0.5% bupivacaine +0.1 mg/kg morphine p.f.). Weight, age, sex, sedation score 15 min after premedication, propofol induction dose,
anaesthesia and surgery durations, infusion duration (TC) and time from premedication to loading dose of saline, dexmedetomidine or ketamine (TP) in minutes.
Results are expressed as mean ± standard deviation, median (minimum-maximum) or number of dogs as appropriate. There was no significant difference, for the
values assessed, among the groups (p < 0.05).
Group Age Weight Sex Sedation Propofol induction dose Surgery duration Anaesthesia duration Tpremed to infusion Tinfusion
(months) (kg) (M/F) score (mg/kg) (minutes) (minutes) (minutes) (minutes)

SP 59 ± 38 20.3 ± 9.0 5/8 9 (6–15) 1.5 (0.5–2.5) 93 ± 35 191 ± 54 99 ± 28 86 (36–864)

KP 59 ± 47 25.5 ± 14.6 6/7 10 (7–14) 1.5 (1.0–3.0) 100 ± 38 211 ± 41 93 ± 13 113 (34–799)
DP 62 ± 44 20.1 ± 9.2 6/7 8 (5–14) 1.5 (1.0–2.5) 122 ± 44 229 ± 61 100 ± 16 109 (20–815)

appropriate.
3. Results
Fifty-two dogs were included in the study and finally 39 (13 dogs in
each group) completed the study between February 2018 and June
2019. Thirteen dogs were excluded due to inability to perform the
epidural drug administration, IV catheter dislodgement, presence of
bradycardia and concurrent hypotension before treatment drug
administration, or cardiopulmonary arrest due to thromboembolism
(confirmed at necropsy) (Fig. 1). There were no statistical differences in
age, weight, sex, sedation level 15 min after premedication, propofol
induction dose, Tpremed to infusion, Tinfusion, and anaesthesia or surgery
durations between treatment groups (Table 2). The surgical procedures
performed are listed in Table 3.
Overall, T0 and T1 propofol infusion rates were similar between
groups (14.3 ± 3.5 mg/kg/h in group SP, 14.0 ± 5.0 mg/kg/h in group
KP and 14.1 ± 4.3 mg/kg/h in group DP overall, Table 4). There were no
statistical differences from T1 to T0 within groups (Table 4). Results
obtained for physiological variables are presented in Table 4. Physio­
logical variables at T0 were similar between groups. At T1, the MAP and
DAP were significantly higher in group DP when compared to groups SP
(14%, p = 0.009 and 22%, p = 0.015, respectively) and KP (17%, p =
0.001 and 26%, p = 0.004, respectively). In group DP heart rate
decreased (24%; p = 0.0003) and blood pressures increased [SAP (17%;
p = 0.030), MAP (14%; p = 0.001), DAP (17%; p = 0.004)] from T0 to
T1, while only SAP increased (3%; p = 0.037) in group KP from T0 to T1.
Oesophageal temperature decreased in all groups from T0 to T1 (<1%; p
= 0.006, p = 0.011 and p = 0.007; groups SP, KP and DP, respectively).
The incidence of hypoventilation after the loading dose of the treatment
drug (T1) was higher in group KP (6 dogs) than in groups SP and DP (1
dog each) (p = 0.025 and p = 0.015, respectively). During the procedure,
overall mean MAP and overall mean DAP were higher in group DP than
in group KP (15%, p = 0.016 and 20%, p = 0.015, respectively) but not
group SP. Overall mean HR, fR, SAP, SpO2, PE'CO2 and T were not
different between groups.
Two dogs required dopamine administration in groups SP and KP
(one each) (5%) and the same dog from group KP also required atropine
administration during surgery, without statistical differences. Use of
mechanical ventilation was needed in 26 of 39 dogs (66%). Need for
mechanical ventilation was higher in group KP than in groups SP and DP
(p = 0.037, both; 7, 12 and 7 dogs in groups; SP, KP and DP, respec­
tively). None of the dogs required additional propofol boluses. There
were no statistical differences in the incidence of intraoperative forelimb
myoclonus between groups (2, 4 and 2 dogs; groups SP, KP and DP,
respectively). Rescue analgesia with fentanyl was not required in any
dog of the present study.
Results for recovery quality, TEX and TST, are shown in Table 5. Re­
covery quality and incidence of adverse events were not statistically
different between groups. Time to extubation was shorter in group KP
than in group DP (p = 0.031) but not group SP (p = 0.423) nor between
groups SP and DP (p = 0.718). Time to sternal recumbency was similar
between groups.
4. Discussion
Results of the present study showed that the administration of either
ketamine or dexmedetomidine CRIs, at the studied dose rates, combined
with epidural anaesthesia did not decrease propofol TIVA requirements
in premedicated dogs nor was associated with improvements in
commonly intraoperative monitored physiological variables, to healthy
dogs undergoing orthopaedic surgery receiving epidural anaesthesia.
Epidural anaesthesia has anaesthetic sparing effects in dogs with
relevant dose reduction in the propofol infusion rate (24 to 9 mg/kg/h)
during ovariohysterectomy (Tusell et al., 2005). The relatively low
propofol requirements used in the present study (14 mg/kg/h, starting
from 18 mg/kg/h) are probably due to the use of epidural anaesthesia.
Under these conditions, the co-administration of ketamine or dexme­
detomidine CRIs did not provide a further reduction on the propofol
infusion rate. Since the effects of ketamine or dexmedetomidine
administered alone (without concurrent epidural anaesthesia) on pro­
pofol requirements were not investigated in the present study, the po­
tential additive or synergistic effects of epidural anaesthesia and
ketamine or dexmedetomidine infusions on propofol anaesthetic re­
quirements cannot be ascertained. Moreover, use of epidural anaes­
thesia may have prevented haemodynamic responses to noxious
stimulation. This resulted in reduced interventions during anaesthetic
maintenance, unlike compared to previous reports of propofol TIVA in
dogs undergoing surgical procedures without epidural analgesia (Mur­
rell et al., 2005; Suarez et al., 2012).
The dose rates of ketamine and dexmedetomidine used in the present
study have been reported to reduce propofol requirements (experi­
mental, using a noxious electrical stimulus) by 30% during anaesthetic
maintenance in unpremedicated dogs (Reed et al., 2015; Smith et al.,
2017). In the present clinical study, factors such as sedatives used,
epidural anaesthesia, type of procedure and criteria used to determine
the propofol requirements have contributed to lack of significant
reduction on propofol requirements when these dose rates of

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R. Bustamante et al. Research in Veterinary Science 143 (2022) 4–12

Table 3 alpha-2 agonists (Sinclair, 2003). The reported haemodynamic effects of

Distribution of surgical orthopaedic procedures performed to 39 dogs under­ ketamine via sympathetic nervous system stimulation (Tweed et al.,
going hindlimb orthopaedic procedures. All dogs were sedated with dexmede­ 1972) were not observed in the present study. Dexmedetomidine used as
tomidine and methadone IM, general anaesthesia was induced with boluses of a premedication in the present study may have reduced sympathetic
propofol (0,5 mg/kg IV) and maintained with either propofol TIVA (18 mg/kg/h outflow and mask the effects of the ketamine infusion (Jacobson et al.,
at initial dose) combined with saline (1 mL/kg/h; group SP, n = 13 dogs), with
1994; Sinclair, 2003). Unlike previous studies, ketamine did not reduce,
ketamine (1.5 mg/kg/h; group KP, n = 13 dogs), or with dexmedetomidine (1
when compared to the control group, the propofol infusion rate required
μg/kg/h; group DP, n = 13 dogs). Lumbosacral epidural anaesthesia was per­
formed in all dogs (1 mg/kg 0.5% bupivacaine +0.1 mg/kg morphine p.f.). to achieve a surgical anaesthetic plan. A further reduction in propofol
Results are expressed as number of dogs. infusion rate could have blunted the expected dose-dependent ketamine
cardiovascular effects (Kennedy and Smith, 2015; Reed et al., 2015;
Type of surgery Group Group Group
SP KP DP
Seliskar et al., 2007).
Two dogs anaesthetised with propofol-saline and propofol-ketamine
Knee arthrotomy 0 0 1
became hypotensive and required dopamine administration in the pre­
Extracapsular stabilization for cranial cruciate 1 1 0
ligament failure (CCLF) sent study, compared to no dogs in dexmedetomidine group. Dexme­
Fracture repair 0 2 3 detomidine cardiovascular effects could explain no dog anaesthetised
Hip arthroplasty 3 3 5 with propofol-dexmedetomidine became hypotensive. Decreased blood
Removal of osteosynthesis material 1 0 0
pressure may be observed when propofol is infused in dogs (Pagel et al.,
Tharsal artrodesis 0 0 2
Tibial Tuberosity Advancement (TTA) 5 7 2
1992; Vainio, 1991) although the reported incidence of hypotension is
Trochleoplasty 2 0 0 low (Keegan and Greene, 1993). The epidural anaesthesia performed in
TTA + Trochleoplasty 1 0 0 the present study could have accounted for hypotension in these two
dogs, due to sympathetic output blockade (Jones, 2001). However, the
incidence of hypotension and therefore need for additional interventions
dexmedetomidine or ketamine CRIs were administered. When propofol
during anaesthesia may be considered as lower in the present study (5%,
was the only drug to be administered as a CRI in previous studies using
or 10% considering excluded dogs) compared to a previous study where
ketamine or dexmedetomidine CRIs, the dose rates ranged from 40 to 46
30% of dogs required treatment for hypotension (Sarotti et al., 2016).
mg/kg/h (Reed et al., 2015; Smith et al., 2017), which is higher than
Due to the appearance of bradycardia after initiation of dopamine
that used in the present study. Moreover, the mean propofol infusion
infusion in one of these dogs, atropine was also administered. Dopamine
rate of 14 mg/kg/h used in the present study is lower than those re­
induced-bradycardia has been previously reported in dogs (Tsompani­
ported (20–25 mg/kg/h) for surgical procedures in premedicated dogs
dou et al., 2013).
(Murrell et al., 2005; Suarez et al., 2012). The administration of potent
Propofol dose-dependently impairs ventilatory response to hypoxia
sedatives (dexmedetomidine) and opioids (methadone) in the current
and hypercapnia producing hypoventilation (Blouin et al., 1993;
study, compared with the administration of atropine and methadone
Goodman et al., 1987). Ketamine also decreases response to CO2
(Murrell et al., 2005) or a low dose of acepromazine (0.01 mg/kg) and
(Hirshman et al., 1975) and both drugs may have additive depressant
morphine (Suarez et al., 2012) might explain the lower mean propofol
effects. These respiratory depressant effects have also been reported
infusion rate used in the current study. Similarly, reduced propofol re­
with a combination of propofol and ketamine despite relevant re­
quirements of up to 9–18 mg/kg/h were obtained by the concurrent
ductions in the propofol infusion rate (Seliskar et al., 2007). The inci­
administration of higher acepromazine doses (0.05 mg/kg) or alpha-2
dence of hypoventilation and mechanical ventilation requirement was
agonists (Hughes and Nolan, 1999; Vainio, 1991). On the other hand, a
significant higher in dogs anaesthetised with propofol and ketamine (all
similar propofol infusion rate (15 mg/kg/h) has been used also for or­
but one) compared to those anaesthetised with propofol and dexmede­
thopaedic procedures with a protocol involving premedication and
tomidine, as reported by previous authors (Kennedy and Smith, 2015;
epidural anaesthesia (Bustamante et al., 2018), similar to the one used in
Pascoe, 2015; Reed et al., 2015). This increased respiratory depressant
the current study.
effect of ketamine strongly suggests the provision of mechanical
In the present study, the dexmedetomidine loading bolus decreased
ventilation.
HR and increased blood pressures, which is in accordance with previous
Myoclonus is a common adverse effect of propofol TIVA (Cattai et al.,
studies (Ebner et al., 2013; Pascoe et al., 2006). However, differences in
2015; Robertson et al., 1992) and we found an overall incidence of
overall MAP and DAP were statistically significant, although not clini­
forelimb myoclonus (20%). However, these episodes resolved sponta­
cally relevant, only between dexmedetomidine and ketamine groups
neously without intervention. The slight, clinically non relevant, oeso­
and this difference is likely due to individual differences. The effect of
phageal temperature decrease can be attributed to depression of the
dexmedetomidine CRI might be beneficial considering MAP and DAP
central nervous system, reduction in muscular activity and blood
were above those observed when this drug was not administered (some
redistribution during general anaesthesia (Brodeur et al., 2017).
12 mmHg above). However, this point may be interpreted with caution
Recovery quality was considered acceptable in most of the dogs,
since dogs anaesthetised with propofol already maintained clinically
similar to previous studies evaluating propofol CRIs (Caines et al., 2014;
acceptable blood pressure values, as previously reported (Bustamante
Suarez et al., 2012). Moreover, the epidural anaesthesia used in the
et al., 2018). In regard of the intraoperative dexmedetomidine CRI, the
present study may have promoted an adequate analgesic plan, thus
short-lived changes recorded in HR and limited increase in blood pres­
favouring the smooth recovery registered. Time to extubation was
sure are likely due to the low dose rates administered, as reported by
shorter when ketamine was co-administered compared to dexmedeto­
other authors (Kaartinen et al., 2010; Pascoe, 2015). The consistent
midine CRI although times to sternal recumbency were similar with both
increase of blood pressure in dogs administered dexmedetomidine CRI
drugs, and there were no differences compared to propofol and saline. In
should be a consequence of the vasoconstriction typically produced by
a previous study using a similar propofol infusion rate (15 mg/kg/h)

9
R. Bustamante et al. Research in Veterinary Science 143 (2022) 4–12

Table 4
Propofol infusion rate and physiologic variables monitored in 39 dogs undergoing hindlimb orthopaedic procedures. All dogs were sedated with dexmedetomidine and
methadone IM, general anaesthesia was induced with boluses of propofol (0,5 mg/kg IV) and maintained with either propofol TIVA (18 mg/kg/h at initial dose)
combined with saline (1 mL/kg/h; group SP, n = 13 dogs), with ketamine (1.5 mg/kg/h; group KP, n = 13 dogs), or with dexmedetomidine (1 μg/kg/h; group DP, n =
13 dogs). Lumbosacral epidural anaesthesia was performed in all dogs (1 mg/kg 0.5% bupivacaine +0.1 mg/kg morphine p.f.). Physiological variables were recorded
at different anaesthetic times (T0) before loading dose of saline (1 mL/kg), ketamine (1.5 mg/kg), dexmedetomidine (1 μg/kg); (T1) values after end of loading
administration of infusion, and (OVERALL) value recorded every 5 min between T1 and the end of the surgery. On the table heart rate (HR), respiratory rate (fR), non-
invasive systolic (SAP), mean (MAP) and diastolic (DAP) blood pressures, haemoglobin oxygen saturation (SpO2), end-tidal carbon dioxide concentration (PE'CO2) and
oesophageal temperature (T). Results expressed as mean ± standard deviation or median (minimum-maximum) as appropriate.
Group Variable

HR (beats/ fR (breaths/ SAP MAP DAP SpO2 PE'CO2 (mmHg; kPa in T (◦ C) Propofol infusion rate
min) min) (mmHg) (mmHg) (mmHg) (%) brackets) (mg/kg/h)

Group T0 55 ± 17 10 [4–25] 110 ± 7 76 ± 7 57 ± 9 99 ± 1 44 ± 5 (5.8 ± 0.6) 37.3 ± 14.3 ± 3.1

SP 0.6
T1 53 ± 17 9 [5–26] 109 ± 6 75 ± 6 55 ± 7 99 ± 1 45 ± 6 (5.9 ± 0.7) 37.2 ± 14.3 ± 3.1
0.6‡
OVERALL 58 ± 19 9 [3− 30] 112 ± 10 77 ± 10 57 ± 9 98 ± 1 44 ± 4 (5.8 ± 0.5) 37.3 ± 14.3 ± 3.5
0.5
Group T0 60 ± 12 10 [4–19] 107 ± 9 71 ± 6 51 ± 5 98 ± 1 45 ± 4 (5.9 ± 0.5) 37.4 ± 15.2 ± 4.1
KP 0.9
T1 60 ± 20 10 [4–14] 111 ± 13 ‡
73 ± 7 †
53 ± 9 †
98 ± 1 45 ± 5 (5.9 ± 0.6) 37.3 ± 14.7 ± 4.1
0.8‡
OVERALL 60 ± 19 10 [7–15] 109 ± 10 73 ± 7 53 ± 7 98 ± 1 40 ± 3 (5.3 ± 0.3) 37.2 ± 14.0 ± 5.0
0.6
Group T0 58 ± 18 9 [7–16] 110 ± 10 75 ± 8 57 ± 8 98 ± 1 42 ± 4 (5.5 ± 0.5) 36.9 ± 16.0 ± 3.9
DP 0.7
T1 44 ± 14 ‡
10 [4–15] 117 ± 10 ‡
86 ± 10* ‡
67 ± 12* ‡
98 ± 1 41 ± 4 (5.4 ± 0.5) 36.8 ± 15.0 ± 4.2
0.8‡
OVERALL 55 ± 14 8 [6–14] 117 ± 9 84 ± 9 †
64 ± 9 †
98 ± 1 43 ± 4 (5.7 ± 0.5) 37.2 ± 14.1 ± 4.3
0.6

*Significant differences from group SP. †Significant differences between groups KP and DP. ‡Significant differences between T1 and T0, same group. P < 0.05.

(Ambros et al., 2008), dogs premedicated with acepromazine needed
more time for extubation (18 ± 7 min) and sternal recumbency (52 ± 22
min) than those in the present study. Premedication used in the study of
Ambros et al. (2008) may account for the observed differences given the
longer acting sedative effect of acepromazine (Hunt et al., 2013).
There are several limitations to the study. Use of premedication as
well as epidural analgesia in the present study may be confounding
factors when evaluating the effect of ketamine and dexmedetomidine
CRIs on propofol requirements. Thus, the contribution of both tech­
niques separately to propofol requirements in different circumstances to
that of the present study cannot be determined. However, the objective
of the present study was to evaluate this effect in a clinical scenario,
where a balanced anaesthesia technique is usually performed, such as
epidural anaesthesia for orthopaedic procedures. Ideally, invasive blood
pressure monitoring should have been used, although it is not a tech­
nique routinely performed in healthy patients. Oscillometric measure­
ments have shown good agreement with direct blood pressure
monitoring in anaesthetized, normotensive dogs (Garofalo et al., 2012).
Considering the expected cardiorespiratory effects of dexmedetomidine
and ketamine boluses, ideally a separate observer to monitor these
adverse effects may have been advisable. However, this was considered
unnecessary as such effects were not always expected as the loading
bolus was administered slowly over 5 min. Besides, potential bias was
limited since the anaesthetist followed objective intervention points
throughout the study. Another limitation of the study is the potential
limited reduction in propofol requirements with the established
adjustment criteria based on clinical signs. However, this study was
designed to evaluate the effects of dexmedetomidine and ketamine CRIs
in a clinical scenario, where clinical signs are used to adjust anaesthetic
plane. Therefore, specific design aiming to establish the minimum
infusion rate of propofol was not considered and results obtained apply
only to this study conditions. Ketamine could also have modified the
clinical signs used to assess anaesthetic plane (Haskins, 2015). To reduce
subjectivity, an adjustment protocol based on a predetermined algo­
rithm was used and this may have reduced any bias. Besides, all dogs
showed similar clinical signs (absent or slight palpebral reflex, ventro­
medial eyeball position, and absent jaw tone) suggesting a similar
anaesthetic stage among the treatment groups. Another limitation is the
lack of homogeneity between surgeries, but also that several surgeons
performed the surgeries with variable experience were involved. How­
ever, the epidural anaesthesia used in the present study may have pre­
vented nociceptive input arising from different orthopaedic surgeries.
Ideally, a single surgeon should have performed all surgeries in order to
reduce variability.
In conclusion, a propofol sparing effect was not noticed when used as
TIVA and combined with either dexmedetomidine 1 μg/kg/h or keta­
mine 1.5 mg/kg/h in dogs undergoing hindlimb orthopaedic surgery
that received epidural anaesthesia. The effects of the infused drugs on
haemodynamic stability were not clinically relevant. Respiratory
depression was present in all groups although most of dogs anaes­
thetised with propofol-ketamine required mechanical ventilation to
maintain normocapnia. Therefore, mechanical ventilation should be
available when using propofol TIVA, especially when combined with
ketamine. The coadministration of either dexmedetomidine or ketamine
at the studied dose rates to a propofol TIVA did not provide any
observable intraoperative advantage to the studied canine patients, who
received epidural anaesthesia.

10
R. Bustamante et al.
Table 5
Recovery quality in 39 dogs undergoing hindlimb orthopaedic procedures. All dogs were sedated with dexmedetomidine and methadone IM, general anaesthesia was
induced with boluses of propofol (0,5 mg/kg IV) and maintained with either propofol TIVA (18 mg/kg/h at initial dose) combined with saline (1 mL/kg/h; group SP, n
= 13 dogs), with ketamine (1.5 mg/kg/h; group KP, n = 13 dogs), or with dexmedetomidine (1 μg/kg/h; group DP, n = 13 dogs). Lumbosacral epidural anaesthesia was
performed in all dogs (1 mg/kg 0.5% bupivacaine +0.1 mg/kg morphine p.f.). Number of dogs per group presenting muscle twitching, paddling, vocalization or
requiring dexmedetomidine administration (1 μg/kg IV) during recovery. Time in minutes from the discontinuation of propofol TIVA and allocated infusion to
extubation is reported as (TEX), time to sternal recumbency (TST). Results are expressed as mean ± standard deviation or number of dogs in each group that showed the
indicated effect.
Group Variable
Muscle twitching Paddling Vocalization Dexmedetomidine administration
Group SP 3 6 2 2
Group KP 2 2 4 2
Group DP 1 4 4 3
*Significant differences from group SP. †Significant differences between groups KP and DP. P < 0.05.
Declaration of Competing Interest
None.
Acknowledgements
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors. Preliminary
results were presented as an oral communication at the 15th National
Spanish Congress of Veterinary Anaesthesia, Toledo, 25th – 27th 2019.
One of the authors (RB) was the recipient of a scholarship from the
Complutense University of Madrid (PhD program UCM CT45/15 –
CT46/15).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.rvsc.2021.12.017.
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