Effect of ketamine on the minimum infusion rate

of propofol needed to prevent motor movement

in dogs

Rachel A. Reed DVM OBJECTIVE

To determine the minimum infusion rate (MIR) of propofol required to
M. Reza Seddighi DVM, PhD prevent movement in response to a noxious stimulus in dogs anesthetized
Agricola Odoi BVM, PhD with propofol alone or propofol in combination with a constant rate infusion
Sherry K. Cox PhD (CRI) of ketamine.
Christine M. Egger DVM, MVSC ANIMALS
Thomas J. Doherty MVB, MSC 6 male Beagles.

Received October 11, 2014. PROCEDURES

Accepted March 31, 2015.
From the Departments of Large Animal Clinical Sciences
(Reed, Seddighi, Doherty), Biomedical and Diagnostic
Sciences (Odoi, Cox), and Small Animal Clinical Sciences
(Egger), College of Veterinary Medicine, University of
Tennessee, Knoxville, TN 37996.
Address correspondence to Dr. Reed (rachel.anne.
reed@gmail.com).
Dogs were anesthetized on 3 occasions, at weekly intervals, with propofol
alone (loading dose, 6 mg/kg; initial CRI, 0.45 mg/kg/min), propofol (loading
dose, 5 mg/kg; initial CRI, 0.35 mg/kg/min) and a low dose of ketamine (loading
dose, 2 mg/kg; CRI, 0.025 mg/kg/min), or propofol (loading dose, 4 mg/kg;
initial CRI, 0.3 mg/kg/min) and a high dose of ketamine (loading dose, 3 mg/kg;
CRI, 0.05 mg/kg/min). After 60 minutes, the propofol MIR required to prevent
movement in response to a noxious electrical stimulus was determined in
duplicate.

RESULTS
Least squares mean ± SEM propofol MIRs required to prevent movement
in response to the noxious stimulus were 0.76 ± 0.1 mg/kg/min, 0.60 ± 0.1
mg/kg/min, and 0.41 ± 0.1 mg/kg/min when dogs were anesthetized with
propofol alone, propofol and low-dose ketamine, and propofol and high-dose
ketamine, respectively. There were significant decreases in the propofol MIR
required to prevent movement in response to the noxious stimulus when
dogs were anesthetized with propofol and low-dose ketamine (27 ± 10%) or
with propofol and high-dose ketamine (30 ± 10%).

CONCLUSIONS AND CLINICAL RELEVANCE

Ketamine, at the doses studied, significantly decreased the propofol MIR
required to prevent movement in response to a noxious stimulus in dogs. (Am
J Vet Res 2015;76:1022–1030)

T otal IV anesthesia is becoming a popular and prac-

tical alternative to inhalation anesthesia of human
patients, primarily because of the pharmacokinetic
improved hemodynamic control, rapid dose titration,
decreased vasodilation and decreased associated hy-
potension, decreased postoperative nausea and vom-
properties of modern injectable anesthetics such as iting, decreased occupational exposure, smoother
propofol, advances in pharmacokinetic modeling, and emergence from anesthesia, and decreased hangover
the availability of computer technology for implemen- effects, compared with inhalation anesthesia.2,3
tation of TIVA.1 A number of reasons can be cited for Desirable qualities of an injectable anesthetic drug
the popularity of TIVA in human anesthesia, including for use in TIVA include rapid onset, short duration, ab-
sence of a context-sensitive half-life, and antinocicep-
ABBREVIATIONS
tion; unfortunately, these qualities are not all satisfied
CRI Constant rate infusion by any individual drug. Propofol is a commonly used
MAC Minimum alveolar concentration drug that provides most of these characteristics4; how-
MAP Mean arterial blood pressure ever, it is not an ideal anesthetic, considering that at
MIR Minimum infusion rate the doses required for surgical anesthesia, it is report-
MIRNM Minimum infusion rate required to prevent
movement in response to a noxious stimulus ed to cause cardiovascular depression characterized
TIVA Total IV anesthesia by decreases in preload mediated by venodilation and
PETCO2 End-tidal partial pressure of CO2 decreases in myocardial contractility.5,6 In addition, its

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 context-sensitive pharmacokinetics can increase re-
covery times as a result of accumulation of propofol
in the tissues, especially after prolonged infusion.7 Ad-
ditionally, propofol lacks substantial antinociceptive
properties.8 Total IV anesthesia is less commonly used
in small animals, perhaps in part because controlled
infusion devices are not commercially available for
animals. Nevertheless, the propofol MIR in various do-
mestic animals has been investigated.9–12
In human patients undergoing anesthesia with
propofol, adjunctive use of ketamine has been rec-
ommended because of its analgesic properties and
to improve hemodynamic stability.13 When ketamine
was administered to dogs in combination with pro-
pofol, there was an increase in heart rate and MAP in
comparison to values recorded when propofol was
administered alone,14 and a CRI of ketamine report-
edly decreased the propofol MIR in cats15 and po-
nies.16 Therefore, we suspected that ketamine would
decrease the propofol MIR in dogs as well.
The purpose of the study reported here was to de-
termine the propofol MIRNM in unpremedicated dogs
anesthetized with propofol alone or with propofol in
combination with a CRI of ketamine.We hypothesized
that ketamine would decrease the propofol MIRNM in
a dose-dependent manner.
Materials and Methods
Animals
The study protocol was approved by the Univer-
sity of Tennessee’s Institutional Animal Care and Use
Committee (protocol No. 2223). Six healthy adult male
Beagles weighing 11 to 13 kg were used in the study.
Food, but not water, was withheld for 12 hours prior
to anesthesia. Each dog was studied on 3 occasions in
a randomized crossover design.
Experimental protocol
Hair over the right cephalic vein was clipped 1
hour prior to each anesthetic episode, a lidocaine
2.5% and prilocaine 2.5% creama was applied to the
skin over the area of anticipated catheter placement,
and the limb was wrapped for a minimum of 40 min-
utes prior to catheter placement. A 20-gauge, 1-inch
catheterb was then placed in the right cephalic vein
for administration of anesthetic drugs and balanced
electrolyte solution.c
Anesthesia was induced with a loading dose of
propofol alone or with a loading dose of propofol and
ketamine as a single bolus administered manually at
a constant rate for 60 seconds. A CRI of propofol or
propofol and ketamine was initiated immediately after
induction of anesthesia with a syringe pump.d The bal-
anced electrolyte solution was administered at a rate
of 3 mL/kg/h. Dogs were tracheally intubated and posi-
tioned in right lateral recumbency. Oxygen was deliv-
ered (2 L/min) with a small animal anesthesia machinee
with a circle breathing system. Dogs were allowed to
breathe spontaneously; however, mechanical ventila-
AJVR • Vol 76 • No. 12 • December 2015
14-10-0265r.indd 1023
tion was instituted if the PETCO2 reached 60 mm Hg.
The PETCO2 was monitored continuously with an infra-
red gas analyzer.f Airway samples were collected at the
proximal end of the endotracheal tube at a rate of 150
mL/min. The gas analyzer was calibrated according to
the manufacturer’s instructions at the start of each an-
esthetic episode.
An 18-gauge, 1.5-inch catheterb was placed in the
left jugular vein to collect blood for measurement of
ketamine and propofol concentrations. Body tempera-
ture was monitored with an esophageal probe,f and a
circulating warm water blanketg was used to maintain
body temperature between 37.5° and 38.5°C. Heart
rate and an ECG were monitored continuously.e,f Blood
pressure was monitored indirectlyf with an oscillomet-
ric technique and an appropriately sized cuff (ie, a cuff
with a width approx 40% of the circumference of the
limb) placed over the right dorsal pedal artery. A do-
butamineh infusion was planned if MAP decreased to
< 60 mm Hg.The urinary bladder was expressed inter-
mittently as needed to prevent overdistension.
Dogs were anesthetized on 3 occasions with pro-
pofoli alone (loading dose, 6 mg/kg; initial CRI, 0.45
mg/kg/min), propofol (loading dose, 5 mg/kg; initial
CRI, 0.35 mg/kg/min) and a low dose of ketaminej
(loading dose, 2 mg/kg; CRI, 0.025 mg/kg/min), or pro-
pofol (loading dose, 4 mg/kg; initial CRI, 0.3 mg/kg/
min) and a high dose of ketamine (loading dose, 3 mg/
kg; CRI, 0.05 mg/kg/min). A bolus of propofol (2 mg/
kg) was given if the loading dose and initial CRI were
insufficient to prevent spontaneous movement in the
first 60 minutes after anesthetic induction. Anesthetic
treatments were performed in random order in indi-
vidual dogs, with a minimum washout period of 7 days
between anesthetic episodes.
Determination of MIRNM was initiated 60 min-
utes after the propofol and ketamine CRIs were start-
ed. A noxious electrical stimulus (50 V and 50 Hz for
10 milliseconds) was deliveredk via two 25-gauge nee-
dle electrodes that were placed SC and 5 cm apart on
the lateral aspect of the left ulna.Two single stimuli of
1 second in duration were delivered initially, followed
by 2 continuous stimuli of 5 seconds’ duration, with
a 5-second interval between stimuli.17 Withdrawal or
twitching of the nonstimulated limbs, movement of
the head, chewing, licking, or swallowing was consid-
ered a positive response. Movement of the stimulated
limb was not considered a positive response. If there
was a response, the propofol infusion rate was in-
creased by 0.025 mg/kg/min; conversely, if there was
no response, the propofol infusion rate was decreased
by 0.025 mg/kg/min. A 15-minute equilibration time
was allowed after each change in infusion rate before
the next stimulus was applied.
For the purpose of this study, the MIRNM was con-
sidered to be the MIR that abolished all motor move-
ments (purposeful and nonpurposeful) in response to
the noxious stimulus. The MIRNM was determined in
duplicate and the mean calculated for each dog. Time
from intubation to completion of MIRNM determina-
1023
11/20/2015 9:45:14 AM
 tion was recorded. At the end of each experiment, the
propofol and ketamine infusions were stopped and
the dogs were allowed to recover. Time from the end
of drug infusion to extubation and time from the end
of drug infusion to when dogs could walk unaided
were recorded. Dogs were continuously observed
throughout the recovery period.
Blood samples were collected for measurement
of plasma propofol, ketamine, and norketamine con-
centrations immediately after the first and second
MIRNM determinations, at the time of extubation, and
when dogs could walk unaided. On each occasion,
6 mL of blood was collected from the left jugular vein
and placed in a tube containing lithium heparin; tubes
were stored on ice prior to centrifugation. Blood sam-
ples were centrifuged,l and the plasma was removed.
Samples taken at the time of the first and second
MIRNM determinations were combined, in equal vol-
umes, for analysis. Plasma samples were then stored at
–80°C until determination of drug concentrations and
analyzed within 4 weeks after collection.
Drug analysis
Plasma ketamine and norketamine concentrations
were measured by means of high-performance liquid
chromatography with UV detection, as described pre-
viously.18 In brief, the system consisted of a separation
module,m 4.6 X 150-mm columnn (particle size, 5 µm)
with a guard column,o absorbance detector,p and anal-
ysis software.q The mobile phase was an isocratic mix-
ture of 0.02M potassium dihydrogen phosphate (pH,
6) with concentrated phosphoric acid and acetonitrile
(84:16). It was prepared fresh daily with double-dis-
tilled, deionized water that was filtered (0.22 µm) and
degassed before use. The flow rate was 1.0 mL/min,
and UV absorbance was measured at 205 nm.
Previously frozen plasma samples were thawed
and vortexed.The sample (1 mL) was placed in a 15-mL
screw cap tube, and 25 µL of trimethoprim (internal
standard; 50 µg/mL) was added. Sodium hydroxide
(200 µL; 1M) and methylene chloride (5 mL) were add-
ed. Tubes were placed on a rocker for 15 minutes and
then centrifuged at 2,050 X g for 15 minutes.The bot-
tom layer was removed and placed in a clean tube and
evaporated with nitrogen. The samples were reconsti-
tuted with 1 mL of mobile phase, and a 100-µL aliquot
of sample was injected into the liquid chromatograph
for analysis. Standard curves for plasma analysis were
prepared by spiking canine plasma with ketamine,
which produced a linear concentration range of 50 to
7,000 ng/mL. Spiked standards were treated exactly
as plasma samples for determination of ketamine con-
centration. Recovery ranged from 83% to 100%, and
intra-assay variability ranged from 0.5% to 6.8%. Inter-
assay variability ranged from 7.3% to 10.1%.
Propofol plasma samples were analyzed with
a reverse-phase high-performance liquid chroma-
tography method. The system consisted of a separa-
tion module,m a fluorescence detector,r and analysis
software.q Propofol was extracted from plasma sam-
1024 AJVR • Vol 76 • No. 12 • December 2015
14-10-0265r.indd 1024
ples by means of liquid extraction. Briefly, previously
frozen samples were thawed and vortexed, and 400 µL
was transferred to a clean test tube, followed by 10 µL
of internal standard (2,4-ditert-butylphenol [100 µg/
mL]). One milliliter of acetonitrile-methanol (75:25)
was added, and the tubes were vortexed, covered, and
placed in a refrigerator for 10 minutes. Tubes were
vortexed for 10 seconds and centrifuged for 15 min-
utes at 1,000 X g. The supernatant was removed to a
clean tube, and the procedure was repeated with an
additional 0.5 mL of acetonitrile-methanol, with the
supernatant added to the initial supernatant. Finally,
tubes were centrifuged for 5 minutes, and the super-
natant was placed in a chromatographic vial, with
40 µL analyzed.
Compounds were separated on a 4.6 X 250-mm,
5-µm columns with a guard column.t The mobile phase
was a mixture of water (adjusted to a pH of 4.0 with
glacial acetic acid) and acetonitrile (31:69). The flow
rate was 1.5 mL/min, and the column temperature
was the same as the ambient temperature.The fluores-
cence detector was set at an excitation of 276 nm and
an emission of 310 nm with the gain at 10X.
Standard curves were prepared by fortifying un-
treated plasma with propofol to produce a linear con-
centration range of 5 to 7,000 ng/mL. Calibration sam-
ples were prepared exactly as plasma samples. Mean
recovery for propofol was 89%, and the intra- and
interassay variability ranged from 2.0% to 8.2%
and from 0.6% to 11%, respectively. The lower limit
of quantification was 5 ng/mL.
Statistical analysis
The effect of anesthetic treatment on percent-
age change in MIRNM was estimated in a generalized
linear mixed model, with dog as a random effect and
percentage change in MIRNM as the dependent vari-
able. Treatment was included as an explanatory vari-
able in the model; other variables controlled for in
the model were week, time, and body weight. Similar
models were used to investigate the effect of treat-
ment on time to extubation and time to walking. In
the model used to investigate the effect of treatment
on time to extubation, the latter was specified as the
dependent variable, whereas treatment, time, week,
and body weight of the dog were specified as fixed ef-
fects (or explanatory variables). Similarly, in the model
investigating the association between treatment and
time to walking, the latter was specified as the de-
pendent variable, whereas treatment, week, time, and
body weight were again specified as fixed effects (or
explanatory variables). Dog was included as a random
effect in all models. Model assumptions of normality
were assessed by means of the Shapiro-Wilk test for
normality of residuals. Where necessary, data were log
transformed to ensure that the residuals met this as-
sumption. Least squares mean values and their SEMs
were computed for all dependent variables and com-
pared across treatments. A 2-tailed value of P < 0.05
was considered significant for all tests of significance.
11/20/2015 9:45:14 AM
 When multiple comparisons were performed, P values
were adjusted by use of the Tukey method. All statisti-
cal analyses were performed with commercially avail-
able statistical software.u
Values for heart rate, respiratory rate, and MAP
were obtained at 15-minute intervals, and values ob-
tained during the first 60 minutes of each anesthetic
episode were compared with values obtained after
the first 60 minutes to elucidate any changes in these
parameters that might have been associated with high
initial plasma propofol and ketamine concentrations
resulting from the loading doses.
Results
Least squares mean ± SEM propofol MIRNMs for
dogs anesthetized with propofol alone, propofol and
low-dose ketamine, and propofol and high-dose ket-
amine were 0.76 ± 0.1 mg/kg/min, 0.60 ± 0.1 mg/kg/
min, and 0.41 ± 0.1 mg/kg/min, respectively. The pro-
pofol MIRNM was significantly lower when dogs were
anesthetized with propofol and low-dose ketamine (P
< 0.001) or with propofol and high-dose ketamine (P =
0.003) than when dogs were anesthetized with propo-
fol alone.The propofol MIRNM when dogs were anes-
thetized with propofol and high-dose ketamine was
significantly (P = 0.002) lower than the MIRNM when
dogs were anesthetized with propofol and low-dose
ketamine. Anesthesia with propofol and low-dose ket-
amine and with propofol and high-dose ketamine was
associated with decreases of 27 ± 10% and 30 ± 10% in
the propofol MIRNM, respectively; however, percent-
age decreases did not differ significantly (P = 0.864)
between the 2 treatments. Least squares mean ± SEM
times from intubation to completion of MIRNM deter-
mination when dogs were anesthetized with propofol
alone, propofol and low-dose ketamine, and propofol
and high-dose ketamine were 185 ± 32 minutes, 230 ±
34 minutes, and 202 ± 34 minutes, respectively; there
were no significant differences among groups.
One dog when anesthetized with propofol alone,
4 dogs when anesthetized with propofol and low-dose
ketamine, and 3 dogs when anesthetized with propo-
fol and high-dose ketamine required an additional pro-
pofol bolus within the first hour of anesthesia to pre-
vent spontaneous movement.There was no significant
(P ≥ 0.05) difference among treatments in regard to
plasma propofol concentrations at the time of MIRNM
determination, extubation, or walking (Table 1).
Plasma ketamine concentrations at the time of
MIRNM determination were significantly (P = 0.005)
greater when dogs were anesthetized with propofol
and high-dose ketamine than when dogs were anes-
thetized with propofol and low-dose ketamine. Plasma
norketamine concentrations at the time of MIRNM
determination did not differ significantly (P = 0.563)
between treatments, and plasma ketamine and norket-
amine concentrations did not differ significantly (P ≥
0.05) between treatments at the time of extubation or
walking (Table 2).
During the first 60 minutes, heart rate was higher
when dogs were anesthetized with propofol and low-
dose ketamine (P = 0.002) or propofol and high-dose
ketamine (P = 0.001) than when dogs were anesthe-
tized with propofol alone (Table 3). Heart rates when
dogs were anesthetized with propofol and low-dose
ketamine were not significantly (P ≥ 0.05) different
from rates when dogs were anesthetized with propo-
fol and high-dose ketamine. After 60 minutes, heart
rates when dogs were anesthetized with propofol
and low-dose ketamine were significantly (P = 0.008)
higher than rates when dogs were anesthetized with
propofol alone, but heart rates when dogs were anes-
thetized with propofol alone did not differ significant-
ly (P ≥ 0.05) from rates when dogs were anesthetized
with propofol and high-dose ketamine, and rates when
dogs were anesthetized with propofol and low-dose
ketamine did not differ significantly (P ≥ 0.05) from
rates when dogs were anesthetized with propofol and
high-dose ketamine. When dogs were anesthetized
with propofol alone, heart rate was significantly (P <
0.001) higher after the first 60 minutes than during
the first 60 minutes. When dogs were anesthetized
with propofol and low-dose ketamine or with propo-
fol and high-dose ketamine, there was no significant
(P ≥ 0.05) difference in heart rates after the first 60
minutes versus during the first 60 minutes.
Respiratory rates when dogs were anesthetized
with propofol and high-dose ketamine were signifi-
cantly higher during the first 60 minutes than rates
when dogs were anesthetized with propofol alone
(P = 0.001) or propofol and low-dose ketamine (P =
0.010; Table 3); however, PETCO2 did not differ signifi-

Table 1—Plasma propofol concentrations (µg/mL) at the time of MIRNM determination in dogs
(n = 6) anesthetized with propofol alone (0.76 ± 0.1 mg/kg/min), propofol (0.60 ± 0.1 mg/kg/min)
and a low dose of ketamine (0.025 mg/kg/min), or propofol (0.41 ± 0.1 mg/kg/min) and a high dose
of ketamine (0.05 mg/kg/min); at the time of extubation; and at the time dogs were first able to walk
unaided after recovering.
Treatment MIRNM determination Extubation Walking
Propofol alone 14.5 ± 1.0 5.8 ± 1.0 3.8 ± 1.0
Propofol and low-dose ketamine 13.3 ± 1.0 4.9 ± 1.0 3.3 ± 1.0
Propofol and high-dose ketamine 10.9 ± 1.0 2.9 ± 1.0 2.3 ± 1.0
Data are least squares mean ± SEM.
In each column, values are not significantly (P ≥ 0.05) different from each other.
In each dog, MIRNM was determined in duplicate for each anesthetic treatment; plasma samples obtained at
the time of each MIRNM determination were combined for analysis.

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 Table 2—Plasma ketamine and norketamine concentrations (ng/mL) at the time of MIRNM determination in dogs (n = 6) anes-
thetized with propofol (0.60 ± 0.1 mg/kg/min) and a low dose of ketamine (0.025 mg/kg/min) or with propofol (0.41 ± 0.1 mg/kg/
min) and a high dose of ketamine (0.05 mg/kg/min), at the time of extubation, and at the time dogs were first able to walk unaided
after recovering.
MIRNM determination Extubation Walking
Treatment Ketamine Norketamine Ketamine Norketamine Ketamine Norketamine
Propofol and low-dose 446 ± 258a 140 ± 90a 95 ± 258a 88 ± 92a 72 ± 272a 105 ± 107a
ketamine
Propofol and high-dose 1,399 ± 258b 346 ± 89a 400 ± 258a 290 ± 90a 229 ± 261a 169 ± 89a
ketamine
a,bWithin a column, values with different superscript letters were significantly (P < 0.05) different.

See Table 1 for remainder of key.

Table 3—Heart rate, PETCO2, respiratory rate, MAP, time to extubation, and time to walking in dogs (n = 6) anesthetized with propofol alone (0.76
± 0.1 mg/kg/min), propofol (0.60 ± 0.1 mg/kg/min) and a low dose of ketamine (0.025 mg/kg/min), or propofol (0.41 ± 0.1 mg/kg/min) and a high
dose of ketamine (0.05 mg/kg/min).
Heart rate PETCO2 Respiratory rate
(beats/min) (mm Hg) (breaths/min) MAP (mm Hg)

During first After first During first During first During first After first Time to Time to
Treatment 60 minutes 60 minutes 60 minutes 60 minutes 60 minutes 60 minutes extubation* walking†

Propofol alone 91 ± 10a,A 107 ± 10a,B 45 ± 2a 7 ± 2a 83 ± 4a,C 92 ± 5a,D 27 ± 5a 66 ± 4a

Propofol and 110 ± 10b,A 116 ± 10b,A 43 ± 2a 10 ± 2a 91 ± 4a,C 98 ± 5a,C 25 ± 5a 57 ± 4a
low-dose ketamine
Propofol and 114 ± 10b,A 113 ± 10a,b,A 42 ± 2a 14 ± 2b 92 ± 4a,C 95 ± 5a,C 17 ± 5a 40 ± 4b
high-dose ketamine

Values for heart rate, PETCO2, respiratory rate, and MAP were obtained at 15-minute intervals, and values obtained during the first 60 minutes of
each anesthetic episode were compared with values obtained after the first 60 minutes. For PETCO2 and respiratory rate, values were not recorded
after the first 60 minutes because several dogs required mechanical ventilation.
*Time to extubation (minutes) was the time from the end of drug infusion to extubation. †Time to walking was the time (minutes) from the end
of drug infusion to walking without assistance.
a,bWithin a column, values with different lowercase superscript letters were significantly (P < 0.05) different. A–DWithin a row, values for each

variable with different uppercase superscript letters were significantly (P < 0.05) different.

cantly (P ≥ 0.05) among treatments during this time.
Respiratory rates when dogs were anesthetized with
propofol alone versus propofol and low-dose ket-
amine did not differ significantly (P ≥ 0.05) during the
first 60 minutes. After 60 minutes, 4 dogs when anes-
thetized with propofol and low-dose ketamine, 3 dogs
when anesthetized with propofol alone, and 3 dogs
when anesthetized with propofol and high-dose ket-
amine required mechanical ventilation because PETCO2
was > 60 mm Hg; thus, respiratory rates and PETCO2
recorded after the first 60 minutes were not analyzed.
Hypotension, defined as MAP < 60 mm Hg, was
not observed at any time; thus, dobutamine was not
administered on any occasion.The MAP was not signif-
icantly (P ≥ 0.05) different among treatments during
the first 60 minutes or after the first 60 minutes.When
dogs were anesthetized with propofol alone, the MAP
was significantly (P = 0.001) greater after the first 60
minutes than during the first 60 minutes. There were
no significant (P ≥ 0.05) differences in MAP between
time periods when dogs were anesthetized with pro-
pofol and low-dose ketamine or with propofol and
high-dose ketamine.
There was no significant difference in time to
extubation among treatments (Table 3). When anes-
thetized with propofol and high-dose ketamine, dogs
had a shorter time to walking than they did when
anesthetized with propofol alone (P < 0.001) or with
propofol and low-dose ketamine (P = 0.012). Five of
the 6 dogs experienced stertorous breathing during
recovery with each treatment; this resolved within 15
to 45 minutes. Recovery was otherwise smooth and
uneventful with all treatments.
Discussion
Results of the present study indicated that ad-
ministration of ketamine at 25 or 50 µg/kg/min sig-
nificantly decreased the propofol MIRNM in dogs in
a dose-dependent, nonadditive fashion. Decreases in
propofol MIRNM of 27% and 30%, respectively, were
found when propofol was administered with ket-
amine at the lower or higher dose, compared with the
MIRNM when propofol was administered alone.These
percentage changes were not significantly different
from each other, likely because of the variability in
propofol infusion rates and plasma propofol concen-
trations and the small sample size. A post hoc power
analysis indicated that a minimum of 10 dogs would
have been needed to detect a significant difference in
MIRNM between treatments with an α value of 0.05
and power of 80%. Regardless, the decrease in pro-
pofol MIRNM associated with ketamine was judged
to be clinically important. Also, the study indicated a
potential need for controlled ventilation during TIVA

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 with propofol or with a combination of propofol and
ketamine because hypoventilation was present with
all 3 treatments.
The MIRNM was chosen as the end point for the
present study because the authors believe that, in
comparison to MIR, it is less subjective, in that observ-
ers do not have to differentiate between purposeful
versus nonpurposeful movements, and more clinically
relevant, given that typically no movement is tolerated
during surgical procedures. The authors consider the
MIRNM to be analogous to the MAC of a volatile anes-
thetic required to prevent all motor movement, pur-
poseful and nonpurposeful, in response to a noxious
stimulus, in all test subjects.19 In contrast, the tradition-
al MAC and MIR end points are the values necessary
to prevent purposeful movement only, in response to
a noxious stimulus, in 50% of the study population.
Given the relationship between MAC and the MAC
required to prevent all motor movement, the MIRNM
could be expected to be approximately 20% greater
than the MIR.19,20
In the present study, mean propofol MIRNM when
dogs were anesthetized with propofol alone was
0.76 mg/kg/min. Not surprisingly, considering that
we measured MIRNM and not MIR, this was higher
than published values for the propofol MIR in dogs.
Studies5,11 of propofol anesthesia in unpremedicated,
nonstimulated dogs have shown that infusion rates
ranging from 0.44 to 0.6 mg/kg/min are necessary to
maintain a light plane of anesthesia. A study12 involv-
ing unpremedicated dogs determined a propofol MIR
of 0.51 mg/kg/min when an electrical stimulus was
used. However, plasma propofol concentrations were
not determined, and it is possible that the MIR was
underestimated in that study12 because stimulation of
the dogs began 10 minutes after administration of the
loading dose. Thus, steady-state plasma propofol con-
centrations may not have been achieved at the time
of MIR determination. A computer simulation study21
indicated that the initial loading dose of propofol has
an effect on plasma concentrations, albeit a diminish-
ing effect over time, but by 120 minutes, the plasma
concentration is wholly dependent on the CRI. On the
basis of these findings, a 60-minute equilibration time
prior to beginning MIRNM determination was allowed
in the present study, with the hope of approaching
a steady-state plasma propofol concentration by the
time of MIRNM determination.21,22 Time from intuba-
tion to the completion of MIRNM determination in
this study was > 180 minutes for all treatments.
A potential weakness in the present study was
that the time (15 minutes) allowed after a change in
the propofol infusion rate may have been insufficient
to achieve a new steady-state plasma propofol con-
centration. To overcome this limitation, longer equili-
bration times or the use of technologies that measure
real-time propofol concentrations23 should be consid-
ered for future studies.
A propofol MIR of 0.9 mg/kg/min has been report-
ed for unpremedicated rabbits subjected to tail clamp-
AJVR • Vol 76 • No. 12 • December 2015
14-10-0265r.indd 1027
ing.24 This high MIR is consistent with the high propo-
fol clearance of 340 mL/kg/min in rabbits,25 compared
with a clearance of 50.1 mL/kg/min in dogs.7 A propo-
fol MIR of 0.15 mg/kg/min was necessary to abolish
the response to tail clamping in unpremedicated cats,
but an MIR of 0.28 mg/kg/min was necessary to abol-
ish the palpebral reflex in response to touching the
medial canthus.15 This latter finding is consistent with
findings of the present study because all dogs retained
the palpebral reflex at the time of MIRNM determina-
tion.This considerably lower MIR in cats can be attrib-
uted to the prolonged propofol elimination half-life in
this species, which could possibly be due to impaired
glucuronidation in cats.26 Propofol plasma concentra-
tions were not reported in that study.
Few studies of propofol MIR have determined
plasma or whole blood concentrations of propofol.
It has been reported that plasma concentrations be-
tween 2.5 and 4.7 µg/mL should be sufficient to main-
tain surgical anesthesia in dogs premedicated with
acepromazine and methadone.27 A study performed at
the authors’ laboratory (data currently in press) pre-
dicted that whole blood propofol concentrations of
7.4 µg/mL would decrease the MAC of sevoflurane
that prevents all motor movement by 100% in unpre-
medicated dogs. In contrast to these findings, a study28
of human patients found that the whole blood con-
centration at which 50% of patients did not respond
to a skin incision was 15.2 µg/mL, close to the plasma
propofol concentration of 14.5 µg/mL in the present
study when MIRNM was determined. Surprisingly, in
the present study, there was no significant difference
in plasma propofol concentrations among treatments
despite the differences in MIRNM, but this could have
been due to the small sample size and large interindi-
vidual variability among animals. According to a post
hoc power analysis, 25 dogs would have been needed
in each treatment group to detect a significant differ-
ence among treatments.
In unpremedicated subjects, there appear to be
significant variations in propofol MIR12,15,24 and mea-
sured and predicted propofol concentrations.24,28
However, making comparisons among studies is diffi-
cult because of differences in experimental design (es-
pecially because some studies analyzed whole blood
and others analyzed plasma) and differences in stor-
age temperature and time. In the present study, plasma
rather than whole blood was analyzed for propofol
concentrations, and this was based on a recent study
(unpublished data) performed at the authors’ laborato-
ry, in which more propofol was recovered from canine
plasma samples than canine whole blood samples and
plasma propofol concentrations were not affected by
storage at –80°C for up to 4 weeks.
A recent study11 investigating the effect of a mix-
ture of propofol and ketamine (1:1 [wt/vol]) in un-
premedicated dogs reported that the propofol MIR
required to maintain a light plane of anesthesia de-
creased from 0.6 mg/kg/min with propofol alone to
0.3 mg/kg/min with the 1:1 mixture (300 µg of ket-
1027
11/20/2015 9:45:14 AM
 amine/kg/min). Although this represented a 50% de-
crease in the propofol MIR, the ketamine infusion rate
in that study11 was much higher than the rate used in
the present study. The ketamine infusion rates in the
present study were chosen to achieve target plasma
concentrations of 600 and 1,100 ng/mL, respectively,
and were based on the effect of ketamine on sevo-
flurane MAC in dogs at these concentrations.18 In the
present study, the ketamine concentrations were dif-
ferent between groups, but there was a high degree
of interindividual variability and the calculated power
was 0.54. To achieve a power of 0.8, 7 dogs/group
would be needed. Mean plasma ketamine concentra-
tions at 25 and 50 µg/kg/min were 446 and 1,399 ng/
mL, respectively. The latter concentration was slightly
higher than expected on the basis of findings report-
ed by Wilson et al,18 in which a ketamine infusion of
50 µg/kg/min resulted in a plasma concentration of
1,057 ng/mL and was associated with a decrease of
40% in the MAC of sevoflurane. In unpremedicated
cats anesthetized with propofol, ketamine infusions of
23 and 46 µg/kg/min resulted in plasma ketamine con-
centrations of 1,170 and 2,270 ng/mL, respectively.15
These values are considerably greater than those of
the present study and were also greater than those au-
thors predicted.15 Those authors attributed this either
to inaccuracies of the pharmacokinetic models or to
the effect of propofol infusion on ketamine metabo-
lism in cats.15 On the basis of recent pharmacokinetic
findings related to ketamine and propofol in cats,26 it
is likely that the latter is the case. Nonetheless, that
study15 found that the propofol MIR decreased from
0.15 to 0.11 mg/kg/min for the groups given ketamine
at rates of 46 and 23 µg/kg/min, respectively.This rep-
resented a decrease of approximately 27% in the pro-
pofol MIR and is similar to the findings of the present
study at an infusion rate of 50 µg/kg/min, albeit at a
much higher plasma ketamine concentration.
An interesting finding of the present study was
that there was no significant difference in MAP among
treatments at any time, and hypotension (MAP < 60
mm Hg) did not occur with any treatment. It has
been reported that propofol causes dose-dependent
cardiovascular depression secondary to reductions in
myocardial contractility and systemic vascular resis-
tance.6,29,30 Previous studies11,14 comparing the effects
of propofol alone and propofol in combination with
ketamine on blood pressure have shown that TIVA
with propofol and ketamine better supports MAP than
does propofol alone. However, in the present study,
blood pressure was not measured prior to induction
of anesthesia, so it is unknown how much the blood
pressure decreased from awake values.
Propofol has a dose-dependent negative chrono-
tropic effect via direct depression of sinoatrial pace-
maker activity.29 The heart rate during the first 60 min-
utes was significantly lower when dogs in the present
study were anesthetized with propofol alone than
when they were anesthetized with propofol and low-
dose ketamine or propofol and high-dose ketamine,
1028 AJVR • Vol 76 • No. 12 • December 2015
14-10-0265r.indd 1028
and this could have been due to the effect of a higher
loading dose of propofol. Ketamine supports heart
rate via direct stimulation of the sympathetic nervous
system,31 and this could have also contributed to the
higher heart rates when dogs were anesthetized with
propofol and low-dose ketamine or propofol and high-
dose ketamine. However, there was no difference in
heart rate between propofol and low-dose ketamine
and propofol and high-dose ketamine, although this
may have been due to the small number of animals in
this study and the ketamine infusion rates that were
used.
Propofol causes respiratory depression and apnea
by depressing the central respiratory center and inhib-
iting the response to hypercapnia.32 Additionally, ket-
amine is associated with dose-dependent respiratory
depression.33 Therefore, it is not surprising that respi-
ratory depression occurred during anesthesia. Dogs
had significantly higher respiratory rates during the
first 60 minutes when anesthetized with propofol and
high-dose ketamine than when anesthetized with pro-
pofol alone or with propofol and low-dose ketamine;
however, PETCO2 did not differ among treatments dur-
ing the first 60 minutes. After the first 60 minutes, in-
termittent positive pressure ventilation was required
for 3 dogs when anesthetized with propofol alone
or with propofol and high-dose ketamine and 4 dogs
when anesthetized with propofol and low-dose ket-
amine owing to PETCO2 > 60 mm Hg. This finding was
consistent with the reported respiratory depressant
effects of propofol in multiple species.11,15,16 The need
for intermittent positive pressure ventilation across
treatments limits the clinical utility of such TIVA pro-
tocols if assisted ventilation cannot be provided.
Recovery was smooth and uneventful across all
treatments in the present study. It has been shown
that recovery time from propofol infusion is depen-
dent on the rate and duration of the infusion in dogs21
and humans.34 Therefore, it is not surprising that dogs
had a significantly shorter time to walking when anes-
thetized with propofol and high-dose ketamine than
when anesthetized with propofol alone or with pro-
pofol and low-dose ketamine. However, time to extu-
bation did not differ among groups.
To the authors’ knowledge, there is no published
information on plasma propofol concentrations at ex-
tubation or walking in unpremedicated dogs anesthe-
tized with propofol. Studies4,7,27 of premedicated dogs
have reported plasma propofol concentrations rang-
ing from 1.6 to 2.3 µg/mL at extubation and 1.03 to
2.2 µg/mL at walking. Therefore, it was not surprising
that the plasma concentrations when dogs in the pres-
ent study were anesthetized with propofol alone were
5.8 µg/mL and 3.8 µg/mL at extubation and walking,
respectively. Plasma propofol concentrations at each
of these times were slightly lower when dogs were
anesthetized with propofol and low-dose ketamine
and propofol and high-dose ketamine, compared with
concentrations when dogs were anesthetized with
propofol alone. These differences were not signifi-
11/20/2015 9:45:14 AM
 cant; however, owing to the high variability in plasma
propofol and ketamine concentrations and the small
sample size, there is a high possibility of a type II error
in these results.
Five of the 6 dogs in the study had a moderate to
severe stertorous breathing pattern during anesthetic
recovery that lasted up to 60 minutes after extubation
and occurred after all 3 treatments. These episodes
were self-limiting, resolved spontaneously, and did
not seem to threaten the well-being of the dogs. The
authors were unable to find any report of this phe-
nomenon in the literature and are unable to explain its
origin or importance; oral examination did not reveal
any abnormalities of the soft palate or larynx in these
dogs. The fact that it occurred after all 3 anesthetic
treatments would suggest that it was associated with
propofol rather than ketamine administration.
Two of the 6 dogs in the present study (1 when
anesthetized with propofol alone and the other when
anesthetized with propofol and low-dose ketamine) de-
veloped myoclonus that persisted throughout anesthe-
sia.At the time, both dogs were receiving their first treat-
ment in the randomized order in which treatments had
been assigned. Neither dog had myoclonus during any
other treatment. At times, the myoclonus was so severe
that it could have been clinically relevant if the patient
had been anesthetized for surgery requiring a motionless
subject.This phenomenon has been reported previously
in dogs,4,35,36 and the incidence of myoclonus associated
with a propofol infusion in clinical cases was 1.2% in a
recent retrospective study.37 The cause of the myoclonus
is uncertain, although it has been theorized that propofol
may have an action similar to strychnine, via antagonism
of glycine at the subcortical level.38,39
Footnotes
a. EMLA Cream, APP Pharmaceuticals Inc, Schaumburg Ill.
b. Surflo IV Catheter,Terumo Medical Corp, Somerset, NJ.
c. Plasmalyte, Abbott Laboratories, North Chicago, Ill.
d. Medfusion 2001, Medox Inc, Ga.
e. Datex-Ohmeda Modulus SE, Planar Systems Inc, Ore.
f. Datex-Ohmeda, Planar Systems Inc, Ore.
g. Gaymar T-pump, Gaymar Industries, Orchard Park, NY.
h. Dobutamine, Hospira Inc, Lake Forest, Ill.
i. Propoflo, Abbott Laboratories, North Chicago, Ill.
j. Ketacine, VetOne Pharmaceuticals, MWI Veterinary Supply,
Boise, Idaho.
k. Grass Instrument Co, Woods Hole, Mass.
l. Compact II Centrifuge, Clay Adams Brand, Becton-Dickinson,
Franklin Lakes, NJ.
m. 2695 Separations Module, Waters Corp, Milford, Mass.
n. Xterra RP18 column, Waters Corp, Milford, Mass.
o. Xterra guard column, Waters Corp, Milford, Mass.
p. 2487 absorbance detector, Waters Corp, Milford, Mass.
q. Empower 3, Waters Corp, Milford, Mass.
r. 2475 Fluorescence Detector, Waters Corp, Milford, Mass.
s. XBridge C18, Waters Corp, Milford, Mass.
t. XBridge C18 guard column, Waters Corp, Milford, Mass.
u. SAS, version 9.3 TS Level 1M2, SAS Institute Inc, Cary, NC.
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