Accepted Manuscript

Effect of predosing versus slow administration of propofol on the dose required for
anaesthetic induction and on physiologic variables in healthy dogs

Mathieu Raillard, Emma J. Love, Pamela J. Murison

PII: S1467-2987(18)30047-3
DOI: 10.1016/j.vaa.2018.02.004
Reference: VAA 246

To appear in: Veterinary Anaesthesia and Analgesia

Received Date: 18 July 2017

Revised Date: 12 February 2018
Accepted Date: 12 February 2018

Please cite this article as: Raillard M, Love EJ, Murison PJ, Effect of predosing versus slow
administration of propofol on the dose required for anaesthetic induction and on physiologic variables in
healthy dogs, Veterinary Anaesthesia and Analgesia (2018), doi: 10.1016/j.vaa.2018.02.004.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

RESEARCH PAPER

Running head (Authors): M Raillard et al.

Running head (short title): Propofol predosing in dogs

Effect of predosing versus slow administration of propofol on the dose required for

PT
anaesthetic induction and on physiologic variables in healthy dogs

RI
Mathieu Raillarda, Emma J Lovea & Pamela J Murisonb
a
Bristol Veterinary School, University of Bristol, Langford, Bristol, UK

SC
b
Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK

U
Correspondence: Mathieu Raillard, Institute of Anaesthesiology and Pain Therapy, Vetsuisse
AN
Faculty, University of Bern, Länggassstrasse 124, CH-3012 Bern, Switzerland. E-mail:

mathieu_raillard@yahoo.it
M
D

Abstract
TE

Objective To investigate the timing of propofol administration on the dose required for

induction of anaesthesia and commonly measured physiological effects.

EP

Study design Randomized, investigator-blinded clinical study.

Animals Thirty-two healthy dogs (18 male, 13 female, one intersex, 6–144 months, 3.5–47.2
C

kg).
AC

Methods Premedication was intramuscular acepromazine (0.025 mg kg−1) and methadone (0.25

mg kg−1). Thirty minutes later one of three treatments was administered to the dogs: propofol

(0.5 mg kg−1; group PP), an equivalent volume of saline (group CP) or a propofol infusion (1.3

mg kg−1 minute−1; group SI). Two minutes later, a propofol infusion (4 mg kg−1 minute−1) was
 ACCEPTED MANUSCRIPT

started in PP and CP whereas the propofol infusion was continued in SI. At this stage an

investigator, blinded to the group assignments, entered the room and decided when each animal

was ready for intubation and stopped the propofol infusion. After intubation, management of

anaesthesia was standardized. Pulse rate (PR), respiratory rate (fR) and mean arterial pressure

PT
(MAP) were recorded before induction, 2 minutes later and 0, 2 and 5 minutes after intubation.

RI
Apnoea >30 seconds was recorded and managed. Sedation, quality of induction and endotracheal

intubation were scored using simple descriptive scales. Data are presented as mean ± standard

SC
deviation.

Results Propofol dose requirement was lower in SI (3.5 ± 1.2 mg kg−1) compared with PP and

U
CP (5.0 ± 0.9 and 4.8 ± 0.6 mg kg−1; p = 0.002 and 0.012) respectively. No statistically
AN
significant differences were found among groups for PR, fR, MAP or incidence of apnoea.
M

Sedation score and quality of induction were similar among groups.

Conclusions Slow administration of propofol reduced the anaesthetic induction dose required
D

compared with predosing and control groups. Effects on PR, fR, MAP and apnoea were similar
TE

among groups.

Clinical relevance Slower injection of propofol reduces the dose required for induction of
EP

anaesthesia.
C

Keywords anaesthesia, co-induction, dogs, induction, predosing, propofol.

AC
 ACCEPTED MANUSCRIPT

Introduction

Propofol is commonly used to induce anaesthesia in dogs and can cause adverse

cardiovascular and respiratory effects (Berry 2015). Co-induction is defined as the administration

of two or more agents together to induce anaesthesia. It has been proposed as a possible way to

PT
reduce dose and side effects of drugs co-administered (Whitwam 1995). The effects of different

RI
drugs administered with propofol for induction of anaesthesia in dogs have been documented,

including midazolam and diazepam (Covey-Crump & Murison 2008; Fayyaz et al. 2009;

SC
Robinson & Borer-Weir 2013; Hopkins et al. 2013; Sánchez et al. 2013; Minghella et al. 2016),

fentanyl, alfentanil and remifentanil (Musk & Flaherty 2007; Covey-Crump & Murison 2008;

U
Auckburally et al. 2008), lidocaine ( Braun et al. 2007; Jolliffe et al. 2007; Panti et al. 2015;
AN
Thompson & Rioja 2015; Cerasoli et al. 2016; Minghella et al. 2016) and ketamine (Lerche et al.

2000; Mair et al. 2009; Henao-Guerrero & Riccó 2014; Martinez-Taboada & Leece 2014). A
M

reduction in propofol dose was demonstrated in some studies. The sequence order of co-
D

induction drugs appears to influence the results. For example, in one study intravenous (IV)
TE

administration of midazolam before propofol resulted in signs of excitement and no reduction in

propofol dose whereas in another study, administration of a bolus of propofol before midazolam
EP

resulted in a lower requirement for propofol and less excitable behaviour (Covey-Crump &

Murison 2008; Robinson & Borer-Weir 2013; Sánchez et al. 2013).

C

Predosing with propofol has been reported in human anaesthesia. The technique is
AC

described as the administration of a fixed dose of propofol 2 minutes before induction of

anaesthesia with propofol (Anderson & Robb 1998; Djaiani & Ribes-Pastor 1999). It reduces the

propofol dose required for induction of anaesthesia (Anderson & Robb 1998; Djaiani & Ribes-

Pastor 1999; Srivastava et al. 2006; Kataria et al. 2010), with variable effects on heart rate and
 ACCEPTED MANUSCRIPT

blood pressure but possibly improved haemodynamic stability (Djaiani & Ribes-Pastor 1999;

Kataria et al. 2010). One study reported a decreased incidence of apnoea at induction following

propofol predosing compared with propofol-midazolam co-induction (Djaiani & Ribes-Pastor

1999). To our knowledge, the effects of propofol predosing in dogs have not been reported. In

PT
sheep the peak in anaesthesia depth is reached 2–3 minutes after the interruption of propofol

RI
administration (Ludbrook & Upton 1997) so it is possible that the dose reduction observed with

the propofol predosing originates from the longer time propofol has to exert its effects.

SC
The aim of this study was to investigate the effects of propofol predosing in dogs on the

total dose of propofol required for endotracheal intubation and the cardiovascular and respiratory

U
effects in the absence of other co-induction agents. Our hypotheses were that propofol predosing
AN
or slower administration of propofol in dogs would reduce the amount of propofol necessary to

induce anaesthesia and reduce adverse cardiovascular and respiratory effects.

M
D

Material and methods

TE

Healthy adult dogs in American Society of Anesthesiologists (ASA) categories I and II

undergoing elective procedures, and for which a standardized anaesthetic protocol was
EP

appropriate, were considered for inclusion in the study. Exclusion criteria included

brachycephalic and giant breeds of dog, dogs at high risk for regurgitation during induction of
C

anaesthesia, nervous or aggressive dogs, dogs suffering from systemic illness or trauma and dogs
AC

receiving drug treatment that could potentially affect the action of the sedative and anaesthetic

agents. Informed owner consent was obtained and the study was conducted with the University

of Bristol ethical committee approval (VIN/14/012). Dogs were allocated to one of three groups

(propofol predosing, control propofol and slow injection of propofol) by block randomization
 ACCEPTED MANUSCRIPT

using www.randomization.com. A sample size calculation was performed using data from a

published study in which a difference in propofol requirement of 1 mg kg−1 was considered

clinically relevant with an estimated standard deviation of 0.75 mg kg−1 (Robinson & Borer-Weir

2013). The estimated sample size was nine animals per group with a study power of 0.8 and an

PT
alpha of 0.05. The same syringe driver (IVAC P7000; Alaris Medical Systems, UK) was used for

RI
propofol administration in all cases. Its calibration was regularly checked during the study period

by filling a syringe and infusion line identical to the ones used in this study with water and

SC
placing the syringe in the syringe driver; different infusion rates and different intervals were set

and the amount of water coming out was weighed on an electronic balance and compared with

U
the expected output. The study syringe driver consistently provided the expected output
AN
throughout the study.

Before any treatment, pulse rate (PR; palpation of a femoral or a peripheral pulse) and
M

respiratory rate (fR; observation of thoracic excursions) were measured. Sedation was scored
D

using a simple descriptive scale: 0, no sedation; 1, mild sedation (quieter than before injection
TE

but still bright and active); 2, moderate sedation (quiet, reluctant to move, possibly slightly ataxic

but able to walk); 3, profound sedation (unable to walk unaided) (Covey-Crump & Murison
EP

2008; Table 1). Activity was scored using a simple descriptive scale: 0, sedation (more sedated

than before co-induction agent injection); 1, no change (compared with before injection); 2,
C

excitement (more activity than before injection) (Covey-Crump & Murison 2008). The activity
AC

score was included in case some excitement occurred during induction of anaesthesia.

Acepromazine (0.025 mg kg−1; ACP, 2 mg mL−1; Novartis, UK) and methadone (0.25 mg

kg−1; Comfortan, 10 mg mL−1 solution for injection; Dechra, UK) were combined in the same

syringe and administered into the cervical epaxial musculature. After administration of
 ACCEPTED MANUSCRIPT

preanaesthetic medication the dogs were kept in a kennel in a quiet area next to the anaesthesia

induction suite. Thirty minutes later, sedation and activity were scored and PR and fR measured

(Table 1). When the dog appeared to be relaxed, a catheter was inserted into a cephalic vein and

the dog was transferred into the anaesthesia induction suite and positioned in sternal recumbency

PT
on a table. Immediately before induction of anaesthesia, PR and fR were measured. Mean arterial

RI
pressure (MAP) was recorded using an appropriately sized cuff on the thoracic limb opposite to

the IV catheter (width 35–40 % of the circumference of the measuring site, on the thoracic limb

SC
above the carpus) (Cardell model 9401; Midmark Animal Health, FL, USA). Propofol (0.5 mg

kg−1; PropoFlo 28; Abbott Animal Health, UK) was injected by hand over 1–3 seconds to dogs

U
in the predosing group (group PP, n = 11) 2 minutes before commencing administration of
AN
propofol (4 mg kg−1 minute−1) IV using the syringe driver (T0; Table 1). In the control group

(group CP, n = 10) saline (equivalent volume to 0.5 mg kg−1 of propofol) was injected IV
M

manually as a rapid bolus 2 minutes before commencing administration of propofol (4 mg kg−1

D

minute−1) IV (T0). The third induction protocol was considered to be slow-induction (group SI, n
TE

= 10) and propofol (1.3 mg kg−1 minute−1) was administered to the dogs using the syringe driver

from the beginning of the induction phase (T0) until intubation. An anaesthetist who was aware
EP

of the treatment group started the process of induction of anaesthesia by administering the

propofol in PP, saline in CP or commencing the propofol infusion in SI. At 2 minutes (T2), this
C

same anaesthetist started the propofol infusion for dogs in PP and CP; the infusion rate to dogs in
AC

SI was unchanged. The infusion rate information on the syringe driver was covered. Then,

another investigator (MR) who was unaware of group assignments entered at 2 minutes after

commencing induction of anaesthesia to assess adequacy for tracheal intubation. Depth of

anaesthesia was continuously assessed using muscular tone, palpebral reflexes, eye rotation and
 ACCEPTED MANUSCRIPT

jaw tone. The dog was considered sufficiently relaxed to allow intubation when it attained lateral

recumbency with no spontaneous head, jaw or tongue movement in response to the anaesthetist

opening its mouth, and jaw tone was mild to absent. Propofol administration was stopped at that

point and the trachea was intubated with a cuffed endotracheal tube (T3). The cuff was initially

PT
inflated until the pressure in the pilot balloon assessed by palpation felt subjectively appropriate

RI
to the anaesthetist; at the end of data collection the cuff was deflated and re-inflated whilst

manual breaths were administered to the animal with the adjustable pressure limiting valve

SC
closed until no leak could be detected at a pressure of 20 cm H2O. If a dog became apnoeic

within 2 minutes of propofol administration, the anaesthetist aware of the treatment and in

U
charge of anaesthesia was instructed to stop drug administration, if appropriate, and manage the
AN
airway as necessary. The dog would have then been excluded from the study.

Anaesthesia was maintained with isoflurane vaporized in oxygen delivered via a

M

breathing system appropriate for the size of the dog. PR, fR and MAP were recorded before the
D

induction process was started (T0), 2 minutes later when the primary investigator re-entered the
TE

room (T2) and 0 (T3), 2 and 5 minutes after intubation (P1 and P2; Table 1). Dogs were

positioned in lateral recumbency for 5 minutes after intubation of the trachea. Apnoea >30
EP

seconds was recorded and managed (lungs were inflated manually twice a minute until return of

spontaneous ventilation). Quality of induction and endotracheal intubation were scored using
C

simple descriptive scales: Intubation score: 0, smooth (no swallowing, coughing, tongue or jaw
AC

movement); 1, fair (some tongue movement, slight cough); 2, poor (marked tongue or jaw

movement and swallowing
or coughing); 3, very poor (as 2 but requiring additional

propofol dose and second attempt at intubation) (Covey-Crump & Murison 2008). Quality

score: 0, smooth (without excitement); 1, fair (slight excitement, muscle twitching or

 ACCEPTED MANUSCRIPT

movement of limbs); 2, poor (marked excitement, muscle twitching, paddling of limbs, head

movements) (Covey-Crump & Murison 2008).

Once data collection was complete, the dogs were prepared for surgery or underwent the

procedure for which they were anaesthetized. Anaesthetic management was adjusted individually

PT
at the discretion of the main investigator.

RI
Statistical analysis

SC
Data were analysed using SPSS for Windows (SPSS 14.0, IL, USA) though SigmaPlot

for Windows Version 10.0 (Systat Software Inc, CA, USA) was used for re-analysis of the data

U
on propofol. Normal distribution of the data was checked using the Shapiro-Wilk test. One-way
AN
analysis of variance (ANOVA) was used for the propofol dose and Bonferroni post hoc test where
M

appropriate; repeated measures ANOVA for PR, fR and MAP; Chi squared exact test for sedation

and activity and quality scores; normal Chi squared for the incidence of apnoea. Significance
D

level was set at p < 0.05 and, unless stated differently, data are presented as mean ± standard
TE

deviation.
EP

Results

A total of 32 client-owned dogs (18 male, 13 female and one intersex, ASA I-II, aged 6–
C

144 months and weighing 3.5–47.2 kg) were recruited between August 2014 and March 2015.
AC

Demographic data were similar among groups (Table 2). Breed distribution was uneven among

the groups, involving 10 crossbreeds, four Springer Spaniels, three Cocker Spaniels and three

Labrador Retrievers, and one each of Collie, Flat Coated Retriever, German Shepherd, Miniature

Schnauzer, Patterdale, Rhodesian Ridgeback, Rottweiler, Staffordshire Bull Terrier, West

 ACCEPTED MANUSCRIPT

Highland White Terrier, Wire-haired Dachshund and Yorkshire Terrier. One dog in PP was

excluded due to perivascular propofol administration. Analysis was carried out on 11 dogs in PP

and 10 each in CP and SI.

Sedation and activity scores did not differ among groups (Table 3). No dog became

PT
apnoeic within the first 2 minutes of induction (between T0 and T2). Propofol dose requirement

RI
was lower in SI (3.7 ± 1.1 mg kg−1) compared with PP (5.0 ± 1.0 mg kg−1) and CP (4.8 ± 0.6 mg

kg−1) (p = 0.002, p = 0.012, respectively; Fig. 1). Quality of induction was smooth in all cases

SC
and similar among groups (Table 3). Median time (range) from T0 to T3 was 3.1 (2.9–3.6)

minutes in PP, 3.2 (3.0–3.4) minutes in CP and 2.6 (2.2–4.5) minutes in SI.

U
No statistically significant difference was found among groups for mean PR, fR, MAP or
AN
incidence of apnoea. Haemodynamic and respiratory variables were not different among groups

(Table 4). Between 1 and 4 dogs per group were apnoeic after induction of anaesthesia (χ2 2.14,
M

p = 0.340). Apnoea occurred in four dogs in PP, two in CP and one dog in SI.
D
TE

Discussion

The main finding of this study was that the speed of injection of propofol had an effect on
EP

the dose requirement, with a slower injection of propofol reducing the dose required for

endotracheal intubation in dogs. Early animal studies indicated that the rate of administration had
C

an impact on the dosage necessary to induce anaesthesia (Glen 1980). In the original study, faster
AC

rates (administration over 1 second) were associated with lower dosages when compared with

administration over 10 seconds in mice (Glen 1980). This is in contrast to later human studies

where slower administrations of propofol resulted in lower dosages necessary to lose verbal

command (Stokes & Hutton 1991). It is difficult to compare human and veterinary studies as the
 ACCEPTED MANUSCRIPT

goals and end point of induction of anaesthesia are different. In both cases propofol should

facilitate the transition from a conscious to an unconscious state, but in dogs propofol is also

used to induce a state suitable for airway management, such as laryngeal mask insertion or

tracheal intubation (Berry 2015). As in humans, slower administration of propofol in

PT
experimental sheep resulted in lower dosages necessary to induce anaesthesia (Ludbrook &

RI
Upton 1997). When using clinically relevant rates of administration of propofol in dogs in the

present study, a slower injection also resulted, as expected, in a lower total dose administered.

SC
Similar findings have recently been reported in cats in a pilot study (Bauquier et al. 2017).

Modes, dosages and speed of injection of propofol for co-induction of anaesthesia in dogs

U
are extremely variable in the literature. Target-controlled infusion (TCI) has been used in several
AN
studies (Musk & Flaherty 2007; Auckburally et al. 2008; Mair et al. 2009; Minghella et al.

2016). Hand injection has also been proposed with variable rates of administration: 4 mg kg−1 as
M

rapid boluses (Lerche et al. 2000), 4 mg kg minute−1 up to 6.5 mg kg−1 over approximately 40
D

seconds (Jolliffe et al. 2007; Covey-Crump & Murison 2008; Robinson & Borer-Weir 2013), 1–
TE

2 mg kg−1 over 30–40 seconds followed by incremental boluses of 0.5 mg kg−1 every 15 seconds

(Sánchez et al. 2013; Panti et al. 2015). This variability confounds comparisons between studies.
EP

In this study, a syringe driver was used for all the inductions to standardize the speed of injection

and to maintain the blinding of the principal investigator. The speed of injection in the PP and
C

CP groups was chosen to be at the lowest end of the manufacturer’s recommendation (4 mg kg

AC

minute−1). For the SI group, the speed was selected to provide an estimated induction

requirement (4 mg kg−1) over a period of 3 minutes, designed to be an equivalent duration to our

estimates of duration of the induction in PP group i.e. 2 minutes predosing and 1 minute titration

to effect).
 ACCEPTED MANUSCRIPT

Given the clinical end points for endotracheal intubation and the number of clinical

measurements during the induction process, it is possible that administering propofol via syringe

driver meant that larger doses were administered compared with intermittent injection

techniques. In fact, dosages of propofol used in the present study were higher than reported in

PT
other co-induction studies with comparable premedications (Covey-Crump & Murison 2008;

RI
Robinson & Borer-Weir 2013; Sánchez et al. 2013). In experimental sheep, it was shown that the

peak in anaesthesia depth was reached 2 to 3 minutes after cessation of propofol administration

SC
(Ludbrook & Upton 1997). The hypothesis that predosing would reduce propofol requirement

was not supported at the dose rates of administration used in this study. This could be a

U
consequence of the technique used for induction of anaesthesia. Another limitation is that the
AN
method of assessment of anaesthetic depth was not very precise. Propofol was administered

rapidly to dogs in PP and CP, and a further 1 mg kg−1 of propofol would have been administered
M

during 15 seconds of assessment of anaesthetic depth. Since it takes propofol some minutes to
D

reach peak effect after the infusion is stopped, the animals in these groups would be more deeply
TE

anaesthetized than in the SI group where the rate of propofol administration was slower

(Ludbrook & Upton 1997). With hindsight, rather than continuous administration, incremental
EP

boluses of propofol at predefined intervals may have been more appropriate.

Many co-induction studies in dogs (excepting those involving ketamine) report a

C

reduction in the propofol dose necessary to induce anaesthesia but, in common with this study,
AC

no clinically relevant differences in the cardiovascular and respiratory effects have been captured

with the noninvasive ways used to measure the variables (Auckburally et al. 2008; Covey-Crump

& Murison 2008; Hopkins et al. 2013; Sánchez et al. 2013; Cerasoli et al. 2016; Minghella et al.

2016). Invasive monitoring of additional variables, such as arterial pressure, cardiac output and
 ACCEPTED MANUSCRIPT

arterial blood gas analysis, might show relevant differences but would not reflect common

anaesthetic practice in healthy animals undergoing procedures within a clinical environment. In

the absence of clinically evident effects on the cardiovascular and respiratory systems in healthy

animals, the value of dose reduction of propofol is questionable. In human patients, some

PT
evidence suggests no correlation between speed of injection of propofol and physiological effects

RI
(Short & Aun 1991; Lam et al. 2013), and prolonged induction time actually may increase the

risk of complications such as desaturation (McNally et al. 2009; Naguib et al. 2016) or aspiration

SC
(Sellick 1961). There are limits to how slow the propofol injection can be given, both practically

(time taken to induce anaesthesia) and clinically (the animal would never be anaesthetized if the

U
clearance rate equals the infusion rate). In dogs, rapid sequence induction provides suitable
AN
conditions for orotracheal intubation, frequent apnoea and a decrease in arterial pressure

comparable to that observed with slow TCI propofol inductions (Musk et al. 2005; Amengual et
M

al. 2012). Apnoea and decrease in arterial pressure could be expected with any induction
D

technique. It is possible that in sick or debilitated animals reducing the dose of propofol required
TE

for induction may have beneficial effects on the cardiovascular and respiratory systems.

However, in these cases it may be inappropriate to extrapolate the results of the majority of co-
EP

induction studies that are performed with healthy subjects (to standardise the population), where

responses to the drugs and doses may be very different.

C

A low number of dogs was included in the study. Whereas the study was appropriately
AC

powered to show difference between the control and the slow induction groups, a post hoc power

calculation revealed that 66 dogs per group would have been necessary to show significant

difference in the propofol dose between control and predosing. A larger number of dogs was not

recruited as the investigators had concerns that the induction technique was not clinically useful
 ACCEPTED MANUSCRIPT

and thus there was limited benefit to collecting more data. Cardiovascular and respiratory data

were also highly variable meaning that a higher number of animals would have been necessary to

show significant differences.

In dogs premedicated with acepromazine and methadone, anaesthesia was induced with

PT
propofol at the rate recommended by the manufacturer, preceded (predosing group) or not

RI
(control group) by propofol predosing or at a slower rate (slow induction group) corresponding

to the expected dose of the control group over the duration of the predosing group. Although this

SC
study failed to show any beneficial effect of the propofol predosing, a slower injection of

propofol reduced the dose required to allow endotracheal intubation in healthy dogs. This

U
reinforces data previously reported in other species. The speed of injection is of particular
AN
importance in studies focusing on the anaesthesia induction dose of propofol.
M

Acknowledgements
D

The authors thank the anaesthesia team at Langford Veterinary Services, University of Bristol for
TE

their assistance, the surgery clinicians for help with dog enrolment, Prof Toby Knowles,

University of Bristol, and Dr Olivier Levionnois, University of Bern, for statistical advice and Dr
EP

Gwen Covey-Crump, University of Bristol, for contributions to project development.

C

Authors’ contributions
AC

MR: study design, data management, interpretation and statistical analysis, preparation of the

manuscript; EJL: study design, data management, interpretation and statistical analysis,

preparation and revision of the manuscript; PJM: study design, data management, interpretation

and statistical analysis, revision of the manuscript.

 ACCEPTED MANUSCRIPT

Conflict of interest statement

Authors declare no conflict of interest.

PT
RI
USC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

References

Amengual M, Flaherty D, Auckburally A et al. (2012) An evaluation of anaesthetic induction in

healthy dogs using rapid intravenous injection of propofol or alfaxalone. Vet Anaesth Analg

40, 115–123.

PT
Anderson L, Robb H (1998) A comparison of midazolam co-induction with propofol predosing

RI
for induction of anaesthesia. Anaesthesia 53, 1117–1120.

Auckburally A, Pawson P, Flaherty D (2008) A comparison of induction of anaesthesia using a

SC
target-controlled infusion device in dogs with propofol or a propofol and alfentanil

admixture. Vet Anaesth Analg 35, 319–325.

U
Bauquier SH, Bayldon W, Warne LN et al. (2017) Influence of two administration rates of
AN
propofol at induction of anaesthesia on its relative potency in cats: a pilot study. J Feline

Med Surg 19, 1297–1301.

M

Berry SH (2015) Injectable anesthetics. In: Lumb & Jones' Veterinary Anesthesia and Analgesia
D

(5th edn). Grimm KA, Lamont LA, Tranquilli WJ et al. (eds). Wiley Blackwell, USA. pp.
TE

277–296.

Braun C, Hofmeister EH, Lockwood AA, Parfitt SL (2007) Effects of diazepam or lidocaine
EP

premedication on propofol induction and cardiovascular parameters in dogs. J Am Anim

Hosp Assoc 43, 8–12.

C

Cerasoli I, Nannarone S, Schauvliege S et al. (2016) The effects of intravenous lidocaine before
AC

propofol induction in premedicated dogs. J Small Anim Pract 57, 435–440.

Covey-Crump GL, Murison PJ (2008) Fentanyl or midazolam for co-induction of anaesthesia

with propofol in dogs. Vet Anaesth Analg 35, 463–472.

Djaiani G, Ribes-Pastor M (1999) Propofol auto-co-induction as an alternative to midazolam co-

 ACCEPTED MANUSCRIPT

induction for ambulatory surgery. Anaesthesia 54, 63–67.

Fayyaz S, Kerr CL, Dyson DH, Mirakhur KK (2009) The cardiopulmonary effects of anesthetic

induction with isoflurane, ketamine-diazepam or propofol-diazepam in the hypovolemic dog.

Vet Anaesth Analg 36, 110–123.

PT
Glen JB (1980) Animal studies of the anesthetic activity of ICI 35 868. Br J Anaesth 52, 731–

RI
742.

Henao-Guerrero N, Riccó CH (2014) Comparison of the cardiorespiratory effects of a

SC
combination of ketamine and propofol, propofol alone, or a combination of ketamine and

diazepam before and after induction of anesthesia in dogs sedated with acepromazine and

oxymorphone. Am J Vet Res 75, 231–239.

U
AN
Hopkins A, Giuffrida M, Larenza MP (2013) Midazolam, as a co-induction agent, has propofol

sparing effects but also decreases systolic blood pressure in healthy dogs. Vet Anaesth Analg
M

41, 64–72.
D

Jolliffe CT, Leece EA, Adams V, Marlin DJ (2007) Effect of intravenous lidocaine on heart rate,
TE

systolic arterial blood pressure and cough responses to endotracheal intubation in propofol-

anaesthetized dogs. Vet Anaesth Analg 34, 322–330.

EP

Kataria R, Singhal A, Prakash S, Singh I (2010) A comparative study of efficacy of propofol

auto-co-induction versus midazolam propofol co-induction using the priming principle.

C

Indian J Anaesth 54, 558–561.

AC

Lam F, Liao CC, Lee YJ et al. (2013) Different dosing regimens for propofol induction in obese

patients. Acta Anaesthesiol Taiwan 51, 53–57.

Lerche P, Nolan AM, Reid J (2000) Comparative study of propofol or propofol and ketamine for

the induction of anaesthesia in dogs. Vet Rec 146, 571–574.

 ACCEPTED MANUSCRIPT

Ludbrook GL, Upton RN (1997) A physiological model of induction of anaesthesia with

propofol in sheep. 2. Model analysis and implications for dose requirements. Br J Anaesth

79, 505–513.

Mair AR, Pawson P, Courcier E, Flaherty D (2009) A comparison of the effects of two different

PT
doses of ketamine used for co-induction of anaesthesia with a target-controlled infusion of

RI
propofol in dogs. Vet Anaesth Analg 36, 532–538.

Martinez-Taboada F, Leece EA (2014) Comparison of propofol with ketofol, a propofol-

SC
ketamine admixture, for induction of anaesthesia in healthy dogs. Vet Anaesth Analg 41,

575–582.

U
McNally EM, Robertson SA, Pablo LS (2009) Comparison of time to desaturation between
AN
preoxygenated and nonpreoxygenated dogs following sedation with acepromazine maleate

and morphine and induction of anesthesia with propofol. Am J Vet Res 70, 1333–1338.
M

Minghella E, Auckburally A, Pawson P et al. (2016) Clinical effects of midazolam or lidocaine

D

co-induction with a propofol target-controlled infusion (TCI) in dogs. Vet Anaesth Analg 43,
TE

472–481.

Musk GC, Flaherty DA (2007) Target-controlled infusion of propofol combined with variable
EP

rate infusion of remifentanil for anaesthesia of a dog with patent ductus arteriosus. Vet

Anaesth Analg 34, 359–364.

C

Musk GC, Pang DSJ, Beths T, Flaherty DA (2005) Target-controlled infusion of propofol in
AC

dogs – evaluation of four targets for induction of anaesthesia. Vet Rec 157, 766–770.

Naguib M, Brewer L, LaPierre C et al. (2016) The myth of rescue reversal in ‘can’t intubate,

can’t ventilate’ scenarios. Anesth Analg 123, 82–92.

Panti A, Cafrita IC, Clark L (2015) Effect of intravenous lidocaine on cough response to
 ACCEPTED MANUSCRIPT

endotracheal intubation in propofol-anaesthetized dogs. Vet Anaesth Analg 43, 405–411.

Robinson R, Borer-Weir K (2013) A dose titration study into the effects of diazepam or

midazolam on the propofol dose requirements for induction of general anaesthesia in client

owned dogs, premedicated with methadone and acepromazine. Vet Anaesth Analg 40, 455–

PT
463.

RI
Sánchez A, Belda E, Escobar M et al. (2013) Effects of altering the sequence of midazolam and

propofol during co-induction of anaesthesia. Vet Anaesth Analg 40, 359–366.

SC
Sellick BA (1961) Cricoid pressure to control regurgitation of stomach contents during induction

of anaesthesia. Lancet 2, 404–406.

U
Short SM, Aun CST (1991) Haemodynamic effects of propofol in children. Anaesthesia 46, 783–
AN
785.

Srivastava U, Sharma D, Kumar A, Saxsena S (2006) Small dose propofol or ketamine as an

M

alternative to midazolam co-induction to propofol. Indian J Anaesth 50, 112–114.

D

Stokes DN, Hutton P (1991) Rate-dependent induction phenomena with propofol: implications
TE

for the relative potency of intravenous anesthetics. Anesth Analg 72, 578–583.

Thompson KR, Rioja E (2015) Effects of intravenous and topical laryngeal lidocaine on heart
EP

rate, mean arterial pressure and cough response to endotracheal intubation in dogs. Vet

Anaesth Analg 43, 371–378.

C

Whitwam JG (1995) Co-induction of anaesthesia: day-case surgery. Eur J Anaesthesiol Suppl 12,
AC

25–34.
 ACCEPTED MANUSCRIPT

Table 1 Timeline for evaluation of three propofol protocols for intravenous induction of

anesthesia (time points T0–T3) in dogs sedated with acepromazine and methadone: group PP,

propofol (0.5 mg kg−1) injected over 3 seconds at T0 and an infusion (4 mg kg−1 minute−1)

starting 2 minutes later at T2; group CP, saline (0.05 mL kg−1) injected at T0 and an infusion of

PT
propofol (4 mg kg−1 minute−1) starting at T2; and group SI, propofol infusion (1.3 mg kg−1

RI
minute−1) starting at T0. All propofol infusions were discontinued at the time of tracheal

intubation (T3).

SC
Measurements Time point

Baseline Premedication Induction of anesthesia Time after

U intubation
AN
T0 T2 T3 P1 P2
M

Physiological PR PR PR PR PR PR PR

fR fR fR fR fR fR fR
D

MAP MAP MAP MAP MAP

TE

Scoring Sedation Sedation

Activity Activity Activity

EP

Intubation

quality
C

Baseline, no drugs; Premedication, 30 minutes after intramuscular acepromazine and methadone;

AC

T0, immediately before induction of anaesthesia; T2, two minutes of protocol administration; T3,

tracheal intubation and discontinuation of propofol infusion; P1, 2 minutes after intubation; P2, 5

minutes after intubation; PR, pulse rate; fR, respiratory rate; MAP, mean arterial pressure.
 ACCEPTED MANUSCRIPT

Table 2 Details of 31 dogs anaesthetized with 3 protocols, control-propofol (CP), propofol pre-

dosing (PP) and propofol slow induction (SI).

Demographic Group

PT
CP PP SI

RI
Sex (m:f:i) 5(2N):5(1N):0 7(0N):3(1N):1 5(4N):5(0N):0

ASA (I:II) 3:7 5:6 3:7

SC
Age (months) 48.9 (6–122) 38.1 (6–103) 56.2 (6–144)

Body weight (kg) 25.2 (4.5–47.2) 14.3 (3.5–20.1) 21.8 (7.4–

U 41.0)
AN
M

m, male; f, female; i, intersex; N, neutered; ASA (I:II), American Society of Anesthesiologists

Class I or II.
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 3 Scores of sedation before and 30 minutes after premedication, activity before induction

of anaesthesia, quality of induction and intubation and number of apnoeic animals after induction

in dogs that were administered one of three induction protocols: control–propofol (CP),

propofol–predosing (PP) and propofol slow induction (SI). Data are median (range).

PT
RI
Scoring system Group Results

Sedation score CP 0 (0-0)

SC
at baseline PP 0 (0-0)

(0–3) SI 0 (0-0)

Sedation score CP 2 (1-2)

U
AN
at 30 minutes after PP 2 (1-3)
M

premedication SI 2 (1-3)

(0–3)
D

Activity score CP 0 (0-0)

TE

at 30 minutes after PP 0 (0-0)

premedication SI 0 (0-0)
EP

(0–2)

Intubation score CP 0 (0-0)

C

(0–3) PP 0 (0-1)
AC

SI 0 (0-1)

Quality score CP 0 (0-0)

(0–2) PP 0 (0-0)

SI 0 (0-0)
 ACCEPTED MANUSCRIPT

Apnoea after CP 2

induction PP 4

(number of dogs) SI 1

Sedation score: 0, no sedation; activity score: 0, sedation and 2, excitement; intubation score: 0,

PT
best conditions for intubation; quality score: 0, best quality of induction.

RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Table 4 Pulse rate (PR), mean arterial pressure (MAP), and respiratory rate (fR) before and 30

minutes after premedication, during induction of anaesthesia (T0–T2), immediately after

endotracheal intubation (T3) and at 2 (P1) and 5 minutes (P2) after endotracheal intubation in 31

dogs assigned to one of three induction protocols: control–propofol (CP), propofol–predosing

PT
(PP) and propofol slow induction (SI). Data are mean ± standard deviation.

RI
Variable Group Time points

Premedi

SC
Baseline T0 T2 T3 P1 P2
cation

PR CP 117 ± 19 100 ± 19 97 ± 21 99 ± 29 123 ± 37 113 ± 33 113 ± 33

(beats PP 117 ± 22 72 ± 13
U
80 ± 19 83 ± 19 94 ± 20 86 ± 20 86 ± 18
AN
minute−1) SI 104 ± 15 76 ± 14 81 ± 17 95 ± 19 90 ± 25 87 ± 23 82 ± 27
M

MAP CP 105 ± 17 91 ± 25 95 ± 17 86 ± 12 89 ± 14

(mmHg) PP 108 ± 21 99 ± 33 85 ± 21 80 ± 10 81 ± 9
D

SI 107 ± 17 102 ± 29 102 ± 17 91 ± 15 93 ± 18

TE

fR CP 52 ± 46 75 ± 75 53 ± 38 49 ± 55 10 ± 11 14 ± 13 19 ± 14

(breaths PP 59 ± 59 55 ± 36 57 ± 51 47 ± 40 7±8 10 ± 7 21 ± 18
EP

minute−1) SI 118 ± 93 58 ± 68 50 ± 37 35 ± 27 24 ± 21 27 ± 21 31 ± 37
C
AC
 ACCEPTED MANUSCRIPT

Figure 1 Propofol dose requirement for induction of anaesthesia in healthy dogs premedicated

with acepromazine (0.025 mg kg−1) and methadone (0.25 mg kg−1) intramuscularly 30 minutes

before induction of anaesthesia with intravenous propofol (4 mg kg−1 minute−1; group CP, n =

10), administration of propofol (0.5 mg kg−1) 2 minutes before propofol (4 mg kg−1 minute−1;

PT
group PP, n = 11) or propofol (1.3 mg kg−1 minute−1; group SI, n = 10). Propofol was

RI
discontinued at the time of endotracheal intubation. Data are mean ± standard deviation.

*Significantly different from PP (p = 0.002) and CP (p = 0.012).

U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC