Content uploaded by Francisco J Funes
Author content
All content in this area was uploaded by Francisco J Funes on Dec 19, 2021
Content may be subject to copyright.
RESEARCH PAPER
Anaesthetic and cardiorespiratory effects of a constant
rate infusion of fentanyl in isoflurane-anaesthetized sheep
Francisco J Funes*, Mar
ıa del Mar Granados*, Juan Morgaz*, Roc
ıo Navarrete*, Andr
es Fern
andez-Sarmiento*,
Rafael G
omez-Villamandos*, Pilar Mu~
noz*, Setefilla Quir
os*, Jos
e M Carrillo†, Ignacio L
opez-Villalba* &
Juan M Dominguez*
*Anaesthesia Unit, Department of Animal Medicine and Surgery, Veterinary Faculty, University of C
ordoba, C
ordoba, Spain
†Department of Animal Medicine and Surgery, Veterinary Faculty, CEU-Cardenal Herrera University, Valencia, Spain
Correspondence: Francisco J Funes, Anaesthesia Unit, Department of Animal Medicine and Surgery, Veterinary Faculty, University of
C
ordoba, C
ordoba 14014, Spain. E-mail: funescagno@hotmail.com
Abstract
Objective To determine the anaesthetic and cardio-
respiratory effects of a constant rate infusion of
fentanyl in sheep anaesthetized with isoflurane and
undergoing orthopaedic surgery.
Study design Prospective, randomised, ‘blinded’
controlled study.
Animals Twenty healthy sheep (weight mean
41.1 SD 4.5 kg).
Methods Sheep were sedated with intravenous
(IV) dexmedetomidine (4 lgkg
1
) and morphine
(0.2 mg kg
1
). Anaesthesia was induced with prop-
ofol (1 mg kg
1
minute
1
to effect IV) and main-
tained with isoflurane in oxygen and a continuous
rate infusion (CRI) of fentanyl 10 lgkg
1
hour
1
(group F) or saline (group P) for 100 minutes. The
anaesthetic induction dose of propofol, isoflurane
expiratory fraction (FE′iso) required for maintenance
and cardiorespiratory measurements were recorded
and blood gases analyzed at predetermined intervals.
The quality of recovery was assessed. Results were
compared between groups using t-tests or Mann–
Whitney as relevant.
Results The propofol induction dose was
4.7 2.4 mg kg
1
.FE′iso was significantly lower
(by 22.6%) in group F sheep than group P (p=0).
Cardiac index (mean SD mL kg
1
minute
1
)
was significantly (p=0.012) lower in group F
(90 15) than group P (102 35). Other mea-
sured cardiorespiratory parameters did not differ
statistically significantly between groups. Recovery
times and recovery quality were statistically similar
in both groups.
Conclusions and clinical relevance Fentanyl
reduced isoflurane requirements without clinically
affecting the cardiorespiratory stability or post-
operative recovery in anaesthetized sheep undergo-
ing orthopaedic surgery.
Keywords anaesthesia, cardiopulmonary, fentanyl,
isoflurane, sheep.
Introduction
Sheep commonly serve as surgical research ani-
mals, and the care and the welfare of animals
enrolled in biomedical research are of paramount
importance. Inhalation anaesthesia using isoflura-
ne in sheep produces a dose-dependent cardiovas-
cular and respiratory depression (Hikasa et al.
2000; Mohamadnia et al. 2008) that could be
limited by its combination with other drugs such as
anaesthetics or analgesics. The use of opioids
intraoperatively is now routine practice as part of
a balanced anaesthetic technique, and in most (but
not all) species they reduce the amount of inhala-
157
Veterinary Anaesthesia and Analgesia, 2015, 42, 157–164 doi:10.1111/vaa.12216
tional or intravenous anaesthetic agents required
to obtund responses to surgical stimuli (Dzikiti
et al. 2010).
Fentanyl is classified as a pure agonist with
potency approximately 100 times that of morphine
(Van Wijngaarden & Soudijn 1968; Stanley 1992)
and is suitable for intravenous (IV) continuous rate
infusion (CRI) because it offers clinically desirable
effects over a wide dose range and has a wide
therapeutic margin (Meredith et al. 2008). Fentanyl
has been shown to reduce the MAC of volatile
anaesthetics in many species, and is now the opioid
used most frequently for supplementation of anal-
gesia during general anaesthesia. Potential side
effects, however, include respiratory depression,
bradycardia, and hypotension (Tranquilli et al.
2007).
The literature on the use of fentanyl in small
ruminants is limited. Waterman et al. (1990)
described a clinically useful period of analgesia in
sheep receiving fentanyl bolus, although some side
effects were recorded. Dzikiti et al. (2010, 2011)
observed respiratory depression and a decrease in
mean arterial blood pressure and heart rate in goats
following fentanyl administration during anaesthe-
sia. Abnormal behavioural signs and restlessness
were observed during recovery of anaesthesia after
fentanyl administration in goats (Dzikiti et al. 2010)
and sheep (Waterman et al. 1990).
Adequate plasma concentrations of fentanyl are
needed during anaesthesia in order to retain signif-
icant antinociceptive and inhalational agent sparing
effect, and this is best achieved using a CRI.
However, Sano et al. (2006) observed that the
elimination of fentanyl was influenced by the dura-
tion of the CRI administration due to its high
liposolubility. Such accumulation could theoreti-
cally prolong the recovery, which could increase the
risk of regurgitation and tympany in sheep.
The use of fentanyl CRI during inhalation anaes-
thesia in sheep has only been described in cardiac
surgery (Kronen et al. 2005; Schauvliege et al.
2006; Levionnois & Kronen 2008), but to the
authors’ knowledge, currently there are no studies
in the literature using fentanyl CRI during inhala-
tion anaesthesia in sheep undergoing experimental
orthopaedic surgery.
We hypothesised that a fentanyl CRI during
isoflurane anaesthesia in sheep would provide
adequate analgesia for surgery while reducing
isoflurane requirements and thus the associated
cardiopulmonary depression. The purpose of the
study was to evaluate the anaesthetic and cardiore-
spiratory effects of the administration of a fentanyl
CRI during isoflurane anaesthesia in sheep under-
going orthopaedic surgery.
Materials and methods
Animals
After institutional ethical committee approval by the
University of C
ordoba Animal Care and Use Commit-
tee, 20 adult female Merino sheep with a mean SD
body weight of 41.1 4.5 kg were used for the
study. All sheep were considered healthy based on
clinical examination, haematology, and serum
chemistry blood work before the study. All sheep
were kept in a large pen in groups with daily access to
pasture. The day before the experiment, the animals
were weighed and moved in pairs into smaller pens
(3 m
2
). Food was withheld for 24 hours, but water
was available ad libitum before surgery. All sheep
underwent experimental orthopaedic surgery on the
right pelvic limb as part of another study. Surgery
was performed always by the same surgeon.
Study design
A prospective, randomised, ‘blinded’ controlled
study was designed. Sheep were allocated randomly
into two groups of ten animals each and, during
maintenance of anaesthesia with isoflurane, were
administered either fentanyl 10 lgkg
1
hour
1
IV
(group F) or, as a placebo, the same volume of saline
(group P). Ringer’s lactate solution (Ringer Lactate;
B. Braun, Spain) was administered IV at a rate of
10 mL kg
1
hour
1
.
Heart rate (HR), respiratory rate (f
R
), and body
temperature (T) were recorded before premedication
(baseline). A 14-gauge over-the-needle catheter was
placed aseptically into the left jugular vein. A venous
blood sample was obtained for measurement of blood
gas values (Gasometer Ciba-Corning, Model 850;
Chiron Diagnostics, Spain).
All sheep were premedicated IV with dexmede-
tomidine (Dexdomitor; Orion Pharma, Spain;
4lgkg
1
) and morphine (Morfina 2%; B. Braun;
0.2 mg kg
1
). Thirty minutes (range 25–35 min-
utes) following preanaesthetic medication, the sheep
were anaesthetized. Prior to anaesthesia, 5 L min-
ute
1
of 100% oxygen was administered for 5 min-
utes by mask. Anaesthesia was then induced
with propofol (1% Propofol Lipuro; B. Braun)
158 ©2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 157–164
Fentanyl in anaesthetized sheep FJ Funes et al.
administered through the left jugular catheter at a
rate of 1 mg kg
1
minute
1
until endotracheal
intubation was possible. The propofol dose required
for induction was recorded. Five minutes after
endotracheal intubation, venous and arterial blood
samples were drawn from the left jugular vein and
the left femoral artery (by needle puncture), respec-
tively, for blood gas pH determination. Body tem-
perature was maintained between 37.5 and 38.5 °C
by the use of a forced warmed air blanket (Equator
TM convective warming; Smiths Medical ASD, UK).
Anaesthesia was maintained with isoflurane
(IsoVet; B. Braun VetCare SA) vaporized in 100%
oxygen (IsoTec 5; Datex-Ohmeda, UK) and delivered
through a rebreathing circle system (S/5 Avance;
Datex-Ohmeda anaesthesia machine, Finland). The
sheep in group F were also administered a CRI of
fentanyl (10 lgkg
1
hour
1
); group P received a
CRI of the same volume of saline. The animals were
allowed to breathe spontaneously. The vaporizer
was set initially at 3% with a fresh gas flow of
50 mL kg
1
minute
1
during the first 5 minutes.
Vaporizer and fresh gas flow were then reduced to
1.5% and 20 mL kg
1
minute
1
, respectively, and
thereafter the vaporizer was adjusted according to
depth of anaesthesia. The depth of anaesthesia was
evaluated every 10 minutes based on clinical signs
including palpebral reflexes, ocular position, absence
of movement in response to surgical stimulation,
and absence of autonomic response (changes in
blood pressure, HR, and f
R
). If no changes were
detected, the vaporizer setting was decreased so as to
achieve a 0.2% reduction in the isoflurane expira-
tory fraction (FE′iso). When the depth of anaesthesia
was considered light, the vaporizer setting was
increased so as to achieve a 0.2% increase in FE′iso
and surgical manipulation was stopped when nec-
essary. This process was repeated until anaesthetic
depth was adequate to perform surgery. The same
anaesthetist (MMG), unaware of the group, carried
out the depth of anaesthesia assessments in all
animals. The required FE′iso to maintain an ade-
quate depth of anaesthesia was recorded.
Monitoring
Physiologic parameters were monitored with a mul-
tiparametric monitor (S/5 Datex-Ohmeda multipara-
metric monitor). Immediately following anaesthetic
induction and endotracheal intubation, the electro-
cardiogram and inspiratory and expiratory gas con-
centrations were measured. A 14 gauge 20 cm
catheter (Certofix; B. Braun Melsungen AG, Ger-
many) then was placed into the right jugular vein and
advanced to the cranial cava vein for measurement
of central venous pressure (CVP) measurement. A
5-French, 50 cm thermodilution catheter (Pulsio-
cath; Pulsion Medical Systems, Germany) was placed
into the left femoral artery and connected to a
pressure transducer (PiCCO Monitoring Kit; Pulsion
Medical Systems). The transducer was placed at the
level of the left atrium, using the manubrium as
reference; the transducer was then zeroed to atmo-
spheric pressure and was connected to the cardiac
output monitor (PiCCO Plus monitor; Pulsion Med-
ical Systems). Calibration was carried out using three
boluses of 10 mL dextrose 5% at a temperature below
8°C injected through the right jugular catheter. The
cardiac output (CO) was calculated from the area
under the arterial pulse curve. PiCCO Plus monitors
the arterial pulse contour and analyzes it to estimate
aortic compliance. From these values, the algorithm
of the pulse contour is calibrated and continuously
measures the stroke volume (SV) of each heartbeat.
Forty-five minutes were needed for instrumentation.
Surgery started at minute 55.
From minute 45 of anaesthesia (after instrumen-
tation and before the beginning of the surgery) and
every 5 minutes up to 100 minutes of anaesthesia,
the following parameters were recorded from the
PiCCO Plus monitor: MAP, systolic and diastolic
arterial pressures (SAP, DAP), CO, systemic vascular
resistance (SVR), stroke volume (SV), stroke volume
variation (SVV), and contractility (dPmx). Cardiac
index (CI), systemic vascular resistance index
(SVRI), and stroke index (SI) were calculated to
bodyweight (i.e. per kg).
End-tidal carbon dioxide (PE′CO
2
), f
R
, HR, and CVP
were measured with the multiparametric monitor
and recorded every 5 minutes during the whole
anaesthesia procedure. Arterial blood samples were
drawn 5, then every 30 minutes after induction of
anaesthesia (T5, T 30, T 60, T 90). Venous and
arterial blood samples were obtained using a hepa-
rinised 1 mL syringe; and blood gas and pH
measured immediately after sample collection.
At the end of the surgery, the vaporizer was
turned off and the fentanyl or saline infusions were
stopped and the sheep were moved to a recovery box.
Recovery
Time to first swallowing attempt, time to first chew-
ing attempt-extubation, and time to maintained
159©2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 157–164
Fentanyl in anaesthetized sheep FJ Funes et al.
head lifted for 5 minutes were recorded (Mohamad-
nia et al. 2008).
The recovery quality was evaluated using a
numerical rating scale from 1 to 4 as follows:
1=poor: marked excitement or struggling and need
for restraint, hyperkinetic when assisted, prolonged
paddling and swimming motion, unable to assume
sternal recumbency or difficulty in maintaining
sternal or standing position; 2 =fair: minor excite-
ment, restlessness but no need for restraint or both;
3=good: relatively smooth recovery and minimal
vocalization, requires assistance to sternal recum-
bency or standing, quiet in sternal recumbency;
4=excellent: smooth recovery, assumes sternal
recumbency with little or no struggling, and may
attempt to stand and walk with little or no difficulty
(Ambros et al. 2008). Once the sheep were stand-
ing, morphine 0.2 mg kg
1
was administered intra-
muscularly (IM) every 4 hours for 24 hours
postoperatively. Buprenorphine (Buprex; RB Phar-
maceuticals Limited, UK) 0.02 mg kg
1
was admin-
istered IM every 6 hours for another 48 hours.
Nonsteroidal anti-inflammatory agents were not
used in order to avoid interferences with the
orthopaedic study.
Statistical analysis
All statistical analyses were performed with the
statistical package SPSS (version 15.0 for Windows;
IBM Corp., UK). Data were checked for normal
distribution using the Kolmogorov–Smisnov test.
Groups were analysed as two independent samples
using a t-test. Comparisons were made to detect
differences between groups for each variable during
the whole procedure and recovery times. In order to
evaluate parameters throughout anaesthesia, data
were compared every 5 minutes between groups.
Blood gases data were compared between groups at
baseline and at minutes 5, 30, 60, and 90.
Additionally, HR, f
R
and pH, values recorded during
anaesthesia were compared with baseline values.
The quality of recovery was assessed using a
numerical rating scale and compared with Mann–
Whitney tests. All data are presented as mean SD
or median (range) as relevant. A value of p<0.05
was considered significant.
Results
There were no significant differences between groups
in the age, sex, or weight of the animals or for the
anaesthesia time (fentanyl group 100 23 min-
utes versus placebo group 102 34 minutes).
The FE′iso was 1.06 0.28 vol% in group F and
1.37 0.57 vol% in group P with significant
differences between groups (p=0). The average
isoflurane requirements were 22.6% lower in sheep
given fentanyl CRI. Isoflurane requirements
decreased progressively along the anaesthesia in
the fentanyl group (Fig. 1a; Table S1).
Cardiac index (Table 1) was the only cardiovas-
cular parameter statistically significantly different
(a)
(b)
5
0.60
0.130
0.120
0.110
0.100
Mean CI Mean FE’Iso
0.090
0.080
0.070
0.80
1.00
1.20
1.40
1.60
Protocol
Fentanyl
Placebo
Protocol
Fentanyl
Placebo
10 15 20 25 30 35 40 45 50
Time
Time
55 60 65 70 75 80 85 90 95
35 40 45 50 55 60 65 70 75 80 85 90 95
100
Figure 1 Mean isoflurane expiratory fraction (FE0iso;
Fig 1a) and cardiac index (CI; Fig 1b) during 100 minutes
in sheep in which anaesthesia was maintained with
isoflurane. CI was measured only from minutes 45 to
100. The sheep received either a continuous rate infusion
of 10 lgkg
1
hour
1
fentanyl (group F) or an equal
volume of saline (group P). For standard deviations, see
Tables S1 and S2.
160 ©2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 157–164
Fentanyl in anaesthetized sheep FJ Funes et al.
between groups. CI was lower (90 15 versus
102 35 mL kg
1
minute
1
) in animals anaes-
thetized with fentanyl and isoflurane (p=0.012;
Fig. 1b; Table S2).
There were no significant differences between
groups in dPmx, CVP, SI arterial blood pressures,
SVV, or SVRI (Table 1, Table S2). The f
R
was
significantly lower (19 7versus 23 7 breaths
minute
1
) in group F (p=0; Table 1). Throughout
anaesthesia, when parameters were compared every
5 minutes, f
R
in group F was significantly lower than
in group P from minutes 65 to 80 (Table S1)
Although CI was lower in the fentanyl group during
the whole procedure, no statistical differences
between groups were found at specific time points.
No significant differences were found in PaO
2
or in
PaCO
2
, between groups (Tables 1 and 2).
Recovery
In group F and group P respectively times in minutes
to first swallowing were 7 9 and 6 4; to
chewing attempt-extubation, 12 11 and 9 4;
to maintain the head lifted for 5 minutes, 34 21
and 38 12 minutes. These recovery times did not
differ significantly between groups.
The quality of recovery was statistically similar in
both groups. In group F, three animals scored 1
(worst quality recovery), one scored 2, four ewes
scored 3, and two scored 4. In group P, one sheep
scored 1, one scored 2; six scored 3 and two scored 4.
Discussion
The administration of a fentanyl CRI in sheep
reduced isoflurane requirements and maintained
cardiorespiratory function without affecting the
recovery times or quality. Cardiorespiratory param-
eters measured were similar in both groups except CI
that was significantly lower in the fentanyl group.
All the sheep had received dexmedetomidine, and
morphine for premedication and propofol for induc-
tion of anaesthesia. Morphine administered for
premedication would have provided an analgesic
and sedative effect with duration close to that of the
surgical procedure performed in the sheep (Riebold
2007). After the administration of a medetomidine
bolus of 2 lgkg
1
during sevoflurane anaesthesia
in sheep, the distribution rate and constant elimi-
nation half-life were very fast, 0.3388 and
33.52 minutes, respectively (Kastner et al. 2006),
so it might be expected that the dexmedetomidine
would not influence isoflurane requirements for the
whole of the surgical procedure. However, no
sympathetic cardiovascular response to surgical
stimulus or increased isoflurane requirements
towards the end of the 100 minute anaesthetic
period were found in any of the sheep, in either the
fentanyl or the placebo group. Propofol produces
dose-dependent respiratory and cardiovascular
depression in sheep (Upton et al. 2009), but the
dose used to induce anaesthesia was equal in
both groups, so should not have influenced any
Table 1 Cardiovascular values (mean SD) during
100 minutes in sheep in which anaesthesia was main-
tained with isoflurane. The sheep received either a contin-
uous rate infusion of 10 lgkg
1
hour
1
fentanyl (group
F) or an equal volume of saline (group P)
Variables Group F Group P
Significance
(p)
HR (beats per
minute)
87 28 87 16 0.746
MAP (mmHg) 68 12 67 19 0.602
SAP (mmHg) 80 12 78 19 0.454
DAP (mmHg) 59 11 59 18 0.989
CI (mL kg
1
minute
1
)
90 15 102 35 0.012*
SVRI (dyn
second
1
cm
5
kg
1
)
38.88 13.91 37.09 21.7 0.56
SI (mL kg
1
) 1.18 0.33 1.29 0.43 0.095
SVV (%) 19 4185 0.39
dPmx (mmHg
per
seconds)
335 85 350 78 0.279
CVP (mmHg) 2 334 0.327
f
R
(breaths
per minute)
19 72370*
pH 7.24 0.06 7.26 0.08 0.208
PaCO
2
(mmHg)
(kPa)
66 10
8.8 1.3
64 7
8.5 0.9
0.337
PaO
2
(mmHg)
(kPa)
275 112
36.7 14.9
248 80
33.1 10.7
0.281
Heart rate (HR), mean (MAP), systolic (SAP) and diastolic (DAP)
arterial pressures, cardiac index (CI), systemic vascular resis-
tance index (SVRI), stroke index (SI), stroke volume variation
(SVV), contractility (dPmx), central venous pressure (CVP),
respiratory rate (f
R
), pH, arterial carbon dioxide (Pa CO
2
) and
oxygen (PaO
2
) partial pressures. HR, f
R
, pH, PaCO
2
and PaO
2
values were measured over the full 100 minutes. MAP, SAP and
DAP values were measured from minute 15 to minute 100 of
anaesthesia. Parameters involving were measured from minute
45 to 100 of anaesthesia. *Significant differences between
groups (p<0.05).
161©2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 157–164
Fentanyl in anaesthetized sheep FJ Funes et al.
subsequent differences between the two groups in
measured parameters.
Isoflurane is a commonly used inhalant anaes-
thetic agent that produces a dose-dependent cardio-
vascular and respiratory depression in sheep (Hikasa
et al. 2000; Mohamadnia et al. 2008). The minimal
alveolar concentration (MAC) of isoflurane in sheep
has been reported to be 1.53 0.12 vol% (Bernards
et al. 1996), but FE′iso in the placebo group was
lower than this, almost certainly due to the effect of
premedication.
The results confirmed the hypothesis that fentanyl
CRI administration during isoflurane anaesthesia in
sheep provides adequate analgesia for surgery while
reducing isoflurane requirements. A continuous rate
infusion of fentanyl has been reported to decrease
the MAC of inhalation anaesthetics in many species
(Criado & Gomez de Segura 2003; Liehmann et al.
2006; Thomasy et al. 2006; Dzikiti et al. 2011).
The dose of fentanyl chosen for our study was based
on those published for the dog, as there are no
published pharmacokinetic studies of this agent in
sheep. The isoflurane sparing effect was 41.6% in
dogs anaesthetized with isoflurane and a continuous
rate infusion of 10 lgkg
1
hour
1
of fentanyl
(Gutierrez-Blanco et al. 2013). In our study, when
fentanyl at 10 lgkg
1
hour
1
was combined with
isoflurane, this latter drug concentration was
reduced by 22.6%. Isoflurane requirements were
reduced in goats by the administration of different
CRI doses of fentanyl in a dose-dependent manner up
to 56.6%. When fentanyl 5 lgkg
1
hour
1
was
administered, a reduction slightly enhanced (27.6%)
than was observed in our study was found, but no
surgery was performed in that study (Dzikiti et al.
2011). In our study isoflurane requirements
decreased progressively throughout anaesthesia in
those sheep that received fentanyl CRI. The decrease
of isoflurane requirements could be due to higher
plasma concentrations of fentanyl due to accumu-
lation over time (Sano et al. 2006).
Fentanyl (10 lgkg
1
IV) has been shown to be
effective against thermal and mechanical stimuli in a
nociceptive model in sheep with a duration of
analgesia of 60 minutes (Waterman et al. 1990)
and, applied as a patch, to provide good post-
operative pain relief following orthopaedic surgery
(Ahern et al. 2009).
In the current study, although compared to the
placebo group, there was a reduction in isoflurane
requirements in the group receiving fentanyl, there
was no improvement in cardiovascular status, and
indeed CI index was statistically significantly lower
in the fentanyl group. SI and dPmx were lower in
sheep that received fentanyl and may explain the
decrease in CI, but no statistical differences were
observed. In our study, throughout anaesthesia, HR
decreased compared with the placebo group,
although overall there was no statically significant
differences, nevertheless a lower HR would explain
a significantly reduced CI whilst SI changes
remained non-significant. There are currently no
Table 2 Blood-gas values (mean SD) at specific time points in sheep in which anaesthesia was maintained with
isoflurane. The sheep received either a continuous rate infusion of 10 lgkg
1
hour
1
fentanyl (group F) or an equal
volume of saline (group P)
TIME minutes
Baseline Induction T 30 T 60 T 90
pH F 7.35 0.49 7.16 0.05* 7.23 0.06 7.25 0.05 7.26 0.06
pH P 7.37 0.06 7.26 0.03 7.27 0.04 7.25 0.09 7.27 0.07
PaCO
2
F (mmHg)
(kPa)
65 11
8.7 1.5
67 10
8.9 1.3
67 12
8.9 1.6
PaCO
2
P (mmHg)
(kPa)
66 10
8.8 1.3
63 6
8.4 0.8
62 5
8.3 0.7
PaO
2
F (mmHg)
(kPa)
274 102
36.5 13.6
293 104
39.1 13.9
272 128
36.3 17.1
PaO
2
P (mmHg)
(kPa)
238 110
31.7 14.7
256 62
34.1 8.3
261 45
34.8 6
pH, arterial carbon dioxide (PaCO
2
) and oxygen (PaO
2
) partial pressures at baseline, induction and every 30 minutes after induction of
anaesthesia. Baseline samples were taken from venous blood. *Significant differences between groups (p<0.05).
162 ©2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 157–164
Fentanyl in anaesthetized sheep FJ Funes et al.
experimental studies using CRI of fentanyl during
inhalation anaesthesia in sheep where CI has been
evaluated. Dzikiti et al. (2011) however observed
that cardiovascular function was not adversely
affected during different doses of fentanyl CRI
administration in goats. Only a significant decrease
of HR and MAP 2 minutes after the administration
of 30 lgkg
1
of fentanyl bolus was described.
Bolus and intravenous infusion administration of
fentanyl reduced MAP and HR in rats, cats, and
dogs anaesthetized with isoflurane or halothane
(Nolan & Reid 1991; Criado & Gomez de Segura
2003; Liehmann et al. 2006).
Fentanyl-associated respiratory depression has
been shown in many studies, reflected by an increase
in PaCO
2
and a decrease in f
R
in dogs (Nolan & Reid
1991), cats (Liehmann et al. 2006), horses (Thom-
asy et al. 2006), goats (Dzikiti et al. 2010), and
sheep (Kronen et al. 2005). However, in this current
study no significant difference in PaCO
2
was shown
when fentanyl was administered, although a
decrease in f
R
was observed. The significantly higher
f
R
in the placebo group from minute 65 to minute 80
could be due to bone drilling, but no changes in
clinical signs, movement in response to surgical
stimulation, or other autonomic response were
observed at this time.
Hypoxaemia was not observed during the study,
but the sheep received oxygen from the time of
induction of anaesthesia. In sheep, Kastner et al.
(2005), found a significant decrease of PaO
2i
after
premedication with dexmedetomidine. In the cur-
rent study during anaesthesia, PaO
2
remained
within the expected range in both groups. This is
contrary to the low PaO
2
value found by Kronen
et al. (2005), in a sheep undergoing mitral valve
reconstruction. A progressive increase of PaO
2
along the anaesthesia was observed in both
groups probably due to the administration of
high inspired concentrations of oxygen during
anaesthesia.
Kronen et al. (2005) observed a prolonged
recovery in a sheep after high doses (0.15–
0.4 lgkg
1
minute) of fentanyl CRI. In our study,
no significant differences were found between groups
in any of the recovery times measured. The more
rapid recovery times in our study compared to the
study of Kronen et al. (2005) could be due to a lower
plasma fentanyl concentration since in our study the
fentanyl administration time was shorter.
Abnormal behavioural signs and restlessness were
observed during anaesthesia recovery after fentanyl
administration in goats (Dzikiti et al. 2010), sheep
(Waterman et al. 1990), and horses (Knych et al.
2009) when higher bolus doses and CRI were
administered during a longer period of time. In this
current study the quality of recovery was statisti-
cally similar in both groups, although fewer sheep
receiving fentanyl had a very good recovery score.
In conclusion, the administration of a fentanyl
CRI in sheep anaesthetized with isoflurane reduces
isoflurane requirements and maintains similar car-
diorespiratory function but decreases respiratory
rate and cardiac index. Recovery quality and times
were similar between groups. This anaesthetic
combination is suitable for surgery in sheep.
Acknowledgements
The authors would like to thank the Garcia Cugat
Foundation for supporting this project. One of the
authors (F.J. F) was the recipient of a grant from the
Ministry of Education, Culture and Sport of Spanish
Government (FPU Program: AP2009-0495). The
authors do not have any financial interest or other
relationship with any commercial company related
to this study.
References
Ahern BJ, Soma LR, Boston RC et al. (2009) Comparison of
the analgesic properties of transdermally administered
fentanyl and intramuscularly administered
buprenorphine during and following experimental
orthopedic surgery in sheep. Am J Vet Res 70, 418–422.
Ambros B, Duke-Novakovski T, Pasloske KS (2008)
Comparison of the anesthetic efficacy and
cardiopulmonary effects of continuous rate infusions of
alfaxalone-2-hydroxypropyl-beta-cyclodextrin and
propofol in dogs. Am J Vet Res 69, 1391–1398.
Bernards CM, Kern C, Cullen BF (1996) Chronic cocaine
administration reversibly increases isoflurane minimum
alveolar concentration in sheep. Anesthesiology 85,
91–95.
Criado AB, Gomez de Segura IA (2003) Reduction of
isoflurane MAC by fentanyl or remifentanil in rats. Vet
Anaesth Analg 30, 250–256.
Dzikiti BT, Stegmann FG, Dzikiti LN et al. (2010) Total
intravenous anaesthesia (TIVA) with propofol-
fentanyl and propofol-midazolam combinations in
spontaneously-breathing goats. Vet Anaesth Analg 37,
519–525.
Dzikiti TB, Stegmann GF, Dzikiti LN et al. (2011) Effects of
fentanyl on isoflurane minimum alveolar concentration
and cardiovascular function in mechanically ventilated
goats. Vet Rec 168, 429.
163
©2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 157–164
Fentanyl in anaesthetized sheep FJ Funes et al.
Gutierrez-Blanco E, Victoria-Mora JM, Ibancovichi-
Camarillo JA et al. (2013) Evaluation of the isoflurane-
sparing effects of fentanyl, lidocaine, ketamine,
dexmedetomidine, or the combination lidocaine-
ketamine-dexmedetomidine during ovariohysterectomy
in dogs. Vet Anaesth Analg 40, 599–609.
Hikasa Y, Saito K, Takase K et al. (2000) Clinical,
cardiopulmonary, hematological and serum
biochemical effects of sevoflurane and isoflurane
anesthesia in oxygen under spontaneous breathing in
sheep. Small Rumin Res 36, 241–249.
Kastner SB, Kull S, Kutter AP et al. (2005)
Cardiopulmonary effects of dexmedetomidine in
sevoflurane-anesthetized sheep with and without nitric
oxide inhalation. Am J Vet Res 66, 1496–1502.
Kastner SB, Pakarinen SM, Ramela MP et al. (2006)
Comparative pharmacokinetics of medetomidine
enantiomers in goats and sheep during sevoflurane
anaesthesia. J Vet Pharmacol Ther 29, 63–66.
Knych HK, Steffey EP, Mama KR et al. (2009) Effects of
high plasma fentanyl concentrations on minimum
alveolar concentration of isoflurane in horses. Am J Vet
Res 70, 1193–1200.
Kronen PW, Levionnois OL, Eckstein FS et al. (2005)
Prolonged recovery and respiratory depression after
fentanyl infusion in a sheep undergoing mitral valve
reconstruction. Lab Anim 39, 428–434.
Levionnois O, Kronen P (2008) Development of post-pump
syndrome in a sheep after mitral valve stenting. Lab
Anim 42, 505–510.
Liehmann L, Mosing M, Auer U (2006) A comparison of
cardiorespiratory variables during isoflurane-fentanyl
and propofol-fentanyl anaesthesia for surgery in
injured cats. Vet Anaesth Analg 33, 158–168.
Meredith JR, O’Keefe KP, Galwankar S (2008) Pediatric
procedural sedation and analgesia. J Emerg Trauma
Shock 1, 88–96.
Mohamadnia AR, Hughes G, Clarke KW (2008)
Maintenance of anaesthesia in sheep with isoflurane,
desflurane or sevoflurane. Vet Rec 163, 210–215.
Nolan AM, Reid J (1991) The use of intraoperative fentanyl
in spontaneously breathing dogs undergoing
orthopaedic surgery. Vet Anaesth Analg 18, 30–34.
Riebold TW (2007) Anesthesia, analgesia, and
immobilization of selected species and classes of animals.
In: Veterinary Anesthesia and Analgesia (4th edn).
Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell
Publishing, Oxford, UK. pp. 1096.
Sano T, Nishimura R, Kanazawa H et al. (2006)
Pharmacokinetics of fentanyl after single intravenous
injection and constant rate infusion in dogs. Vet Anaesth
Analg 33, 266–273.
Schauvliege S, Narine K, Bouchez S et al. (2006) Refined
anaesthesia for implantation of engineered experimental
aortic valves in the pulmonary artery using a right heart
bypass in sheep. Lab Anim 40, 341–352.
Stanley TH (1992) The history and development of the
fentanyl series. J Pain Symptom Manage 7, S3–S7.
Thomasy SM, Steffey EP, Mama KR et al. (2006) The effects
of i.v. fentanyl administration on the minimum alveolar
concentration of isoflurane in horses. Br J Anaesth 97,
232–237.
Tranquilli WJ, Thurmon JC, Grim KA et al. (2007) Lumb &
Jones’ Veterinary Anesthesia and Analgesia. Blackwell,
Oxford.
Upton RN, Martinez AM, Grant C (2009) Comparison of the
sedative properties of CNS 7056, midazolam, and
propofol in sheep. Br J Anaesth 103, 848–857.
Van Wijngaarden I, Soudijn W (1968) The metabolism and
excretion of benzetimide hydrochloride (R 4929) by rats.
Life Sci 7, 225–229.
Waterman AE, Livingston A, Amin A (1990) The
antinociceptive activity and respiratory effects of
fentanyl in sheep. J Assoc Vet Anaesth 17, 20–23.
Received 11 July 2013; accepted 3 November 2013.
Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Table S1. Respiratory rate and isoflurane expira-
tory fraction (mean SD) during 100 minutes in
sheep in which anaesthesia was maintained with
isoflurane. The sheep received either a continuous
rate infusion of 10 lgkg
1
hour
1
fentanyl (group
F) or an equal volume of saline (group P)
Table S2. Cardiovascular values (mean SD)
during 100 minutes in sheep in which anaesthesia
was maintained with isoflurane. The sheep received
either a continuous rate infusion of 10 lgkg
1
hour
1
fentanyl (group F) or an equal volume of
saline (group P).
164 ©2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 157–164
Fentanyl in anaesthetized sheep FJ Funes et al.
