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Veterinary Anaesthesia and Analgesia, 2015, 42, 3038

doi:10.1111/vaa.12176

RESEARCH PAPER

Influence of ketamine or xylazine supplementation on


isoflurane anaesthetized horses- a controlled clinical trial
Nina P
oppel*, Klaus Hopster*, Florian Geburek* & Sabine K
astner*,
*Equine Clinic, University of Veterinary Medicine Hanover, Foundation, Hanover, Germany
Center for Systems Neuroscience Hanover, University of Veterinary Medicine Hanover, Hanover, Germany

Correspondence: Klaus Hopster, Equine Clinic, University of Veterinary Medicine Hanover, Foundation, B
unteweg 9, 30559 Hanover,
Germany. Email: klaus.hopster@tiho-hannover.de

Abstract
Objectives To determine the influence of ketamine
or xylazine constant rate infusions on isoflurane
requirements, cardiovascular parameters and quality
of anaesthesia in horses undergoing elective surgery.
Study design Prospective, matched paired clinical
trial.
Animals Fifty four adult Warmblood horses.
Methods After premedication with acepromazine,
xylazine and butorphanol, anaesthesia was induced
with ketamine-midazolam and maintained with
isoflurane alone (I), isoflurane with either
1 mg kg 1 hour 1 ketamine (IK) or same dose of
xylazine (IX). End tidal concentration of isoflurane
(FEIso) was adjusted by the same anaesthetist in all
horses according to a scoring system. Dobutamine was
infused to maintain mean arterial pressure (MAP)
70 mmHg. Arterial blood gases, heart rate (HR),
respiratory rate, MAP and cardiac output (lithium
dilution) were measured. Groups I and IK received
xylazine before recovery. Recovery quality was scored.
Results Mean  SD averaged FEIso (volume%) was
significantly lower in IX (0.95  0.07) and IK
(0.97  0.08) than in I (1.16  0.13). In group
IX, HR was significantly lower and averaged MAP
(90  13 mmHg) significantly higher than in
groups I (71  7 mmHg) and IK (76  7 mm
Hg). Differences in other cardiopulmonary variables

did not reach statistical significance. All horses


recovered well with best score in group IX.
Conclusions Both CRIs of xylazine and of ketamine
resulted in pronounced reduction of isoflurane
requirements and blood pressure support based on
routinely monitored parameters. Cardiac output
appeared well maintained in all three protocols, but
lithium dilution induced errors mean the results are
untrustworthy. The work requires repetition with
another mode of measurement of cardiac output.
Clinical relevance All three protocols provided good
clinical anaesthesia with clinically acceptable
cardiovascular effects.
Keywords balanced anaesthesia, constant rate infusion, equine, ketamine, xylazine.

Introduction
Anaesthesia in horses carries a much higher risk of
mortality than in humans and small animals (Johnston et al. 2002; Bidwell et al. 2007; Brodbelt
2009;). In Johnston et al. (2002)s survey, 30.4%
of deaths occurred in the recovery period, mainly
due to fractures, and to myopathies. A major risk
factor for post-anaesthetic myopathy is reduced
muscle perfusion during anaesthesia (Weaver et al.
1984; Lindsay et al. 1989), which is closely related
to mean arterial blood pressure (MAP) and cardiac
_ (Richey et al. 1990; Lee et al. 1998;
output(Qt)
Edner et al. 2002). Therefore, to reduce periopera30

Xylazine and ketamine balanced anaesthesia in horses N Poppel et al.

tive morbidity and mortality in horses it is crucial to


maintain cardiovascular function during general
anaesthesia.
Inhalational agents such as isoflurane, allow easy
control of anaesthetic depth and fast recovery
(Steffey et al. 1977), but they are accompanied by
_
dose-related cardiovascular depression affecting Qt,
blood pressures and muscle perfusion (Steffey &
Howland 1978, 1980). Ideally concentrations of
inhalation anaesthetics should be kept as low as
possible, and reduction of minimal alveolar concentration (MAC) can be achieved by additional administration of sedatives and/or analgesics during
inhalation anaesthesia (Bettschart-Wolfensberger &
Larenza 2007). However, this does not necessarily
mean that overall cardiovascular performance is
improved compared to isoflurane alone.
Ketamine is a dissociative anaesthetic agent with
analgesic, anaesthetic and central sympathomimetic
properties (Muir 2010), usually resulting in an
_ in a plasma
increase of heart rate (HR), MAP and Qt
concentration-related way (Muir et al. 1977; Muir &
Sams 1992). It is also known to reduce the MAC of
inhalation agents in horses (Muir & Sams 1992).
However, ketamine and its metabolites accumulate
with time (Lankveld et al. 2006) leading to a
prolonged elimination time and to effects such as
muscle tremor and rigidity, excitation and ataxia
during recovery.
Xylazine is an alpha-2 adrenoreceptor agonist
with sedative, analgesic and muscle relaxant effects
(Daunt & Steffey 2002). Xylazines potential to
reduce the MAC of inhalation agents has been
demonstrated in horses (Steffey et al. 2000), but
xylazine produces bradycardia and blood pressure
changes in horses (Kerr et al. 1972; Wagner et al.
1992; England & Clarke 1996), and therefore the
cardiopulmonary effects might be additive to those of
the inhalation anaesthesia when the two agents are
given in combination (Teixeira Neto et al. 2004).
The aim of this study was to compare the influence
of ketamine or xylazine constant rate infusion (CRI) on
cardiopulmonary function, anaesthetic requirements
and recovery in horses in which anaesthesia was
maintained by isoflurane in a controlled clinical trial.
Materials and methods
Animals
Fifty-four client-owned horses of various ages
(119 years), breeds (49 Warmbloods, two Friesian,
31

two German Riding Ponies and one Polo Pony) and a


minimum body weight of 300 kg scheduled for
elective surgery with an anticipated anaesthetic
duration between 90 and 180 minutes were selected
for the study. The horses were determined to be
healthy based on clinical examination before inclusion into this study. Surgeries where the eyes were
covered were excluded. The experimental protocol
was approved by the State Office for Consumer
Protection and Food Safety in accordance to the
German Animal Welfare Law. Informed consent by
the owners was obtained for inclusion of their
animals in the study.
Anaesthetic protocol and instrumentation
The horses were assigned to one of three treatment
groups, by the method of matched pairs according to
type of surgery and positioning: isoflurane alone (I),
isoflurane in combination with a CRI of either
ketamine (IK) or xylazine (IX). This method of
assignment meant, for example that the first horse
for arthroscopy in lateral recumbency was allocated
to randomly group IK, then next horse with
arthroscopy in lateral recumbency allocated to
group I or IX and the third horse with same
recumbency and comparable surgery to the remaining group. Food was withheld for at least six hours,
but horses had free access to water. A catheter was
placed into a jugular vein (EquiCath Fastflow; Braun
Vet Care; Germany) under local anaesthesia (mepivacaine; Scandicain; AstraZeneca; Germany).
Thirty minutes before induction of anaesthesia all
horses were premedicated with acepromazine
(Vetranquil; Albrecht; Germany) (0.03 mg kg 1
intramuscularly), flunixin meglumine (Flunidol;
CP-Pharma; Germany) (1.1 mg kg 1 intravenously
(IV)) and antimicrobial agents depending on the
surgical case.
Horses were sedated with xylazine (Xylazin 2%;
CP-Pharma; Germany) (0.5 mg kg 1) and butorphanol (Alvegesic; CP-Pharma; Germany) (0.025 mg
kg 1) IV. If sedation was inadequate additional boli
of 0.15 mg kg 1 xylazine were given to effect and
the final dose recorded. Anaesthesia was induced IV
with ketamine (Narketan; Vetoquinol) and midazolam (Midazolam-ratiopharm; Ratiopharm; Germany) at a dose of 2.2 mg kg 1 and 0.06 mg
kg 1 respectively. Once the horse was laterally
recumbent, the trachea was intubated, the horse
hoisted onto the operating table and positioned in
lateral or dorsal recumbency.

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Xylazine and ketamine balanced anaesthesia in horses N Poppel et al.


Connection of the endotracheal tube to a breathing system (Vet.-Tec. Model JAVC 2000; J.D.
Medical Distributing Company, AZ, USA) was
defined as time point zero (T0) and horses lungs
were ventilated using a pressure limited large
animal respirator (modified Bird Mark 7). Intermittent positive pressure ventilation (IPPV) was performed with a peak inspiratory pressure between 20
and 30 cm H2O. The respiratory frequency was
adjusted to maintain end-expiratory partial pressure
of carbon dioxide (PECO2) between 4.7 and 6 kPa
(4560 mmHg). Isoflurane was administered in
oxygen (6 L minute 1) until an end-tidal isoflurane
concentration (FEIso) of 1.0% was reached. From
T15 onwards the isoflurane concentration was
adjusted according to the anaesthetic level (see
depth of anaesthesia). Horses in group IK and IX
received a CRI of 1 mg kg 1 hour 1 ketamine or
1 mg kg 1 hour 1 xylazine in addition. In group
IK, ketamine infusion was reduced to 50% after an
anaesthetic duration of two hours and stopped after
three hours of infusion or at least 20 minutes before
the end of anaesthesia.
A 20 gauge cannula (Venocan; Jrgen Kruuse;
Denmark) was placed in the facial or transverse
facial artery. The arterial cannula was connected to
an electronic pressure transducer (BD DTXPlus
Transducer; Becton Dickinson; NJ, USA) positioned
at the level of the heart. To prevent clotting and
dampening of the arterial waveform, the arterial line
was flushed intermittently with heparinised saline
(5 IU heparin mL 1).
Ringers solution (Ringer; Braun; Germany) was
infused for the duration of anaesthesia at a rate of
5 mL kg 1 hour 1. All horses received a CRI of
dobutamine (Dobutamin-ratiopharm; Ratiopharm;
Germany) at 0.3 lg kg 1 minute 1 until blood
pressure monitoring was connected. After the first
arterial pressure reading the dose was adjusted in
steps of 0.10.2 lg kg 1 minute 1 every 5 minutes
to maintain MAP above 70 mmHg. If MAP remained
<70 mmHg after reaching 1.25 lg kg 1 minute 1
dobutamine, the rate of Ringers solution was
increased to 10 mL kg 1 hour 1. At the end of
anaesthesia the total amount of dobutamine given
was recorded and expressed as lg kg 1 minute 1
[total dobutamine (lg kg 1)/anaesthetic duration
(minutes)]. In addition, the dobutamine amount
during the first hour [total dobutamine between T0
and T60 (lg kg 1)/60 (minutes)] and between T65
and T90 [total dobutamine between T65 and T90
(lg kg 1)/25 (minutes)] was recorded. All CRIs were

delivered by an automatic syringe infusion pump


(Perfusor compact; Braun; Germany).
Depth of anaesthesia and isoflurane administration were evaluated and adjusted by the same
anaesthetist (NFP) using a previously published
scoring system (Enderle et al. 2008). Evaluation
started 15 minutes after induction and was performed every 5 minutes. Based upon clinical signs
such as presence or absence of palpebral reflex,
nystagmus, body movements and variation in MAP,
the expiratory isoflurane concentration (FEIso) was
adjusted as required. Before surgical incision all
parameters excluding MAP were used for assessment
of anaesthetic depth. First baseline MAP was
assessed immediately before start of surgery and an
increase of greater 15% resulted in a score of +1 and
therefore in an increase of FEIso of 0.1%. The scoring
system comprised scores from score -1 (very deep
anaesthesia) to score 4 (very light anaesthesia),
where score 0 demonstrated the adequate anaesthetic level. Horses with a score between 2 and 4
received a bolus of thiopental-sodium (Trapanal
2.5 g; Nycomed; Switzerland) (0.51.5 mg kg 1 IV)
to deepen anaesthesia and the amount of thiopental
was recorded.
At the end of surgery the horses were weaned
from IPPV and isoflurane. After return of spontaneous breathing, the horses were placed in a recovery
box and horses in groups I and IK received
0.25 mg kg 1 xylazine IV, whereas horses in IX
received 0.1 mg kg 1 xylazine IV only if they
showed early nystagmus before hoisting. Phenylephrine-hydrochloride (Phenylephrin-L
osung; L
owenApotheke; Germany) was instilled into the ventral
nasal meatus to reduce mucosal swelling. During
recovery oxygen was insufflated at 15 L minute 1
as long as horses were recumbent. Times to first
movement, to achieve sternal recumbency and to
standing were recorded. Quality of recovery was
scored by the same observer for all horses using a
100-point standardised form (Appendix S1) published previously (Clark-Price et al. 2008). The most
excellent recovery could achieve 11 points and the
worst possible one 100 points.
Experimental protocol
Technical monitoring was carried out with a multiparameter monitor (Datex-Ohmeda Cardiocap/5;
GE Healthcare, UK). HR, respiratory rate (fR), MAP
_
and FEIso were recorded every 10 minutes. The Qt
(L minute

) was measured every 30 minutes by

2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 3038

32

Xylazine and ketamine balanced anaesthesia in horses N Poppel et al.

lithium dilution method using a commercial


machine (LiDCOplus; LiDCO Ltd.; UK) (Hallowell &
Corley 2005) and cardiac index (CI) per kg bodyweight
was
calculated.
Lithium
chloride
(2.250 mmol) was compounded by a local pharmacy (Lowen-Apotheke; Germany). Haemoglobin
concentration (Sysmex KX-21; Sysmex; Germany)
and sodium concentration were measured before
premedication and during anaesthesia (ABL 800
Flex; Radiometer; Germany) to adjust the lithium
dilution equipment. During anaesthesia blood samples were anaerobically taken from the arterial line
_ determination time point and were
at each Qt
analysed for saturation of haemoglobin with oxygen
in arterial blood (SaO2; calculated) and arterial
partial pressure of carbon dioxide (PaCO2) and
oxygen (PaO2) (ABL 800 Flex; Radiometer;
Germany).
Statistical analysis
Statistical analysis was performed with commercial
software (SAS 9.2; SAS Inc., NC, USA). Different time
points were denominated as T0 (connection to
breathing system), T10 (10 minutes after induction),
T20 (20 minutes after induction) and so on. Time
points after T90 were not analysed to obtain
balanced data sets. Gaussian distribution was tested
by visual inspection of histograms and the KolmogorovSmirnov test.
For HR, fR, MAP, FEIso, PaO2 and PaCO2 the
mean over the whole anaesthetic period for each
horse was calculated [sum of measurements/
number of measurements] and compared between
groups by one-way analysis of variance (ANOVA) to
eliminate differences in length of anaesthetic duration.
Normally distributed data were analysed using a
two-way ANOVA for repeated measurements.

Table 1 Mean cardiovascular variables and median dose of dobutamine in horses during maintenance
of anaesthesia with isoflurane (I) or
isoflurane supplemented with a
constant rate infusion (CRI) of
either ketamine (IK) at 1 mg
kg 1 hour 1 or xylazine (IX) at
1 mg kg 1 hour 1

Non-parametric data were analysed by the KruskalWallis test, followed by the Wilcoxon-Mann
Whitney test, if significance level had been reached.
For non-parametric data influences by time
were detected using Wilcoxon signed-rank test.
Categorical data were analysed by the Fishers exact
test.
Significance level was set at p < 0.05. Normally
distributed data are presented as mean  SD and
non-parametric data are shown as median [range].
Results
There were no significant differences between groups
in age, body weight, timepoint at which surgery
started and duration of anaesthesia (Table S1). All
groups required a mean dose of xylazine of
0.6  0.1 mg kg 1 before induction of anaesthesia.
Additional boli of thiopental to deepen anaesthesia
were required in nine and seven horses in group I
and group IK, respectively. Both groups were significantly different to group IX in which none of the
horses required additional thiopental. Horses
received thiopental at a maximum of three times
per anaesthesia and never in quick succession.
Median [range] total additional doses of thiopental
in groups I and IK were 0.831 [02.99] mg kg 1
and 0 [02.77] mg kg 1, respectively.
Group IX had significantly (p = 0.0022) lower
values for mean HR (Table 1) and significantly
(p < 0.0001) higher values for mean MAP compared to groups I and IK, respectively (Fig. 1).
Groups IX and IK required significantly (p < 0.001)
less isoflurane than group I (Fig. 2). Horses in group
IX also required significantly less (p < 0.0001)
dobutamine than in groups I and IK (Table 1). No
_ and arterial blood gases
significant differences in Qt,
occurred between groups (Table 2).

HR (beats minute 1)
MAP (mmHg)
dob (lg kg 1 minute 1)
dob_p1 (lg kg 1 minute 1)
dob_p2 (lg kg 1 minute 1)

Group I

Group IK

Group IX

37  5
71  8
0.38 [0.161.00]
0.50 [0.231.35]*
0.42 [0.001.21]

35  4
76  7
0.22 [0.071.20]
0.35 [0.151.03]*
0.00 [0.001.62]

31  3*
91  13*
0.07 [0.020.32]*
0.10 [0.050.30]*
0.00 [0.000.30]*

HR, heart rate; MAP, mean arterial pressure; dob, dose of dobutamine; dob_p1, dose of
dobutamine during p1 (=T0 - T60); dob_p2, dose of dobutamine during p2 (=T65 - T90);
Normally distributed data are presented as mean  SD. Non-parametric data are
presented as median [range]. *Significantly different from other groups (p < 0.05).

33

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Xylazine and ketamine balanced anaesthesia in horses N Poppel et al.


Table 2 Arterial blood gases and cardiac index (CI) in
horses during maintenance of anaesthesia with isoflurane
(I) or isoflurane supplemented with a constant rate infusion
(CRI) of either ketamine (IK) or xylazine (IX)
Group

Figure 1 Mean arterial pressure (MAP) (mean  SD) at


different time points (T2090; minutes after induction)
during isoflurane anaesthesia (I) or isoflurane anaesthesia
supplemented with a continuous rate infusion (CRI) of
either ketamine (IK) or xylazine (IX). Both groups significantly different from T20. aSignificantly different from both
other groups. bSignificantly different from group I. Significance was set at p < 0.05.

Figure 2 Mean  SD End tidal concentration of isoflurane


(FEIso) measured at different time points (T2090; minutes
after induction) during isoflurane anaesthesia (I) or isoflurane anaesthesia supplemented with a constant rate
infusion (CRI) of either ketamine (IK) or xylazine (IX).
*Significantly different from T20. **Significantly different
from T50. Letters indicates significant differences between
groups: aSignificantly different from both other groups,
c
from group IK, dfrom group IX. Significance was set at
p < 0.05.

During the first 60 minutes of anaesthesia MAP


increased significantly from 64 and 68 mmHg (T20)
to 71 mmHg and 78 mmHg (T60) in groups I and
IK, respectively (Fig. 1). Thereafter MAP remained
unchanged until end of anaesthesia.
Isoflurane requirements (FEIso) increased in I
between T20 (1.1  0.18) and T90 (1.26  0.16)
continuously with end tidal values during the last
30 minutes being significantly higher than baseline
(Fig. 2).

T30

PaO2 (mmHg)
I
354  95
IK
396  104
IX
394  97
PaO2 (kPa)
I
47  13
IK
53  14
IX
52  13
PaCO2 (mmHg)
I
44  4
IK
44  7
IX
43  5
PaCO2 (kPa)
I
5.9  0.5
IK
5.9  0.9
IX
5.7  0.6
CI (mL kg 1 minute 1)
I
74 [3598]
IK
78 [4396]
IX
66 [54125]

T60

T90

350  94
403  118
364  90**

326  114**
366  112*, **
359  95**

46  13
54  16
48  12**

43  15**
49  15*, **
48  13**

46  5
44  6
45  5

46  6
45  5
47  6**

6.2  0.7
5.9  0.8
5.9  0.7

6.1  0.8
6.0  0.7
6.3  0.8**

78 [51121]
78 [5893]
60 [43170]

66 [5489]*
65 [5074]*
79 [54149]

No differences were observed between groups. PaO2, arterial


pressure of oxygen; PaCO2, arterial pressure of carbon dioxide;
CI, cardiac index. Data are presented as mean  SD (blood
gases) or as median [range] (CI). *Significantly different from
T60; **Significantly different from T30. Significance was set at
p < 0.05. CI was measured by lithium dilution and it is probable
that certainly for group IX and probably group IK this induced a
measurement error.

In groups I and IK the CI (p = 0.022) decreased


significantly between T60 and T90 (Table 2). There
was no statistical difference between time points for
CI in group XI, but the range of CI was very wide,
with some very high results which may have been
due to measurement error (see discussion).
Arterial blood gases were not different between
groups. PaO2 decreased (p < 0.0001) over anaesthesia time in all groups, whereas PaCO2 significantly increased only in group IX (p = 0.0018)
between T30 and T90 (Table 2).
There was an influence of the anaesthetic period
on dobutamine requirements, with the highest
values during period 1 of anaesthesia (T0 to T60) in
each group. After instrumentation only six horses in
group IX were still receiving a small amount of
dobutamine, whereas dobutamine was stopped in
only two horses in group IK and in none of the
horses in group I during period 1 (Table 1).

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Xylazine and ketamine balanced anaesthesia in horses N Poppel et al.

All horses recovered well. For statistical analysis of


recovery characteristics two horses (one of IK and
one of I) were excluded; one exclusion due to
prolonged anaesthesia time (260 minutes) and the
other due to a fire alert once the horse had been
placed in the recovery box. None of the horses in
group IX required additional sedation after general
anaesthesia. There were no differences between
groups in any of the recovery time variables, but
recovery quality was significantly (p = 0.0407)
better in group IX compared to group IK, respectively
(Table 3).
Discussion
All three tested anaesthetic protocols were able to
maintain cardiopulmonary function within a clinically acceptable range without clinically relevant
differences in recovery quality. Isoflurane requirements to maintain an adequate level of anaesthesia
were reduced with both partial intravenous anaesthesia protocols.
One aim of this study was to compare the effects of
these three protocols on cardiovascular conditions,
_ However, we measured Qt
_ by the
including on Qt.
lithium dilution indicator method (LiDCO). The
LiDCO technique has been validated and reported
to be a safe and simple to perform in anaesthetized
foals and adult horses (Linton et al. 2000; Corley
et al. 2002), making it suitable for clinical patients.
However, recent studies (published after the commencement of this current work) have shown a

Table 3 Recovery times and recovery scores in horses after


maintenance of anaesthesia with isoflurane (I) or isoflurane
supplemented with a constant rate infusion (CRI) of either
ketamine (IK) or xylazine (IX)

First movement
(minutes)
Sternal recumbency
(minutes)
Standing Position
(minutes)
Score

Group I

Group IK

Group IX

20 [734]

16 [536]

20 [740]

25 [1739]

26 [1050]

30 [1560]

37 [1755]

40 [2058]

42 [17100]

20 [1330]

22 [1345]*

15 [1142]

Recovery times (minutes) and recovery score (points 11100;


11 = best, 100 = worst). Values are presented as median
[range]. *Significant difference between group I and IK; Significant difference between group I and IX. Significance was set at
p < 0.05.

35

large positive bias for lithium dilution compared to


bolus thermodilution (BTD) in horses anaesthetized
with volatile anaesthesia receiving xylazine alone
(Hopster et al. (2014) in press) or xylazine, ketamine, and midazolam infusions (Ambrisko et al.
2012). These authors hypothesized that some of
these drugs may interact with the LiDCO sensor and
potentially influence its accuracy. A follow-up in
vitro study found that a number of drugs (including
xylazine and ketamine) influenced the accuracy of
this sensor in a way which may lead to overestima_ values obtained by LiDCO (Ambrisko et al.
tion of Qt
2013a). This was further proved in a study using
blood taken a single clinically relevant dose of
xylazine in healthy awake horses (Ambrisko &
Moens 2013b). In group IX a high variation in of
_ values was observed with two horses having
Qt
_ values of 80120 L minexceedingly high of Qt
1
ute , repeatedly, and indeed in one case a measurement of 170 L minute 1 was obtained, a value
unbelievable at the HR measured at the same time.
To date it still is not known at which infusion rates
or drug plasma concentrations the sensor will be
affected and to what degree. Our own data (Hopster
et al. 2014) showed a strong correlation between
xylazine plasma concentration and overestimation
of LiDCO when compared to BTD. In addition sensor
voltage changes predicted the presence of such an
error. In this current study we did not measure
plasma concentration of the drugs or did we look at
sensor voltages in detail so it is difficult to estimate
possible bias of LiDCO. Even for the groups I and IK,
the xylazine used at induction of anaesthesia could
well have influenced the subsequent LiDCO readings,
in particular at the earlier time points. Further it is
possible that there are interactions between LiDCO
sensors and the ketamine or other drugs used. Other
studies need to clarify whether ketamine CRI in these
doses lead to errors in LiDCO measurements. There_ data, but
fore, we decided to report obtained Qt
inferences relating to treatment group comparisons
will not be drawn from them.
In horses of groups I and IK, MAP increased over
time which might be attributed to sympathetic
nervous activation by surgical stimulation. In
horses, MAP is recommended to be maintained at
70 mmHg or higher to provide adequate muscle
perfusion (Richey et al. 1990), although it should be
remembered that this recommendation was based
mainly on horses anaesthetized with halothane. This
value of MAP was achieved without increased fluid
requirements or dobutamine infusion only in

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Xylazine and ketamine balanced anaesthesia in horses N Poppel et al.


animals receiving a CRI of xylazine. In contrast,
hypotension occurred frequently during the first
40 minutes in I and IK before surgical stimulation
began. The subsequent increase of MAP might be
due to cardiovascular support (Ringers solution and
dobutamine) and to the start of surgery.
Isoflurane-xylazine anaesthesia was characterised
by strikingly steady cardiopulmonary conditions,
even during surgical stimulation. Marcilla et al.
(2012) hypothesised that additional sedation and
analgesia provided by infusion of alpha-2 adrenoreceptor agonists might blunt the autonomic response
to noxious stimulation. Xylazine supplementation
reduced isoflurane requirements in the current study
by 21%, which lead to FEIso values comparable with
a previously published study using a CRI of medetomidine (3.5 lg kg 1 hour 1) in horses anaesthetized with isoflurane (Kalchofner et al. 2006), but is
in contrast to other clinical studies using detomidine
and romifidine, in which the authors failed to
demonstrate any isoflurane sparing effects (Devisscher et al. 2010; Schauvliege et al. 2011). In an
experimental study from Steffey et al. (2000), xylazine was administered as a bolus and dose- and timedependent decrease in isoflurane MAC was seen. In
our study we adapted anaesthetic depth according to
a previously published scoring system that should be
more or less objective. Nevertheless there were some
limitations. First is that the anaesthetist was aware
of the drugs being administered. Secondly, the
system was mainly based on movement and reflexes,
but during balanced anaesthesia most reflexes, eye
movement and position differ from inhalation
anaesthesia. Thirdly, we used the MAP just before
surgery as reference value, but because this reference was very low in two groups, FEIso had to be
increased as soon as normotension was achieved
(according to the scoring system), resulting in not
only seemingly increased isoflurane requirements,
but also increased needs for dobutamine and lower
values for MAP in those groups. A final limitation
was that the different treatment drugs also have
cardiovascular effects, so this influences MAP and
the decision making according to the scoring system.
To better assess the influence on isoflurane requirements, a real MAC study is recommended.
If partial intravenous anaesthesia techniques are
used, palpebral reflexes, eye movement and eye
position differ from those seen under inhalation
anaesthesia (Kalchofner et al. 2006; BettschartWolfensberger & Larenza 2007; Ringer et al.
2007). Eye reflexes are less depressed and horses

appear more lightly anaesthetized even if adequate


anaesthesia is provided. With the scoring algorithm
used we tried to achieve an objective evaluation of
anaesthetic depth at an adequate level of anaesthesia. However it remains a weak point of this study as
the drugs used to balance isoflurane anaesthesia
have differential cardiovascular and central effects
influencing blood pressure and degree of central
depression.
In the current study we failed to demonstrate a
significant improvement of measured cardiovascular
parameters during isoflurane-ketamine anaesthesia,
which we had expected to occur due to sympathomimetic or isoflurane sparing effects of ketamine.
Centrally mediated indirect sympathomimetic properties of ketamine (Muir et al. 1977) can be seen at
plasma concentrations above 1 lg mL 1 (Muir &
Sams 1992) in halothane anaesthetized horses,
which is also reported as being the required plasma
concentration to induce anaesthesia in horses
(Muir & Sams 1992; Fielding et al. 2006; Lankveld
et al. 2006; Peterbauer et al. 2008). Antinociceptive effects of ketamine occurred with a subanaesthetic dose of 1.2 mg kg 1 hour 1 (Peterbauer
et al. 2008), whereas Fielding et al. (2006)
failed to demonstrate an analgesic effect of
0.8 mg kg 1 hour 1 ketamine. However, in our
study some antinociceptive or anaesthetic sparing
effects of ketamine are evident by the reduction of
isoflurane requirements by up to 19.6% compared to
the control group. Whether higher doses of ketamine
would lead to more pronounced isoflurane sparing
effects or more central sympathomimetic activation
with improved cardiovascular function is not
known. However, increasing doses of ketamine can
lead to decreased recovery quality with muscle
tremor and rigidity, excitation and ataxia (Muir &
Sams 1992). With our data we cannot explain the
lack of cardiovascular improvement despite the
decrease in isoflurane requirements, but direct
negative inotropic effects of ketamine on the myocardium (Treese et al. 1973; Diaz et al. 1976) might
have disguised the isoflurane sparing effect.
In groups IK and I isoflurane requirements during
the first 40 minutes of anaesthesia were lower than
later in the anaesthetic period, probably related to
ongoing effects of premedication and induction
agents and absence of surgical stimulation. After
start of surgical stimulation, isoflurane concentrations had to be increased due to insufficient anaesthetic depth, resulting in a requirement for
thiopental administration in many horses. As a

2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 3038

36

Xylazine and ketamine balanced anaesthesia in horses N Poppel et al.

result of low isoflurane requirements at the beginning of anaesthesia, the mean averaged FEIso
(1.16  0.13) measurements were much lower
than published data for MAC (1.31.6) in isoflurane-anaesthetized horses (Steffey et al. 1977, 2000).
However, these MAC studies were performed in
animals that were administered inhalants alone.
The quality of unassisted recovery was good and
unremarkable for all tested protocols, but sedation
with a xylazine bolus in horses of groups I and IK
before recovery might have minimised differences
between groups. As sedation for recovery has
become general practice (Clark-Price et al. 2008)
we decided to include xylazine for recovery in the
client-owned horses. The slightly better recovery
quality of IX compared to IK seems not to be
clinically relevant as all horses recovered well and a
median score of 22 in IK was still low on a scale from
11 to 100 points.
In conclusion, it was possible to maintain the
(successfully) measured cardiopulmonary variables
within clinical acceptable ranges with all three
protocols without clinically relevant differences in
recovery quality, but with pronounced differences in
blood pressure support. Both xylazine and ketamine
supplementations resulted in a pronounced reduction of anaesthetic requirements to maintain an
adequate anaesthetic level with less blood pressure
support being required.
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Received 4 July 2013; accepted 6 October 2013.

Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Table S1. Demographic data and information
about recumbency, type of surgery and anaesthetic
duration in horses during maintenance of anaesthesia with isoflurane (I) or isoflurane supplemented
with a constant rate infusion (CRI) of either
ketamine (IK) or xylazine (IX).
Appendix S1. Scoring system used to score
recovery.

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38

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