Assessment of Alfaxalone

as an anaesthetic induction agent in mute

swans ( Cygnus olor)

Submitted in part fulfilment of the requirements for the Royal College of

Veterinary Surgeons’ Diploma in Zoological Medicine

2014

Word count 7,566

2

Contents

Page

Introduction

3

Method

16

Results

24

Discussion

31

Conclusions

39

References

40

Acknowledgements

49

Appendix 1. Table of body condition score descriptions

50

Appendix 2. Example anaesthetic monitoring sheet

51

Appendix 3. Photographs of anaesthetic monitoring equipment 52 Appendix 4. Raw data tables

53

3

Introduction

1. Avian anaesthesia

Anaesthesia is commonly used in avian medicine to facilitate clinical examination,

diagnostic procedures and surgical interventions, which would be expected to be

accomplished conscious in mammalian or reptilian species, as birds do not tolerate

prolonged manual restraint. The aim of anaesthesia should be to provide a smooth,

reliable induction with adequate restraint, muscle relaxation and analgesia, followed

by a fast, uneventful recovery (Lawton, 1996).

There are no anaesthetic agents specifically licensed for use in the mute swan

(Cygnus olor) and therefore products licensed for other species are used on

application of the ‘Cascade’ as set out in the Veterinary Medicines Regulations

(Veterinary Medicines Directorate, Guidance Note 13). Isoflurane is a volatile

anaesthetic agent licensed for induction and maintenance of anaesthesia of

ornamental birds and it is widely used in many avian species including waterfowl.

There are no injectable anaesthetic agents currently licensed for birds and most

available dosage data pertaining to off licence use of such drugs is anecdotal, or

based on published case reports.

1.1 Anatomy and physiology

The mute swan is a member of the waterfowl family Anatidae, alongside ducks and

geese, and included in the order Anseriformes. It is native to much of Europe and

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Asia and found as an introduced species in North America, Australasia and Southern

Africa.

The basic anatomy and physiology of the avian cardiovascular and respiratory

system is very different from mammals and is associated with an increased

anaesthetic risk in birds, compared to mammals (Longley, 2008).

The avian respiratory system has separate ventilatory and gas exchange

compartments, making it highly efficient compared with other vertebrates (Hawkins

and Pascoe, 2007). A continuous unidirectional flow of gas over the lungs in a cross

current exchange system permits up to ten times more oxygen to be absorbed in

birds, compared to mammals (O’Malley, 2005). This adaptation leads to birds

possessing a limited functional reserve capacity and they are therefore extremely

sensitive to hypoxia, secondary to reduced ventilation (Divers, 2014). The typical

avian trachea is longer and wider than comparably sized mammals, which increases

the tracheal dead space volume (Edling, 2006). To overcome this birds have an

increased tidal volume and relatively slower, deeper rate of breathing than mammals

of comparable size (Bouverot, 1978). Birds with long necks, such as swans, have a

respiratory rate of as little as 10 breaths per minute (O’Malley, 2005).

The avian cardiovascular system differs significantly from that of mammals,

exhibiting adaptations for the high metabolic demands of flight. Birds have a

proportionally larger heart, higher stroke volume, cardiac output and resting mean

arterial blood pressure compared with mammals (Smith et al., 2000). Heart rates

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vary significantly among species, with average resting rates ranging from 150 to

greater than 350 beats per minute (O’Malley, 2005).

Birds have a high basal metabolic rate compared to mammals and this would be

expected to have implications for drug metabolism and dosage requirements,

especially when trying to extrapolate from data available for domestic mammal

species.

1.2 Types of anaesthesia

Providing respiration and circulation are maintained, inhalant anaesthetics are

readily eliminated from the body and are often considered safer than injectable

agents (Muir, 2007). Anaesthesia with isoflurane is generally preferred for avian

species due to its effectiveness and rapid onset and recovery (Granone et al., 2012)

giving it a wide margin of safety. Sevoflurane is a more recent volatile agent licensed

for anaesthesia in dogs and also reported in birds. It appears to be safe and the

agent’s low blood solubility means rapid changes in anaesthetic depth are possible

(Girling, 2003). In contrast, injectable agents rely on redistribution within the body,

biotransformation and excretion and therefore there is less control over the

elimination process.

Swans have anatomical and physiological characteristics which make anaesthetic

induction with inhalant agents less favourable and injectable drugs are usually

preferred. ‘Masking down’ with a volatile agent is stressful, with an increased risk of

injury to both the patient and staff, and prolonged manual restraint can lead to

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capture myopathy. There is a high risk of exposure of personnel to volatile agents

escaping into the atmosphere with mask induction. Use of a tight fitting face mask to

reduce this can reportedly trigger a ‘stress’ response in waterfowl, thought to be due

to stimulation of trigeminal nerve receptors in the beak and nares, leading to periods

of apnoea and bradycardia which will prevent induction (Edling, 2006; Kearns, 2003;

Mulcahy, 2007). This may, however, be mitigated by premedication with anti-anxiety

drugs such as midazolam (Girling, 2003; Raftery, 2013).

When administering injectable induction agents the intravenous route is preferred

over the intramuscular route in order to bypass the absorption phase of the drug,

which may be unreliable in waterfowl, so that onset and intensity of action are less

variable (Machin and Caulkett, 1998a; Muir, 2007). Intravenous injection is relatively

straightforward in the swan using the large, superficial, medial tarsal vein and this

may be accomplished by a single operator if necessary.

2. Current injectable anaesthetic protocols for wat erfowl

The ideal injectable anaesthetic should produce unconsciousness and amnesia

alongside analgesia and muscle relaxation (Posner and Burns, 2009) whilst having a

wide margin of safety, a short duration of action and being non-cumulative.

2.1 Ketamine and an alpha 2-adrenergic agonist

Ketamine is a dissociative anaesthetic producing dose-related unconsciousness and

analgesia with minimal muscle relaxation. Xylazine hydrochloride is an alpha2-

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agonist with sedative, analgesic and muscle relaxant actions. Both drugs have been

reported as single induction agents in avian species (Jones, 1977). Samour and

others (1984) report poor muscle relaxation and the need for manual restraint in

large birds during induction and recovery with ketamine alone and the same study

demonstrated prolonged induction periods and respiratory depression in birds

anaesthetised with xylazine alone.

Despite poor results when used as the sole agent for anaesthesia, studies have

demonstrated ketamine and xylazine may be combined together in the same syringe

prior to intravenous administration to produce ‘balanced anaesthesia’. This

combination provides more rapid induction and smoother recovery than when

ketamine is used alone (Samour et al., 1984; Sinn, 1999) and the sedative and

analgesic effects of xylazine are enhanced (Edling, 2006). The combination of

ketamine and xylazine is widely used to produce short acting surgical anaesthesia in

domestic and wild animals, including avian species (Al-Sobayil et al., 2009; Heavner,

1996) although hypoxaemia, hypoventilation and hypercapnia have been reported to

occur (Paul-Murphy and Fialkowski, 2001). The use of medetomidine in combination

with ketamine is also reported (Mulcahy, 2007; Paul-Murphy and Fialkowski, 2001).

Routh (2000) documents an anaesthetic induction protocol for mute swans

comprising 12.5mg/kg ketamine hydrochloride combined with 0.28mg/kg xylazine

administered intravenously via the medial tarsal vein, allowing subsequent

endotracheal intubation and the provision of oxygen plus a volatile agent such as

isoflurane as required. Routh (2000) does not routinely reverse the xylazine when

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this combination is used in swans, however the use of atipamezole is documented in

other waterfowl species (Machin and Caulkett, 1998a).

2.2 Propofol

Propofol is an alkyl-phenol derivative available as an emulsion for intravenous use

for the induction and maintenance of anaesthesia in dogs and cats. It has a fast

onset of action and produces rapid, smooth induction and recovery. Its use is

reported in avian species including waterfowl (Goulden, 1995; Muller et al., 2011;

Routh, 2000) however some authors report a narrow safety margin and significant

respiratory depression, especially following rapid administration, so caution is

advised and artificial ventilation recommended if it is used (Cooke, 1995; Divers,

2014; Machin and Caulkett, 2000; Paul-Murphy and Fialkowski, 2001; Posner and

Burns, 2009). Mulcahy (2007) states that apnoea should be expected in all waterfowl

and shorebirds given propofol.

2.3 Tiletamine-zolazepam

A combination of tiletamine and zolazepam has been used for anaesthesia in raptors

and other avian species by both the intramuscular and oral route (Longley, 2008).

Tiletamine is a dissociative agent chemically related to ketamine but with a longer

duration of action (Kastner, 2007). Zolazepam is a benzodiazepine with muscle

relaxant and anticonvulsant properties. Tiletamine-zolazepam is rarely used in

waterfowl as it does not provide adequate analgesia for painful procedures (Mulcahy,

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2007), however a dose rate of 13mg/kg showed adequate anaesthesia for liver

biopsy in Pekin ducks (Carp et al., 1991).

3. Alfaxalone

The progesterone derivative alfaxalone is a neuroactive steroid anaesthetic with a

relatively wide margin of safety, little cardiovascular or respiratory depression, and

minimal induction and recovery excitement (Grimm and Lamont, 2007). It exerts a

general anaesthetic effect by binding to gamma amino butyric acid (GABA) subtype

A receptors in the central nervous system (CNS). GABA is a major inhibitory

neurotransmitter in the CNS. Alfaxalone enhances the effects of GABA at the

GABAA receptors resulting in opening of channels into the cells and an influx of

chloride ions. This causes hyperpolarisation of the cells and inhibition of neural

impulse transmission controlling arousal and awareness (Posner and Burns, 2009).

Alfaxalone is rapidly metabolised by the liver with no cumulative effect, making it

suitable for continuous rate infusion (Murrell, 2009).

In the past a product containing 9mg/ml alfaxalone and 3mg/ml alphadalone acetate,

another neurosteroid, was available commercially (Saffan, Schering-Plough Animal

Health, UK). This formulation was associated with severe adverse reactions in dogs,

related to histamine release and anaphylaxis. The solubilising agent cremophor, a

derivative of castor oil, was reported to be responsible (MacPherson, 2001). The

product is no longer available.

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A new formulation of alfaxalone was launched in the UK in 2007 (Alfaxan, Jurox UK

Ltd). This formulation does not include alphadalone or cremophor; it is solubilised by

binding to large sugar molecules called cyclodextrins. ’Alfaxan’ is licensed for use

both as an induction agent prior to inhalation anaesthesia and as a constant rate

infusion to maintain anaesthesia in the dog and cat in the UK.

Alfaxalone in cyclodextrin has been shown to have a wide safety margin in the

species groups for which it is licensed: supraclinical doses of 5 times the

recommended induction dose in healthy dogs caused no clinically significant

modification of the pharmacokinetic parameters of the drug (Ferré et al., 2006).

Whilst many of the quoted studies examining safety and efficacy have used healthy

subjects undergoing anaesthesia for routine surgical procedures or investigation,

there are reports of its use in sick animals. A study by Psatha et al. (2011)

specifically evaluated the clinical efficacy and cardiorespiratory effects of alfaxalone

as an anaesthetic induction agent in dogs with moderate to severe systemic disease

and found it to be a clinically acceptable induction agent in sick dogs.

4. Alfaxalone use in other species

Since its launch alfaxalone in cyclodextrin has received favourable reports and is

now used ‘off licence’ under the Cascade in a variety of species across most

taxonomic groups. It is non irritant to perivascular tissues and as such may also be

used via the intramuscular route (Murrell, 2009) increasing its flexibility of use,

especially in small species where intravenous access is impractical. Its safety and

efficacy has been demonstrated in a variety of domestic mammal species both in a

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clinical setting and under field conditions (Goodwin et al., 2011; Grint et al., 2008;

Keates, 2003; Klöppel and Leece, 2011; Leece et al., 2009; Marsh et al., 2009).

The use of alfaxalone has not been limited to mammalian species: it has been widely

used as an induction agent in reptiles via both the intravenous and intramuscular

route (Bertelsen and Sauer, 2011; Eatwell, 2010; Goodman, 2009; Johnson, 2007;

Kischinovsky et al., 2013; Rowland, 2009 & 2011). It has been used in amphibian

species and fish via water immersion and branchial or transcutaneous application

(Bauquier et al., 2011; McMillan and Leece, 2011; Minter et al., 2012) and it has also

been successful for anaesthesia of crustaceans (Minter et al., 2013).

The main reported adverse effect of alfaxalone in many of the species studied for

both on- and off-licence use has been hypoventilation and apnoea following

induction, demonstrated in several studies to be a dose dependent effect (Muir et al.,

2008 & 2009) and possibly also related to speed of injection (Amengual et al., 2013).

Some studies report agitation and hyperaesthesia during the recovery period

(Jimenez et al., 2012; Mathis et al., 2012; Posner and Burns, 2009).

5. Alfaxalone use in birds

Considering the multitude of recently published papers demonstrating the use of

alfaxalone in cyclodextrin in mammalian, reptilian, amphibian and fish species there

are few references to its use in swans, or indeed any other avian species. This is

likely due to the fact that volatile agents such as isoflurane and sevoflurane are

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generally considered the induction agents of choice, especially in psittacines birds,

raptors, passerines and some smaller waterfowl species (Girling, 2003).

There are two published references to the use of alfaxalone in cyclodextrin in avian

species. Punch (2001) reports its use at a dose of 10mg/kg to induce anaesthesia

prior to the surgical treatment of various wild raptor casualties, whilst Smith and

Rodriguez-Barbon (2008) cite a dose rate for waterfowl of 5-10mg/kg IV or IM,

however the authors acknowledge that the safety margin is not fully determined.

Despite the paucity of information on alfaxalone in cyclodextrin, the previously

available formulation of alfaxalone-alphadalone in cremophor has been reported in a

range of avian species and the new formulation should be expected to produce

similar results.

Alfaxalone-alphadalone has been reported as a successful anaesthetic induction

agent via the intravenous or intramuscular route in raptors, with a reported duration

of action of 5-10 minutes (Cooper, 1985; Holt, 1977; Samour et al., 1984), although

Camburn and Stead (1978) cite unsatisfactory results with the intramuscular route.

Transient apnoea is reported by Cooper (1985) as a common occurrence in raptors

and adverse reactions, including death, have been documented specifically in red

tailed hawks (Cooper and Redig, 1975).

Dose rates of 16-156mg/kg of alfaxalone-alphadalone are reported by the

intramuscular and intraperitoneal route in the budgerigar (Curtis et al., 1977), Lawton

(2000) states a ‘general’ avian dose rate for alfaxalone-alphadalone of 5-10mg/kg IV

or 36mg/kg IM, whilst Jones (1977) reports higher doses of 30mg/kg IV or 70mg/kg

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IM to produce light anaesthesia in pheasants and waterfowl. Cribb and Haigh (1977)

experienced a high incidence of sinus arrest and post-induction tachycardia in

mallard ducks (Anas platyrhynchos) and Canada geese (Branta canadensis)

following doses of 3-12mg/kg alfaxalone-alphadalone IV, although all study birds

recovered fully from anaesthesia.

Samour et al. (1984) considered alfaxalone-alphadalone to be the induction agent of

choice in long-legged birds such as cranes, flamingos and storks. Smooth rapid

induction, good muscle relaxation and uneventful recoveries are reported by Bailey

et al. (1999) in three species of crane following induction of anaesthesia with 6.5-

7mg/kg alfaxalone-alphadalone IV, with incremental doses administered for

maintenance of anaesthesia.

Intravenous alfaxalone-alphadalone has been reported in larger waterfowl including

swans (Cooke, 2003; Cracknell, 2004) at a dose rate of 7mg/kg, although this was

associated with a brief period of apnoea post induction. Cooke (1995) reports a dose

of 3-4mg/kg IV to provide safe and reliable anaesthesia in mute swans specifically,

with halothane administered via endotracheal tube for maintenance if required, and

birds being wrapped in a blanket during recovery to avoid self-trauma.

6. Anaesthetic monitoring

A combination of monitoring oxygenation and ventilation gives maximum information

on the respiratory and cardiovascular status of the patient. Measurement of arterial

oxygen saturation using a pulse oximeter indicates trends during anaesthesia,

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however readings are not consistently accurate in birds (Schmidt et al., 1998).

Measuring oxygenation alone is not considered satisfactory for assessment of

ventilation since birds can be well oxygenated, but concurrently hypercapnic (Edling,

2006).

Respiratory rate and depth may be measured by visual assessment, however

monitoring respiratory rate alone also does not provide an accurate assessment of

ventilation in birds as the combination of isoflurane and high inspired oxygen levels

leads to a reduction in tidal volume and therefore a normal respiratory rate does not

necessarily indicate adequate ventilation (Edling et al., 2001). Intermittent positive

pressure ventilation (IPPV) during anaesthesia allows control over the rate and depth

of respiration, the patient’s oxygenation and the prevention of hypercapnia (Lawton,

2000).

Measurement of the end tidal carbon dioxide (PETCO2) of the anaesthetised bird by

capnography is the recommended ‘gold standard’ to assess ventilation (Longley,

2008). Side stream sampling is preferred to mainstream sampling to minimise

additional dead space in the circuit. PETCO2 marginally overestimates arterial CO2

due to the efficiency of carbon dioxide excretion in birds (Edling et al., 2001),

however this is unlikely to be of clinical significance.

Heart rate and rhythm should be monitored with a stethoscope or pulse rate by

Doppler ultrasound or pulse oximeter. Electrocardiogram monitoring is increasingly

being used in birds, however reference ranges may be difficult to find for many

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species. Indirect blood pressure monitoring should also be considered, especially for

longer procedures.

Whatever monitoring equipment is used it is most informative to measure trends in

the parameters over time, rather than absolute values.

Rationale and aims of the study

There are no licensed anaesthetic agents available for mute swans and medications

used off licence mainly rely on case reports and anecdotal opinion for information.

Injectable agents are preferable in large waterfowl species due to the practical and

physiological difficulties associated with inducing anaesthesia with a volatile agent.

Alfaxalone in cyclodextrin has shown good results in both domestic and exotic

species and it would therefore be expected to be of use in waterfowl. Unlike

ketamine it is not a controlled drug so could be of more use in field situations due to

reduced storage and administrative requirements.

The aim of the study was to establish whether intravenous alfaxalone is an

appropriate anaesthetic induction agent in the mute swan and how anaesthesia

induced with intravenous alfaxalone compares to anaesthesia induced with an

intravenous combination of ketamine and xylazine.

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Methods

Approximately 300-400 swans are presented each year to a wildlife hospital in the

UK. The most common presenting problems are lead toxicity, fishing hook and line

injuries and musculoskeletal problems. Swans are regularly anaesthetised for

diagnostic imaging, including radiography and air sac endoscopy, and for procedures

such as gizzard flushing to remove ingested lead, surgical removal of fishing litter

and treatment of traumatic wounds.

The study group comprised 58 mute swans under the care of the wildlife hospital,

presented for general anaesthesia for diagnostic tests or surgical treatment. This

was an opportunistic clinical study using the standard clinic anaesthetic induction

protocol (group K - ketamine/xylazine) and comparing this with a new proposed

induction protocol (group A - alfaxalone). Swans were randomly selected for

inclusion in the study. All swans had been acclimatised to the hospital environment

for at least 24 hours prior to anaesthesia.

Procedure

All swans underwent a full clinical examination on admission to the hospital and a

blood sample was submitted to Veterinary Laboratories Agency Shrewsbury,

Shropshire, UK for measurement of lead concentration, according to the standard

hospital protocol, as lead toxicity is reported to affect up to 25% of swans. The

remaining blood sample from each swan was submitted to an external laboratory

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(Pinmoore Animal Laboratory Services Ltd, Cheshire, UK) for manual PCV and white

blood cell count estimation.

Body weight was measured in kilograms (kg) immediately prior to anaesthesia and

condition score was determined by manual palpation of the keel (Appendix 1). Age

(adult or juvenile) was determined by appearance of plumage, with presence of grey

feathers (present up to 2 years old) taken to indicate a juvenile bird and absence of

grey feathers an adult (Wildlife Information Network, http://wildpro.twycrosszoo.org).

As sexual dimorphism in swans is limited to a greater bodyweight and lager size of

the caruncle on the upper mandible of adult male birds there is inevitable overlap

between small male and large female birds. Therefore gender was recorded only for

individual birds undergoing endoscopic examination where the gonad was directly

visualised. In the absence of endoscopic confirmation birds’ gender was recorded as

unknown. Resting heart rate and respiratory rate, determined by thoracic

auscultation and observation of chest excursions, were recorded immediately prior to

anaesthetic induction.

Study swans received either 10mg/kg alfaxalone administered via intravenous

injection into the medial tarsal vein over 60 seconds (group A) or a combination of

12.5mg/kg ketamine (Narketan, Vetoquinol UK Ltd) and 0.28mg/kg xylazine

(Rompun, Bayer, UK) mixed together in the same syringe and given by slow

intravenous injection via the medial tarsal vein (group K). All anaesthetic procedures

were undertaken by the author. No routine premedication was administered,

however a small number of swans had been undergoing treatment with meloxicam

(Metacam, Boehringer Ingelheim Ltd) and/or amoxicillin-clavulanic acid (Synulox,

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Zoetis UK Ltd) prior to anaesthesia, to treat musculoskeletal disease or superficial

wounds.

Immediately following induction of anaesthesia, subjects were intubated with an

uncuffed endotracheal tube (size 5-6 as appropriate) and isoflurane (IsoFlo, Abbot

Laboratories Ltd., UK) administered in oxygen via an Ayre’s T-piece circuit to

maintain an appropriate level of anaesthesia for the procedure being undertaken.

Anaesthetic depth was judged by assessment of palpebral and corneal reflex,

muscle relaxation and jaw tone (Longley, 2008). In the event of apnoea (defined for

the purpose of the study as failure of spontaneous ventilation for greater than 30

seconds) manual ventilation was performed at a rate of 2-4 breaths per minute until

spontaneous ventilation resumed. Swans were maintained in lateral recumbency

where possible as this is preferable to sternal or dorsal recumbency to minimise

effects of visceral weight on ventilation (Longley, 2008).

The following parameters were recorded during each procedure (see Appendix 2 for

sample monitoring sheet):

⋅ Time from administration of the induction agent to intubation (measured from

immediately after full induction dose administered)

⋅ Heart rate and respiratory rate immediately prior to induction, immediately

after intubation and at 5 minute intervals during anaesthesia

⋅ End tidal CO2 concentration (PETCO2) immediately after intubation and at 5

minute intervals during anaesthesia

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⋅ Estimated arterial oxygenation (SPO2) immediately after intubation and at 5

minute intervals during anaesthesia

⋅ Concentration of isoflurane required for maintenance of adequate depth of

anaesthesia recorded every 5 minutes

End tidal carbon dioxide concentration (PETCO2), respiratory rate, estimated arterial

oxygen saturation (SPO2) and heart rate were measured using the Vetronic Vitalstore

multiparameter monitor (Vetronic Services Ltd, Devon, UK). The pulse oximetry

probe was attached to the patient’s tongue, with the sidestream capnograph device

attached between the endotracheal tube and the anaesthetic circuit (Appendix 3).

Following completion of diagnostic procedure or treatment isoflurane was

discontinued and oxygen provided until extubation at the point of purposeful head

movement. Swans were monitored until they were standing without assistance.

The following observations were recorded during recovery from anaesthesia:

⋅ Duration of anaesthesia (defined as time between anaesthetic induction and

cessation of isoflurane)

⋅ Time from cessation of isoflurane to extubation

⋅ Time from cessation of isoflurane to first lifting head

⋅ Time from cessation of isoflurane to achievement of sternal recumbency

⋅ Time from cessation of isoflurane to cessation of head and neck ataxia

⋅ Quality of anaesthesia

⋅ Quality of recovery

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Quality of anaesthesia and recovery were scored by the author in all cases. A

subjective scale of 1-5 was used where 1=very poor and 5=excellent (Tables 1 and

2).

Table 1. Scoring system for quality of anaesthesia

Score Quality Description

5 Excellent Smooth induction, good muscle relaxation, physiological

parameters stable

4 Very good Smooth induction, some muscle tension during procedure but

physiological parameters stable

3 Good Minor agitation on induction, muscle tension during procedure,

physiological parameters stable but higher concentration isoflurane

required

2 Poor Agitated induction, muscle tension during procedure, transient

apnoea post induction, transient IPPV required

1 Very poor Agitated induction, poor muscle relaxation, prolonged apnoea

following induction, IPPV required

Table 2. Scoring system for quality of recovery

Score Description Description

5 Excellent Smooth, calm recovery, standing at first attempt

4 Very good Smooth, calm recovery, mild ataxia when attempting to stand

3 Good Some wing movements or ataxia but no manual restraint required

2 Poor Moderate wing flapping, disorientation, manual restraint required

1 Very poor Violent wing flapping, rolling or ataxia, manual restraint required

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As this was an opportunistic study completed during routine clinical work and both

alfaxalone and ketamine/xylazine are considered suitable anaesthetic induction

agents for mute swans no Home Office licence was required.

Study subjects

Of the 58 swans in the study group, 27 swans were included in group A and 31 in

group K. Distribution of age, sex, mean bodyweight and mean body condition score

within each group is outlined in Table 3 . Reasons for anaesthesia of individuals in

each group are summarised in Table 4 and outcomes in Table 5 . 10 swans in group

A and 7 swans in group K were euthanased whilst under anaesthesia as a result of

diagnostic findings which would preclude successful rehabilitation and release back

to the wild (severe joint pathology on radiography, extensive aspergillosis or

abdominal infection found at endoscopy). Recovery data was therefore not available

for these individuals. The remaining swans went on to rehabilitation and were either

released or euthanased if later deemed to be unsuitable for release.

Table 3. Distribution of age, sex, mean bodyweight (Kg) and mean body condition score (BCS)

of swans undergoing anaesthesia with alfaxalone (Gr oup A) or ketamine/xylazine (Group K)

n Adult Juvenile Male Female Sex

unknown

Weighta BCSa

Group A 27 18 9 16 7 4 6.73 ±1.73

(3.65-9.8)

1.5 ±0.63

(0.5-3)

Group K 31 21 10 13 9 9 7.7 ±1.42

(4.75-10.0)

2.0 ±0.55

(0.5-3)

a Values shown as mean ± SD (range)

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Table 4. Reason for anaesthesia of swans in the stu dy

Group A (n=27) Group K (n=31)

Air sac endoscopy 22 21

Radiography 1 4

Suture wound or debride abscess 3 3

Remove severely damaged feathers 1 2

Remove external fixator 0 1

Table 5. Outcome of each case anaesthetised in the study

n Euthanased whilst

under anaesthesia

Recovered but

subsequently

euthanased

Recovered and

subsequently

released

Group A 27 10 7 10

Group K 31 7 11 13

Total 58 17 18 23

Statistical analysis

Statistical analysis was independently performed by Heather Bacon MRCVS and Ian

Handel MRCVS using Minitab version 16. Study data were tested for normality and

the non-parametric Kruskal-Wallis test was selected for analyses as the data were

not normally distributed. For all statistical tests a p value less than 0.05 was taken to

indicate statistical significance.

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A stratification matrix of confounding factors then ruled out the influence of lead

poisoning, pre-operative analgesia, reason for anaesthesia, haematological status,

gender, body condition score, life stage and resting heart rate as confounding factors

on the anaesthetic parameters measured. Through this analysis ‘time to tube’ and

‘median respiratory rate’ were found to be significantly confounded by other variables

and therefore could not be established to be significantly different between

anaesthetic groups.

Euthanasia under anaesthesia was excluded as a cofounding variable therefore

induction and anaesthetic monitoring data for these individuals has been included in

the statistical analysis, although recovery data is missing.

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Results

The median duration of anaesthesia for group A was 18 minutes (range 12-51

minutes) and for group K was 17 minutes (range 7-52 minutes). All swans that

recovered from anaesthesia did so without complication. Median time (minutes)

taken to fully recover from anaesthesia (absence of ataxia or uncontrolled head and

neck movements, minutes) was 24 ± 6.5 in group A and 19 ± 8.7 in group K.

Physiological parameters of swans in group A and group K, prior to and during

anaesthesia are shown in Tables 6 and 7 .

Table 6. Data collected from swans immediately prio r to and during anaesthesia with

alfaxalone (Group A) or Ketamine/xylazine (Group K) . Values presented as median ± SD

(range). Significant differences shown in bold. *In dicates confounded value.

Parameter Group A

(n=27)

Group K

(n=31)

P

Resting heart rate (beats per minute) 92 ±22

(60-160)

88 ±16

(40-104)

0.03

Resting respiratory rate (breaths per minute) 8 ±3

(4-14)

8 ±3

(6-16)

0.72

Time to intubation (seconds) 60 ±10.9

(30-90)

60 ±5.5

(45-90)

0.02*

Heat rate immediately post induction 176 ±36

(94-250)

64 ±16

(46-120)

<0.01

Heart rate at 5 minutes post induction 155 ±40

(70-280)

68 ±17

(40-130)

<0.01

Median heart rate during anaesthesia 144 ±27

(93-210)

66 ±17

(41-120)

<0.01

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Table 7. Data collected from swans immediately prio r to and during anaesthesia with

alfaxalone (Group A) or Ketamine/xylazine (Group K) . Values presented as median ± SD

(range) unless otherwise stated. Significant differ ences shown in bold. *Indicates confounded

value.

Parameter Group A

(n=27)

Group K

(n=31)

P

Number of swans with initial apnoea (%) 12 (44)a 1 (3.2)a <0.01

Duration of apnoea if present /mins 6.5 ±4.0 4b 0.49

Respiratory rate immediately post induction (if no apnoea) 14 ±4

(4-19)

9 ±4

(4-17)

<0.01

Respiratory rate 5 minutes post induction (if no apnoea) 16 ±6

(4-24)

9 ±4

(4-18)

<0.01

Median respiratory rate during anaesthesia (excluding

apnoea)

13 ±5

(6-22)

10 ±3

(4-14)

0.03*

PETCO2 immediately post induction (if no apnoea) 42 ±15.4

(11-73)

46 ±11.4

(12-61)

0.41

PETCO2 5 minutes post induction (if no apnoea) 51 ±15.7

(11-73)

46 ±12.1

(9-73)

0.13

Median PETCO2 during anaesthesia (excluding apnoea) 53.3 ±8.7

(15-73)

47 ±11.8

(12-70)

0.13

PO2 immediately post induction 99 ±0.93

(97-100)

98 ±1.23

(95-100)

0.36

PO2 5 minutes post induction 99 ±0.96

(97-100)

99 ±1.24

(96-100)

0.86

Median PO2 during anaesthesia 99 ±0.75

(98-100)

99 ±1.06

(96-100)

0.43

Isoflurane concentration immediately post induction 2.5±1.08

(1.5-5)

2 ±0.65

(0-3)

<0.01

Isoflurane concentration 5 minutes post induction 2.5±0.75

(1.5-5)

2 ±0.6

(1-3)

<0.01

Median isoflurane concentration required during procedure 2.5±0.78

(1-5)

1.5±0.52

(1-3)

<0.01

aTotal number (percentage of the group), bOnly 1 individual in this group demonstrated apnoea

so SD not calculated

26

Baseline data

There was a significant difference in resting heart rate between groups. Median

resting heart rate in Group A was 92 ± 22 and in Group K was 88 ± 16 (p=0.03).

There was no significant difference in resting respiratory rates between groups.

Median resting respiratory rate in Group A was 8 ± 3 and in Group K was 8 ± 3,

p=0.72).

Anaesthetic monitoring data

All birds were successfully intubated at first attempt. At first analysis induction time

(time from completion of IV induction agent to intubation, seconds) was significantly

different between groups (group A = 60 ± 10.9, group K 60 ± 5.5, P=0.02), however

this result was significantly confounded by a number of variables and so this

significance was later eliminated.

Median heart rate increased following induction with alfaxalone and decreased

following induction with ketamine-xylazine. It was significantly higher for group A

during anaesthesia (144 ± 27) than for group K (66 ± 17) p=<0.01 (Figure 1 ).

There was a significantly higher incidence of apnoea in group A compared to group

K, with 12% of swans in group A requiring IPPV for between 2-14 minutes,

compared to 4% of swans (equivalent to one individual) in group K (p=<0.01) with

this swan requiring IPPV for 4 minutes. In swans not demonstrating apnoea median

respiratory rate in group A was significantly higher than in group K (group A 13 ± 5,

group K 10 ± 3, p=0.03) at first analysis, however this result was significantly

27

confounded by a number of variables and significance was later eliminated. There

were no significant differences in PETCO2 or PO2 during anaesthesia between

groups.

The median isoflurane concentration required to maintain an appropriate level of

anaesthesia was higher in group A than in group K (median isoflurane concentration

group A 2.5 ± 0.78, group K 1.5 ± 0.52, p=<0.01).

Figure 1. Median heart rates of study swans during anaesthesia following induction with

alfaxalone or ketamine-xylazine

2001751501251007550

Median heart rate per swan

Ketamine Median HR

Alfaxan Median HR

Variable

Dotplot of Alfaxan Median HR, Ketamine Median HR

28

Anaesthetic recovery data

There was a significant difference between groups in time (seconds) from cessation

of isoflurane to lifting head (group A 12 ± 6, group K 6 ± 2.8, p=<0.01). There were

no further significant differences in recovery times between groups. Table 8 shows

parameters measured during recovery from anaesthesia.

Table 8. Median ± SD (range) time from cessation of isoflurane to different recovery points in

groups of swans induced with alfaxalone (group A) o r ketamine-xylazine (group K) and

maintained on isoflurane. Significant differences s hown in bold.

Parameter Group A (n=17) Group K (n=24) P

Time to extubation 3 ± 1.6

(1-7)

3 ± 2.4

(1-13)

0.21

Time to sternal recumbency 4 ± 2.9

(2-13)

3.5 ± 3.5

(1-16)

0.30

Time to lifting head 12 ± 6.0

(5-29)

6 ± 2.8

(2-14)

<0.01

Time to no ataxia 24 ± 6.5

(12-36)

19 ± 8.7

(12-45)

0.28

29

Quality of anaesthesia and recovery

There was a significant difference in subjective score of anaesthetic quality between

groups, with group K scoring significantly higher than group A (group K 4 ± 0.82,

group A 4 ± 0.75, p=<0.01). A significant difference in recovery quality was also

found between groups with a median recovery score following alfaxalone of 2 ± 0.94

(poor), range 1-4 (very poor to very good) compared to a median recovery score of 4

± 1.08 (very good), range 2-5 (poor to excellent) in the ketamine group (p=<0.01).

Anaesthetic quality and recovery scores are shown in Table 9 and figures 2 and 3.

Table 9. Subjective scores of quality of anaesthesi a and recovery in study swans following

induction of anaesthesia with alfaxalone (Group A) or ketamine/xylazine (Group K). Values

presented as median ± SD (range). Significant diffe rences shown in bold.

Group A Group K P

Anaesthetic quality 4 ± 0.75 (2-5)a 4 ± 0.82 (2-5)b <0.01

Recovery quality 2 ± 0.94 (1-4)c 4 ± 1.08 (2-5)d <0.01 an=27, bn=31, cn=17, dn=24

30

Figure 2. Subjective scores for anaesthetic quality in study swans following induction

with alfaxalone or ketamine/xylazine

Ketamine Quality GAAlfaxan Quality GA

5

4

3

2

1

0

Su

bje

cti

ve

qu

alit

y o

f G

A s

co

re

Individual Value Plot of Alfaxan Quality GA, Ketamine Quality GA

Figure 3. Subjective scores for quality of recovery in study swans following

anaesthetic induction with alfaxalone or ketamine/x ylazine

Ketamine Quality recoveryAlfaxan Quality recovery

5

4

3

2

1

Su

bje

cti

ve

re

co

ve

ry s

co

re

Individual Value Plot of Alfaxan Quality , Ketamine Quality

31

Discussion

All swans which were not euthanased recovered from anaesthesia without

complication. A number of swans were subsequently euthanased on welfare grounds

as they were unable to be released, either due to a deterioration in clinical condition

or development of complications related to rehabilitation. Euthanasia of these cases

was unrelated to anaesthetic agent used in the study.

Initial data analysis indicated a significant difference in time to intubation between

the groups, however stratifying analysis of potential confounding variables

demonstrated that time to intubation was confounded by multiple variables and

therefore the difference was not significant once these were accounted for. All swans

were intubated at the first attempt and induction was smooth and calm in both

groups so any difference is unlikely to be clinically significant. Both protocols can

therefore be considered effective for anaesthetic induction in mute swans. Calm

induction facilitating rapid, easy intubation is important to reduce both handling

stress for the animal and the risk of operator injury. The chance of exposure of staff

to volatile anaesthetic agents is minimised if the anaesthetic plane does not need to

be deepened by mask prior to intubation and repeated doses of injectable agents,

which may have cumulative effects on respiratory or cardiovascular parameters, are

also avoided.

There was a difference in resting heart rates between groups, with the median

resting heart rate for group A significantly higher than for group K (p=0.03). A

stratifying analysis of initial heart rate as a potential confounding variable indicates

32

that differences in median heart rate throughout anaesthesia remain significantly

different between group A and group K regardless of initial heart rate.

Heart rate decreased following anaesthetic induction in the ketamine group and

remained lower than resting rates throughout anaesthesia. Conversely, heart rate

increased in the alfaxalone group following anaesthetic induction and this elevation

was maintained for the duration of anaesthesia. The difference in median heart rate

between the induction protocols was significant (p=<0.01) even taking into account

the higher resting heart rate in group A. Alfaxalone causes hypotension in dogs and

cats, primarily due to myocardial depression, with some contribution from peripheral

vasodilation. This hypotension is accompanied by a compensatory increase in heart

rate immediately following induction (Murrell, 2009). It is difficult to determine the

cause of the elevated heart rates seen in the alfaxalone group, as blood pressure

was not measured during the procedures so hypotension has not been

demonstrated. It is unlikely to have been due to pain as a result of an inadequate

plane of anaesthesia since the effect was seen immediately after induction, prior to

application of any noxious stimulus. Post induction tachycardia has been seen

following higher doses of alfaxalone in mammals (Muir et al., 2008) and this would

be worth exploring in future studies in swans.

Median respiratory rates were initially found to be significantly different between

groups (excluding apnoeic swans), p=0.03 however this result was significantly

confounded by a number of variables and so this significance was later eliminated.

33

A significantly higher occurrence of post induction apnoea was observed in the

alfaxalone group (44%) compared to the ketamine/xylazine group (3.2%), p=<0.01.

The apnoea may be dose dependent, as demonstrated in dogs and cats by Muir et

al. (2008 & 2009) or possibly related to speed of injection (Amengual et al., 2013).

The alfaxalone was administered over 60 seconds, as recommended in other

species (Grint et al., 2008; Psatha et al., 2011), therefore speed of injection is not

expected to be the cause of the apnoea seen here. Clinical studies during the

licensing of alfaxalone demonstrated an incidence of post induction apnoea of 44%

in dogs and 19% in cats following drug administration, although mean duration of

apnoea was shorter than in the study swans, at 100 seconds in dogs and 60

seconds in cats (SPC Alfaxan, Jurox UK Ltd). Post induction apnoea has also been

demonstrated in a recent study of alfaxalone in rabbits where individuals given an

intravenous induction dose of 10mg/kg all developed apnoea for a period of up to 27

minutes (Navarrete-Calvo et al., 2014). This was thought to be due to both the dose

rate used and the rapid administration of the drug in this study. The study concluded

that IPPV is mandatory following alfaxalone induction in rabbits.

In the author’s experience swans are difficult to maintain on a mechanical ventilator

during anaesthesia as there is inevitable leakage of gas around the endotracheal

tube, leading to inadequate ventilator pressure. Uncuffed tubes are used due to the

risk of pressure necrosis and stricture formation if cuffs are overinflated (Longley,

2008). Manual ventilation using the reservoir bag should be considered during

anaesthesia.

34

Dilution of alfaxalone 1:1 with water for injection is reported to result in a significant

reduction in the dose required for induction of anaesthesia in cats when the infusion

rate is controlled (Leece et al., 2012). This would be worth investigating further in

swans, as lower doses may reduce the occurrence of post induction apnoea and a

dose rate of 10mg/kg results in considerable volumes of drug used, which may be

prohibitively costly in a wild species predominantly being treated by charitable

organisations. The cost of a single dose of alfaxalone (10mg/kg) for a 10Kg swan is

approximately £18, whilst the cost of a single induction dose of ketamine-xylazine for

a 10Kg swan is approximately £3. Any reduction of dose of alfaxalone required may

result in considerable reduction of cost, making this a more economically viable

option.

Although there was no significant difference between groups, mean PETCO2 readings

were generally higher than expected in comparison to published ranges for other

avian species, with readings as high as 74mmHg in some individuals. There are few

published values of PETCO2 in birds and documented ranges generally apply to small

birds of less than 1kg. Edling et al. (2001) found a PETCO2 concentration of 30-

45mmHg indicated adequate ventilation in Grey parrots, although the same study

demonstrated that capnography may overestimate the arterial CO2 concentration by

up to 5mmHg. Machin and Caulkett (1998b) report a desired range for PETCO2 of 30-

50mmHg and suggest an artificial ventilation rate of 1 breath per 5 seconds if

capnography is not available. Edling et al. (2001) report that PETCO2 above 70-

80mmHg is associated with unacceptable respiratory acidosis (blood pH of <7.2).

35

The high PETCO2 readings could have been due to rebreathing of carbon dioxide,

especially if fresh gas flow rates were inadequate, however inspired CO2 readings

were consistently zero so this does not appear to have been the case.

Hypoventilation associated with anaesthesia is also possible and the drugs used in

both induction protocols in this study have been demonstrated to cause respiratory

depression, as has the maintenance agent isoflurane (Ludders, 2001; Paul-Murphy

and Fialkowski, 2001). A study by Ludders et al. (1990) demonstrated isoflurane to

be associated with significant hypoventilation in ducks, with average ETCO2

readings of 57-92mmHg depending on the concentration of isoflurane administered.

As all swans were maintained on isoflurane following anaesthetic induction this may

have contributed to the values observed.

Cushing and McClean (2010) found emus under general anaesthesia with a

combination of thiafentanil and medetomidine had a mean PaCO2 of 54.46mmHg,

measured by venous blood gas analysis, thought to be due to hypoventilation post

anaesthetic induction. Compromise of ventilation due to the position of the patient is

also a possible cause of elevated PETCO2 (Raftery, 2013), however most swans were

maintained in lateral recumbency for the duration of anaesthesia so this is less likely

to be a contributing factor. Raftery (2013) also states underlying respiratory system

pathology to be potentially related to PETCO2 concentrations. In this study a large

number of swans were diagnosed with air sacculitis due to aspergillosis, which may

in theory have an effect on PETCO2, however this clinical finding did not correlate

with high PETCO2 concentrations so can be excluded.

36

PETCO2 readings in some individuals were lower than expected and this is likely to be

due to leakage of expired gas around the ET tube and/or dilution of expired gases by

incoming fresh gas flow.

The need for higher doses of isoflurane to maintain an adequate plane of

anaesthesia in the alfaxalone group indicates ketamine-xylazine has a greater

isoflurane sparing effect than alfaxalone. Both induction agents have a similar

duration of action so this is unlikely to have had an effect on the isoflurane

requirements. Cooper (1992) reports a duration of action of intravenous alfaxalone-

alphadalone of 10-15 minutes, with total recovery within one hour, whereas

ketamine/xylazine has a duration of action of 5-10 minutes (Wildlife Information

Network, http://wildpro.twycrosszoo.org).

Overall, subjective scores for quality of anaesthesia were good for all subjects in the

study, however there was a significant difference between groups. Scores were

better for the ketamine group, however once analysed within life stage, this was only

significant between juveniles (p=0.004). Future studies should focus on larger

sample sizes of adults and juveniles to explore this further.

Although some swans had analgesic or antibiotic treatment prior to anaesthesia due

to pre-existing disease, this did not have a statistically significant effect on the results

and a lack of analgesia in these cases would also have been a potentially

confounding variable. It will be difficult to standardise this in future studies as data is

collected from ongoing clinical cases, where management prior to anaesthesia will

be variable depending on case history.

37

Time taken to lifting head following cessation of isoflurane was slightly faster in

group K, however overall recovery times were not significantly different between

groups and time until no ataxia was not significantly different so recovery times can

be considered similar between groups. Subjective scores for quality of recovery

were, however, significantly poorer with alfaxalone. Poor recoveries were associated

with wing flapping and ataxia, in some cases necessitating manual restraint of

individuals to prevent self trauma. Agitation during the recovery period has been

inconsistently associated with alfaxalone in other species and is referenced in the

data sheet to be encountered in a minority of dogs and cats but to be of no clinical

insignificance (SPC, Alfaxan, Jurox UK Ltd). Cooke (1995) reports rapid recovery in

swans following induction of anaesthesia with alfaxalone-alphadalone, however this

author also recommends the legs to be tied loosely over the tail and the swan to be

wrapped in a blanket until it can stand unaided, to avoid self trauma, suggesting

some excitation response was seen. Muller at al. (2011) report excitation on

recovery from propofol anaesthesia in 55% of swans.

Premedication with an anxiolytic such as midazolam may mitigate the agitation seen

during recovery from anaesthesia with alfaxalone, however this result did not occur

when midazolam was combined with alfaxalone/alphadalone in mallard ducks

(Machin and Caulkett, 1998a). The data sheet for alfaxalone states that the use of

benzodiazepines as sole premedicants in dogs and cats prior to alfaxalone may lead

to a suboptimal quality of anaesthesia and also an increased likelihood of

psychomotor excitation on recovery, but a benzodiazepine combined with other

premedicants may be safely and effectively used (SPC, Alfaxan, Jurox UK Ltd). This

should be considered in future studies.

38

This was not a blinded study so operator bias with respect to subjective

assessments of anaesthesia cannot be definitively excluded, however the data

acquired represents an opportunistic study and provides useful information as to the

effects of these drugs in the mute swan. Physiological parameters were objectively

measured using standardised monitoring equipment, eliminating operator bias.

Future studies should focus on assessment of varying doses of alfaxalone,

investigating the effects of dilution of the drug prior to use and also the effect of

premedication on quality of anaesthesia and recovery.

39

Conclusions

Alfaxalone at a dose of 10mg/kg intravenously, administered over 60 seconds,

produces smooth induction of anaesthesia in the mute swan, adequate for

endotracheal intubation. A period of apnoea may be seen following alfaxalone

induction so manual ventilation should be provided. Ataxia and agitation may be

seen during recovery, necessitating manual restraint in some cases.

Alfaxalone is a suitable anaesthetic induction agent in mute swans undergoing brief

anaesthesia for diagnostic or minor surgical procedures. However, in comparison to

ketamine/xylazine there is a greater incidence of post induction apnoea and also a

greater incidence of agitation on recovery.

40

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49

Acknowledgements

Many thanks to Michael Stanford FRCVS for being my supervisor and for reviewing

the manuscript.

Many thanks to Keith Simpson MRCVS, Vetronic Services Ltd, for use of the

anaesthetic monitoring equipment and for technical support. Thanks also to

Vetoquinol for support of the study.

Many thanks also to Heather Bacon MRCVS and Ian Handel MRCVS for the

statistical analysis and to the staff of the wildlife hospital for the clinical care of the

swans.

50

Appendix 1

Body condition scoring system used in the study, based on www.pfma.org.uk.

Score Description

1 Emaciated – Keel bone very sharp

2 Thin – Keel bone easy to palpate and

sharp

3 Ideal - Keel bone easy to palpate not

sharp

4 Overweight – Keel bone difficult to

palpate

5 Obese – Keel bone impossible to palpate

51

Appendix 2

Swan anaesthetic monitoring chart Date_________

Case number _____________ Reason for anaesthesia__________________ Adult/Juvenile

Weight__________ Pb level___________ Body condition______/5______ Sex_______

Resting heart rate_________ Resting resp rate___________

Induction agent used______________ Volume administered___________ Time_________

Time to intubation____________

x Heart rate 0 Resp rate ⋅End tidal CO2 ∧ % Oxygenation ≠ Isoflurane concentra6on

100

95

90

85

80

75

70

65

60

55

50

45

40

35

30

25

20

15

10

5

0

Time of discontinuing isoflurane _______ Total duration of anaesthesia _______________

Time at extubation ___________ Time at sternal recumbency __________

Time holding head up _________ Quality of anaesthesia (1=poor, 5=excellent) _________

Time no head ataxia______________ Quality of recovery (1=poor, 5=excellent__________

Outcome of procedure/findings________________________________________________

52

Appendix 3 – Photographs of anaesthetic monitoring equipment

Mute swan under anaesthesia with capnograph and pulse oximeter attached

Mute swan under anaesthesia, prepared for air sac endoscopy

Vetronic Vitalstore monitor, used for collection of anaesthetic monitoring data

53

Appendix 3. Raw data tables. Swan euthanased_no_0_yes_1 PCV WBCC Reason Adult_1_Juvenile_0 M_1_F_2_unk_3 BCS weight Ket_1_Alfaxan_2 Pb_level Resting_RR

35785 0 36 51 xray 0 3 2 7.5 1 0.48 8

41615 0 39 8.1 xray and scope 0 2 1.5 6.1 1 4.72 8

35737 0 40 12 wound 1 3 2 9 1 1.01 8

35632 0 38 1.6 scope 1 2 2 8 1 0.95 6

35467 0 44 5.2 scope 1 1 2 9 1 1.91 8

35696 0 39 21 pluck feathers 1 3 2.5 9.05 1 1 8

35697 0 39 6.3 pluck feathers 0 3 3 10 1 1.4 6

35760 0 46 2.7 scope 0 1 2 8 1 1.79 6

35700 0 28 38.8 suture wound 1 3 2.5 7 1 1.14 8

35648 0 42 17 scope 1 1 2 6.85 1 1.2 8

35772 0 37 6.2 scope 1 1 3 9.75 1 6 6

35841 0 48 4.7 scope 1 1 1.5 7.1 1 1.5 10

41644 0 35 7.3 remove ex fix 0 3 2 8.1 1 3.84 6

36114 0 40 6.3 scope 1 2 2.5 8.05 1 0.55 12

36011 0 28 28.8 scope 1 1 1.5 7.45 1 1.21 16

36048 0 35 7.6 xray thorax 0 3 2 9.05 1 0.79 10

35960 0 54 4.1 scope 1 2 1.5 6.6 1 1.3 10

36088 0 40 8.4 suture wound 0 3 1.5 5.5 1 1.33 16

36186 0 38 3.6 scope 1 1 2 8.95 1 0.68 12

36009 0 48 6 scope 1 2 2 6.3 1 3.7 8

38121 0 44 5.2 scope 1 1 1.5 8 1 2.74 8

37565 0 57 5 scope 1 2 1.5 5.85 1 30.78 10

41504 0 52 13 scope 1 1 2.5 8.75 1 1.96 6

37425 0 37 17.1 xray thorax 1 3 2.5 9 1 0.49 8

41530 1 35 10 xray hips 1 1 2.5 9.5 1 1.58 10

35673 1 45 8.1 scope 1 1 2 8.2 1 1.42 6

35672 1 40 3.4 scope 1 2 2 9.05 1 1.48 8

37053 1 29 5.8 scope 0 1 1.5 7.2 1 0.87 8

36165 1 38 6.8 scope 0 2 0.5 4.75 1 9.21 10

36061 1 28 28 scope 0 1 2.5 6.2 1 1.37 12

54

Swan euthanased_no_0_yes_1 PCV WBCC Reason Adult_1_Juvenile_0 M_1_F_2_unk_3 BCS weight Ket_1_Alfaxan_2 Pb_level Resting_RR

41515 1 23 25 scope 1 2 1 5 1 1.2 6

41078 0 45 5.2 debride abscess 1 3 3 9.5 2 0.5 6

41234 0 28 4.4 scope 1 2 1.5 5.95 2 1.33 8

41477 0 32 24 suture wound 0 3 3 7.8 2 2.5 10

39583 0 35 6 scope 1 2 1.5 7.3 2 0.4 8

37484 0 28 37.6 scope 0 1 2 4.35 2 0.7 8

41198 0 17 11 scope 0 1 1.5 5 2 0.19 8

40573 0 36 11 scope 1 2 1.5 5.7 2 3.19 14

40794 0 40 9 scope 1 2 2 7.25 2 1.25 12

40879 0 44 8.7 scope 0 1 1.5 6.85 2 0.42 12

40351 0 41 7 pluck feathers 0 3 1.5 4.8 2 0.22 10

41310 0 36 2.7 debride bumblefoot 1 1 3 9.35 2 0.95 8

39385 0 25 8.8 scope 1 1 1.5 5.3 2 4.23 6

41556 0 48 4.6 xray thorax 0 3 2 6.7 2 0.9 10

41532 0 36 9.8 scope 1 1 2 7.25 2 0.51 4

41535 0 42 12.4 scope 1 1 1.5 6.9 2 1.14 8

38547 0 37 6 scope 1 1 1 7.9 2 1.5 8

41541 0 39 7.4 scope 1 1 1.5 9.8 2 2.5 6

41539 1 40 6.3 scope 1 1 1.5 7.3 2 1.76 4

39571 1 38 10 Ix mass on neck/scope 1 2 2.5 9.1 2 1.6 12

41047 1 20 2.6 scope 1 1 1 6 2 0.69 6

41285 1 36 18 scope 1 1 2 8.65 2 0.96 4

41409 1 42 17 scope 0 2 2 5.95 2 0.31 8

41451 1 32 18 scope 0 1 2 5 2 0.98 10

41095 1 27 11 scope 1 2 0.5 4.1 2 0.21 8

40968 1 35 30 scope 1 1 1 5.65 2 0.89 10

39823 1 37 28 scope 0 1 1.5 3.65 2 0.66 8

38823 1 52 11 scope 1 1 1 8.5 2 3.71 8

55

Swan Resting_HR Time_to_tube First_HR HR_5m HR_10m HR_15m HR_20m HR_25m HR_30m HR_35m HR_40m HR_45m HR_50m

35785 80 90 66 76 80 83 89

41615 92 60 58 60 55 51 58 49

35737 88 60 70 81 80 79 78 88 80 82 80 80 80

35632 92 90 63 69 67 71 69

35467 78 90 46 45 41 39 37

35696 88 60 50 65 61 55 52 51 49 45 42

35697 96 60 69 66 65 58

35760 100 90 64 56 58 60 55 51 49

35700 98 60 60 70 78 80 80 80 78 76 64 68 80

35648 92 65 120 130 126 101 84

35772 100 90 83 79 76 73 75

35841 104 45 80 90 88 90 88

41644 76 60 47 48 50 50

36114 80 55 74 80 75 70

36011 72 60 59 61 63 69

36048 88 60 67 66 66 67

35960 88 50 63 75 64

36088 74 60 66 77 76 69 61 61 57 62

36186 56 50 62 64 61

36009 65 60 50 43

38121 66 90 46 50 43 41

37565 66 60 97 99 97

41504 100 60 70 68 85

37425 60 75 51 63 55

41530 80 90 60 65 65 66

35673 92 90 71 71 82 66 54

35672 100 60 82 76 81 94

37053 56 60 50 50 50 48 47

36165 88 60 73 68

36061 100 90 62 64 72

56

Swan Resting_HR Time_to_tube First_HR HR_5m HR_10m HR_15m HR_20m HR_25m HR_30m HR_35m HR_40m HR_45m HR_50m

41515 40 45 97 88 92

41078 112 60 99 70 80 81 82 95 90 100 98 100

41234 100 60 150 125 146 115 115

41477 100 60 250 280 214 152 152 149 152 149 136

39583 120 60 180 143 149 115

37484 140 75 220 125 118 153 184

41198 108 45 196 155 150 111 95

40573 80 45 179 173 108

40794 102 60 200 200 190 190

40879 84 60 183 155 132 96

40351 112 60 180 200 210 210 220 220 220

41310 96 60 176 130 155 156 122 103 100 91

39385 88 60 132 127 150 100 112

41556 80 60 200 200 157 137 117

41532 64 60 132 127 91 97

41535 60 45 150 145 127 124

38547 88 60 94 144 135 86

41541 88 45 170 166 180 147

41539 92 60 139 130 128

39571 72 90 140 120 185 140 132 120 136 101 113

41047 100 60 180 180 160 160

41285 100 30 170 161 142

41409 92 60 129 165 120 128

41451 160 60 180 194

41095 80 45 182 135 135

40968 80 50 118 188 178

39823 72 60 140 195 89 87

38823 100 60 200 140 120

57

Swan Apnoea_no_0_yes_1 Duration_apnoea_minsFirst_RR RR_5m RR_10m RR_15m RR_20m RR_25m RR_30m RR_35m RR_40m RR_45m RR_50m

35785 0 9 18 10 12 13

41615 1 4 0 5 4 5 8 11

35737 0 13 11 11 9 10 10 9 12 8 9 10

35632 0 6 5 6 8 6

35467 0 4 4 4 6 4

35696 0 10 9 9 9 11 9 7 11 18

35697 0 17 18 11 10

35760 0 5 12 10 20 13 12 11

35700 0 4 9 8 6 7 5 8 8 7 6 7

35648 0 5 7 8 9 8

35772 0 5 14 10 10 12

35841 0 15 10 10 14 13

41644 0 14 8 8 13

36114 0 10 9 9 6

36011 0 8 8 12 8

36048 0 9 10 6 12

35960 0 11 8 14

36088 0 11 12 11 10 11 8 12 10

36186 0 8 5 9

36009 0 10 14

38121 0 13 15 17 13

37565 0 6 8 8

41504 0 11 10 9

37425 0 8 7 10

41530 0 10 10 8 6

35673 0 4 6 4 6 7

35672 0 14 13 20 14

37053 0 4 4 4 11 8

36165 0 9 8

36061 0 10 14 8

58

Swan Apnoea_no_0_yes_1 Duration_apnoea_minsFirst_RR RR_5m RR_10m RR_15m RR_20m RR_25m RR_30m RR_35m RR_40m RR_45m RR_50m

41515 0 12 12 10

41078 1 14 0 0 15 15 10 10 12 10 12 10

41234 1 2 0 5 7 4 8

41477 0 0 12 17 20 12 11 10 12 11 12

39583 0 0 15 15 10 15

37484 0 0 12 11 13 10 7

41198 1 4 0 24 21 19 17

40573 0 0 12 11 8

40794 0 0 16 16 17 12

40879 0 0 13 19 21 23

40351 0 0 17 16 11 13 13 13 13

41310 1 7 0 0 6 13 9 5 15 11

39385 0 0 4 4 12 14 8

41556 1 4 0 16 11 13 16

41532 1 8 0 0 12 13

41535 1 6 0 0 10 12 10

38547 0 0 19 18 19 23

41541 1 8 0 0 8 10

41539 1 14

39571 0 0 16 18 16 18 17 12 12 15 12

41047 0 0 14 15 14 15

41285 1 8 0 0 6

41409 1 2 0 24 22 15

41451 0 0 17 19

41095 1 4 0 10 10

40968 0 0 6 8 6

39823 0 0 14 20 17 12

38823 0 0 11 12 10

59

Swan First_ETCO2 ETCO2_5m ETCO2_10m ETCO2_15m ETCO2_20m ETCO2_25m ETCO2_30m ETCO2_35m ETCO2_40m ETCO2_45m ETCO2_50m

35785 43 44 51 56 57

41615 28 27 30 31 21

35737 43 56 63 54 44 52 50 52 50 55 60

35632 47 46 52 53 55

35467 60 55 52 49 44

35696 42 51 48 54 53 51 49 40 39

35697 55 48 54 52

35760 46 41 54 40 36 43 42

35700 61 73 71 74 73 72 65 62 69 70 65

35648 61 60 65 61 61

35772 28 32 28 26 30

35841 46 33 43 38 40

41644 39 44 25 28

36114 50 36 38 49

36011 50 46 54 42

36048 52 54 54 55

35960 49 51 67

36088 49 56 51 63 56 60 43 48

36186 47 35 69

36009 36 51

38121 43 31 43 32

37565 44 40 45

41504 24 44 29

37425 12 9 12

41530 40 50 48 45

35673 58 54 51 65 64

35672 42 48 51 77

37053 46 46 42 34 25

36165 22 28

36061 44 40 43

60

Swan First_ETCO2 ETCO2_5m ETCO2_10m ETCO2_15m ETCO2_20m ETCO2_25m ETCO2_30m ETCO2_35m ETCO2_40m ETCO2_45m ETCO2_50m

41515 45 33 37

41078 58 58 65 70 65 68 65 70

41234 59 66 68 34

41477 27 67 71 71 73 63 68 72 62

39583 73 73 74 65

37484 38 30 58 57 53

41198 17 48 19 68

40573 57 50 60

40794 57 51 55 66

40879 11 11 38 19

40351 72 68 70 60 64 69 69

41310 14 44 6 22 10 72

39385 42 44 49 72 67

41556 57 60 68 50 71

41532 38 46 42

41535 54 57 52

38547 33 57 60 50

41541 64 63

41539

39571 33 56 57 60 47 56 56 55 50

41047 42 39 45 38

41285 45 52 46

41409 38 44 56 52

41451 26 46

41095 38 46 34

40968 47 33 30

39823 37 54 43 34

38823 51 58 59

61

Swan First_Pulse_ox PO_5m PO_10m PO_15m PO_20m PO_25m PO_30m PO_35m PO_40m PO_45m PO_50m

35785 100 100 100 100 100

41615 100 100 100 100 100 100

35737 100 98 100 98 100 100 98 100 100 100 100

35632 98 100 100 100 100

35467 98 100 100 100 100

35696 100 100 100 100 100 99 98 98 98

35697 98 100 99 100

35760 98 99 99 97 98 98 99

35700 99 98 98 100 98 98 99 99 99 100 99

35648 96 99 98 100 100

35772 98 96 98 98 99

35841 99 100 100 100 99

41644 98 100 100 100

36114 99 100 100 100

36011 98 96 99 100

36048 97 99 98 100

35960 98 98 96

36088 99 99 99 100 100 100 100 98

36186 98 99 98

36009 95 96

38121 98 98 98 99

37565 98 100 97

41504 100 99 99

37425 99 100 100

41530 100 100 100 100

35673 97 98 99 98 99

35672 100 98 96 98

37053 100 100 100 100 100

36165 98 99

36061 98 99 100

62

Swan First_Pulse_ox PO_5m PO_10m PO_15m PO_20m PO_25m PO_30m PO_35m PO_40m PO_45m PO_50m

41515 98 99 99

41078 99 99 99 100 98 99 98 100 98 100

41234 100 100 100 100 100

41477 97 98 98 100 100 100 99 100 99

39583 100 100 100 100

37484 100 100 98 99 97

41198 100 98 99 100 100

40573 98 99 100

40794 98 97 100 100

40879 98 99 100 100

40351 100 100 100 100 100 100 98

41310 98 100 98 98 100 100 100 100

39385 99 98 100 100 100

41556 98 98 98 99 100

41532 100 100 100 100

41535 98 98 97 98

38547 100 99 99 100

41541 99 98 98 100

41539 98 98 99

39571 99 98 100 99 99 99 99 100 99

41047 98 99 98 98

41285 98 100 100

41409 100 100 100 100

41451 98 100

41095 98 100 99

40968 99 100 100

39823 98 98 99 98

38823 99 99 99

63

Swan Initial_iso_% Iso_5m Iso_10m Iso_15m Iso_20m Iso_25m Iso_30m Iso_35m Iso_40m Iso_45m Iso_50m

35785 1 1 1 1 1

41615 2 1 1 1 2.5 2.5

35737 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

35632 3 3 3 3 2

35467 2 2.5 1.5 0 0

35696 2 2 1.5 1.5 1.5 1.5 1.5 1.5 0

35697 1.5 1.5 1.5 0

35760 2 1.5 1.5 1.5 1.5 1.5 1.5

35700 2 2 1.5 1.5 1.5 1.5 1 1 1 1 1

35648 2 2 1.5 1.5 0

35772 0 2 2 1.5 2

35841 2 2 2 2 0

41644 2.5 2.5 2 2

36114 1 1 1 1

36011 1.5 2 2 2

36048 1 1 1 1

35960 2 2 0

36088 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5

36186 1.5 1.5 1.5

36009 2 2

38121 3 3 1 1

37565 2 1.5 1

41504 2 1.5 1.5

37425 1.5 1.5 1.5

41530 3 3 3 3

35673 2 1.5 1.5 3 3

35672 2 2 3 3

37053 1.5 1.5 1.5 1.5 1.5

36165 2 2

36061 1.5 1.5 2.5

64

Swan Initial_iso_% Iso_5m Iso_10m Iso_15m Iso_20m Iso_25m Iso_30m Iso_35m Iso_40m Iso_45m Iso_50m

41515 3 3 3

41078 3 3 3 3 3 3 3 3 3 3

41234 2 2 3.5 3.5 2

41477 2.5 2.5 2 2 4 4 4 2 2

39583 3.5 3.5 2.5 2.5

37484 5 3 3 3 2

41198 2 2 1 1 1

40573 2 2 2

40794 3 3 3 3

40879 2.5 2.5 2 2

40351 3 2 3 3 3 3 3

41310 5 3 3 3 3 3 1.5 1.5

39385 2 1.5 2.5 2 2

41556 2 2 2.5 2.5 2.5

41532 5 3 3 3

41535 4 3 3 3

38547 3 3.5 2.5 2.5

41541 2 2 3 2

41539 5 5 5

39571 3 3 3 3 2.5 2.5 2.5 2.5 2.5

41047 2 2 1 1

41285 2 2 2

41409 3.5 2 2 2

41451 2.5 3

41095 1.5 2.5 2.5

40968 2 2 2

39823 2 1.5 1 1

38823 3.5 2.5 3

65

Swan Duration_GA Time_end_iso_to_extubate Time_end_iso_to_sternal Time_end_iso_to_holding_head_up Time_to_no_head_ataxia

35785 18 3 3 4 35

41615 29 3 3 6 26

35737 41 13 16 14 45

35632 20 3 11 11 35

35467 17 6 7 6 16

35696 29 3 7 5 19

35697 11 2 3 4 12

35760 31 2 2 5 19

35700 52 2 5 4 16

35648 15 3 9 8 30

35772 21 3 7 7 15

35841 19 2 2 3 21

41644 15 1 1 8 14

36114 17 2 2 3 29

36011 16 4 5 8 20

36048 17 2 2 3 18

35960 7 2 3 6 15

36088 37 3 2 3 18

36186 15 4 4 7 35

36009 12 2 4 6 33

38121 22 1 1 2 18

37565 13 3 5 7 15

41504 13 5 6 9 21

37425 17 2 2 4 19

41530

35673

35672

37053

36165

36061

66

Swan Duration_GA Time_end_iso_to_extubate Time_end_iso_to_sternal Time_end_iso_to_holding_head_upTime_to_no_head_ataxia

41515

41078 51 4 4 5 18

41234 19 6 6 20 30

41477 33 1 3 9 12

39583 15 3 3 7 28

37484 19 3 3 9 22

41198 16 3 4 9 19

40573 12 4 13 17 33

40794 15 2 4 15 21

40879 17 2 4 10 22

40351 34 2 3 12 14

41310 36 3 4 8 24

39385 23 4 8 20 25

41556 21 3 4 12 26

41532 14 4 5 17 28

41535 15 6 9 16 30

38547 18 2 2 13 20

41541 15 7 9 29 36

41539

39571

41047

41285

41409

41451

41095

40968

39823

38823

67

Swan Quality_GA Quality_recovery Outcome Final_outcome

35785 5 4 shoulder path euthanased

41615 5 5 mild air sacculitis euthanased due to lameness

35737 3 3 sutured wound released

35632 4 3 air sacculitis euthanased

35467 4 2 Ongoing ABs released

35696 5 3 Released released

35697 5 5 Released released

35760 4 3 NAD on scope euthanased

35700 4 5 Released released

35648 3 3 NAD on scope euthanased

35772 4 4 air sacculitis euthanased

35841 5 3 air sacculitis released

41644 5 4 fx healed released

36114 5 5 mild air sacculitis released

36011 5 5 NAD on scope euthanased

36048 5 5 fractured clavicles euthanased

35960 5 5 NAD on scope released

36088 5 5 Released released

36186 4 2 air sacculitis euthanased

36009 5 4 Released released

38121 4 5 air sacculitis released

37565 5 4 leaded released

41504 4 5 mild air sacculitis euthanased

37425 2 2 fractured coracoid euthanased

41530 5 Euthanased dislocated hip

35673 4 Euthanased air sacculitis

35672 3 Euthanased air sacculitis

37053 5 Euthanased air sacculitis

36165 4 Euthanased ovary abscess

36061 3 Euthanased air sacculitis

68

Swan Quality_GA Quality_recovery Outcome Final_outcome

41515 4 Euthanased air sacculitis

41078 3 2 FB reaction

41234 4 3 air sacculitis euthanased

41477 4 2 Released released

39583 4 4 scope normal euthanased

37484 3 3 mild air sacculitis euthanased

41198 4 4 mild air sacculitis euthanased

40573 3 2 air sacculitis euthanased

40794 4 2 air sacculitis released

40879 5 4 mild air sacculitis euthanased

40351 2 1 plucked damaged feathers released

41310 4 2 debrided foot abscess released

39385 3 2 NAD on scope released

41556 4 3 No fracture released

41532 3 1 mild air sacculitis released

41535 3 2 mild air sacculitis euthansed

38547 4 3 mild air sacculitis released

41541 4 3 mild air sacculitis

41539 3 Euthanased air sacculitis

39571 2 Euthanased air sacculitis

41047 3 Euthanased abnormal liver

41285 3 Euthanased air sacculitis

41409 4 Euthanased air sacculitis

41451 5 Euthanased air sacculitis

41095 3 Euthanased air sacculitis

40968 3 Euthanased air sacculitis

39823 4 Euthanased air sacculitis

38823 4 Euthanased renal gout