towards total intravenous anaesthesia in goats tb_phd thesis complete.pdf · introduction benefits...
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Towards Total Intravenous Anaesthesia in Goats
PhD Thesis (Introduction)
Dzikiti T B
Companion Animal Clinical Studies
University of Pretoria
Promoter: Prof LJ Hellebrekers, Utrecht University
Co-Promoter: Prof GF Stegmann, UP
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General Scope
• Goats have been used as biomedical
research models for years
• Paucity of information on goat anaesthesia
Antognini & Eisele 1993; Fulton et al. 1994; Larenza et al. 2005
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Thesis Introduction
• Total intravenous anaesthesia (TIVA) is
gaining popularity, esp. with dogs & horses
• Information on TIVA in goats would be really useful to the veterinary practitioner or biomedical scientist
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Introduction
Benefits of TIVA
• Balanced anaesthesia – ‘Triad of
anaesthesia’ fulfilment (unconsciousness,
analgesia, muscle relaxation)
• Less pollution of working environment
• Inexpensive
Gray & Rees 1952, Hasley 1991; Nolan 2004
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Introduction
Applications for TIVA
• Field anaesthesia
• MRI anaesthesia
• Research
Dundee & McMurray 1984; Carroll et al. 1997 ; Larenza et al. 2005
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General Objectives
• Investigate effects of relevant sedatives
• Investigate isoflurane-sparing effects of
relevant drugs: midazolam, fentanyl and
propofol
• Evaluate efficacy of relevant drug
combinations for TIVA in goats
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Achievement of Objectives
Series of 5 studies (Protocol V045/06)
i) sedative, propofol-sparing and
cardiopulmonary effects of acepromazine,
midazolam, butorphanol and combinations
of butorphanol with acepromazine or
midazolam in goats
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Achievement of Objectives Series of 5 studies
ii) effects of different dosages of midazolam on isoflurane minimum alveolar concentration and cardiovascular function in mechanically-ventilated goats.
iii) effects of different dosages of fentanyl on isoflurane minimum alveolar concentration and cardiovascular function in mechanically-ventilated goats.
iv) effects of different dosages of propofol on isoflurane minimum alveolar concentration and cardiovascular function in mechanically-ventilated goats.
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Achievement of Objectives
Series of 5 studies
v) efficacy of propofol and fentanyl, and
propofol and midazolam for total
intravenous anesthesia in
spontaneously-breathing goats.
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The Goats
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Sedative and cardiopulmonary effects of acepromazine, midazolam, butorphanol,
acepromazine-butorphanol and midazolam-butorphanol on propofol
anaesthesia in goats
TB Dzikiti, GF Stegmann, REJ Auer,
LN Dzikiti, LJ Hellebrekers
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Introduction
• Concept of sedation before anaesthesia (premedication) well accepted in veterinary practice
• Premedicants reduce adverse effects related to induction agents
• Literature on premedication in goats is scant.
Kojima et al 2002, Sano et al 2003
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Acepromazine • Most common tranquilliser in veterinary practice
• Anxiolysis, peripheral vasodilation, hypotension,
hypothermia, behaviour modification
Hall et al 2001, Mehlisch 2002
Introduction
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Midazolam • Water-soluble benzodiazepine
• Sedation, muscle-relaxation, anti-epileptic
• GABAA-mediated CNS effects
• Mild cardio-respiratory effects
Hall et al 2001, Mehlisch 2002
Introduction
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Introduction
Butorphanol
• κ-opioid receptor agonist and μ-opioid
receptor antagonist
• Analgesia, some sedative effects, potential
excitatory behaviour in goats
Doherty et al 2002
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Introduction
Propofol
• Common induction agent in goats
• GABAA-mediated CNS effects
• Dose-dependent cardio-respiratory depression
Grossherr et al 2006, Reid et al 1993
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Introduction
Assessment
• Quality of sedation
• Reduction of dose of propofol required for
induction
• Physiological impact
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Materials and Methods Study Design
• 6 goats (3 does, 3 wethers)
• Starved for 18-24hrs for the study
• Randomised crossover design
• Six treatments, on separate occasions
• 3-week intervals between treatments
(wash-out period)
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Materials and Methods Study Design
• Healthy (physical exam, complete
blood count, serum biochemistry)
• Age (5 – 9 months)
• Weight (21.0 - 24.5 kg)
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Materials and Methods Study Design
SAL ACE BUT ACEBUT MIDBUT
MID
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Materials and Methods Catheterisation
• Auricular artery catheterised (24G)
- blood sampling
- arterial blood
pressure readings
• Cephalic vein catheterised (18G)
- fluid administration
- propofol administration
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• Premedication intramuscularly
• Assessor of degree of sedation, quality of
induction, and quality of recovery blinded to
treatments
Materials and Methods Treatments
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Materials and Methods Treatments (Sedation)
Treatment Agent Dosage
SAL Saline 1 ml
ACE Acepromazine 0.05 mg/kg
MID Midazolam 0.3 mg/kg
BUT Butorphanol 0.1 mg/kg
ACEBUT Acepromazine
Butorphanol
0.05 mg/kg
0.1 mg/kg
MIDBUT Midazolam
Butorphanol
0.3 mg/kg
0.1 mg/kg
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Materials and Methods Sedation Scoring: At 20 minutes after
treatment
Score Score Description
0 No sedation
1 Mild sedation
Drooping head; easily arousable
2 Moderate sedation
Not easily arousable but able to maintain
sternal position
3 Severe sedation
Failing to maintain sternal position
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Materials and Methods Induction of general anaesthesia
• Propofol 30 minutes after
sedation
- 10mg/kg calculated
- ¼ bolus in 30 sec
- rest slowly till intubation
• Total required dose recorded
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Materials and Methods Peri-anaesthetic period
• Endotracheal tube (7.5mm) placed
by aid of laryngoscope blade
• Goats allowed to breathe room air
• Ringer Lactate administered at
4ml/kg/hr
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Materials and Methods Quality of induction Scoring
Score Score Description
0
(Poor)
Excitement, intubation impossible
1
(Fair)
Mild excitement, slightly prolonged (>
2 minutes)
2
(Good)
Smooth, no excitement
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Materials and Methods Parameters Measured and Recorded
• Heart rate
• Arterial blood pressure (systolic, diastolic, mean)
• Respiratory rate
• Body temperature
[Before sedation, 20 minutes after sedation,
1 minute after induction, then at
10, 20, 30 minutes after induction]
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Materials and Methods Parameters Measured and Recorded
• Arterial blood gas analysis (PaO2,
SaO2, PaCO2, pHa, [HCO3-])
[before sedation, 20 minutes after
sedation, 20 minutes after induction]
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Materials and Methods Recovery Period
Recorded
• Time to extubation
• Time to sternal
position
• Recovery score
Score Score Description
0 (Poor) Restless
1 (Fair) Mild restlessness
2 (Good) Smooth
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Materials and Methods Statistical Analysis
• Data assumed to be non-parametric
• Presented as [median (inter-quartile
range).
• R Statistical Software, Version 2.7.2
• P < 0.05 considered significant
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Friedman Test
Wilcoxon Test (post hoc)
ANOVA by ranks &
Wilcoxon as post hoc
Sedation scores
Propofol induction dose
Reduction in Propofol dose
Induction Scores
Time to extubation
Time to sternal
Time to standing
Recovery score
Heart rate
Resp Rate
Blood pressure
SpO2
Blood gas parameters
Temperature
Materials and Methods Statistical Analysis
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Results Sedation Scores & Induction Quality
Group # Sedation
Score
# Propofol
Dose (mg/kg)
# Dose
Reduction (%)
# Induction
Score
SAL 0 (0-0) 5.1 (4.7-5.6) NA 1 (1-2)
ACE 1.5 (1-2)* 4.5 (3.4-4.7) 20.1 2 (2-2)
MID 2 (1-2)* 3.1 (3.0-3.3)* 39.7* 2 (2-2)
BUT 1 (1-1) 3.9 (3.8-4.4) 22.1 2 (1-2)
ACEBUT 1.5 (1-2) 3.9 (3.8-4.0)* 27.8* 2 (2-2)
MIDBUT 1 (1-2) 3.3 (3.2-3.6)* 38.1* 2 (2-2)
#: Significant differences (P<0.05) between the six groups, *: Significantly different (p<0.05) from SAL (control) group
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Results
Quality of recovery from anaesthesia
Group # Extubation Time
(mins)
# Sternal Position
Time (mins)
Recovery
Score
SAL 3.0 (1.5-3.0) 4.0 (4.0-4.8) 2 (1-2)
ACE 4.0 (3.0-6.5) 6.5 (3.0-6.5) 2 (2-2)
MID 6.5 (5.3-7.0) 9.0 (8.0-10.0) 2 (1-2)
BUT 3.5 (3.0-4.8) 6.0 (5.0-9.3) 2 (2-2)
ACEBUT 5.5 (5.0-9.0) 9.0 (7.3-10.0) 2 (2-2)
MIDBUT 9.0 (8.3-9.8) 13.5 (10.8-17.0) 2 (2-2)
#: Significant differences (P<0.05) between the six groups,
NB: No significantly differences (p<0.05) from SAL (control) group
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Results Notable adverse effects
• Induction apnoea (> 30 seconds)
in 1 goat each from ACE and
MIDBUT group
• Bloat in 1 goat from
ACEBUT group
• Clonic-tonic convulsions during
recovery in a few goats across all
groups
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• Acepromazine and midazolam sedative
effects in goats supported by literature
• Lack of improvement in degree of sedation
in butorphanol combinations unexpected
according to popular literature
• Butorphanol has been reported to cause
excitation
Discussion Group Profiles & Degree of sedation
Bertens et al 1993, Valverde & Gunkel 2005, Carroll et al 2001
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Discussion Induction Characteristics
• Induction dose of propofol in
unpremedicated goats similar in
literature
• Premedication regimens that include
midazolam reduced induction dose
• Muscle-relaxing properties of
midazolam could have made the
difference
Pablo et al 1997, Hall et al 2001
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Discussion Propofol anaesthesia characteristics
• Good quality of induction and recovery
from anaesthesia could be due to the
well known superiority of propofol as
an induction agent and good
temperament of goats.
• Indiscriminate myoclonus could be due
to inherent propofol characteristics
• Myoclonic activity not ameriolated by
premedicants used in this study
Pablo et al 1997, Prassinos et al 2005, Reid et al 1993
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Discussion Cardio-respiratory effects
Very minimal effects on cardiovascular, respiratory and blood-gas analysis parameters from all regimens.
Could be because low, but clinically-
relevant drug dosages were used
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Conclusion
• All sedation regimens tested in this study caused
some degree of sedation and reduction in
propofol requirements for induction
• Significant sedation and reduction in propofol
noticed in midazolam-based regimens
• All sedation regimens tested caused minimal
cardio-respiratory depression
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Effects of midazolam on isoflurane minimum alveolar concentration and
cardiovascular function in mechanically-ventilated goats.
TB Dzikiti, GF Stegmann,
LN Dzikiti, LJ Hellebrekers
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Introduction
• Midazolam reduces inhalation anaesthetic
requirements in humans and other species
• No literature on its effects on inhalation
anaesthetic requirements in goats.
• Effects of midazolam on isoflurane MAC
studied in goats.
Taira 2000; Lemke 2007; Hendrickx 2008
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Introduction
Isoflurane MAC
• Lowest alveolar (expired) concentration required
to prevent gross purposeful movement in
response to a supramaximal stimulus
• Major index of anaesthetic potency
• Stimulus: claw-clamping with a Vulsellum
forceps
• Isoflurane MAC (goat): 1.3 - 1.5%
Merkel & Eger 1963; Hikasa 2002; Doherty 2004,Lemke 2007
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Introduction
Factors that can lower MAC
• Hypothermia
• Severe hypotension
• Hypoxaemia (PaO2 < 40 mmHg)
• Anaemia
• Most anaesthetic agents
Quasha 1980
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Introduction
Hypotheses
• Midazolam does not affect isoflurane MAC
vs
• Midazolam reduces isoflurane MAC
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49
Materials and Methods Study Design
• 6 goats
(3 does, 3 wethers): ~ 28 kg, ~12 months
• Randomised crossover design
• Three treatments: LMID, MMID & HMID
• 4-week intervals between treatments (wash-out period)
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50
Materials and Methods Study Design
Induction:
Iso MACb
determination:
Iso MACt
determination: +
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51
Materials and Methods Study Design: Treatments
GROUP TREATMENT
Control (Baseline MAC)
Isoflurane, to effect
Midazolam Isoflurane
Bolus (mg/kg) CRI (mg/kg/hr)
LMID 0.1 0.1 To effect
MMID 0.2 0.2 To effect
HMID 0.9 0.9 To effect
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52
Materials and Methods Preanaesthestic Period
• Starvation 18-24 hours
• Healthy (physical exam, complete
blood count, serum biochemistry
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53
Materials and Methods Catheterisations
• Auricular artery (24G): blood pressure
measurements
• Rt Cephalic artery (18G): LRS and
Midazolam administration
• Rt Jugular vein (18G): midazolam plasma
concentration analysis.
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54
Materials and Methods Induction of Anaesthesia
• Induction by Facemask
• Oxygen: 6.0 L/min
• Isoflurane: 0.5 Vol% increments until
3.5 Vol% reached
• Intubation: 7.5 mm tube with cuff inflated
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Materials and Methods Early Anaesthetic Period
• Left lateral recumbency
• Oxygen Flow: 2.0 L/min
• Initial Et[isoflurane] target: 1.6 Vol%
• Mechanical Ventilation: 20 cmH2O,
resp rate at 6 – 10 per min,
Et[CO2] at 35 - 45 mmHg.
• Lactated Ringers Solution at 4 mL/kg/hr
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Materials and Methods Monitoring
• Anaesthetic depth: claw clamping
• Isoflurane: inspired & expired
• Heart rate
• Pulse-oximetry
• Blood pressure: SAP, DAP, MAP
• CRT
• Respiratory rate
• CO2: inspired & expired
• Oesophageal Temperature
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Materials and Methods Stimulus for MAC determination
• Vulsellum forceps clamped up to the second ratchet to the claw about 1cm below the coronary band for 60 seconds or until purposeful movement occurred
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58
Materials and Methods Baseline Isofl MAC determination
• Starting at Et[ISO] of 1.6 Vol%
• Adjusted downwards (10 %) for
non-response
• Response to claw clamping tested every 15
minutes
• Iso MAC = Et[ISO] response + Et[ISO] non-response (last)
2
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59
Materials and Methods Baseline Isoflurane MAC determination
• Clockwise direction used
for consecutive
claw-clamping
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Materials and Methods Midazolam Treatments
GROUP TREATMENT
Control (Baseline MAC)
Isoflurane, to effect
Midazolam Isoflurane
Bolus (mg/kg) CRI (mg/kg/hr)
LMID 0.1 0.1 To effect
MMID 0.2 0.2 To effect
HMID 0.9 0.9 To effect
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Materials and Methods Treatment Isofl MAC determination
• Starting at Et[ISO] of Baseline Isofl MAC
• Adjusted downwards (10 %) for non-
response
• Response to claw clamping tested every 15
minutes
• Iso MAC = Et[ISO] response + Et[ISO] non-response (last)
2
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62
Materials and Methods Blood samples
• Jugular: 4.5 mL in heparinised vacutainer
• At time 0, 1, 15, 30, every 30 of
midazolam administration
• Centrifuged, plasma stored at -20 °C
• Technical issues hindered analysis
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Materials and Methods Recovery Period
Recorded
• Time to extubation
• Time to sternal
• Time to standing
• Quality of recovery
Score
Recovery
Score Description
0 (Poor) Restless
1 (Fair) Mild restlessness
2 (Good) Smooth
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Materials and Methods Statistical Analysis
• All data assumed non-parametric
• Presented as median (IQR)
• R Statistical Software Version 2.7.2
• P < 0.05 considered significant
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Materials and Methods Statistical Analysis
Friedman Test &
Wilcoxon as post-hoc
ANOVA by ranks &
Wilcoxon as post hoc
MAC
MAC reduction (%)
MAC determination time
Time to extubation
Time to sternal
Time to standing
Recovery score
Heart rate
Blood pressure
SpO2
Temperature
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Materials and Methods Results: MAC Data Treatment Isoflurane MAC
(%vol) (%) Change
post-treatment
MAC determination
time (minutes)
Control 1.40 (1.38-1.41) * Not applicable 70.0 (70.0-73.8)
LMID 1.18 (1.15-1.20)* -16.8 (12.7-19.1)* 67.5 (60.0-75.0)
MMID 0.91 (0.85-0.95)* -35.07 (29.9-40.4)* 90.0 (75.0-105.0)
HMID 0.65 (0.63-0.68)* -54.7 (48.6-56.3)* 90.0 (90.0-90.0)#
*: statistically significantly different (P <0.05) from all other treatments #: statistically significantly different (P <0.05) from LMID treatment
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Materials and Methods Results: MAC Data Treatment Isoflurane MAC
(%vol)
(%) Change post-treatment
MAC determination
time (minutes)
Control 1.40 (1.38-1.41) * Not applicable 70.0 (70.0-73.8)
LMID 1.18 (1.15-1.20)* -16.8 (12.7-19.1)* 67.5 (60.0-75.0)
MMID 0.91 (0.85-0.95)* -35.07 (29.9-40.4)* 90.0 (75.0-105.0)
HMID 0.65 (0.63-0.68)* -54.7 (48.6-56.3)* 90.0 (90.0-90.0)#
*: statistically significantly different (P <0.05) from all other treatments #: statistically significantly different (P <0.05) from LMID treatment
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0.017
0.013
0.017
0.013
0.013
0.017
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70
Materials and Methods Results: MAC Data Treatment Isoflurane MAC
(%vol)
(%) Change
post-treatment
MAC determination time (minutes)
Control 1.40 (1.38-1.41) * Not applicable 70.0 (70.0-73.8)
LMID 1.18 (1.15-1.20)* -16.8 (12.7-19.1)* 67.5 (60.0-75.0)
MMID 0.91 (0.85-0.95)* -35.07 (29.9-40.4)* 90.0 (75.0-105.0)
HMID 0.65 (0.63-0.68)* -54.7 (48.6-56.3)* 90.0 (90.0-90.0)#
*: statistically significantly different (P <0.05) from all other treatments #: statistically significantly different (P <0.05) from LMID treatment
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71
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Materials and Methods Results: Quality of Recovery Treatment
Extubation
(minutes) Sternal Position
(minutes) Standing
(minutes) Recovery Score
LMID 3.0 (2.3-3.0) 4.0 (1.5-5.0) 12.5 (10.0-15.0) 2 (2-2)
MMID 3.0 (2.3-4.5) 3.0 (1.5-4.5) 13.5 (10.5-18.8) 2 (2-2)
HMID 5.0 (2.8-5.0) 5.0 (1.5-7.0) 26.0 (20.5-33.8) 2 (2-2)
Note: No statistically significant differences (P<0.05) between any groups
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Discussion
Isoflurane MAC
• Observed Iso MAC lies within range (Literature)
Observed Isoflurane MAC 1.4 %
Antognini & Eisele 1993 1.5 %
Hikasa 2002, Doherty 2004 1.4 %
Hikasa 1998, Doherty 2002a/b 1.23 – 1.29 %
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Discussion
Isoflurane MAC Reduction
• Midazolam reduced isoflurane MAC in a
dose-dependent manner.
• Similar finding in humans
• Reduction of isoflurane dose results in
less isoflurane-associated adverse effects
Inagaki 1993; Antognini & Eisele 1993; Hikasa et al. 2002
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Discussion
Cardiovascular Effects
• Minimal changes in cardiovascular
parameters
• Typical of midazolam
Mehlisch 2002; Lemke 2007
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Discussion
Recovery from anaesthesia
• Good, fast and smooth recovery as
expected of both isoflurane and
midazolam
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Conclusion
• Midazolam reduces isoflurane MAC in
dose-dependent manner in goats
• Minimal cardiovascular effects
• Smooth recovery
• Midazolam may be used as an adjunct to
isoflurane anaesthesia in goats.
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Effects of fentanyl on isoflurane minimum alveolar concentration and
cardiovascular function in mechanically-ventilated goats.
TB Dzikiti, GF Stegmann,
LN Dzikiti, LJ Hellebrekers
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80
Introduction
• General anaesthesia consists of
unconsciousness, muscle relaxation and
analgesia
• Isoflurane only a hypnotic agent
• The potential of fentanyl as an analgesic
adjunct to isoflurane anaesthesia in goats
studied
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81
Introduction
Hypotheses
• Fentanyl does not affect isoflurane MAC
vs
• Fentanyl reduces isoflurane MAC
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Materials and Methods Study Design
• 6 goats
(3 does,3 wethers): ~ 36 kg, ~15 months
• Randomised crossover design
• Three treatments: LFENT, MFENT & HFENT
• 3-week intervals between treatments (wash-out period)
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Materials and Methods Study Design: Treatments
GROUP TREATMENT
Control (Baseline MAC)
Isoflurane, to effect
Fentanyl Isoflurane
Bolus (mg/kg) CRI (mg/kg/hr)
LFENT 0.005 0.005 To effect
MFENT 0.015 0.015 To effect
HFENT 0.03 0.03 To effect
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Materials and Methods Preanaesthestic Period
• Starvation 18-24 hours
• Healthy (physical exam, complete
blood count, serum biochemistry
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85
Materials and Methods Catheterisations
• Auricular artery (24G): blood pressure
measurements
• Rt Cephalic artery (18G): LRS and
Fentanyl administration
• Rt Jugular vein (18G): fentanyl plasma
concentration analysis.
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86
Materials and Methods Induction of Anaesthesia
• Induction by Facemask
• Oxygen: 6.0 L/min
• Isoflurane: 0.5 Vol% increments until
3.5 Vol% reached
• Intubation: 7.5 mm tube with cuff inflated
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87
Materials and Methods Baseline Isofl MAC determination
• Starting at Et[ISO] of 1.6 Vol%
• Adjusted downwards (10 %) for non-
response
• Response to claw clamping tested every 15
minutes
• Iso MAC = Et[ISO] response + Et[ISO] non-response (last)
2
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Materials and Methods Fentanyl Treatments
GROUP TREATMENT
Control (Baseline MAC)
Isoflurane, to effect
Fentanyl Isoflurane
Bolus (mg/kg) CRI (mg/kg/hr)
LFENT 0.005 0.005 To effect
MFENT 0.015 0.015 To effect
HFENT 0.03 0.03 To effect
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89
Materials and Methods Treatment Isofl MAC determination
• Starting at Et[ISO] of Baseline Isofl MAC
• Adjusted downwards (10 %) for non-
response
• Response to claw clamping tested every 15
minutes
• Iso MAC = Et[ISO] response + Et[ISO] non-response (last)
2
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Materials and Methods Blood samples
• Jugular: 4.5 mL in heparinised vacutainer
• At time 0, 1, 15, 30, every 30 of fentanyl
administration
• Centrifuged, plasma stored at -20 °C
• Technical issues hindered analysis
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Materials and Methods Recovery Period
Recorded
• Time to extubation
• Time to sternal
• Time to standing
• Quality of recovery
Score
Recovery
Score Description
0 (Poor) Restless
1 (Fair) Mild restlessness
2 (Good) Smooth
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Materials and Methods Statistical Analysis
• All data assumed non-parametric
• Presented as median (IQR)
• R Statistical Software Version 2.7.2
• P < 0.05 considered significant
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Materials and Methods Statistical Analysis
Friedman Test &
Wilcoxon as post-hoc
ANOVA by ranks &
Wilcoxon as post hoc
MAC
MAC reduction (%)
MAC determination time
Time to extubation
Time to sternal
Time to standing
Recovery score
Heart rate
Blood pressure
SpO2
Temperature
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Materials and Methods Results: MAC Data
Treatment Isoflurane MAC (%vol)
(%) Change
post-treatment
MAC determination
time (minutes)
Control 1.32 (1.29-1.36) * Not applicable 67.5 (65.0-70.0)
LFENT 0.98 (0.92-1.01) * -27.6 (24.9-29.3)* 75.0 (75.0-75.0)
MFENT 0.75 (0.69-0.79) # -40.7 (40.0-47.7)* 97.5 (90.0-116.3)#
HFENT 0.58 (0.51-0.65) # -56.6 (51.9-60.8)* 120.0 (108.8-120.0)#
*: statistically significantly different (P <0.05) from all other groups #: statistically significantly different (P <0.05) from Control treatment and LFENT treatment
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Materials and Methods Results: MAC Data
Treatment Isoflurane MAC
(%vol)
(%) Change
post-treatment
MAC determination
time (minutes)
Control 1.32 (1.29-1.36) * Not applicable 67.5 (65.0-70.0)
LFENT 0.98 (0.92-1.01) * -27.6 (24.9-29.3)* 75.0 (75.0-75.0)
MFENT 0.75 (0.69-0.79) # -40.7 (40.0-47.7)* 97.5 (90.0-116.3)#
HFENT 0.58 (0.51-0.65) # -56.6 (51.9-60.8)* 120.0 (108.8-120.0)#
*: statistically significantly different (P <0.05) from all other groups #: statistically significantly different (P <0.05) from Control treatment and LFENT treatment
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97
0.017
0.029
0.017
0.026
0.013
0.017
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98
Materials and Methods Results: MAC Data
Treatment Isoflurane MAC
(%vol)
(%) Change
post-treatment
MAC determination time (minutes)
Control 1.32 (1.29-1.36) * Not applicable 67.5 (65.0-70.0)
LFENT 0.98 (0.92-1.01) * -27.6 (24.9-29.3)* 75.0 (75.0-75.0)
MFENT 0.75 (0.69-0.79) # -40.7 (40.0-47.7)* 97.5 (90.0-116.3)#
HFENT 0.58 (0.51-0.65) # -56.6 (51.9-60.8)* 120.0 (108.8-120.0)#
*: statistically significantly different (P <0.05) from all other groups #: statistically significantly different (P <0.05) from Control treatment and LFENT treatment
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Materials and Methods Results: Quality of Recovery Treatment
Extubation
(minutes) Sternal Position
(minutes) Standing
(minutes) Recovery Score
LFENT 2.0 (2.0-2.8) 3.0 (3.0-4.5) 5.0 (5.0-7.3) 2 (2-2)
MFENT 3.0 (3.0-3.0) 4.0 (3.0-5.0) 9.0 (7.25-11.5) 2 (2-2)
HFENT 3.0 (3.0-3.0) 3.0 (3.0-4.5) 10.0 (8.5-10.0) 1.5 (1-2)
Note: No statistically significant differences (P <0.05) between any treatments
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Materials and Methods Results: Quality of Recovery
• Good scores, but exaggerated
tail-wagging observed 4 out of 6 times
following MFENT and HFENT
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Discussion
Isoflurane MAC
• Observed isoflurane MAC (1.3%) is similar
to that observed in earlier study with same
goats and similar to literature values
• MAC remains the same within a species
Quasha 1980; Hikasa et al. 2002; Doherty 2002a/b; Wilson 2008
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Discussion
Isoflurane MAC Reduction
• Fentanyl reduced isoflurane MAC in a dose-dependent manner.
• Similar findings in humans, but less consistently so in animals
• Order of fentanyl MAC reducing potency: dogs > goats > horses, pigs
• Existence of variation in pharmacologic action of fentanyl
Moon 1995; Criado 2003; Thomas 2006; Wilson 2006
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Discussion
Cardiovascular Effects
• Cardiovascular parameters stayed stable
• Heart rate and MAP decreased 2 minutes
after HFENT bolus administration, but still
within acceptable physiological limits
• Potent opioids administered at low
dosages cause minimal cardiovascular
depression
Shibutani 1995; Mama 2006
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Discussion
Recovery from anaesthesia
• Good and short recovery
• Fentanyl has a very short duration of action
• Exaggerated tail-wagging observed was quite harmless, but reason for it is unknown
• Increased vocalisation and activity has been reported by Carroll et al 1999
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Conclusion
• Fentanyl reduces isoflurane MAC in dose-
dependent manner in goats
• Minimal cardiovascular effects
• Smooth recovery, inexplicable tail-wagging
• Fentanyl may be used as an analgesic
adjunct to isoflurane anaesthesia in goats.
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107
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Effects of propofol on isoflurane minimum alveolar concentration and
cardiovascular function in mechanically-ventilated goats.
TB Dzikiti, GF Stegmann,
D Cromarty, LN Dzikiti, LJ Hellebrekers
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Introduction
• Injectable hypnotics (propofol) are usually
used for induction of general anaesthesia
• Inhalants (isoflurane) are usually used for
maintenance of general anaesthesia
• Can the two be used together for
maintenance of anaesthesia at lower
dosages of each in goats?
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Introduction
Hypotheses
• Propofol does not affect isoflurane MAC
vs
• Propofol reduces isoflurane MAC
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Materials and Methods Study Design
• 6 goats
(3 does, 3 wethers): ~ 42 kg, ~18 months
• Randomised crossover design
• Three treatments: LPROP, MPROP & HPROP
• 4-week intervals between treatments (wash-out period)
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Materials and Methods Study Design: Treatments
GROUP TREATMENT
Control (Baseline MAC)
Isoflurane, to effect
Propofol Isoflurane
Bolus (mg/kg) CRI (mg/kg/hr)
LPROP 0.5 0.05 To effect
MPROP 1.0 0.1 To effect
HPROP 2.0 0.2 To effect
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Materials and Methods Preanaesthestic Period
• Starvation 18-24 hours
• Healthy (physical exam, complete
blood count, serum biochemistry
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Materials and Methods Catheterisations
• Auricular artery (24G): blood pressure
measurements
• Rt Cephalic artery (18G): LRS and
Propofol administration
• Rt Jugular vein (18G): Propofol plasma
concentration analysis.
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Materials and Methods Induction of Anaesthesia
• Induction by Facemask
• Oxygen: 6.0 L/min
• Isoflurane: 0.5 Vol% increments until
3.5 Vol% reached
• Intubation: 7.5 mm tube with cuff inflated
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Materials and Methods Early Anaesthetic Period
• Left lateral recumbency
• Oxygen Flow: 2.0 L/min
• Initial Et[isoflurane] target: 1.6 Vol%
• Mechanical Ventilation: 20 cmH2O,
Resp rate at 6 – 10 per min,
Et[CO2] at 35 - 45 mmHg.
• Lactated Ringers Solution at 4 mL/kg/hr
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Materials and Methods Monitoring
• Anaesthetic depth: claw clamping
• Isoflurane: inspired & expired
• Heart rate
• Pulse-oximetry
• Blood pressure: SAP, DAP, MAP
• CRT
• Respiratory rate
• CO2: inspired & expired
• Oesophageal Temperature
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Materials and Methods Baseline Isofl MAC determination
• Starting at Et[ISO] of 1.6 Vol%
• Adjusted downwards (10 %) for non-
response
• Response to claw clamping tested every 15
minutes
• Iso MAC = Et[ISO] response + Et[ISO] non-response (last)
2
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Materials and Methods Propofol Treatments
GROUP TREATMENT
Control (Baseline MAC)
Isoflurane, to effect
Propofol Isoflurane
Bolus (mg/kg) CRI (mg/kg/hr)
LPROP 0.5 0.05 To effect
MPROP 1.0 0.1 To effect
HPROP 2.0 0.2 To effect
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Materials and Methods Treatment Isofl MAC determination
• Starting at Et[ISO] of Baseline Isofl MAC
• Adjusted downwards (10 %) for non-
response
• Response to claw clamping tested every 15
minutes
• Iso MAC = Et[ISO] response + Et[ISO] non-response (last)
2
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Materials and Methods Blood samples
• Jugular: 4.5 mL in heparinised vacutainer
• At time 0, 1, 15, 30, every 30 of propofol
administration
• Centrifuged, plasma stored at -20 °C
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Materials and Methods Recovery Period
Recorded
• Time to extubation
• Time to sternal
• Time to standing
• Quality of recovery
Score
Recovery
Score Description
0 (Poor) Restless
1 (Fair) Mild restlessness
2 (Good) Smooth
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Materials and Methods Statistical Analysis
• All data assumed non-parametric
• Presented as median (IQR)
• R Statistical Software Version 2.7.2
• P < 0.05 considered significant
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Materials and Methods Statistical Analysis
Friedman Test &
Wilcoxon as post-hoc
ANOVA by ranks &
Wilcoxon as post hoc
MAC
MAC reduction (%)
MAC determination time
Time to extubation
Time to sternal
Time to standing
Recovery score
Heart rate
Blood pressure
SpO2
Temperature
Plasma propofol conc.
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Materials and Methods Statistical Analysis
• Spearman Rank Correlation Test:
Isoflurane MAC versus plasma propofol
concentration
• Simple linear regression:
Isoflurane MAC versus plasma propofol
concentration
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Materials and Methods Results: MAC Data Treatment
Isoflurane MAC (%vol)
(%) Change
post-treatment
Time (minutes)a
Control 1.37 (1.36-1.37)* Not applicable 65.0 (65.0-65.0)
LPROP 1.15 (1.08-1.15)* -16.4 (16.1-16.4)* 60.0 (60.0-71.3)
MPROP 0.90(0.87-0.93)* -34.7 (32.3-36.3)* 75.0 (75.0-75.0)#
HPROP 0.55 (0.49-0.58)* -59.7 (57.4-64.3)* 112.5 (105.0-120.0)*
* : statistically significantly different (P <0.05) from other three treatments # : statistically significantly different (P <0.05) from LPROP treatment a : indicates time taken to determine isoflurane MAC following beginning of respective treatment
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127
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Materials and Methods Results: MAC Data Treatment
Isoflurane MAC
(%vol)
(%) Change post-treatment
Time (minutes)a
Control 1.37 (1.36-1.37)* Not applicable 65.0 (65.0-65.0)
LPROP 1.15 (1.08-1.15)* -16.4 (16.1-16.4)* 60.0 (60.0-71.3)
MPROP 0.90(0.87-0.93)* -34.7 (32.3-36.3)* 75.0 (75.0-75.0)#
HPROP 0.55 (0.49-0.58)* -59.7 (57.4-64.3)* 112.5 (105.0-120.0)*
* : statistically significantly different (P <0.05) from other three treatments # : statistically significantly different (P <0.05) from LPROP treatment a : indicates time taken to determine isoflurane MAC following beginning of respective treatment
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0.015
0.029
0.017
0.013
0.029
0.017
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Materials and Methods Results: MAC Data Treatment
Isoflurane MAC
(%vol)
(%) Change
post-treatment
Time (minutes)a
Control 1.37 (1.36-1.37)* Not applicable 65.0 (65.0-65.0)
LPROP 1.15 (1.08-1.15)* -16.4 (16.1-16.4)* 60.0 (60.0-71.3)
MPROP 0.90(0.87-0.93)* -34.7 (32.3-36.3)* 75.0 (75.0-75.0)#
HPROP 0.55 (0.49-0.58)* -59.7 (57.4-64.3)* 112.5 (105.0-120.0)*
* : statistically significantly different (P <0.05) from other three treatments # : statistically significantly different (P <0.05) from LPROP treatment a : indicates time taken to determine isoflurane MAC following beginning of respective treatment
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131
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Materials and Methods Results: Plasma propofol concentration data
(µg/mL)
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Materials and Methods Results: Quality of Recovery Treatment Extubation
(minutes)
Sternal position
(minutes)
Standing
(minutes)
Recovery Score
LPROP 2.5 (1.3-3.0) 4.0 (2.3-5.0) 6.0 (5.0-7.0) 2 (2-2)
MPROP 2.0 (2.0-2.8) 2.0 (2.0-2.8) 5.0 (3.5-8.0) 2 (2-2)
HPROP 2.5 (2.0-3.0) 2.5 (2.0-3.0) 5.0 (5.0-7.3) 2 (2-2)
Note: No statistically significant differences (P<0.05) between any treatments
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Discussion
Isoflurane MAC
• Observed isoflurane MAC (1.37%) is
similar to that observed in earlier study
with same goats and similar to literature
values
Hikasa et al. 2002; Doherty 2002a/b; Wilson 2008
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Discussion
Isoflurane MAC Reduction
• Propofol reduced isoflurane MAC in a
dose-dependent manner
• Both propofol and isoflurane are known to
depress the CNS via GABA-ergic
potentiation
• Both directly depress dorsal horn neuronal
responses to noxious stimuli
Larsen 1998; Antognini 2000
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Discussion
Propofol plasma concentrations
• Propofol plasma concs observed in
present study are slightly higher than
those observed in sheep, ponies, dogs
• Species differences in drug metabolism
could be the reason for the differences
Correia 1996; Nolan 1996; Beths 2001; Nolan & Reid 1993
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Discussion
Recovery from anaesthesia
• Both isoflurane and propofol known to be
associated with rapid and smooth
recoveries as observed in present study
Reid 1993; Antognini & Eisele 1993
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Conclusion
• Propofol reduces isoflurane MAC in dose-
dependent manner in goats
• Minimal cardiovascular effects
• Smooth recovery
• Propofol and isoflurane may be co-
administered for general anaesthesia
• Both drugs lack analgesic effect!
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141 141
Total Intravenous Anaesthesia (TIVA) with propofol-fentanyl and propofol-
midazolam in spontaneously-breathing goats
TB Dzikiti, GF Stegmann,
LN Dzikiti, LJ Hellebrekers
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Introduction
• Total intravenous anaesthesia (TIVA):
use of only intravenously administered
drugs to obtain general anaesthesia
• TIVA usually involves co-administration
of a hypnotic agent (propofol) and an
opioid (fentanyl, sufentanil, remifentanil)
and/or a benzodiazepine (midazolam)
Reid 1993, Nolan 2004
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Introduction
• TIVA developing at a slow pace in
veterinary anaesthesia
• Few suitable drugs available
• Complicated dosing regimens
Reid 1993, Nolan 2004, Vuyk 1998; Fresenius Kabi, South Africa
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• Are combinations of propofol with either
fentanyl or midazolam suitable for TIVA
in goats?
• What’s their impact on vital physiological
functions?
Introduction Questions to answer
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Materials and Methods Study Design
• 6 goats (3 does, 3 wethers): ~21months old
~44kg
• Randomised crossover design
• Two treatments (FP = fentanyl-propofol, MP = midazolam-propofol)
• 3-week intervals between treatments (wash-out period)
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Materials and Methods Study Design
FP MP
Induction:
Maintenance:
Fentanyl & Propofol Midazolam & Propofol
Treatment:
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Materials and Methods Pre-anaesthetic Period
• Starvation: 18-24 hours
• Healthy (physical exam, complete
blood count, serum biochemistry)
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Materials and Methods Catheterisation
• Auricular artery catheterised (24G)
- blood sampling
- arterial blood
pressure readings
• Both cephalic veins catheterised (18G)
- fluids & fentanyl or midazolam
- propofol
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Materials and Methods Catheterisation
• Auricular artery catheterised (24G)
- blood sampling
- arterial blood
pressure readings
• Both cephalic veins catheterised (18G)
- fluids & fentanyl or midazolam
- propofol
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Materials and Methods Treatments (Induction)
• Fentanyl 0.02 mg/kg (FP) or
midazolam 0.3 mg/kg (MP) followed
a minute later by
propofol ~ 4 mg/kg for both groups.
• All drugs administered intravenously
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Materials and Methods Peri-anaesthetic period
• Endotracheal tube (7.5mm) placed by aid of
laryngoscope blade
• Goats allowed to breathe spontanously, while connected to a circle system for delivery of oxygen only at 2 L/min
• Ringer Lactate administered at 4 ml/kg/hr
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Quality of induction Scoring
Score
Score Description
0
Poor
Excited, unable to intubate
1
Fair
Mild excitement, slightly prolonged (> 2 minutes)
2
Good
Smooth, no excitement
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Treatments (Maintenance of GA)
Treatment
Propofol
(mg/kg/min)
Fentanyl
(mg/kg/hr)
Midazolam
(mg/kg/hr)
FP
0.2; to effect
0.02
-
MP
0.2; to effect
-
0.3
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Materials and Methods Maintenance of General Anaesthesia
• Target to maintain goats in Stage 3 / plane II of anaesthesia.
• Depth of anaesthesia assessed every 10 minutes by clamping of claw using a Vulsellum forceps.
• Propofol CRI adjusted by 10% depending on responds to claw clamping
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Materials and Methods Parameters Recorded
• Heart rate
• Arterial blood pressure (systolic, diastolic, mean)
• SpO2
• Respiratory rate
• End-tidal carbon dioxide
• Body temperature
Before anaesthesia, at 3, 5 and every 10 minutes
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Materials and Methods Parameters Recorded
Arterial blood gas analysis
(PaO2, SaO2, PaCO2, pHa, [HCO3-])
• [before anaesthesia, at 3, 30 and 60
minutes after induction]
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Materials and Methods Recovery from anaesthesia
• General anaesthesia maintained using
TIVA for 90 minutes
• Allowed to breathe room air after
recovery
• Endotracheal tube removed at return of
swallowing reflex
• Final delivery rate (mg/kg/hr) for
propofol recorded
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Materials and Methods Recovery Period
Recorded
• Time to extubation
• Time to sternal
position
• Recovery score
Score
Recovery
Score Description
0 (Poor) Restless
1 (Fair) Mild restlessness
2 (Good) Smooth
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Materials and Methods Statistical Analysis
• All data assumed non-parametric
• Presented as [median (range)].
• R Statistical Software, Version 2.7.2
• P < 0.05 considered significant
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160 160
Materials and Methods Statistical Analysis
Wilcoxon Matched-Pairs
Signed Rank Test
ANOVA by ranks &
Wilcoxon as post hoc
Sedation scores
Propofol induction dose
Induction Scores
Propofol maintenance dose
Time to extubation
Time to sternal
Time to standing
Recovery score
Heart rate
Respiratory Rate
Blood pressure
SpO2
ETCO2
Blood gas parameters
Temperature
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Results Group Profiles & Propofol dosages
• Quality of induction was very good in
both groups
Group Induction Propofol
(mg/kg)
*Maintenance Propofol
(mg/kg/min)
FP 4.00 (3.96 - 4.01) 0.2
MP 3.97 (3.91- 4.00) 0.3
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Extubation
(mins)
Sternal Position
(mins)
Standing
(mins)
Recovery
Score
FP
3.0 (3.0 -3.0)
4.5 (3.3 – 5.0)
13.0 (10.3 – 15.0)
0.5(0-2)
MP
4.5 (3.3 – 5.0)
5.0 (5.0 – 6.5)
15.0 (11.3 – 17.3)
2(2-2)
Recovery Quality
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Results Adverse effects observed
• Hypersalivation in all goats throughout
anaesthetic procedure
• Regurgitation was rare
• Abnormal behavioural signs (exaggerated
tail-wagging, nibbling at surrounding
objects, restlessness) observed in fentanyl
propofol group at recovery from
anaesthesia
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Discussion
• Dose of propofol for induction similar to
those in literature for premedicated goats
• Good induction characteristics of
propofol allowed rapid tracheal intubation
• TIVA from both combinations was
satisfactory
Bertens et al 1993, Carroll et al 1998, Prassinos 2005
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Discussion Effects on Vital Body Fuctions
• Minimal impact on cardio-respiratory
functions confirm superiority of combination
anaesthesia over mono-anaesthesia
• Low respiratory rates probably compensated
by higher tidal volumes
• Oxygen supplementation might also have
offset impact of low respiratory rates
Bettschart-Wolfensberger et al 2007, Clutton 1998
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Discussion Recovery from anaesthesia
• Quick recovery from anaesthesia (essential
in ruminants) achieved with both TIVA
combination in this study
• Recovery characteristics similar to those
observed in premedicated goats
Carroll et al 1998, Carroll et al 2001, Smith et al 2000
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Discussion Recovery from anaesthesia
• Excitatory signs associated with fentanyl
previously reported
• Sedation of goats prior to recover from
fentanyl anaesthesia advisable
Carroll et al 1998, Carroll et al 2001, Smith et al 2000
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Conclusion
• TIVA is safely achievable with propofol-
fentanyl or propofol-midazolam in
spontaneously- breathing, oxygen-
supplemented goats
• Sedation required to offset CNS excitement
that might accompany recovery from
fentanyl-associated anaesthesia in goats
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Towards Total Intravenous Anaesthesia in Goats
General Conclusions
Dzikiti T B
Companion Animal Clinical Studies
University of Pretoria
Promoter: Prof LJ Hellebrekers, Utrecht University
Co-Promoter: Prof GF Stegmann, UP
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General Objectives
• Investigate cardiopulmonary effects of relevant sedatives: ACP, midazolam, butorphanol
• Investigate isoflurane-sparing effects of relevant drugs: midazolam, fentanyl, propofol
• Evaluate efficacy of relevant drug combinations for TIVA in goats: fentanyl-propofol, midazolam-propofol
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General Conclusion
Premedicants
ACP, Midazolam, Butorphanol, ACP-Butorphanol, Midazolam-Butorphanol
• All sedation regimens tested in this study
caused some degree of sedation and
reduction in propofol requirements for
induction
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General Conclusion
Premedicants
ACP, Midazolam, Butorphanol, ACP-Butorphanol, Midazolam-Butorphanol
• Significant sedation and reduction in
propofol noticed in midazolam-based
regimens
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General Conclusions Midazolam MAC effects
• Midazolam reduces isoflurane MAC in
dose-dependent manner in goats
• Minimal cardiovascular effects
• Smooth recovery
• Midazolam may be used as an adjunct to
isoflurane anaesthesia in goats.
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General Conclusions Fentanyl MAC effects
• Fentanyl reduces isoflurane MAC in dose-
dependent manner in goats
• Minimal cardiovascular effects
• Smooth recovery, inexplicable tail-wagging
• Fentanyl may be used as an analgesic
adjunct to isoflurane anaesthesia in goats.
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General Conclusions Propofol MAC effects
• Propofol reduces isoflurane MAC in dose-
dependent manner in goats
• Minimal cardiovascular effects
• Smooth recovery
• Propofol and isoflurane may be co-
administered for general anaesthesia
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General Conclusions Propofol-fentanyl, Propofol-midazolam TIVA
• TIVA is safely achievable with propofol-fentanyl or propofol-midazolam in spontaneously-breathing, oxygen-supplemented goats
• Sedation required to offset CNS excitement that might accompany recovery from fentanyl-associated anaesthesia in goats
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Conclusion Publications (1)
Sedative and cardiopulmonary effects of acepromazine,
midazolam, butorphanol, acepromazine-butorphanol
and midazolam-butorphanol on propofol anaesthesia in
goats.
Dzikiti T B, Stegmann G F, Hellebrekers L J, Auer R E J,
Dzikiti L N
Journal of the South African Veterinary Association (2009)
Vol 80,10–16
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Conclusion Publications (2)
Total intravenous anaesthesia (TIVA) with propofol-
fentanyl and propofol-midazolam combinations in
spontaneously-breathing goats
Brighton T Dzikiti*, Frik G Stegmann*, Loveness N Dzikiti
& Ludo J Hellebrekers
Veterinary Anaesthesia and Analgesia (2010) Vol 37,
519–525
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181
Conclusion Publications (3)
Effects of propofol on isoflurane minimum alveolar
concentration and cardiovascular function in
mechanically ventilated goats
Brighton T Dzikiti*, Frik G Stegmann, Duncan Cromarty ,
Loveness N Dzikiti, Ludo J Hellebrekers
Veterinary Anaesthesia and Analgesia Vol 38, 44-53
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Conclusion Publications (4)
Effects of fentanyl on isoflurane minimum alveolar
concentration and cardiovascular function in
mechanically ventilated goats
Brighton T Dzikiti*, Frik G Stegmann, Loveness N Dzikiti,
Ludo J Hellebrekers
Veterinary Record, (Unconditionally Accepted)
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Conclusion Publications (5)
Effects of midazolam on isoflurane minimum alveolar
concentration and cardiovascular function in
mechanically ventilated goats
Brighton T Dzikiti*, Frik G Stegmann, Loveness N Dzikiti,
Ludo J Hellebrekers
Small Ruminant Research, (Unconditionally accepted)
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Acknowledgements
• Prof LJ Hellebrekers
• Prof GF Stegmann
• Prof P Stadler
• Prof R Kirberger
• Prof J Schoeman
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Acknowledgements
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Acknowledgements
• Lebo Sentle & Monicca Ngobeni, UPBRC
• Craig Murdoch
• Prof V Naidoo
• Mrs Motjie Mulders
• Mr C Lekame & R Molekoa, OTAU
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• Family & Friends
Acknowledgements
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Acknowledgements
The Goats, at the beginning
The Goats, at the end
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Thank You
The more I learn,
the more I realise how little I know
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