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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

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

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

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

Introduction

Applications for TIVA

• Field anaesthesia

• MRI anaesthesia

• Research

Dundee & McMurray 1984; Carroll et al. 1997 ; Larenza et al. 2005

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

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

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.

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.

The Goats

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

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

Acepromazine • Most common tranquilliser in veterinary practice

• Anxiolysis, peripheral vasodilation, hypotension,

hypothermia, behaviour modification

Hall et al 2001, Mehlisch 2002

Introduction

Midazolam • Water-soluble benzodiazepine

• Sedation, muscle-relaxation, anti-epileptic

• GABAA-mediated CNS effects

• Mild cardio-respiratory effects

Hall et al 2001, Mehlisch 2002

Introduction

Butorphanol

• κ-opioid receptor agonist and μ-opioid

receptor antagonist

• Analgesia, some sedative effects, potential

excitatory behaviour in goats

Doherty et al 2002

Introduction

Propofol

• Common induction agent in goats

• GABAA-mediated CNS effects

• Dose-dependent cardio-respiratory depression

Grossherr et al 2006, Reid et al 1993

Introduction

Assessment

• Quality of sedation

• Reduction of dose of propofol required for

induction

• Physiological impact

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)

• Healthy (physical exam, complete

blood count, serum biochemistry)

• Age (5 – 9 months)

• Weight (21.0 - 24.5 kg)

SAL ACE BUT ACEBUT MIDBUT

Materials and Methods Catheterisation

• Auricular artery catheterised (24G)

- blood sampling

- arterial blood

pressure readings

• Cephalic vein catheterised (18G)

- fluid administration

- propofol administration

• Premedication intramuscularly

• Assessor of degree of sedation, quality of

induction, and quality of recovery blinded to

treatments

Materials and Methods Treatments

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

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

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

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

Materials and Methods Quality of induction Scoring

(Poor)

Excitement, intubation impossible

(Fair)

Mild excitement, slightly prolonged (>

2 minutes)

(Good)

Smooth, no excitement

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]

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]

Materials and Methods Recovery Period

Recorded

• Time to extubation

• Time to sternal

position

• Recovery score

0 (Poor) Restless

1 (Fair) Mild restlessness

2 (Good) Smooth

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

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

Blood gas parameters

Temperature

Results Sedation Scores & Induction Quality

Group # Sedation

# Propofol

Dose (mg/kg)

# Dose

Reduction (%)

# Induction

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

Results

Quality of recovery from anaesthesia

Group # Extubation Time

(mins)

# Sternal Position

Time (mins)

Recovery

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

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

• 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

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

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

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

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

Effects of midazolam on isoflurane minimum alveolar concentration and

cardiovascular function in mechanically-ventilated goats.

TB Dzikiti, GF Stegmann,

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

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

Introduction

Factors that can lower MAC

• Hypothermia

• Severe hypotension

• Hypoxaemia (PaO2 < 40 mmHg)

• Anaemia

• Most anaesthetic agents

Quasha 1980

Introduction

Hypotheses

• Midazolam does not affect isoflurane MAC

• Midazolam reduces isoflurane MAC

• 6 goats

(3 does, 3 wethers): ~ 28 kg, ~12 months

• Three treatments: LMID, MMID & HMID

• 4-week intervals between treatments (wash-out period)

Induction:

Iso MACb

determination:

Iso MACt

determination: +

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

Materials and Methods Preanaesthestic Period

• Starvation 18-24 hours

blood count, serum biochemistry

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.

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

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

Materials and Methods Monitoring

• Anaesthetic depth: claw clamping

• Isoflurane: inspired & expired

• Heart rate

• Pulse-oximetry

• Blood pressure: SAP, DAP, MAP

• CRT

• CO2: inspired & expired

• Oesophageal Temperature

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

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)

Materials and Methods Baseline Isoflurane MAC determination

• Clockwise direction used

for consecutive

claw-clamping

Materials and Methods Midazolam Treatments

GROUP TREATMENT

Midazolam Isoflurane

LMID 0.1 0.1 To effect

MMID 0.2 0.2 To effect

HMID 0.9 0.9 To effect

Materials and Methods Treatment Isofl MAC determination

• Starting at Et[ISO] of Baseline Isofl MAC

• Adjusted downwards (10 %) for non-

response

minutes

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

Recorded

• Time to sternal

• Time to standing

• Quality of recovery

Recovery

Score Description

0 (Poor) Restless

2 (Good) Smooth

• All data assumed non-parametric

• Presented as median (IQR)

• R Statistical Software Version 2.7.2

Friedman Test &

Wilcoxon as post-hoc

ANOVA by ranks &

MAC reduction (%)

MAC determination time

Time to extubation

Time to sternal

Time to standing

Recovery score

Heart rate

Blood pressure

Temperature

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

(%vol)

(%) Change post-treatment

MAC determination

time (minutes)

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)#

(%vol)

(%) Change

post-treatment

MAC determination time (minutes)

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)#

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

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 %

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

Discussion

Cardiovascular Effects

• Minimal changes in cardiovascular

parameters

• Typical of midazolam

Mehlisch 2002; Lemke 2007

Discussion

Recovery from anaesthesia

• Good, fast and smooth recovery as

expected of both isoflurane and

midazolam

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.

Effects of fentanyl on isoflurane minimum alveolar concentration and

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

Introduction

Hypotheses

• Fentanyl does not affect isoflurane MAC

• Fentanyl reduces isoflurane MAC

• 6 goats

(3 does,3 wethers): ~ 36 kg, ~15 months

• Three treatments: LFENT, MFENT & HFENT

GROUP TREATMENT

Fentanyl Isoflurane

LFENT 0.005 0.005 To effect

MFENT 0.015 0.015 To effect

HFENT 0.03 0.03 To effect

measurements

Fentanyl administration

• Rt Jugular vein (18G): fentanyl plasma

3.5 Vol% reached

response

minutes

Materials and Methods Fentanyl Treatments

GROUP TREATMENT

Fentanyl Isoflurane

LFENT 0.005 0.005 To effect

MFENT 0.015 0.015 To effect

HFENT 0.03 0.03 To effect

response

minutes

• At time 0, 1, 15, 30, every 30 of fentanyl

administration

• Technical issues hindered analysis

Recorded

• Time to sternal

Recovery

Score Description

0 (Poor) Restless

2 (Good) Smooth

Friedman Test &

ANOVA by ranks &

MAC reduction (%)

Time to extubation

Time to sternal

Time to standing

Recovery score

Heart rate

Blood pressure

Temperature

Materials and Methods Results: MAC Data

Treatment Isoflurane MAC (%vol)

(%) Change

post-treatment

MAC determination

time (minutes)

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

Treatment Isoflurane MAC

(%vol)

(%) Change

post-treatment

MAC determination

time (minutes)

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)#

Treatment Isoflurane MAC

(%vol)

(%) Change

post-treatment

MAC determination time (minutes)

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)#

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

Materials and Methods Results: Quality of Recovery

• Good scores, but exaggerated

tail-wagging observed 4 out of 6 times

following MFENT and HFENT

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

Discussion

• 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

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

Discussion

• 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

Conclusion

• Fentanyl reduces isoflurane MAC in dose-

dependent manner in goats

• Smooth recovery, inexplicable tail-wagging

• Fentanyl may be used as an analgesic

adjunct to isoflurane anaesthesia in goats.

Effects of propofol on isoflurane minimum alveolar concentration and

D Cromarty, LN Dzikiti, LJ Hellebrekers

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?

Introduction

Hypotheses

• Propofol does not affect isoflurane MAC

• Propofol reduces isoflurane MAC

• 6 goats

(3 does, 3 wethers): ~ 42 kg, ~18 months

• Three treatments: LPROP, MPROP & HPROP

GROUP TREATMENT

Propofol Isoflurane

LPROP 0.5 0.05 To effect

MPROP 1.0 0.1 To effect

HPROP 2.0 0.2 To effect

measurements

Propofol administration

• Rt Jugular vein (18G): Propofol plasma

3.5 Vol% reached

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

Materials and Methods Monitoring

• Anaesthetic depth: claw clamping

• Isoflurane: inspired & expired

• Heart rate

• Pulse-oximetry

• Blood pressure: SAP, DAP, MAP

• CRT

• CO2: inspired & expired

• Oesophageal Temperature

response

minutes

Materials and Methods Propofol Treatments

GROUP TREATMENT

Propofol Isoflurane

LPROP 0.5 0.05 To effect

MPROP 1.0 0.1 To effect

HPROP 2.0 0.2 To effect

response

minutes

• At time 0, 1, 15, 30, every 30 of propofol

administration

Recorded

• Time to sternal

Recovery

Score Description

0 (Poor) Restless

2 (Good) Smooth

Friedman Test &

ANOVA by ranks &

MAC reduction (%)

Time to extubation

Time to sternal

Time to standing

Recovery score

Heart rate

Blood pressure

Temperature

Plasma propofol conc.

• Spearman Rank Correlation Test:

Isoflurane MAC versus plasma propofol

concentration

• Simple linear regression:

Isoflurane MAC versus plasma propofol

concentration

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

Isoflurane MAC

(%vol)

(%) Change post-treatment

Time (minutes)a

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)*

Isoflurane MAC

(%vol)

(%) Change

post-treatment

Time (minutes)a

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)*

Materials and Methods Results: Plasma propofol concentration data

(µg/mL)

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

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

Discussion

• 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

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

Discussion

• Both isoflurane and propofol known to be

associated with rapid and smooth

recoveries as observed in present study

Reid 1993; Antognini & Eisele 1993

Conclusion

• Propofol reduces isoflurane MAC in dose-

• Smooth recovery

• Propofol and isoflurane may be co-

administered for general anaesthesia

• Both drugs lack analgesic effect!

141 141

Total Intravenous Anaesthesia (TIVA) with propofol-fentanyl and propofol-

midazolam in spontaneously-breathing goats

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

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

• 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

• 6 goats (3 does, 3 wethers): ~21months old

• Two treatments (FP = fentanyl-propofol, MP = midazolam-propofol)

Induction:

Maintenance:

Fentanyl & Propofol Midazolam & Propofol

Treatment:

Materials and Methods Pre-anaesthetic Period

• Starvation: 18-24 hours

blood count, serum biochemistry)

- blood sampling

- arterial blood

pressure readings

• Both cephalic veins catheterised (18G)

- fluids & fentanyl or midazolam

- propofol

- blood sampling

- arterial blood

pressure readings

• Both cephalic veins catheterised (18G)

- fluids & fentanyl or midazolam

- propofol

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

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

Quality of induction Scoring

Score Description

Excited, unable to intubate

Mild excitement, slightly prolonged (> 2 minutes)

Smooth, no excitement

Treatments (Maintenance of GA)

Treatment

Propofol

(mg/kg/min)

Fentanyl

(mg/kg/hr)

Midazolam

(mg/kg/hr)

0.2; to effect

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

Materials and Methods Parameters Recorded

• Heart rate

• Arterial blood pressure (systolic, diastolic, mean)

• SpO2

• End-tidal carbon dioxide

• Body temperature

Before anaesthesia, at 3, 5 and every 10 minutes

Materials and Methods Parameters Recorded

Arterial blood gas analysis

(PaO2, SaO2, PaCO2, pHa, [HCO3-])

• [before anaesthesia, at 3, 30 and 60

minutes after induction]

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

Recorded

• Time to sternal

position

• Recovery score

Recovery

Score Description

0 (Poor) Restless

2 (Good) Smooth

• Presented as [median (range)].

• R Statistical Software, Version 2.7.2

160 160

Wilcoxon Matched-Pairs

Signed Rank Test

ANOVA by ranks &

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

Blood gas parameters

Temperature

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

Extubation

(mins)

Sternal Position

(mins)

Standing

(mins)

Recovery

3.0 (3.0 -3.0)

4.5 (3.3 – 5.0)

13.0 (10.3 – 15.0)

0.5(0-2)

4.5 (3.3 – 5.0)

5.0 (5.0 – 6.5)

15.0 (11.3 – 17.3)

2(2-2)

Recovery Quality

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

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

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

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

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

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

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

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

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

General Conclusion

Premedicants

ACP, Midazolam, Butorphanol, ACP-Butorphanol, Midazolam-Butorphanol

• Significant sedation and reduction in

propofol noticed in midazolam-based

regimens

General Conclusions Midazolam MAC effects

• Midazolam reduces isoflurane MAC in

dose-dependent manner in goats

• Smooth recovery

• Midazolam may be used as an adjunct to

isoflurane anaesthesia in goats.

General Conclusions Fentanyl MAC effects

• Fentanyl reduces isoflurane MAC in dose-

• Smooth recovery, inexplicable tail-wagging

• Fentanyl may be used as an analgesic

adjunct to isoflurane anaesthesia in goats.

General Conclusions Propofol MAC effects

• Propofol reduces isoflurane MAC in dose-

• Smooth recovery

• Propofol and isoflurane may be co-

administered for general anaesthesia

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

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

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

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

Effects of fentanyl on isoflurane minimum alveolar

Brighton T Dzikiti*, Frik G Stegmann, Loveness N Dzikiti,

Ludo J Hellebrekers

Veterinary Record, (Unconditionally Accepted)

Effects of midazolam on isoflurane minimum alveolar

Brighton T Dzikiti*, Frik G Stegmann, Loveness N Dzikiti,

Ludo J Hellebrekers

Small Ruminant Research, (Unconditionally accepted)

Acknowledgements

• Prof LJ Hellebrekers

• Prof GF Stegmann

• Prof P Stadler

• Prof R Kirberger

• Prof J Schoeman

Acknowledgements

• Lebo Sentle & Monicca Ngobeni, UPBRC

• Craig Murdoch

• Prof V Naidoo

• Mrs Motjie Mulders

• Mr C Lekame & R Molekoa, OTAU

• Family & Friends

Acknowledgements

The Goats, at the beginning

The Goats, at the end

Thank You

The more I learn,

the more I realise how little I know

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