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Dr. JC Murrell, Sectie Anesthesiologie, Faculteit Diergeneeskunde,
Universiteit Utrecht
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Medetomidine usage for pre-anaesthetic
medication in small animal practice
Pre-anaesthetic medication is an essential component of anaesthesia,
and has the following aims:
• Provide sedation and
anxiolysis before the induction of anaesthesia
• Reduce the dose of other
anaesthetic agents, contributing to a balanced anaesthesia
technique
• Counteract unwanted effects
of other anaesthetic agents, for example muscle rigidity caused
by ketamine
• Provide extra analgesia
Medetomidine (Domitor™) is a selective alpha2 adrenoceptor
agonist (a2 agonist) with potent sedative, hypnotic and analgesic
effects. Although it is commonly used for sedation of both
cats and dogs in the U.K., in contrast to continental Europe,
the use of medetomidine for pre-anaesthetic medication is
limited. This follows concerns about the specific cardiovascular
changes induced by medetomidine, particularly in a background
of general anaesthesia. Certainly medetomidine, in common
with all a2 agonists, has unique effects on the cardiovascular
system and the profound sedation and analgesia following medetomidine
has a significant impact on the characteristics of the ensuing
anaesthesia. Use of medetomidine for premedication of healthy
patients can have tremendous advantages, however in order
to use the drug safely and confidently, it is important to
understand the effects of a2 agonists on the body, particularly
with respect to the cardiovascular system.
Medetomidine for pre-anaestethic medication:
what are the advantages?
1. Reliable and profound sedation: Reduces the stress
that can be associated with induction of anaesthesia for both
the patient and personnel. Medetomidine is superior to other
commonly used premedication agents in this respect.
2. Provision of analgesia: Medetomidine has a significant
dose dependent analgesic action that is thought to last for
about an hour following administration of a pre-anaesthetic
dose. This contributes to the provision of improved pre and
intra-operative analgesia providing a stable analgesic background
throughout surgery.
3. Drug sparing action: Premedication with medetomidine
dramatically reduces the amount of all other anaesthetic agents
that must be administered to maintain anaesthesia. This is
important both during the induction and maintenance phase
of anaesthesia and relates equally to intravenous and volatile
anaesthetic agents. Most anaesthetic drugs, such as propofol
and thiopental (induction agents) and isoflurane and halothane
(maintenance agents) have cardiovascular and respiratory side
effects that are dose dependent. Therefore a reduction in
the dose of these agents can lead to improved cardiovascular
stability and contributes to the provision of balanced anaesthesia.
This drug sparing action results from both the intrinsic potency
of medetomidine and a reduction in the rate of hepatic metabolism
of other drugs.
4. Temperature conservation: It is noticeable, clinically,
that animals given medetomidine appear to be more resistant
to a fall in body temperature during anaesthesia than animals
premedicated with other agents. This results from the peripheral
vasoconstriction caused by medetomidine.
5. Reversibility: Medetomidine sedation can be reversed
at the end of anaesthesia by the administration of the specific
a2 antagonist atipamezole (Antisedan™). This provides
a rapid, predictable and smooth recovery from anaesthesia
so that the high risk recovery period, when patient monitoring
and observation may not be optimal, is minimised.
Important clinical effects of medetomidine
• CNS: Sedation
and analgesia
• Cardiovascular system:
Biphasic effect on blood pressure (initial increase followed
by a return to normal or slightly below normal values) (see
figure 1). Heart rate is decreased throughout the period of
medetomidine administration
• Respiratory system:
Minimal effects - most animals will breathe spontaneously
throughout anaesthesia as long as a relative "overdose"
of other anaesthetic agents is not administered
• Renal system:
Urine production is increased due to a reduction in vasopressin
and renin secretion. This is of minimal clinical significance
in most animals
• Pancreas: Endogenous
insulin secretion is reduced leading to a transient hyperglycaemia.
This is usually of minimal clinical significance, and does
not result in an osmotic diuresis
• Liver: Both liver
blood flow and the rate of metabolism of other drugs by the
liver are reduced during medetomidine administration.
Figure 1.
How does medetomidine cause these effects?
Alpha2 adrenoreceptors (a2 receptors) are found
throughout the body and are of vital importance in mediating
some of the effects of the sympathetic nervous system. Noradrenaline
is the sympathetic hormone that normally binds to these receptors.
Medetomidine produces it's myriad of effects by acting as
an agonist at these a2 receptors and mimicking the effects
of noradrenaline.
The role of a2 receptors in the sympathetic nervous system
is complicated because these receptors may be located either
pre synaptically or post synaptically in different tissues.
Activation of post synaptic a2 receptors produces the effects
of sympathetic stimulation in that tissue, however activation
of pre synaptic a2 receptors causes a reduction in sympathetic
tone. This results from a reduction in noradrenaline release,
signalled by the activation of the pre synaptic a2 receptor.
Consequently in tissues in which a2 receptors are located
predominantly pre synaptically, medetomidine causes a reduction
in the level of sympathetic tone. This is demonstrated in
the CNS where medetomidine causes profound sedation, reflecting
a reduced level of activation of the sympathetic nervous system
(see figure 2).
Figure 2.
Conversely in tissues where a2 receptors are found predominantly
post - synaptically, administration of medetomidine causes
the effects of sympathetic stimulation of the tissue. This
is particularly evident in peripheral blood vessels where
medetomidine causes pronounced vasoconstriction, mimicking
the effects of sympathetic stimulation of the peripheral vasculature
(see figure 3).
Figure 3.
How does this relate to the cardiovascular
changes caused by medetomidine?
A persistent reduction in heart rate is a characteristic feature
of medetomidine, and is produced by two different mechanisms.
The predominant mechanism at a particular time is determined
by time interval after medetomidine administration; two phases
can be recognised. It is important to understand the origin
of the reduced heart rate in order to use medetomidine safely
and effectively for pre-anaesthetic medication.
Phase 1: The reduction in heart rate is a normal physiological
response to an increase in blood pressure.
medetomidine administration
peripheral vasoconstriction
blood pressure
reflex bradycardia
Phase 2: The initial intense vasoconstriction wanes
after about 15-20 minutes. A central reduction in sympathetic
tone becomes the predominant mechanism underlying the reduction
in heart rate.
sympathetic tone in the CNS
persistent reduction in heart rate
Do these cardivascular changes affect
organ blood flow and tissue oxygenation?
Cardiac output is reduced following administration of medetomidine
in dogs (Pypendop and Verstegen 1998), principally as a consequence
of the peripheral vasoconstriction and therefore increased
afterload. Interestingly the cardiovascular effects of medetomidine,
including changes in cardiac output, do not appear to be dose
dependent, unlike most other anaesthetic agents. The cardiovascular
changes induced by medetomidine appear to plateau at doses
greater than 5 µg.kg-1, with higher doses
producing greater and longer lasting sedation, without a further
increase in cardiovascular effects (Pypendop and Verstegen
1998). A number of studies have investigated the consequences
of this fall in cardiac output following administration of
medetomidine or dexmedetomidine (the active isomer in medetomidine)
on organ blood flow and oxygenation in dogs. Lawrence et al
(1996) investigated the effects of dexmedetomidine on blood
flow to the heart, brain, kidney, liver, muscles and skin,
in anaesthetised dogs. The study demonstrated that dexmedetomidine
preserved blood flow to the vital organs (brain, heart, liver
and kidneys) at the expense of less vital organs such as the
gut and flow through arteriovenous shunts. Blood flow in the
vital organs remained well above the levels known to induce
underperfusion supporting the idea that the redistribution
of cardiac output induced by dexmedetomidine is appropriate.
The specific effects of dexmedetomidine on the coronary vasculature
have also been investigated (Roekaerts et al 1996) and showed
that despite vasoconstriction of the coronary blood vessels,
flow to the heart endocardium did not change. Unchanged oxygen
and lactate extraction indicated adequate adaptation of myocardial
blood flow to meet metabolic requirements.
Recently Pypendop and Verstegen (2000) compared renal, intestinal
and muscle microvascular blood flow in dogs anaesthetised
with either isoflurane alone or isoflurane and a combination
of medetomidine, midazolam and butorphanol. This study also
demonstrated that the medetomidine combination decreased intestinal
and skeletal blood flow while renal blood flow was similar
to the dogs given isoflurane alone.
Therefore the results of studies that have investigated the
effects of medetomidine on organ blood flow indicate that
although medetomidine causes a fall in cardiac output, in
healthy animals this is accompanied by a redistribution of
blood flow away from peripheral tissues to the vital organs
such as the brain, heart, kidney and liver. Blood flow to
these vital organs is adequate to meet oxygen requirement
and there is no evidence to suggest that organ function is
compromised following administration of medetomidine.
What happens if atropine is given to
increase heart rate?
The initial reduction in heart rate is physiological, therefore
increasing heart rate by the routine administration of atropine
concurrent with medetomidine has severe deleterious consequences
for the cardiovascular system. It results in tachycardia and
hypertension, (Alibhai et al 1996) and routine administration
of atropine with medetomidine is not advocated (see figure
4).
Figure 4.
Using medetomidine in practice
1. Patient selection
• Cardiac function: Medetomidine
is only suitable for the premedication of healthy animals
with a normal functioning cardiovascular system. The cardiovascular
effects of medetomidine are usually well tolerated, however
in animals with reduced cardiovascular reserve, medetomidine
may result in a marked deterioration of cardiovascular function
due to an inability to maintain cardiac output in the presence
of a peripheral vasoconstriction and bradycardia
• Liver disease: Avoid
in animals with liver disease due to the reduction in liver
blood flow
• Young animals: Young
animals are less able to maintain cardiac output in the presence
of a bradycardia due to immaturity of the Frank-Starling mechanism.
It is advisable to avoid medetomidine in animals younger than
4 months of age
2. Combination with other drugs
Medetomidine has been combined with a wide variety of different
intravenous and volatile anaesthetic agents, including propofol,
thiopental, ketamine, halothane and isoflurane. It is important
to ensure that the drug sparing effect of medetomidine is
remembered and doses appropriately reduced. Furthermore, intravenous
agents should be given slowly and to effect. It may take slightly
longer for intravenous agents to take effect because of the
reduced rate of circulation. Duration of effect of other anaesthetic
agents will tend to be longer due to the reduced rate of liver
metabolism associated with medetomidine.
3. anaesthetic monitoring
• Animals that have received
medetomidine "look" very different, however clinical
monitoring of depth of anaesthesia is unchanged.
• Heart rate: Expect heart
rates to be between 40 - 60 beats per minute (unless combined
with ketamine when they are usually higher)
• Pulse quality: Peripheral
pulses may be more difficult to feel due to peripheral vasoconstriction.
The femoral pulse should be of good quality. Reduced peripheral
pulses can lead to unreliable readings from a pulse oximeter
placed on the tongue.
• Mucous membranes: Appear
pale due to peripheral vasoconstriction. Don't expect to see
the usual pinkness associated with volatile agent anaesthesia.
Sometimes the mucous membranes can adopt a bluish hue that
can be worrying because this is usually taken to be a sign
of poor tissue oxygenation. However, it is important to remember
that following medetomidine mixed venous oxygen extraction
is increased (Lawrence et al. 1996). Therefore the concentration
of oxygen in venous blood is reduced, and this can lead to
a bluish colouration of the mucous membranes, but this does
not necessarily mean that the tissues are poorly oxygenated.
• Pulse oximetry: Pulse
oximeters placed on the tongue may be unreliable following
administration of medetomidine. In order to calculate oxygen
saturation, pulse oximeters are reliant on first detecting
a peripheral pulse. The peripheral vasoconstriction that follows
medetomidine can prevent the pulse oximeter from locating
a pulse, therefore the oximeter is unable to give an accurate
measurement of oxygen saturation. Different pulse oximeters
are affected to different degrees by this vasoconstriction,
and some newer models are reliable.
• Respiratory system: Most
animals will breathe spontaneously as long as they are at
an appropriate depth of anaesthesia. Numerous studies have
demonstrated that arterial oxygen and carbon dioxide tensions
are maintained within normal limits, indicating that respiratory
system function is preserved. Measurement of arterial oxygen
tension simultaneously with pulse oximetry clearly demonstrates
that pulse oximeters can be unreliable and indicate a low
saturation when arterial oxygen tension and saturation are
high. Mucous membrane colour is a reflection of the peripheral
vasoconstriction, combined with increased mixed venous oxygen
extraction, rather than a reflection of poor oxygenation.
However it is advisable to provide supplemental oxygen following
sedation or anaesthesia with all anaesthetic agents.
4. Analgesia
Medetomidine for premedication can provide the backbone of
intra-operative analgesia. However in order to optimise peri-operative
analgesia, it is advisable to support the medetomidine with
administration of an opioid and NSAID, such as carprofen.
Reversal of the medetomidine sedation with atipamezole will
also reverse the analgesia, therefore post operative analgesia
must be provided.
5. Reversal of medetomidine with atipamezole
• Atipamezole administered
intramuscularly at the end of anaesthesia will provide a rapid,
smooth recovery from anaesthesia
• Animals are usually able
to stand 10-15 minutes after atipamezole administration
• It is possible to reduce
the dose of atipamezole in animals that have had a prolonged
anaesthesia where the effects of medetomidine may be reduced.
By this time (one hour or longer after medetomidine administration)
much of the medetomidine given preoperatively will have been
metabolised and a reduced dose of atipamezole will be sufficient
for reversal
• Ketamine: Delay the administration
of atipamezole until at least 45 minutes after the ketamine
to prevent the "unmasking" of ketamine excitation
• Intravenous atipamezole
can result in a very sudden recovery from anaesthesia that
may be associated with transient excitation
Conclusions
Use of medetomidine for premedication has a profound effect
on the characteristics of the whole anaesthetic regimen. The
excellent sedation and analgesia afforded by a2 agonists offers
tremendous advantages, facilitating induction of anaesthesia
and providing an incredibly stable anaesthetic and analgesic
background to the entire anaesthesia. Doses of other anaesthetic
drugs are significantly reduced contributing to a balanced
anaesthesia technique. Medetomidine causes unique changes
in the cardiovascular system, with a reduction in heart rate
being the most obvious clinical effect. These changes are
well tolerated in healthy animals. Numerous studies demonstrate
that blood flow to vital organs such as the heart, brain liver
and kidneys are well maintained following use of medetomidine
for premedication. However it is not a suitable agent to use
in animals with reduced cardiovascular reserve. In summary
use in medetomidine for pre-anaesthetic medication in healthy
animals provides the following benefits:
• Reliable sedation
• Intra-operative analgesia
• Stable anaesthetic and
analgesic background throughout anaesthesia
• Drug sparing effect
• Temperature conservation
• Reversibility
References:
Alibhai HI, Clarke KW, Lee YH, and Thompson J Cardiopulmonary
effects of combinations of medetomidine hydrochloride and
atropine sulphate in dogs.
Veterinary record (1996) 138 11-13
Lawrence CJ, Prinzen FW and de Langer S The effect of dexmedetomidine
on nutrient organ blood flow.
Anaesthesia and Analagesia (1996) 83 1160-1165
Pypendop BH and Verstegen JP Effects of medetomidine-midazolam-butorphanol
combination on renal cortical, intestinal and muscle microvascualr
blood flow in isoflurane anaesthetized dogs: a laser Doppler
study.
Veterinary Anaesthesia and Analgesia (2000) 27 36-44
Pypendop BH and Verstegen JP Haemodynamic effects of medetomidine
in the dog: A dose titration study.
Veterinary Surgery (1998) 27 612-622
Roekaerts PM, Prinzen FW, de Lange S.
Coronary vascular effects of dexmedetomidine during reactive
hyperemia in the anesthetized dog.
J Cardiothorac Vasc Anesth. 1996 Aug;10(5):619-26.
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