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Introduction to Sedation,

Anaesthesia, Analgesia.
Tom Woodcock FRCA
August 2008.
Sedation, anaesthesia and analgesia.

• Anaesthesia is a drug-induced reversible

coma in which the patient
– 1/ does not move in response to a noxious
stimulus (spinal cord effect)
– 2/ has no explicit recall of the noxious event (brain
• Anaesthetised patients are not “asleep”!
Sedation, anaesthesia and analgesia.

• In dose-finding studies, anaesthesia has been induced when the patient

stops obeying commands or loses lash reflex.
• Maintenance doses of anaesthesia prevent movement in response to
surgical stimulus (typically groin incision for hernia or varicose vein
– Minimum infusion rate for IV agents, minimum alveolar
concentration for volatile agents.
– MIR and MAC are spinal cord phenomena, brain dead organ
donors have normal MIR or MAC requirements.
• Most anaesthetic combinations are additive.
Sedation, anaesthesia and analgesia.

• A number of techniques have been used in research

to assess recovery from anaesthesia;
– Time to obey simple command or answer
(correctly) a simple question.
– Posting shapes into a box.
– Deleting ‘p’ from a page of random letters.
– Critical flicker fusion threshhold.
– Choice-reaction time.
Sedation, anaesthesia and analgesia.

• Sedation is a drug-induced reversible stupor using

doses less than those that achieve the state of
• Can be assessed using the tools for researching
recovery from anaesthesia.
• “Sedation Scales” are recommended for monitoring
sedation in critical care practice.
• Analgesia in critical care practice is commonly
achieved with mu opioid receptor agonists like
morphine or fentanyl, and they are are also sedative
in higher doses.
Sedation, anaesthesia and analgesia.

• The following slides highlight some

aspects of anatomy and physiology
relevant to a modern understanding of
the ways in which sedation, anaesthesia
and analgesia can be achieved.
Understanding these permits rational
selection of a ‘balanced’ therapeutic
• The tuberomammillary
nucleus is a
subnucleus of the
posterior third of the
hypothalamus. QuickTimeª and a
• Mostly histamine- are needed to see this picture.

secreting neurons
involved with the control
of arousal, sleep and
circadian rhythm.
• Axons project to the cerebral cortex,
thalamus, basal ganglia, basal forebrain, and
• The histaminergic projections to the cerebral
cortex directly increase cortical activation and
arousal (H1 receptors), and projections to
acetylcholinergic neurons of the basal
forebrain and dorsal pons do so indirectly, by
increasing the release of acetylcholine in the
cerebral cortex.
• The ventrolateral preoptic
nucleus is a group of neurons in
the hypothalamus. Active during
sleep, and inhibit other neurons
that are involved in wakefulness.
• The VLPO neurons release the QuickTimeª and a
inhibitory neurotransmitters are needed to see this picture.
galanin and GABA to inhibit the
monaminergic cell groups in the
locus ceruleus, the raphe
nucleus, and the
tuberomammillary nucleus.
• VLPO is activated by various somnogens
(substances inducing sleep).
• A2A receptor (adenosine) is an important
• VLPO is inhibited by arousal transmitters
such as norepinephrine and acetylcholine
• The locus ceruleus is in the
dorsal wall of the rostral pons
in the lateral floor of the fourth
ventricle. This nucleus is the
principal site for synthesis of
norepinephrine in the brain
• The norepinephrine from the QuickTimeª and a
LC has an excitatory effect on decompressor
are needed to see this picture.
most of the brain, mediating
arousal and priming the brain
neurons to be activated by
stimuli, while inhibiting the
Raphe nuclei
• a cluster of nuclei found in
the brain stem.
• Release serotonin to the rest
of the brain
• Modulating mood, memory,
sleep and cognition. QuickTimeª and a
are needed to see this picture.

• Projections to dorsal horn of

spinal cord grey matter
modulate pain perception
through enkephalin release.
Spinal cord
• The glycine receptor chloride
channel (GlyR) is a member
of the nicotinic acetylcholine
receptor family of ligand-
gated ion channels. GlyRs
are involved in motor reflex
circuits of the spinal cord and
provide inhibitory synapses QuickTimeª and a
are needed to see this picture.
onto pain sensory neurons.
• Enkephalin-releasing
interneurons in the dorsal
horn grey matter stimulate
mu opioid receptors and
thereby inhibit pain
Brain states.
• Arousal/ consciousness is supported by TMN
histaminergic neurons firing at about 2Hz to directly
activate the cerebral cortex, and indirectly via the
cholinergic neurons of the basal forebrain and dorsal
• Adrenergic neurons of the LC and orexinergic neurons
throughout the hypothalamus sustain arousal; orexins
help re-establish consciousness during recovery from
• Accumulation of adenosine predisposes to sleep.
(Caffeine antagonises effect of adenosine).
Brain states.
• Slow wave sleep occurs when TMN
histaminergic neurons firing rate falls to about
0.5Hz so that cortical activation is greatly
• Rapid eye movement sleep occurs when the
TMN is turned off…
• … by the VLPO which is activated by various
somnogens including adenosine (A2A
receptors). VLPO GABA-ergic and galanin-
ergic neurons also inhibit the LC and raphe
Brain states.
• Sedation/anaesthesia can be induced by a variety of means
– Two-pore potassium channel activators which stabilise the resting membrane
potential of all neurons (e.g. isoflurane, halothane).
– GABA receptor agonists (e.g. propofol and etomidate on the gamma subunit
increase pore opening duration, benzodiazepines on the beta subunit increase
pore opening frequency. Isoflurane, halothane).
– NMDA receptor antagonists (e.g. ketamine, cyclopropane, nitrous oxide)
– Thiopentone, a short acting barbiturate, works at both GABA and NMDA sites.
– Mu opioid receptor agonists which are inhibitory, especially on pain pathways
(e.g. morphine, fentanyl).
– Alpha 2 receptor agonists which inhibit norepinephrine release, especially in
the LC (e.g. clonidine, dexmedetomidine)
– Facilitation of GlyR activation to suppress spinal cord reflexes (most
anaesthetic drugs).
Brain states.
• Encephalopathy /coma can also be induced by a variety of means
– Interleukin-1 induction and intense IL-1 receptor activation induces
drowsiness and pyrexia in sepsis.
– Prostaglandin D2 enhances adenosine release (A2A agonist).
– Kynurenic acid (NMDA antagonist) in tick-borne encephalitis and HIV
– Allopregnanolone (tetrahydroprogesterone), an endogenous neurosteroid
(GABA agonist) in hepatic encephalopathy.
– LC destruction causes encephalitis lethargica.
Brain states.
• Brain stem death. It is believed that
arousal/consciousness is not possible
when brain stem function ceases, so
patients with irreversible loss of brain
stem function are regarded by most
people as dead even if other parts of
the brain remain functional.
A balanced sedative or
anaesthetic technique.
• A GABAA agonist plus mu opioid agonist, e.g. morphine
and midazolam or fentanyl and propofol.
• One of each type of GABAA agonist for “co-induction” of
anaesthesia, e.g midazolam and propofol.
• A GABAA agonist plus NMDA antagonist, e.g. isoflurane
in nitrous oxide, midazolam plus ketamine.
• Add an alpha 2 agonist…
• Why are antihistamines sedating?
• How does clonidine reduce the MAC of isoflurane?
• In the wake of the next major flu epidemic we may see new cases of encephalitis
lethargica; where is the anatomic lesion?
• Individuals with narcolepsy often have reduced numbers of orexin-producing neurons
in their brains; why does this reduction lead to excessive somnolence?
• Would you expect narcoleptic individuals to take longer to recover from propofol
anaesthesia? Why?
• Compare and contrast the anaesthetic mechanisms for thiopentone, isoflurane,
propofol and ketamine.
• Hypermagnesaemia is associated with slow ankle jerk reflex; which receptor do you
think magnesium is potentiating?
• Physostigmine and tacrine, anti-cholinesterases that cross the blood-brain barrier,
were used as analeptic agents. How did they work?