Introduction To Sedation, Anaesthesia, Analgesia.: Tom Woodcock Frca August 2008

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 effect).

• Anaesthetised patients are not “asleep”!

Sedation, anaesthesia and analgesia. • •

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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 surgery). – 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 anaesthesia. • 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 approach.

TMN • The tuberomammillary nucleus is a subnucleus of the posterior third of the hypothalamus. • Mostly histaminesecreting neurons involved with the control of arousal, sleep and circadian rhythm.

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TMN • Axons project to the cerebral cortex, thalamus, basal ganglia, basal forebrain, and hypothalamus. • 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.

VLPO • 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 inhibitory neurotransmitters galanin and GABA to inhibit the monaminergic cell groups in the locus ceruleus, the raphe nucleus, and the tuberomammillary nucleus.

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VLPO • VLPO is activated by various somnogens (substances inducing sleep). • A2A receptor (adenosine) is an important activator. • VLPO is inhibited by arousal transmitters such as norepinephrine and acetylcholine

LC • 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 LC has an excitatory effect on most of the brain, mediating arousal and priming the brain neurons to be activated by stimuli, while inhibiting the VLPO.

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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. • Projections to dorsal horn of spinal cord grey matter modulate pain perception through enkephalin release.

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Spinal cord • The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligandgated ion channels. GlyRs are involved in motor reflex circuits of the spinal cord and provide inhibitory synapses onto pain sensory neurons. • Enkephalin-releasing interneurons in the dorsal horn grey matter stimulate mu opioid receptors and thereby inhibit pain pathways.

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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 pons. • Adrenergic neurons of the LC and orexinergic neurons throughout the hypothalamus sustain arousal; orexins help re-establish consciousness during recovery from anaesthesia. • 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 diminished. • 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 galaninergic neurons also inhibit the LC and raphe nuclei.

Brain states.

• Sedation/anaesthesia can be induced by a variety of means including; – 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 including; – 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 infection. – 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…

Self-assessment • 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?