"Gentlemen, this is no humbug" Dr John Collins Warren, 17 October : Horace Wells 1846: William T. Morton

Transcription

1 "Gentlemen, this is no humbug" Dr John Collins Warren, 17 October : Horace Wells 1846: William T. Morton

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4 Characteristic differences between anesthesia and sleep Anesthesia Sleep Onset Maintenance Offset Drug-induced No homeostatic control Failure to initiate is non-existent Not altered by environmental factors Duration dependent on dose Depth at a given anesthetic dose is constant Failure to maintain is non-existent Altered minimally by environmental factors Returns to normal wakefulness in hours to days Duration of anesthesia and elimination of agent governs timing of wakefulness Endogenously generated Homeostatic and circadian regulation Failure to initiate is a recognized pathology Significantly modulated by environmental factors Duration function of homeostatic and circadian factors Depth fluctuates rhythmically and spontaneously Failure to maintain is a recognized pathology Significantly altered by environmental factors Return to normal wakefulness within minutes Timing of wakefulness governed by environment, sleep duration, and circadian rhythm

5 Goals of general anesthesia different mechanisms of actions / different anatomical targets Amnesia partial or complete loss of memory Sedation decreased level of arousal Hypnosis impairment of neural functions that are required to respond to verbal commands Immobility lack of movements in response to noxious stimuli myorelaxation, analgesia, anxiolysis

6 Can one drug apply for all these features? Do all general anesthetics can induce these features? Anesthesia mechanisms? Where? How?

7 Neuroanatomical substrates for anesthesia

8 Molecular mechanisms of actions of anesthesia first hypothesis: Meyer-Overton rule

9 Effects of currently used anesthetics on ligand-gated ion channels Nicotinic receptor superfamily Ionotropic gluta amate receptors GABA A Glycine nach 5-HT 3 AMPA kainate NMDA Etomidate ND ND ND Propofol Barbiturates Ketamine Isoflurane Sevoflurane ND ND ND Nitrous oxide : significant potentiation; +: weak potentiation; --: significant inhibition; -: weak inhibition; 0: no effect; ND: remains to be determined.

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11 Functional switch in GABAergic neurotransmission during development Cl - KCC2 Cl - NKCC1 Na +, K + Cl - excitation Na + GABAAR Cl - GLU-R K + Cl - NKCC1 Na +, K + Cl - Cl - hyperpolarization GABAAR GLU-R

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13 How to study efficacy of anesthesia in laboratory animals? tail clamp test (classic for MAC determination) locomotor activity (i.e. sedation) righting reflex / sedation score (hypnotic activity) hindlimb withdrawal reflex (immobilizing action)

14 How to study receptors and receptor subtypes mediating anesthesia effects? receptor knock-out mice knock-in transgenic approach (point mutations)

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17 Adenosine receptors

18 How to monitor anesthesia? physiological signs (BP, HR, RR) isolated arm test ( Gold Standard ) EEG BIS (and related qeeg) Transcranial Doppler, NIRS

19 Arthur Guedel M.D.

20 EEG monitoring and anesthesia (I) scalp EEG: voltage detected on the scalp measure mean dendritic currents (post-synaptic potential) of hundreds to millions of cortical neurons that underlie the active electrode

21 EEG monitoring and anesthesia (II)

22 Bispectral index (BIS) monitoring

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24 Memory formation during anesthesia Explicit: awareness Implicit: unconscious (but detectable/testable) Memory for mock crisis - Levinson 1965

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26 Explicit memory formation during anesthesia (II) Incidence (prospective studies are the only valid methodology Overall: : > 1.2% : % Cardiac surgery: % (type of anesthesia, commorbidities) Obstetrical surgery: : > 1.2% : 0.4%

27 Explicit memory formation during anesthesia (I) Explicit recall of events during general anesthesia is detected by direct (non-suggestive) questioning: What was the last thing you remember before you went to sleep? What was the first thing you remember when you woke up? Can you remember anything in between these periods? Did you dream during your operation? More than one interview is needed Credibility of reports should always be verified

28 Explicit memory formation during anesthesia (III)

29 Implicit memory formation during anesthesia (II) Occurence: strong association with BIS>50 (studies were conducted under anesthesia in the absence of surgery! ) Does implicit memory matter? Research in psychology suggests that even this very rudimentary activity may have profound effects on behaviour and emotion Priming does not induce novel behaviours; it enhances existing tendencies

30 Implicit memory formation during anesthesia (I) Methods to test: Hypnosis (Memory for mock crisis - Levinson 1965 ) Perceptual priming def.: perceptual priming represent temporarily increased activation of a word or idea in memory method: word stem completion (eg. tractor per-op then asscociation tra- (traffic, tractor, travail etc...) post-op Conceptual priming def.: conceptual priming refers to activation of related knowledge method: e.g. Robinson Crusoe test ( Friday )

31 Dreaming during anesthesia Incidence : 1-81% Predictors : patient factors : women > men young > old > anesthetics : ketamine-based * opioid-based ** propofol-based ** volatiles ** depth of anesthesia : light > heavy Consequences? * bizarre, hallucinating ** pleasant (family, work, recreation, sexual)