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Dr John Collins Warren, 17 October 1846 1844

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Dr John Collins Warren, 17 October 1846 1844 "Gentlemen, this is no humbug" Dr John Collins Warren, 17 October 1846 1844: Horace Wells 1846: William T. Morton Characteristic differences between anesthesia and sleep Anesthesia Sleep Drug-induced Endogenously generated No homeostatic control Homeostatic and circadian regulation Failure to initiate is non-existent Failure to initiate is a recognized pathology Onset Not altered by environmental factors Significantly modulated by environmental factors Duration function of homeostatic and Duration dependent on dose circadian factors Depth at a given anesthetic dose is Depth fluctuates rhythmically and constant spontaneously Failure to maintain is non-existent Failure to maintain is a recognized Altered minimally by environmental pathology Maintenance factors Significantly altered by environmental factors Return to normal wakefulness within Returns to normal wakefulness in hours minutes to days Timing of wakefulness governed by Duration of anesthesia and elimination of environment, sleep duration, and circadian Offset agent governs timing of wakefulness rhythm Goals of general anesthesia 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 different anatomical targets anatomical different Immobility different mechanisms / of actions different lack of movements in response to noxious stimuli myorelaxation, analgesia, anxiolysis Can one drug apply for all these features? Do all general anesthetics can induce these features? Anesthesia mechanisms? Where? How? Levels of organization of sleep Nature Reviews Neuroscience 2002 Vol.3, 679 Neuroanatomical substrates for anesthesia Molecular mechanisms of actions of anesthesia first hypothesis: Meyer-Overton rule Effects of currently used anesthetics on ligand-gated ion channels Ionotropic glutamate Nicotinic receptor superfamily receptors GABAA Glycine nACh 5-HT3 AMPA kainate NMDA Etomidate ++ + - 0 ND ND ND Propofol ++ + - - - 0 - Barbiturates ++ + -- -- -- -- - Ketamine + 0 -- -- 0 0 -- Isoflurane ++ ++ -- -- -- ++ - Sevoflurane ++ ++ -- -- ND ND ND Nitrous oxide + + -- -- - -- -- ++: significant potentiation; +: weak potentiation; --: significant inhibition; -: weak inhibition; 0: no effect; ND: remains to be determined. Functional switch in GABAergic neurotransmission during development Cl- KCC2 K+ - Cl Cl- GABAAR GABAAR Cl- Cl- - - Cl Cl NKCC1 NKCC1 Na+, K+ GLU-R GLU-R Na+, K+ hyperpolarization Na+ excitation 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) How to study receptors and receptor subtypes mediating anesthesia effects? receptor knock-out mice knock-in transgenic approach (point mutations) Adenosine receptors How to monitor anesthesia? physiological signs (BP, HR, RR) isolated arm test (“Gold Standard”) EEG BIS (and related qEEG) Transcranial Doppler, NIRS Arthur Guedel M.D. 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 EEG monitoring and anesthesia (II) Bispectral index (BIS) monitoring Memory formation during anesthesia Explicit: awareness Implicit: unconscious (but detectable/testable) Memory for mock crisis - Levinson 1965 Explicit memory formation during anesthesia (II) Incidence (prospective studies are the only valid methodology Overall: 1960-70: > 1.2% 1990-2000: 0.1-0.2% Cardiac surgery: 0.5-23% (type of anesthesia, commorbidities) Obstetrical surgery: 1960-70: > 1.2% 1990-2000: 0.4% 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 Explicit memory formation during anesthesia (III) 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 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”) Dreaming during anesthesia Incidence : 1-81% Predictors : patient factors : women > men young > old anesthetics : ketamine-based* opioid-based** volatiles** propofol-based** > * bizarre, hallucinating ** pleasant (family, work, recreation, sexual) depth of anesthesia : light > heavy Consequences?.
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