5. thomas lew how anaesthetic works (and why knowing matters)

How Anaesthesia Works:

And Why Knowing MattersThomas WK Lew Mmed, EDIC

Department of Anaesthesiology, Intensive Care & Pain MedicineTan Tock Seng Hospital, Singapore

March 2016

Panel from monument in Boston commemorating Morton's demonstration of the anesthetic use of ether

Safe anaesthesia has been widely accepted as one of the greatest medical advancements in the modern era:

Are we saving lives every day or harming lives?

http://en.wikipedia.org/wiki/File:Ether_monument-Boston.JPG

http://en.wikipedia.org/wiki/File:WilliamMorton.jpg

Panel from monument in Boston commemorating Morton's demonstration of the anesthetic use of ether

Ether – Medicine or Industrial Solvent?

http://en.wikipedia.org/wiki/File:Ether_monument-Boston.JPG

http://en.wikipedia.org/wiki/File:WilliamMorton.jpg

We starting getting patients to breathe industrial solvents……. And become unconscious

General anaesthesia is, in fact, a reversible drug-induced coma.

At levels appropriate for surgery, general anaesthesia can functionally approximate brain-stem death, because patients are unconscious, have depressed brain-stem reflexes, do not respond to nociceptive stimuli, have no apnoeic drive, and require cardiorespiratory and thermoregulatory support.

• “How consciousness arises in the brain remains unknown. Yet, for nearly two centuries our ignorance has not hampered the use of general anesthesia for routinely extinguishing consciousness during surgery.”

• Michael T. Alkire,1 Anthony G. Hudetz,2 Giulio Tononi3*• 7 NOVEMBER 2008 VOL 322 SCIENCE

•What are the key characteristics of Anaesthesia• Analgesia?• Unconsciousness?• Loss of Sensory perception? • Loss of reaction to sensory perception?• Motor Relaxation?• Amnesia?

Outline• Overarching Theories of Consciousness• The Neurobiology of Anaesthetics• Theories of Consciousness (and Unconsciousness in anaesthesia)

• Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination• Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination

• Making sense of clinical signs & symptoms of anaesthetic depth, responses, and their implications

• EEG signals of General Anaesthesia • Some drugs and their effects on consciousness

• Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting consciousness • EEG patterns to assess anaesthetic depth of different GA agents• Burst suppression – role in emergence delirium and dementia • General considerations fro Neurotoxicity

Where is consciousness?• Two primary components of consciousness:• 1) Contents of consciousness

• Generally thought to be cortical.• Cortical lesions change the nature of a person’s consciousness according to the area

that is damaged• 2) Level of consciousness

• Generally thought to be subcortical.• Mid-line brain structures contribute to the level of consciousness• Brainstem lesions change the level of a person’s consciousness. Arousal is needed for

awareness

• Anesthetic effects in both areas will likely impact consciousness

WHAT IS CONSCIOUNESS

Integrated Unified Whole of the Brain (“Global neuroal workspace”)

Diversity of sensory inputs -

Fronto-parietal corticocortical exchanges

Dependent on active feedback loops and connectivity

Exchanges from non-specific thalamocortical pathways




• one-arm tourniquet test, • Arousal versus awareness• Consciousness versus memory and amnesia

• Clinical & Pathophysiological implications • Dosing• Awareness; Amnesia • Complications – elderly; cognitive disorder; young – neurotoxicity theories• Opportunities for new technology – EEG Symmetry and synchrony• Lessons for pathological states of nonawareness and consciousness

The neurobiology of anaesthetics • Site of Action:

• Receptor site inhibition (e.g., NMDA) or potentiation (e,g,, GABA)• Potassium-ion channels

• regulate synaptic transmission and membrane potentials in key regions of the brain and spinal cord.

• Targets are differentially sensitive to various anaesthetic agents• Neuronal ionic flux

• hyperpolarize neurons by increasing inhibition or decreasing excitation and alter neuronal activity.

• Neuronal output • As anaesthetic depth increases, transition from the low voltage, high-frequency

pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern

• Transition from a tonic to a burst (and) suppression characterises general anaesthesia

Ionic mechanisms and Targets of some anaesthetics

Privotal roles of the GABA(alpha) and NMDA receptors in cortex, brainstem, thalamus, striatum targets small number of inhibitory interneurons control large number of excitatory pyramidal neurons

http://en.wikipedia.org/wiki/File:Activated_NMDAR.PNG

Neurotoxicity of Anesthetics • As many as one-third of all synapses in

Mammalian brains are GABAnergic.

• GABAA receptors, which are chloride-permeable, ligand-gated ion channels.

• Inhibitory function in synaptic transmission

• Activation generally leads to an influx of chloride, hyperpolarization of cell membrane, shunting of excitatory input, and reduced excitability of the neurons.

The neurobiology of anaesthetics • Site of Action:

• Receptor site inhibition (e.g., NMDA) or potentiation (e,g,, GABA)• Potassium-ion channels

• regulate synaptic transmission and membrane potentials in key regions of the brain and spinal cord.

• Targets are differentially sensitive to various anaesthetic agents• Neuronal ionic flux

• hyperpolarize neurons by increasing inhibition or decreasing excitation and alter neuronal activity.

• Neuronal output • As anaesthetic depth increases, transition from the low voltage, high-frequency

pattern of wakefulness (known as activated EEG), to the slow-wave EEG of deep NREM sleep, and finally to an EEG burst-suppression pattern

• Transition from a tonic to a burst (and) suppression characterises general anaesthesia

• Most anaesthetics potentiate GABA and inhibit NMDA receptors in the cortex, thalamus, brainstem and striatum

• Potentiate inhibitory interneurons – control large numbers of excitatory pyramidal neurons, efficiently inactivate large regions of the brain and contribute to unconsciousness

Propofol binds post-synaptically and enhances GABAergic inhibition, counteracting arousal inputs to the pyramidal neuron, decreasing its excitatory activity, and contributing to unconsciousness

• Low doses – causes profound amnesia • Higher doses – unable to respond because working memory is

blocked and immediately forget what to do • Somewhere between flat EEG and this state – unconsciousness must

ensue • E.g., isolated forearm technique

• The most consistent regional effect produced by anesthetics at (or near) loss of consciousness is a reduction of thalamic metabolism and blood flow (Fig. 1), suggesting that the thalamus may serve as a consciousness switch

The Thalamus: Centre of Consciousness or “Postbox”?

Approx 50 nuclei and subnuclei with rich interconnections to other structures in the brain.

Thalamic nuclei can be classified as specific (mediating relay of peripheral information to a particular area of sensory cortex) and

nonspecific (mediating multimodal integration of information)

MT Alkire, AG Hudetz, G Tononi; 37 NOVEMBER 2008 VOL 322 SCIENCE

4 possible roles of thalamus in “unconsciousness”

• Thalamus as a “switch” of anesthetic-induced unconsciousness• Pivotal “Causal” Role: Based neuroimaging, pivotal depression of thalamus ‘switches’ off consciousness in the

brain in both VA & TIVA

• Thalamus as a “read-out” of anaesthetic-induced unconsciousness• Passenger “Effect” role: Cortex is the site mediating anaesthetic-induced unconsciousness; thalamus depression is

a consequence of / and occurs after the cortical events

• Thalamus as a “participant” in anaesthesia-induced unconsciousness• Under GA, thalamus generates synchronous alpha oscillations, thus interrupting flexible corticocortical

communications; interrupts external sensory inputs from periphery to cortex

• Thalamus as “epiphenomenal” to anaesthetic-induced unconsciousness• Thalamus is not critical to maintenance of consciousness – athalamic animals are seemingly conscious (but

oblivious to their srroundings – due to lack of sensory awareness)

• Mashour GA, Alkire MT Anesthesiology 2013; 118:13-5

Role of the Thalamus • Role of the thalamus in propofol-induced unconsciousness:

• Studied 8 patients in deep sedation using MRI • Connectivity analysis using specific and non-specific thalamic nuclei mapped to

cortical regions

• Findings:• Sensory transfer from the periphery (via specific nuclei) were well preserved • Functional (non-specific) nuclei mediating integration of cortical computation were

reduced. • Strongest correlation of cognitive function with non-specific nuclei activity • Findings reversible on restoration of consciousness

• Liu X, Lauer KK, Ward BD, Li S-J, Hudetz AG: Anesthesiology 2013; 118:59–69

Role of the thalamus in propofol-induced unconsciousness:• Relates primarily to the functional connections of nonspecific nuclei to the cortex (i.e., mediating multimodal

integration of information) and not to specific sensory nuclei mediating flow of information to cortex

• Thalamus as a “switch” - Does not relate primarily to specific sensory nuclei • Thalamus as a “read-out”- Does not answer this question directly• Thalamus as a “participant” Propofol does not seem to affect sensory inputs relay nuclei • Thalamus as “epiphenomenal” – not true

• Liu X, Lauer KK, Ward BD, Li S-J, Hudetz AG: Anesthesiology 2013; 118:59–69


Integrated Unified Whole of the Brain (“Global neuronal workspace”)





UNCONSCIOUNESS

Failure of whole brain to act as an integrated whole – anaesthetics (causes a loss of cortical interactions & a loss of cortical capacity for information exchange)

Homogeneity of Inputs (“Coherence” of EEG from both hemispheres)

Loss of activation of higher-order associative cortices (fronto-parietal cortical pathways)

Amnesia


Integrated Unified Whole of the Brain (“Global neuronal workspace”)





Emery Brown, Ralph Lydic, Nicholas D. Schiff, N Engl J Med. 2010 December 30; 363(27):

4 EEG Patterns in GA:

• Phase 1: Light GA >Delta Alpha < Beta (Slower waves)

• Phase 2: Intermediate GA>Delta Alpha < Beta & Anteriorization

• Phase 3: Deeper GA– Burst suppression – flat with Alpha Beta

• Phase 4: Longer suppression to isoelectric EEG

• burst suppression is believed to be a strong, synchronized outflow of thalamic discharges to a widely unresponsive cortex (Fig. 1).

Emery Brown, Ralph Lydic, Nicholas D. Schiff, N Engl J Med. 2010 December 30; 363(27):

4 EEG Patterns in GA:• Phase 1: Light GA >Delta Alpha < beta

• Phase 2: Intermediate>Delta Alpha < beta & Anteriorization

• Phase 3: Deeper– Burst suppression – flat with Alpha Beta

• Phase 4: Longer suppression to isoelectric EEG

Brown E., NEJM 2010





• Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting consciousness • EEG patterns to assess anaesthetic depth of different GA agents• Burst suppression – role in emergence delirium and dementia • General considerations fro Neurotoxicity

Study Disorders of Consciousness: Anaesthetic Coma • Anaesthesia represents reversible coma – studies of disorders of consciousness (DOC) – what

‘happens” in anaesthetic coma? • Disorders of Consciousness (DOC)

• Brainstem coma (irreversible = brainstem / brain death)• Not awake; not aware ; no brainstem reflexes

• Comas • Not awake; not aware

• “vegetative state” or Unresponsive Wakefulness Syndrome.• Awake; Not aware

• minimally conscious state• Awake; minimally aware

• Laureys et al. Brain connectivity in pathological and pharmacological Frontiers in Systems Neuroscience 20 December 2010

Disorder of Consciousness & Anaesthetic Coma • Anaesthesia represents reversible coma –

• study of disorders of consciousness (DOC) – what ‘lights-up” in anaesthetic coma? • Disorders of Consciousness (DOC)

• Brainstem coma (irreversible = brainstem / brain death)• Not awake; not aware ; no brainstem reflexes

• Comas• Not awake; not aware (Anaesthetic Coma Model – Classic Agents)

• “vegetative state” or unresponsive wakefulness syndrome.• Not aware; awake (Dissociative Anaesthesia e.g., Ketamine – Agents difficult to study)

• minimally conscious state• minimally aware; awake (Sedation model)


• Using GA “Model”: Disorders of Consciousness (DOC) studies show: • That a specific brain region is, to some degree, still able to activate and process relevant

sensory stimuli (as viewed via neuroimaging protocol) does not = consciousness • Anesthetic coma show residual activation of segregated cortical islands in response to

external stimuli (auditory, visual, or somatosensory) encompassing the brainstem, thalamus, and “low-level” primary cortices, similar to findings obtained in unconscious DOC patients.

• A large frontoparietal network encompassing bilateral frontal and temporo-parietal associative cortices (‘higher-order) has its activity commonly impaired during altered states of consciousness


Opioids, Ketamine, Dexmedetomidine Neostigmine & Actions

• Fentanyl & Morphine • Risk of awareness with high dose morphine alone • Fentanyl is anti-cholinergic – bradycardia

• Ketamine • excitatory state with altered consciousness

• Dexmedetomidine • anti-noradrenergic pathway to sedation

• Role of Neostigmine in reversing emergence delirium • Neostogmine being pre-cholinergic – acts against propofol induced anti-

cholinergic pathways • Avoid Atropine because of anti-cholinergic effect in CNS

• Opioids reduce arousal by inhibiting the release of acetylcholine from neurons projecting to the medial pontine reticular formation and to the thalamus, by binding to opioid receptors in the periaqueductal gray and rostral ventral

(A) Ketamine binds preferentially to N-methyl-D-aspartate (NMDA) receptors on inhibitoryinterneurons in the cortex, limbic system (amygdala), and hippocampus, promoting anuncoordinated increase in neural activity, an active EEG pattern, andUnconsciousness

(B) In the spinal cord, ketamine decreases arousal by blocking NMDA glutamate (Glu)–mediated nociceptive signals from peripheral afferent neurons in the dorsal-root ganglion to projecting neurons,

Hallucinations may result because the aberrant activation allows the association of information in a manner that is inconsistent in time and space. The hallucinations can be mitigated by the concurrent administration of a benzodiazepine, which presumably acts to enhance GABAA-mediated activity of the inter-neurons and hence leads to sedation.

(A) Ketamine binds preferentially to N-methyl-D-aspartate (NMDA) receptors on inhibitoryinterneurons in the cortex, limbic system (amygdala), and hippocampus, promoting anuncoordinated increase in neural activity, an active EEG pattern, andUnconsciousness

(B) In the spinal cord, ketamine decreases arousal by blocking NMDA glutamate (Glu)–mediated nociceptive signals from peripheral afferent neurons in the dorsal-root ganglion to projecting neurons,

Hallucinations may result because the aberrant activation allows the association of information in a manner that is inconsistent in time and space. The hallucinations can be mitigated by the concurrent administration of a benzodiazepine, which presumably acts to enhance GABAA-mediated activity of the inter-neurons and hence leads to sedation.

Ketamine messes up the Brain normal transmissions by generating a disorderly & active EEG

• Dexmedetomidine INHIBITS THE INHIBITOR OF an INHIBITOR NUCLEUS (VLPON)• binds to α2 receptors on neurons from the locus ceruleus, inhibiting norepinephrine release (dashed line) in the ventrolateral

preoptic nucleus, as shown in Panel B. The disinhibited ventrolateral preoptic nucleus reduces arousal by means of GABAalpha-mediated and galanin-mediated inhibition of the midbrain, hypothalamic, and pontine arousal nuclei.


• Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination

• Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination



• Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting

consciousness • EEG patterns to assess anaesthetic depth of different GA agents

• We are familiar with spectral analysis of EEG breaking down into the relative strengths of power and frequency

(Purdon et al, 2013, PNAS)

Coherence is the measurement of homogenous outputs (from different hemisphere) and EEG pattern seen from bilateral hemispheres – with the onset of Loss of Consciousness

(Purdon et al, 2013, PNAS)

Coherence is the measurement of homogenous outputs (from different hemisphere) and EEG pattern seen from bilateral hemispheres – with the onset of Loss of Consciousness

Another investigation proposed hypersynchrony of α as a mechanism of propofol-induced unconsciousness, with the alternative interpretation that flexible corticocortical communication is interrupted as a result of stereotyped oscillations. (Supp GG, Siegel M, Hipp JF, Engel AK: Cortical hypersynchrony predicts breakdown of sensory processing during loss of consciousness. Curr Biol 2011; 21:1988–93)

Power Spectogram with coherence as signals densities shows a time-sensitive pattern of change with induction, LOC and emergence from GA e.g., Propofol

Pattern shows strong alpha waves n the frontal cortices bilaterally (anteriorization)


• Role of the thalamus; fronto-parietal cortical loops; integration, feedback, discrimination

• Making sense of clinical signs & symptoms of anaesthetic depth and responses • Consciousness, Making sense of information – integration; feedback; discrimination



• Using this information clinically • Effects of anaesthesia on consciousness to study pathological states affecting

consciousness • EEG patterns to assess anaesthetic depth of different GA agents• Anaesthetic Depth and Post-operative Cognitive Decline or Delirium

Depth of Anaesthesia and Delirium/POCD• Study group–Patients >6o years of age undergoing surgery (n=1,657)• Interventions – BIS- guided anesthesia vs. standard care‐• Results –OR for delirium with BIS–0.58(0.41-- 0.80), cognitive ‐

performance was similar between groups at 1week after surgery, patients in the BIS group had a lower rate of POCD at 3month compared with routine care (10.2%vs.14.7%; adjusted OR 0.67(0.32-- 0.98)‐

• Conclusion – BIS-- guided anesthesia reduced anesthetic exposure and ‐decreased POD and the risk of POCD at 3months, but not at 1week after surgery

• Chan et al. J Neurosurg Anesthesiol 2013;25:33

BIS & Postoperative delirium and POCD• Study group–Patients undergoing surgery (n=1,277)• Interventions - BIS guided anaesthesia . Standard care, anaesthesia not ‐

standardized, BIS levels not standardized • Results Postoperative delirium - 16.7% in BIS group vs. 21.4% in control

group. BIS<20 predictive of delirium. No difference in POCD on postop day 7

• Conclusion–BIS-- guided anesthesia reduced postoperative delirium, ‐possibly by reducing extreme low BIS values

• Radtke et al. Br J Anaesth2013;110:i98

Sedation Depth During Spinal Anesthesiafor Hip Fracture

• Study group – double-blind, randomized controlled trial at an academic medical center of elderly patients (≥65 years) without preoperative delirium or severe dementia who underwent hip fracture repair under spinal anesthesia with propofol sedation. (n=114)

• Intervention – patients were randomized to receive either deep (BIS, approximately 50) or light (BIS, ≥80) sedation. Delirium measured on POD 2 using CAM.

• Results – delirium 19% in light sedation vs. 40% in deep sedation• Conclusion – limiting depth of sedation during spinal anesthesia may

reduce postoperative delirium

• Sieber et al. Mayo Clin Proc 2010;85:18-26

Research Question: Whether general anaesthesia in infancy has any effect on neurodevelopmentaloutcome. Secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial.

Subjects: Infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks’ gestation, and who had inguinal herniorrhaphy,

Centres: 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand; randomly assigned (1:1) awake-regional anaesthesia or sevoflurane-GA

Lancet 2016; 387: 239–50

Outcome Measures: Lancet 2016; 387: 239–50The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years.

The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years.

The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin.

Results : 2007 – 2013: 724 infants randomised. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group.

In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98·6 (14·2) in the awake-regional group and 98·2 (14·7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0·169, 95% CI –2·30 to 2·64). The median duration of anaesthesia in the general anaesthesia group was 54 min.

Interpretation: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia.

Preventing Emergence Delirium • Avoidance of anti-cholinergics

– Use of glycopyrrolate and not atropine because of anti-cholinergic effect in CNS

• Role of Neostigmine in reversing emergence delirium • Neostigmine being pre-cholinergic – acts against propofol induced anti-

cholinergic pathways

– Avoiding burst suppression in anaesthetic depth? • Selective Amnesia helpful in preventing awareness as trend towards lighter GA

evolves

1846 – 2016

How understanding the Neurobiology of anaesthetics within the Neuroanatomical Circuitry of the brain enable us to understand it roles in Reversible Unconsciousness

Understand the Neuroimaging, EEG and correlation with Clinical signs during GA

Study DOC, tailor safer therapies, better monitoring, lower complications, understand place of General Anaesthesia in Modern Medicine Michael T Alkire

5. thomas lew how anaesthetic works (and why knowing matters)

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