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TotalIntravenousAnesthesia:
TheoreticalFoundationand
PracticalConsiderations
TalmageD.Egan,M.D.
UniversityofUtahSchoolofMedicine
©TalmageD.Egan
October21
st
,2022
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Disclosures
Inthelast2years,Dr.Eganhasthefollowingindustry
relationshipstodisclose:
• Founderandequitypartner:Medvis
• Researchsupport:Medtronic
• ScientificAdvisoryBoardMember:AcaciaPharma
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(Brief introduction to TIVA theory and practice…)
Outline
• TIVAvsInhaledAnesthesiafromaDrugDeliveryPerspective
• PosologicalConsiderationsinTIVA
‒ AVenndiagram
‒ Asurfinganalogy
‒ 3practicedomains
• Pharmacokinetic/DynamicModelsandSimulationAppliedtoTIVA
• “MustKnow”Pharmacokinetic/DynamicAttributesofTIVADrugs
• Propofol&OpioidKineticsandTIVA
• TipsandTricksforTIVA
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OverallGoal
Establishthescientificand
practicalfoundationuponwhich
tobaseaTIVApractice.
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TIVAvsInhaledDrugDelivery
Gainingaccesstothecirculationvia
thelungaffordsfundamental
advantagesthat havesetastandard
forinnovationinTIVApracticesince
themid1990s.
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Egan (J Clin Anesth 1996)
(Circa1990s)
.
AnesthesiaPosology
Anesthesiaposology(thestudy
ofdrugdosing)isfundamentally
differentthanotherspecialties
ofmedicine.
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Kuck & Egan (Br J Anaesth 2017)
Alasttryatpopularizing
theterm“posology….”
“CombiningtheGreekwords
‘posos’(howmuch)and‘logos’
(science),posologycanbethought
ofmoresimplyas‘dosology’.”
Egan (Anesth Analg 2018)
GeneralApproachtoAnesthesiaPosology
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Kuck & Egan (Br J Anaesth 2017)
AnesthesiaPosology
Asurfinganalogyishelpfulin
understandingthemodern
approachtoanesthesiaposology.
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Egan & Shafer (Anesthesiology 2003)
TIVAPracticeDomains
TherearethreeTIVApractice
domains(i.e.,dose,concentration,
&eff ect).Theeffectdomainis
optimal.
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Egan (Anesth Analg 2018)
Three TIVA Practice Domains
Egan (Anesth Analg 2018)
The Dose Domain
Simple to use
Familiar to all
Ignores temporal
changes
Slow to steady-state
Ignores intersubject
variability
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Egan (Anesth Analg 2018)
The Concentration Domain
Automates dosage
calculations
Accounts for temporal
changes
Quick to steady-state
Accounts for co-
variate effects (PK)
Ignores intersubject
variability
Less familiar (USA)
Egan (Anesth Analg 2018)
The Effect Domain
Automates dosage
calculations
Accounts for temporal
changes
Quick to steady-state
Accounts for co-
variate effects (PKPD)
Accounts for intersub-
ject variability
Complicated control
system (automated)
Suboptimal sensors
Less familiar
Unintended conse-
quences?
(orOpenLoop)
UsuallyBest!
Mostimportant!
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Egan (Anesth Analg 2018)
?
CrucialDrugBehaviorsandTIVA
Certainpharmacokineticattributes
informTIVAposologyforbolusand
infusionsconditions.Theseattributes
arebestunderstoodthroughPK‐PD
simulation.
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Obara & Egan
(in Hemmings & Egan, Elsevier 2019)
Simulations
Normalized to
peak Ce!
Any anesthetic drug…
Fast, medium, &
slow drugs…
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Surprisingly long for
most anesthetic drugs…
Steady State
What amount of decrease
is required? How long will
it take?
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A given decrement almost
always takes longer
with longer infusions…
Longer and longer…
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CrucialDrugBehaviorsandTIVA
Certainpharmacodynamicconcepts
informTIVAposology.Chiefamong
thesearepropofol‐opioid
pharmacodynamicinteractions.
Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
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Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
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Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
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Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
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Ogura & Egan (in Hemmings & Egan, Elsevier 2019)
2
nd
mostimportantfeature?
Mostimportantfeature?
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PropofolClinicalPharmacology&TIVA
Simulationofpropofol’s
pharmacokineticbehaviorhelps
informposologicaldecisionsinTIVA .
Rapidonset,moderately
rapidoffset(dependsondose)…
50‐year‐old,75kg,175cmmale
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Concentrationsrisethroughoutthe
courseofatypicallengthcase…
Inductionbolusproduces“supra‐
therapeutic”concentrationsfora
time,thengradualrisebegins…
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Target Controlled Infusion!
Back‐endbehaviorchanges
astheinfusiongoeson…
Standard Infusion!
Back‐endbehaviorslightly
differentforstandardinfusions
(i.e.,notatsteady‐state)…
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Obara & Egan (in Hemmings & Egan, Elsevier 2019)
Contextsensitivehalf‐time
assumesTCIadministration…
OpioidClinicalPharmacology&TIVA
Simulationofremif entaniland
fentanylpharmacokineticbehavior
helpsinformposologicaldecisionsin
TIVA.
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Fentanylslowerpeak,
muchsloweroffset…
Normalized to
peak Ce!
Remifentanilreachessteady‐
staterapidly;fentanyldoes
notreachsteady‐state…
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Remifentanillevels
rapidlydecline...
Egan et al (Anesthesiology 1993)
RemifentanilistheonlyTIVA
drugwithatimeindependent
contextsensitivehalf‐time…
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Theclinicalstatechanges
quiteabitwiththesefentanyl
fluctuations…
Theclinicalstatechangesquiteabit
betweenfentanylboluses(arrows);
remifentanillocksinasteady‐stateat
thesweetspot…
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Fentanylisagood
“transitionopioid”
becauseitpeaksafter
bolusinjectionquickly…
TipsandTricksoftheTIVATrade
Certainpracticaltipsarehelpfulfor
successfulTIVApractice.
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Obara & Egan (in Hemmings & Egan, Elsevier 2019)
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Obara & Egan (in Hemmings & Egan, Elsevier 2019)
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SupplementaryMaterial
Egan (Anesthesiology 2003)
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Egan et al (Br J Anaesth 2020)
Target Controlled Infusion Practice
TCIisthemost
sophisticatedtitration…
