Explaining anaesthetic hysteresis with effect-site equilibration.
effect-site concentration
hysteresis
mechanisms of anaesthesia
modelling
pharmacokinetics
Journal
British journal of anaesthesia
ISSN: 1471-6771
Titre abrégé: Br J Anaesth
Pays: England
ID NLM: 0372541
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
19
06
2020
revised:
16
08
2020
accepted:
07
09
2020
pubmed:
22
10
2020
medline:
29
1
2021
entrez:
21
10
2020
Statut:
ppublish
Résumé
Anaesthetic induction occurs at higher plasma drug concentrations than emergence in animal studies. Some studies find evidence for such anaesthetic hysteresis in humans, whereas others do not. Traditional thinking attributes hysteresis to drug equilibration between plasma and the effect site. Indeed, a key difference between human studies showing anaesthetic hysteresis and those that do not is in how effect-site equilibration was modelled. However, the effect-site is a theoretical compartment in which drug concentration cannot be measured experimentally. Thus, it is not clear whether drug equilibration models with experimentally intractable compartments are sufficiently constrained to unequivocally establish evidence for the presence or absence of anaesthetic hysteresis. We constructed several models. One lacked hysteresis beyond effect-site equilibration. In another, neuronal dynamics contributed to hysteresis. We attempted to distinguish between these two systems using drug equilibration models. Our modelling studies showed that one can always construct an effect-site equilibration model such that hysteresis collapses. So long as the concentration in the effect-site cannot be measured directly, the correct effect-site equilibration model and the one that erroneously collapses hysteresis are experimentally indistinguishable. We also found that hysteresis can naturally arise even in a simple network of neurones independently of drug equilibration. Effect-site equilibration models can readily collapse hysteresis. However, this does not imply that hysteresis is solely attributable to the kinetics of drug equilibration.
Sections du résumé
BACKGROUND
BACKGROUND
Anaesthetic induction occurs at higher plasma drug concentrations than emergence in animal studies. Some studies find evidence for such anaesthetic hysteresis in humans, whereas others do not. Traditional thinking attributes hysteresis to drug equilibration between plasma and the effect site. Indeed, a key difference between human studies showing anaesthetic hysteresis and those that do not is in how effect-site equilibration was modelled. However, the effect-site is a theoretical compartment in which drug concentration cannot be measured experimentally. Thus, it is not clear whether drug equilibration models with experimentally intractable compartments are sufficiently constrained to unequivocally establish evidence for the presence or absence of anaesthetic hysteresis.
METHODS
METHODS
We constructed several models. One lacked hysteresis beyond effect-site equilibration. In another, neuronal dynamics contributed to hysteresis. We attempted to distinguish between these two systems using drug equilibration models.
RESULTS
RESULTS
Our modelling studies showed that one can always construct an effect-site equilibration model such that hysteresis collapses. So long as the concentration in the effect-site cannot be measured directly, the correct effect-site equilibration model and the one that erroneously collapses hysteresis are experimentally indistinguishable. We also found that hysteresis can naturally arise even in a simple network of neurones independently of drug equilibration.
CONCLUSIONS
CONCLUSIONS
Effect-site equilibration models can readily collapse hysteresis. However, this does not imply that hysteresis is solely attributable to the kinetics of drug equilibration.
Identifiants
pubmed: 33081972
pii: S0007-0912(20)30779-0
doi: 10.1016/j.bja.2020.09.022
pmc: PMC7844350
pii:
doi:
Substances chimiques
Anesthetics
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
265-278Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM088156
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM124023
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS113366
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
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