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Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations

Obstructive and central sleep apnea affects ~1 billion people globally and may lead to serious cardiovascular and neurocognitive consequences, but treatment options are limited. High loop gain (ventilatory instability) is a major pathophysiological mechanism underlying both types of sleep apnea and...

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Autores principales: Schmickl, Christopher N., Landry, Shane, Orr, Jeremy E., Nokes, Brandon, Edwards, Bradley A., Malhotra, Atul, Owens, Robert L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547551/
https://www.ncbi.nlm.nih.gov/pubmed/34699135
http://dx.doi.org/10.14814/phy2.15071
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author Schmickl, Christopher N.
Landry, Shane
Orr, Jeremy E.
Nokes, Brandon
Edwards, Bradley A.
Malhotra, Atul
Owens, Robert L.
author_facet Schmickl, Christopher N.
Landry, Shane
Orr, Jeremy E.
Nokes, Brandon
Edwards, Bradley A.
Malhotra, Atul
Owens, Robert L.
author_sort Schmickl, Christopher N.
collection PubMed
description Obstructive and central sleep apnea affects ~1 billion people globally and may lead to serious cardiovascular and neurocognitive consequences, but treatment options are limited. High loop gain (ventilatory instability) is a major pathophysiological mechanism underlying both types of sleep apnea and can be lowered pharmacologically with acetazolamide, thereby improving sleep apnea severity. However, individual responses vary and are strongly correlated with the loop gain reduction achieved by acetazolamide. To aid with patient selection for long‐term trials and clinical care, our goal was to understand better the factors that determine the change in loop gain following acetazolamide in human subjects with sleep apnea. Thus, we (i) performed several meta‐analyses to clarify how acetazolamide affects ventilatory control and loop gain (including its primary components controller/plant gain), and based on these results, we (ii) performed physiological model simulations to assess how different baseline conditions affect the change in loop gain. Our results suggest that (i) acetazolamide primarily causes a left shift of the chemosensitivity line thus lowering plant gain without substantially affecting controller gain; and (ii) higher controller gain, higher paCO(2) at eupneic ventilation, and lower CO(2) production at baseline result in a more pronounced loop gain reduction with acetazolamide. In summary, the combination of mechanistic meta‐analyses with model simulations provides a unified framework of acetazolamide’s effects on ventilatory control and revealed physiological predictors of response, which are consistent with empirical observations of acetazolamide's effects in different sleep apnea subgroups. Prospective studies are needed to validate these predictors and assess their value for patient selection.
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spelling pubmed-85475512021-11-01 Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations Schmickl, Christopher N. Landry, Shane Orr, Jeremy E. Nokes, Brandon Edwards, Bradley A. Malhotra, Atul Owens, Robert L. Physiol Rep Original Articles Obstructive and central sleep apnea affects ~1 billion people globally and may lead to serious cardiovascular and neurocognitive consequences, but treatment options are limited. High loop gain (ventilatory instability) is a major pathophysiological mechanism underlying both types of sleep apnea and can be lowered pharmacologically with acetazolamide, thereby improving sleep apnea severity. However, individual responses vary and are strongly correlated with the loop gain reduction achieved by acetazolamide. To aid with patient selection for long‐term trials and clinical care, our goal was to understand better the factors that determine the change in loop gain following acetazolamide in human subjects with sleep apnea. Thus, we (i) performed several meta‐analyses to clarify how acetazolamide affects ventilatory control and loop gain (including its primary components controller/plant gain), and based on these results, we (ii) performed physiological model simulations to assess how different baseline conditions affect the change in loop gain. Our results suggest that (i) acetazolamide primarily causes a left shift of the chemosensitivity line thus lowering plant gain without substantially affecting controller gain; and (ii) higher controller gain, higher paCO(2) at eupneic ventilation, and lower CO(2) production at baseline result in a more pronounced loop gain reduction with acetazolamide. In summary, the combination of mechanistic meta‐analyses with model simulations provides a unified framework of acetazolamide’s effects on ventilatory control and revealed physiological predictors of response, which are consistent with empirical observations of acetazolamide's effects in different sleep apnea subgroups. Prospective studies are needed to validate these predictors and assess their value for patient selection. John Wiley and Sons Inc. 2021-10-26 /pmc/articles/PMC8547551/ /pubmed/34699135 http://dx.doi.org/10.14814/phy2.15071 Text en © 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Schmickl, Christopher N.
Landry, Shane
Orr, Jeremy E.
Nokes, Brandon
Edwards, Bradley A.
Malhotra, Atul
Owens, Robert L.
Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations
title Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations
title_full Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations
title_fullStr Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations
title_full_unstemmed Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations
title_short Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations
title_sort effects of acetazolamide on control of breathing in sleep apnea patients: mechanistic insights using meta‐analyses and physiological model simulations
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547551/
https://www.ncbi.nlm.nih.gov/pubmed/34699135
http://dx.doi.org/10.14814/phy2.15071
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