title: Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain.
abstract: Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2 ) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2 ) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2 , or PtiO2 . During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml(-1)·min(-1) (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) μmol·ml(-1)·min(-1), P < 0.05] and a dramatic decline in PtiO2 [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml·100 ml(-1)·min(-1) (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) μmol·ml(-1)·min(-1) (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia.
authors.affiliation: Center for Functional MRI, Department of Radiology, University of California, San Diego, California; School of Medicine, University of California, San Diego, California; and.
authors.forename: Kang
authors.initials: K
authors.lastname: Wang
authors.affiliation: Center for Functional MRI, Department of Radiology, University of California, San Diego, California;
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Smith
authors.affiliation: Center for Functional MRI, Department of Radiology, University of California, San Diego, California;
authors.forename: Richard B
authors.initials: RB
authors.lastname: Buxton
authors.affiliation: Department of Medicine, University of Washington and Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Swenson
authors.affiliation: Center for Functional MRI, Department of Radiology, University of California, San Diego, California; dubowitz@ucsd.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dubowitz
mesh_terms: D000086:Acetazolamide / Q000627:therapeutic use*; D000328:Adult; D000465:Algorithms; D000532:Altitude Sickness / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects*; D002196:Capillaries / Q000503:physiopathology; D002245:Carbon Dioxide / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002245:Carbon Dioxide; D000086:Acetazolamide; D010100:Oxygen
keywords: acetazolamide; cerebral blood flow; cerebral oxygen metabolism; cerebral oxygenation; hypoxia; magnetic resonance imaging