title: Impact of hypocapnia and cerebral perfusion on orthostatic tolerance.
abstract: We examined two novel hypotheses: (1) that orthostatic tolerance (OT) would be prolonged when hyperventilatory-induced hypocapnia (and hence cerebral hypoperfusion) was prevented; and (2) that pharmacological reductions in cerebral blood flow (CBF) at baseline would lower the 'CBF reserve', and ultimately reduce OT. In study 1 (n = 24; aged 25 ± 4 years) participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope; end-tidal carbon dioxide (P ET , CO 2) was clamped at baseline levels (isocapnic trial) or uncontrolled. In study 2 (n = 10; aged 25 ± 4 years), CBF was pharmacologically reduced by administration of indomethacin (INDO; 1.2 mg kg(-1)) or unaltered (placebo) followed by LBNP to pre-syncope. Beat-by-beat measurements of middle cerebral artery blood flow velocity (MCAv; transcranial Doppler), heart rate (ECG), blood pressure (BP; Finometer) and end-tidal gases were obtained continuously. In a subset of subjects' arterial-to-jugular venous differences were obtained to examine the independent impact of hypocapnia or cerebral hypoperfusion (following INDO) on cerebral oxygen delivery and extraction. In study 1, during the isocapnic trial, P ET , CO 2 was successfully clamped at baseline levels at pre-syncope (38.3 ± 2.7 vs. 38.5 ± 2.5 mmHg respectively; P = 0.50). In the uncontrolled trial, P ET , CO 2 at pre-syncope was reduced by 10.9 ± 3.9 mmHg (P ≤ 0.001). Compared to the isocapnic trial, the decline in mean MCAv was 15 ± 4 cm s(-1) (35%; P ≤ 0.001) greater in the uncontrolled trial, yet the time to pre-syncope was comparable between trials (544 ± 130 vs. 572 ± 180 s; P = 0.30). In study 2, compared to placebo, INDO reduced resting MCAv by 19 ± 4 cm s(-1) (31%; P ≤ 0.001), but time to pre-syncope remained similar between trials (placebo: 1123 ± 138 s vs. INDO: 1175 ± 212 s; P = 0.53). The brain extracted more oxygen in face of hypocapnia (34% to 53%) or cerebral hypoperfusion (34% to 57%) to compensate for reductions in delivery. In summary, cerebral hypoperfusion either at rest or induced by hypocapnia at pre-syncope does not impact OT, probably due to a compensatory increase in oxygen extraction.
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada Nia.Lewis@ubc.ca.
authors.forename: Nia C S
authors.initials: NC
authors.lastname: Lewis
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Bain
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: MacLeod
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Wildfong
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Smith
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Willie
authors.affiliation: MIRA, University of Twente, Enschede, The Netherlands.
authors.forename: Marit L
authors.initials: ML
authors.lastname: Sanders
authors.affiliation: MIRA, University of Twente, Enschede, The Netherlands.
authors.forename: Tianne
authors.initials: T
authors.lastname: Numan
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada Jozef Stefan Institute, Ljubljana, Slovenia.
authors.forename: Shawnda A
authors.initials: SA
authors.lastname: Morrison
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Foster
authors.affiliation: New York Medical College, New York, USA.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Stewart
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan, Canada.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Ainslie
mesh_terms: D000328:Adult; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006985:Hyperventilation / Q000150:complications / Q000503:physiopathology; D016857:Hypocapnia / Q000209:etiology / Q000503:physiopathology*; D007213:Indomethacin / Q000008:administration & dosage; D008150:Lower Body Negative Pressure; D008297:Male; D010100:Oxygen / Q000502:physiology; D011187:Posture / Q000502:physiology; D012727:Sex Characteristics; D019462:Syncope, Vasovagal / Q000209:etiology / Q000503:physiopathology; D055815:Young Adult
chemical_list: D016861:Cyclooxygenase Inhibitors; D010100:Oxygen; D007213:Indomethacin