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Introduction: Cerebrovascular reactivity (CVR) describes the vasculature's response to vasoactive stimuli, where prior investigations relied solely on mean data, rather than exploring cardiac cycle differences., Methods: Seventy-one participants (46 females and 25 males) from two locations underwent TCD measurements within the middle or posterior cerebral arteries (MCA, PCA). Females were tested in the early-follicular phase. The hypercapnia response was assessed using a rebreathing protocol (93% oxygen and 7% carbon dioxide) or dynamic end-tidal forcing as a cerebral blood velocity (CBv) change from 40 to 55-Torr. The hypocapnia response was quantified using a hyperventilation protocol as a CBv change from 40 to 25-Torr. Absolute and relative CVR slopes were compared across cardiac cycle phases, vessels, and biological sexes using analysis of covariance with Tukey post-hoc comparisons., Results: No differences were found between hypercapnia methods used (p > 0.050). Absolute hypercapnic slopes were highest in systole (p < 0.001), with no cardiac cycle differences for absolute hypocapnia (p > 0.050). Relative slopes were largest in diastole and smallest in systole for both hypercapnia and hypocapnia (p < 0.001). Females exhibited greater absolute CVR responses (p < 0.050), while only the relative systolic hypercapnic response was different between sexes (p = 0.001). Absolute differences were present between the MCA and PCA (p < 0.001), which vanished when normalizing data to baseline values (p > 0.050)., Conclusion: Cardiac cycle variations impact CVR responses, with females displaying greater absolute CVR in some cardiac phases during the follicular window. These findings are likely due to sex differences in endothelial receptors/signalling pathways. Future CVR studies should employ assessments across the cardiac cycle., Competing Interests: Declarations. Conflict of Interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Cerebrovascular reactivity (CVR) reflects the ability of cerebral blood vessels to adjust their diameter in response to vasoactive stimuli, which is crucial for maintaining brain health. Traditional CVR assessments commonly use a two-point measurement, assuming a linear relationship between cerebral blood flow (CBF) and arterial CO 2 . However, this approach fails to capture non-linear characteristics, particularly the plateaus at extreme CO 2 levels., New Method: This study introduces a cost-effective, ramp-based end-tidal CO 2 (PETCO 2 ) protocol to assess non-linear aspects of CVR. Using transcranial Doppler ultrasound, we monitored blood velocity responses to progressive increases in arterial CO 2 levels in eleven healthy adults, covering a spectrum from hypocapnia to hypercapnia., Results: All eleven participants successfully completed the protocol, with an average PETCO 2 range of 26 ± 4 mmHg and blood velocity changes from -29 % to + 50 % relative to baseline. Non-linear CVR characteristics were observed in all subjects. Sigmoid models provided significantly better fits to the CVR data than linear models, while Bayesian approaches followed expected physiological ranges more accurately than least squares regression methods., Comparison With Existing Methods: Unlike traditional CVR methods, this ramp protocol captures the full, non-linear CVR profile. The sigmoid modeling approach offers a more accurate representation of cerebrovascular dynamics, particularly at CO 2 extremes., Conclusions: The PETCO 2 ramp protocol with non-linear CVR modeling shows promise as an accessible and reliable tool for assessing CBF dynamics. With high completion rates, straightforward implementation, and low equipment cost, this approach holds significant potential for clinical applications in cerebrovascular health evaluation., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Premature birth impairs cardiac and ventilatory responses to both hypoxia and hypercapnia, but little is known about cerebrovascular responses. Both at sea level and after 2 days at high altitude (3375 m), 16 young preterm-born (gestational age, 29 ± 1 weeks) and 15 age-matched term-born (40 ± 0 weeks) adults were exposed to two consecutive 4 min bouts of hyperoxic hypercapnic conditions (3% CO 2 -97% O 2 ; 6% CO 2 -94% O 2 ), followed by two periods of voluntary hyperventilation-induced hypocapnia. We measured middle cerebral artery blood velocity, end-tidal CO 2 , pulmonary ventilation, beat-by-beat mean arterial pressure and arterialized capillary blood gases. Baseline middle cerebral artery blood velocity increased at high altitude compared with sea level in term-born (+24 ± 39%, P = 0.036), but not in preterm-born (-4 ± 27%, P = 0.278) adults. The end-tidal CO 2 , pulmonary ventilation and mean arterial pressure were similar between groups at sea level and high altitude. Hypocapnic cerebrovascular reactivity was higher at high altitude compared with sea level in term-born adults (+173 ± 326%, P = 0.026) but not in preterm-born adults (-21 ± 107%, P = 0.572). Hypercapnic reactivity was altered at altitude only in preterm-born adults (+125 ± 144%, P < 0.001). Collectively, at high altitude, term-born participants showed higher hypocapnic (P = 0.012) and lower hypercapnic (P = 0.020) CO 2 reactivity compared with their preterm-born peers. In conclusion, exposure to high altitude revealed different cerebrovascular responses in preterm- compared with term-born adults, despite similar ventilatory responses. These findings suggest a blunted cerebrovascular response at high altitude in preterm-born adults, which might predispose these individuals to an increased risk of high-altitude illnesses. KEY POINTS: Cerebral haemodynamics and cerebrovascular reactivity in normoxia are known to be similar between term-born and prematurely born adults. In contrast, acute exposure to high altitude unveiled different cerebrovascular responses to hypoxia, hypercapnia and hypocapnia. In particular, cerebral vasodilatation was impaired in prematurely born adults, leading to an exaggerated cerebral vasoconstriction. Cardiovascular and ventilatory responses to both hypo- and hypercapnia at sea level and at high altitude were similar between control subjects and prematurely born adults. Other mechanisms might therefore underlie the observed blunted cerebral vasodilatory responses in preterm-born adults at high altitude., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

Background: This study aimed to investigate the associations between dyscapnia, ventilatory variables, and mortality. We hypothesized that the association between mechanical power or ventilatory ratio and survival is mediated by dyscapnia. Methods: Patients with moderate or severe acute respiratory distress syndrome (ARDS), who received mechanical ventilation within the first 48 h after admission to the intensive care unit for at least 48 h, were included in this retrospective single-center study. Values of arterial carbon dioxide (PaCO 2 ) were categorized into "hypercapnia" (PaCO 2  ≥ 50 mm Hg), "normocapnia" (PaCO 2 36-49 mmHg), and "hypocapnia" (PaCO 2  ≤ 35 mm Hg). We used path analyses to assess the associations between ventilatory variables (mechanical power and ventilatory ratio) and mortality, where hypocapnia or hypercapnia were included as mediating variables. Results: Between December 2017 and April 2021, 435 patients were included. While there was a significant association between mechanical power and hypercapnia (B EM  = 0.24 [95% CI: 0.15; 0.34], P  < .01), there was no significant association between mechanical power or hypercapnia and ICU mortality. The association between mechanical power and intensive care unit (ICU) mortality was fully mediated by hypocapnia (B EM  = -0.10 [95% CI: -0.19; 0.00], P  = .05; B MO  = 0.38 [95% CI: 0.13; 0.63], P  < .01). Ventilatory ratio was significantly associated with hypercapnia (B = 0.23 [95% CI: 0.14; 0.32], P  < .01). There was no significant association between ventilatory ratio, hypercapnia, and mortality. There was a significant effect of ventilatory ratio on mortality, which was fully mediated by hypocapnia (B EM  = -0.14 [95% CI: -0.24; -0.05], P  < .01; B MO  = 0.37 [95% CI: 0.12; 0.62], P  < .01). Conclusion: In mechanically ventilated patients with moderate or severe ARDS, the association between mechanical power and mortality was fully mediated by hypocapnia. Likewise, there was a mediating effect of hypocapnia on the association between ventilatory ratio and ICU mortality. Our results indicate that the debate on dyscapnia and outcome after ARDS should consider the impact of ventilatory variables., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JG received consultant fees and speaker's honoraria from Drägerwerk AG & Co. KGaA and GE HealthCare Technologies, Inc. SK received research support from Cytosorbents and Daiichi Sankyo, lecture honoraria from ADVITOS, Biotest, Daiichi Sankyo, Fresenius Medical Care, Gilead, Mitsubishi Tanabe Pharma, MSD, Pfizer, Shionogi and Zoll, consultant fees from Fresenius, Gilead, MSD and Pfizer. Maria Schroeder received research support and speaker's honoraria from Pfizer Pharma GmbH.

Prior studies have identified variable effects of aging on neurovascular coupling (NVC). Carbon dioxide (CO 2 ) affects both cerebral blood velocity (CBv) and NVC, but the effects of age on NVC under different CO 2 conditions are unknown. Therefore, we investigated the effects of aging on NVC in different CO 2 states during cognitive paradigms. Seventy-eight participants (18-78 yr), with well-controlled comorbidities, underwent continuous recordings of CBv by bilateral insonation of middle (MCA) and posterior (PCA) cerebral arteries (transcranial Doppler), blood pressure, end-tidal CO 2 , and heart rate during poikilocapnia, hypercapnia (5% CO 2 inhalation), and hypocapnia (paced hyperventilation). Neuroactivation via visuospatial (VS) and attention tasks (AT) was used to stimulate NVC. Peak percentage and absolute change in MCAv/PCAv, were compared between CO 2 conditions and age groups (≤30, 31-60, and >60 yr). For the VS task, in poikilocapnia, younger adults had a lower NVC response compared with older adults [mean difference (MD): -7.92% (standard deviation (SD): 2.37), P = 0.004], but comparable between younger and middle-aged groups. In hypercapnia, both younger [MD: -4.75% (SD: 1.56), P = 0.009] and middle [MD: -4.58% (SD: 1.69), P = 0.023] age groups had lower NVC responses compared with older adults. Finally, in hypocapnia, both older [MD: 5.92% (SD: 2.21), P = 0.025] and middle [MD: 5.44% (SD: 2.27), P = 0.049] age groups had greater NVC responses, compared with younger adults. In conclusion, the magnitude of NVC response suppression from baseline during hyper- and hypocapnia, did not differ significantly between age groups. However, the middle age group demonstrated a different NVC response while under hypercapnic conditions, compared with hypocapnia. NEW & NOTEWORTHY This study describes the effects of age on neurovascular coupling under altered CO 2 conditions. We demonstrated that both hypercapnia and hypocapnia suppress neurovascular coupling (NVC) responses. Furthermore, that middle age exhibits an NVC response comparable with younger adults under hypercapnia, and older adults under hypocapnia.

Age is the strongest risk factor for cerebrovascular disease; however, age-related changes in cerebrovascular function are still not well understood. The objective of this study was to measure cerebral vasomotor reactivity (CVMR) during hypo- and hypercapnia across the adult lifespan. One hundred fifty-three healthy participants (21-80 years) underwent measurements of cerebral blood flow velocity (CBFV) via transcranial Doppler, mean arterial pressure (MAP) via plethysmograph, and end-tidal CO 2 (EtCO 2 ) via capnography during hyperventilation (hypocapnia) and a modified rebreathing protocol (hypercapnia). Cerebrovascular conductance (CVCi) and resistance (CVRi) indices were calculated from the ratios of CBFV and MAP. CVMRs were assessed by the slopes of CBFV and CVCi in response to changes in EtCO 2 . The baseline CBFV and CVCi decreased and CVRi increased with age. Advanced age was associated with progressive declines in CVMR during hypocapnia indicating reduced cerebral vasoconstriction, but increases in CVMR during hypercapnia indicating increased vasodilation. A negative correlation between hypo- and hypercapnic CVMRs was observed across all subjects (CBFV%/ EtCO 2 : r  = -0.419, CVCi%/ EtCO 2 : r  = -0.442, P  < 0.0001). Collectively, these findings suggest that aging is associated with decreases in CBFV, increases in cerebrovascular resistance, reduced vasoconstriction during hypocapnia, but increased vasodilatory responsiveness during hypercapnia.

Background: Prior methods evaluating the changes in cerebral arterial blood volume (∆C a BV) assumed that brain blood transport distal to big cerebral arteries can be approximated with a non-pulsatile flow (CFF) model. In this study, a modified ∆C a BV calculation that accounts for pulsatile blood flow forward (PFF) from large cerebral arteries to resistive arterioles was investigated. The aim was to assess cerebral hemodynamic indices estimated by both CFF and PFF models while changing arterial blood carbon dioxide concentration (EtCO 2 ) in healthy volunteers., Materials and Methods: Continuous recordings of non-invasive arterial blood pressure (ABP), transcranial Doppler blood flow velocity (CBFV a ), and EtCO 2 were performed in 53 young volunteers at baseline and during both hypo- and hypercapnia. The time constant of the cerebral arterial bed (τ) and critical closing pressure (CrCP) were estimated using mathematical transformations of the pulse waveforms of ABP and CBFV a , and with both pulsatile and non-pulsatile models of ∆C a BV estimation. Results are presented as median values ± interquartile range., Results: Both CrCP and τ gave significantly lower values with the PFF model when compared with the CFF model (p ≪ 0.001 for both). In comparison to normocapnia, both CrCP and τ determined with the PFF model increased during hypocapnia [CrCP PFF (mm Hg): 5.52 ± 8.78 vs. 14.36 ± 14.47, p = 0.00006; τ PFF (ms): 47.4 ± 53.9 vs. 72.8 ± 45.7, p = 0.002] and decreased during hypercapnia [CrCP PFF (mm Hg): 5.52 ± 8.78 vs. 2.36 ± 7.05, p = 0.0001; τ PFF (ms): 47.4 ± 53.9 vs. 29.0 ± 31.3, p = 0.0003]. When the CFF model was applied, no changes were found for CrCP during hypercapnia or in τ during hypocapnia., Conclusion: Our results suggest that the pulsatile flow forward model better reflects changes in CrCP and in τ induced by controlled alterations in EtCO 2 .

Purpose: To describe the prevalence of hypocapnia and hypercapnia during the earliest period of mechanical ventilation, and determine the association between P a CO 2 and mortality., Materials and Methods: A cohort study using an emergency department registry of mechanically ventilated patients. P a CO 2 was categorized: hypocapnia (<35mmHg), normocapnia (35-45mmHg), and hypercapnia (>45mmHg). The primary outcome was survival to hospital discharge., Results: A total of 1,491 patients were included. Hypocapnia occurred in 375 (25%) patients and hypercapnia in 569 (38%). Hypercapnia (85%) had higher survival rate compared to normocapnia (74%) and hypocapnia (66%), P<0.001. P a CO 2 was an independent predictor of survival to hospital discharge [hypocapnia (aOR 0.65 (95% confidence interval [CI] 0.48-0.89), normocapnia (reference category), hypercapnia (aOR 1.83 (95% CI 1.32-2.54)]. Over ascending ranges of P a CO 2 , there was a linear trend of increasing survival up to a P a CO 2 range of 66-75mmHg, which had the strongest survival association, aOR 3.18 (95% CI 1.35-7.50)., Conclusions: Hypocapnia and hypercapnia occurred frequently after initiation of mechanical ventilation. Higher P a CO 2 levels were associated with increased survival. These data provide rationale for a trial examining the optimal P a CO 2 in the critically ill., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Key Points: Cerebral blood flow increases during hypercapnia and decreases during hypocapnia; it is unknown if vasomotion of the internal carotid artery is implicated in these responses. Indomethacin, a non-selective cyclooxygenase inhibitor (used to inhibit prostaglandin synthesis), has a unique ability to blunt cerebrovascular carbon dioxide reactivity, while other cyclooxygenase inhibitors have no effect. We show significant dilatation and constriction of the internal carotid artery during hypercapnia and hypocapnia, respectively. Indomethacin, but not ketorolac or naproxen, reduced the dilatatory response of the internal carotid artery to hypercapnia The differential effect of indomethacin compared to ketorolac and naproxen suggests that indomethacin inhibits vasomotion of the internal carotid artery independent of prostaglandin synthesis inhibition., Abstract: Extra-cranial cerebral blood vessels are implicated in the regulation of cerebral blood flow during changes in arterial CO2 ; however, the mechanisms governing CO2 -mediated vasomotion of these vessels in humans remain unclear. We determined if cyclooxygenase inhibition with indomethacin (INDO) reduces the vasomotor response of the internal carotid artery (ICA) to changes in end-tidal CO2 (P ETC O2). Using a randomized single-blinded placebo-controlled study, participants (n = 10) were tested on two occasions, before and 90 min following oral INDO (1.2 mg kg(-1) ) or placebo. Concurrent measurements of beat-by-beat velocity, diameter and blood flow of the ICA were made at rest and during steady-state stages (4 min) of iso-oxic hypercapnia (+3, +6, +9 mmHg P ETC O2) and hypocapnia (-3, -6, -9 mmHg P ETC O2). To examine if INDO affects ICA vasomotion independent of cyclooxygenase inhibition, two participant subsets (each n = 5) were tested before and following oral ketorolac (post 45 min, 0.25 mg kg(-1) ) or naproxen (post 90 min, 4.2 mg kg(-1) ). During pre-drug testing in the INDO trial, the ICA dilatated during hypercapnia at +6 mmHg (4.72 ± 0.45 vs. 4.95 ± 0.51 mm; P < 0.001) and +9 mmHg (4.72 ± 0.45 mm vs. 5.12 ± 0.47 mm; P < 0.001), and constricted during hypocapnia at -6 mmHg (4.95 ± 0.33 vs. 4.88 ± 0.27 mm; P < 0.05) and -9 mmHg (4.95 ± 0.33 vs. 4.82 ± 0.27 mm; P < 0.001). Following INDO, vasomotor responsiveness of the ICA to hypercapnia was reduced by 67 ± 28% (0.045 ± 0.015 vs. 0.015 ± 0.012 mm mmHg P ETC O2(-1) ). There was no effect of the drug in the ketorolac and naproxen trials. We conclude that: (1) INDO markedly reduces the vasomotor response of the ICA to changes in P ETC O2; and (2) INDO may be reducing CO2 -mediated vasomotion via a mechanism(s) independent of cyclooxygenase inhibition., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

In addition to cerebrovascular resistance (CVR) zero flow pressure (ZFP), effective cerebral perfusion pressure (CPPe) and the resistance area product (RAP) are supplemental determinants of cerebral blood flow (CBF). Until now, the interrelationship of PaCO2-induced changes in CBF, CVR, CPPe, ZFP, and RAP is not fully understood. In a controlled crossover trial, we investigated 10 anesthetized patients aiming at PaCO2 levels of 30, 37, 43, and 50 mm Hg. Cerebral blood flow was measured with a modified Kety-Schmidt-technique. Zero flow pressure and RAP was estimated by linear regression analysis of pressure-flow velocity relationships of the middle cerebral artery. Effective cerebral perfusion pressure was calculated as the difference between mean arterial pressure and ZFP, CVR as the ratio CPPe/CBF. Statistical analysis was performed by one-way RM-ANOVA. When comparing hypocapnia with hypercapnia, CBF showed a significant exponential reduction by 55% and mean VMCA by 41%. Effective cerebral perfusion pressure linearly decreased by 17% while ZFP increased from 14 to 29 mm Hg. Cerebrovascular resistance increased by 96% and RAP by 39%; despite these concordant changes in mean CVR and Doppler-derived RAP correlation between these variables was weak (r=0.43). In conclusion, under general anesthesia hypocapnia-induced reduction in CBF is caused by both an increase in CVR and a decrease in CPPe, as a consequence of an increase in ZFP.

The effect of moderately extended, intermittent-hypoxia (IH) on cerebral perfusion during changes in CO2 was unknown. Thus, we assessed the changes in cerebral vascular conductance (CVC) and cerebral tissue oxygenation (ScO2) during experimental hypocapnia and hypercapnia following 14-day normobaric exposures to IH (10% O2). CVC was estimated from the ratio of mean middle cerebral arterial blood flow velocity (transcranial Doppler sonography) to mean arterial pressure (tonometry), and ScO2 in the prefrontal cortex was monitored by near-infrared spectroscopy. Changes in CVC and ScO2 during changes in partial pressure of end-tidal CO2 (PETCO2, mass spectrometry) induced by 30-s paced-hyperventilation (hypocapnia) and during 6-min CO2 rebreathing (hypercapnia) were compared before and after 14-day IH exposures in eight young nonsmokers. Repetitive IH exposures reduced the ratio of %ΔCVC/ΔPETCO2 during hypocapnia (1.00 ± 0.13 vs 1.94 ± 0.35 vs %/mmHg, P = 0.026) and the slope of ΔCVC/ΔPETCO2 during hypercapnia (1.79 ± 0.37 vs 2.97 ± 0.64 %/mmHg, P = 0.021), but had no significant effect on ΔScO2/ΔPETCO2. The ventilatory response to hypercapnia during CO2 rebreathing was significantly diminished following 14-day IH exposures (0.83 ± 0.07 vs 1.14 ± 0.09 L/min/mmHg, P = 0.009). We conclude that repetitive normobaric IH exposures significantly diminish variations of cerebral perfusion in response to hypercapnia and hypocapnia without compromising cerebral tissue oxygenation. This IH-induced blunting of cerebral vasoreactivity during CO2 variations helps buffer excessive oscillations of cerebral underperfusion and overperfusion while sustaining cerebral O2 homeostasis., (© 2014 by the Society for Experimental Biology and Medicine.)

Objective: Partial pressure of arterial carbon dioxide (PaCO2) is a major regulator of cerebral blood flow (CBF). Derangements in PaCO2 have been thought to worsen clinical outcomes after many forms of cerebral injury by altering CBF. Our aim was to systematically analyze the biomedical literature to determine the effects of PaCO2 derangements on clinical outcomes after cerebral injury., Methods: We performed a search of Cochrane Library, PUBMED, CINHAL, conference proceedings, and other sources using a comprehensive strategy. Study inclusion criteria were (1) human subjects; (2) cerebral injury; (3) mechanical ventilation post-injury; (4) measurement of PaCO2; and (5) comparison of a clinical outcome measure (e.g. mortality) between different PaCO2 exposures. We performed a qualitative analysis to collate and summarize effects of PaCO2 derangements according to the recommended methodology from the Cochrane Handbook., Results: Seventeen studies involving different etiologies of cerebral injury (six traumatic brain injury, six post-cardiac arrest syndrome, two cerebral vascular accident, three neonatal ischemic encephalopathy) met all inclusion and no exclusion criteria. Three randomized control trials were identified and only one was considered a high quality study as per the Cochrane criteria for assessing risk of bias. In 13/17 (76%) studies examining hypocapnia, and 7/10 (70%) studies examining hypercapnia, the exposed group (hypercapnia or hypocapnia) was associated with poor clinical outcome., Conclusion: The majority of studies in this report found exposure to hypocapnia and hypercapnia after cerebral injury to be associated with poor clinical outcome. However, the optimal PaCO2 range associated with good clinical outcome remains unclear., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This study compared changes in cross-sectional area (CSA) and flow (Q) between the middle cerebral artery (MCA) and the internal carotid artery (ICA) at baseline and during 5 min of hypercapnia (HC; 6% CO2) and hypocapnia (HO; hyperventilation) and quantified how these changes contribute to estimates of cerebrovascular reactivity (CVR). Measures of MCA CSA were made using 3T magnetic resonance imaging. On a separate day, MCA flow velocity was measured with transcranial Doppler ultrasound and ICA diameters and flow velocity were measured with duplex ultrasound. Fourteen subjects (23 ± 3 yr, 7 females) participated, providing data for 11 subjects during HC and 9 subjects during HO. An increase in MCA CSA (P < 0.05) was observed within the first minute of HC. During HO, the decrease in MCA CSA (P < 0.05) was delayed until minute 4. No changes were observed in ICA CSA during HC or HO. The relative changes in QICA and QMCA were similar during HC and HO. Therefore, the MCA, but not ICA, dilates and constricts during 5 min of HC and HO, respectively. The consequent impact on QMCA significantly affects estimates of CVR, and reactivity cannot be attributed solely to changes in smaller arterioles., (Copyright © 2015 the American Physiological Society.)

To establish the accuracy of transcranial Doppler ultrasound (TCD) measures of middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) as a surrogate of cerebral blood flow (CBF) during hypercapnia (HC) and hypocapnia (HO), we examined whether the cross-sectional area (CSA) of the MCA changed during HC or HO and whether TCD-based estimates of CBFV were equivalent to estimates from phase contrast (PC) magnetic resonance imaging. MCA CSA was measured from 3T magnetic resonance images during baseline, HO (hyperventilation at 30 breaths/min), and HC (6% carbon dioxide). PC and TCD measures of CBFV were measured during these protocols on separate days. CSA and TCD CBFV were used to calculate CBF. During HC, CSA increased from 5.6 ± 0.8 to 6.5 ± 1.0 mm(2) (P < 0.001, n = 13), while end-tidal carbon dioxide partial pressure (PETCO2) increased from 37 ± 3 to 46 ± 5 Torr (P < 0.001). During HO, CSA decreased from 5.8 ± 0.9 to 5.3 ± 0.9 mm(2) (P < 0.001, n = 15), while PetCO2 decreased from 36 ± 4 to 23 ± 3 Torr (P < 0.001). CBFVs during baseline, HO, and HC were compared between PC and TCD, and the intraclass correlation coefficient was 0.83 (P < 0.001). The relative increase from baseline was 18 ± 8% greater (P < 0.001) for CBF than TCD CBFV during HC, and the relative decrease of CBF during HO was 7 ± 4% greater than the change in TCD CBFV (P < 0.001). These findings challenge the assumption that the CSA of the MCA does not change over modest changes in PETCO2., (Copyright © 2014 the American Physiological Society.)

In the evaluation of cerebrovascular CO2 reactivity measurements, it is often assumed that the diameter of the large intracranial arteries insonated by transcranial Doppler remains unaffected by changes in arterial CO2 partial pressure. However, the strong cerebral vasodilatory capacity of CO2 challenges this assumption, suggesting that there should be some changes in diameter, even if very small. Data from previous studies on effects of CO2 on cerebral artery diameter [middle cerebral artery (MCA)] have been inconsistent. In this study, we examined 10 healthy subjects (5 women, 5 men, age 21-30 yr). High-resolution (0.2 mm in-plane) MRI scans at 7 Tesla were used for direct observation of the MCA diameter during hypocapnia, -1 kPa (-7.5 mmHg), normocapnia, 0 kPa (0 mmHg), and two levels of hypercapnia, +1 and +2 kPa (7.5 and 15 mmHg), with respect to baseline. The vessel lumen was manually delineated by two independent observers. The results showed that the MCA diameter increased by 6.8 ± 2.9% in response to 2 kPa end-tidal P(CO2) (PET(CO2)) above baseline. However, no significant changes in diameter were observed at the -1 kPa (-1.2 ± 2.4%), and +1 kPa (+1.4 ± 3.2%) levels relative to normocapnia. The nonlinear response of the MCA diameter to CO2 was fitted as a continuous calibration curve. Cerebral blood flow changes measured by transcranial Doppler could be corrected by this calibration curve using concomitant PET(CO2) measurements. In conclusion, the MCA diameter remains constant during small deviations of the PET(CO2) from normocapnia, but increases at higher PET(CO2) values., (Copyright © 2014 the American Physiological Society.)

Hypercapnia and hypocapnia commonly complicate conditions that are present in critically ill patients. Both conditions have important physiologic effects that may impact the clinical management of these patients. For instance, hypercapnia results in bronchodilation and enhanced hypoxic vasoconstriction, leading to improved ventilation/perfusion matching. Hypocapnia reduces cerebral blood volume through arterial vasoconstriction. These effects have also been exploited for therapeutic aims. In patients with traumatic brain injury (TBI), hypocapnia is often utilized to control intracranial pressure. However, this effect is not sustained, and prolonged hypocapnia increases the risk of mortality and severe disability in patients with TBI. Hypercapnia and hypercapnic acidosis are common consequences of lung-protective ventilation in ARDS. Hypercapnic acidosis reduces ischemic lung injury and preserves lung compliance, but concern has arisen over hypercapnia-induced immunosuppression and the potential for bacterial proliferation in sepsis. Experimental studies suggest that buffering hypercapnic acidosis attenuates these effects, whereas hypocapnia appears to potentiate lung injury through increased capillary permeability and decreased lung compliance. Several areas of uncertainty surround the role of hypercapnia/hypocapnia in treating TBI and ARDS. Current data support recommendations to avoid hypocapnia in treating TBI, with the exception of emergent treatment of elevated intracranial pressure, while awaiting definitive management. Permissive hypercapnia is commonly accepted as a consequence of lung-protective ventilation in ARDS, but there is insufficient evidence to support the induction of hypercapnic acidosis in clinical practice. Buffering hypercapnic acidosis should be considered only for a specific clinical indication (eg, hemodynamic instability). For clinicians choosing to buffer hypercapnic acidosis, tris-hydroxymethyl aminomethane is recommended over sodium bicarbonate, as it is more effective in correcting pH and is not associated with increased carbon dioxide production. Future studies should aim to address these areas of uncertainty to help guide clinicians in the therapeutic use and management of hypercapnia/hypocapnia in critically ill patients., (Copyright © 2014 by Daedalus Enterprises.)

Cerebrovascular reactivity (CVR) is a mechanism responsible for maintaining stable perfusion pressure within the brain via smooth muscle mediated modulations of vascular tone. The amplitude of cerebral blood flow (CBF) change in response to a stimulus has been evaluated using Blood Oxygen Level Dependent (BOLD) MRI, however the relationship between the stimulus and the measured signal remains unclear. CVR measured invasively in animal models and using blood-velocity based measurements in humans has demonstrated a sigmoidal relationship between cerebral blood flow and CO2 partial pressure. Using an ultra-high magnetic field strength (7T) MRI scanner and a computer controlled gas delivery system, we examined the regional and voxel-wise CVR response in relation to a targeted progressively increasing hypo- to hypercapnic stimulus. The aim of this study was to assess the non-linearity/sigmoidal behavior of the CVR response at varying arterial CO2 (PaCO2) levels. We find that a sigmoidal model provides a better description of the BOLD signal response to increasing PaCO2 than a linear model. A distinct whole-brain and gray matter BOLD-CVR signal plateau was observed in both voxel-wise and regional analysis. Furthermore, we demonstrate that a progressively increasing stimulus in combination with a sigmoidal response model can be used to obtain CVR values and provides additional physiologically relevant information (such as linear and non-linear response domains, and maximum response amplitudes) that may be more difficult to obtain from blocked CVR experiments. Considering these results, we propose an alternative way in which to define CVR based on the derivative of the BOLD-CVR response curve, which can potentially be used to differentiate between healthy and diseased vascular states., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Arterial partial pressure alteration of CO2 ((Equation is included in full-text article.)) affects not only the cerebral blood flow velocity but also the systemic arterial blood pressure (BP). At the same time, BP can affect the cerebral blood flow. The objective of the present research is to study the impact of the (Equation is included in full-text article.)level on cerebrovascular CO2 reactivity ((Equation is included in full-text article.)) and BP as well as the impact of BP upon (Equation is included in full-text article.)alteration by hypercapnia and hypocapnia., Materials and Methods: Cerebral blood flow velocity was recorded by means of transcranial Doppler in both middle cerebral arteries (MCAv left and right). The mean arterial pressure (MAP) was studied using the finger photoplethysmography method, arterial blood oxygen saturation was estimated by the pulse oximetry method, and end-tidal (Equation is included in full-text article.)((Equation is included in full-text article.)) was measured with an infrared capnograph. After a recording of the reference values of all the parameters, all the volunteers underwent a rebreathing as well as a hyperventilation., Results: At rest, (Equation is included in full-text article.)was 33.6 (SD 3.1) mmHg. At rebreathing, MCAv increased at 38 mmHg (Equation is included in full-text article.), MAP - at 43 mmHg (Equation is included in full-text article.). By hyperventilation, MCAv decreased at 28 mmHg (Equation is included in full-text article.), MAP - at 26 mmHg (Equation is included in full-text article.). When (Equation is included in full-text article.)reached 43 mmHg, (Equation is included in full-text article.)increased from 2.3 (SD 1.4) to 3.3 (SD 1.2)%/mmHg (P<0.01). When (Equation is included in full-text article.)decreased to 26 mmHg, (Equation is included in full-text article.)increased from -3.6 (SD 2.5) to -5.9 (SD 3.9)%/mmHg (P<0.01)., Conclusion: Within the alteration of (Equation is included in full-text article.)above 43 and under 26 mmHg, BP increased and decreased, respectively, leading to a change in (Equation is included in full-text article.).

This study investigated the changes in cerebral near-infrared spectroscopy (NIRS) signals, cerebrovascular and ventilatory responses to hypoxia and CO2 during altitude exposure. At sea level (SL), after 24 hours and 5 days at 4,350 m, 11 healthy subjects were exposed to normoxia, isocapnic hypoxia, hypercapnia, and hypocapnia. The following parameters were measured: prefrontal tissue oxygenation index (TOI), oxy- (HbO2), deoxy- and total hemoglobin (HbTot) concentrations with NIRS, blood velocity in the middle cerebral artery (MCAv) with transcranial Doppler and ventilation. Smaller prefrontal deoxygenation and larger ΔHbTot in response to hypoxia were observed at altitude compared with SL (day 5: ΔHbO2-0.6±1.1 versus -1.8±1.3 μmol/cmper mm Hg and ΔHbTot 1.4±1.3 versus 0.7±1.1 μmol/cm per mm Hg). The hypoxic MCAv and ventilatory responses were enhanced at altitude. Prefrontal oxygenation increased less in response to hypercapnia at altitude compared with SL (day 5: ΔTOI 0.3±0.2 versus 0.5±0.3% mm Hg). The hypercapnic MCAv and ventilatory responses were decreased and increased, respectively, at altitude. Hemodynamic responses to hypocapnia did not change at altitude. Short-term altitude exposure improves cerebral oxygenation in response to hypoxia but decreases it during hypercapnia. Although these changes may be relevant for conditions such as exercise or sleep at altitude, they were not associated with symptoms of acute mountain sickness.

Physical activity may influence cerebrovascular function. The objective of this study was to determine the impact of life-long aerobic exercise training on cerebral vasomotor reactivity (CVMR) to changes in end-tidal CO2 (EtCO2) in older adults. Eleven sedentary young (SY, 27±5 years), 10 sedentary elderly (SE, 72±4 years), and 11 Masters athletes (MA, 72±6 years) underwent the measurements of cerebral blood flow velocity (CBFV), arterial blood pressure, and EtCO2 during hypocapnic hyperventilation and hypercapnic rebreathing. Baseline CBFV was lower in SE and MA than in SY while no difference was observed between SE and MA. During hypocapnia, CVMR was lower in SE and MA compared with SY (1.87±0.42 and 1.47±0.21 vs. 2.18±0.28 CBFV%/mm Hg, P<0.05) while being lowest in MA among all groups (P<0.05). In response to hypercapnia, SE and MA exhibited greater CVMR than SY (6.00±0.94 and 6.67±1.09 vs. 3.70±1.08 CBFV1%/mm Hg, P<0.05) while no difference was observed between SE and MA. A negative linear correlation between hypo- and hypercapnic CVMR (R(2)=0.37, P<0.001) was observed across all groups. Advanced age was associated with lower resting CBFV and lower hypocapnic but greater hypercapnic CVMR. However, life-long aerobic exercise training appears to have minimal effects on these age-related differences in cerebral hemodynamics.

In 11 healthy volunteers 21 +/- 3.7 years old was monitored cerebral blood flow (CBF) by transcranial Doppler (TCD) of middle cerebral artery and mean hemodynamic arterial blood pressure (MAP) by continuous non-invasive measurement "beat-to-beat" at normocapnia, hypercapnia and hypocapnia. Hypercapnia was creating by rebreathing, hypocapnia was creating by spontaneous hyperventilation. The partial pressure of CO2 in alveolar air (PetCO2) was monitored by capnograph, embedded in the TCD-analyzer. During hypercapnia the velocity of CBF and PetCO2 were significantly increased already at 10 s, which was considerably earlier than the increase in the MAP (30 s). During hypocapnia velocity CBF and PetCO2 were significantly decreased at 10 s, and MAP was not changed. We have installed the threshold PetCO2 42 (41; 44) mm Hg, below which amplification CBF occurs at a constant MAP and reflects the true cerebrovascular reactivity to CO2.

Primary Objective: This study examined the effects of mild traumatic brain injury (mTBI) on cerebrovascular reactivity (CVR)., Research Design: A repeated measures design was used to examine serial changes in CVR., Methods and Procedures: Twenty subjects who recently suffered a mTBI were subjected to a respiratory challenge consisting of repeated 20 s breath-holds (BH) and hyperventilations (HV). Testing occurred on days 2 (D2), 4 (D4) and 8 (D8) post-injury as well as a baseline (BASE) assessment (after return-to-play). Transcranial Doppler was used to assess mean cerebral blood velocity (vMCA) and expired gas analysis provided end-tidal carbon dioxide (PETCO2) levels., Results: There was no significant difference in resting vMCA across all testing days for mTBI. No significant differences in PETCO2 were found throughout the testing protocol. A significant effect (p < 0.001) of testing day on vMCA was found during BH and HV challenges for mTBI. Post-hoc analysis revealed significant differences (p < 0.05) in vMCA between D2 and the other testing days., Conclusions: These data suggest that, following mTBI: (1) CVR is not impaired at rest; (2) CVR is impaired in response to respiratory stress; and (3) the impairment may be resolved as early as 4 days post-injury.

We investigated the effects of hypocapnia in normal subjects on airway tone while controlling airway cooling and drying. We hypothesized that airway tone is positively related to the degree of hypocapnia. Participants (8; 2 women) underwent 3 protocols consisting of 20 min of hyperpnea (breathing frequency = 20 breaths min-1; tidal volume = 2.5 L) and 10 min recovery. End-tidal PCO2 was maintained at +1 Torr above rest (ISO; 37.9 ± 1.2 Torr), 8 Torr below resting values (H-8; 29.2 ± 1.7 Torr) or 15 Torr below resting values (H-15; 23.2 ± 2.9 Torr). Breath-by-breath lung conductance (GL) was calculated from flow, volume, and esophageal pressure. GL responses to hyperpnea varied widely across subjects. However, individual responses during ISO correlated highly with responses during H-8 (r = 0.976, p < 0.001) and H-15 (r = 0.952, p < 0.001), with the magnitude of change inversely related to basal GL (r = -0.555, p = 0.006). Thus, inter-subject variation in GL was due to hyperpnea, with no detectable effect of hypocapnia., (Copyright © 2011. Published by Elsevier B.V.)

Background: Changes in partial pressure of carbon dioxide (PaCO2) are associated with a decrease in cerebral blood flow (CBF) during hypocapnia and an increase in CBF during hypercapnia. However, the effects of changes in PaCO2 on cerebral arterial compliance (Ca) are unknown., Methods: We assessed the changes in Ca in 20 normal subjects using monitoring of arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). Cerebral arterial blood volume (CaBV) was extracted from CBFV. Ca was defined as the ratio between the pulse amplitudes of CaBV (AMPCaBV ) and ABP (AMPABP). All parameters were recorded during normo-, hyper-, and hypocapnia., Results: During hypocapnia, Ca was significantly lower than during normocapnia (.10±.04 vs. .17±.06; P<.001) secondary to a decrease in AMPCaBV (1.3±.4 vs. 1.9±.5; P<.001) and a concomitant increase in AMPABP (13.8±3.4 vs. 11.6±1.7 mmHg; P<.001). During hypercapnia, there was no change in Ca compared with normocapnia. Ca was inversely correlated with the cerebrovascular resistance during hypo- (R2=0.86; P<.001), and hypercapnia (R2=0.61; P<.001)., Conclusion: Using a new mathematical model, we have described a reduction of Ca during hypocapnia. Further studies are needed to determine whether Ca may be an independent predictor of outcome in pathological conditions., (Copyright © 2009 by the American Society of Neuroimaging.)

Background: cerebral autoregulation (CA) is the ability to control cerebral blood flow during fluctuations in arterial blood pressure (ABP). It is impaired in a number of conditions including acute stroke, though studies so far have not found a decline in CA with age. CA is very sensitive to changes in pCO₂., Objective: this study investigates the effect of ageing on CA using a moving-window autoregressive moving average (MW-ARMA) to calculate CA as autoregulatory index (ARMA-ARI) during hypercapnia and hypocapnia, to ascertain whether this method would detect age-related differences in CA due to change in pCO₂., Method: ECG was used to measure R-R interval, Finapres to measure ABP and capnography to measure end-tidal CO₂. Transcranial Doppler ultrasonography was used to measure left and right middle cerebral artery cerebral blood flow velocity (CBFV). Hypercapnia was induced by a breath-hold, hypocapnia by hyperventilation., Results: thirty volunteers of mean age 25 ± 6 years and 30 volunteers of mean age 64 ± 4 years were recruited. CBFV was higher and change in CBFV due to respiratory manoeuvre was significantly greater in the younger group compared with the older group. However, no difference in ARMA-ARI was found between the groups., Conclusion: these findings suggest that CA is not affected by healthy ageing.

Cerebrovascular reactivity to vasodilatory hypercapnic and vasoconstrictive hypocapnic challenges is known to be altered in several hemodynamic disorders, which is often attributable to changes in smooth muscle-mediated vascular compliance. Recently, attenuated reactivity to hypercapnia but enhanced reactivity to hypocapnia was observed in patients with chronic stroke. We hypothesize that the latter observation could be explained by a change in the basal vascular tone. In particular, reduced cerebral perfusion pressure, as is prevalent in these patients, may cause vasodilation through autoregulatory mechanisms, and this compensatory baseline condition may alter reactivity to vasoconstrictive hypocapnic challenges. To test this hypothesis, a predilated vascular condition was created in young, healthy subjects (n=11; age=23 to 36 years) using inhalation of 4% CO(2). Using blood oxygenation level-dependent functional magnetic resonance imaging at 3 T, breath holding and cued deep breathing respiratory challenges were administered to assess hypercapnia and hypocapnia reactivity, respectively. During the predilated condition, vasoconstrictive reactivity to hypocapnia was significantly (21.1%, P=0.016) enhanced throughout the gray matter, whereas there was no significant change (6.4%, P=0.459) in hypercapnic vasodilatory reactivity. This suggests that baseline vasodilation may explain the enhanced hypocapnia reactivity observed in some stroke patients, and that hypocapnia challenges may help identify the level of vascular compliance in patients with reduced cerebral perfusion pressure.

The roles of the alveolar and systemic CO₂ on the lung mechanics were investigated in dogs subjected to cardiopulmonary bypass. Low-frequency pulmonary impedance data (Z(L)) were collected in open-chest dogs with an alveolar CO₂ level (FA(CO₂)) of 0.2-7% and during systemic hypercapnia before and after elimination of the vagal tone. Airway resistance (R(aw)), inertance (I(aw)), parenchymal damping (G) and elastance (H) were estimated from the Z(L). The highest R(aw) observed at 0.2% FA(CO₂),which decreased markedly up to a FA(CO₂) of 2% (212 ± 24%), and remained unchanged under normo- and hypercapnia (FA(CO₂) 2-7%). These changes were associated with smaller decreases in I(aw) (-16.6 ± 3.7%), mild elevations in G (25.7 ± 4.7%), and no change in H. Significant increases in all mechanical parameters were observed following systemic hypercapnia; atropine counteracted the R(aw) rises. We conclude that severe alveolar hypocapnia may contribute to minimization of the ventilation-perfusion mismatch by constricting the airways in poorly perfused lung regions. The constrictor potential of systemic hypercapnia is mediated by vagal reflexes., (Copyright © 2010. Published by Elsevier B.V.)

It is widely assumed in fMRI that the relationship between cerebral blood flow (CBF) and volume (CBV) changes observed during end-tidal CO(2) (PETCO(2)) perturbations is equivalent to that elicited by neuronal activation. This assumption has been validated in PET studies insofar as relating total flow to total CBV changes, but remains unconfirmed for venous CBV changes, which pertains to the primary vascular compartment modulating the BOLD signal. In this study, we measured CBF and venous CBV changes in healthy subjects in response to graded hypercapnia and hypocapnia, induced using computerized end-tidal CO(2) targeting, with a DeltaPETCO(2) range of between -6 and +9 mm Hg. Hypercapnia was found to elicit robust increases in CBF and venous CBV, while hypocapnia produced decreases in both. We used steady-state flow and volume changes to estimate the power-law relationship for cortical and subcortical brain regions, and did not observe significant difference between the two. The combined fit resulted in a power coefficient of 0.18+/-0.02, substantially lower than Grubb's coefficient of 0.38, but comparable to previous observations during neuronal activation. These results confirm that the BOLD-specific flow-volume relationship during CO(2) challenges is similar to that characterizing neuronal activation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effects of various combinations of PaCO2 and PaO2 values on brain morphometrics., Animals: 6 healthy adult dogs., Procedures: A modified Latin square design for randomization was used. Dogs were anesthetized with propofol (6 to 8 mg/kg, IV), and anesthesia was maintained with isoflurane (1.7%) and atracurium (0.2 mg/kg, IV, q 30 min). Three targeted values of PaCO2 (20, 40, and 80 mm Hg) and 2 values of PaO2 (100 and 500 mm Hg) were achieved in each dog, yielding 6 combinations during a single magnetic resonance (MR) imaging session. When the endpoints were reached, dogs were given at least 5 minutes for physiologic variables to stabilize before T1-weighted MR images were obtained. Total brain volume (TBV) and lateral ventricular volume (LVV) were calculated from manually drawn contours of areas of interest by use of a software program, with each dog serving as its own control animal. Three blinded investigators subjectively evaluated the lateral ventricular size (LVS) and the cerebral sulci width (CSW). Brain morphometric values were compared among the target blood gas states., Results: No significant differences in TBV were found among target states. The LVV was significantly greater during hypocapnia, compared with hypercapnia at the same PaO2 value. With regard to the subjective evaluations, there were no significant differences among evaluators or among combinations of PaO2 and PaCO2 values., Conclusions and Clinical Relevance: The changes observed in LVV during hypocapnia and hypercapnia may serve as a potential confounding factor when neuromorphometric evaluations are performed in anesthetized dogs.

Alterations in cerebrovascular reactivity to CO2, an index of cerebrovascular function, have been associated with increased risk of stroke. We hypothesised that cerebrovascular reactivity is impaired with increasing age and in patients with symptomatic coronary artery disease (CAD). Cerebrovascular and cardiovascular reactivity to CO2 was assessed at rest and during hypercapnia (5% CO2) and hypocapnia (hyperventilation) in subjects with symptomatic CAD (n=13) and age-matched old (n=9) and young (n=20) controls without CAD. Independent of CAD, reductions in middle cerebral artery blood velocity (transcranial Doppler) and cerebral oxygenation (near-infrared spectroscopy) were correlated with increasing age (r = -0.68, r = -0.51, respectively, P < 0.01). In CAD patients, at rest and during hypercapnia, cerebral oxygenation was lower (P < 0.05 vs. young). Although middle cerebral artery blood velocity reactivity was unaltered in the hypercapnic range, middle cerebral artery blood velocity reactivity to hypocapnia was elevated in the CAD and age-matched controls (P < 0.01 vs. young), and was associated with age (r = 0.62, P < 0.01). Transient drops in arterial PCO2 occur in a range of physiological and pathophysiological situations, therefore, the elevated middle cerebral artery blood velocity reactivity to hypocapnia combined with reductions in middle cerebral artery blood velocity may be important mechanisms underlying neurological risk with aging. In CAD patients, additional reductions in cerebral oxygenation may place them at additional risk of cerebral ischaemia.

Dynamic cerebral autoregulation (CA) is the transient response of cerebral blood flow (CBF) to rapid blood pressure changes: it improves in hypocapnia and becomes impaired during hypercapnia. Batch-processing techniques have mostly been used to measure CA, providing a single estimate for an entire recording. A new approach to increase the temporal resolution of dynamic CA parameters was applied to transient hypercapnia and hypocapnia to describe the time-varying properties of dynamic CA during these conditions. Thirty healthy subjects (mean +/- SD: 25 +/- 6 yr, 9 men) were recruited. CBF velocity was recorded in both middle cerebral arteries (MCAs) with transcranial Doppler ultrasound. Arterial blood pressure (Finapres), end-tidal CO(2) (ET(CO(2)); infrared capnograph), and a three-lead ECG were also measured at rest and during repeated breath hold and hyperventilation. A moving window autoregressive moving average model provided continuous values of the dynamic CA index [autoregulation index (ARI)] and unconstrained gain. Breath hold led to significant increase in ET(CO(2)) (+5.4 +/- 6.1 mmHg), with concomitant increase in CBF velocity in both MCAs. Continuous dynamic CA parameters showed highly significant changes (P < 0.001), with a temporal pattern reflecting a delayed dynamic response of CA to changes in arterial Pco(2) and a maximal reduction in ARI of -5.1 +/- 2.4 and -5.1 +/- 2.3 for the right and left MCA, respectively. Hyperventilation led to a marked decrease in ET(CO(2)) (-7.2 +/- 4.1 mmHg, P < 0.001). Unexpectedly, CA efficiency dropped significantly with the inception of the metronome-controlled hyperventilation, but, after approximately 30 s, the ARI increased gradually to show a maximum change of 5.7 +/- 2.9 and 5.3 +/- 3.0 for the right and left MCA, respectively (P < 0.001). These results confirm the potential of continuous estimates of dynamic CA to improve our understanding of human cerebrovascular physiology and represent a promising new approach to improve the sensitivity of clinical applications of dynamic CA modeling.

We tested whether breath hold divers (BHD) and obstructive sleep apnea (OSA) subjects had similar middle cerebral artery velocity (MCAV) responses to hypercapnea and hypocapnea. We analyzed changes in MCAV (cm/s) in response to hypocapnea and hyperoxic hypercapnea during placebo or after 90 min of oral indomethacin (100 mg) in BHD (N=7) and OSA (N=7). During control hypercapnea MCAV increased for 54.4% in BHD and 48.4% in OSA. Indomethacin blunted the MCAV increase in response to hypercapnea in BHD (P=0.02), but not in OSA. Indomethacin attenuated the mean arterial pressure response in BHD, but not in OSA. The blunted MCAV responses to hypercapnea with indomethacin in BHD, but not in OSA patients suggests that (a) the normal contribution of local vasodilating mechanisms to the cerebrovascular responses to hypercapnea is absent in OSA patients and (b) exposure to chronic/repeated apneas is not causal per se in limiting the contribution of vasodilating mechanisms to the cerebrovascular responses to hypercapnea in OSA.

Lung injury in ventilated premature infants occurs primarily through the mechanism of volutrauma, often due to the combination of high tidal volumes in association with a high end-inspiratory volume and occasionally end-expiratory alveolar collapse. Tolerating a higher level of arterial partial pressure of carbon dioxide (PaCO2) is considered as 'permissive hypercapnia' and when combined with the use of low tidal volumes may reduce volutrauma and lead to improved pulmonary outcomes. Permissive hypercapnia may also protect against hypocapnia-induced brain hypoperfusion and subsequent periventricular leukomalacia. However, extreme hypercapnia may be associated with an increased risk of intracranial hemorrhage. It may therefore be important to avoid large fluctuations in PaCO2 values. Recent randomized clinical trials in preterm infants have demonstrated that mild permissive hypercapnia is safe, but clinical benefits are modest. The optimal PaCO2 goal in clinical practice has not been determined, and the available evidence does not currently support a general recommendation for permissive hypercapnia in preterm infants.

The relationship between cerebral blood volume (CBV) and flow (CBF) has been widely studied. One of the most significant early studies was by Grubb et al (1974 Stroke 5 630-9), who conducted hypercapnia studies in primates with positron emission tomography (PET) and empirically found CBV = 0.8 CBF(0.38). The exponent used here has since been known as the Grubb's exponent. In this paper, we define a similar exponent known as the modified Grubb's exponent, G', which is based on CBV and cerebral blood flow velocity (CBFV) estimated by near infrared spectroscopy (NIRS) and transcranial Doppler respectively, i.e. G' = log(CBV/CBV(0))/log(CBFV/CBFV(0)), where CBV(0) and CBFV(0) are baseline values. The aim of this study was to estimate the nominal value of the modified Grubb's exponent in healthy human brains. We conducted hypercapnia and hypocapnia studies on 14 healthy adult subjects. The correlation coefficient between log(CBV/CBV(0)) and log(CBFV/CBFV(0)) is 0.71 (p < 0.0001). We found a modified Grubb's exponent of 0.13 (the 95% confidence bounds are 0.10 and 0.17) which is expectedly lower than the conventional Grubb's exponents estimated by other techniques. The modified Grubb's exponent is a simple measure to quantify the hemodynamics between local CBV and global CBFV in the brain and as such may provide insight on brain physiology. Both NIRS and transcranial Doppler techniques are non-invasive and portable, facilitating future studies in other population groups such as brain-injured patients.

Objectives: Short exposures to buffeting in a vehicle driving over rough terrain induce an increase in the frequency of respiration resulting in hyperpnoea and hypocapnia. The present study investigates the adaptation to buffeting-induced hyperpnoea., Methods: We monitored ventilation and cardiovascular function in nine healthy young adults prior to, throughout and post a 30 minute simulation of buffeting., Results: All subjects had a consistent elevation of respiratory frequency throughout motion. End-tidal CO(2) decreased during the first 5 minutes of buffeting due to a transient increase in minute ventilation. Elevation of respiratory frequency was facilitated by shortening of inspiration without change in expiratory time. Tidal volume was maintained which resulted in an increase in mean inspiratory flow during buffeting. At later stages of motion there was a partial return to normal for mean inspiratory flow, minute ventilation and end-tidal CO(2)because of a slight reduction in tidal volume whilst inspiratory time remained shortened. Salivary cortisol levels were unaffected by motion, suggesting that the hyperpnoea was not secondary to non-specific stress., Interpretation: The cause of elevated respiratory frequency during buffeting could be due to mechanical action on the torso, vestibular-respiratory drive or a protective reinforcement of the torso.

Cerebral blood flow (CBF) is highly regulated by changes in arterial Pco(2) and arterial Po(2). Evidence from animal studies indicates that various vasoactive factors, including release of norepinephrine, endothelin, adrenomedullin, C-natriuretic peptide (CNP), and nitric oxide (NO), may play a role in arterial blood gas-induced alterations in CBF. For the first time, we directly quantified exchange of these vasoactive factors across the human brain. Using the Fick principle and transcranial Doppler ultrasonography, we measured CBF in 12 healthy humans at rest and during hypercapnia (4 and 8% CO(2)), hypocapnia (voluntary hyperventilation), and hypoxia (12 and 10% O(2)). At each level, blood was sampled simultaneously from the internal jugular vein and radial artery. With the exception of CNP and NO, the simultaneous quantification of norepinephrine, endothelin, or adrenomedullin showed no cerebral uptake or release during changes in arterial blood gases. Hypercapnia, but not hypocapnia, increased CBF and caused a net cerebral release of nitrite (a marker of NO), which was reflected by an increase in the venous-arterial difference for nitrite: 57 +/- 18 and 150 +/- 36 micromol/l at 4% and 8% CO(2), respectively (both P < 0.05). Release of cerebral CNP was also observed during changes in CO(2) (hypercapnia vs. hypocapnia, P < 0.05). During hypoxia, there was a net cerebral uptake of nitrite, which was reflected by a decreased venous-arterial difference for nitrite: -96 +/- 14 micromol/l at 10% O(2) (P < 0.05). These data indicate that there is a differential exchange of NO across the brain during hypercapnia and hypoxia and that CNP may play a complementary role in CO(2)-induced CBF changes.

Background: The arterial partial pressure of carbon dioxide (PaCO2) represents the balance between CO2 production and consumption. Abnormal increase or decrease in PaCO2 can affect the body's internal environment and function. Permissive hypercapnia has aroused more attention as a novel ventilatory therapy. The aim of this study was to elucidate the effects of hypercapnia and hypocapnia on the functions of such neonatal organs as the lung and brain., Data Sources: The PubMed database was searched with the keywords "hypocapnia", "hypercapnia" and "newborn"., Results: Hypocapnia is a risk factor for potential damage to the central nervous system, such as periventricular leukomalacia, intraventricular hemorrhage, cerebral palsy, cognition developmental disorder, and auditory deficit. Hyperventilation can lessen pulmonary artery hypertension to certain extent, but hypocapnia can aggravate ischemia/reperfusion-induced acute lung injury. Severe hypercapnia can induce intracranial hemorrhage, even consciousness alterations, cataphora, and hyperspasmia. Permissive hypercapnia can improve lung injury caused by diseases of the respiratory system, lessen mechanical ventilation-associated lung injury, reduce the incidence of bronchopulmonary dysplasia and protect against ventilation-induced brain injury. In addition, permissive hypercapnia plays a role in expanding cerebral vessels and increasing cerebral blood flow., Conclusions: Severe hypercapnia and hypocapnia can cause neonatal brain injury and lung injury. Permissive hypercapnia can increase the survival of neonates with brain injury or respiratory system disease, and lessen the brain injury and lung injury caused by mechanical ventilation. However, the mechanism of permissive hypercapnia needs further exploration to confirm its safety and therapeutic utility.

Carbon dioxide is known to affect consciousness in animals and humans. We surmised that changes in end-tidal carbon dioxide during anaesthesia might affect the Bispectral Index. Twenty-four patients due to undergo surgery were anaesthetised with fentanyl and a propofol infusion. The Bispectral Index, pulse rate and blood pressure were recorded while end-tidal carbon dioxide levels were changed. The patients acted as their own controls as they were subjected to high, normal and low levels of end-tidal carbon dioxide (3-12 kPa) according to a randomised sequence. There were no changes in the Bispectral Index or haemodynamic variables resulting from manipulation of the end-tidal carbon dioxide. At the level of hypnosis involved in this study, changes in end-tidal carbon dioxide, within the range tested, do not result in changes in the Bispectral Index.

Background: Anesthetic management during functional endoscopic sinus surgery is aimed at minimizing bleeding and establishing a near-perfect surgical field. We investigated whether deliberate intraoperative hypercapnia and hypocapnia may affect blood loss and quality of surgical field through a proposed modulating effect of different carbon dioxide (CO2) tension levels on nasal vasculature., Methods: One hundred and eighty patients were randomly assigned to normocapnia (end-tidal CO2 [ETco2] 37 +/- 2 mm Hg), hypercapnia (ETco2 60 +/- 2 mm Hg), and hypocapnia (ETco2 27 +/- 2 mm Hg) groups. Anesthetic management was with propofol and remifentanil infusions, nitrous oxide, and moderate controlled hypotension. Blood loss and operating conditions were assessed by the surgeon who was blinded to group assignment. Differences among the study groups, the effect of the study group and time on ETco2 levels and hemodynamic variables, and the association of blood loss with surgical covariates were analyzed., Results: There were no differences in blood loss and quality of surgical field among the study groups. Patients in the hypocapnia group demonstrated the highest, and in the hypercapnia group, the lowest, requirements for remifentanil, labetalol, and administration of the antihypertensive medications in general. The computed tomography-graded severity of sinonasal disease and duration of surgery were the only independent predictors of intraoperative blood loss., Conclusions: CO2 management during functional endoscopic sinus surgery does not influence operating conditions or blood loss.

Phrenic long-term facilitation (LTF) has been extensively studied in anesthetized animals under well-defined physiological conditions but the factors underlying its possible manifestation under clinically relevant conditions are not well understood. Here, we examine the stability of LTF in the face of hypercapnic or hypocapnic challenges in anesthetized, paralyzed and mechanically ventilated rats. Sixty minutes after induction of phrenic LTF by intermittent hypoxia the animal was exposed to one of four conditions for 5 min with or without positive end-expiratory pressure (PEEP, 3-4 cmH(2)O): hypocapnic apnea, hypocapnia (5 Torr below resting level), 5% CO(2) and 10% CO(2). LTF at 60 min post-intermittent hypoxia was approximately 39% above baseline. Following the above CO(2) tests, LTF almost invariably returned to the corresponding pre-test level after recovery for 20 min. The only exception was the combination of hypocapnic apnea and PEEP, which resulted in a marked decrease in mean arterial pressure (to 38-55mmHg) during test and a subsequent paradoxical sustained attenuation of LTF (to approximately 8% above baseline) even after mean arterial pressure had fully recovered. The results suggest that LTF, once developed, is highly robust to changes in CO(2) levels and is attenuated only after severe hypotension secondary to excessive hyperventilation under PEEP.

In humans, lung ventilation exhibits breath-to-breath variability and dynamics that are nonlinear, complex, sensitive to initial conditions, unpredictable in the long-term, and chaotic. Hypercapnia, as produced by the inhalation of a CO(2)-enriched gas mixture, stimulates ventilation. Hypocapnia, as produced by mechanical hyperventilation, depresses ventilation in animals and in humans during sleep, but it does not induce apnea in awake humans. This emphasizes the suprapontine influences on ventilatory control. How cortical and subcortical commands interfere thus depend on the prevailing CO(2) levels. However, CO(2) also influences the variability and complexity of ventilation. This study was designed to describe how this occurs and to test the hypothesis that CO(2) chemoreceptors are important determinants of ventilatory dynamics. Spontaneous ventilatory flow was recorded in eight healthy subjects. Breath-by-breath variability was studied through the coefficient of variation of several ventilatory variables. Chaos was assessed with the noise titration method (noise limit) and characterized with numerical indexes [largest Lyapunov exponent (LLE), sensitivity to initial conditions; Kolmogorov-Sinai entropy (KSE), unpredictability; and correlation dimension (CD), irregularity]. In all subjects, under all conditions, a positive noise limit confirmed chaos. Hypercapnia reduced breathing variability, increased LLE (P = 0.0338 vs. normocapnia; P = 0.0018 vs. hypocapnia), increased KSE, and slightly reduced CD. Hypocapnia increased variability, decreased LLE and KSE, and reduced CD. These results suggest that chemoreceptors exert a strong influence on ventilatory variability and complexity. However, complexity persists in the quasi-absence of automatic drive. Ventilatory variability and complexity could be determined by the interaction between the respiratory central pattern generator and suprapontine structures.

Aim: Transcranial Doppler sonography (TCD) is increasingly used in cerebrovascular disease for monitoring brain perfusion. It allows estimation of cerebral blood flow (CBF) by the measurement of cerebral blood flow velocity (CBFV). The CBFV as well as CBF are intimately associated with the intravascular CO2-concentration. Thus, hyper- or hypocapnia can be used to induce a defined range of blood flows. The aim of our study was the comparison of vasomotor reactivity assessed with simultaneous TCD and quantitative regional CBF-measurements (rCBF) by PET (serving as the reference method for in-vivo quantification of rCBF)., Patients, Methods: Six healthy young volunteers participated in this study. CBF was measured using 15O-butanol PET. A flow and dispersion-model was fitted to the measured time activity curves using arterial input curves. Each subject underwent five scans at five different end-tidal CO2 levels (EtCO2): 25, 32, 40, 48, and 55 mmHg. CBFV was assessed by continuous bilateral TCD of the middle cerebral artery (MCA). Volumes of interest for rCBF determination were placed in grey matter of the prefrontal cortex (PFC) as determined from individual MRIs. Comparisons between the rCBF, EtCO2 and CBFV were carried out with regression and correlation analysis and paired t-tests., Results: Strong positive linear correlations of rCBF and CBFV with the CO2-concentration and linear relationships between rCBF and CBFV were found in each individual. Normalised CO2-reactivities measured by TCD and PET were closely correlated., Conclusions: TCD-measurements of vascular reactivity in healthy volunteers show a high correlation to those acquired with PET that serves as the reference method of quantitative rCBF-measurement. The results of the MCA insonation are a close approximation of the rCBF changes induced by variations of EtCO2.

This study examined the time course of early scotopic threshold sensitivity during dark adaptation under mild to moderate hypoxia, moderate hypocapnia and hyperoxia, measuring detection time displacement relative to normoxia. Cone rod inflection and early rod adaptation were highlighted using progressively dimmer green flash stimuli. Early scotopic sensitivity was significantly delayed by hypoxia and hastened by hypocapnia and hyperoxia. Effects of respiratory disturbance on dark adaptation include temporal shifts of early scotopic sensitivity while human rod photoreceptors appear functionally hypoxic when breathing air at one atmosphere. At night, supplementary oxygen may benefit aircrew visual sensitivity, even at ground level.

Hypercapnia induces cerebral vasodilation and increases cerebral blood volume (CBV), and hypocapnia induces cerebral vasoconstriction and decreases CBV. Cerebral blood volume measured by positron emission tomography (PET) is the sum of three components, that is, arterial, capillary, and venous blood volumes. Changes in arterial blood volume (V(a)) and CBV during hypercapnia and hypocapnia were investigated in humans using PET with H(2)(15)O and (11)CO. Arterial blood volume was determined from H(2)(15)O PET data by means of a two-compartment model that takes V(a) into account. Baseline CBV and values during hypercapnia and hypocapnia in the cerebral cortex were 0.034+/-0.003, 0.038+/-0.003, and 0.031+/-0.003 mL/mL (mean+/-s.d.), respectively. Baseline V(a) and values during hypercapnia and hypocapnia were 0.015+/-0.003, 0.025+/-0.011, and 0.007+/-0.003 mL/mL, respectively. Cerebral blood volume changed significantly owing to changes in PaCO(2), and V(a) changed significantly in the direction of CBV changes. However, no significant change was observed in venous plus capillary blood volume (=CBV-V(a)). This indicates that changes in CBV during hypercapnia and hypocapnia are caused by changes in arterial blood volume without changes in venous and capillary blood volume.

The purpose of this study was to establish the relationship between regional CBF and CBV at normal, resting cerebral metabolic rates. Eleven healthy volunteers were investigated with PET during baseline conditions, and during hyper- and hypocapnia. Values for rCBF and rCBV were obtained using 15O-labelled water and carbon monoxide, respectively. The mean value of rCBF using PET was 62 +/- 18 ml 100 g(-1) min(-1) during baseline conditions, with an average increase of 46% during hypercapnia, and a decrease of 29% during hypocapnia; baseline rCBV was 7.7 ml/100 g, with 27% increase during hypercapnia and no significant decrease during hypocapnia. A regionally uniform exponential relationship was confirmed between PaCO2 and rCBF as well as rCBV. It is shown that the theoretical implication of this is that the rCBV vs. rCBF relationship should be modelled by a power function; however, due to pronounced intersubject variability, the goodness of fit for linear and nonlinear models were not significantly different. The results of the study are applied to a numerical estimation of regional brain deoxy-haemoglobin content. Independently of the choice of model for the rCBV vs. rCBF relationship, a nonlinear deoxy-haemoglobin vs. rCBF relationship was predicted, and the implications for the BOLD response are discussed.

Exposure to hypercapnic hypoxia (asphyxia), but not hyperoxic hypercapnia, results in increased sympathetic activity that persists after exposure. To determine the contribution of CO2 to the post-hypoxia sympathoexcitation, we exposed 12 normal volunteers to hypocapnic and hypercapnic hypoxia (SaO2 approximately 85%) for 20 min each on different days. We measured plethysmographic forearm blood flow, muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), and heart rate. MSNA increased during both exposures but remained elevated for 15 min only after asphyxia. Following asphyxia, MAP returned to pre-exposure values, but after hypocapnic hypoxia MAP decreased below baseline for 15 min. There were sustained decreases in heart rate after hypocapnic, but not hypercapnic hypoxia. Forearm vascular resistance (FVR) decreased below baseline during both exposures, reached its highest value above baseline after asphyxia and then declined. After hypocapnic hypoxia FVR rose to baseline after exposure. Hemodynamics are differently altered by hypercapnic relative to hypocapnic 20 min hypoxia, while only hypercapnic hypoxia produces sustained elevation of MSNA during recovery.

This study examined the relationship between cerebral blood flow (CBF) and end-tidal PCO2 (PETCO2) in humans. We used transcranial Doppler ultrasound to determine middle cerebral artery peak blood velocity responses to 14 levels of PETCO2 in a range of 22 to 50 Torr with a constant end-tidal PO2 (100 Torr) in eight subjects. PETCO2 and end-tidal PO2 were controlled by using the technique of dynamic end-tidal forcing combined with controlled hyperventilation. Two protocols were conducted in which PETCO2 was changed by 2 Torr every 2 min from hypocapnia to hypercapnia (protocol I) and vice-versa (protocol D). Over the range of PETCO2 studied, the sensitivity of peak blood velocity to changes in PETCO2 (CBF-PETCO2 sensitivity) was nonlinear with a greater sensitivity in hypercapnia (4.7 and 4.0%/Torr, protocols I and D, respectively) compared with hypocapnia (2.5 and 2.2%/Torr). Furthermore, there was evidence of hysteresis in the CBF-PETCO2 sensitivity; for a given PETCO2, there was greater sensitivity during protocol I compared with protocol D. In conclusion, CBF-PETCO2 sensitivity varies depending on the level of PETCO2 and the protocol that is used. The mechanisms underlying these responses require further investigation.

Hypercapnia induces cerebral vasodilation and increases cerebral blood flow (CBF), and hypocapnia induces cerebral vasoconstriction and decreases CBF. The relation between changes in CBF and cerebral blood volume (CBV) during hypercapnia and hypocapnia in humans, however, is not clear. Both CBF and CBV were measured at rest and during hypercapnia and hypocapnia in nine healthy subjects by positron emission tomography. The vascular responses to hypercapnia in terms of CBF and CBV were 6.0 +/- 2.6%/mm Hg and 1.8 +/- 1.3%/mm Hg, respectively, and those to hypocapnia were -3.5 +/- 0.6%/mm Hg and -1.3 +/- 1.0%/mm Hg, respectively. The relation between CBF and CBV was CBV = 1.09 CBF0.29. The increase in CBF was greater than that in CBV during hypercapnia, indicating an increase in vascular blood velocity. The degree of decrease in CBF during hypocapnia was greater than that in CBV, indicating a decrease in vascular blood velocity. The relation between changes in CBF and CBV during hypercapnia was similar to that during neural activation; however, the relation during hypocapnia was different from that during neural deactivation observed in crossed cerebellar diaschisis. This suggests that augmentation of CBF and CBV might be governed by a similar microcirculatory mechanism between neural activation and hypercapnia, but diminution of CBF and CBV might be governed by a different mechanism between neural deactivation and hypocapnia.

Hypercapnia has been shown in animal experiments to induce pulmonary hypertension. This study measured the sensitivity and time course of the human pulmonary vascular response to sustained (4 h) hypercapnia and hypocapnia. Twelve volunteers undertook three protocols: 1) 4-h euoxic (end-tidal Po(2) = 100 Torr) hypercapnia (end-tidal Pco(2) was 10 Torr above normal), followed by 2 h of recovery with euoxic eucapnia; 2) 4-h euoxic hypocapnia (end-tidal Pco(2) was 10 Torr below normal) followed by 2 h of recovery; and 3) 6-h air breathing (control). Pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by using Doppler echocardiography via the maximum tricuspid pressure gradient during systole. Results show progressive changes in pressure gradient over 1-2 h after the onset or offset of the stimuli, and sensitivities of 0.6 to 1 Torr change in pressure gradient per Torr change in end-tidal Pco(2). The human pulmonary circulatory response to changes in Pco(2) has a slower time course and greater sensitivity than is commonly assumed. Vascular tone in the normal pulmonary circulation is substantial.