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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.

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.)

Orthostatic hypotension (OH) is a form of orthostatic intolerance (OI) and a key physiological indicator of autonomic dysfunction that is associated with an increased risk of major cerebrocardiovascular events. Symptoms of cerebral hypoperfusion have been reported in patients with OH, which worsens symptoms and increases the risk of syncope. Since pharmacological interventions increase blood pressure (BP) independent of posture and do not restore normal baroreflex control, nonpharmacological treatments are considered the foundation of OH management. While reductions in cerebral blood flow velocity (CBF v ) during orthostatic stress are associated with a decrease in end-tidal CO 2 (EtCO 2 ) and hypocapnia in patients with OI, their contribution to the severity of OH is not well understood. These measures have been physiological targets in a wide variety of biofeedback interventions. This study explored the relationship between cardiovascular autonomic control, EtCO 2 and cerebral hypoperfusion in patients (N = 72) referred for OI. Patients with systolic OH were more likely to be male, older, demonstrate reduced adrenal and vagal baroreflex sensitivity, and reduced cardiovagal control during head-up tilt (HUT) than patients without systolic OH. Greater reduction in CBF v during HUT was associated with a larger reduction in ETCO 2 and systolic BP during HUT. While deficits in cardiovascular autonomic control played a more important role in systolic OH, reduced EtCO 2 was a major contributor to orthostatic cerebral hypoperfusion. These findings suggest that biofeedback treatments targeting both the autonomic nervous system and EtCO 2 should be part of nonpharmacological interventions complementing the standard of care in OH patients with symptoms of cerebral hypoperfusion., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Extracorporeal membrane oxygenation (ECMO) is often associated with disturbances in acid/base status that can be triggered by the underlying pathology or the ECMO circuit itself. Extracorporeal membrane oxygenation is known to cause hypocapnia, but the impact of reduced partial pressure of carbon dioxide (pCO 2 ) on biomarkers of tissue perfusion during veno-arterial (VA)-ECMO has not been evaluated. To study the impact of low pCO 2 on perfusion indices in VA-ECMO, we placed Sprague-Dawley rats on an established VA-ECMO circuit using either an oxygen/carbon dioxide mixture (O 2 95%, CO 2 5%) or 100% O 2 delivered through the oxygenator (n = 5 per cohort). Animals receiving 100% O 2 developed a significant VA CO 2 difference (pCO 2 gap) and rising blood lactate levels that were inversely proportional to the decrease in pCO 2 values. In contrast, pCO 2 gap and lactate levels remained similar to pre-ECMO baseline levels in animals receiving the O 2 /CO 2 mixture. More importantly, there was no significant difference in venous oxygen saturation (SvO 2 ) between the two groups, suggesting that elevated blood lactate levels observed in the rats receiving 100% O 2 were a response to oxygenator induced hypocapnia and alkaline pH rather than reduced perfusion or underlying tissue hypoxia. These findings have implications in clinical and experimental extracorporeal support contexts., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Introduction: The sharpened Romberg test (SRT) is a physical maneuver that has been used to identify ataxia in individuals in resource-limited settings. Previous research has suggested that performance on balance testing may be affected by hypocapnia. In this study, we sought to determine whether acute hyperventilation-induced hypocapnia affects performance on the SRT at 501 meters above sea level., Methods: We recruited 22 healthy subjects. Each subject performed a baseline SRT. Subjects were then asked to hyperventilate to the point of hypocapnia, confirmed by measurement with a capnometer. Subjects were then asked to re-perform SRT. The primary endpoint was time to loss of balance, measured as time-to-stepout., Results: Time-to-stepout (TTS) on SRT at baseline had a mean ± standard deviation of 101 ± 117 s. In the hypocapnic condition, TTS was reduced to 48 ± 68 s. TTS normalized to 121 ± 132 s after recovery to normal capnic levels. Time-to-stepout was found to be significantly shorter in the hypocapnic measurement compared to the baseline measurement ( P  = .0128). Statistical analysis was conducted using one-tailed, paired sample T-tests using a P -value of < .05., Conclusions: Our study found a statistically and clinically significant reduction in performance on a balance test (SRT) when exposed to acute hyperventilation-induced hypocapnia compared to a eucapnic control. Our results suggest that acute hypocapnia may contribute to neurological dysfunction independently of hypobaric hypoxia., 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: Drs. Stepanek and Pradhan are inventors on USPTO patent number 11529492 (methods and materials for treating hypocapnia).

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.

Current guidelines suggest a target of partial pressure of carbon dioxide (PaCO 2 ) of 32-35 mmHg (mild hypocapnia) as tier 2 for the management of intracranial hypertension. However, the effects of mild hyperventilation on cerebrovascular dynamics are not completely elucidated. The aim of this study is to evaluate the changes of intracranial pressure (ICP), cerebral autoregulation (measured through pressure reactivity index, PRx), and regional cerebral oxygenation (rSO 2 ) parameters before and after induction of mild hyperventilation. Single center, observational study including patients with acute brain injury (ABI) admitted to the intensive care unit undergoing multimodal neuromonitoring and requiring titration of PaCO 2 values to mild hypocapnia as tier 2 for the management of intracranial hypertension. Twenty-five patients were included in this study (40% female), median age 64.7 years (Interquartile Range, IQR = 45.9-73.2). Median Glasgow Coma Scale was 6 (IQR = 3-11). After mild hyperventilation, PaCO 2 values decreased (from 42 (39-44) to 34 (32-34) mmHg, p < 0.0001), ICP and PRx significantly decreased (from 25.4 (24.1-26.4) to 17.5 (16-21.2) mmHg, p < 0.0001, and from 0.32 (0.1-0.52) to 0.12 (-0.03-0.23), p < 0.0001). rSO 2 was statistically but not clinically significantly reduced (from 60% (56-64) to 59% (54-61), p < 0.0001), but the arterial component of rSO 2 (ΔO 2 Hbi, changes in concentration of oxygenated hemoglobin of the total rSO 2 ) decreased from 3.83 (3-6.2) μM.cm to 1.6 (0.5-3.1) μM.cm, p = 0.0001. Mild hyperventilation can reduce ICP and improve cerebral autoregulation, with minimal clinical effects on cerebral oxygenation. However, the arterial component of rSO 2 was importantly reduced. Multimodal neuromonitoring is essential when titrating PaCO 2 values for ICP management., (© 2024. The Author(s).)

Aims: Both hypercapnia and hypocapnia are common in patients with acute heart failure (AHF), but the association between partial pressure of arterial carbon dioxide (PaCO 2 ) and AHF prognosis remains unclear. The objective of this study was to investigate the connection between PaCO 2 within 24 h after admission to the intensive care unit (ICU) and mortality during hospitalization and at 1 year in AHF patients., Methods and Results: AHF patients were enrolled from the Medical Information Mart for Intensive Care IV database. The patients were divided into three groups by PaCO 2 values of <35, 35-45, and >45 mmHg. The primary outcome was to investigate the connection between PaCO 2 and in-hospital mortality and 1 year mortality in AHF patients. The secondary outcome was to assess the prediction value of PaCO 2 in predicting in-hospital mortality and 1 year mortality in AHF patients. A total of 2374 patients were included in this study, including 457 patients in the PaCO 2  < 35 mmHg group, 1072 patients in the PaCO 2  = 35-45 mmHg group, and 845 patients in the PaCO 2  > 45 mmHg group. The in-hospital mortality was 19.5%, and the 1 year mortality was 23.9% in the PaCO 2  < 35 mmHg group. Multivariate logistic regression analysis showed that the PaCO 2  < 35 mmHg group was associated with an increased risk of in-hospital mortality [hazard ratio (HR) 1.398, 95% confidence interval (CI) 1.039-1.882, P = 0.027] and 1 year mortality (HR 1.327, 95% CI 1.020-1.728, P = 0.035) than the PaCO 2  = 35-45 mmHg group. The PaCO 2  > 45 mmHg group was associated with an increased risk of in-hospital mortality (HR 1.387, 95% CI 1.050-1.832, P = 0.021); the 1 year mortality showed no significant difference (HR 1.286, 95% CI 0.995-1.662, P = 0.055) compared with the PaCO 2  = 35-45 mmHg group. The Kaplan-Meier survival curves showed that the PaCO 2  < 35 mmHg group had a significantly lower 1 year survival rate. The area under the receiver operating characteristic curve for predicting in-hospital mortality was 0.591 (95% CI 0.526-0.656), and the 1 year mortality was 0.566 (95% CI 0.505-0.627) in the PaCO 2  < 35 mmHg group., Conclusions: In AHF patients, hypocapnia within 24 h after admission to the ICU was associated with increased in-hospital mortality and 1 year mortality. However, the increase in 1 year mortality may be influenced by hospitalization mortality. Hypercapnia was associated with increased in-hospital mortality., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: The purpose of this study was to investigate whether people with fibromyalgia (FM) have dysfunctional breathing by examining acid-base balance and comparing it with healthy controls., Methods: Thirty-six women diagnosed with FM and 36 healthy controls matched for age and gender participated in this cross-sectional study. To evaluate acid-base balance, arterial blood was sampled from the radial artery. Carbon dioxide, oxygen, bicarbonate, base excess, pH and lactate were analysed for between-group differences. Blood gas analyses were performed stepwise on each individual to detect acid-base disturbance, which was categorized as primary respiratory and possible compensation indicating chronicity. A three-step approach was employed to evaluate pH, carbon dioxide and bicarbonate in this order., Results: Women with FM had significantly lower carbon dioxide pressure ( p = 0.013) and higher lactate ( p = 0.038) compared to healthy controls at the group level. There were no significant differences in oxygen pressure, bicarbonate, pH and base excess. Employing a three-step acid-base analysis, 11 individuals in the FM group had a possible renally compensated mild chronic hyperventilation, compared to only 4 among the healthy controls ( p = 0.042)., Conclusions: In this study, we could identify a subgroup of individuals with FM who may be characterized as mild chronic hyperventilators. The results might point to a plausible dysfunctional breathing in some women with FM., (© 2024 the author(s), published by De Gruyter.)

Background: High normal resting pCO 2 is a risk factor for salt sensitivity of blood pressure (BP) in normotensive humans and has been associated with higher resting systolic BP in postmenopausal women. To date, however, no known studies have investigated the effects of regular practice of voluntary mild hypocapnic breathing on BP in hypertensive patients. The objective of the present research was to test the hypothesis that capnometric feedback training can decrease both resting pCO 2 and 24-h BP in a series of mildly hypertensive postmenopausal women., Methods: A small portable end tidal CO 2 (etCO 2 ) monitor was constructed and equipped with software that determined the difference between the momentary etCO 2 and a pre-programmed criterion range. The monitor enabled auditory feedback for variations in CO 2 outside the criterion range. 16 mildly hypertensive postmenopausal women were individually trained to sustain small decreases in etCO 2 during six weekly sessions in the clinic and daily sessions at home. 24-h BP monitoring was conducted before and after the intervention, and in 16 prehypertensive postmenopausal women in a control group who did not engage in the capnometric training., Results: Following the intervention, all 16 capnometric training participants showed decreases in resting etCO 2 (- 4.3 ± 0.4 mmHg; p < .01) while 15 showed decreases in 24-h systolic BP (- 7.6 ± 2.0 mmHg; p < .01). No significant changes in either measure was observed in the control group. In addition, nighttime (- 9.5 ± 2.6; p < .01) and daytime (- 6.7 ± 0.2 mmHg) systolic BP were both decreased following capnometric training, while no significant changes in nighttime (- 2.8 ± 2.2 mmHg; p = .11) or daytime (- 0.7 ± 1.0 mmHg; p ≤ .247) systolic BP were observed in the control group., Conclusions: These findings support the hypothesis that regular practice of mild hypocapnic breathing that decreases resting etCO 2 reliably decreases 24-h blood pressure in hypertensive postmenopausal women. The extent to which these effects persist beyond the training period or can be observed in other hypertensive subgroups remains to be investigated., (© 2021. The Author(s).)

The high metabolic demand of cerebral tissue requires that local perfusion is tightly coupled with local metabolic rate (neurovascular coupling; NVC). During chronic altitude exposure, where individuals are exposed to the antagonistic cerebrovascular effects of hypoxia and hypocapnia, pH is maintained through renal compensation and NVC remains stable. However, the potential independent effect of acute hypocapnia and respiratory alkalosis on NVC remains to be determined. We hypothesized that acute steady-state hypocapnia via voluntary hyperventilation would attenuate the magnitude of NVC. We recruited 17 healthy participants and insonated the posterior cerebral artery (PCA) with transcranial Doppler ultrasound. NVC was elicited using a standardized strobe light stimulus (6 Hz; 5 × 30 s on/off) where absolute delta responses from baseline (BL) in peak, mean, and total area under the curve (tAUC) were quantified. From a BL end-tidal (P ET )CO 2  level of 36.7 ± 3.2 Torr, participants were coached to hyperventilate to reach steady-state hypocapnic steps of Δ-5 Torr (31.6 ± 3.9) and Δ-10 Torr (26.0 ± 4.0; p < 0.001), which were maintained during the presentation of the visual stimuli. We observed a small but significant reduction in NVC peak (ΔPCAv) from BL during controlled hypocapnia at both Δ-5 (-1.58 cm/s) and Δ-10 (-1.37 cm/s), but no significant decrease in mean or tAUC NVC response was observed. These data demonstrate that acute respiratory alkalosis attenuates peak NVC magnitude at Δ-5 and Δ-10 Torr P ET CO 2 , equally. Although peak NVC magnitude was mildly attenuated, our data illustrate that mean and tAUC NVC are remarkably stable during acute respiratory alkalosis, suggesting multiple mechanisms underlying NVC., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.

Abstract Twenty minutes of voluntary hypocapnic hyperventilation prior to exercise reduces the aerobic metabolic rate with a compensatory increase in the anaerobic metabolic rate without affecting exercise performance during the Wingate anaerobic test (WAnT). Thus, pre-exercise hypocapnic hyperventilation may be a useful means of stressing the anaerobic energy system during training, ultimately improving anaerobic exercise performance. However, it remains unclear whether a shorter (e.g., 5 min) pre-exercise hypocapnic hyperventilation is sufficient to reduce the aerobic metabolic rate during high-intensity exercise. We therefore compared the effects of 5-min and 20-min pre-exercise hypocapnic hyperventilation on aerobic metabolism during the 30-s WAnT. Ten healthy young males and one female performed the WAnT following 20 min of spontaneous breathing (control trial) or 5 or 20 min of voluntary hypocapnic hyperventilation. Both the 5-min and 20-min hyperventilation reduced end-tidal CO 2 partial pressure (an index of arterial CO 2 partial pressure) to ∼23 mmHg, whereas it remained unchanged during the spontaneous breathing. The peak, mean and minimum power outputs during the WAnT did not differ among the three trials. Oxygen uptake during the WAnT was lower in both the 5-min (1493 ± 257 mL min -1 ) and 20-min (1397 ± 447 mL min -1 ) hyperventilation trials than during the control trial (1847 ± 286 mL min -1 ), and was similar in the two hyperventilation trials. These results suggest that 5 min of pre-exercise hypocapnic hyperventilation reduces aerobic metabolism during the 30-s WAnT to a level similar to that seen with the 20-min hyperventilation. Moreover, exercise performance was unaffected, which implies anaerobic metabolism was enhanced.

A high sodium (Na + ) meal impairs peripheral vascular function. In rodents, chronic high dietary Na + impairs cerebral vascular function, and in humans, habitual high dietary Na + is associated with increased stroke risk. However, the effects of acute high dietary Na + on the cerebral vasculature in humans are unknown. The purpose of this study was to determine if acute high dietary Na + impairs cerebrovascular reactivity in healthy adults. Thirty-seven participants (20F/17M; 25 ± 5 years; blood pressure [BP]: 107 ± 9/61 ± 6 mm Hg) participated in this randomized, cross-over study. Participants were given a low Na + meal (LSM; 138 mg Na + ) and a high Na + meal (HSM; 1,495 mg Na + ) separated by ≥ one week. Serum Na + , beat-to-beat BP, middle cerebral artery velocity (transcranial Doppler), and end-tidal carbon dioxide (P ET CO 2 ) were measured pre- (baseline) and 60 min post-prandial. Cerebrovascular reactivity was assessed by determining the percent change in middle cerebral artery velocity to hypercapnia (via 8% CO 2 , 21% oxygen, balance nitrogen) and hypocapnia (via mild hyperventilation). Peripheral vascular function was measured using brachial artery flow-mediated dilation (FMD). Changes in serum Na + were greater following the HSM (HSM: Δ1.6 ± 1.2 mmol/L vs. LSM: Δ0.7 ± 1.2 mmol/L, p < .01). Cerebrovascular reactivity to hypercapnia (meal effect: p = .41) and to hypocapnia (meal effect: p = .65) were not affected by the HSM. Contrary with previous findings, FMD was not reduced following the HSM (meal effect: p = .74). These data suggest that a single high Na + meal does not acutely impair cerebrovascular reactivity, and suggests that despite prior findings, a single high Na + meal does not impair peripheral vascular function in healthy adults., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The time constant of the cerebral arterial bed ("tau") estimates how fast the blood entering the brain fills the arterial vascular sector. Analogous to an electrical resistor-capacitor circuit, it is expressed as the product of arterial compliance (Ca) and cerebrovascular resistance (CVR). Hypocapnia increases the time constant in healthy volunteers and decreases arterial compliance in head trauma. How the combination of hyocapnia and trauma affects this parameter has yet to be studied. We hypothesized that in TBI patients the intense vasoconstrictive action of hypocapnia would dominate over the decrease in compliance seen after hyperventilation. The predominant vasoconstrictive response would maintain an incoming blood volume in the arterial circulation, thereby lengthening tau. We retrospectively analyzed recordings of intracranial pressure (ICP), arterial blood pressure (ABP), and blood flow velocity (FV) obtained from a cohort of 27 severe TBI patients [(39/30 years (median/IQR), 5 women; admission GCS 6/5 (median/IQR)] studied during a standard clinical CO 2 reactivity test. The reactivity test was performed by means of a 50-min increase in ventilation (20% increase in respiratory minute volume). CVR and Ca were estimated from these recordings, and their product calculated to find the time constant. CVR significantly increased [median CVR pre-hypocapnia/during hypocapnia: 1.05/1.35 mmHg/(cm 3 /s)]. Ca decreased (median Ca pre-hypocapnia/during hypocapnia: 0.130/0.124 arbitrary units) to statistical significance (p = 0.005). The product of these two parameters resulted in a significant prolongation of the time constant (median tau pre-hypocapnia/during hypocapnia: 0.136 s/0.152 s, p ˂ .001). Overall, the increase in CVR dominated over the decrease in compliance, hence tau was longer. We demonstrate a significant increase in the time constant of the cerebral circulation during hypocapnia after severe TBI, and attribute this to an increase in cerebrovascular resistance which outweighs the decrease in cerebral arterial bed compliance.

A common inclusion criterion when assessing cerebrovascular (CVR) metrics is for individuals to abstain from exercise for 12-24 hr prior to data collections. While several studies have examined CVR during exercise, the literature describing CVR throughout post-exercise recovery is sparse. The current investigation examined CVR measurements in nine participants (seven male) before and for 8 hr following three conditions: 45-min moderate-continuous exercise (at ~50% heart-rate reserve), 25-min high-intensity intervals (ten, one-minute intervals at ~85% heart-rate reserve), and a control day (30-min quiet rest). The hypercapnic (40-60 mmHg) and hypocapnic (25-40 mmHg) slopes were assessed via a modified rebreathing technique and controlled stepwise hyperventilation, respectively. All testing was initiated at 8:00a.m. with transcranial Doppler ultrasound measurements to index cerebral blood velocity performed prior to the condition (pre) with serial follow-ups at zero, one, two, four, six, and eight hours within the middle and posterior cerebral artery (MCA, PCA). Absolute and relative MCA and PCA hypercapnic slopes were attenuated following high-intensity intervals at hours zero and one (all p < .02). No alterations were observed in either hypocapnic or hypercapnic slopes following the control or moderate-continuous exercise (all p > .13), aside from a reduced relative hypercapnic MCA slope at hours zero and one following moderate-continuous exercise (all p < .005). The current findings indicate the common inclusion criteria of a 12-24 hr time restriction on exercise can be reduced to two hours when performing CVR measures. Furthermore, the consistent nature of the CVR indices throughout the control day indicate reproducible testing sessions can be made between 8:00a.m. and 7:00p.m., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: There is an association between hypocapnia and adverse neurodevelopmental outcome in infants with neonatal encephalopathy (NE). Our aim was to test the safety and feasibility of 5% CO 2 and 95% air inhalation to correct hypocapnia in mechanically ventilated infants with NE undergoing therapeutic hypothermia., Methods: Ten infants were assigned to this open-label, single-center trial. The gas mixture of 5% CO 2 and 95% air was administered through patient circuits if the temperature-corrected PCO 2 ≤40 mm Hg. The CO 2 inhalation was continued for 12 h or was stopped earlier if the base deficit (BD) level decreased <5 mmol/L. Follow-up was performed using Bayley Scales of Infant Development II., Results: The patients spent a median 95.1% (range 44.6-98.5%) of time in the desired PCO 2 range (40-60 mm Hg) during the inhalation. All PCO 2 values were >40 mm Hg, the lower value of the target range. Regression modeling revealed that BD and lactate had a tendency to decrease during the intervention (by 0.61 and 0.55 mmol/L/h, respectively), whereas pH remained stable. The rate of moderate disabilities and normal outcome was 50%., Conclusions: Our results suggest that inhaled 5% CO 2 administration is a feasible and safe intervention for correcting hypocapnia.

Background: Mechanical ventilation to alter and improve respiratory gases is a fundamental feature of critical care and intraoperative anesthesia management. The range of inspired O 2 and expired CO 2 during patient management can significantly deviate from values in the healthy awake state. It has long been appreciated that hyperoxia can have deleterious effects on organs, especially the lung and retina. Recent work shows intraoperative end-tidal (ET) CO 2 management influences the incidence of perioperative neurocognitive disorder (POND). The interaction of O 2 and CO 2 on cerebral blood flow (CBF) and oxygenation with alterations common in the critical care and operating room environments has not been well studied., Methods: We examine the effects of controlled alterations in both ET O 2 and CO 2 on cerebral blood flow (CBF) in awake adults using blood oxygenation level-dependent (BOLD) and pseudo-continuous arterial spin labeling (pCASL) MRI. Twelve healthy adults had BOLD and CBF responses measured to alterations in ET CO 2 and O 2 in various combinations commonly observed during anesthesia., Results: Dynamic alterations in regional BOLD and CBF were seen in all subjects with expected and inverse brain voxel responses to both stimuli. These effects were incremental and rapid (within seconds). The most dramatic effects were seen with combined hyperoxia and hypocapnia. Inverse responses increased with age suggesting greater risk., Conclusions: Human CBF responds dramatically to alterations in ET gas tensions commonly seen during anesthesia and in critical care. Such alterations may contribute to delirium following surgery and under certain circumstances in the critical care environment., Trial Registration: ClincialTrials.gov NCT02126215 for some components of the study. First registered April 29, 2014.

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.

Key Points: The control of cerebral blood flow in hypoxia, anaemia and hypocapnia is reviewed with an emphasis on the links between cerebral blood flow and possible stimuli. A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model demonstrates that hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, an effect exacerbated when blood flow regulation is impaired. The suitability of brain hypoxia as a common regulator of cerebral blood flow in hypoxia and anaemia was explored, although we failed to find support for this hypothesis. Rather, cerebral blood flow appears to be related to arterial oxygen concentration in both anaemia and hypoxia., Abstract: A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model simulation assesses the physiological plausibility of some currently hypothesized cerebral blood flow control mechanisms in hypoxia and anaemia, and also examines the impact of anaemia and hypoxia on brain hypoxia. In addition, carbon dioxide is examined for its impact on brain hypoxia in the context of concomitant changes associated with anaemia and hypoxia. The model calculations are based on a single compartment of brain tissue with constant metabolism and perfusion pressure, as well as previously developed equations describing oxygen and carbon dioxide carriage in blood. Experimental data are used to develop the control equations for cerebral blood flow regulation. The interactive model illustrates that there are clear interactions of anaemia, hypoxia and carbon dioxide in the determination of cerebral blood flow and brain tissue oxygen tension. In both anaemia and hypoxia, cerebral blood flow increases to maintain oxygen delivery, with brain hypoxia increasing when cerebral blood flow control mechanisms are impaired. Hypocapnia superimposes its effects, increasing brain hypoxia. Hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, and this effect is exacerbated when blood flow regulation is degraded by conditions that negatively impact cerebrovascular control. Differences in brain hypoxia in anaemia and hypoxia suggest that brain oxygen tension is not a plausible sensor for cerebral blood flow control., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Background: In traumatic brain injury (TBI) the patterns of intracranial pressure (ICP) waveforms may reflect pathological processes that ultimately lead to unfavorable outcome. In particular, ICP slow waves (sw) (0.005-0.05 Hz) magnitude and complexity have been shown to have positive association with favorable outcome. Mild-moderate hypocapnia is currently used for short periods to treat critical elevations in ICP. Our goals were to assess changes in the ICP sw activity occurring following sudden onset of mild-moderate hypocapnia and to examine the relationship between changes in ICP sw activity and other physiological variables during the hypocapnic challenge., Methods: ICP, arterial blood pressure (ABP), and bilateral middle cerebral artery blood flow velocity (FV), were prospectively collected in 29 adult severe TBI patients requiring ICP monitoring and mechanical ventilation in whom a minute volume ventilation increase (15-20% increase in respiratory minute volume) was performed as part of a clinical CO 2 -reactivity test. The time series were first treated using FFT filter (pass-band set to 0.005-0.05 Hz). Power spectral density analysis was performed. We calculated the following: mean value, standard deviation, variance and coefficient of variation in the time domain; total power and frequency centroid in the frequency domain; cerebrospinal compliance (Ci) and compensatory reserve index (RAP)., Results: Hypocapnia led to a decrease in power and increase in frequency centroid and entropy of slow waves in ICP and FV (not ABP). In a multiple linear regression model, RAP at the baseline was the strongest predictor for the decrease in the power of ICP slow waves (p < 0.001)., Conclusion: In severe TBI patients, a sudden mild-moderate hypocapnia induces a decrease in mean ICP and FV, but also in slow waves power of both signals. At the same time, it increases their higher frequency content and their morphological complexity. The difference in power of the ICP slow waves between the baseline and the hypocapnia period depends on the baseline cerebrospinal compensatory reserve as measured by RAP.

We analysed mean arterial blood pressure, cerebral blood flow velocity, oxygenated haemoglobin and deoxygenated haemoglobin signals to estimate dynamic cerebral autoregulation. We compared macrovascular (mean arterial blood pressure-cerebral blood flow velocity) and microvascular (oxygenated haemoglobin-deoxygenated haemoglobin) dynamic cerebral autoregulation estimates during three different conditions: rest, mild hypocapnia and hypercapnia. Microvascular dynamic cerebral autoregulation estimates were created by introducing the constant time lag plus constant phase shift model, which enables correction for transit time, blood flow and blood volume oscillations (TT-BF/BV correction). After TT-BF/BV correction, a significant agreement between mean arterial blood pressure-cerebral blood flow velocity and oxygenated haemoglobin-deoxygenated haemoglobin phase differences in the low frequency band was found during rest (left: intraclass correlation=0.6, median phase difference 29.5° vs. 30.7°, right: intraclass correlation=0.56, median phase difference 32.6° vs. 39.8°) and mild hypocapnia (left: intraclass correlation=0.73, median phase difference 48.6° vs. 43.3°, right: intraclass correlation=0.70, median phase difference 52.1° vs. 61.8°). During hypercapnia, the mean transit time decreased and blood volume oscillations became much more prominent, except for very low frequencies. The transit time related to blood flow oscillations was remarkably stable during all conditions. We conclude that non-invasive microvascular dynamic cerebral autoregulation estimates are similar to macrovascular dynamic cerebral autoregulation estimates, after TT-BF/BV correction is applied. These findings may increase the feasibility of non-invasive continuous autoregulation monitoring and guided therapy in clinical situations.

Background: Cerebral blood flow (CBF) is sensitive to changes in arterial CO2, referred to as cerebral vasomotor reactivity (CVMR). Whether CVMR is altered in patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer disease (AD), is unclear., Objective: To determine whether CVMR is altered in aMCI and is associated with cognitive performance., Methods: Fifty-three aMCI patients aged 55 to 80 and 22 cognitively normal subjects (CN) of similar age, sex, and education underwent measurements of CBF velocity (CBFV) with transcranial Doppler and end-tidal CO2 (EtCO2) with capnography during hypocapnia (hyperventilation) and hypercapnia (rebreathing). Arterial pressure (BP) was measured to calculate cerebrovascular conductance (CVCi) to normalize the effect of changes in BP on CVMR assessment. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and neuropsychological tests focused on memory (Logical Memory, California Verbal Learning Test) and executive function (Delis-Kaplan Executive Function Scale; DKEFS)., Results: At rest, CBFV and MMSE did not differ between groups. CVMR was reduced by 13% in CBFV% and 21% in CVCi% during hypocapnia and increased by 22% in CBFV% and 20% in CVCi% during hypercapnia in aMCI when compared to CN (all p < 0.05). Logical Memory recall scores were positively correlated with hypocapnia (r = 0.283, r = 0.322, p < 0.05) and negatively correlated with hypercapnic CVMR measured in CVCi% (r = -0.347, r = -0.446, p < 0.01). Similar correlations were observed in D-KEFS Trail Making scores., Conclusion: Altered CVMR in aMCI and its associations with cognitive performance suggests the presence of cerebrovascular dysfunction in older adults who have high risks for AD.

Background: Systemic blood flow in patients on extracorporeal assist devices is frequently not or only minimally pulsatile. Loss of pulsatile brain perfusion, however, has been implicated in neurological complications. Furthermore, the adverse effects of absent pulsatility on the cerebral microcirculation are modulated similarly as CO 2 vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO 2 ) that determine cerebral oxygen delivery are not uncommon-especially when CO 2 is eliminated by the respirator as well as via the gas exchanger of an extracorporeal membrane oxygenation machine. We, therefore, investigated whether non-pulsatile flow affects cerebrovascular CO 2 reactivity (CVR) and regional brain oxygenation (rSO 2 )., Methods: In this prospective, single-centre case-control trial, we studied 32 patients undergoing elective cardiac surgery. Blood flow velocity in the middle cerebral artery (MCAv) as well as rSO 2 was determined during step changes of PaCO 2 between 30, 40, and 50 mmHg. Measurements were conducted on cardiopulmonary bypass during non-pulsatile and postoperatively under pulsatile blood flow at comparable test conditions. Corresponding changes of CVR and concomitant rSO 2 alterations were determined for each flow mode. Each patient served as her own control., Results: MCAv was generally lower during hypocapnia than during normocapnia and hypercapnia (p < 0.0001). However, the MCAv/PaCO 2 slope during non-pulsatile flow was 14.4 cm/s/mmHg [CI 11.8-16.9] and 10.4 cm/s/mmHg [CI 7.9-13.0] after return of pulsatility (p = 0.03). During hypocapnia, non-pulsatile CVR (4.3 ± 1.7%/mmHg) was higher than pulsatile CVR (3.1 ± 1.3%/mmHg, p = 0.01). Independent of the flow mode, we observed a decline in rSO2 during hypocapnia and a corresponding rise during hypercapnia (p < 0.0001). However, the relationship between ΔrSO 2 and ΔMCAv was less pronounced during non-pulsatile flow., Conclusions: Non-pulsatile perfusion is associated with enhanced cerebrovascular CVR resulting in greater relative decreases of cerebral blood flow during hypocapnia. Heterogenic microvascular perfusion may account for the attenuated ΔrSO 2 /ΔMCAv slope. Potential hazards related to this altered regulation of cerebral perfusion still need to be assessed., Trial Registration: The study was retrospectively registered on October 30, 2018, with Clinical Trial.gov (NCT03732651).

Objective: Mathematical modeling of cerebral hemodynamics by descriptive equations can estimate the underlying pulsatile component of cerebral arterial blood volume (CaBV). This way, clinical monitoring of changes in cerebral compartmental compliances becomes possible. Our aim is to validate the most adequate method of CaBV estimation in neurocritical care., Approach: We retrospectively reviewed patients with severe traumatic brain injury (TBI) [admitted from 1992-2012] and continuous transcranial Doppler (TCD) monitoring of cerebral blood flow velocity (FV) displaying either plateau waves of intracranial pressure (ICP), episodes of controlled, mild hypocapnia, or vasopressor-induced increases in arterial blood pressure (ABP). Each cohort was analyzed with continuous flow forward (CFF, pulsatile blood inflow and steady blood outflow) or pulsatile flow forward (PFF, both blood inflow and outflow are pulsatile) modeling approaches for estimating the pulse component of CaBV. Spectral pulsatility index (sPI, the first harmonic of the FV pulse/mean FV) can be estimated using the compliance of the vascular bed (Ca) and the cerebrovascular resistance (CVR - here, Ra). We compared three possible methods of assessing Ca (C1: the CFF model, C2 and C3: the PFF models based on ABP or cerebral perfusion pressure (CPP) pulsations, respectively) and combined them with three possible methods of assessing Ra (Ra1= ABP/FV, Ra2= the resistance area product, and Ra3= CPP/FV). Linear regression techniques were applied to describe the strength of each CaBV estimator (a combination of Ca and Ra) against sPI., Main Results: The combination of C1 and Ra3 (PI&#95;C1Ra3) was the superior descriptor of CaBV as approximated by sPI for both the plateau waves and the hypocapnia cohorts (r = 0.915 and r = 0.955, respectively). The combination of C1 and Ra1 (PI&#95;C1Ra1) was nearly as robust in the vasopressors cohort (r = 0.938 and r = 0.931, respectively)., Significance: TCD-based estimation of CaBV pulsations seems to be feasible when employing the CFF modeling approach., (Copyright © 2019 IPEM. Published by Elsevier Ltd. All rights reserved.)

High-altitude ascent imposes a unique cerebrovascular challenge due to two opposing blood gas chemostimuli. Specifically, hypoxia causes cerebral vasodilation, whereas respiratory-induced hypocapnia causes vasoconstriction. The conflicting nature of these two superimposed chemostimuli presents a challenge in quantifying cerebrovascular reactivity (CVR) in chronic hypoxia. During incremental ascent to 4240 m over 7 days in the Nepal Himalaya, we aimed to (a) characterize the relationship between arterial blood gas stimuli and anterior, posterior and global (g)CBF, (b) develop a novel index to quantify cerebral blood flow (CBF) in relation to conflicting steady-state chemostimuli, and (c) assess these relationships with cerebral oxygenation (rSO 2 ). On rest days during ascent, participants underwent supine resting measures at 1045 m (baseline), 3440 m (day 3) and 4240 m (day 7). These measures included pressure of arterial (Pa)CO 2 , PaO 2 , arterial O 2 saturation (SaO 2 ; arterial blood draws), unilateral anterior, posterior and gCBF (duplex ultrasound; internal carotid artery [ICA] and vertebral artery [VA], gCBF [{ICA + VA} × 2], respectively) and rSO 2 (near-infrared spectroscopy). We developed a novel stimulus index (SI), taking into account both chemostimuli (PaCO 2 /SaO 2 ). Subsequently, CBF was indexed against the SI to assess steady-state cerebrovascular responsiveness (SS-CVR). When both competing chemostimuli are taken into account, (a) SS-CVR was significantly higher in ICA, VA and gCBF at 4240 m compared to lower altitudes, (b) delta SS-CVR with ascent (1045 m vs. 4240 m) was higher in ICA vs. VA, suggesting regional differences in CBF regulation, and (c) ICA SS-CVR was strongly and positively correlated (r = 0.79) with rSO 2 at 4240 m.

Background: Hypocapnia is a common alteration during anesthesia in neonates., Aim: To investigate the effects of hypocapnia and hypocapnia combined with hypotension (HCT) on cerebral perfusion and tissue oxygenation in anesthetized piglets., Method: Thirty anesthetized piglets were randomly allocated to groups: moderate hypocapnia (mHC), severe hypocapnia (sHC), and HCT. Cerebral monitoring comprised a tissue oxygen partial pressure and a laser Doppler probe inserted into the brain tissue as well as a near-infrared spectroscopy (NIRS) sensor placed on the skin, measuring regional oxygen saturation. Hypocapnia was induced by hyperventilation (target PaCO 2 mHC: 3.7-4; sHC: 3.1-3.3 kPa) and hypotension by blood withdrawal and nitroprusside infusion (mean blood pressure: 35-38 mm Hg). Data were analyzed at baseline, during (Tr20, Tr40, Tr60) and after (Post20, Post40, Post60) treatment., Results: Compared to baseline, tissue oxygen partial pressure decreased significantly and equally during all treatments (mean [SD] at baseline: mHC 35.7 [32.45]; sHC: 28.1 [20.24]; HCT 25.4 [10.3] and at Tr60: mHC: 29.9 [27.36]; sHC: 22.2 [18.37]; HCT: 18.4 [9.5] mm Hg). Decreased laser Doppler flow was detected with all treatments at Tr20 (mHC: 0.9 [0.18]; sHC: 0.88 [0.15]; HCT: 0.97 [0.13] proportion from baseline). Independently of group, regional oxygen saturation varied only after reverting and not during treatment. Blood lactate, pH, HCO 3 - , and PaO 2 increased during treatment with no differences between groups., Conclusion: This animal model revealed reduced cerebral blood flow and brain tissue oxygenation during hypocapnia without detectable changes in regional oxygen saturation as measured by NIRS. Changes occurred as early as during moderate hypocapnia., (© 2019 John Wiley & Sons Ltd.)

New Findings: What is the central question of this study? What are the independent effects of hypoxia and hypocapnia on cerebral haemodynamics and cognitive function? What is the main finding and its importance? Exposure to hyperventilation-induced hypocapnia causes cognitive impairment in both normoxia and hypoxia. In addition, supplementation of carbon dioxide during hypoxia alleviates the cognitive impairment and reverses hypocapnia-induced vasoconstriction of the cerebrovasculature. These data provide new evidence for the independent effect of hypocapnia on the cognitive impairment associated with hypoxia., Abstract: Hypoxia, which is accompanied by hypocapnia at altitude, is associated with cognitive impairment. This study examined the independent effects of hypoxia and hypocapnia on cognitive function and assessed how changes in cerebral haemodynamics may underpin cognitive performance outcomes. Single reaction time (SRT), five-choice reaction time (CRT) and spatial working memory (SWM) tasks were completed in 20 participants at rest and after 1 h of isocapnic hypoxia (IH, end-tidal oxygen partial pressure ( P ET O 2 ) = 45 mmHg, end-tidal carbon dioxide partial pressure ( P ETC O 2 ) clamped at normal) and poikilocapnic hypoxia (PH, P ET O 2  = 45 mmHg, P ETC O 2 not clamped). A subgroup of 10 participants were also exposed to euoxic hypocapnia (EH, P ET O 2  = 100 mmHg, P ETC O 2 clamped 8 mmHg below normal). Middle cerebral artery velocity (MCAv) and prefrontal cerebral haemodynamics were measured with transcranial Doppler and near infrared spectroscopy, respectively. IH did not affect SRT and CRT performance from rest (566 ± 50 and 594 ± 70 ms), whereas PH (721 ± 51 and 765 ± 48 ms) and EH (718 ± 55 and 755 ± 34 ms) slowed response times (P < 0.001 vs. IH). Performance on the SWM task was not altered by condition. MCAv increased during IH compared to PH (P < 0.05), which was unchanged from rest. EH caused a significant fall in MCAv and prefrontal cerebral oxygenation (P < 0.05 vs. baseline). MCAv was moderately correlated to cognitive performance (R 2  = 0.266-0.289), whereas prefrontal cerebral tissue perfusion and saturation were not (P > 0.05). These findings reveal a role of hyperventilation-induced hypocapnia per se on the development of cognitive impairment during normoxic and hypoxic exposures., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO 2 (EtCO 2 , capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60 s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9 cm s -1 (11.1), old 51.7 (12.9) vs. 37.8 cm s -1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7 mmHg (16.0), old 33.9 (13.5) vs. 39.3 mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09 mmHg cm s -1 (11.07), old 1.16 (0.34) vs. 1.34 mmHg cm s -1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals.

Purpose: Carbon dioxide (CO 2 ) is a potent cerebral vasomotor agent. Despite reduction in CO 2 levels (hypocapnia) being described in several acute diseases, there is no clear data on baseline CO 2 values in acute stroke. The aim of the study was to systematically assess CO 2 levels in acute stroke., Material and Methods: Four online databases, Web of Science, MEDLINE, EMBASE and CENTRAL, were searched for articles that described either partial pressure of arterial CO 2 (PaCO 2 ) and end-tidal CO 2 (EtCO 2 ) in acute stroke., Results: After screening, based on predefined inclusion and exclusion criteria, 20 studies were retained. There were 5 studies in intracerebral hemorrhage and 15 in ischemic stroke, totalling 660 stroke participants. Acute stroke was associated with a significant decrease in CO 2 levels compared to controls. Cerebral haemodynamic studies using transcranial Doppler ultrasonography demonstrated a significant reduction in cerebral blood flow velocities and cerebral autoregulation in acute stroke patients., Conclusion: The evidence from this review suggests that acute stroke patients are significantly more likely than controls to be hypocapnic, supporting the value of routine CO 2 assessment in the acute stroke setting. Further studies are required in order to evaluate the clinical impact of these findings., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Swallow and breathing are highly coordinated behaviors reliant on shared anatomical space and neural pathways. Incremental ascent to high altitudes results in hypoxia/hypocapnic conditions altering respiratory drive, however it is not known whether these changes also alter swallow. We examined the effect of incremental ascent (1045 m, 3440 m and 4371 m) on swallow motor pattern and swallow-breathing coordination in seven healthy adults. Submental surface electromyograms (sEMG) and spirometry were used to evaluate swallow triggered by saliva and water infusion. Swallow-breathing phase preference was different between swallows initiated by saliva versus water. With ascent, saliva swallows changed to a dominate pattern of occurrence during the transition from inspiration to expiration. Additionally, water swallows demonstrated a significant decrease in submental sEMG duration and a shift in submental activity to earlier in the apnea period, especially at 4371 m. Our results suggest that there are changes in swallow-breathing coordination and swallow production that likely increase airway protection with incremental ascent to high altitude. The adaptive changes in swallow were likely due to the exposure to hypoxia and hypocapnia, along with airway irritation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Hyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO 2 ), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD)., Methods: This prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score < 9 at presentation and with ICP monitoring, PbrO 2 , and/or microdialysis (MD) probes during ICU admission within 36 h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50 min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4-4.7 kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate., Results: Eleven patients (64% males, mean age 36 ± 14 years) with an initial median GCS score of 7 (IQR 3-8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO 2 showed a statistically significant reduction but remained within the normal range., Conclusion: Moderate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation., Trial Registration: NCT03822026 . Registered on 30 January 2019.

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 .

The objective of the study was to identify markers of hypocapnic cerebral hypoperfusion (HYCH) in patients with orthostatic intolerance (OI) without tachycardia and without orthostatic hypotension. This single center, retrospective study included OI patients referred for autonomic evaluation with the 10 min tilt test. Heart rate, end-tidal CO2 (ET-CO2), blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery were monitored. HYCH was defined by: (1) Symptoms of OI; (2) Orthostatic hypocapnia (low ET-CO2); (3) Abnormal decline in orthostatic CBFv due to hypocapnia; 4) Absence of tachycardia, orthostatic hypotension, or other causes of low CBFv or hypocapnia. Sixteen subjects met HYCH criteria (15/1 women/men, age 38.5±8.0 years) and were matched by age and gender to postural tachycardia patients (POTS, n = 16) and healthy controls (n = 16). During the tilt, CBFv decreased more in HYCH (-22.4±7.7%, p<0.0001) and POTS (-19.0±10.3%, p<0.0001) compared to controls (-3.0±5.0%). Orthostatic ET-CO2 was lower in HYCH (26.4±4.2 (mmHg), p<0.0001) and POTS (28.6±4.3, p<0.0001) compared to controls (36.9 ± 2.1 mmHg). Orthostatic heart rate was normal in HYCH (89.0±10.9 (BPM), p<0.08) and controls (80.8 ±11.2), but was higher in POTS (123.7±11.2, p<0.0001). Blood pressure was normal and similar in all groups. It is concluded that both HYCH and POTS patients have comparable decrease in CBFv which is due to vasoconstrictive effect of hypocapnia. Blood flow velocity monitoring can provide an objective biomarker for HYCH in OI patients without tachycardia., Competing Interests: The author has declared that no competing interests exist.

The present study examined whether preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease. Among 65 adult patients with ischemic moyamoya disease, 19 had misery perfusion in the precentral region on preoperative 15 O positron emission tomography and underwent arterial bypass surgery for that region. Brain technetium-99 m-labeled ethyl cysteinate dimer single-photon emission computed tomography (SPECT) was preoperatively performed with and without hyperventilation challenge and relative cerebrovascular contractile reactivity to hypocapnia (RCVCR hypocap ) (%/mmHg) was calculated in the precentral region. Development of cerebral hyperperfusion syndrome was determined using perioperative changes of symptoms and brain N-isopropyl-p-[ 123 I]-iodoamphetamine SPECT performed after surgery. RCVCR hypocap was significantly lower in the 6 patients with cerebral hyperperfusion syndrome (-2.85 ± 1.10%/mmHg) than in the 13 patients without cerebral hyperperfusion syndrome (0.18 ± 1.97%/mmHg; p = 0.0050). Multivariate analysis demonstrated low RCVCR hypocap as an independent predictor of cerebral hyperperfusion syndrome (95% confidence interval, 0.04-0.96; p = 0.0433). Preoperatively reduced cerebrovascular contractile reactivity to hypocapnia by hyperventilation is associated with development of cerebral hyperperfusion syndrome after arterial bypass surgery for adult patients with cerebral misery perfusion due to ischemic moyamoya disease.

The purpose of this study was to identify the dose-dependent effects of heat strain and orthostasis [via lower body negative pressure (LBNP)], with and without mild hypohydration, on systemic function and cerebral perfusion. Eleven men (means ± SD: 27 ± 7 y; body mass 77 ± 6 kg), resting supine in a water-perfused suit, underwent progressive passive heating [0.5°C increments in core temperature (T c ; esophageal to +2.0°C)] while euhydrated (EUH) or hypohydrated (HYPO; 1.5-2% body mass deficit). At each thermal state, mean cerebral artery blood velocity (MCAv mean ; transcranial Doppler), partial pressure of end-tidal carbon dioxide ([Formula: see text]), heart rate (HR) and mean arterial blood pressure (MAP; photoplethysmography) were measured continuously during LBNP (0, -15, -30, and -45 mmHg). Four subjects became intolerant before +2.0°C T c , unrelated to hydration status. Without LBNP, decreases in [Formula: see text] accounted fully for reductions in MCAv mean across all T c . With LBNP at heat tolerance (+1.5 or +2.0°C), [Formula: see text] accounted for 69 ± 25% of the change in MCAv mean . The HYPO condition did not affect MCAv mean or any cardiovascular variables during combined LBNP and passive heat stress (all P > 0.13). These findings indicate that hypocapnia accounted fully for the reduction in MCAv mean when passively heat stressed in the absence of LBNP and for two- thirds of the reduction when at heat tolerance combined with LBNP. Furthermore, when elevations in T c are matched, mild hypohydration does not influence cerebrovascular or cardiovascular responses to LBNP, even when stressed by a combination of hyperthermia and LBNP.

Oxygen therapy, usually administered by a facemask or nasal cannulae, is the current default treatment of respiratory failure. Since respiration entails intake of oxygen and release of carbon dioxide from tissues as waste product, the notion of administering carbon dioxide in respiratory failure appears counter-intuitive. However, carbon dioxide stimulates the chemosensitive area of the medulla, known as the central respiratory chemoreceptor, which activates the respiratory groups of neurones in the brainstem and stimulates inspiration thereby initiating oxygen intake during normal breathing. This vital initiation of normal breathing is via a reduction in the pH of the cerebrospinal fluid and the medullary interstitial fluid. We hypothesise that in cases of type I respiratory failure in which the P a CO 2 is low, administration of carbon dioxide by inhalation would stimulate the respiratory groups of brainstem neurones and facilitate breathing, which would be of therapeutic value. Preliminary clinical evidence in favour of this hypothesis is presented and we recommend that a formal randomised study be carried out., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Elevating core temperature at rest causes increases in minute ventilation (V̇e), which lead to reductions in both arterial CO 2 partial pressure (hypocapnia) and cerebral blood flow. We tested the hypothesis that in resting heated humans this hypocapnia diminishes the ventilatory sensitivity to rising core temperature but does not explain a large portion of the decrease in cerebral blood flow. Fourteen healthy men were passively heated using hot-water immersion (41°C) combined with a water-perfused suit, which caused esophageal temperature (T es ) to reach 39°C. During heating in two separate trials, end-tidal CO 2 partial pressure decreased from the level before heating (39.4 ± 2.0 mmHg) to the end of heating (30.5 ± 6.3 mmHg) ( P = 0.005) in the Control trial. This decrease was prevented by breathing CO 2 -enriched air throughout the heating such that end-tidal CO 2 partial pressure did not differ between the beginning (39.8 ± 1.5 mmHg) and end (40.9 ± 2.7 mmHg) of heating ( P = 1.00). The sensitivity to rising T es (i.e., slope of the T es  - V̇ E relation) did not differ between the Control and CO 2 -breathing trials (37.1 ± 43.1 vs. 16.5 ± 11.1 l·min -1 ·°C -1 , P = 0.31). In both trials, middle cerebral artery blood velocity (MCAV) decreased early during heating (all P < 0.01), despite the absence of hyperventilation-induced hypocapnia. CO 2 breathing increased MCAV relative to Control at the end of heating ( P = 0.005) and explained 36.6% of the heat-induced reduction in MCAV. These results indicate that during passive heating at rest ventilatory sensitivity to rising core temperature is not suppressed by hypocapnia and that most of the decrease in cerebral blood flow occurs independently of hypocapnia. NEW & NOTEWORTHY Hyperthermia causes hyperventilation and concomitant hypocapnia and cerebral hypoperfusion. The last may underlie central fatigue. We are the first to demonstrate that hyperthermia-induced hyperventilation is not suppressed by the resultant hypocapnia and that hypocapnia explains only 36% of cerebral hypoperfusion elicited by hyperthermia. These new findings advance our understanding of the mechanisms controlling ventilation and cerebral blood flow during heat stress, which may be useful for developing interventions aimed at preventing central fatigue during hyperthermia.

Objective: Brain arterial critical closing pressure (CrCP) has been studied in several diseases such as traumatic brain injury (TBI), subarachnoid haemorrhage, hydrocephalus, and in various physiological scenarios: intracranial hypertension, decreased cerebral perfusion pressure, hypercapnia, etc. Little or nothing so far has been demonstrated to characterise change in CrCP during mild hypocapnia., Method: We retrospectively analysed recordings of intracranial pressure (ICP), arterial blood pressure (ABP) and blood flow velocity from 27 severe TBI patients (mean 39.5 ± 3.4 years, 6 women) in whom a ventilation increase (20% increase in respiratory minute volume) was performed over 50 min as part of a standard clinical CO 2 reactivity test. CrCP was calculated using the Windkessel model of cerebral arterial flow. Arteriolar wall tension (WT) was calculated as a difference between CrCP and ICP. The compartmental compliances arterial (C a ) and cerebrospinal fluid space (C i ) were also evaluated., Results: During hypocapnia, ICP decreased from 17±6.8 to 13.2±6.6 mmHg (p < 0.000001). Wall tension increased from 14.5 ± 9.9 to 21.7±9.1 mmHg (p < 0.0002). CrCP, being a sum of WT + ICP, changed significantly from 31.5 ± 11.9 mmHg to 34.9±11.1 mmHg (p < 0.002), and the closing margin (ABP-CrCP) remained constant at an average value of 60 mmHg. C a decreased significantly during hypocapnia by 30% (p < 0.00001) and C i increased by 26% (p < 0.003)., Conclusion: During hypocapnia in TBI patients, ICP decreases and WT increases. CrCP increases slightly as the rise in wall tension outweighs the decrease in ICP. The closing margin remained unchanged, suggesting that the risk of hypocapnia-induced ischemia might not be increased.

Central chemoreceptors are highly sensitive neurons that respond to changes in pH and CO2 levels. An increase in CO2/H+ typically reflects a rise in the firing rate of these neurons, which stimulates an increase in ventilation. Here, we present an ionic current model that reproduces the basic electrophysiological activity of individual CO2/H+-sensitive neurons from the locus coeruleus (LC). We used this model to explore chemoreceptor discharge patterns in response to electrical and chemical stimuli. The modeled neurons showed both stimulus-evoked activity and spontaneous activity under physiological parameters. Neuronal responses to electrical and chemical stimulation showed specific firing patterns of spike frequency adaptation, postinhibitory rebound, and post-stimulation recovery. Conversely, the response to chemical stimulation alone (based on physiological CO2/H+ changes), in the absence of external depolarizing stimulation, showed no signs of postinhibitory rebound or post-stimulation recovery, and no depolarizing sag. A sensitivity analysis for the firing-rate response to the different stimuli revealed that the contribution of an applied stimulus current exceeded that of the chemical signals. The firing-rate response increased indefinitely with injected depolarizing current, but reached saturation with chemical stimuli. Our computational model reproduced the regular pacemaker-like spiking pattern, action potential shape, and most of the membrane properties that characterize CO2/H+-sensitive neurons from the locus coeruleus. This validates the model and highlights its potential as a tool for studying the cellular mechanisms underlying the altered central chemosensitivity present in a variety of disorders such as sudden infant death syndrome, depression, and anxiety. In addition, the model results suggest that small external electrical signals play a greater role in determining the chemosensitive response to changes in CO2/H+ than previously thought. This highlights the importance of considering electrical synaptic transmission in studies of intrinsic chemosensitivity.

High-Altitude High Opening (HAHO) is a military operational procedure in which parachute jumps are performed at high altitude requiring supplemental oxygen, putting personnel at risk of acute hypoxia in the event of oxygen equipment failure. This study was initiated by the Norwegian Army to evaluate potential outcomes during failure of oxygen supply, and to explore physiology during acute severe hypobaric hypoxia. A simulated HAHO without supplemental oxygen was carried out in a hypobaric chamber with decompression to 30,000 ft (9,144 m) and then recompression to ground level with a descent rate of 1,000 ft/min (305 m/min). Nine subjects were studied. Repeated arterial blood gas samples were drawn throughout the entire hypoxic exposure. Additionally, pulse oximetry, cerebral oximetry, and hemodynamic variables were monitored. Desaturation evolved rapidly and the arterial oxygen tensions are among the lowest ever reported in volunteers during acute hypoxia. Pa O 2 decreased from baseline 18.4 (17.3-19.1) kPa, 138.0 (133.5-143.3) mmHg, to a minimum value of 3.3 (2.9-3.7) kPa, 24.8 (21.6-27.8) mmHg, after 180 (60-210) s, [median (range)], N = 9. Hyperventilation with ensuing hypocapnia was associated with both increased arterial oxygen saturation and cerebral oximetry values, and potentially improved tolerance to severe hypoxia. One subject had a sharp drop in heart rate and cardiac index and lost consciousness 4 min into the hypoxic exposure. A simulated high-altitude airdrop scenario without supplemental oxygen results in extreme hypoxemia and may result in loss of consciousness in some individuals. NEW & NOTEWORTHY This is the first study to investigate physiology and clinical outcome of oxygen system failure in a simulated HAHO scenario. The acquired knowledge is of great value to make valid risk-benefit analyses during HAHO training or operations. The arterial oxygen tensions reported in this hypobaric chamber study are among the lowest ever reported during acute hypoxia., (Copyright © 2017 the American Physiological Society.)

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.)

Purpose: To investigate the effect of voluntary hypocapnic hyperventilation or moderate hypoxia on metabolic and heart rate responses during high-intensity intermittent exercise., Methods: Ten males performed three 30-s bouts of high-intensity cycling [Ex1 and Ex2: constant-workload at 80% of the power output in the Wingate anaerobic test (WAnT), Ex3: WAnT] interspaced with 4-min recovery periods under normoxic (Control), hypocapnic or hypoxic (2500 m) conditions. Hypocapnia was developed through voluntary hyperventilation for 20 min prior to Ex1 and during each recovery period., Results: End-tidal CO 2 pressure was lower before each exercise in the hypocapnia than control trials. Oxygen uptake ([Formula: see text]) was lower in the hypocapnia than control trials (822 ± 235 vs. 1645 ± 245 mL min -1 ; mean ± SD) during Ex1, but not Ex2 or Ex3, without a between-trial difference in the power output during the exercises. Heart rates (HRs) during Ex1 (127 ± 8 vs. 142 ± 10 beats min -1 ) and subsequent post-exercise recovery periods were lower in the hypocapnia than control trials, without differences during or after Ex2, except at 4 min into the second recovery period. [Formula: see text] did not differ between the control and hypoxia trials throughout., Conclusions: These results suggest that during three 30-s bouts of high-intensity intermittent cycling, (1) hypocapnia reduces the aerobic metabolic rate with a compensatory increase in the anaerobic metabolic rate during the first but not subsequent exercises; (2) HRs during the exercise and post-exercise recovery periods are lowered by hypocapnia, but this effect is diminished with repeated exercise bouts, and (3) moderate hypoxia (2500 m) does not affect the metabolic response during exercise.

The venous-arterial difference in CO 2 (ΔCO 2 ) has been proposed as an index of the adequacy of tissue perfusion in shock states. We hypothesized that the variation in PaCO 2 (hyper- or hypocapnia) could impact ΔCO 2 , partly through microcirculation adaptations. Fifteen healthy males volunteered to participate. For hypocapnia condition (hCO 2 ), the subjects were asked to hyperventilate, while they were asked to breathe a gas mixture containing 8 % CO 2 for hypercapnia condition (HCO 2 ). The 2 conditions were randomly assigned. Blood gases were measured at baseline before each condition, and after 5-7 min of either hCO 2 or HCO 2 condition. Microcirculation was assessed by the muscle reoxygenation slope measured with near infrared spectroscopy following a vascular occlusion test and by skin circulation with in vivo reflectance confocal microscopy. ΔCO 2 was significantly increased with hCO 2 while it tended to decrease with HCO 2 (non-significant). HCO 2 induced a moderate increase of the resaturation slope of NIRS oxygenation. Skin microcirculatory blood flow significantly dropped with hCO 2 , while it remained unchanged with hypercapnia. Our results warrant cautious interpretation of ΔCO 2 as an indicator of tissue perfusion during respiratory alkalosis.

Vasovagal reactions are conventionally understood as resulting from systemic changes in cardiovascular activity; however, there exists a complementary perspective focused on specific changes in cerebral vasoconstriction associated with hyperventilation-induced hypocapnia. The present study investigated the role of cardiovascular and respiratory activity in self-reported pre-syncopal vasovagal reactions to a surgery video in a sample of 49 healthy women. Participants who indicated more previous real-life episodes of dizziness reported experiencing significantly more symptoms in the laboratory consistent with a vasovagal response. They also showed lower total peripheral resistance and higher pre-ejection period in general, suggesting lower sympathetic nervous system activity. Significant decreases in end-tidal carbon dioxide (P ET CO 2 ) occurred during the surgery video among susceptible participants, without significant increases in respiration rate. Further, participants who experienced reductions from the neutral video in P ET CO 2 , systolic blood pressure, or both, reported vasovagal symptoms during the surgery video. The results suggest that patterns of respiration associated with decreases in P ET CO 2 may contribute to vasovagal symptoms reported in non-clinical groups as well as those with blood-injection-injury phobia and are associated with susceptibility to dizziness., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Study Objectives: To determine whether arousals that terminate obstructive events in obstructive sleep apnea (OSA) (1) induce hypocapnia and (2) subsequently reduce genioglossus muscle activity following the return to sleep., Methods: Thirty-one untreated patients with OSA slept instrumented with sleep staging electrodes, nasal mask and pneumotachograph, end-tidal CO2 monitoring, and intramuscular genioglossus electrodes. End-tidal CO2 was monitored, and respiratory arousals were assigned an end-arousal CO2 change value (PETCO2 on the last arousal breath minus each individual's wakefulness PETCO2). This change value, in conjunction with the normal sleep related increase in PETCO2, was used to determine whether arousals induced hypocapnia and whether the end-arousal CO2 change was associated with genioglossus muscle activity on the breaths following the return to sleep., Results: Twenty-four participants provided 1137 usable arousals. Mean ± SD end-arousal CO2 change was -0.2 ± 2.4 mm Hg (below wakefulness) indicating hypocapnia typically developed during arousal. Following the return to sleep, genioglossus muscle activity did not fall below prearousal levels and was elevated for the first two breaths. End-arousal CO2 change and genioglossus muscle activity were negatively associated such that a 1 mm Hg decrease in end-arousal CO2 was associated with an ~2% increase in peak and tonic genioglossus muscle activity on the breaths following the return to sleep., Conclusions: Arousal-induced hypocapnia did not result in reduced dilator muscle activity following return to sleep, and thus hypocapnia may not contribute to further obstructions via this mechanism. Elevated dilator muscle activity postarousal is likely driven by non-CO2-related stimuli., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Little is known about the response of the cerebrovasculature to acute exercise in children and how these responses might differ with adults. Therefore, we compared changes in middle cerebral artery blood velocity (MCAV mean ), end-tidal Pco 2 ([Formula: see text]), blood pressure, and minute ventilation (V̇e) in response to incremental exercise between children and adults. Thirteen children [age: 9 ± 1 (SD) yr] and thirteen sex-matched adults (age: 25 ± 4 yr) completed a maximal exercise test, during which MCAV mean , [Formula: see text], and V̇e were measured continuously. These variables were measured at rest, at exercise intensities specific to individual ventilatory thresholds, and at maximum. Although MCAV mean was higher at rest in children compared with adults, there were smaller increases in children (1-12%) compared with adults (12-25%) at all exercise intensities. There were alterations in [Formula: see text] with exercise intensity in an age-dependent manner [ F (2.5,54.5) = 7.983, P < 0.001; η 2 = 0.266], remaining stable in children with increasing exercise intensity (37-39 mmHg; P > 0.05) until hyperventilation-induced reductions following the respiratory compensation point. In adults, [Formula: see text] increased with exercise intensity (36-45 mmHg, P < 0.05) until the ventilatory threshold. From the ventilatory threshold to maximum, adults showed a greater hyperventilation-induced hypocapnia than children. These findings show that the relative increase in MCAV mean during exercise was attenuated in children compared with adults. There was also a weaker relationship between MCAV mean and [Formula: see text] during exercise in children, suggesting that cerebral perfusion may be regulated by different mechanisms during exercise in the child. NEW & NOTEWORTHY These findings provide the first direct evidence that exercise increases cerebral blood flow in children to a lesser extent than in adults. Changes in end-tidal CO 2 parallel changes in cerebral perfusion in adults but not in children, suggesting age-dependent regulatory mechanisms of cerebral blood flow during exercise., (Copyright © 2017 the American Physiological Society.)

Leigh syndrome (LS) is a neurogenetic disorder of children caused by mutations in at least 75 genes which impair mitochondrial bioenergetics. The changes have typical localization in basal ganglia and brainstem, and typical histological picture of spongiform appearance, vascular proliferation and gliosis. ATP deprivation, free radicals and lactate accumulation are suspected to be the causes. Hypocapnic hypothesis proposed in the paper questions the energy deprivation as the mechanism of LS. We assume that the primary harmful factor is hypocapnia (decrease in pCO 2 ) and respiratory alkalosis (increase in pH) due to hyperventilation, permanent or in response to stress. Inside mitochondria, the pH signal of high pH/low bicarbonate ion (HCO - 3 ) is transmitted by soluble adenyl cyclase (sAC) through cAMP dependent manner. The process can initiate brain lesions (necrosis, apoptosis, hypervascularity) in OXPHOS deficient cells residing at the LS area of the brain. The major message of the article is that it is not the ATP depletion but intracellular alkalization (and/or hyperoxia?) which seem to be the cause of LS. The paper includes suggestions concerning the methodology for further research on the LS mechanism and for therapeutic strategy., (Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.)

Spontaneous ventilation in mammals is driven by automatic brainstem networks that generate the respiratory rhythm and increase ventilation in the presence of increased carbon dioxide production. Hypocapnia decreases the drive to breathe and induces apnea. In humans, this occurs during sleep but not during wakefulness. We hypothesized that hypocapnic breathing would be associated with respiratory-related cortical activity similar to that observed during volitional breathing, inspiratory constraints, or in patients with defective automatic breathing (preinspiratory potentials). Nineteen healthy subjects were studied under passive (mechanical ventilation, n = 10) or active (voluntary hyperventilation, n = 9) profound hypocapnia. Ventilatory and electroencephalographic recordings were performed during voluntary sniff maneuvers, normocapnic breathing, hypocapnia, and after return to normocapnia. EEG recordings were analyzed with respect to the ventilatory flow signal to detect preinspiratory potentials in frontocentral electrodes and to construct time-frequency maps. After passive hyperventilation, hypocapnia was associated with apnea in 3 cases and ventilation persisted in 7 cases (3 and 6 after active hyperventilation, respectively). No respiratory-related EEG activity was observed in subjects with hypocapnia-related apneas. In contrast, preinspiratory potentials were present at vertex recording sites in 12 of the remaining 13 subjects (p < 0.001). This was corroborated by time-frequency maps. This study provides direct evidence of a cortical substrate to hypocapnic breathing in awake humans and fuels the notion of corticosubcortical cooperation to preserve human ventilation in a variety of situations. Of note, maintaining ventilatory activity at low carbon dioxide levels is among the prerequisites to speech production insofar as speech often induces hypocapnia., Significance Statement: Human ventilatory activity persists, during wakefulness, even when hypocapnia makes it unnecessary. This peculiarity of human breathing control is important to speech and speech-breathing insofar as speech induces hypocapnia. This study evidences a specific respiratory-related cortical activity. This suggests that human hypocapnic breathing is driven, at least in part, by cortical mechanisms similar to those involved in volitional breathing, in breathing against mechanical constraints or with weak inspiratory muscle, and in patients with defective medullary breathing pattern generators. This fuels the notion that the human ventilatory drive during wakefulness often results from a corticosubcortical cooperation, and opens new avenues to study certain ventilatory and speech disorders., (Copyright © 2016 the authors 0270-6474/16/3610674-10$15.00/0.)