Effects of Pre-Exercise Voluntary Hyperventilation on Metabolic and Cardiovascular Responses During and After Intense Exercise.

Purpose: We investigated the effects of pre-exercise voluntary hyperventilation and the resultant hypocapnia on metabolic and cardiovascular responses during and after high-intensity exercise. Methods: Ten healthy participants performed a 60-s cycling exercise at a workload of 120% peak oxygen uptake in control (spontaneous breathing), hypocapnia and normocapnia trials. Hypocapnia was induced through 20-min pre-exercise voluntary hyperventilation. In the normocapnia trial, voluntary hyperpnea was performed with CO2 inhalation to prevent hypocapnia. Results: Pre-exercise end-tidal CO2 partial pressure was lower in the hypocapnia trial than the control or normocapnia trial, with similar levels in the control and normocapnia trials. Average V˙O2 during the entire exercise was lower in both the hypocapnia and normocapnia trials than in the control trial (1491 ± 252vs.1662 ± 169vs.1806 ± 149 mL min-1), with the hypocapnia trial exhibiting a greater reduction than the normocapnia trial. Minute ventilation during exercise was lower in the hypocapnia trial than the normocapnia trial. In addition, minute ventilation during the first 10s of the exercise was lower in the normocapnia than the control trial. Pre-exercise hypocapnia also reduced heart rates and arterial blood pressures during the exercise relative to the normocapnia trial, a response that lasted through the subsequent early recovery periods, though end-tidal CO2 partial pressure was similar in the two trials. Conclusions: Our results suggest that pre-exercise hyperpnea and the resultant hypocapnia reduce V˙O2 during high-intensity exercise. Moreover, hypocapnia may contribute to voluntary hyperventilation-mediated cardiovascular responses during the exercise, and this response can persist into the subsequent recovery period, despite the return of arterial CO2 pressure to the normocapnic level.

Cerebrovascular reactivity and cerebral autoregulation are improved in the supine posture compared to upright in healthy men and women.

Cerebrovascular reactivity and cerebral autoregulation are two major mechanisms that regulate cerebral blood flow. Both mechanisms are typically assessed in either supine or seated postures, but the effects of body position and sex differences remain unclear. This study examined the effects of body posture (supine vs. seated vs. standing) on cerebrovascular reactivity during hyper and hypocapnia and on cerebral autoregulation during spontaneous and slow-paced breathing in healthy men and women using transcranial Doppler ultrasonography of the middle cerebral artery. Results indicated significantly improved cerebrovascular reactivity in the supine compared with seated and standing postures (supine = 3.45±0.67, seated = 2.72±0.53, standing = 2.91±0.62%/mmHg, P<0.0167). Similarly, cerebral autoregulatory measures showed significant improvement in the supine posture during slow-paced breathing. Transfer function measures of gain significantly decreased and phase significantly increased in the supine posture compared with seated and standing postures (gain: supine = 1.98±0.56, seated = 2.37±0.53, standing = 2.36±0.71%/mmHg; phase: supine = 59.3±21.7, seated = 39.8±12.5, standing = 36.5±9.7°; all P<0.0167). In contrast, body posture had no effect on cerebral autoregulatory measures during spontaneous breathing. Men and women had similar cerebrovascular reactivity and similar cerebral autoregulation during both spontaneous and slow-paced breathing. These data highlight the importance of making comparisons within the same body position to ensure there is not a confounding effect of posture.

Steady-state cerebral blood flow regulation at altitude: interaction between oxygen and carbon dioxide.

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 (rSO2). 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)CO2, PaO2, arterial O2 saturation (SaO2; arterial blood draws), unilateral anterior, posterior and gCBF (duplex ultrasound; internal carotid artery [ICA] and vertebral artery [VA], gCBF [{ICA + VA} × 2], respectively) and rSO2 (near-infrared spectroscopy). We developed a novel stimulus index (SI), taking into account both chemostimuli (PaCO2/SaO2). 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 rSO2 at 4240 m.

Effects of moderate and severe hypocapnia on intracerebral perfusion and brain tissue oxygenation in piglets.

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 PaCO2 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, HCO3- , and PaO2 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.

Non-pulsatile blood flow is associated with enhanced cerebrovascular carbon dioxide reactivity and an attenuated relationship between cerebral blood flow and regional brain oxygenation.

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 CO2 vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO2) that determine cerebral oxygen delivery are not uncommon-especially when CO2 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 CO2 reactivity (CVR) and regional brain oxygenation (rSO2). 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 rSO2 was determined during step changes of PaCO2 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 rSO2 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/PaCO2 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 ΔrSO2 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 ΔrSO2/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).

Renal reactivity: acid-base compensation during incremental ascent to high altitude.

KEY POINTS: Ascent to high altitude imposes an acid-base challenge in which renal compensation is integral for maintaining pH homeostasis, facilitating acclimatization and helping prevent mountain sicknesses. The time-course and extent of plasticity of this important renal response during incremental ascent to altitude is unclear. We created a novel index that accurately quantifies renal acid-base compensation, which may have laboratory, fieldwork and clinical applications. Using this index, we found that renal compensation increased and plateaued after 5 days of incremental altitude exposure, suggesting plasticity in renal acid-base compensation mechanisms. The time-course and extent of plasticity in renal responsiveness may predict severity of altitude illness or acclimatization at higher or more prolonged stays at altitude. ABSTRACT: Ascent to high altitude, and the associated hypoxic ventilatory response, imposes an acid-base challenge, namely chronic hypocapnia and respiratory alkalosis. The kidneys impart a relative compensatory metabolic acidosis through the elimination of bicarbonate (HCO3- ) in urine. The time-course and extent of plasticity of the renal response during incremental ascent is unclear. We developed an index of renal reactivity (RR), indexing the relative change in arterial bicarbonate concentration ([HCO3- ]a ) (i.e. renal response) against the relative change in arterial pressure of CO2 ( PaCO2 ) (i.e. renal stimulus) during incremental ascent to altitude ( Δ[HCO3-]a/ΔPaCO2 ). We aimed to assess whether: (i) RR magnitude was inversely correlated with relative changes in arterial pH (ΔpHa ) with ascent and (ii) RR increased over time and altitude exposure (i.e. plasticity). During ascent to 5160 m over 10 days in the Nepal Himalaya, arterial blood was drawn from the radial artery for measurement of blood gas/acid-base variables in lowlanders at 1045/1400 m and after 1 night of sleep at 3440 m (day 3), 3820 m (day 5), 4240 m (day 7) and 5160 m (day 10) during ascent. At 3820 m and higher, RR significantly increased and plateaued compared to 3440 m (P < 0.04), suggesting plasticity in renal acid-base compensations. At all altitudes, we observed a strong negative correlation (r ≤ -0.71; P < 0.001) between RR and ΔpHa from baseline. Renal compensation plateaued after 5 days of altitude exposure, despite subsequent exposure to higher altitudes. The time-course, extent of plasticity and plateau in renal responsiveness may predict severity of altitude illness or acclimatization at higher or more prolonged stays at altitude.

The Influence of CO2 on Genioglossus Muscle After-Discharge Following Arousal From Sleep.

Objectives: Ventilatory after-discharge (sustained elevation of ventilation following stimulus removal) occurs during sleep but not when hypocapnia is present. Genioglossus after-discharge also occurs during sleep, but CO2 effects have not been assessed. The relevance is that postarousal after-discharge may protect against upper airway collapse. This study aimed to determine whether arousal elicits genioglossus after-discharge that persists into sleep, and whether it is influenced by CO2. Methods: Twenty-four healthy individuals (6 female) slept with a nasal mask and ventilator. Sleep (EEG, EOG, EMG), ventilation (pneumotachograph), end-tidal CO2 (PETCO2), and intramuscular genioglossus EMG were monitored. NREM eucapnia was determined during 5 minutes on continuous positive airway pressure (4 cmH2O). Inspiratory pressure support was increased until PETCO2 was ≥2 mm Hg below NREM eucapnia. Supplemental CO2 was added to reproduce normocapnia, without changing ventilator settings. Arousals were induced by auditory tones and genioglossus EMG compared during steady-state hypocapnia and normocapnia. Results: Eleven participants (4 female) provided data. Prearousal PETCO2 was less (p < .05) during hypocapnia (40.74 ± 2.37) than normocapnia (43.82 ± 2.89), with differences maintained postarousal. After-discharge, defined as an increase in genioglossus activity above prearousal levels, occurred following the return to sleep. For tonic activity, after-discharge lasted four breaths irrespective of CO2 condition. For peak activity, after-discharge lasted one breath during hypocapnia and 6 breaths during normocapnia. However, when peak activity following the return to sleep was compared between CO2 conditions no individual breath differences were observed. Conclusions: Postarousal genioglossal after-discharge may protect against upper airway collapse during sleep. Steady-state CO2 levels minimally influence postarousal genioglossus after-discharge.

IDH3 mediates apoptosis of alveolar epithelial cells type 2 due to mitochondrial Ca2+ uptake during hypocapnia.

In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.

Effect of Volume Guarantee in Preterm Infants on High-Frequency Oscillatory Ventilation: A Pilot Study.

Objectives Although adding volume guarantee (VG) to conventional ventilation has been a well-established respiratory management for preterm infants, the evidence of VG combined with high-frequency oscillatory ventilation (HFOV) has not been studied well. The aim of this study was to investigate the effect of VG added to HFOV on respiratory and other physiological parameters. Methods We conducted a pilot study in extremely low-birth-weight infants ventilated with HFOV + VG with stable pulmonary status after 28 days of age. VG was applied for 6 hours and removed for the following 6 hours, and data were collected during these 12 hours. Results Six neonates were included in this study (gestational age: 22w5d-23w6d, birthweight: 424-584 g). High-frequency expired tidal volume per weight and amplitude were similar between periods with and without VG. Fluctuation of SpO2, but not heart rate, was significantly smaller when babies were ventilated with VG than without VG. Fluctuation of minute volume and carbon dioxide diffusion coefficient significantly increased after VG removal. The proportion of time with SpO2 < 80% was decreased by VG overall, especially in three cases. Conclusion This pilot study suggests VG combined with HFOV attenuates fluctuation of SpO2 and CO2 clearance, which may prevent hypoxemia and hypocapnia.

Correlation Between Cerebral Autoregulation and Carbon Dioxide Reactivity in Patients with Traumatic Brain Injury.

OBJECTIVE: Cerebral blood flow autoregulation is commonly impaired in patients with traumatic brain injury (TBI). This study was to investigate correlations between cerebral autoregulation and CO2 reactivity in patients with TBI during transient mild hypocapnia. METHODS: Patients with TBI who were on mechanical ventilation were hyperventilated for approximately 60 min. Indices of autoregulation, based on a model of the relationship between arterial blood pressure and blood flow velocity (FV) (ARIabp) and, separately, between cerebral perfusion pressure and FV (ARIcpp), were calculated. Mean flow index (Mx) was also calculated. RESULTS: We investigated 31 consecutive patients. At baseline, median PaCO2 was 5.09 kPa (range 4.30-5.67 kPa); during hyperventilation, median PaCO2 was 4.38 kPa (range 3.72-4.96 kPa). ARI was associated with Mx (ARIabp vs. Mx: r = -0.39, p = 0.04; ARIcpp vs Mx: r = -0.67, p < 0.001). CO2 reactivity showed significant correlation with ARIcpp (r = 0.41, p = 0.04) and Mx (r = -0.37, p = 0.04). ARI after hyperventilation was significantly higher than ARI at baseline (ARIcpp: p = 0.02; ARIabp: p < 0.001). CONCLUSIONS: Cerebral autoregulation seemed to be well linked to CO2 reactivity during transient hyperventilation. ARIcpp had a stronger correlation with CO2 reactivity than ARIabp. ARI indicated improvement of autoregulation during hyperventilation. Cerebral autoregulation indices (ARI, Mx) were associated with each other.

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 : role of carotid body CO2.

We asked if the type of carotid body (CB) chemoreceptor stimulus influenced the ventilatory gain of the central chemoreceptors to CO2 . The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body PCO2 ≈ 22, 41 and 68 mmHg, respectively) on the ventilatory CO2 sensitivity of central chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with PCO2 of 19-75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean central CO2 response slopes were increased 303% for minute ventilation (V̇I)(P ≤ 0.01) and 251% for mean inspiratory flow rate (VT /TI ) (P ≤ 0.05) when the CB was hypercapnic vs. hypocapnic; central CO2 response slopes for tidal volume (VT ), breathing frequency (fb ) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean central CO2 response slopes were also increased 237% for V̇I(P ≤ 0.01) and 249% for VT /TI (P ≤ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body chemoreceptors are driven by a wide range of O2 and/or CO2 .

Regulation of cerebral autoregulation by carbon dioxide.

Cerebral autoregulation describes a mechanism that maintains cerebral blood flow stable despite fluctuating perfusion pressure. Multiple nonperfusion pressure processes also regulate cerebral perfusion. These mechanisms are integrated. The effect of the interplay between carbon dioxide and perfusion pressure on cerebral circulation has not been specifically reviewed. On the basis of the published data and speculation on the aspects that are without supportive data, the authors offer a conceptualization delineating the regulation of cerebral autoregulation by carbon dioxide. The authors conclude that hypercapnia causes the plateau to progressively ascend, a rightward shift of the lower limit, and a leftward shift of the upper limit. Conversely, hypocapnia results in the plateau shifting to lower cerebral blood flows, unremarkable change of the lower limit, and unclear change of the upper limit. It is emphasized that a sound understanding of both the limitations and the dynamic and integrated nature of cerebral autoregulation fosters a safer clinical practice.

Hyperthermia modulates regional differences in cerebral blood flow to changes in CO2.

The purpose of this study was to assess blood flow responses to changes in carbon dioxide (CO2) in the internal carotid artery (ICA), external carotid artery (ECA), and vertebral artery (VA) during normothermic and hyperthermic conditions. Eleven healthy subjects aged 22 ± 2 (SD) yr were exposed to passive whole body heating followed by spontaneous hypocapnic and hypercapnic challenges in normothermic and hyperthermic conditions. Right ICA, ECA, and VA blood flows, as well as left middle cerebral artery (MCA) mean blood velocity (Vmean), were measured. Esophageal temperature was elevated by 1.53 ± 0.09°C before hypocapnic and hypercapnic challenges during heat stress. Whole body heating increased ECA blood flow and cardiac output by 130 ± 78 and 47 ± 26%, respectively (P < 0.001), while blood flow (or velocity) in the ICA, MCA, and VA was reduced by 17 ± 14, 24 ± 18, and 12 ± 7%, respectively (P < 0.001). Regardless of the thermal conditions, ICA and VA blood flows and MCA Vmean were decreased by hypocapnic challenges and increased by hypercapnic challenges. Similar responses in ECA blood flow were observed in hyperthermia but not in normothermia. Heat stress did not alter CO2 reactivity in the MCA and VA. However, CO2 reactivity in the ICA was decreased (3.04 ± 1.17 vs. 2.23 ± 1.03%/mmHg; P = 0.039) but that in the ECA was enhanced (0.45 ± 0.47 vs. 0.95 ± 0.61%/mmHg; P = 0.032). These results indicate that hyperthermia is capable of altering dynamic cerebral blood flow regulation.

Influence of cerebrovascular resistance on the dynamic relationship between blood pressure and cerebral blood flow in humans.

We examined the hypothesis that changes in the cerebrovascular resistance index (CVRi), independent of blood pressure (BP), will influence the dynamic relationship between BP and cerebral blood flow in humans. We altered CVRi with (via controlled hyperventilation) and without [via indomethacin (INDO, 1.2 mg/kg)] changes in PaCO2. Sixteen subjects (12 men, 27 ± 7 yr) were tested on two occasions (INDO and hypocapnia) separated by >48 h. Each test incorporated seated rest (5 min), followed by squat-stand maneuvers to increase BP variability and improve assessment of the pressure-flow dynamics using linear transfer function analysis (TFA). Beat-to-beat BP, middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv), and end-tidal Pco2 were monitored. Dynamic pressure-flow relations were quantified using TFA between BP and MCAv/PCAv in the very low and low frequencies through the driven squat-stand maneuvers at 0.05 and 0.10 Hz. MCAv and PCAv reductions by INDO and hypocapnia were well matched, and CVRi was comparably elevated (P < 0.001). During the squat-stand maneuvers (0.05 and 0.10 Hz), the point estimates of absolute gain were universally reduced, and phase was increased under both conditions. In addition to an absence of regional differences, our findings indicate that alterations in CVRi independent of PaCO2 can alter cerebral pressure-flow dynamics. These findings are consistent with the concept of CVRi being a key factor that should be considered in the correct interpretation of cerebral pressure-flow dynamics as indexed using TFA metrics.

Cerebrovascular and systemic hemodynamic response to carbon dioxide in humans.

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

Transient outwardly rectifying A currents are involved in the firing rate response to altered CO2 in chemosensitive locus coeruleus neurons from neonatal rats.

The effect of hypercapnia on outwardly rectifying currents was examined in locus coeruleus (LC) neurons in slices from neonatal rats [postnatal day 3 (P3)-P15]. Two outwardly rectifying currents [4-aminopyridine (4-AP)-sensitive transient current and tetraethyl ammonium (TEA)-sensitive sustained current] were found in LC neurons. 4-AP induced a membrane depolarization of 3.6 ± 0.6 mV (n = 4), while TEA induced a smaller membrane depolarization of 1.2 ± 0.3 mV (n = 4). Hypercapnic acidosis (HA) inhibited both currents. The maximal amplitude of the TEA-sensitive current was reduced by 52.1 ± 4.5% (n = 5) in 15% CO2 [extracellular pH (pHo) 7.00, intracellular pH (pHi) 6.96]. The maximal amplitude of the 4-AP-sensitive current was reduced by 34.5 ± 3.0% (n = 6) in 15% CO2 (pHo 7.00, pHi 6.96), by 29.4 ± 6.8% (n = 6) in 10% CO2 (pHo 7.15, pHi 7.14), and increased by 29.0 ± 6.4% (n = 6) in 2.5% CO2 (pHo 7.75, pHi 7.35). 4-AP completely blocked hypercapnia-induced increased firing rate, but TEA did not affect it. When LC neurons were exposed to HA with either pHo or pHi constant, the 4-AP-sensitive current was inhibited. The data show that the 4-AP-sensitive current (likely an A current) is inhibited by decreases in either pHo or pHi. The change of the A current by various levels of CO2 is correlated with the change in firing rate induced by CO2, implicating the 4-AP-sensitive current in chemosensitive signaling in LC neurons.

Normalizing CO2 in chronic hyperventilation by means of a novel breathing mask: a pilot study.

INTRODUCTION: Chronic idiopathic hyperventilation (CIH) is a form of dysfunctional breathing that has proven hard to treat effectively. OBJECTIVES: To perform a preliminary test of the hypothesis that by periodically inducing normocapnia over several weeks, it would be possible to raise the normal resting level of CO2 and achieve a reduction of symptoms. METHODS: Six CIH patients were treated 2 h a day for 4 weeks with a novel breathing mask. The mask was used to induce normocapnia in these chronically hypocapnic patients. Capillary blood gases and acid/base parameters [capillary CO2 tension (PcapCO2 ), pH, and standard base excess (SBE)] were measured at baseline and once each week at least 3 h after mask use, as well as spirometric values, breath-holding tolerance and hyperventilation symptoms as per the Nijmegen Questionnaire (NQ). RESULTS: The mask treatment resulted in a significant increase of resting PcapCO2 (+0.45 kPa, P = 0.028), a moderate increase in SBE (+1.4 mEq/L, P = 0.035) and a small reduction in daily symptoms (-3.8 NQ units, P = 0.046). The effect was most pronounced in the first 2 weeks of treatment. CONCLUSION: By inducing normocapnia with the breathing mask 2 h a day for 4 weeks, the normal resting CO2 and acid/base levels in chronically hyperventilating patients were partially corrected, and symptoms were reduced.

Influence of sympathoexcitation at high altitude on cerebrovascular function and ventilatory control in humans.

We sought to determine the influence of sympathoexcitation on dynamic cerebral autoregulation (CA), cerebrovascular reactivity, and ventilatory control in humans at high altitude (HA). At sea level (SL) and following 3-10 days at HA (5,050 m), we measured arterial blood gases, ventilation, arterial pressure, and middle cerebral blood velocity (MCAv) before and after combined α- and ß-adrenergic blockade. Dynamic CA was quantified using transfer function analysis. Cerebrovascular reactivity was assessed using hypocapnia and hyperoxic hypercapnia. Ventilatory control was assessed from the hypercapnia and during isocapnic hypoxia. Arterial Pco(2) and ventilation and its control were unaltered following blockade at both SL and HA. At HA, mean arterial pressure (MAP) was elevated (P < 0.01 vs. SL), but MCAv remained unchanged. Blockade reduced MAP more at HA than at SL (26 vs. 15%, P = 0.048). At HA, gain and coherence in the very-low-frequency (VLF) range (0.02-0.07 Hz) increased, and phase lead was reduced (all P < 0.05 vs. SL). Following blockade at SL, coherence was unchanged, whereas VLF phase lead was reduced (-40 ± 23%; P < 0.01). In contrast, blockade at HA reduced low-frequency coherence (-26 ± 20%; P = 0.01 vs. baseline) and elevated VLF phase lead (by 177 ± 238%; P < 0.01 vs. baseline), fully restoring these parameters back to SL values. Irrespective of this elevation in VLF gain at HA (P < 0.01), blockade increased it comparably at SL and HA (∼43-68%; P < 0.01). Despite elevations in MCAv reactivity to hypercapnia at HA, blockade reduced (P < 0.05) it comparably at SL and HA, effects we attributed to the hypotension and/or abolition of the hypercapnic-induced increase in MAP. With the exception of dynamic CA, we provide evidence of a redundant role of sympathetic nerve activity as a direct mechanism underlying changes in cerebrovascular reactivity and ventilatory control following partial acclimatization to HA. These findings have implications for our understanding of CBF function in the context of pathologies associated with sympathoexcitation and hypoxemia.

Arterial carbon dioxide partial pressure influences CYP4A distribution in the rat brain.

PaCO(2) is an important factor in the regulation of cerebral circulation, and it is often used to reduce intracranial pressure through hyperventilation during neurosurgery. Changes in concentration can cause changes in CBF (cerebral blood flow). 20-HETE is a product of CYP4A-mediated AA (arachidonic acid) metabolism and is a powerful endogenous vasoconstrictor; however, its effect on cerebral vasoconstriction in cats, dogs and rats remains to be confirmed. It is known that changes in PaCO(2) can influence the expression of CYP4A in the rat brain, demonstrating the important role of 20-HETE in the mechanism of CO(2)-mediated cerebrovascular reactivity. Thirty healthy adult male Wistar rats that weighed between 200 g and 250 g were randomly divided into three groups (A, B, and C; n=10): group A, normocapnia (PaCO(2) was maintained at approximately 40-45 mmHg); group B, hypocapnia (PaCO(2) was maintained at approximately 20-25 mmHg); and group C, hypercapnia (PaCO(2) was maintained at approximately 60-65 mmHg). Physiological parameters, including HR (heart rate), MBP(mean blood pressure), PH and PaCO(2) were recorded every 30 min, and there were no significant hemodynamic or body temperature differences. The head was removed after 3.5 h to investigate brain CYP4A by immunohistochemistry. Relative to group A, group B exhibited the following changes: an increased pH, decreased PaCO(2), and increased brain CYP4A protein expression (P<0.05). In contrast, group C exhibited decreased PH, increased PaCO(2) and decreased CYP4A protein expression (P<0.05). CO(2) can decrease the expression of brain CYP4A during hypercapnia and increase its expression during hypocapnia.

Dynamic cerebral autoregulation assessed by respiratory manoeuvres in non-insulin-treated Type 2 diabetes mellitus.

AIMS: This study investigated dynamic cerebral autoregulation in Type 2 diabetes, where dynamic cerebral autoregulation may be impaired as a consequence of microvascular changes and/or autonomic neuropathy. METHODS: Eleven healthy control subjects and 11 age- and sex-matched patients with Type 2 diabetes controlled with lifestyle modifications or oral anti-diabetes treatment were recruited. Dynamic cerebral autoregulation was calculated by the autoregressive moving average autoregulatory index from a continuous blood pressure and R-R interval (time between each ventricular systole) recording. End-tidal carbon dioxide was also monitored and changes in response to breath holding and hyperventilation as a metabolic stimulus were measured. RESULTS: No significant differences were seen in cerebral blood flow velocity at baseline, or in response to breath holding between people with diabetes and control subjects, although the cerebral blood flow velocity response associated with hyperventilation was significantly reduced in the diabetes group. No significant differences in dynamic cerebral autoregulation were seen at baseline or in response to respiratory manoeuvres between the groups. CONCLUSIONS: Dynamic cerebral autoregulation is not impaired in patients with Type 2 diabetes, although a small difference could not be excluded as the study was only powered to detect an autoregulatory index difference > 2 units. Further study in a larger population with a spectrum of disease severity may reveal clinically important differences.