Subjects Breathed Room Air Research Articles

Breathing 5% carbon dioxide for 1 minute increases cerebral blood flow during lower body negative pressure

Objective: Lower body negative pressure (LBNP) is an established surrogate of hypergravity to investigate responses to central hypovolemia, including the reduction in cerebral blood flow. Increased inspired carbon dioxide (CO2) causes cerebrovascular dilation and increases cerebral blood flow. We aimed to determine whether breathing 5% CO2 for 1 minute increased cerebral blood flow during LBNP. We hypothesized 5% inspired CO2 would increase cerebral blood flow during LBNP. Methods: We collected data from 15 (9 M/6 F, 31±8 yr, 25.6±3.2 kg/m2) healthy individuals. Subjects breathed room air or a mix of 5% CO2, 21% oxygen, balance nitrogen gas for 1 minute prior to initiation of 2 minutes of -60 mmHg LBNP and throughout the duration of LBNP. We allowed a 2-minute wash-out between trials. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound and continuous, non-invasive blood pressure (MAP) with a finger plethysmograph. We corrected MCAv for MAP and present it as cerebrovascular conductance index (CVCi). We also measure ventilation and gas exchange with a pneumotachometer and gas analyzer. Results: All measured variables were similar prior to the initiation of room air and 5% CO2 prebreathe ( p > 0.05). Inspired (1±1 vs. 36±1 mmHg) and end-tidal (38±4 vs. 47±3 mmHg) CO2 were greater during the 5% inspired CO2 trial ( p < 0.05, main effect of gas). LBNP caused an increase in heart rate, decrease in stroke volume, decrease in cardiac output, and an increase in total peripheral resistance ( p < 0.05, main effect of LBNP). These variables were similar regardless of inspiratory gas. MCAv (40±16 vs. 53±19 cm/s), MAP (94±10 vs. 99±11 mmHg), and CVCi (0.46±0.22 vs 0.56±0.24 cm/s/mmHg) were all greater during the 5% inspired CO2 trials ( p < 0.05, main effect of gas). Discussion: Breathing a mixture of 5% CO2 for 1 minute increased cerebral blood flow and blood pressure during a mimic of hypergravity stress. Despite technical challenges of integration into high-performance aircraft, increasing inspired CO2 could contribute to better tolerance to hypergravity stress. Funding was provided by the Air Force Offce of Scientific Research and King’s College London. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Hyperoxia on Coronary Circulation in Patients with Peripheral Artery Diseases (PAD)

It is well‐known that hyperoxia evokes different effects in patients with different dieaseas conditions. Studies from this lab and others have shown that hyperoxia is a potent coronary vasoconstrictor. Recently, we found that hyperoxia exaggerates systolic blood pressure (BP) response in patients with PAD. The aim of this study is to characterize the coronary circulatory effects of hyperoxia in PAD patients and healthy controls. We recruited 20 PAD patients (14M, 6F, 66 ± 6yrs), and 16 age‐matched control subjects (10M, 6F, 65 ± 8yrs). The ankle‐brachial pressure index (ABI) in the most affected limbs of the patients was 0.58 ± 0.15, compared to the controls ABI of 1.04 ± 0.09. For the hyperoxia procedure the subjects breathed room air for three minutes and 100% oxygen for five minutes. BP and heart rate (HR) were monitored during baseline and hyperoxia. The rate pressure product (RPP), an index of myocardial oxygen consumption, was calculated as the product of systolic BP and HR. Transthoracic Coronary Echocardiography was used to record early and late peak coronary blood flow velocities (CBV1 and CBV2) in the left anterior descending artery. Early and late coronary vascular conductances (peak coronary blood velocity/diastolic blood pressure, CVC1 and CVC2) and coronary perfusion time fraction (CPTF, coronary perfusion time/R‐R interval) were calculated. All data was compared across time and between groups using Repeated Measures Analyses of Variance (RMANOVA).ResultsAt the baseline, RPP and coronary parameters (CBV2, CVC1, and CVC2) were higher in the PAD group compared to controls, also the PAD group showed significantly shorter CPTF. During hyperoxia, CBV1, CBV2, CVC1, and CVC2 decreased to varying degrees in both groups. However, no significant interactions were observed for RPP and all coronary parameters during hyperoxia between the groups (Table). Our findings suggest that the effect of hyperoxia on coronary circulation was not significantly different between PAD and healthy controls.

Dexmedetomidine-Tiletamine-Zolazepam Followed by Inhalant Anesthesia in Spectacled Bears (Tremarctos ornatus)

Background: The spectacled bear (Tremarctos ornatus) is the only bear species inhabiting South America and is classified as vulnerable according to the International Union for Conservation of Nature (IUCN) Red List. Among the few publications on the use of general anesthesia and advanced monitoring of ursids in veterinary hospital settings, little is described regarding chemical restraint, general anesthesia and monitoring of spectacled bears. This case series describes the use of a dexmedetomidine-tiletamine-zolazepam chemical restraint combination and its effects on cardiorespiratory variables and arterial blood gases observed in two spectacled bears submitted to isoflurane anesthesia for imaging and/or surgical procedures.Cases: Two female, one adult and one senile, all-term captive spectacled bears were referred to the Veterinary Medical Teaching Hospital at the Universidade Estadual Paulista - Unesp, Botucatu campus, both with a presumable history of recent trauma. After immobilization with an intramuscular (IM) administration of tiletamine-zolazepam (3.8 - 4.3 mg/kg) and dexmedetomidine (6.4 - 7.6 µg/kg), anesthesia induction was achieved by means of intravenous (IV) propofol (1 - 2 mg/kg). The patients then underwent isoflurane inhalant anesthesia and were submitted to intermittent positive-pressure ventilation through the remainder of the procedures. Initial settings of inspiratory flow rate were adjusted to obtain Ppeak of 10 cmH2O and tidal volumes (Vt) of 10 mL/kg, as well as respiratory rates (ƒR)and inspiration-to-expiration (I:E) ratio of 10 breaths/min and 1:2, respectively, and were then adjusted throughout anesthesia to maintain normocapnia (end-tidal carbon dioxide concentrations between35 and 45 mmHg). One of the individuals was chemically restrained (6.4 mg/kg of tiletamine-zolazepam and 7.7 µg/kg of dexmedetomidine) on a second anesthetic event for imaging procedures. Arterial blood gas analysis were performed with the subjects breathing room air and oxygen-enriched air. Both animals exhibited severe hypoxemia (partial pressure of oxygen [PaO2] < 60 mmHg) while breathing room air (inspired oxygen fraction [FiO2] ≅ 0.21). An impaired blood oxygenation (PaO2/FiO2 < 400) was still observed despite mechanical ventilation and the provision of 1.0 FiO2. Alveolar recruitment maneuvers (3 sequential mechanical sights with peak airway pressure at 20 - 30 cmH2O during 15 - 30 s each) were then performed, which resulted in improved PaO2/FiO2 ratios. All other blood gas, electrolytes and acid-base variables did not appear to be importantly altered by chemical restraint and general anesthesia.Discussion: Dexmedetomidine-tiletamine-zolazepam resulted in reliable chemical restraints and is a feasible option for immobilizing spectacled bears, though severe hypoxemia may proceed. Hypoxemia is the most commonly described complication in bear anesthesia, and was also evidenced in the current report. However, low PaO2/FiO2 ratios tend to be accompanied by hypercapnia and therefore counteracted by oxygen supplementation in bears, which was not observed in the present report. In fact, blood oxygenation only reached regular values after alveolar recruitment maneuvers, which is compatible to an atelectasis-related hypoxemia. Therefore, either inhalant anesthesia or field chemical restraint should be accompanied by advanced monitoring (cardiorespiratory variables and blood gas analysis) in until further studies address the management of hypoxemia in spectacled bear. since Advanced monitoring was of major importance for a safe outcome and an uneventful recovery in this species.Keywords: balanced anesthesia, dexmedetomidine, general anesthesia, spectacled bear, Tremarctos ornatus, wildlife.

Renal and segmental artery hemodynamic response to acute, mild hypercapnia

Profound increases (>15 mmHg) in arterial carbon dioxide (i.e., hypercapnia) reduce renal blood flow. However, a relatively brief and mild hypercapnia can occur in patients with sleep apnea or in those receiving supplemental oxygen therapy during an acute exacerbation of chronic obstructive pulmonary disease. We tested the hypothesis that a brief, mild hypercapnic exposure increases vascular resistance in the renal and segmental arteries. Blood velocity in 14 healthy adults (26 ± 4 yr; 7 women, 7 men) was measured in the renal and segmental arteries with Doppler ultrasound while subjects breathed room air (Air) and while they breathed a 3% CO2, 21% O2, 76% N2 gas mixture for 5 min (CO2). The end-tidal partial pressure of CO2 ([Formula: see text]) was measured via capnography. Mean arterial pressure (MAP) was measured beat to beat via the Penaz method. Vascular resistance in the renal and segmental arteries was calculated as MAP divided by blood velocity. [Formula: see text] increased with CO2 (Air: 45 ± 3, CO2: 48 ± 3 mmHg, P < 0.01), but there were no changes in MAP (P = 0.77). CO2 decreased blood velocity in the renal (Air: 35.2 ± 8.1, CO2: 32.2 ± 7.3 cm/s, P < 0.01) and segmental (Air: 24.2 ± 5.1, CO2: 21.8 ± 4.2 cm/s, P < 0.01) arteries and increased vascular resistance in the renal (Air: 2.7 ± 0.9, CO2: 3.0 ± 0.9 mmHg·cm-1·s, P < 0.01) and segmental (Air: 3.9 ± 1.0, CO2: 4.4 ± 1.0 mmHg·cm-1·s, P < 0.01) arteries. These data provide evidence that the kidneys are hemodynamically responsive to a mild and acute hypercapnic stimulus in healthy humans.

AltitudeOmics: Baroreflex Sensitivity During Acclimatization to 5,260 m.

Introduction: Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Little is known concerning the adaptive responses of BRS during acclimatization to high altitude at rest and during exercise.Methods: Twenty-one healthy sea-level residents were tested near sea level (SL, 130 m), the 1st (ALT1) and 16th day (ALT16) at 5,260 m using radial artery catheterization. BRS was calculated using the sequence method (direct interpretation of causal link between BP and heartrate). At rest, subjects breathed a hyperoxic mixture (250 mmHg O2, end tidal) to isolate the preponderance of CO2 chemoreceptors. End-tidal CO2 varied from 20 to 50 mmHg to assess peripheral chemoreflex. Rebreathing provoked incremental increase in CO2, increasing BP to assess baroreflex. During incremental cycling exercise to exhaustion, subjects breathed room air.Results: Resting BRS decreased in ALT1 which was exacerbated in ALT16. This decrease in ALT1 was reversible upon additional inspired CO2, but not in ALT16. BRS decrease during exercise was greater and occurred at lower workloads in ALT1 compared to SL. At ALT16, this decrease returned toward SL values.Discussion/Conclusion: This study is the first to report attenuated BRS in acute hypoxia, exacerbated in chronic hypoxia. In ALT1, hypocapnia triggered BRS reduction whilst in ALT16 resetting of chemoreceptor triggered BRS reduction. The exercise BRS resetting was impaired in ALT1 but normalized in ALT16. These BRS decreases indicate decreased control of BP and may explain deteriorations of cardiovascular status during exposure to high altitude.

Bubble and macroaggregate methods differ in detection of blood flow through intrapulmonary arteriovenous anastomoses in upright and supine hypoxia in humans

Blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) increases in healthy humans breathing hypoxic gas and is potentially dependent on body position. Previous work in subjects breathing room air has shown an effect of body position when Q̇IPAVA is detected with transthoracic saline contrast echocardiography (TTSCE). However, the potential effect of body position on Q̇IPAVA has not been investigated when subjects are breathing hypoxic gas or with a technique capable of quantifying Q̇IPAVA. Thus the purpose of this study was to quantify the effect of body position on Q̇IPAVA when breathing normoxic and hypoxic gas at rest. We studied Q̇IPAVA with TTSCE and quantified Q̇IPAVA with filtered technetium-99m-labeled macroaggregates of albumin (99mTc-MAA) in seven healthy men breathing normoxic and hypoxic (12% O2) gas at rest while supine and upright. On the basis of previous work using TTSCE, we hypothesized that the quantified Q̇IPAVA would be greatest with hypoxia in the supine position. We found that Q̇IPAVA quantified with 99mTc-MAA significantly increased while subjects breathed hypoxic gas in both supine and upright body positions (ΔQ̇IPAVA = 0.7 ± 0.4 vs. 2.5 ± 1.1% of cardiac output, respectively). Q̇IPAVA detected with TTSCE increased from normoxia in supine hypoxia but not in upright hypoxia (median hypoxia bubble score of 2 vs. 0, respectively). Surprisingly, Q̇IPAVA magnitude was greatest in upright hypoxia, when Q̇IPAVA was undetectable with TTSCE. These findings suggest that the relationship between TTSCE and 99mTc-MAA is more complex than previously appreciated, perhaps because of the different physical properties of bubbles and MAA in solution. NEW & NOTEWORTHY Using saline contrast bubbles and radiolabeled macroaggregrates (MAA), we detected and quantified, respectively, hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) in supine and upright body positions in healthy men. Upright hypoxia resulted in the largest magnitude of Q̇IPAVA quantified with MAA but the lowest Q̇IPAVA detected with saline contrast bubbles. These surprising results suggest that the differences in physical properties between saline contrast bubbles and MAA in blood may affect their behavior in vivo.

Breath-hold and free-breathing 2D phase-contrast MRI for quantification of oxygen-induced changes of pulmonary circulation dynamics in healthy volunteers.

To evaluate the effect of inhaled 100% oxygen on pulmonary circulation dynamics in healthy volunteers using 2D phase-contrast magnetic resonance imaging (2D PC MRI). Twenty-one healthy volunteers were examined at 1.5T. Through-plane 2D PC MRI measurements were performed in the main pulmonary artery during free-breathing and breath-hold. Acceleration time and volume, maximum and minimum area, area change, average and maximum mean velocity, forward volume, heart rate, as well as blood pressure were determined. At baseline, subjects breathed room air. After application of a closed-fit full face mask, three further measurements were conducted: at room air (control), directly after starting 15 L/min 100% oxygen (wash-in), and after 5 minutes during continuous oxygen supply (saturation). Data were analyzed with a mixed linear model. Skewed distributed variables were rank-transformed. Tukey contrasts with family-wise adjusted P-values were applied for pairwise comparisons. Inhaled oxygen affected several hemodynamic parameters. Average mean velocity (P < 0.01: breath-hold during wash-in and saturation, P = 0.03: free-breathing during saturation) and maximum mean velocity (P < 0.01: breath-hold and free-breathing during saturation) decreased. When obtained during free-breathing, acceleration volume (P = 0.02: saturation), area change (P = 0.02: saturation), and maximum area (P = 0.02: wash-in, P = 0.03: saturation) increased, while minimum area and forward volume did not change. Oxygen alters pulmonary circulation dynamics in the main pulmonary artery of healthy volunteers, which can be reliably detected using 2D phase-contrast MRI. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1698-1706.

The Impact of Nitrate Supplementation on the Peripheral Chemoreceptor Reflex to Hypoxia in Older Adults

Peripheral chemoreceptors located within the carotid bodies activate cardiorespiratory reflexes in response to hypoxia. Carotid body chemoreceptor activity has been shown to be enhanced in conditions such as congestive heart failure, hypertension, and possibly aging. Nitric oxide (NO) has been proposed as an inhibitory modulator of carotid body chemosensitivity in response to hypoxia. Additionally, NO bioavailability is often reduced with cardiovascular risk factors such as aging. In the present study, we tested the hypothesis that increasing NO bioavailability via dietary nitrate (NO3) supplementation would reduce cardiorespiratory responses to hypoxia in older adults. A double‐blind, randomized, placebo‐controlled, cross‐over study design was used to evaluate minute ventilation (VE) and heart rate (HR) responses to acute hypoxia in 7 older adults (66±2 years; 5M/2F) before and after 4 weeks of NO3 supplementation (beetroot powder) and placebo (beetroot powder devoid of NO3). On each study visit, subjects underwent two separate isocapnic hypoxic tests (self‐regulating, partial rebreathing system with 10% O2). Subjects remained on 10% O2 until SpO2 reached ≤80%. The hypoxic exposures were separated by a 15‐minute washout period with the subjects breathing room air. VE, HR, and SpO2 were continuously monitored throughout each hypoxic exposure. Data were grouped together using a 7‐breath average with the slope of the linear regression line for each dependent variable (VE and HR) versus SpO2 serving as a measure of peripheral chemosensitivity. The slopes for the two hypoxia tests on each study visit were averaged and used for statistical comparisons. On study day one (true baseline) acute hypoxia increased both VE and HR (P&lt;0.05 for both). Four weeks of NO3 supplementation reduced the hypoxic ventilatory response (−0.16 ± −0.05 vs. −0.06 ± −0.03 L/minute/%SpO2, P&lt;0.05), whereas no change was observed following the placebo phase of the study (−0.14 ± −0.07 vs. −0.14 ± −0.08 L/minute/%SpO2, P=0.67). Additionally, the heart rate responses to acute hypoxia were also reduced following NO3 supplementation (−0.49 ± −0.08 vs. −0.30 ± −0.05 beats/minute/%SpO2, P&lt;0.05), but not with placebo (−0.54 ± −0.11 vs. −0.45 ± −0.08 beats/minute/%SpO2, P=0.21). Our preliminary findings suggest that supplementation of NO3 to boost NO bioavailability in older adults blunts the cardiorespiratory responses to hypoxia. Future studies should examine the therapeutic potential of NO3 in patient populations exhibiting exaggerated peripheral chemosensitivity.Support or Funding InformationResearch supported by Neogenis Inc.

Decreased arterial PO2, not O2 content, increases blood flow through intrapulmonary arteriovenous anastomoses at rest.

The mechanism(s) that regulate hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) are currently unknown. Our previous work has demonstrated that the mechanism of hypoxia-induced QIPAVA is not simply increased cardiac output, pulmonary artery systolic pressure or sympathetic nervous system activity and, instead, it may be a result of hypoxaemia directly. To determine whether it is reduced arterial PO2 (PaO2) or O2 content (CaO2) that causes hypoxia-induced QIPAVA , individuals were instructed to breathe room air and three levels of hypoxic gas at rest before (control) and after CaO2 was reduced by 10% by lowering the haemoglobin concentration (isovolaemic haemodilution; Low [Hb]). QIPAVA , assessed by transthoracic saline contrast echocardiography, significantly increased as PaO2 decreased and, despite reduced CaO2 (via isovolaemic haemodilution), was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA , although where and how this is detected remains unknown. Alveolar hypoxia causes increased blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) in healthy humans at rest. However, it is unknown whether the stimulus regulating hypoxia-induced QIPAVA is decreased arterial PO2 (PaO2) or O2 content (CaO2). CaO2 is known to regulate blood flow in the systemic circulation and it is suggested that IPAVA may be regulated similar to the systemic vasculature. Thus, we hypothesized that reduced CaO2 would be the stimulus for hypoxia-induced QIPAVA . Blood volume (BV) was measured using the optimized carbon monoxide rebreathing method in 10 individuals. Less than 5days later, subjects breathed room air, as well as 18%, 14% and 12.5% O2 , for 30min each, in a randomized order, before (CON) and after isovolaemic haemodilution (10% of BV withdrawn and replaced with an equal volume of 5% human serum albumin-saline mixture) to reduce [Hb] (Low [Hb]). PaO2 was measured at the end of each condition and QIPAVA was assessed using transthoracic saline contrast echocardiography. [Hb] was reduced from 14.2±0.8 to 12.8±0.7gdl(-1) (10±2% reduction) from CON to Low [Hb] conditions. PaO2 was no different between CON and Low [Hb], although CaO2 was 10.4%, 9.2% and 9.8% lower at 18%, 14% and 12.5% O2 , respectively. QIPAVA significantly increased as PaO2 decreased and, despite reduced CaO2, was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA . Whether the low PO2 is detected at the carotid body, airway and/or the vasculature remains unknown.

Oxygen requirement to reverse altitude-induced hypoxemia with continuous flow and pulsed dose oxygen.

Hypoxemia secondary to reduced barometric pressure is a complication of ascent to altitude. We designed a study to compare the reversal of hypobaric hypoxemia at 14,000 ft with continuous flow oxygen from a cylinder and pulsed dose oxygen from a portable concentrator. There were 30 healthy volunteers who were randomized to one of three study groups, placed in an altitude chamber, and ascended to 14,000 ft. There were 10 subjects in each study group. Subjects breathed room air for 10 min to induce hypoxemia. Oxygen was then delivered via a nasal cannula from a cylinder at 1, 2, or 3 lpm of continuous flow for 10 min. The subjects again breathed room air at altitude for 10 min and were then placed on pulsed dose oxygen and titrated to obtain the continuous flow Spo2 equivalent. Spo2, Etco2, RR, HR, Hgb, and tissue oxygenation (Sto2) were continuously recorded. The 1-lpm group's Spo2 range was 89-99%. The 2-lpm group's Spo2 range was 95-98%, and the 3-lpm group's Spo2 range was 95-99%. The 2-lpm and 3-lpm flows were able to correct hypoxemia in every subject. The mean pulsed dose required to achieve an equivalent Spo2 ranged from 36.8 ml ± 18.9 ml in the 1-lpm arm, and 102.4 ml ± 53.8 in the 3-lpm arm. Portable oxygen concentrators using pulsed dose technology corrected hypoxemia in every subject. Oxygen concentrators may be an alternative to liquid oxygen or cylinders for use during aeromedical evacuation.

Assessment of Short-Term Changes in Optic Nerve Head Hemodynamics in Hyperoxic Conditions with Laser Speckle Flowgraphy

Purpose: To evaluate laser speckle flowgraphy (LSFG) measurements of the optic nerve head (ONH) blood flow (BF) response to hyperoxia.Methods: This prospective study included 30 eyes of 30 healthy volunteers (mean age: 28.5 ± 4.0, male:female = 13:17). The testing protocol had three phases: in the baseline phase, subjects breathed room air; in the hyperoxic phase, they breathed pure oxygen (6 L/min) for 15 min; and in the recovery phase, they were room air for 15 min. LSFG measurements of mean blur rate (MBR), which represents ONH BF, were taken every minute. The MBR ratio in the hyperoxic and recovery phases was calculated with reference to this baseline. Clinical parameters, including systemic blood pressure, pulse rate, and saturation of pulse-oximetry oxygen (SpO2), were measured every 5 min.Results: SpO2 increased significantly during hyperoxia (97.3 ± 1.1% to 99.3 ± 0.7%, p < 0.001). While clinical parameters were similar in hyperoxia and baseline, MBR decreased significantly after 2 min of hyperoxia (90.8 ± 12.6%, p = 0.02), stayed steady throughout hyperoxia (mean: 89.5 ± 10.8%, p range: <0.001–0.04) compared with baseline, and returned to baseline 1 min after recovery (93.7 ± 10.3%, p = 0.25). A linear regression using a third-order polynomial fitting curve analysis revealed that the time to reach minimum MBR was 7.78 min (adjusted R2 = 0.87).Conclusion: LSFG could effectively assess ONH BF changes during hyperoxia.

Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans.

To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FI O2 = 0.11) and hyperoxia (FI O2 = 1); and at altitude (FI O2 = 0.21 and 1). Skeletal muscle P2Y2 receptor protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FI O2 . The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses respectively (P < 0.05), and by 22% during the infusion with high adenosine doses. Hyperoxic breathing did not modify the response to vasodilators at sea level or at altitude. P2Y2 receptor expression remained unchanged with altitude residence. Short-term residence at altitude increases arterial blood pressure and reduces the vasodilatory responses to adenosine and ATP.

Blood flow does not redistribute from respiratory to leg muscles during exercise breathing heliox or oxygen in COPD.

In patients with chronic obstructive pulmonary disease (COPD), one of the proposed mechanisms for improving exercise tolerance, when work of breathing is experimentally reduced, is redistribution of blood flow from the respiratory to locomotor muscles. Accordingly, we investigated whether exercise capacity is improved on the basis of blood flow redistribution during exercise while subjects are breathing heliox (designed to primarily reduce the mechanical work of breathing) and during exercise with oxygen supplementation (designed to primarily enhance systemic oxygen delivery but also to reduce mechanical work of breathing). Intercostal, abdominal, and vastus lateralis muscle perfusion were simultaneously measured in 10 patients with COPD (forced expiratory volume in 1 s: 46 ± 12% predicted) by near-infrared spectroscopy using indocyanine green dye. Measurements were performed during constant-load exercise at 75% of peak capacity to exhaustion while subjects breathed room air and, then at the same workload, breathed either normoxic heliox (helium 79% and oxygen 21%) or 100% oxygen, the latter two in balanced order. Times to exhaustion while breathing heliox and oxygen did not differ (659 ± 42 s with heliox and 696 ± 48 s with 100% O2), but both exceeded that on room air (406 ± 36 s, P < 0.001). At exhaustion, intercostal and abdominal muscle blood flow during heliox (9.5 ± 0.6 and 8.0 ± 0.7 ml · min(-1)·100 g(-1), respectively) was greater compared with room air (6.8 ± 0.5 and 6.0 ± 0.5 ml·min(-1)·100 g·, respectively; P < 0.05), whereas neither intercostal nor abdominal muscle blood flow differed between oxygen and air breathing. Quadriceps muscle blood flow was also greater with heliox compared with room air (30.2 ± 4.1 vs. 25.4 ± 2.9 ml·min(-1)·100 g(-1); P < 0.01) but did not differ between air and oxygen breathing. Although our findings confirm that reducing the burden on respiration by heliox or oxygen breathing prolongs time to exhaustion (at 75% of maximal capacity) in patients with COPD, they do not support the hypothesis that redistribution of blood flow from the respiratory to locomotor muscles is the explanation.

Direct demonstration that blood flow through intrapulmonary arteriovenous anastomoses worsens pulmonary gas exchange efficiency

Pulmonary gas exchange efficiency is defined and quantified by the alveolar‐arterial PO2 difference (AaDO2). Sources of venous admixture (QVA/QT) that increase AaDO2 are ventilation‐perfusion (V/Q) inequality, diffusion limitation, and shunt (QS/QT). Intravenous infusion of epinephrine (EPI) increases blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA) in healthy humans at rest, as detected by saline contrast echocardiography, but whether or not this is a source of shunt remains controversial. We hypothesized that QIPAVA is a source of shunt, and therefore, AaDO2 would increase during EPI infusion in healthy humans at rest when QIPAVA is increased. From baseline to max EPI infusion (320 ng/kg/min), AaDO2 increased from 4.9 to 9.4 mmHg and QVA/QT increased from 2.8 to 3.8% in healthy subjects breathing room air (n=3). We repeated these measurements in the same subjects breathing 40% O2 which increases alveolar PO2 and reduces O2 equilibration time from ~0.6 to &lt;0.2 sec, thereby eliminating QVA/QT contributions from diffusion limitation and V/Q inequality, but still allowing for QIPAVA to occur. From baseline to max EPI infusion breathing 40% O2, AaDO2 increased from 17.3 to 23.7 mmHg and QS/QT increased from 4.4 to 5.4%. We conclude that QIPAVA is a source of shunt, because QVA/QT and QS/QT both increased by 1% during max EPI infusion. Support: American Heart Association Predoctoral Fellowship

Catecholamine-induced opening of intrapulmonary arteriovenous anastomoses in healthy humans at rest

The mechanism or mechanisms that cause intrapulmonary arteriovenous anastomoses (IPAVA) to either open during exercise in subjects breathing room air and at rest when breathing hypoxic gas mixtures, or to close during exercise while breathing 100% oxygen, remain unknown. During conditions when IPAVA are open, plasma epinephrine (EPI) and dopamine (DA) concentrations both increase, potentially representing a common mechanism. The purpose of this study was to determine whether EPI or DA infusions open IPAVA in resting subjects breathing room air and, subsequently, 100% oxygen. We hypothesized that these catecholamine infusions would open IPAVA. We performed saline-contrast echocardiography in nine subjects without a patent foramen ovale before and during serial EPI and DA infusions while breathing room air and then while breathing 100% oxygen. Bubble scores (0-5) were assigned based on the number and spatial distribution of bubbles in the left ventricle. Pulmonary artery systolic pressure (PASP) was estimated using Doppler ultrasound, while cardiac output (Q(C)) was measured using echocardiography. Bubble scores were significantly greater during EPI infusions of 80-320 ng·kg(-1)·min(-1) compared with baseline when subjects breathed room air; however, bubble scores did not increase when they breathed 100% oxygen. At comparable Q(C) and PASP, intravenous DA (16 μg·kg(-1)·min(-1)) and EPI (40 ng·kg(-1)·min(-1)) resulted in identical bubble scores. Subsequent studies revealed that β-blockade did not prevent hypoxia-induced opening of IPAVA. We suggest that increases in Q(C) or PASP (or both) secondary to EPI or DA infusions open IPAVA in normoxia. The closing mechanism associated with breathing 100% oxygen is independent from the opening mechanisms.

Does hypoxic vasoconstriction influence the normal distribution of human pulmonary blood flow?

elevation of regional pulmonary resistance in response to local alveolar hypoxia is a near-universal response of the mammalian lung to optimize arterial oxygenation ([14][1]). Given the heterogeneity of regional ventilation observed in a normal lung ([11][2], [16][3]), it appears plausible that

Acute Cardiovascular and Sympathetic Effects of Nicotine Replacement Therapy

Sympathetic overactivity is implicated in the increased cardiovascular risk of cigarette smokers. Excitatory nicotinic receptors are present on peripheral chemoreceptor cells. Chemoreceptors located in the carotid and aortic bodies increase ventilation (Ve), blood pressure (BP), heart rate (HR), and sympathetic nerve activity to muscle circulation (MSNA) in response to hypoxia. We tested the hypothesis that nicotine replacement therapy (NRT) increases MSNA and chemoreceptor sensitivity to hypoxia. Sixteen young healthy smokers were included in the study (8 women). After a randomized and blinded sublingual administration of a 4-mg tablet of nicotine or placebo, we measured minute Ve, HR, mean BP, and MSNA during normoxia and 5 minutes of isocapnic hypoxia. Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia. Nicotine increased HR by 7+/-3 bpm, mean BP by 5+/-2 mm Hg, and MSNA by 4+/-1 bursts/min, whereas subjects breathed room air (all P<0.05). During hypoxia, nicotine also raised HR by 8+/-2 bpm, mean BP by 2+/-1 mm Hg, and MSNA by 7+/-2 bursts/min (all P<0.05). Nicotine increased MSNA during the apneas performed in normoxia and hypoxia (P<0.05). Nicotine also raised the product of systolic BP and HR, a marker of cardiac oxygen consumption, during normoxia, hypoxia, and the apneas (P<0.05). Ve, apnea duration, and O2 saturation during hypoxia and the apneas remained unaffected. In conclusion, sympathoexcitatory effects of NRT are not because of an increased chemoreflex sensitivity to hypoxia. NRT increases myocardial oxygen consumption in periods of reduced oxygen availability.

Measurement of cerebrospinal fluid oxygen partial pressure in humans using MRI

Fluid-attenuated inversion recovery (FLAIR) images obtained during the administration of supplemental oxygen demonstrate a hyperintense signal within the cerebrospinal fluid (CSF) that is likely caused by T1 changes induced by paramagnetic molecular oxygen. Previous studies demonstrated a linear relationship between the longitudinal relaxation rate (R1 = 1/T1) and oxygen content, which permits quantification of the CSF oxygen partial pressure (P(csf)O2). In the current study, CSF T1 was measured at 1.5 T in the lateral ventricles, third ventricle, cortical sulci, and basilar cisterns of eight normal subjects breathing room air or 100% oxygen. Phantom studies performed with artificial CSF enabled absolute P(csf)O2 quantitation. Regional P(csf)O2 differences on room air were observed, from 65 +/- 27 mmHg in the basilar cisterns to 130 +/- 49 mmHg in the third ventricle. During 100% oxygen, P(csf)O2 increases of 155 +/- 45 and 124 +/- 34 mmHg were measured in the basilar cisterns and cortical sulci, respectively, with no change observed in the lateral or third ventricles. P(csf)O2 measurements in humans breathing room air or 100% oxygen using a T1 method are comparable to results from invasive human and animal studies. Similar approaches could be applied to noninvasively monitor oxygenation in many acellular, low-protein body fluids.

Ventilatory acclimatization in response to very small changes in Po2 in humans

Ventilatory acclimatization to hypoxia (VAH) consists of a progressive increase in ventilation and decrease in end-tidal Pco(2) (Pet(CO(2))). Underlying VAH, there are also increases in the acute ventilatory sensitivities to hypoxia and hypercapnia. To investigate whether these changes could be induced with very mild alterations in end-tidal Po(2) (Pet(O(2))), two 5-day exposures were compared: 1) mild hypoxia, with Pet(O(2)) held at 10 Torr below the subject's normal value; and 2) mild hyperoxia, with Pet(O(2)) held at 10 Torr above the subject's normal value. During both exposures, Pet(CO(2)) was uncontrolled. For each exposure, the entire protocol required measurements on 13 consecutive mornings: 3 mornings before the hypoxic or hyperoxic exposure, 5 mornings during the exposure, and 5 mornings postexposure. After the subjects breathed room air for at least 30 min, measurements were made of Pet(CO(2)), Pet(O(2)), and the acute ventilatory sensitivities to hypoxia and hypercapnia. Ten subjects completed both protocols. There was a significant increase in the acute ventilatory sensitivity to hypoxia (Gp) after exposure to mild hypoxia, and a significant decrease in Gp after exposure to mild hyperoxia (P < 0.05, repeated-measures ANOVA). No other variables were affected by mild hypoxia or hyperoxia. The results, when combined with those from other studies, suggest that Gp varies linearly with Pet(O(2)), with a sensitivity of 3.5%/Torr (SE 1.0). This sensitivity is sufficient to suggest that Gp is continuously varying in response to normal physiological fluctuations in Pet(O(2)). We conclude that at least some of the mechanisms underlying VAH may have a physiological role at sea level.

Aberrant respiratory sensitivity to CO 2 as a trait of familial panic disorder

Background: According to three earlier studies, well individuals with a family history of panic disorder experience more anxiety following a single breath of 35% CO 2 than do those without such a family history. This study sought to determine whether a heightened sensitivity to CO 2 manifests specifically in respiratory changes. Methods: Subjects were 18–35 years old and had no history of panic attacks and no current DSM-IV diagnosis other than simple or social phobia. Those at high risk for panic disorder (HR-P) ( n = 46) had a first-degree relative with treated panic disorder. Low-risk control subjects (LR-C) ( n = 39) had no first-degree relative with panic disorder. Respiratory measurements were taken continuously while subjects breathed room air through an attached mask for 3 min and, subsequently, while they breathed a 5% CO 2/air mixture for an additional 3 min. Results: HR-P subjects did not differ from control subjects by group means of the principal measure of respiratory response, changes in minute volume (MV) during CO 2 inhalation. However, these values assumed clearly different distributions in the two groups. Fifteen (32.6%) of the HR-P subjects showed a paradoxical decrease in MV while breathing CO 2 and six (13%) displayed a particularly rapid increase in MV. Only one (2.6%) of the control subjects had a negative MV slope and none had a high value [χ 2(1) = 12.3, p < .001, p = .021, Fisher exact test, respectively]. Though the subjects with high MV increases also described greater increases in anxiety after breathing CO 2, a regression analysis indicated that the MV increase was the more important in discriminating high-risk from control subjects. Conclusions: These results suggest that respiratory sensitivity to CO 2 inhalation is operative in the familial transmission of panic disorder.