Ventilatory Recruitment Threshold Research Articles

Links between systemic inflammation and the chemoreflex control of breathing following COVID-19

The emergence of SARS-CoV-2 resulted in millions of hospitalizations and 6.9 million deaths to-date. Many individuals who recover from COVID-19 report prolonged dyspnea, with this symptom persisting for months following recovery. Furthermore, data suggests COVID-19 has been linked to systemic and neuronal inflammation which may have downstream impacts on the neural control of breathing. As such, we hypothesized that individuals recovered from COVID-19 may exhibit changes in their ventilatory chemosensitivity to CO2 and/or O2 and that these changes may be linked to higher levels of systemic inflammation. To test this hypothesis, we measured baseline ventilatory patterns and chemoreflex sensitivity using a modified rebreathing technique in individuals recovered from COVID-19 (n = 77), as well as an age and sex-matched control group (n = 41). Peripheral blood samples were also collected for inflammatory profiling. Recovered participants demonstrated lower ventilatory responses to hypercapnia, particularly under a combined hypoxic stimulus (p = 0.032). Furthermore, higher levels of plasma IL-1β and IL-6 were associated with lower hypoxic ventilatory responses (R2 = -0.53, p = 0.025; R2 = -0.49, p = 0.04), highlighting a potential link between systemic inflammation and ventilatory chemoreflex sensitivity. When separated by time-post-recovery, we observed a decreased ventilatory recruitment threshold (VRT) beginning at 4 months post-recovery (p = 0.019) that returned to baseline after one-year post-recovery. A decrease in sensitivity to CO2 was also noted immediately after recovery with no return to baseline observed within the two-year tested time frame (p = 0.023). Overall, this data indicates that (1) COVID-19 may have impacts on the neural control of breathing, and (2) systemic inflammation may play a role in modulating ventilatory chemoreflex sensitivity. These findings may have implications for the pathology of long-COVID symptoms, including sleep disturbance and prolonged dyspnea. This work was funded by the Health Disparities Research Center and the OASIS center at University of California, Riverside. 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.

The ventilatory response to modified rebreathing is unchanged by hyperoxic severity: implications for the hyperoxic hyperventilation paradox.

Normobaric hyperoxia stimulates ventilation (V̇e) in a time- and dose-dependent manner. Whether this occurs via an oxygen (O2)-specific mechanism or secondary to carbon dioxide (CO2) retention at the central chemoreceptors remains unclear. We measured the ventilatory response to hyperoxic CO2 rebreathing with O2 clamped at increasingly higher pressures. We hypothesized that the V̇e versus Pco2 relationship is fixed and independent of Po2. On four occasions, 20 participants (10 F; mean ± SD age: 24 ± 4 yr) performed three repetitions of modified rebreathing in four, randomized, isoxic-hyperoxic conditions: mild: Po2 = 150 mmHg; moderate: Po2 = 200 mmHg; high: Po2 = 300 mmHg; and extreme: Po2 ≈ 700 mmHg. Breath-by-breath V̇e, end-tidal CO2 ([Formula: see text]), and O2 ([Formula: see text]) were measured by pneumotach and gas analyzer. For each rebreathing trial, the [Formula: see text] at which V̇e rose was identified as the ventilatory recruitment threshold (VRT, mmHg), data before VRT provided baseline V̇e (V̇eBSL, L·min-1) and the slope of the response above VRT gave central chemoreflex sensitivity (V̇eS, L·min-1·mmHg-1). For each condition, VRT, V̇eBSL, and V̇eS from like-trials were averaged, and repeated measures ANOVA assessed between-condition differences. There were no effects of [Formula: see text] on V̇eBSL (mild: 7.4 ± 4.2 L·min-1; moderate: 6.9 ± 4.2 L·min-1; high: 6.5 ± 3.7 L·min-1; extreme: 7.5 ± 2.7 L·min-1; P = 0.24), VRT (mild: 42.8 ± 3.2 mmHg; moderate: 42.5 ± 2.7 mmHg; high: 42.3 ± 2.7 mmHg; extreme: 41.8 ± 2.7 mmHg; P = 0.07), or V̇eS (mild: 4.88 ± 2.6 L·min-1·mmHg-1; moderate: 4.76 ± 2.2 L·min-1·mmHg-1; high: 4.81 ± 2.3 L·min-1·mmHg-1; extreme: 4.39 ± 1.9 L·min-1·mmHg-1; P = 0.41). The V̇e-Pco2 relationship is unaltered across a range of mild to extreme Po2. Brief exposure to normobaric hyperoxia may not independently stimulate breathing nor does it alter central chemoreflex sensitivity.NEW & NOTEWORTHY Normobaric hyperoxia stimulates ventilation (V̇e) in a time- and dose-dependent manner. Whether this occurs directly or indirectly through heightened central carbon dioxide pressure (Pco2) or via central chemoreflex sensitization is unclear. Participants who performed modified rebreathing at high oxygen pressures (Po2) of 150, 200, 300, and ≈700 mmHg exhibited no changes to their ventilatory responses to Pco2. Brief exposure to normobaric hyperoxia may not independently stimulate breathing nor does it alter central chemoreflex sensitivity.

Strategies to improve respiratory chemoreflex characterization by Duffin's rebreathing.

What is the central question of this study? We assessed the test-retest variability of respiratory chemoreflex characterization by Duffin's modified rebreathing method and explored whether signal averaging of repeated trials improves confidence in parameter estimation. What is the main finding and its importance? Modified rebreathing is a reproducible method to characterize responses of central and peripheral respiratory chemoreflexes. Signal averaging of multiple repeated tests minimizes within- and between-test variability, improves the confidence of chemoreflex characterization and reduces the minimal change in parameters required to establish an effect. Future experiments that apply this method might benefit from signal averaging to improve its discriminatory effect. We assessed the test-retest variability of central and peripheral respiratory chemoreflex characterization by Duffin's modified rebreathing method and explored whether signal averaging of repeated trials improves confidence in parameter estimation. Over four laboratory visits, 13 participants (mean±SD age, 25±5years) performed six repetitions of modified rebreathing in isoxic-hypoxic conditions [end-tidal ( ) = 50mmHg] and isoxic-hyperoxic conditions ( =150mmHg). End-tidal ( ), and minute ventilation ( E ) were measured breath-by-breath, by gas analyser and pneumotachograph. The E versus relationships were fitted with a piecewise model to estimate the ventilatory recruitment threshold (VRT) and the slope above the VRT ( E S). Breath-by-breath data from the three within- and between-day trials were averaged using two approaches [simple average (fit then average) and ensemble average (average then fit)] and compared with a single-trial fit. Variability was assessed by intraclass correlation (ICC) and coefficient of variance (CV), and the minimal detectable change was computed for each approach using two independent sets of three trials. Within days, the VRT and E S exhibited excellent test-retest variability in both hyperoxic conditions (VRT: ICC=0.965, CV=2.3%; E S: ICC=0.932, CV=15.5%) and hypoxic conditions (VRT: ICC=0.970, CV=2.9%; E S: ICC=0.891, CV=17.2%). Between-day reproducibility was also excellent (hyperoxia, VRT: ICC=0.930, CV=2.2%; E S: ICC=0.918, CV=14.2%; and hypoxia, VRT: ICC=0.940, CV=3.0%; E S: ICC=0.880, CV=18.1%). Compared with a single-trial fit, there were no differences in VRT or E S using the simple average or ensemble average approaches; however, ensemble averaging reduced the minimal detectable change for E S from 2.95 to 1.39Lmin-1 mmHg-1 (hyperoxia) and from 3.64 to 1.82 Lmin-1 mmHg-1 (hypoxia). Single trials of modified rebreathing are reproducible; however, signal averaging of repeated trials improves confidence in parameter estimation.

Reproducibility of Respiratory Chemoreflex Characterization by Modified Rebreathing

Modified hypoxic and hyperoxic rebreathing is used to characterize central and peripheral respiratory chemoreflexes in humans. This study examined within‐ and between‐day reproducibility of the key parameters that are identified by this method: ventilatory recruitment threshold (VRT) and chemoreflex sensitivity. Seven healthy males (mean ± SD; age: 27±5 years) visited the laboratory on 4 occasions to performrepetitions of modified rebreathing tests in isoxic‐hypoxic (end‐tidal PO2 (PETO2) =50 mmHg) and ‐hyperoxic conditions (PETO2=150 mmHg). Days 1 and 2 consisted of three repeatedhyperoxic and three hypoxic trials, respectively; Days 3 and 4 included both a hyperoxic and a hypoxic trial completed in a counterbalanced order. Ventilation, end‐tidal PCO2 (PETCO2) and PETO2 were measured breath‐by‐breath by pneumotach and dual gas analyser. For each rebreathing trial, the PETCO2 at which ventilation began to rise was identified as the VRT (mmHg) and the slope of the response above VRT provided respiratory chemoreflex sensitivity (L∙min‐1∙mmHg‐1). Within‐ and between‐day reproducibility was assessed by one‐way ANOVA and intraclass correlation (ICC) analyses. The VRT was not different between trials performed on a single day for bothhyperoxic (44±2, 45±3, vs 44±3 mmHg; for Trials 1, 2, vs 3, respectively; p=0.50; ICC=0.926) and hypoxic rebreathing (40±3, 40±4, vs 40±4 mmHg; p=0.66; ICC=0.994). Chemoreflex sensitivity also was not different between trials performed on the same day in hyperoxic (4.3±2.2, 5.0±3.1, vs4.8±2.3 L∙min‐1∙mmHg‐1; p=0.33; ICC=0.955) or hypoxic conditions (5.6±2.2, 6.2±2.7, 5.7±2.0 L∙min‐1∙mmHg‐1; p=0.33; ICC=0.953). Between days, the VRT was not different for hyperoxic rebreathing (44±3 vs 44±2 vs 45±2 mmHg for Days 1, 3, vs 4, respectively; p=0.10; ICC=0.813) but was different for hypoxic rebreathing (40±3 vs 40±2 vs 41±3 mmHg for Days 2‐4, respectively; p=0.01; ICC=0.931). Chemoreflex sensitivity was not different between days for either hyperoxic (4.8±2.5,4.4±2.7, vs 4.9±2.0 L∙min‐1∙mmHg‐1; p=0.01; ICC=0.906) or hypoxic rebreathing (5.8±2.2, 5.8±2.6, vs 7.8±2.8 L∙min‐1∙mmHg‐1; p=0.01; ICC=0.750). Collectively, these data indicate that model parameters derived from hyperoxic and hypoxic modified rebreathing have good‐to‐excellent test‐retest reproducibility when repeated on the same or different days.

Acute hyperglycemia does not affect central respiratory chemoreflex responsiveness to CO2 in healthy humans

The central respiratory chemoreceptor complex (CCRC) is comprised of brainstem neurons and surrounding interoceptors, which collectively increase ventilation in response to elevated brainstem tissue CO2/[H+] (i.e., central chemoreflex; CCR). The extent that the CCRC detects/responds to other metabolically related chemostimuli is unknown. We aimed to test the effects of acute oral glucose ingestion on CCR reactivity in heathy human participants (n = 38). We instrumented participants with a pneumotachometer (minute ventilation) and a gas sample line connected to a dual gas analyzer (pressure of end-tidal CO2). Following a baseline (BL) period and capillary blood [glucose] (BG) sample, fasted (F) participants underwent a modified hyperoxic rebreathing test to assess CCR reactivity. Participants then consumed a 75 g standard glucose beverage (glucose loaded; GL). Following 30-min, they underwent a second BL, BG sample and hyperoxic rebreathing test. BG and metabolic rate were higher in GL, confirming the metabolic stimulus. However, the ventilatory recruitment threshold and the CCR responses were unchanged between F and GL states.

Elevated exercise ventilation in mild COPD is not linked to enhanced central chemosensitivity

BackgroundThe purpose of this study was to determine if altered central chemoreceptor characteristics contributed to the elevated ventilation relative to carbon dioxide production (V̇E/V̇CO2) response during exercise in mild chronic obstructive pulmonary disease (COPD). MethodsTwenty-nine mild COPD and 19 healthy age-matched control participants undertook lung function testing followed by symptom-limited incremental cardiopulmonary exercise testing . On a separate day, basal (non-chemoreflex) ventilation (V̇EB), the central chemoreflex ventilatory recruitment threshold for CO2 (VRTCO2), and central chemoreflex sensitivity (V̇ES) were assessed using the modified Duffin’s CO2 rebreathing method. Resting arterialized blood gas data were also obtained. ResultsAt standardized exercise intensities, absolute V̇E and V̇E/V̇CO2 were consistently elevated and the end-tidal partial pressure of CO2 was relatively decreased in mild COPD versus controls (all p < 0.05). There were no between-group differences in resting arterialized blood gas parameters, basal V̇E, VRTCO2, or V̇ES (all p > 0.05). ConclusionThese data have established that excessive exercise ventilation in mild COPD is not explained by altered central chemosensitivity.

Unchanged cerebrovascular CO2 reactivity and hypercapnic ventilatory response during strict head-down tilt bed rest in a mild hypercapnic environment.

Carbon dioxide levels are mildly elevated on the International Space Station and it is unknown whether this chronic exposure causes physiological changes to astronauts. We combined ∼4mmHg ambient with the strict head-down tilt bed rest model of spaceflight and this led to the development of optic disc oedema in one-half of the subjects. We demonstrate no change in arterialized , cerebrovascular reactivity to CO2 or the hypercapnic ventilatory response. Our data suggest that the mild hypercapnic environment does not contribute to the development of spaceflight associated neuro-ocular syndrome. Chronically elevated carbon dioxide (CO2 ) levels can occur in confined spaces such as the International Space Station. Using the spaceflight analogue 30 days of strict 6° head-down tilt bed rest (HDTBR) in a mild hypercapnic environment ( = ∼4mmHg), we investigated arterialized , cerebrovascular reactivity and the hypercapnic ventilatory response in 11 healthy subjects (five females) before, on days 1, 9, 15 and 30 of bed rest (BR), and 6 and 13 days after HDTBR. During all HDTBR time points, arterialized was not significantly different from the pre-HDTBR measured in the 6° HDT posture, with a mean (95% confidence interval) increase of 1.2mmHg (-0.2 to 2.5mmHg, P = 0.122) on day 30 of HDTBR. Respiratory acidosis was never detected, although a mild metabolic alkalosis developed on day 30 of HDTBR by a mean (95% confidence interval) pH change of 0.032 (0.022-0.043; P<0.001), which remained elevated by 0.021 (0.011-0.031; P<0.001) 6 days after HDTBR. Arterialized pH returned to pre-HDTBR levels 13 days after BR with a change of -0.001 (-0.009 to 0.007; P = 0.991). Compared to pre-HDTBR, cerebrovascular reactivity during and after HDTBR did not change. Baseline ventilation, ventilatory recruitment threshold and the slope of the ventilatory response were similar between pre-HDTBR and all other time points. Taken together, these data suggest that the mildly increased ambient combined with 30 days of strict 6° HDTBR did not change arterialized levels. Therefore, the experimental conditions were not sufficient to elicit a detectable physiological response.

Cerebrovascular carbon dioxide reactivity is influenced by sex despite comparable hemodynamic and respiratory chemosensitivity in young fit individuals

Cerebral blood flow (CBF) is generally higher in women compared to men at rest. Although accumulating evidence supports sex differences in CBF regulation, findings remain contradictory for dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to carbon dioxide (CVRCO2). Cardiorespiratory fitness represents an indicator of cardiovascular health. However, we have recently reported that dCA is reduced in young fit men compared to controls, and that dCA is attenuated in young fit women compared to fit men. However, the influence of sex on CVRCO2 in these young fit individuals remains misunderstood. The aim of this study was to examine the influence of sex on CVRCO2 in young fit individuals. Changes in middle cerebral artery mean blood velocity (MCAvmean; transcranial doppler), mean arterial pressure (MAP; photoplethysmography), heart rate (HR; ECG) and pulmonary ventilation (spirometer) were measured in 29 young fit individuals (women n=10, men n=19), in response to changes in end‐tidal partial pressure of carbon dioxide (PETCO2; gas analyzer) during the modified Duffin hyperoxic rebreathing test. Women were tested in the early follicular phase. CVRCO2, as well as hemodynamic and ventilatory chemosensitivity, were characterized using linear regressions on the rebreathing portion of the test after the determined ventilatory recruitment threshold. While age was not different between groups (26 ± 6 vs. 27 ± 5 years, P = 0.92), height: (1.64 ± 0.06 vs. 1.77 ± 0.08 m; P &lt; 0.0001), body weight (60 ± 6 vs. 72 ± 10 kg; P = 0.0009) and maximal oxygen uptake (48.4 ± 3.8 vs. 57.9 ± 6.8 mL−1kg−1min−1; P &lt; 0.0001) were lower in women. At rest, MCAvmean (72 ± 8 cm/s vs. 62 ± 11 cm/s; P = 0.02) and HR (73 ± 8 vs. 64 ± 11 bpm; P = 0.02) were higher in women, whereas MAP was not different between groups (100 ± 19 vs. 97 ± 10 mm Hg; P = 0.73). CVRCO2 was higher in women compared to men, both in absolute (1.59 ± 0.78 vs. 0.35 ± 1.51 cm/s/mm Hg, P = 0.01) and normalized terms (2.19 ± 0.97 vs. 0.54 ± 2.41 %/mm Hg, P = 0.02). Hemodynamic and respiratory chemosensitivity responses during CO2 rebreathing were not different between groups (all P &gt; 0.05). These results indicate that the cerebrovasculature of young fit women is more sensitive to CO2 than men despite comparable hemodynamic and ventilatory chemosensitivity responses.Support or Funding InformationS.I., L.L. and S.M. have been supported by a doctoral training scholarship from the Fonds de recherche du Québec ‐ Santé (FRQS)

Reproducibility of hypercapnic ventilatory response measurements with steady-state and rebreathing methods

In this study, the hypercapnic ventilatory response (HCVR) was measured, defined as the ventilation response to carbon dioxide tension (PCO2). We investigated which method, rebreathing or steady-state, is most suitable for measurement of the HCVR in healthy subjects, primarily based on reproducibility. Secondary outcome parameters were subject experience and duration.20 healthy adults performed a rebreathing and steady-state HCVR measurement on two separate days. Subject experience was assessed using numeric rating scales (NRS). The intraclass correlation coefficient (ICCs) of the sensitivity to carbon dioxide above the ventilatory recruitment threshold and the projected apnoea threshold were calculated to determine the reproducibility of both methods.The ICCs of sensitivity were 0.89 (rebreathing) and 0.56 (steady-state). The ICCs of the projected apnoea threshold were 0.84 (rebreathing) and 0.25 (steady-state). The steady-state measurement was preferred by 16 out of 20 subjects; the differences in NRS scores were small.The hypercapnic ventilatory response measured using the rebreathing setup provided reproducible results, while the steady-state method did not. This may be explained by high variability in end-tidal PCO2. Differences in subject experience between the methods are small.

Influence of prior hyperventilation duration on respiratory chemosensitivity and cerebrovascular reactivity during modified hyperoxic rebreathing

What is the central question of this study? We characterized and compared the cardiorespiratory and cerebrovascular responses to the 'Duffin' modified hyperoxic CO2 rebreathing test by randomly altering the prior hyperventilation duration. What is the main finding and its importance? Our main finding was that prior hyperventilation duration (1, 3 or 5min) had no effect on cardiorespiratory and cerebrovascular responses to the hyperoxic rebreathing test, within individuals. These findings suggest that the standard 5min prior hyperventilation duration used to clear body CO2 stores is unnecessary and can reasonably be shortened to 1min, reducing protocol times and improving participant comfort. The 'Duffin' modified hyperoxic rebreathing test allows investigators to characterize and quantify the ventilatory and cerebrovascular responses to CO2 across a large physiological range, allowing quantification of basal ventilation and the ventilatory recruitment threshold (VRT). Although the standard protocol includes 5min of prior hyperventilation to clear body CO2 stores, there is no experimental evidence that a full 5min is required. We hypothesized that there would be no within-individual differences in the cardiorespiratory or cerebrovascular responses to rebreathing with shortened hyperventilation duration prior to hyperoxic rebreathing. Using a rebreathing apparatus, transcranial Doppler ultrasound and beat-to-beat blood pressure monitoring, we tested 19 participants in the supine position using three randomly assigned hyperoxic rebreathing tests with 1, 3 or 5min of prior hyperventilation. We measured VRT (in Torr CO2 ), time to VRT (in seconds), central respiratory chemoreflex (breathing frequency, tidal volume and minute ventilation), cerebrovascular (middle and posterior cerebral artery velocity) and cardiovascular (heart rate and mean arterial pressure) responses to CO2 during hyperoxic rebreathing. Using linear regression and repeated-measures ANOVAs, we found no differences in any of the cardiorespiratory or cerebrovascular response magnitudes between trials (P>0.05). The only difference observed was in the time to VRT (in seconds), whereby 1min prior hyperventilation duration was shorter (135.4±19.7s) than with 3 or 5min prior hyperventilation (176.3±15.1 and 187.2±11.6s, respectively; P<0.001). Our findings indicate that 5min of prior hyperventilation is unnecessary during modified rebreathing when using it to quantify respiratory or cerebrovascular responses and can be reasonably shortened to 1min, reducing protocol times and improving participant comfort.

Chapter 9 - The effects of head-up and head-down tilt on central respiratory chemoreflex loop gain tested by hyperoxic rebreathing

Central respiratory chemosensitivity is mediated via chemoreceptor neurons located throughout brain stem tissue. These receptors detect proximal CO2/[H(+)] (i.e., controller gain) and modulate breathing in a classic negative feedback loop. Loop gain (responsiveness) is the theoretical product of controller (chemoreceptors), mixing/feedback (cardiovascular and cerebrovascular systems), and plant (pulmonary system) gains. The level of chemoreceptor stimulation is determined by interactions between mixing and plant gains. The extent to which steady-state changes in body position may affect central chemoreflex loop gain in response to CO2 is unclear. Because of the potential effects of tilt on pulmonary mechanics, we hypothesized that plant gain would be altered by head-up and head-down tilt (HUT, HDT) during hyperoxic rebreathing, which theoretically isolates plant gain by eliminating systemic arterial-tissue gradients. Sixteen subjects (eight females) underwent hyperoxic rebreathing tests on a tilt table to quantify central chemoreflex loop gain in five steady-state positions: 90° HUT, 45° HUT, supine, 45° HDT, and 90° HDT. Respiratory responses (tidal volume, VT; frequency, fR; minute ventilation, VE) were quantified during steady-state and increases in CO2 during rebreathing by linear regression above the ventilatory recruitment threshold (VRT). Using one-factor analysis of variance, we found that there were no differences in the respiratory responses between the five positions (VRT, P=0.711; VT, P=0.290; fR, P=0.748; VE, P=0.325). Our findings suggest that during steady-state orthostatic stress, the ability of subjects to mount a normal ventilatory response to increased CO2 was unaffected, despite any potential changes in pulmonary mechanics associated with positional challenges.

Effects of a Single Bout of Interval Hypoxia on Cardiorespiratory Control in Patients With Type 1 Diabetes

Hypoxemia is common in diabetes, and reflex responses to hypoxia are blunted. These abnormalities could lead to cardiovascular/renal complications. Interval hypoxia (IH) (5–6 short periods of hypoxia each day over 1–3 weeks) was successfully used to improve the adaptation to hypoxia in patients with chronic obstructive pulmonary disease. We tested whether IH over 1 day could initiate a long-lasting response potentially leading to better adaptation to hypoxia. In 15 patients with type 1 diabetes, we measured hypoxic and hypercapnic ventilatory responses (HCVRs), ventilatory recruitment threshold (VRT-CO2), baroreflex sensitivity (BRS), blood pressure, and blood lactate before and after 0, 3, and 6 h of a 1-h single bout of IH. All measurements were repeated on a placebo day (single-blind protocol, randomized sequence). After IH (immediately and after 3 h), hypoxic and HCVR increased, whereas the VRT-CO2 dropped. No such changes were observed on the placebo day. Systolic and diastolic blood pressure increased, whereas blood lactate decreased after IH. Despite exposure to hypoxia, BRS remained unchanged. Repeated exposures to hypoxia over 1 day induced an initial adaptation to hypoxia, with improvement in respiratory reflexes. Prolonging the exposure to IH (>2 weeks) in type 1 diabetic patients will be a matter for further studies.

Effects of a Single Bout of Interval Hypoxia on Cardiorespiratory Control and Blood Glucose in Patients With Type 2 Diabetes

OBJECTIVEHypoxia may cause functional autonomic imbalance in diabetes. Intermittent hypoxia (IH), a technique improving the adaptation to hypoxia, might improve cardiorespiratory reflexes and, ultimately, blood glucose concentrations in patients with type 2 diabetes. We tested whether a single bout of IH could initiate a long-lasting response potentially leading to better adaptation to hypoxia.RESEARCH DESIGN AND METHODSIn 14 patients with type 2 diabetes without autonomic complications, we measured blood pressure, heart rate, oxygen saturation, chemoreflex (hypoxic and hypercapnic ventilatory responses, ventilatory recruitment threshold), and baroreflex sensitivity before, immediately after, and 3 and 6 h after a 1-h single bout of IH (6-min breathing of 13% oxygen mixture 5 times each separated by 6-min recovery). The measurements were repeated on a placebo day (at least 1 week apart, in random sequence) when subjects were only breathing room air (single-blind protocol).RESULTSIH significantly increased hypercapnic ventilatory responses and reduced ventilatory recruitment threshold, and increased oxygen saturation and blood pressures, whereas increases in heart rate variability and baroreflex sensitivity were not significant. Blood glucose significantly decreased after IH. No such changes were observed during the placebo day, except an increase in oxygen saturation. Some of the effects lasted 3 h after IH, and some even persisted until 6 h after IH.CONCLUSIONSA single bout of IH induced an initial adaptation to hypoxia, with improvement in cardiorespiratory reflexes and reduction in blood glucose. Patients with type 2 diabetes could potentially benefit from the application of a full (>2 weeks) IH intervention.

The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebo‐controlled trial

We recently showed that testosterone therapy worsens sleep-disordered breathing at 6-7weeks, but not after 18weeks, in men with obstructive sleep apnea. Changes in ventilatory chemoreflexes may be responsible. The effect of testosterone on ventilatory chemoreflexes in men with obstructive sleep apnea has not been systematically studied before. Twenty-one obese men with obstructive sleep apnea, a subgroup of our recent report, were randomised in an 18-week, randomised, double-blind, placebo-controlled, parallel group trial to three intramuscular injections (0, 6, 12weeks) of either 1000mg testosterone undecanoate (n=10) or placebo (n=11). Awake ventilatory chemoreflex testing was performed before (week 0), during (week 6) and at the end of treatment (week 18) to determine the ventilatory carbon dioxide recruitment threshold and chemosensitivity. Sleep and breathing was assessed by overnight polysomnography at 0, 7 and 18weeks. Serum hormones levels were measured at every visit. A significant increase in blood testosterone levels (5.65nmol L(-1) , 0.51-10.8nmol L(-1) , P=0.03) and lean muscle mass (2.36kg, 0.8-3.9kg, P=0.007) between the two groups was observed as expected. No significant differences were seen in ventilatory chemoreflexes between the two groups at 6weeks or at 18weeks. However, positive correlations were observed between changes in serum testosterone and hyperoxic ventilatory recruitment threshold (r=0.55, P=0.03), and between changes in hyperoxic ventilatory recruitment threshold and time spent with oxygen saturations during sleep <90% (r=0.57, P=0.03) at 6-7weeks, but not at 18weeks. Time-dependent alterations in ventilatory recruitment threshold may therefore mediate the time-dependent changes in sleep breathing observed with testosterone.

P39 Ventilatory Response Amongst Scuba Divers and Non-Divers

PurposeTo investigate the ventilatory response to CO2 in hyperoxia, hypoxia, and during exercise amongst experienced scuba divers and matched controls.MethodsThree studies were performed comparing the ventilatory response to CO2 of...

Resting and exercise ventilatory chemosensitivity across the menstrual cycle

We hypothesized that resting and exercise ventilatory chemosensitivity would be augmented in women when estrogen and progesterone levels are highest during the luteal phase of the menstrual cycle. Healthy, young females (n = 10; age = 23 ± 5 yrs) were assessed across one complete cycle: during early follicular (EF), late follicular (LF), early luteal, and mid-luteal (ML) phases. We measured urinary conjugates of estrogen and progesterone daily. To compare values of ventilatory chemosensitivity and day-to-day variability of measures between sexes, males (n = 10; age = 26 ± 7 yrs) were assessed on 5 nonconsecutive days during a 1-mo period. Resting ventilation was measured and hypoxic chemosensitivity assessed using an isocapnic hypoxic ventilatory response (iHVR) test. The hypercapnic ventilatory response was assessed using the Read rebreathing protocol and modified rebreathing tests. Participants completed submaximal cycle exercise in normoxia and hypoxia. We observed a significant effect of menstrual-cycle phase on resting minute ventilation, which was elevated in the ML phase relative to the EF and LF phases. Compared with males, resting end-tidal CO(2) was reduced in females during the EF and ML phases but not in the LF phase. We found that iHVR was unaffected by menstrual-cycle phase and was not different between males and females. The sensitivity to chemical stimuli was unaffected by menstrual-cycle phase, meaning that any hormone-mediated effect is of insufficient magnitude to exceed the inherent variation in these chemosensitivity measures. The ventilatory recruitment threshold for CO(2) was generally lower in women, which is suggestive of a hormonally related lowering of the ventilatory recruitment threshold. We detected no effect of menstrual-cycle phase on submaximal exercise ventilation and found that the ventilatory response to normoxic and hypoxic exercise was quantitatively similar between males and females. This suggests that feed-forward and feed-back influences during exercise over-ride the effects of naturally occurring changes in sex hormones.

Phenotyping interindividual variability in obstructive sleep apnoea response to temazepam using ventilatory chemoreflexes during wakefulness

Centrally active agents have a variable impact in patients with obstructive sleep apnoea (OSA) that is unexplained. How to phenotype the individual OSA response is clinically important, as it may help to identify who will be at risk of respiratory depression and who will benefit from a centrally active agent. Based on loop gain theory, we hypothesized that OSA patients with higher central chemosensitivity have higher breathing instability following the use of a hypnosedative, temazepam. In 20 men with OSA in a double-blind, placebo-controlled cross-over trial we tested the polysomnographically (PSG) measured effects of temazepam 10 mg versus placebo on sleep apnoea. Treatment nights were at least 1 week apart. Ventilatory chemoreflexes were also measured during wakefulness in each subject. The patients (mean ± standard deviation; 44 ± 12 years) had predominantly mild-to-moderate OSA [baseline apnoea-hypopnoea index (AHI) = 16.8 ± 14.1]. Patients' baseline awake central chemosensitivity correlated significantly with both the change of SpO₂ nadir between temazepam and placebo (r = -0.468, P = 0.038) and oxygen desaturation index (ODI; r = 0.485, P = 0.03), but not with the change of AHI (r = 0.18, P = 0.44). Peripheral chemosensitivity and ventilatory recruitment threshold were not correlated with the change of SpO₂ nadir, ODI or AHI (all P > 0.05). Mild-moderate OSA patients with higher awake central chemosensitivity had greater respiratory impairment during sleep with temazepam. Relatively simple daytime tests of respiratory control may provide a method of determining the effect of sedative-hypnotic medication on breathing during sleep in OSA patients.

Differences in the control of breathing between Himalayan and sea‐level residents

We compared the control of breathing of 12 male Himalayan highlanders with that of 21 male sea-level Caucasian lowlanders using isoxic hyperoxic ( = 150 mmHg) and hypoxic ( = 50 mmHg) Duffin's rebreathing tests. Highlanders had lower mean +/- s.e.m. ventilatory sensitivities to CO(2) than lowlanders at both isoxic tensions (hyperoxic: 2.3 +/- 0.3 vs. 4.2 +/- 0.3 l min(1) mmHg(1), P = 0.021; hypoxic: 2.8 +/- 0.3 vs. 7.1 +/- 0.6 l min(1) mmHg(1), P < 0.001), and the usual increase in ventilatory sensitivity to CO(2) induced by hypoxia in lowlanders was absent in highlanders (P = 0.361). Furthermore, the ventilatory recruitment threshold (VRT) CO(2) tensions in highlanders were lower than in lowlanders (hyperoxic: 33.8 +/- 0.9 vs. 48.9 +/- 0.7 mmHg, P < 0.001; hypoxic: 31.2 +/- 1.1 vs. 44.7 +/- 0.7 mmHg, P < 0.001). Both groups had reduced ventilatory recruitment thresholds with hypoxia (P < 0.001) and there were no differences in the sub-threshold ventilations (non-chemoreflex drives to breathe) between lowlanders and highlanders at both isoxic tensions (P = 0.982), with a trend for higher basal ventilation during hypoxia (P = 0.052). We conclude that control of breathing in Himalayan highlanders is distinctly different from that of sea-level lowlanders. Specifically, Himalayan highlanders have decreased central and absent peripheral sensitivities to CO(2). Their response to hypoxia was heterogeneous, with the majority decreasing their VRT indicating either a CO(2)-independent increase in activity of peripheral chemoreceptor or hypoxia-induced increase in [H(+)] at the central chemoreceptor. In some highlanders, the decrease in VRT was accompanied by an increase in sensitivity to CO(2), while in others VRT remained unchanged and their sub-threshold ventilations increased, although these were not statistically significant.

The effect of hypoxia on the ventilatory and cerebral blood flow (CBF) responses to CO2

ObjectivesThis study examines the proposed approach to a standard measurement regime for characterizing the respiratory chemoreflexes as detailed by Duffin (2007) and develops a similar approach to characterize cerebrovascular responsiveness to hypoxia and CO2. We measured the effect of hypoxia on the isoxic modified rebreathing ventilatory and CBF responses to CO2 in terms of sensitivity, ventilatory recruitment threshold and wakefulness ventilation at 2 levels of isoxia (PO2 = 50 mmHg &amp; 150 mmHg). We also measured the effect of hypercapnia on the isocapnic steady‐state (SS) ventilatory and CBF responses to hypoxia at 3 levels of hypercapnia (PCO2 = 4, 7 &amp; 10 mmHg above resting). Finally we compared the isoxic rebreathing measurements with the SS isocapnic measurements.MethodCustom designed software controlling a specialized gas blending device (RespirAct™; Thornhill Research) was used to implement the steady state and modified rebreathing protocols. Ventilation (VE), PetCO2 and PetO2, middle cerebral artery velocity (MCAv), and blood pressure (BP) were recorded.Results9 subjects completed the tests (6 male).This graph displays the SS response of VE, MCAv and BP to CO2 (PCO2 = 50 mmHg) first in hyperoxia (PO2 = 150 mmHg) and then in hypoxia (PO2 = 50 mmHg). We compared the SS and rebreathing ventilation and CBF responses.Rebreathing analysis (figures above) gives us interesting results. Ventilation shows a higher slope (increase of sensitivity) as well as a lower threshold during the Hypoxic phase as expected. For the MCAv, the interindividual variability is larger than expected. This example shows same slope, as expected. Comparison with SS method is more complex. Some subjects might have limitations of the MCAv increase. Further analysis still need to be done.

The increased ventilatory response to exercise in pregnancy reflects alterations in the respiratory control systems ventilatory recruitment threshold for CO2

We tested the hypothesis that the magnitude of the pregnancy-induced increase in exercise hyperpnea is predictable based on the level at which Pa CO2 is regulated at rest. We performed a detailed retrospective analysis of previous data from 25 healthy young women who performed exercise and rebreathing tests in the third trimester (TM(3); 36.5+/-0.2 weeks gestation; mean+/-SEM) and again 20.4+/-1.7 weeks post-partum (PP). At rest, arterialized venous blood was obtained for the estimation of Pa CO2, [H(+)] and [HCO(3)(-)]; and serum progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) concentrations. Duffin's modified hyperoxic rebreathing procedure was used to evaluate changes in central ventilatory chemoreflex control characteristics at rest. Breath-by-breath ventilatory and gas exchange variables were measured at rest and during symptom-limited incremental cycle exercise tests. At rest in TM(3) compared with PP: Pa CO2, [H(+)], [HCO(3)(-)] and the central chemoreflex ventilatory recruitment threshold for Pa CO2 (VRT CO2) decreased, while ventilation (V E), [P(4)], [E(2)] and central chemoreflex sensitivity (V ES) increased (all p<or=0.001). The slope of the linear relation between V E and V CO2 during exercise was significantly higher in TM(3) vs. PP (31.2+/-0.6 vs. 27.5+/-0.5, p<0.001). The magnitude of this change in the VE-V CO2 slope correlated significantly with concurrent reductions in each of the VRT CO2 (R(2)=0.619, p<0.001), Pa CO2 (R(2)=0.203, p=0.024) and [HCO(3)(-)] (R(2)=0.189, p=0.030); and was independent (p>0.05) of changes in [P(4)], [E(2)] and V ES. In conclusion, the increased ventilatory response to exercise in pregnancy can be explained, in large part, by reductions in the respiratory control system's resting Pa CO2 equilibrium point as manifest primarily by reductions in the VRT CO2.