Increase In Hypoxic Ventilatory Response Research Articles

The effects of P2Y12 adenosine receptors' inhibitors on central and peripheral chemoreflexes.

Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors' sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved. Methods: We measured peripheral chemoreceptors' sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors' sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478. Results: Ticagrelor significantly increased both HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L min-1%-1; p < 0.01) and HCVR (1.05 ± 0.64 vs. 1.75 ± 1.04Lmin-1mmHg-1; p < 0.01). The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR (0.63 ± 0.32 vs. 0.58 ± 0.33 L min-1%-1; p = 0.53) and HCVR (1.22 ± 0.67 vs. 1.2 ± 0.64Lmin-1mmHg-1; p = 0.79). Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation. Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated.

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep

People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short‐ and long‐term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2) and 40% carbon dioxide (CO2) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V .E.), tidal volume (V .T.), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short‐term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long‐term facilitation following AIH in either group.

Clinical implications of opioid-induced ventilatory impairment.

Opioid-induced ventilatory impairment is the primary mechanism of harm from opioid use. Opioids suppress the activity of the central respiratory centres and are sedating, leading to impairment of alveolar ventilation.Respiratory physiological changes induced with acute opioid use include depression of the hypercapnic ventilatory response and hypoxic ventilatory response. In chronic opioid use a compensatory increase in hypoxic ventilatory response maintains ventilation and contributes to the onset of sleep-disordered breathing patterns of central sleep apnoea and ataxic breathing. Supplemental oxygen use in those at risk of opioid-induced ventilatory impairment requires careful consideration by the clinician to prevent failure to detect hypoventilation, if oximetry is being relied on, and the overriding of hypoxic ventilatory drive. Obstructive sleep apnoea and opioid-induced ventilatory impairment are frequently associated, with this interrelationship being complex and often unpredictable. Monitoring the patient for opioid-induced ventilatory impairment poses challenges in the areas of reliability, avoidance of alarm fatigue, cost, and personnel demands. Many situations remain in which patients cannot be provided effective analgesia without opioids, and for these the clinician requires a comprehensive knowledge of opioid-induced ventilatory impairment.

Neuronal HIF-1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia.

We hypothesized that hypoxia inducible factor 1α (HIF-1α) in CNS respiratory centres is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time-dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF-1α in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild-type mice with CH. Conditional deletion of HIF-1α in glutamatergic neurons of the nucleus tractus solitarius during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate, nor CO2 , and there were no changes in the HVR in normoxic mice. HIF-1α mediated changes in gene expression in CNS respiratory centres are necessary in addition to plasticity of arterial chemoreceptors for normal VAH. Chronic hypoxia (CH) produces a time-dependent increase of resting ventilation and the hypoxic ventilatory response (HVR) that is called ventilatory acclimatization to hypoxia (VAH). VAH involves plasticity in arterial chemoreceptors and the CNS [e.g. nucleus tractus solitarius (NTS)], although the signals for this plasticity are not known. We hypothesized that hypoxia inducible factor 1α (HIF-1α), an O2 -sensitive transcription factor, is necessary in the NTS for normal VAH. We tested this in two mouse models using loxP-Cre gene deletion. First, HIF-1α was constitutively deleted in CNS neurons (CNS-HIF-1α-/- ) by breeding HIF-1α floxed mice with mice expressing Cre-recombinase driven by the calcium/calmodulin-dependent protein kinase IIα promoter. Second, HIF-1α was deleted in NTS neurons in adult mice (NTS-HIF-1α-/- ) by microinjecting adeno-associated virus that expressed Cre-recombinase in HIF-1α floxed mice. In normoxic control mice, HIF-1α deletion in the CNS or NTS did not affect ventilation, nor the acute HVR (10-15min hypoxic exposure). In mice acclimatized to CH for 1week, ventilation in hypoxia was blunted in CNS-HIF-1α-/- and significantly decreased in NTS-HIF-1α-/- compared to control mice (P<0.0001). These changes were not explained by differences in metabolic rate or CO2 . Immunofluorescence showed that HIF-1α deletion in NTS-HIF-1α-/- was restricted to glutamatergic neurons. The results indicate that HIF-1α is a necessary signal for VAH and the previously described plasticity in glutamatergic neurotransmission in the NTS with CH. HIF-1α deletion had no effect on the increase in normoxic ventilation with acclimatization to CH, indicating this is a distinct mechanism from the increased HVR with VAH.

Effects of non‐steroid anti‐inflammatory drugs on the human hypoxic ventilatory response and acclimatization

Recent studies show that inflammation contributes to respiratory chemoreflex plasticity during chronic hypoxia. Ibuprofen (a non‐steroidal anti‐inflammatory drug, NSAID) prevents the normal time‐dependent increase in the hypoxic ventilatory response (HVR) in chronically hypoxic rats (Respir. Physiol. Neurobiol. 178: 381–386, 2011). We hypothesized that inflammatory pathways contribute to ventilatory acclimatization to hypoxia in humans also. To test this, we measured the isocapnic HVR in 5 subjects at sea level and at high altitude (3,800m) using a randomized, double‐blind, repeated measures protocol. Ibuprofen or placebo was administered (400mg TID) over 48 hours at sea level and over 48 hours at 3,800m. We measured HVR at 24 and 48 hours of treatment at sea level and 3,800m. Results showed no significant difference in the HVR between placebo and ibuprofen treatments at sea level. A significant increase in the HVR at altitude occurred with placebo, indicating normal ventilatory acclimatization. However, ibuprofen blocked the increase in HVR at altitude, showing significantly less HVR increase with ibuprofen versus placebo. The results may have implications for the treatment of acute mountain sickness at high altitude with NSAIDs. Supported by UC White Mt. Res. St., NIH RO1 HL‐ 081823 &amp; 1P01 HL 098053.

Two patterns of daily hypoxic exposure and their effects on measures of chemosensitivity in humans

The purpose of this study was to compare chemoresponses following two different intermittent hypoxia (IH) protocols in humans. Ten men underwent two 7-day courses of poikilocapnic IH. The long-duration IH (LDIH) protocol consisted of daily 60-min exposures to normobaric 12% O(2). The short-duration IH (SDIH) protocol comprised twelve 5-min bouts of 12% O(2), separated by 5-min bouts of room air, daily. Isocapnic hypoxic ventilatory response (HVR) was measured daily during the protocol and 1 and 7 days following. Hypercapnic ventilatory response (HCVR) and CO(2) threshold and sensitivity (by the modified Read rebreathing technique) were measured on days 1, 8, and 14. Following 7 days of IH, the mean HVR was significantly increased from 0.47 +/- 0.07 and 0.47 +/- 0.08 to 0.70 +/- 0.06 and 0.79 +/- 0.06 l.min(-1).%Sa(O(2))(-1) (LDIH and SDIH, respectively), where %Sa(O(2)) is percent arterial oxygen saturation. The increase in HVR reached a plateau after the third day. One week post-IH, HVR values were unchanged from baseline. HCVR increased from 3.0 +/- 0.4 to 4.0 +/- 0.5 l.min(-1).mmHg(-1). In both the hyperoxic and hypoxic modified Read rebreathing tests, the slope of the CO(2)/ventilation plot was unchanged by either intervention, but the CO(2)/ventilation curve shifted to the left following IH. There were no correlations between the changes in response to hypoxia and hypercapnia. There were no significant differences between the two IH protocols for any measures, indicating that comparable changes in chemoreflex control occur with either protocol. These results also suggest that the two methods of measuring CO(2) response are not completely concordant and that the changes in CO(2) control do not correlate with the increase in the HVR.

Characterisation of the ventilatory response to hypoxia in a model of transgenic anemic mice

Both polycythemia and the increase in hypoxic ventilatory response (HVR) are considered as important factors of acclimatization to hypoxia. The objective of this study was to characterise the ventilation pattern at different inspired oxygen fraction in a model of chronic anemic mice. These mice have a targeted disruption in the 5' untranslated region of the Epo gene that reduces Epo expression such that the homozygous animal is severely anemic. Ventilation in normoxia in Epo-TAg(h) mice was significantly greater than in wild type, and the difference was mainly due to a higher tidal volume. HVR was higher in Epo-TAg(h) mice at every FIO2 suggesting a higher chemosensitivity. Resting oxygen consumption was maintained in anemic mice. Maximal oxygen consumption was 30% lower while hemoglobin was 60% lower in anemic mice compared to wild type. This small decrease in maximal oxygen consumption is probably due a greater cardiac output and/or a better tissue oxygen extraction and would allow these anemic mice to acclimatize to hypoxia in spite of low oxygen carrying capacity. In conclusion, Epo-TAg(h) anemic mice showed increased ventilation and hypoxic ventilatory response. However, whether these adaptations will contribute to acclimatization in chronic hypoxia remains to be determined.

VENTILATORY CHEMOSENSIVITY OF JUNIOR ELITE CYCLISTS AT ALTITUDE

Early acclimatization to altitude is characterized by an increase in resting ventilation facilitated by an increase in hypoxic ventilatory response (HVR), but there is little information comparing ventilatory chemosensitivity of athletes undergoing short-term altitude training with those native to altitude. PURPOSE To examine ventilatory adaptation following short-term or life-long residence at 2690m altitude in elite junior cyclists. METHODS Subjects were seven members of the Australian men's U23 cycling team (AU) and six from the State of Mexico men's U19 cycling team (MX). For AU, end-tidal CO2 pressure (PETCO2), HVR and oxyhemoglobin saturation (SpO2) were measured at sea level (SL) and after 15 d at altitude (D15). Hypercapnic ventilatory response (HCVR) was measured at SL and after 10 d at altitude (D10). For MX, all variables were measured at altitude. RESULTS At D15, PETCO2 for AU was lower (p < 0.001) than at SL. PETCO2 tended to be lower for AU than MX (32.1 ±3.3 vs 34.1 ±0.9mmHg; p = 0.18; F-ratio for variances, p < 0.01) and SpO2 was lower for AU than MX (94.0 ±1.7 vs 95.8 ±0.7%; p < 0.05). There was a significant correlation between SpO2 and PETCO2 at D15 for AU (r = −0.92, p < 0.005), but not for MX (r=0.28). HVR tended to be higher for AU than MX (0.69 ±0.49 vs 0.25 ±0.17L.min−1.%−1; p = 0.06), as was HCVR (2.03 ±0.62 vs 1.42 ±0.43L.min−1.mmHg−1; p = 0.07). For AU, the HVR at SL was correlated with SpO2 (r=0.78) and PETCO2 (p = −0.81) at D15, and HCVR at D10 was correlated with SpO2 (r=0.81) and PETCO2 (r = −0.81) at D15 (all p < 0.05). There were no significant correlations amongst HVR, HCVR and SpO2 or PETCO2 for MX. CONCLUSION For elite junior cyclists undergoing short-term altitude exposure, HVR and HCVR play a role in ventilatory acclimatization and maintenance of SpO2, but these variables are not related to PETCO2 or SpO2 in cyclists who are life-long altitude residents. This research was supported by an Australian Sports Comission grant

Measuring ventilatory acclimatization to hypoxia: comparative aspects

Acclimatization to hypoxia increases the hypoxic ventilatory response (HVR) in mammals. The literature on humans shows that several protocols can quantify this increase in HVR if isocapnia is maintained, regardless of the exact level of Pa CO 2 . In rats, the isocapnic HVR also increases with chronic hypoxia and this cannot be explained by a non-specific effect of increased ventilatory drive on the HVR. Changes in arterial pH are predicted to increase the HVR during chronic hypoxia in rats but this has not been quantified. Limitations in determining mechanisms of change in the HVR from reflex experiments are discussed. Chronic hypoxia changes some, but not all, indices of ventilatory motor output that are useful for normalization between experiments on anesthetized rats. Finally, ducks also show time-dependent increases in ventilation during chronic hypoxia and birds provide a good experimental model to study reflex interactions. However, reflexes from intrapulmonary CO 2 chemoreceptors can complicate the measurement of changes in the isocapnic HVR during chronic hypoxia in birds.

The Effect of Flumazenil on Midazolam-induced Depression of the Ventilatory Response to Hypoxia during Isohypercarbia

While flumazenil reverses benzodiazepine-induced sedation, its ability to antagonize the ventilatory depressant effects of benzodiazepines has not been fully established. A randomized, double-blind study was conducted to determine whether flumazenil effectively reverses midazolam-induced depression of the hypoxic ventilatory response. Twelve healthy male volunteers received intravenous midazolam 0.12 +/- 0.01 mg.kg-1 followed by either flumazenil 1.0 mg or placebo. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: as Spo2 decreased to 70% VE and tidal volume were continuously recorded. Hypoxic response determinations were performed before and after midazolam, as well as 3, 30, 60, 120, and 180 min after flumazenil or placebo. After midazolam, the slope of the hypoxic ventilatory response curve (VE vs. SpO2) decreased to 0.59 +/- 0.05 (means +/- SE) times its premidazolam baseline; likewise, at Spo2 = 90%, minute ventilation (VE90) and tidal volume (TV90) decreased to 0.70 +/- 0.04 and 0.62 +/- 0.03 times baseline, respectively. Three minutes after flumazenil, the slope increased to 1.10 +/- 0.13 times baseline (P < 0.05 vs. postmidazolam), while following placebo, it was only 0.81 +/- 0.09 times baseline (P = NS vs. postmidazolam, P < 0.05 between treatments). VE90 and TV90, after flumazenil, increased to 1.45 +/- 0.15 and 1.27 +/- 0.09 times baseline, respectively (P < 0.05 vs. postmidazolam); these increases were significantly greater than the corresponding changes observed after placebo (P < 0.05 between treatments). It was concluded that, after sedation with midazolam, flumazenil causes a greater increase in hypoxic ventilatory response during isohypercarbic conditions than does placebo, and may, therefore, be useful in the treatment of midazolam-induced ventilatory depression.

Combined effects of female hormones and exercise on hypoxic ventilatory response

Mild elevations in metabolic rate may influence hypoxic ventilatory response (HVR) differently in men and women. The possible involvement of the female hormones in accounting for this gender difference is supported by observations that mild exercise raised HVR in ovariectomized women treated with estrogen and progestin but not in the same women treated with placebo (Regensteiner et al., 1989). We compared the effects of mild exercise on HVR in 12 women in the follicular phase vs the luteal phase of the menstrual cycle and during MPA (medroxyprogesterone acetate, 20 mg tid) vs placebo treatment. End-tidal P CO 2 fell in the luteal compared to the follicular phase and in the follicular MPA compared to the follicular placebo condition. Resting HVR was similar in subjects in the follicular versus the luteal phases of the menstrual cycle and in MPA-treated vs placebo-treated subjects at either the existing (eucapnia) or follicular placebo (normocapnia) end-tidal P CO 2 . Mild exercise increased expired ventilation but not HVR in placebo-treated subjects in the follicular or luteal placebo conditions. In MPA-treated subjects, exercise raised HVR in the luteal phase ( P < 0.05) and tended to increase HVR in the follicular phase ( P = 0.08). The increase in HVR with exercise was greater in MPA-treated subjects than in women given placebo ( Δ rest to exercise = 26% vs 9%, P < 0.05). We concluded that elevations in progrestin levels achieved by administering progestin in the luteal phase of the menstrual cycle potentiated the effect of metabolic rate on HVR.

Combined effects of female hormones and metabolic rate on ventilatory drives in women

Increased resting ventilation (VE) and hypoxic and hypercapnic ventilatory responses occur during pregnancy in association with elevations in female hormones and metabolic rate. To determine whether increases in progestin, estrogen, and metabolic rate produced a rise in VE and hypoxic ventilatory response (HVR) similar in magnitude to that observed at full-term pregnancy, we studied 12 postmenopausal women after 1 wk of treatment with placebo, progestin (20 mg tid medroxyprogesterone acetate), estrogen (1.25 mg bid conjugated equine estrogens), and combined progestin and estrogen. Progestin alone or with estrogen raised VE at rest and decreased end-tidal PCO2 (PETCO2) by 3.9 +/- 0.8 and 3.3 +/- 0.6 Torr, respectively (both P less than 0.05), accounting for approximately one-fourth of the rise in VE and three-fourths of the PETCO2 reduction seen at full-term pregnancy. The addition of mild exercise sufficient to raise metabolic rate by 33-36% produced the remaining three-fourths of the rise in VE but no further decline in PETCO2. Combined progestin and estrogen raised HVR and hypercapnic ventilatory response more consistently than progestin alone and could account for one-half of the increase in HVR seen at full-term pregnancy. Mild exercise alone did not raise HVR, but when exercise was combined with progestin and estrogen administration, HVR rose by amounts equal to that seen at full-term pregnancy. We concluded that female hormones together with mild elevation in metabolic rate were likely responsible for the pregnancy-associated increases in VE and HVR.

Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia.

Mechanisms of ventilatory acclimatization to chronic hypoxia remain unclear. To determine whether the sensitivity of peripheral chemoreceptors to hypoxia increases during acclimatization, we measured ventilatory and carotid sinus nerve responses to isocapnic hypoxia in seven cats exposed to simulated altitude of 15,000 ft (barometric pressure = 440 Torr) for 48 h. A control group (n = 7) was selected for hypoxic ventilatory responses matched to the preacclimatized measurements of the experimental group. Exposure to 48 h of hypobaric hypoxia produced acclimatization manifested as decrease in end-tidal PCO2 (PETCO2) in normoxia (34.5 +/- 0.9 Torr before, 28.9 +/- 1.2 after the exposure) as well as in hypoxia (28.1 +/- 1.9 Torr before, 21.8 +/- 1.9 after). Acclimatization produced an increase in hypoxic ventilatory response, measured as the shape parameter A (24.9 +/- 2.6 before, 35.2 +/- 5.6 after; P less than 0.05), whereas values in controls remained unchanged (25.7 +/- 3.2 and 23.1 +/- 2.7; NS). Hypoxic exposure was associated with an increase in the carotid body response to hypoxia, similarly measured as the shape parameter A (24.2 +/- 4.7 in control, 44.5 +/- 8.2 in acclimatized cats). We also found an increased dependency of ventilation on carotid body function (PETCO2 increased after unilateral section of carotid sinus nerve in acclimatized but not in control animals). These results suggest that acclimatization is associated with increased hypoxic ventilatory response accompanied by enhanced peripheral chemoreceptor responsiveness, which may contribute to the attendant rise in ventilation.

Increased HVR in pregnancy: relationship to hormonal and metabolic changes.

In prior studies at high altitude, we have found that pregnancy increases maternal hypoxic ventilatory response (HVR) but the factors responsible are unknown. Changes in metabolic rate and hormones that occur during pregnancy have previously been shown to influence HVR. We therefore sought to determine the contribution of metabolic rate and hormonal changes to the pregnancy-associated rise in HVR. Pregnancy increased HVR in each of 20 normal, low-altitude (1,600 m) residents. As measured by the shape parameter A, HVR at week 36 was 237 +/- 26 (SE) or twofold higher than the 124 +/- 13 value measured 3 mo postpartum (P less than 0.01) despite the presence of the potentially depressant effects of hypocapnia [change in alveolar partial pressure of CO2 (delta PACO2) = -4 +/- 1 mmHg] and alkalosis [change in arterial pH (delta pHa) = 0.02 +/- 0.01 U] during pregnancy. Sixty percent of the increase in HVR values had occurred by week 20 of gestation at which time O2 consumption (VO2) and CO2 production (VCO2) were unchanged relative to values measured postpartum. The remaining 40% rise in HVR paralleled increases in VO2 and VCO2, and further elevation in VO2 and VCO2 with moderate exercise produced an additional increase in HVR. Serum estradiol and progesterone levels increased with pregnancy, but levels did not correlate with HVR. The women reporting the greatest symptoms of dyspnea had higher HVR A values at week 36 than the least dyspneic women (285 +/- 28 vs. 178 +/- 34, respectively, P less than 0.05). We concluded that factors intrinsic to pregnancy in combination with increased metabolic rate raised HVR twofold with pregnancy and may have contributed to the often-reported symptoms of dyspnea in pregnant women.