The ventilatory effects of sustained isocapnic hypoxia during exercise in humans.

To investigate how the ventilatory response to isocapnic hypoxia is modified by steady-state exercise, five subjects were studied at rest and performing 70 W bicycle exercise. At rest, isocapnic hypoxia (end-tidal PO2 50 Torr) for 25 min resulted in a biphasic response: an initial increase in ventilation was followed by a subsequent decline (HVD). During exercise, an end-tidal PO2 of 55-60 Torr was used. The magnitude of the initial ventilatory response to isocapnic hypoxia was increased from a mean +/ SE of 1.43 +/- 0.323 L/min per % arterial desaturation at rest to 2.41 +/- 0.424 L/min per % during exercise (P less than 0.05), but the magnitude of the HVD was reduced from 0.851 +/- 0.149 L/min per % at rest to 0.497 +/- 0.082 L/min per % during exercise (P less than 0.05). The ratio of HVD to the acute hypoxia response was reduced from 0.696 +/- 0.124 at rest to 0.202 +/- 0.029 during exercise (P less than 0.01). We conclude that while exercise augments the ventilatory sensitivity to hypoxia, it also has a direct effect on the mechanisms by which sustained hypoxia depresses peripheral chemosensitivity.     

Nicotine increases chemoreflex sensitivity to hypoxia in non-smokers

BACKGROUND: The peripheral chemoreflex contributes to cardiovascular regulation and represents the first line of defence against hypoxia. The effects of nicotine on chemoreflex regulation in non-smoking humans are unknown. METHOD: We conducted a prospective, randomized, crossover, and placebo-controlled study in 20 male non-smokers to test the hypothesis that nicotine increases chemoreflex sensitivity. The effects of two intakes of 2 mg nicotine tabs and placebo on sympathetic nerve activity to muscle circulation (muscle sympathetic nerve activity; MSNA), minute ventilation (Ve), blood pressure and heart rate were assessed during normoxia, moderate isocapnic hypoxia, hyperoxic hypercapnia and an isometric handgrip in 10 subjects. Maximal end-expiratory apnoeas were performed at baseline and at the end of the fifth minute of hypoxia. In a second experimental setting, we studied the ventilatory response to a more marked isocapnic hypoxia in 10 other volunteers. RESULTS: Mean MSNA and Ve were not modified by nicotine during the 5 min of normoxia or moderate hypoxia. In the presence of nicotine MSNA was related to oxygen desaturation (P < 0.01). The sympathoexcitatory effects of nicotine became especially evident when apnoeas achieved oxygen saturations less than 85% (511 +/- 44% increase in MSNA after the first intake, and 436 +/- 43% increase after the second intake versus 387 +/- 56% and 338 +/- 31% with placebo, respectively, P < 0.05). Nicotine also increased the ventilatory response compared with placebo when oxygen saturation decreased to less than 85% (P < 0.05). CONCLUSION: This is the first study to demonstrate that nicotine increases peripheral chemoreflex sensitivity to large reductions in arterial oxygen content in healthy non-smokers.     

Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea

BACKGROUND: The chemoreflexes are an important mechanism for regulation of both breathing and autonomic cardiovascular function. Abnormalities in chemoreflex mechanisms may be implicated in increased cardiovascular stress in patients with obstructive sleep apnea (OSA). We tested the hypothesis that chemoreflex function is altered in patients with OSA. METHODS AND RESULTS: We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor test in 16 untreated normotensive patients with OSA and 12 normal control subjects matched for age and body mass index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the patients with OSA than in the control subjects (43+/-4 versus 21+/-3 bursts per minute; P<0. 001). During hypoxia, patients with OSA had greater increases in minute ventilation (5.8+/-0.8 versus 3.2+/-0.7 L/min; P=0.02), heart rate (10+/-1 versus 7+/-1 bpm; P=0.03), and mean arterial pressure (7+/-2 versus 0+/-2 mm Hg; P=0.001) than control subjects. Despite higher ventilation and blood pressure (both of which inhibit sympathetic activity) in OSA patients, the MSNA increase during hypoxia was similar in OSA patients and control subjects. When the sympathetic-inhibitory influence of breathing was eliminated by apnea during hypoxia, the increase in MSNA in OSA patients (106+/-20%) was greater than in control subjects (52+/-23%; P=0.04). Prolongation of R-R interval with apnea during hypoxia was also greater in OSA patients (24+/-6%) than in control subjects (7+/-5%) (P=0.04). Autonomic, ventilatory, and blood pressure responses to hypercapnia and the cold pressor test in OSA patients were not different from those observed in control subjects. CONCLUSIONS: OSA is associated with a selective potentiation of autonomic, hemodynamic, and ventilatory responses to peripheral chemoreceptor activation by hypoxia.     

Slow breathing reduces chemoreflex response to hypoxia and hypercapnia, and increases baroreflex sensitivity.

OBJECTIVE: To investigate whether breathing more slowly modifies the sensitivity of the chemoreflex and baroreflex. DESIGN SETTING: University of Pavia, IRCCS Policlinico S. Matteo. PARTICIPANTS: Fifteen healthy individuals. INTERVENTIONS: Progressive isocapnic hypoxia and progressive hyperoxic hypercapnia were measured during spontaneous breathing and during a breathing rate fixed at 6 and 15 breaths per minute (b.p.m.). Main outcome measures: Variations in chemo- and baroreflex sensitivity (by monitoring ventilation, oxygen saturation, end-tidal carbon dioxide, R-R interval and blood pressure) induced by different breathing rates. RESULTS: Breathing at 6 b.p.m. depressed (P < 0.01) both hypoxic and hypercapnic chemoreflex responses, compared with spontaneous or 15 b.p.m. controlled breathing. Hypoxic and hypercapnic responses during spontaneous breathing correlated with baseline spontaneous breathing rate (r = -0.52 and r = +0.51, respectively; P = 0.05). Baroreflex sensitivity was greater (P < 0.05) during slow breathing at baseline and remained greater at end rebreathing. CONCLUSIONS: Slow breathing reduces the chemoreflex response to both hypoxia and hypercapnia. Enhanced baroreflex sensitivity might be one factor inhibiting the chemoreflex during slow breathing. A slowing breathing rate may be of benefit in conditions such as chronic heart failure that are associated with inappropriate chemoreflex activation.     

Reduced inspiratory drive following laryngeal chemoreflex apnea during hypoxia.

Respiratory inhibition following laryngeal water administration was investigated by breath-by-breath analysis of inspiratory ventilation (VI) and central inspiratory drive (P0.1) in 15 unanesthetized lambs studied in 0.21 FIO2 (PaO2: 82-92 torr, PaCO2 41-43 torr) and in 0.1 FIO2 (Pao2 30-34 torr, PaCO2 32-33 torr). During the 30 sec period after stimulation, VI decreased significantly compared to prestimulation levels both in 0.21 FIO2 (-22, -21 and -18%) and in 0.1 FI(O2), (-16, -23 and -19%) at 5, 16 and 29 days, respectively. In contrast, P0.1 remained at prestimulation levels during normoxia in all age groups (1, 10 and 9%, NS), but decreased significantly during hypoxia (-11 and -13%, P < 0.05) at 16 and 29 days, respectively. Poststimulation apnea duration was significantly related to the decrease in VI (P < 0.001) but not to the change in P0.1. Laryngeal stimulation during hypoxemia/hypocapnia induces a prolonged decrease of central inspiratory drive in postneonatal lambs, a finding of potential significance for the mechanisms of sudden infant death syndrome.     

Effects of dopamine and domperidone on ventilation during isocapnic hypoxia in humans.

In order to investigate the role of dopamine in the ventilatory response to sustained, isocapnic hypoxia six subjects were studied three times in each of three pharmacological conditions: (1) in the absence of any drug administration, (2) during i.v. infusion of dopamine (3 micrograms.kg-1.min-1), and (3) after pretreatment with domperidone. Otherwise the experimental protocol was identical on each day and consisted of holding the subjects' end-tidal PO2 at 100 Torr for 10 min, then 50 Torr for 20 min and finally at 100 Torr again for 5 min. End-tidal PCO2 was held constant 2-3 Torr above normal throughout the experiment. Domperidone increased, and dopamine decreased the magnitudes of both the fast on- and off-responses, but neither drug affected the magnitude of the hypoxic ventilatory decline (HVD). The results of this study suggests: (1) that a peripheral dopaminergic mechanism is not involved in the genesis of HVD, and (2) the peripheral chemoreflex may be modulated peripherally to produce HVD.     

Cerebrocortical oxygenation and ventilatory response during sustained hypoxia

Cerebrocortical oxygenation was monitored in 8 healthy adults during exposure to sustained isocapnic hypoxia. Subjects were maintained at an arterial oxygen saturation (SaO2) of 80% for 12 min with a rebreathing circuit while cerebrocortical oxygenation was assessed non-invasively using near-infrared (NIR) spectroscopy to measure changes in the oxidation state of cytochrome a,a3 (Cyt a,a3) and changes in cortical blood volume (tBV). During sustained hypoxia, subjects demonstrated a biphasic ventilatory response. The mean minute ventilation (VE) peak response was 255% of baseline at an average of 3.4 +/- 0.5 min (mean +/- SE) after the initiation of hypoxia. A subsequent significant attenuation of VE to 163% (P less than 0.05) of baseline occurred after an additional 8.6 min. NIR monitoring revealed a significant (P less than 0.05) decrease in oxidized Cyt a,a3 as well as a significant (P less than 0.05) increase in tissue blood volume (tBV) at the time of peak VE. Both Cyt a,a3 and tBV remained stable during the remainder of the hypoxic period, despite attenuation of VE during sustained hypoxia. The data suggest that cerebrocortical oxygenation and blood flow remain constant when the ventilatory attenuation is observed during sustained hypoxia.     

Effect of isocapnic hypoxia on systolic time intervals in conscious man

The effects of progressive isocapnic hypoxia on the systolic time intervals were studied in 10 healthy human subjects. We induced hypoxia by a rebreathing method and monitored the arterial oxygen saturation continuously and non-invasively by means of an ear oximeter. Arterial oxygen saturation (SaO2) was allowed to fall to a level of 75 per cent and was then held constant for five minutes. As SaO2 fell, heart rate increased linearly, with a mean increase of 0.83 beats/min per one per cent fall in SaO2. The pre-ejection phase index decreased from a mean of 127.2 ms at full oxygen saturation to 120.1 ms at steady-state hypoxia levels, while the ratio of the pre-ejection phase to left ventricular ejection time decreased from a mean of 0.330 to 0.301. The left ventricular ejection time index increased from 417.4 ms to 429.3 ms, while no statistically significant difference was found in the length of electromechanical systole.     

Short-term isocapnic hypoxia and coagulation activation in patients with sleep apnea

Hemostatic changes might contribute to the increased risk of cardiovascular and cerebrovascular events in patients with obstructive sleep apnea (OSA). We investigated the effect of a short-term isocapnic hypoxic challenge on coagulation activation markers thrombin/antithrombin III complexes (TAT) and D-dimer in OSA. Thirty-two OSA patients (mean age 48 +/- 11 years) inhaled a gas mixture containing 10% O(2) and 90% N(2) and further adjusted to yield pulse oximetry saturation of 80-85% for 5 minutes. Plasma levels of TAT and D-dimer were measured immediately before and immediately after the hypoxic challenge. The hypoxic challenge provoked a significant increase in TAT (p < 0.001) and in D-dimer (p = 0.037). Mean nocturnal oxygen saturation from the sleep recordings correlated with D-dimer increase (r = -0.37, p = 0.041). Also, OSA patients with a history of hypertensive parents had greater D-dimer increase in response to hypoxia than patients having normotensive parents (p = 0.035). Parental hypertension independently explained 15% of the variance in D-dimer increase after hypoxia (p = 0.035). Oxygen desaturation during sleep may predispose OSA patients, in particular those with a parental history of hypertension, to a hypercoagulable state providing one explanation for the increased risk of atherothrombotic events in this population.     

Mild isocapnic hypoxia enhances the bronchial response to methacholine in asthmatic subjects

We studied the effect of mild isocapnic hypoxia (FIO2 = 15.5%) on lung mechanics, heart rate, circulating plasma catecholamines, and bronchial responsiveness to methacholine in ten asthmatic adults. Hypoxia did not alter lung mechanics (i.e., dynamic pulmonary compliance [CLdyn], pulmonary resistance [RL]) nor did it increase plasma catecholamines, but it significantly increased bronchial responsiveness to aerosolized methacholine, as assessed by the fall in forced expiratory volume in one second (FEV1: 1.2 +/- 0.18 versus 0.9 +/- 0.14 L/s, p less than 0.05), the rise in RL (RL: 19.1 +/- 1.4 versus 8.4 +/- 1 cm H2O/L/s, p less than 0.05), and the steeper slope of the dose-response curve to methacholine. We concluded that the hypoxic characteristic of asthmatic attacks may aggravate airflow obstruction.     

Effect of isocapnic hypoxia on systolic time intervals in conscious man.

The effects of progressive isocapnic hypoxia on the systolic time intervals were studied in 10 healthy human subjects. We induced hypoxia by a rebreathing method and monitored the arterial oxygen saturation continuously and non-invasively by means of an ear oximeter. Arterial oxygen saturation (SaO2) was allowed to fall to a level of 75 per cent and was then held constant for five minutes. As SaO2 fell, heart rate increased linearly, with a mean increase of 0.83 beats/min per one per cent fall in SaO2. The pre-ejection phase index decreased from a mean of 127.2 ms at full oxygen saturation to 120.1 ms at steady-state hypoxia levels, while the ratio of the pre-ejection phase to left ventricular ejection time decreased from a mean of 0.330 to 0.301. The left ventricular ejection time index increased from 417.4 ms to 429.3 ms, while no statistically significant difference was found in the length of electromechanical systole.     

Effects of intermittent hypoxia on the isocapnic hypoxic ventilatory response and erythropoiesis in humans

Isocapnic hypoxic ventilatory response (HVR) and hematological variables were measured in nine adult males (age: 29.3+/-3.4) exposed to normobaric intermittent hypoxia (IH, 2 h daily at FI(O(2))=0.13, equivalent to 3800 m altitude) for 12 days. Mean HVR significantly increased during IH, however, after reaching a peak on Day 5 (0.79+/-0.12 vs. 0.27+/-0.11 L.min(-1).%(-1) on Day 1, P<0.05), it progressively decreased toward a lower value (0.46+/-0.16 L min(-1) x %(-1) on Day 12). In contrast, the subjects showed no changes in the ventilatory data and arterial O(2)-saturation in normoxia or poikilocapnic hypoxia (PET(CO(2)) uncontrolled). Hematocrit and hemoglobin concentration did not change, but the reticulocyte count increased by Day 5 (P<0.01). Our results suggest that moderate intermittent hypoxia induces changes in ventilatory O(2)-sensitivity and triggers the hematological acclimatization by increasing the percentage of reticulocytes in the blood. Normal ventilatory acclimatization to hypoxia was, however, not observed and the mechanisms involved in the biphasic changes in HVR we observed remain to be determined.     

Dobutamine potentiates the peripheral chemoreflex in patients with congestive heart failure

BACKGROUND: beta-Adrenergic agonists may increase chemoreflex sensitivity to hypoxia in normal humans. Chemoreflex function is important in the pathophysiology of heart failure. Whether the beta-1 agonist dobutamine, which is frequently administered to patients with heart failure, alters their chemoreflex sensitivity is not known. METHODS: We tested the hypothesis that dobutamine increases chemoreflex sensitivity in patients with congestive heart failure (CHF) using a randomized, double-blinded, placebo-controlled study design. We assessed the influence of dobutamine on minute ventilation and hemodynamics during normoxic breathing and during peripheral chemoreflex deactivation by hyperoxia (100% O(2)) in 9 patients with CHF. RESULTS: Dobutamine increased minute ventilation in patients with CHF (9.4+/-0.9 versus 8.4+/-0.7 L/min, P=.005) during normoxia. Peripheral chemoreflex deactivation by hyperoxia suppressed the ventilatory effects of dobutamine (10.4+/-1.4 L/min for dobutamine versus 10.0+/-1.2 L/min for placebo, P=.34). CONCLUSIONS: Dobutamine increases ventilation during normoxia, but not during hyperoxia in patients with CHF. We conclude that dobutamine enhances peripheral chemoreflex sensitivity in patients with congestive heart failure.     

Role of alpha 2-adrenergic receptors in the carotid body response to isocapnic hypoxia.

Alpha-2 adrenergic receptors have been identified in numerous tissues containing norepinephrine. Carotid bodies are sensory organs that detect changes in partial pressure of arterial oxygen and contain substantial amounts of norepinephrine. However, neither the presence nor the functional significance of alpha 2-receptors in the carotid body is known. The purpose of the present study was two-fold: (1) to determine the alpha 2-receptor density in the carotid body and (2) to assess their participation in the chemoreceptor responses to hypoxia. Experiments were performed on 27 anesthetized, paralyzed and artificially ventilated cats. Alpha-2 receptor binding determined by [125I]p-iodoclonidine averaged 10 +/- 2 fmol/mg of protein (n = 18 carotid bodies). Intracarotid infusion of an alpha 2-agonist (guanabenz; 0.5, 1, and 5 micrograms/min for 5 min) caused a dose-dependent depression of the baseline activity and 5 micrograms/min reduced the magnitude of the chemoreceptor response to isocapnic hypoxia by 61% (n = 8). Systemic administration of an alpha 2-antagonist (SKF-86466, 0.5-2 mg/kg) prevented the effects of guanabenz on the chemoreceptor activity. Furthermore, alpha 2-antagonist (0.5-2 mg/kg, i.v.) alone significantly increased baseline discharge by 68% and potentiated the chemoreceptor response to isocapnic hypoxia by 46% (n = 10). These results demonstrate that (1) alpha 2-adrenergic receptors are present in the carotid body and (2) they exert an inhibitory influence on chemoreceptor response to hypoxia. It is suggested that norepinephrine may tune the carotid body responses to hypoxia in part by its action on alpha 2-receptors.     

Ventilatory response to 2-h sustained hypoxia in humans

We used two protocols to determine if hypoxic ventilatory decline (HVD) involves changes in slope and/or intercept of the isocapnic HVR (hypoxic ventilatory response, expressed as the increase in VI per percentage decrease in SaO2). Isocapnia was defined as 1.5 mmHg above hyperoxic PET(CO2). HVD was recorded in protocol I during two sequential 25 min exposures to isocapnic hypoxia (85 and 75% SaO2, n=7) and in protocol II during 14 min of isocapnic hypoxia (90% SaO2, FIO2=0.13, n=15), extended to 2 h of hypoxia with CO2-uncontrolled in eight subjects. HVR was measured by the step reduction to sequentially lower levels of SaO2 in protocol I and by 3 min steps to 80% SaO2 at 8, 14 and 120 min in protocol II. The intercept of the HVR (VI predicted at SaO2=100%) decreased after 14 and 25 min in both protocols (P<0.05). Changes in slope were observed only in protocol I at SaO2=75%, suggesting that the slope of the HVR is more sensitive to depth than duration of hypoxic exposure. After 2 h of hypoxia the HVR intercept returned toward control value (P<0.05) with still no significant changes in the HVR slope. We conclude that HVD in humans involves a decrease in hyperoxic ventilatory drive that can occur without significant change in slope of the HVR. The partial reversal of the HVD after 2 h of hypoxia may reflect some components of ventilatory acclimatization to hypoxia.     

Assessment of chemoreflex sensitivity in free breathing young subjects by correction for respiratory influence

BACKGROUND: The assessment of autonomic function is an important tool for risk stratification in critically ill patients. Peripheral cardiac chemoreflex sensitivity has been considered a marker for increased risk of sudden cardiac death. In normals, the evaluation of peripheral cardiac chemoreflex sensitivity is performed under controlled breathing conditions during inhalation of hypoxic gas. Since this is poorly tolerated by patients, they are commonly studied under hyperoxic conditions, which are not physiological. METHODS: We studied 20 healthy volunteers who underwent free and controlled breathing of a hypoxic gas mixture (10% O2 in N2) over 5 min. Values of peripheral cardiac chemoreflex sensitivity, corrected for respiratory influence, were compared with the results obtained experimentally under controlled breathing conditions in the same subjects. RESULTS: We found a substantial difference between values obtained during free and controlled breathing (3.64 +/- 0.81 vs. 1.53 +/- 0.32 ms/mmHg, respectively; P < 0.05). After application of a respiratory correction, described and validated in this article, no significant difference was seen for these values (0.89 +/-0.91 vs. 1.53 +/- 0.32 ms/mmHg, P = 0.46). CONCLUSIONS: This approach allows the evaluation of peripheral cardiac chemoreflex sensitivity in free breathing subjects. This correction could improve the assessment of cardiac chemoreflex sensitivity in patients with cardiorespiratory disorders, who find it difficult to control their breathing according to an experimental protocol.     

Acute sustained hypoxia suppresses the cough reflex in healthy subjects

RATIONALE: An intact cough reflex is important to protect the lung from injurious substances and to clear excess secretions. A blunted cough reflex may be harmful or even fatal in respiratory disease. Hypoxia is common in respiratory disorders and has been shown to have depressant effects on respiratory sensation and ventilation. We hypothesized that it might also suppress the cough reflex. OBJECTIVES: To determine if acute hypoxia increases cough threshold and cough tachyphylaxis to inhaled capsaicin. METHODS: On two occasions, 16 healthy subjects inhaled a saline control followed by doubling doses of capsaicin aerosol (range, 0.49-500 microM) every minute for 15 s during controlled ventilation (approximately 190% baseline) with isocapnic hypoxia (SpO2, approximately 80%) or isocapnic normoxia, in random order. When a subject responded to a dose with five or more coughs, the next doubling dose of capsaicin was administered continuously for 60 s to assess acute tachyphylaxis. MAIN RESULTS: The capsaicin concentration required to elicit five coughs was significantly higher during isocapnic hypoxia compared with normoxia (29.6 +/- 16.0 vs. 23.4 +/- 15.6 microM, p = 0.01). During continuous capsaicin inhalation, significantly more coughs were evoked in the first 10 s compared with the last (2.3 +/- 0.3 vs. 1.3 +/- 0.3, p < 0.01), indicating cough tachyphylaxis. However, the decrease was the same during hypoxia and normoxia (-1.3 +/- 0.4 vs. -0.9 +/- 0.6, p = 0.54). CONCLUSIONS: Acute isocapnic hypoxia suppresses cough reflex sensitivity to inhaled capsaicin. This finding raises the possibility that the cough reflex may be impaired during acute exacerbations of hypoxic-respiratory disorders.     

Changes in erythropoiesis and renal ultrastructure during exposure of mice to hypoxia.

During hypoxia, elevated ESF levels occur which are accompanied by increased erythropoietic activity resulting in progressive elevation of the haemoglobin and haematocrit concentration. An attempt has been made to correlate ultrastructural changes in the kidney with changes in serum ESF concentrations and the erythropoietic state of mice exposed to continuous hypoxia for 3 weeks. A series of changes in the epitheloid and proximal tubules cells occurred which may be related to the biogenesis of erythropoietin. However, no detectable ESF or renal erythropoietic factor could be extracted from the kidneys at the time of maximal ultrastructural changes. Although some ESF-inhibitory material was demonstrated, it could not be extracted into lipid solvents. It is suggested that the failure to consistently extract an erythropoietic factor from the kidneys of hypoxic mice may be related to the absence of renal storage at the onset of increased peripheral demand. Other levels and durations of hypoxia may help to elucidate the role of the kidneys in regulating serum ESF levels.