Acute Hypoxic Response Research Articles

Amyloid ? peptides mediate physiological remodelling of the acute O sensitivity of adrenomedullary chromaffin cells following chronic hypoxia

The non-neurogenic response of the neonatal adrenal medulla is vital in cardiovascular and respiratory development and to the survival of newborns exposed to hypoxic stress. Here, we examined the acute hypoxic response of immortalised rat adrenomedullary chromaffin cells following exposure to chronic hypoxia (CH; 6% O(2) for 24 h). Ca(2+) and K(+) channel currents were recorded using by whole-cell patch-clamp. Following incubation in CH, the acute O(2) sensitivity of K(+) current in immortalised adrenomedullary chromaffin (MAH) cells was enhanced due to a selective increase in the density of an O(2)-sensitive Ca(2+)-dependent K(+) current, secondary to ROS-mediated augmentation of voltage-gated Ca(2+) currents. The effect of CH on Ca(2+) currents was not additive to exogenous Abeta(1-40) and was blocked by the gamma-secretase inhibitors gamma-X and gamma-VI, demonstrating a role for amyloid beta peptide (AbetaP) production. Ca(2+) current enhancement was abolished in the presence of the transcription inhibitor actinomycin D but unaffected by the vacuolar H(+) ATPase inhibitor bafilomycin A1. AbetaP production and transcriptional regulation during CH regulated the properties of a peripheral chemosensory cell, defining a role for these enigmatic peptides in the signalling pathway of a physiological response to CH in the developing cardiovascular system.

Simultaneous Measurement and Integrated Analysis of Analgesia and Respiration after an Intravenous Morphine Infusion

To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans. Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (gamma), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM. Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter gamma was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01). Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.

Ventilatory, cerebrovascular, and cardiovascular interactions in acute hypoxia: regulation by carbon dioxide.

This study examined the effect of high, normal, and uncontrolled end-tidal Pco(2) (Pet(CO(2))) on the ventilatory, peak cerebral blood flow velocity (V(p)), and mean arterial blood pressure (MAP) responses to acute hypoxia. Nine healthy subjects undertook, in random order, three hypoxic protocols (end-tidal Po(2) was held at eight steps between 300 and 45 Torr) in conditions of hypercapnia, isocapnia, or poikilocapnia (Pet(CO(2)) +7.5 Torr, +1.0 Torr, or uncontrolled, respectively). Transcranial Doppler ultrasound was used to measure V(p) in the middle cerebral artery. The slopes of the linear regressions of ventilation, V(p), and MAP with arterial O(2) saturation were significantly greater in hypercapnia than in both isocapnia and poikilocapnia (P < 0.05). Strong, significant correlations were observed between ventilation, V(p), and MAP with each Pet(CO(2)) condition. These data suggest that 1). a high acute hypoxic ventilatory response (AHVR) decreases the acute hypoxic cerebral blood flow responses during poikilocapnia hypoxia, due to hypocapnic-induced cerebral vasoconstriction; and 2). in hypercapnic hypoxia, a high AHVR is associated with a high acute hypoxic cerebral blood flow response, demonstrating a linkage of individual sensitivities of ventilation and cerebral blood flow to the interaction of Pet(CO(2)) and hypoxia. In summary, the between-individual variability in AHVR is shown to be firmly linked to the variability in V(p) and MAP responses to hypoxia. Individuals with a high AHVR are found also to have high V(p) and MAP responses to hypoxia.

Post-transcriptional Control of Human maxiK Potassium Channel Activity and Acute Oxygen Sensitivity by Chronic Hypoxia

Various cardiorespiratory diseases (e.g. congestive heart failure, emphysema) result in systemic hypoxia and patients consequently demonstrate adaptive cellular responses which predispose them to conditions such as pulmonary hypertension and stroke. Central to many affected excitable tissues is activity of large conductance, Ca2+-activated K+ (maxiK) channels. We have studied maxiK channel activity in HEK293 cells stably co-expressing the most widely distributed of the human alpha- and beta-subunits that constitute these channel following maneuvers which mimic severe hypoxia. At all [Ca2+]i, chronic hypoxia (approximately 18 mm Hg, 72 h) increased K+ current density, most markedly at physiological [Ca2+]i K+ currents in cells cultured in normoxia showed a [Ca2+]i-dependent sensitivity to acute hypoxic inhibition ( approximately 25 mm Hg, 3 min). However, chronic hypoxia dramatically changed the Ca2+ sensitivity of this acute hypoxic inhibitory profile such that low [Ca2+]i could sustain an acute hypoxic inhibitory response. Chronic hypoxia caused no change in alpha-subunit immunoreactivity with Western blotting but evoked a 3-fold increase in beta-subunit expression. These observations were fully supported by immunocytochemistry, which also suggested that chronic hypoxia augmented alpha/beta-subunit co-localization at the plasma membrane. Using a novel nuclear run-on assay and RNase protection we found that chronic hypoxia did not alter mRNA production rates or steady-state levels, which suggests that this important environmental cue modulates maxiK channel function via post-transcriptional mechanisms.

Pharmacology (83)

Influence of tramadol on the ventilatory response to hypoxia in humans. (University of Edinburgh, Edinburgh, United Kingdom) Br J Anaesth 2000;85:211–216.In this study, the effect of tramadol on the ventilatory response to 7 min acute isocapnic hypoxia during steady mild hypercapnia in 14 healthy volunteers (7 male, 7 female) was studied. The acute hypoxic response was measured before and 1 h after oral placebo or tramadol (100 mg). After tramadol, ventilation during mild hypercapnia (mean 11.28 liters min−1) was significantly less (P &lt; 0.05) than during placebo baseline (13.93 liters min−1), tramadol baseline (14.63 liters min−1), or after placebo (14.9 liters min−1), confirming that tramadol has a small depressive effect on the hypercapnic ventilatory response. There was no significant difference in the hypoxic ventilation/Spo2 response measured during the placebo baseline (0.99), placebo (1.18), tramadol baseline (0.78) or tramadol (0.68) runs. These data suggest that tramadol does not depress the hypoxic ventilatory response.

Effects of haemoconcentration and haemodilution on acute hypoxia-induced pulmonary hypertension and changes in vascular compliance of isolated rabbit lungs.

Erythrocytes influence the magnitude of hypoxia-induced pulmonary artery pressure increase. It is, however, unknown to what extent haemoconcentration and haemodilution affect this response and whether intrapulmonary blood volume (and thus vessel dimensions) alters the magnitude of pressure increase. Furthermore, it is unclear whether the haemodilution/ haemoconcentration-dependent pressure increase is flow-related, via flow-dependent changes in vasomotor tone or rheologic effects, or can also be observed under no-flow conditions. Experimental study in isolated rabbit lungs (n = 12) perfused with autologous blood at constant flow (100 ml/min) and ventilated with 5% carbon dioxide in air. Laboratory for experimental studies. Haemoconcentration (centrifugation) and haemodilution (Krebs-Henseleit/albumin) were carried out, resulting in haematocrits between 50% and 0%. During hypoxic ventilation, inspiratory oxygen fraction was reduced from 0.20 to 0.03. Under constant flow conditions, haemodilution (from a Hct of 34-36% to 0-1%) decreased hypoxic pulmonary artery pressure response to one-third (from 10.8 +/- 2.3 cmH2O to 3.1 +/- 1.0 cmH2O, P < 0.05), while haemoconcentration did not affect the magnitude of hypoxic response (10.5 +/- 2.0 cmH2O). For all haematocrit values an increase in pulmonary blood volume (by 5 ml) decreased the magnitude of pressure response. Hypoxia-induced changes in static vascular filling pressure (double occlusion pressure) and vascular compliance were used to assess the strength of hypoxic vasoconstriction under static conditions. Neither haemoconcentration nor haemodilution altered hypoxia-induced changes in either variable. The magnitude of the acute hypoxic pressure response is not altered by haemoconcentration, but significantly reduced by haemodilution. In contrast, neither haemoconcentration nor haemodilution influenced hypoxia-induced changes in static vascular filling pressure and compliance. This suggests that the degree of hypoxic pulmonary vasoconstriction is not affected under static conditions and that the red blood cell-dependence of the magnitude of hypoxic pressure response is based on flow-related mechanisms.

Influence of tramadol on the ventilatory response to hypoxia in humans

We studied the effect of tramadol on the ventilatory response to 7 min acute isocapnic hypoxia (SpO2 85.1 (SD 0.4)%) during steady mild hypercapnia (PE'CO2 0.7 kPa above normoxic baseline) in 14 healthy volunteers (seven male). The acute hypoxic response was measured before and 1 h after oral placebo or tramadol (100 mg). After tramadol, ventilation during mild hypercapnia (mean 11.28 litres min-1) was significantly less (P < 0.05) than during placebo baseline (13.93 litres min-1), tramadol baseline (14.63 litres min-1), or after placebo (14.95 litres min-1), confirming that tramadol has a small depressive effect on the hypercapnic ventilatory response. There was no significant difference in the hypoxic ventilation/SpO2 response (1 min-1 %-1) measured during the placebo baseline (0.99), placebo (1.18), tramadol baseline (0.78) or tramadol (0.68) runs. These data suggest that tramadol does not depress the hypoxic ventilatory response.

Signaling pathways of the acute hypoxic ventilatory response in the nucleus tractus solitarius

The nucleus tractus solitarii (nTS) provides the initial central synaptic relay to peripheral chemoreceptor afferent inputs elicited by changes in oxygen tension. Insofar, the overall cumulative evidence pointing towards the N-methyl- d-aspartate (NMDA) glutamate receptor as the critical receptor underlying the early component of the hypoxic ventilatory response (HVR) is reviewed in detail. In addition, we will present recent findings supporting a role for platelet-derived growth factor (PDGF) β receptor activation in modulation of the late phase of HVR. This evidence underscores the proposal of a working model for intracellular signaling pathways, downstream to the NMDA glutamate and PDGF-β receptors in nTS neurons, which may contribute to both the ventilatory characteristics of the acute hypoxic response and to subsequently occurring functional adaptations and synaptic plasticity phenomena.

Effects of alfentanil on the ventilatory response to sustained hypoxia.

The ventilatory response to acute hypoxia is biphasic, with an initial rapid increase followed by a slower decline. In humans, there is evidence that the magnitude of the decline in ventilation is proportional to the size of the initial increase. This study was done to define the role of exogenous opioids in the ventilatory decline seen with prolonged hypoxia. Ten healthy persons were exposed to isocapnic hypoxia for 25 min, followed by 5 min of isocapnic normoxia and 5 min of isocapnic hypoxia. These conditions were repeated during a computer-controlled alfentanil infusion. Serum alfentanil levels were constant among the volunteers (38+/-12 ng/ml). Alfentanil decreased both the initial and second acute hypoxic responses (from 1.27+/-0.73 to 0.99+/-0.39 l x min(-1) x %(-1), P < 0.05; and from 0.99+/-0.70 to 0.41+/-0.29 l x min(-1) x %(-1), P < 0.05, respectively). The magnitude of the decrease in ventilation during the 25 min of hypoxia was not changed (10+/-3.3 l/min for control; 12.3+/-7.5 l/min for alfentanil). Alfentanil reduced the acute ventilatory response to hypoxia. The absolute value of hypoxic ventilatory decline was not increased, but a measure of residual hypoxic ventilatory decline (the ratio of ventilation between the second and first steps into hypoxia) was decreased, which supports the hypothesis that opioids potentiate centrally mediated ventilatory decline.

In vitro responses of VLM neurons to hypoxia after normobaric hypoxic acclimatization

Hypoxic acclimatization involves an initial rapid ventilatory response followed by a more gradual increase in ventilation over a period of 24 to 48 h in both humans and rats. In addition, the acute ventilatory response to hypoxia is accentuated following hypoxic acclimatization. The purpose of the present investigation was to determine if hypoxic acclimatization augments the acute hypoxic response of neurons in the ventrolateral medulla (VLM). Brain slices (400 μm) containing the ventrolateral medulla were prepared from Sprague-Dawley rats acclimatized to hypoxia (10% O 2) for 4–5 days ( n = 4) and 9–10 days ( n = 4) and from rats maintained in a normoxic environment ( n = 4). Extracellular recordings demonstrated that there were no significant differences in the basal pattern or discharge rate of VLM neurons from animals exposed to short (10.8 ± 0.9 Hz, n = 51), or long (10.1 ± 1.1 Hz, n = 59) periods of hypoxia compared to control neurons (10.8 ± 1.1 Hz, n = 52). The proportion of neurons stimulated (∼70%), inhibited (∼20%) and unaffected (∼10%) by an acute bout of hypoxia (10% O 2) was also similar among groups. However, acute hypoxia elicited a greater increase in discharge frequency in neurons from rats exposed to the short period of hypoxia compared to the responses from neurons in the control and longer acclimatization groups. Thus, the responsivity of VLM neurons during the early stages of hypoxic acclimatization is altered in a manner consistent with the respiratory responses associated with acclimatization.

Influence of oral clonidine on the ventilatory response to acute and sustained isocapnic hypoxia in human males

Animal studies suggest that alpha 2 agonists inhibit the chemoreceptor response to hypoxia. We have examined the effect of oral clonidine on the ventilatory response to sustained, isocapnic hypoxia (SpO2 79.7% (SD 1.1%) for 20 min) in eight male subjects. The hypoxic ventilatory response was measured before and after both clonidine and placebo. Clonidine had no significant effect on baseline ventilation or gas exchange. After clonidine, the acute hypoxic response (AHR) (mean 5.81 (95% confidence limits 1.94, 9.68) litre min-1) was significantly less than control (10.40 (5.97, 14.83) litre min-1) and hypoxic ventilatory decline (HVD) (3.42(2.35, 4.49) litre min-1) was also significantly less than control (6.49(3.92, 9.06) litre min-1) (P < 0.05). After placebo, AHR was similar to control but HVD was significantly larger (6.82(5.28, 8.36) litre min-1) than control (4.79(3.03, 6.55) litre min-1) (P < 0.05). Thus clonidine reduced both AHR and HVD but the absolute level of ventilation at the end of hypoxia was unchanged.

Acute hypoxic pulmonary vascular response does not accompany plasma endothelin-1 elevation in subjects susceptible to high altitude pulmonary edema.

We have previously shown that high altitude pulmonary edema-susceptible subjects (HAPE-S) have an accentuated pulmonary vascular response to hypoxia. In this study, we investigated the relationship between plasma endothelin-1 (ET-1) levels and the acute hypoxic pulmonary vascular response in HAPE-S and control subjects. In six HAPE-S and seven healthy subjects, we evaluated acceleration time/right ventricular ejection time (AcT/RVET) using Doppler echocardiography, and measured plasma ET-1 levels by radioimmunoassay (RIA) before and after 5 minutes of breathing 10% oxygen. The HAPE-S showed a significantly increased pulmonary vascular response to hypoxia compared with healthy subjects. However, no statistically significant changes of plasma ET-1 levels were observed before and after hypoxia in both groups. We conclude that the increased pulmonary vascular response to acute hypoxia in HAPE-S may not be related to ET-1 release.

Influences of subanesthetic isoflurane on ventilatory control in humans.

The purpose of this study was to quantify in humans the effects of subanesthetic isoflurane on the ventilatory control system, in particular on the peripheral chemoreflex loop. Therefore we studied the dynamic ventilatory response to carbon dioxide, the effect of isoflurane wash-in upon sustained hypoxic steady-state ventilation, and the ventilatory response at the onset of 20 min of isocapnic hypoxia. Study 1: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.5 mmHg) were performed in eight healthy volunteers at 0 and 0.1 minimum alveolar concentration (MAC) isoflurane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set (apneic threshold). Study 2: The ventilatory changes due to the wash-in of 0.1 MAC isoflurane, 15 min after the induction of isocapnic hypoxia, were studied in 11 healthy volunteers. Study 3: The ventilatory responses to a step decrease in end-tidal oxygen (end-tidal oxygen tension from 110 to 44 mmHg within 3-4 breaths; duration of hypoxia 20 min) were assessed in eight healthy volunteers at 0, 0.1, and 0.2 MAC isoflurane. Values are reported as means +/- SF. Study 1: The peripheral carbon dioxide sensitivities averaged 0.50 +/- 0.08 (control) and 0.28 +/- 0.05 l.min-1.mmHg-1 (isoflurane; P < 0.01). The central carbon dioxide sensitivities (control 1.20 +/- 0.12 vs. isoflurane 1.04 +/- 0.11 l.min-1.mmHg-1) and off-sets (control 36.0 +/- 0.1 mmHg vs. isoflurane 34.5 +/- 0.2 mmHg) did not differ between treatments. Study 2: Within 30 s of exposure to 0.1 MAC isoflurane, ventilation decreased significantly, from 17.7 +/- 1.6 (hypoxia, awake) to 15.0 +/- 1.5 l.min-1 (hypoxia, isoflurane). Study 3: At the initiation of hypoxia ventilation increased by 7.7 +/- 1.4 (control), 4.1 +/- 0.8 (0.1 MAC; P < 0.05 vs. control), and 2.8 +/- 0.6 (0.2 MAC; P < 0.05 vs. control) l.min-1. The subsequent ventilatory decrease averaged 4.9 +/- 0.8 (control), 3.4 +/- 0.5 (0.1 MAC; difference not statistically significant), and 2.0 +/- 0.4 (0.2 MAC; P < 0.05 vs. control) l.min-1. There was a good correlation between the acute hypoxic response and the hypoxic ventilatory decrease (r = 0.9; P < 0.001). The results of all three studies indicate a selective and profound effect of subanesthetic isoflurane on the peripheral chemoreflex loop at the site of the peripheral chemoreceptors. We relate the reduction of the ventilatory decrease of sustained hypoxia to the decrease of the initial ventilatory response to hypoxia.

Clinical aspects of hypoxic pulmonary vasoconstriction

Although frequently unrecognized, hypoxic pulmonary vascular disease is an important cofactor in the morbidity and mortality of a wide spectrum of disease processes. The hypoxic response incorporates two distinct phases, the acute hypoxic vasoconstrictor response and vascular remodelling associated with prolonged alveolar hypoxia. Understanding of the mechanisms causing both processes has increased rapidly and may result in the near future in specific treatment aimed at correcting underlying physiological abnormalities. However, currently available therapies remain limited to correction of the hypoxaemia and generalized non-specific pulmonary vasodilatation. The recent development of inhaled NO therapy represents a significant advance in the management of the acute hypoxic pulmonary vasoconstriction occurring during critical illness.

Influence of a Subanesthetic Concentration of Halothane on the Ventilatory Response to Step Changes into and out of Sustained Isocapnic Hypoxia in Healthy Volunteers

In humans the ventilatory response to isocapnic hypoxia is biphasic: an initial increase in minute ventilation (VE) from baseline, the acute hypoxic response, is followed after 3-5 min by a slow ventilatory decay, the hypoxic ventilatory decline, and a new steady state, 25-40% greater than baseline VE, is reached in about 15-20 min. The transition from 20 min of isocapnic hypoxia into normoxia results in a rapid decrease in VE, the off-response. In humans, halothane, at subanesthetic concentrations, is known to decrease the acute hypoxic response. In order to investigate the effects of halothane on sustained hypoxia we quantified the effects of 0.15 minimum alveolar concentration halothane on the ventilatory response at the onset of 20 min of hypoxia and at the termination of 20 min of hypoxia by normoxia in healthy volunteers. Step changes in end-tidal oxygen tension were performed against a background of constant mild hypercapnia (end-tidal carbon dioxide tension about 1 mmHg above individual resting values) in fourteen male subjects. The end-tidal oxygen tension was forced as follows: 5-10 min at 110 mmHg, 20 min at 44 mmHg, and 10 min at 110 mmHg. In each subject we performed one trial before and one during 0.15 minimum alveolar concentration halothane administration. Ten responses into hypoxia and nine out of hypoxia were considered for analysis. All control trials were performed during wakefulness. Using behavioral characteristics, the central nervous system arousal state of the subjects during halothane inhalation was defined as "anesthesia-induced hypnosis." The acute hypoxic response averaged 10.4 +/- 4.7 l/min for control versus 3.7 +/- 2.4 l/min for halothane trials (P < 0.01). The hypoxic ventilatory decline was 4.8 +/- 2.5 l/min versus 3.9 +/- 2.9 l/min (NS), the off-response was 6.7 +/- 3.2 l/min versus 3.7 +/- 3.0 l/min (P < 0.05) for control versus halothane, respectively. All values are mean +/- SD. Our results indicate that halothane caused VE to be less than control levels during acute and sustained hypoxia as well as when sustained hypoxia is replaced by normoxia. It is argued that the depression of VE during acute hypoxia is attributed to an effect of halothane on the peripheral chemoreceptors. During sustained hypoxia halothane had no effect on the magnitude of the hypoxic ventilatory decrease, which is probably related to an increase by halothane of inhibitory neuromodulators within the central nervous system. With halothane, the ventilatory decrease when sustained hypoxia is replaced by normoxia is related to the removal of the hypoxic drive at the site of the peripheral chemoreceptors.

Effect of a Subanesthetic Minimum Alveolar Concentration of Isoflurane on Two Tests of the Hypoxic Ventilatory Response

These experiments were designed to study the effect of 0.1 minimum alveolar concentration isoflurane on the hypoxic ventilatory response as measured by two common methods of hypoxic testing: when normocapnic hypoxia was induced abruptly and when it was induced gradually. We hypothesized that any disparity in results would be due to an isoflurane effect that was manifested differently in the two tests. After 20 min for uptake and equilibration of 0.1 minimum alveolar concentration end-tidal isoflurane or carrier gas in hyperoxia, isocapnic hypoxia was induced either abruptly over 60-80 s ("step" test) or gradually over 10 min ("ramp" test), followed by 20 min of isocapnic hypoxia at 45 mmHg end-tidal oxygen. Control of the hypoxic and isocapnic stimuli was accomplished accurately by a computer-controlled dynamic end-tidal forcing system. Eight subjects performed each test in the presence and absence of isoflurane. For both step tests and ramp tests, 0.1 minimum alveolar concentration isoflurane had no effect on minute ventilation during the defined periods of hypoxia. With isoflurane, delta VE45, the acute change in ventilation from hyperoxia to hypoxia, was 97 +/- 20% (mean +/- SEM) of the control response for step tests and 100 +/- 25% of the control response for ramp tests. The step tests produced significantly larger acute hypoxic responses than did the ramp tests, but by the end of 20 min of hypoxia, ventilation was similar for both tests. Neither method of hypoxic testing demonstrated the level of isoflurane effect reported by others. A comparison of the two methods of hypoxic testing suggests that ramp tests, as commonly performed, do not allow adequate time for full expression of the acute hypoxic ventilatory response. Step tests also better separated the opposing hypoxic effects of carotid body stimulation and central ventilatory depression.

Effects of Subanesthetic Halothane on the Ventilatory Responses to Hypercapnia and Acute Hypoxia in Healthy Volunteers

The peripheral chemoreceptors are responsible for the ventilatory response to hypoxia (acute hypoxic response) and for 30% of the normoxic hypercapnic ventilatory response. To quantify the effects of subanesthetic concentrations of halothane on the respiratory control system, in particular on the peripheral chemoreceptors, we studied the response of humans to carbon dioxide and oxygen at two subanesthetic concentrations of halothane. Square-wave changes in end-tidal carbon dioxide tension (7.5-11.3 mmHg) and step decreases in end-tidal oxygen tension (arterial hemoglobin oxygen saturation 82 +/- 2%; duration of hypoxia 5 min) were performed in nine healthy male subjects during 0, 0.05 (HA-1), and 0.1 minimum alveolar concentration (HA-2) halothane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set. Fifty-six carbon dioxide responses and 27 oxygen responses were obtained. The peripheral carbon dioxide sensitivities averaged to 0.76 +/- 0.14 l.min-1.mmHg-1 (control), 0.50 +/- 0.12 l.min-1.mmHg-1 (HA-1), and 0.30 +/- 0.08 l.min-1.mmHg-1 (HA-2; P < 0.01 vs. control). The central carbon dioxide sensitivity did not differ significantly among treatment groups (control, 1.47 +/- 0.22 l.min-1.mmHg-1; HA-1, 1.41 +/- 0.51 l.min-1.mmHg-1; and HA-2, 1.23 +/- 0.30 l.min-1.mmHg-1). The time constants of the central chemoreflex loop showed a large decrease during the administration of 0.1 minimum alveolar concentration halothane. The acute hypoxic response declined from 15.0 +/- 3.9 l.min-1 to 10.9 +/- 2.9 l.min-1 (HA-1) and 4.8 +/- 1.4 l.min-1 (HA-2; P < 0.01 vs. control and HA-1). All values are means +/- SEM. The results show depression of the ventilatory responses to hypoxia and hypercapnia during inhalation of subanesthetic concentrations of halothane. The depression is attributed to a selective effect of halothane on the peripheral chemoreflex loop. The oxygen and carbon dioxide responses mediated by the peripheral chemoreceptors are affected proportionally. It is argued that the decrease in central time constants is caused by an effect of halothane on central neuronal dynamics.

Effects of 20% nitrous oxide on the ventilatory response to hypercapnia and sustained isocapnic hypoxia in man

To examine the effects of a sub-anaesthetic concentration of nitrous oxide on ventilation, we have studied the ventilatory response to carbon dioxide and isocapnic hypoxia (FIN2O 0.2). In five subjects, we performed step decreases in PE'O2 to 6.7 kPa for 15 min and step increases in PE'CO2 (delta PE'CO2 1.5 kPa). The carbon dioxide responses were partitioned into a fast peripheral and slow central component. All control oxygen responses were biphasic: the acute hypoxic response was 7.2 (4.6) litre min-1 and the subsequent decline 4.2 (2.6) litre min-1. With nitrous oxide, the acute hypoxic response was 10.3 (6.7) litre min-1, but was followed by a nonsignificant decline of 3.8 (3.0) litre min-1 because of a progressive increase in breathing frequency in the hypoxic period. None of the variables obtained from the carbon dioxide responses differed between groups. Our data indicate that a sub-anaesthetic concentration of nitrous oxide did not affect the peripheral chemoreflex loop. The hyperventilatory response to prolonged hypoxia was sustained better with nitrous oxide compared with control.

The ventilatory response to CO2 of the peripheral and central chemoreflex loop before and after sustained hypoxia in man.

1. The ventilatory response to sustained hypoxia is characterized by a fast increase due to the peripheral chemoreceptors followed by a slow decline. The mechanism of this decline is unknown. 2. To investigate the characteristics of the ventilatory response to sustained hypoxia ten healthy subjects were exposed to two consecutive periods of isocapnic hypoxia (arterial saturation 78%) separated by a 5 min exposure to isocapnic normoxia. 3. The acute hypoxic response to the second exposure to hypoxia (mean increase in ventilation +/- S.E.M., 7.2 +/- 0.8 l min-1) was significantly depressed (P = 0.04) compared to the first one (9.5 +/- 1.3 l min-1). 4. To investigate whether this depression was due to central or peripheral effects or both we measured, in the same ten subjects, the normoxic ventilatory response to CO2 before and after a period of 25 min of hypoxia using the technique of dynamic end-tidal forcing. 5. Each response was separated into a fast peripheral and slow central component characterized by a CO2 sensitivity, time constant, time delay and an off-set. 6. A total of thirty-six prehypoxic and thirty posthypoxic responses were analysed. The ventilatory CO2 sensitivities of the peripheral and central chemoreflex loops and the overall off-set (apnoeic threshold) after 25 min of hypoxia were somewhat larger than their prehypoxic values, but this effect was not significant. 7. We argue that the hypoxic ventilatory decline in man is due to a change in the off-set of the peripheral chemoreflex loop.

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 P o 2 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 P o 2 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 <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<0.05). The ratio of HVD to the acute hypoxic response was reduced from 0.696±0.124 at rest to 0.202±0.029 during exercise ( P<0.01). We conclude that while exercise augments the ventilatory sensitivity to hypoxia, it also has a direct effect on the mechanism by which sustained hypoxia depresses peripheral chemosensitivity.