Marzieh Fatemian

Identification of fast and slow ventilatory responses to carbon dioxide under hypoxic and hyperoxic conditions in humans

1 Under conditions of both euoxia and hypoxia, it is generally accepted that the ventilatory response to CO2 has both rapid (peripheral chemoreflex) and slow (central chemoreflex) components. However, under conditions of hyperoxia, it is unclear in humans whether the fast component is completely abolished or merely attenuated in magnitude. 2 The present study develops a technique to determine whether or not a two‐compartment model fits the ventilatory response to CO2 significantly better than a one‐compartment model. Data were collected under both hypoxic (end‐tidal PO2= 50 Torr) conditions, when two components would be expected, and under hyperoxic (end‐tidal PO2= 200 Torr) conditions, when the presence of the fast compartment is under question. 3 Ten subjects were recruited, of whom nine completed the study. The end‐tidal PCO2 of each subject was varied according to a multi‐frequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia lasting altogether 1408 s. 4 In four out of nine subjects in hypoxia, and six out of nine subjects in hyperoxia, the two‐compartment model fitted the data significantly better than the one‐compartment model (F ratio test on residuals). This improvement in fit was significant for the pooled data in both hypoxia (P < 0·05) and hyperoxia (P < 0·005). Mean ventilatory sensitivities for the central chemoreflex were (mean ± s.e.m.) 1·69 ± 0·39 l min−1 Torr−1 in hypoxia and 2·00 ± 0·32 l min−1 Torr−1 in hyperoxia. Mean ventilatory sensitivities for the peripheral chemoreflex were 2·42 ± 0·36 l min−1 Torr−1 in hypoxia and 0·75 ± 0·16 l min−1 Torr−1 in hyperoxia. 5 It is concluded that the rapid and slow components of the ventilatory response to CO2 can be separately identified, and that a rapid component persists under conditions of hyperoxia.

The respiratory response to carbon dioxide in humans with unilateral and bilateral resections of the carotid bodies.

The acute hypercapnic ventilatory response (AHCVR) arises from both peripheral and central chemoreflexes. In humans, one technique for identifying the separate contributions of these chemoreflexes to AHCVR has been to associate the rapid component of AHCVR with the peripheral chemoreflex and the slow component with the central chemoreflex. Our first aim was to validate this technique further by determining whether a single slow component was sufficient to describe AHCVR in patients with bilateral carotid body resections (BR) for glomus cell tumours. Our second aim was to determine whether the slow component of AHCVR was diminished following carotid body resection as has been suggested by studies in experimental animals. Seven BR subjects were studied together with seven subjects with unilateral resections (UR) and seven healthy controls. A multifrequency binary sequence in end‐tidal PCO2 was employed to stimulate ventilation dynamically under conditions of both euoxia and mild hypoxia. Both two‐ and one‐compartment models of AHCVR were fitted to the data. For BR subjects, the two‐compartment model fitted significantly better on 1 out of 13 occasions compared with 22 out of 28 occasions for the other subjects. Average values for the chemoreflex sensitivity of the slow component of AHCVR differed significantly (P < 0.05) between the groups and were 0.95, 1.38 and 1.50 l min−1 Torr−1 for BR, UR and control subjects, respectively. We conclude that, without the peripheral chemoreflex, AHCVR is adequately described by a single slow component and that BR subjects have sensitivities for the slow component that are lower than those of control subjects.

Changes in cerebral blood flow during and after 48 h of both isocapnic and poikilocapnic hypoxia in humans

During acclimatization to the hypoxia of altitude, the cerebral circulation is exposed to arterial hypoxia and hypocapnia, two stimuli with opposing influences on cerebral blood flow (CBF). In order to understand the resultant changes in CBF, this study examined the responses of CBF during a period of constant mild hypoxia both with and without concomitant regulation of arterial PCO2. Nine subjects were each exposed to two protocols in a purpose‐built chamber: (1) 48 h of isocapnic hypoxia (Protocol I), where end‐tidal PO2 (PET,O2) was held at 60 Torr and end‐tidal PCO2 (PET,CO2) at the subjects resting value prior to experimentation; and (2) 48 h of poikilocapnic hypoxia (Protocol P), where PET,O2 was held at 60 Torr and PET,CO2 was uncontrolled. Transcranial Doppler ultrasound was used to assess CBF. At 24 h intervals during and after the hypoxic exposure CBF was measured and the sensitivity of CBF to acute variations in PO2 and PCO2 was determined. During Protocol P, PET,CO2 decreased by 13% (P < 0.001) and CBF decreased by 6% (P < 0.05), whereas during Protocol I, PET,CO2 and CBF remained unchanged. The sensitivity of CBF to acute variations in PO2 and PCO2 increased by 103% (P < 0.001) and 28% (P < 0.01), respectively, over the 48 h period of hypoxia. These changes did not differ between protocols. In conclusion, CBF decreases during mild poikilocapnic hypoxia, indicating that there is a predominant effect on CBF of the associated arterial hypocapnia. This fall occurs despite increases in the sensitivity of CBF to acute variations in PO2/PCO2 arising directly from the hypoxic exposure.

Determinants of ventilation and pulmonary artery pressure during early acclimatization to hypoxia in humans

Lung ventilation and pulmonary artery pressure rise progressively in response to 8 h of hypoxia, changes described as ‘acclimatization to hypoxia’. Acclimatization responses differ markedly between humans for unknown reasons. We explored whether the magnitudes of the ventilatory and vascular responses were related, and whether the degree of acclimatization could be predicted by acute measurements of ventilatory and vascular sensitivities. In 80 healthy human volunteers measurements of acclimatization were made before, during, and after a sustained exposure to 8 h of isocapnic hypoxia. No correlation was found between measures of ventilatory and pulmonary vascular acclimatization. The ventilatory chemoreflex sensitivities to acute hypoxia and hypercapnia all increased in proportion to their pre‐acclimatization values following 8 h of hypoxia. The peripheral (rapid) chemoreflex sensitivity to CO2, measured before sustained hypoxia against a background of hyperoxia, was a modest predictor of ventilatory acclimatization to hypoxia. This finding has relevance to predicting human acclimatization to the hypoxia of altitude.

Effects of 8 h of Isocapnic Hypoxia with and without Muscarinic Blockade on Ventilation and Heart Rate in Humans

This study examined the role of muscarinic parasympathetic mechanisms in generating the progressive increases in ventilation (V̇E) and heart rate previously reported with 8 h exposures to hypoxia. The sensitivities of V̇E (Gp) and heart rate (GHR) to acute variations in hypoxia, and V̇E and heart rate during acute hyperoxia were assessed in 10 subjects before and after two 8 h exposures to isocapnic hypoxia (end‐tidal PO2= 50 mmHg). The responses were measured during muscarinic blockade with glycopyrrolate (0.015 mg kg−1) and without glycopyrrolate, as a control. There were significant increases in Gp (P < 0.01) and V̇E during hyperoxia (P < 0.01) following hypoxic exposure, but these were unaffected by glycopyrrolate. GHR increased significantly by 0.29 ± 0.08 beats min−1%−1 (mean ± S.E.M.) following exposure to hypoxia under control conditions, but only non‐significantly by 0.10 ± 0.08 beats min−1%−1 with glycopyrrolate. This difference was significant. Changes in heart rate during hyperoxia were slight and inconclusive. We conclude that muscarinic mechanisms play little role in the progressive ventilatory changes that occur over 8 h of hypoxia, but that they do mediate much of the progressive increase in heart rate.

Long-haul flights may induce respiratory changes similar to ventilatory acclimatisation to altitude.

Ventilatory acclimatisation to altitude is associated with a progressive increase in ventilation, a progressive decrease in end-tidal PCO2 (PETCO2)1 and a progressive increase in the acute ventilatory sensitivity to hypoxia (AHVR)2. The duration and severity of hypoxia generally associated with these changes are both substantially greater than those associated with commercial airline flight. Nevertheless, commercial airline flight normally involves some reduction in cabin pressure, and this study sought to determine whether the associated reduction in inspired PO2 could also induce acclimatisation.

Modeling the ventilatory response to variations in end-tidal PCO2 in patients who have undergone bilateral carotid body resection.

Studies on patients who have had bilateral carotid body resection for the relief of asthmatic symptoms1,2 or bilateral carotid endarterectomy for transient cerebral ischemia3 suggest that the fast component of ventilatory response to CO2 arises from carotid body activity. However it is also possible that the effect on the ventilatory response to CO2 was related to their underlying respiratory or vascular disease. The current study sought to examine the ventilatory responses to CO2 of adult human subjects who had undergone bilateral carotid body resections for glomus tumors. These subjects have normal lung and vascular function.

Cardiovascular Effects of 8 h of Isocapnic Hypoxia with and without Beta‐Blockade in Humans

This study seeks to confirm the progressive changes in cardiac output and heart rate previously reported with 8 h exposures to constant hypoxia, and to examine the role of sympathetic mechanisms in generating these changes. Responses of ten subjects to four 8 h protocols were compared: (1) air breathing with placebo; (2) isocapnic hypoxia (end‐tidal PO2 = 50 mmHg) with placebo; (3) isocapnic hypoxia with beta‐blockade; and (4) air breathing with beta‐blockade. Regular measurements of heart rate and cardiac output (using ultrasonography and N2O rebreathing techniques) were made with subjects seated in the upright position. The sensitivity of heart rate to rapid variations in hypoxia (GHR) and heart rate in the absence of hypoxia were measured at times 0, 4 and 8 h. No significant progressive effect of hypoxia on cardiac output was detected. There was a gradual rise in heart rate with hypoxia of 11 ± 2 beats min‐1 in the placebo protocol and of 10 ± 2 beats min‐1 in the beta‐blockade protocol over 8 h, compared to the air breathing protocols. The rise in heart rate was progressive (P < 0.001) and accompanied by progressive increases in both GHR (P < 0.001) and heart rate measured in the absence of hypoxia (P < 0.05). No significant effect of beta‐blockade was detected on any of these progressive changes. We conclude that sympathetic mechanisms that act via beta‐receptors play little role in the progressive changes in heart rate observed over 8 h of moderate hypoxia.

Changes in Respiratory Control during and after 48 Hours of Both Isocapnic and Poikilocapnic Hypoxia in Humans

During an 8 h period of either isocapnic or poikilocapnic hypoxia, tests of the acute ventilatory response to hypoxia (AHVR) have shown that there is an increase in hypoxic sensitivity (2) accompanied by an increase in ventilation under conditions of acute hyperoxia (3). These changes were similar between the two protocols suggesting a direct effect of hypoxia per se.

Respiratory control during air-breathing exercise in humans following an 8 h exposure to hypoxia

Hypoxic exposure lasting a few hours results in an elevation of ventilation and a lowering of end-tidal PCO2(PETCO2) that persists on return to breathing air. We sought to determine whether this increment in ventilation is fixed (hypothesis 1), or whether it increases in proportion to the rise in metabolic rate associated with exercise (hypothesis 2). Ten subjects were studied on two separate days. On 1 day, subjects were exposed to 8 h of isocapnic hypoxia (end-tidal PO2 55 Torr) and on the other day to 8 h of euoxia as a control. Before and 30 min after each exposure, subjects undertook an incremental exercise test. The best fit of a model for the variation in PETCO2 with metabolic rate gave a residual squared error that was ∼20-fold less for hypothesis 2 than for hypothesis 1 (p < 0.005, F-ratio test). We conclude that the alterations in respiratory control induced during early ventilatory acclimatization to hypoxia better reflect those associated with hypothesis 2 rather than hypothesis 1.