Non-dimensional quantification of the interactions between hypoxia, hypercapnia and exercise on ventilation in humans.

The purpose of this study was to develop a non-dimensional approach towards the description of interaction between the three respiratory stimuli of hypoxia, hypercapnia and exercise and to use this approach to quantify the relative strengths of their interactions. Only a part of the study related to the overall interaction of the three stimuli is presented here. Nine volunteers took part in the study and their ventilatory responses to hypoxia were measured under four different conditions of rest-eucapnia, rest-hypercapnia, exercise-eucapnia and exercise-hypercapnia. Non-dimensional linear functions of hypercapnia (x), hypoxia (y) and exercise (z) were defined such that a value of one would double the resting ventilation. Non-dimensional ventilation v was derived as: v(x,y,z) = 1+ x + y + z + g1xy + g2xz + g3yz + g4xyz, where g1, g2, g3 and g4 provide non-dimensional measures of the strength of stimulus interaction. These interactions were calculated from the parameters obtained by fitting simple respiratory models to the data. The values for g1, g3 and g4 were significantly different from zero (p < 0.05, t-test). An intriguing result of this study is the overall negative interaction of the three stimuli, which may suggest that the linear, stimulus-response models commonly used to describe respiratory data may not be adequate for describing these complex interactions.

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 (V(E)) and heart rate previously reported with 8 h exposures to hypoxia. The sensitivities of V(E) (G(p)) and heart rate (G(HR)) to acute variations in hypoxia, and V(E) and heart rate during acute hyperoxia were assessed in 10 subjects before and after two 8 h exposures to isocapnic hypoxia (end-tidal P(O2) = 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 G(p) (P < 0.01) and V(E) during hyperoxia (P < 0.01) following hypoxic exposure, but these were unaffected by glycopyrrolate. G(HR) 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. Experimental Physiology (2001) 86.4, 529-538.

Very mild exposure to hypoxia for 8 h can induce ventilatory acclimatization in humans.

Ventilatory acclimatization to altitude is associated with a progressive increase in ventilation, a progressive decrease in end-tidal PCO2 and a progressive increase in the acute ventilatory sensitivity to hypoxia. Ventilatory acclimatization has been observed with mild exposure to hypoxia when the duration of exposure has been of some length (e.g. days), and with shorter duration exposures (e.g. 8 h) when the degree of hypoxia has been more severe. The purpose of this study was to determine whether short-duration exposures to very mild hypoxia, such as are commonly associated with the reduction in cabin pressure during commercial airline flight, can also induce some degree of ventilatory acclimatization. Twelve subjects were exposed in a chamber to both 8 h mild hypoxia (inspired PO2 127 mmHg) and 8 h air-breathing as a control. Exposures were on different days in random order. Following the hypoxic exposure, there was a significant reduction in end-tidal PCO2 during air breathing (from 39.2+/-1.8 to 38.11+/-1.5 mmHg, mean +/- SD, P<0.05), and a significant increase in ventilatory sensitivity to hypoxia (from 0.84+/-0.54 l/min/% to 1.13+/-0.66 l/min/%, P<0.05). We conclude that shortterm exposures to very mild hypoxia do induce significant acclimatization within the respiratory control system.

Selected contribution: chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans.

The ventilatory sensitivity to CO2, in hyperoxia, is increased after an 8-h exposure to hypoxia. The purpose of the present study was to determine whether this increase arises through an increase in peripheral or central chemosensitivity. Ten healthy volunteers each underwent 8-h exposures to 1) isocapnic hypoxia, with end-tidal PO2 (PET(O2)) = 55 Torr and end-tidal PCO2 (PET(CO2)) = eucapnia; 2) poikilocapnic hypoxia, with PET(O2) = 55 Torr and PET(CO2) = uncontrolled; and 3) air-breathing control. The ventilatory response to CO2 was measured before and after each exposure with the use of a multifrequency binary sequence with two levels of PET(CO2): 1.5 and 10 Torr above the normal resting value. PET(O2) was held at 250 Torr. The peripheral (Gp) and the central (Gc) sensitivities were calculated by fitting the ventilatory data to a two-compartment model. There were increases in combined Gp + Gc (26%, P < 0.05), Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase in chemosensitivity to CO2 within the peripheral chemoreflex.

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 mm Hg) 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 in humans induced by 8 h of hyperoxia.

In humans, 8 h of isocapnic hypoxia causes a progressive rise in ventilation associated with increases in the acute ventilatory responses to hypoxia (AHVR) and hypercapnia (AHCVR). To determine whether 8 h of hyperoxia causes the converse of these effects, three 8-h protocols were compared in 14 subjects: 1) poikilocapnic hyperoxia, with end-tidal PO(2) (PET(O(2))) = 300 Torr and end-tidal PCO(2) (PET(CO(2))) uncontrolled; 2) isocapnic hyperoxia, with PET(O(2)) = 300 Torr and PET(CO(2)) maintained at the subject's normal air-breathing level; and 3) control. Ventilation was measured hourly. AHVR and AHCVR were determined before and 0.5 h after each exposure. During isocapnic hyperoxia, after an initial increase, ventilation progressively declined (P < 0.01, ANOVA). After exposure to hyperoxia, 1) AHVR declined (P < 0.05); 2) ventilation at fixed PET(CO(2)) decreased (P < 0.05); and 3) air-breathing PET(CO(2)) increased (P < 0.05); but 4) no significant changes in AHCVR or intercept were demonstrated. In conclusion, 8 h of hyperoxia have some effects opposite to those found with 8 h of hypoxia, indicating that there may be some "acclimatization to hypoxia" at normal sea-level values of PO(2).

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.

Changes in respiratory control during and after 48 h of isocapnic and poikilocapnic hypoxia in humans.

Ventilatory acclimatization to hypoxia is associated with an increase in ventilation under conditions of acute hyperoxia (VEhyperoxia) and an increase in acute hypoxic ventilatory response (AHVR). This study compares 48-h exposures to isocapnic hypoxia (protocol I) with 48-h exposures to poikilocapnic hypoxia (protocol P) in 10 subjects to assess the importance of hypocapnic alkalosis in generating the changes observed in ventilatory acclimatization to hypoxia. During both hypoxic exposures, end-tidal PO2 was maintained at 60 Torr, with end-tidal PCO2 held at the subject's prehypoxic level (protocol I) or uncontrolled (protocol P). VEhyperoxia and AHVR were assessed regularly throughout the exposures. VEhyperoxia (P < 0.001, ANOVA) and AHVR (P < 0.001) increased during the hypoxic exposures, with no significant differences between protocols I and P. The increase in VEhyperoxia was associated with an increase in slope of the ventilation-end-tidal PCO2 response (P < 0.001) with no significant change in intercept. These results suggest that changes in respiratory control early in ventilatory acclimatization to hypoxia result from the effects of hypoxia per se and not the alkalosis normally accompanying hypoxia.

Human ventilatory response to CO2 after 8 h of isocapnic or poikilocapnic hypoxia.

During ventilatory acclimatization to hypoxia (VAH), the relationship between ventilation (VE) and end-tidal PCO2 (PETCO2) changes. This study was designed to determine 1) whether these changes can be seen early in VAH and 2) if these changes are present, whether the responses differ between isocapnic and poikilocapnic exposures. Ten healthy volunteers were studied by using three 8-h exposures: 1) isocapnic hypoxia (IH), end-tidal PO2 (PETO2) = 55 Torr and PETCO2 held at the subject's normal prehypoxic value; 2) poikilocapnic hypoxia (PH), PETO2 = 55 Torr; and 3) control (C), air breathing. The VE-PETCO2 relationship was determined in hyperoxia (PETO2 = 200 Torr) before and after the exposures. We found a significant increase in the slopes of VE-PETCO2 relationship after both hypoxic exposures compared with control (IH vs. C, P < 0.01; PH vs. C, P < 0.001; analysis of covariance with pairwise comparisons). This increase was not significantly different between protocols IH and PH. No significant changes in the intercept were detected. We conclude that 8 h of hypoxia, whether isocapnic or poikilocapnic, increases the sensitivity of the hyperoxic chemoreflex response to CO2.

Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study.

We report the results of a randomized single-centre study designed to assess the effects of simvastatin on blood lipids, blood biochemistry, haematology and other measures of safety and tolerability in preparation for a large-scale multicentre mortality study. Six hundred and twenty-one individuals considered to be at increased risk of coronary heart disease were randomized, following a 2-month placebo 'run-in' period, to receive 40 mg daily simvastatin, 20 mg daily simvastatin or matching placebo. Their mean age was 63 years, 85% were male, 62% had a history of prior myocardial infarction (MI), and the mean baseline total cholesterol was 7.0 mmol.l-1. Median follow-up in the present report is 3.4 years. Eight weeks after randomization, 40 mg daily simvastatin had reduced non-fasting total cholesterol by 29.2% +/- 1.1 (2.03 +/- 0.08 mmol.l-1) and 20 mg daily simvastatin had reduced it by 26.8% +/- 1.0 (1.87 +/- 0.07 mmol.l-1). Almost all of the difference in total cholesterol at 8 weeks was due to the reduction in LDL cholesterol (40.8% +/- 1.6 and 38.2% +/- 1.4 among patients allocated 40 mg and 20 mg of simvastatin daily respectively), but simvastatin also reduced triglycerides substantially (19.0% and 17.3%) and produced a small increase in HDL cholesterol (6.4% and 4.8%). These effects were largely sustained over the next 3 years, with 40 mg daily simvastatin producing a slightly greater reduction in total cholesterol at 3 years (25.7% +/- 1.9 reduction) than did 20 mg daily simvastatin (22.2% +/- 1.8). There were no differences between the treatment groups in the numbers of reports of 'possible adverse effects' of treatment or of a range of different symptoms or conditions (including those related to sleep or mood) recorded at regular clinic follow-up. Mean levels of alanine aminotransferase, aspartate aminotransferase and creatine kinase were slightly increased by treatment, but there were no significant differences between the treatment groups in the numbers of patients with significantly elevated levels. A slightly lower platelet count in the simvastatin group was the only haematological difference from placebo, with no difference in the numbers of patients with low platelet counts. In summary, the simvastatin regimens studied produced large sustained reductions in total cholesterol, LDL cholesterol and triglyceride and small increases in HDL cholesterol. They were well tolerated, with no evidence of serious side-effects during the first 3 years of this study.(ABSTRACT TRUNCATED AT 400 WORDS)