1. Under conditions of both euoxia and hypoxia, it is generally accepted that the ventilatory response to COµ 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 COµ significantly better than a one-compartment model. Data were collected under both hypoxic (end-tidal POµ = 50 Torr) conditions, when two components would be expected, and under hyperoxic (end-tidal POµ = 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 PCOµ 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 twocompartment 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¢ Torr¢ in hypoxia and 2·00 ± 0·32 l min¢ Torr¢ in hyperoxia. Mean ventilatory sensitivities for the peripheral chemoreflex were 2·42 ± 0·36 l min¢ Torr¢ in hypoxia and 0·75 ± 0·16 l min¢ Torr¢ in hyperoxia. 5. It is concluded that the rapid and slow components of the ventilatory response to COµ can be separately identified, and that a rapid component persists under conditions of hyperoxia.9773

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)

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.

Numerous investigations have been carried out over many decades to gain a better understanding of the adaptations that occur during the process of acclimatization to the hypoxia of altitude. These studies have included descriptions of the changes in cerebral blood flow (CBF) during acclimatization, which are of some importance because of the potential role that changes in CBF may have in the aetiology of diseases such as acute mountain sickness and high altitude cerebral oedema.On exposure to the hypoxia of high altitude (altitude, 3810-4300 m; arterial PJ (P a,J ), ~43-45 Torr), there is an initial increase in CBF, which then slowly declines towards pre-hypoxic levels (Severinghaus et al. 1966;Huang et al. 1987). However, understanding the origin of these changes is complicated by the fact that the cerebral circulation is exposed to the competing influences of arterial hypoxia, which tends to cause vasodilatation, and arterial hypocapnia, which tends to cause vasoconstriction. Furthermore, these stimuli are not constant over time, because ventilatory acclimatization to hypoxia progressively increases the degree of hypocapnia and reduces the degree of hypoxia. In a set of experimental studies in sheep, Krasney and colleagues (Krasney et al. 1984(Krasney et al. , 1985(Krasney et al. , 1986) have attempted to separate the effects of hypoxia from those of hypocapnia by studying isocapnic hypoxia (where they added CO 2 to the inspired gas of the animal during hypoxia in order to prevent the arterial hypocapnia that normally results from the increase in pulmonary ventilation). They concluded that the adaptation of CBF back towards pre-hypoxic levels in poikilocapnic hypoxia was not a primary adaptation of the response of CBF to hypoxia, but was due to other factors, including the associated hypocapnia (Krasney et al. 1990).The broad aim of the present study was to undertake an investigation in human volunteers that was related to the work of Krasney and colleagues in sheep. In particular, we wished to study a sustained (48 h) period of constant hypoxia (regulated in the face of changing pulmonary 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 P CO 2 . Nine subjects were each exposed to two protocols in a purpose-built chamber: (1) 48 h of isocapnic hypoxia (Protocol I), where end-tidal PJ (P ET, J) was held at 60 Torr and end-tidal P CO 2 (P ET,CO 2 ) at the subject's resting value prior to experimentation; and (2) 48 h of poikilocapnic hypoxia (Protocol P), where P ET, J was held at 60 Torr and P ET,CO 2 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 var...

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.