Oxygen isotope fractionation in healthy subjects and in patients with COPD.

We determined the oxygen isotope fractionation degree for oxygen utilized (delta(U)) in expired alveolar gas relative to inspired air in patients with chronic obstructive lung disease (COPD) and, for comparison, in two groups of healthy subjects, old and young. In addition, we determined Delta(rel)R(vent) and Delta(rel)R(tot). These determinants of delta(U) (=Delta(rel)R(tot)-Delta(rel)R(vent)) are related to the oxygen isotope fractionation which occurs in the first part of the O(2) pathway by ventilation of alveolar gas (Delta(rel)R(vent)) and by O(2) transport and utilization in the rest of the O(2) pathway from the alveolar space (Delta(rel)R(tot)). Mean delta(U) values for the three groups of subjects were close: 9.0, 9.0 and 9.9 per thousand, respectively, with no significant differences between groups. Mean Delta(rel)R(vent) for patients with COPD was substantially larger than for young, healthy subjects, 4.0 per thousand versus 0.94 per thousand, with P<10(-3). This result indicates that the contribution of intrapulmonary gas transport by diffusion to Delta(rel)R(vent) is larger for patients with COPD than for young, healthy subjects. Mean Delta(rel)R(tot) for patients with COPD was also larger than for young, healthy subjects, 13.0 per thousand versus 10.84 per thousand, but this difference was not significant (P=0.06). Further, Delta(rel)R(tot) was much larger than Delta(rel)R(vent) for all groups of subjects (P<10(-7)).

A discussion regarding the contribution of intrapulmonary gas mixing to O2 isotope fractionation by respiration using experimental data for 36Ar and 40Ar.

We determined the argon (Ar) isotope ratio in samples of expired alveolar gas gathered during Ar washout from residual gas relative to this ratio in samples of expired alveolar gas gathered just before the beginning of this washout in 13 young, healthy human subjects at rest. These data were determined for a limited number of breaths in early washout and were used to calculate the relative difference between the alveolar ventilations of (36)Ar and (40)Ar (Delta(rel)V (A)((36)Ar,(40)Ar)). Mean Delta(rel)V (A)((36)Ar,(40)Ar) amounted to 1.6 per thousand (S.D.=1.3 per thousand). This result was then used to discuss the contribution of intrapulmonary gas mixing by diffusion to oxygen isotope fractionation of alveolar gas by respiration. On the basis of our finding for Delta(rel)V (A)((36)Ar,(40)Ar) and further theoretical considerations we arrived at the conclusion that this contribution for subjects at rest is small (about 1 per thousand) and that this contribution is negative irrespective of the level of exercise.

The influence of training on oxygen isotope fractionation in healthy subjects.

We determined the oxygen isotope fractionation in expired alveolar gas relative to inspired air (delta(A-I)) in eight young, healthy subjects at rest and at five levels of exercise up to maximal workload both before and after a training period of about 4 weeks which increased maximum oxygen uptake by about 10%. The data for delta(A-I) were used to compute the relative difference (deltaU) between the resistances of 16O18O and 16O2 for oxygen transport from the alveolar space and utilization in the mitochondria. Prior to training, deltaU decreased from 15 per thousand at rest to 5 per thousand at the highest level of exercise and after training from 12 to 5 per thousand. The difference between the results for deltaU before and after training was significant for rest (P < or = 5) but not for exercise conditions. Accordingly, we conclude that for exercise conditions the non-fractionating oxygen transport by blood flow to and the fractionating oxygen transport by diffusion in the muscles have improved by training to more or less the same degree. The decrease in deltaU in rest after training suggests that oxygen transport by diffusion in other tissues also benefits from the effects of training.

Modeling of the expiratory flow pattern of spontaneously breathing cats.

A mathematical model was developed describing the entire expiratory flow pattern during spontaneous, tidal breathing in the absence of expiratory muscle activity. It provides estimates for the time constants of the respiratory system (tau RS(model)) and of the decay of continuing inspiratory muscle activity in early expiration (tau mus(model)). In ten anesthetized, tracheostomized cats flow, tracheal pressure and diaphragmatic EMG were measured during normal expirations and expirations with four different added resistances. No significant differences were found between tau RS(model) (0.21-0.49 sec) obtained by fitting the model to the flow data and tau RS obtained from the straight part of the expiratory flow-volume curve. tau mus(model) (0.050-0.052 sec) was comparable to similar time constants obtained from the integrated diaphragmatic EMG or from end-inspiratory, tracheal occlusion pressure. Fitted peak flow and time to peak tidal expiratory flow were not significantly different from those measured. In conclusion, for spontaneously breathing, anesthetized cats our model provides a close fit of the expiratory flow and parameter estimates were comparable with independently measured values.

The ratio of the alveolar ventilations of SF6 and He in patients with lung emphysema and in healthy subjects.

This study assess the possible impact of changes in the morphometry of acinar airways and air spaces on the efficacy of intrapulmonary gas mixing for sulphur hexafluoride (SF6) relative to that for helium (He). To that end the alveolar ventilations of He and SF6 were determined in patients with macroscopic lung emphysema and in healthy subjects. He-SF6 washout tests were performed in 17 patients (15 emphysema, 2 chronic bronchitis) and 21 healthy subjects. Using a three-compartment model, the data obtained were used to estimate the overall, effective, alveolar ventilations of SF6 and He, and their ratio VAASF6/VAHe. Mean VAASF6/VAHe (+/- S.D.) for patients (0.80 +/- 0.06) was significantly smaller (P < 0.001) than the value for the group of age-matched healthy subjects (0.90 +/- 0.05) which was non-significantly smaller than the result for the group of young, healthy subjects (0.93 +/- 0.03). In our patients, we also determined a score for emphysema using high resolution computed tomography, and this score correlated inversely with VAASF6/VAHe (r = -0.56, P = 0.018). We have interpreted our observations to mean that in patients with lung emphysema, the efficacy of intrapulmonary gas mixing for SF6 as compared with that for He reflected by VAASF6/VAHe is diminished due to increased diffusive path-lengths within the enlarged air spaces of their lungs which impair diffusive gas mixing for SF6 more than for He.

Collateral gas transport by diffusion across tissue in the healthy, human lung; effects on dead space.

The effects of collateral gas transport by diffusion across lung tissue on the Bohr and Fowler dead spaces were quantified for resting breathing conditions. The dead spaces (VD) of He, Xe and SF(6) were determined from expirograms obtained from the simultaneous washout of these test gases. The experiments were performed on seven healthy subjects. The contribution of collateral gas transport by diffusion on VD was obtained from the difference between VD(SF(6)) and VD(Xe). These two gases have comparable diffusion coefficients (D) in residual gas but in lung tissue D(Xe) is roughly 25 times larger than D(SF(6)) due to the higher solubility of Xe in aqueous tissues. The data showed that the reducing effect of collateral gas transport by diffusion on VD(Xe) amounts to about 2 ml for both the Bohr and the Fowler dead space. The smallness of this effect means that the alveolar ventilation for Xe hardly benefits from this additional mechanism of intrapulmonary gas mixing.

Fatigue associated with obstructive sleep apnea in a patient with sarcoidosis.

Many patients with sarcoidosis suffer from persistent constitutional symptoms such as fatigue and general weakness, even though physiological measures of disease activity returned within normal limits. The following case report demonstrates a sarcoidosis patient with recurring fatigue caused by an obstructive sleep apnea syndrome developed during the course of the disease.

Intrapulmonary gas mixing and the sloping alveolar plateau in COPD patients with macroscopic emphysema.

Chronic obstructive pulmonary disease patients, especially those with emphysema, show steep slopes of the alveolar plateau (S). This study tested the hypothesis that continued gas exchange between poorly and well-ventilated lung units by means of collateral ventilation would contribute to S in these patients. Nine young volunteers, nine older volunteers and 11 patients with macroscopic emphysema performed wash-out tests with helium (He) and sulphur hexafluoride (SF6). S was determined for breaths 1-5 (range 1), and for breaths between 95% and 98% of complete wash-out (range 2). An unequal ventilation index (UVI) was defined as the ratio between the estimated mean alveolar pressure and the end tidal pressure (PET) of each tracer gas, calculated over range 2. Over the same range, a phase III ratio was calculated by dividing PET by the estimated pressure at Fowler dead space. In all groups of subjects, the S for He and SF6 were greater for range 2 than for range 1 (p< or =0.012). In the emphysema patients, the correlations between S and UVI were 0.72 for He (p=0.012) and 0.81 for SF6 (p=0.002), while the mean phase III ratios were 1.7 for He and 2.4 for SF6, much less than their theoretical maxima. It was concluded that in patients collateral ventilation may account for only a small part of the increase in the alveolar plateau slope between ranges 1 and 2, and that this increase was mainly caused by unequal ventilation in combination with sequential emptying of lung units. The degree of sequential emptying, however, was modest compared with its full potential.

Time to peak tidal expiratory flow and the neuromuscular control of expiration.

The ratio of the time needed to reach peak tidal expiratory flow (tPTEF) and the duration of expiration (tE) is used to detect airflow obstruction in young children. tPTEF is decreased in patients with asthma, but knowledge about the physiological determinants of this parameter is scarce. This study examined the relationship between tPTEF and postinspiratory activities of inspiratory muscles and evaluated the effects of changing sensory information from the lung. Airflow patterns and electromyographic (EMG) activity of inspiratory muscles were recorded in seven spontaneously breathing, anaesthetized cats. The trachea was cannulated and, as a result, the larynx and upper airways were bypassed. Changes in postinspiratory muscle activity were induced by changing afferent sensory nerve information (by cooling the vagus nerves, by administration of histamine and by additional application of continuous positive airway pressure (CPAP)). Durations of postinspiratory activities of the diaphragm and intercostal muscles (characterized by their time constants tau diaphr and tau interc) correlated strongly with tPTEF (r=0.85 and 0.77, respectively). Tau diaphr, tau interc and tPTEF were significantly increased during cooling of the vagus nerves (4-8 degrees C) compared with values at 22 and 37 degrees C (p<0.05). Conversely, administration of histamine and CPAP caused significant decreases in tau diaphr, tau interc and tPTEF, which were absent during cooling of the vagus nerves. In conclusion, the time needed to reach peak tidal expiratory flow is highly influenced by the activities of inspiratory muscles during the early phase of expiration which, in turn, depend on the activities of vagal receptors in the lung.

Breathing efficiency during inspiratory threshold loading in patients with chronic obstructive pulmonary disease.

Patients with chronic obstructive pulmonary disease (COPD) demonstrate an increased oxygen cost of breathing. It is as yet unclear whether this is related to a decreased breathing efficiency. The aim of the present study was to compare breathing efficiency in 16 patients with COPD (11 men, five women) and 16 healthy elderly subjects (seven men, nine women), and to investigate a possible relationship between breathing efficiency and resting energy expenditure (REE). REE was measured using a ventilated hood system. Breathing efficiency was assessed by measuring oxygen consumption (V'O2), mean inspiratory mouth pressure (MIP) and flow during breathing at rest and subsequently during breathing against an inspiratory threshold (40% of maximal inspiratory pressure). During loaded breathing there was a significant increase in V'O2, MIP, and external work of breathing compared with unloaded breathing in both groups. As intended, ventilation did not increase significantly during the breathing efficiency test in the patients with COPD. The breathing efficiency (median, range) of the patients with COPD was similar (3.7%, 1.4-8.7%) to that of the healthy elderly subjects (3.2%, 1.7-8.3%). Breathing efficiency was not correlated with REE in either group. In the present study, in which dynamic hyperinflation was probably prevented, no difference in breathing efficiency was found between healthy elderly subjects and COPD patients when breathing against an external inspiratory threshold. Furthermore, breathing efficiency was not related to REE in both groups.

Breathing pattern during bronchial challenge in humans.

Increases in minute ventilation (V'E) have been observed during exacerbations of asthma and in response to administration of histamine. However, it is not yet clear how the breathing pattern is affected, and whether the increase in V'E is found in general. In the present study, the effects of inhalation of histamine on respiratory frequency (fR), tidal volume (VT), V'E, and on functional residual capacity (FRC) were evaluated in 63 humans. Forty four subjects were hyperresponsive (BHR+). In each of these subjects, the doses of histamine applied for the present study (mean 3.5 mg x mL(-1)) caused a decrease in forced expiratory volume in one second (FEV1) that was greater than 20% of the control value. The dose of histamine applied in the 19 nonhyperresponsive subjects (BHR-) was substantially larger (8.0 mg x mL(-1)) whilst for this dose the decrease in FEV1 was less than 20% of control value. After histamine, fR was significantly increased in both subgroups of subjects, BHR+ and BHR-. The increase in V'E was significant in BHR- but not significant in BHR+. In general, the changes in V'E,fR and VT were not uniform; comparable numbers of subjects responded with increases (n=33) and decreases (n=30) in V'E. For fR 40 subjects responded with an increase and 23 with a decrease, and for VT these numbers were 26 and 37, respectively. The increase in FRC after histamine was significantly larger in BHR+ subjects than in BHR-. These findings may be interpreted to indicate that different mechanisms with opposite effects may be operating simultaneously, e.g. excitation of central inspiratory activity by stimulation of rapidly-adapting pulmonary stretch receptors, which will promote increases in respiratory frequency, tidal volume and minute ventilation, and bronchoconstriction with increased airway resistance, which will promote decreases in these parameters. As a consequence, depending on the net result of these opposite contributions to, e.g. minute ventilation, administration of histamine will cause an increase in minute ventilation in one subject and a decrease in another.

Histamine induced bronchoconstriction and end tidal inspiratory activity in man.

BACKGROUND: End tidal inspiratory activity (ETIA) in diaphragm and parasternal intercostal muscles can be evoked in man and in animals by administration of histamine. Exacerbations of asthma and administration of histamine are often accompanied by hyperinflation. The aims of the study were to determine (1) the magnitude of ETIA in response to histamine in man, (2) the relative contributions of chemical and mechanical stimulation of airway receptors to ETIA, and (3) the importance of ETIA to hyperinflation. METHODS: The effects of inhalation of histamine on the electrical activities of the diaphragm and parasternal intercostal muscles measured with surface electrodes were studied in 21 subjects. The experiments were repeated after inhalation of 600 micrograms of salbutamol to prevent histamine induced bronchoconstriction and concomitant mechanical stimulation of airway receptors. Subjects were connected to a closed breathing circuit to measure the changes in functional residual capacity (FRC) for the different experiments. RESULTS: The mean values of histamine induced ETIA were 60.6% and 46.9% of peak inspiratory activities during control conditions for the diaphragm and intercostal muscles, respectively. After salbutamol histamine induced ETIA was reduced to about one quarter of pre-salbutamol values. FRC increased by 427 ml as a result of inhalation of histamine, but after salbutamol this increase was only 53 ml. The data for ETIA and FRC were interpreted as indicating that the contributions of airflow limitation and ETIA to histamine induced hyperinflation are comparable. CONCLUSIONS: Histamine is a forceful stimulus for inducing ETIA. Both chemical and mechanical stimulation of airway receptors contribute to evoke ETIA, of which the contribution of mechanical stimulation is the more important one. ETIA contributes substantially to histamine induced hyperinflation.