Ventilatory response to incremental and constant-workload exercise in the presence of a thoracic restriction.

In the presence of an externally applied thoracic restriction, conflicting ventilatory responses to exercise have been reported, which could be accounted for by differences in exercise protocol. Seven male subjects performed two incremental and two constant-workload ergometer tests either unrestricted or in the presence of an inelastic corset. Ventilatory variables and arterial estimates of PCO(2) were obtained breath by breath. Subjects hyperventilated in the presence of restriction during the constant-workload test (38.4 +/- 3.0 vs. 32.8 +/- 3.0 l/min for the average of the last 3 min of exercise, P < 0.05), whereas, at an equivalent workload during the incremental test, ventilation was similar to unrestricted values (unrestricted = 26.3 +/- 1.6 vs. restricted = 27.9 +/- 2.3 l/min, P = 0.36). We used a first-order linear model to describe the effects of change in workload on minute ventilation (24). When the time constants and minute ventilation values measured during unrestricted and restricted constant-workload exercise were used to predict the ventilatory response to the respective incremental exercise tests, no significant difference was observed. This suggests that hyperventilation is not seen in the restricted incremental test because the temporal dynamics of the ventilatory response are altered.

Alpha-toxin damages the air-blood barrier of the lung in a rat model of Staphylococcus aureus-induced pneumonia.

We have shown that injury to alveolar epithelial type I cells may account, in part, for damage to the air-blood barrier of the lung in a rat model of Staphylococcus aureus pneumonia. We have also shown that alpha-toxin is an important cause of damage to the air-blood barrier; however, our data suggest that the toxin is not acting directly on alveolar type I cells.

External thoracic restriction, respiratory sensation, and ventilation during exercise in men.

Multiple factors may contribute to the dyspnea associated with restrictive ventilatory disease (RVD). Simple models that examine specific features of this problem are likely to provide insight into the mechanisms. Previous models of RVD utilizing elastic loads may not represent completely the impact on pulmonary and chest wall receptors derived from breathing at low thoracic volumes. The purpose of this study was to investigate the sensory consequences of breathing at low lung volumes induced by external thoracic restriction in an attempt to further elucidate the etiology of dyspnea in this setting. Ten men were studied, with and without an inelastic corset applied at residual volume (restriction resulted in mean reductions in vital capacity, functional residual capacity, residual volume, and forced expired volume in 1 s of 44, 31, 12.5, and 42%, respectively). During 10-min steady-state exercise tests (at a workload set to achieve approximately 65% maximum heart rate), restriction resulted in significant increases, compared with control, in minute ventilation (61 vs. 49 l/min), respiratory frequency (43 vs. 23 breaths/min), and visual analog scale measurements of respiratory discomfort (65 vs. 20 mm). Alveolar hyperventilation (end-tidal PCO2 = 39 vs. 44 Torr for control) and mild O2 desaturation (arterial blood O2 saturation = 93 vs. 95% for control) occurred. Hypoxemia, atelectasis, increased work and effort of breathing, or a decrease in the volume-related feedback from chest wall and/or lungs could be responsible for the increased dyspnea reported. External thoracic restriction provides a useful model to study mechanisms of dyspnea in RVD.

Breathing during wakefulness and NREM sleep in humans without an upper airway.

The increase in PCO2 that occurs during sleep may reflect an inadequate ventilatory compensation to an increase in upper airway resistance. To address this question in humans, we examined changes in breathing during wakefulness and non-rapid-eye-movement sleep in eight laryngectomized subjects who breathed through a tracheal stoma. In these subjects, any sleep-related increase in upper airway resistance could not affect ventilation. Healthy subjects breathing via an intact upper airway were studied as controls. The mean increase in end-tidal PCO2 from wakefulness to sleep was 2.7 +/- 2.6 (SD) Torr (P = 0.05) in laryngectomized subjects and 1.6 +/- 1.4 Torr (P = 0.02) in control subjects. During wakefulness, ventilation was lower in laryngectomized subjects compared with control subjects, although this difference was not statistically significant (6.8 +/- 1.9 vs. 7.4 +/- 1.2 l/min; P > 0.05). During sleep, the fall in ventilation was similar in the two groups (1.1 +/- 2.1 vs. 0.8 +/- 2.1 l/min; P > 0.05). Our observations are not consistent with the view that increases in upper airway resistance are obligatory for sleep-related CO2 retention in humans.

Self-control of level of mechanical ventilation to minimize CO2 induced air hunger.

Hypercapnia produces an uncomfortable urge to breathe ('air hunger'), which is alleviated by increasing breathing. It has been postulated that awake humans control breathing partly to minimize these sensations; such behavioral control presumably involves the forebrain. To test this postulate, we compared the ventilatory response to hypercapnia when the subject breathed spontaneously to the response when the subject used forebrain commands to control ventilation--on the basis of minimizing air hunger (achieved with subject-controlled positive pressure ventilation). In six healthy adults during hypercapnia (46 mmHg), spontaneous ventilation significantly exceeded, by 17%, the level of (mechanical) ventilation needed to alleviate air hunger. This suggests that spontaneous breathing is not behaviorally controlled to minimize discomfort. Alternatively, mechanical ventilation confers an additional relief of air hunger beyond that provided by spontaneous breathing. Since mechanical ventilation (with reduced respiratory muscle contraction) was more effective than spontaneous breathing in relieving air hunger, our results also suggest afferents that signal the degree of respiratory muscle contraction do not contribute to air hunger relief.

Ventilatory relief of the sensation of the urge to breathe in humans: are pulmonary receptors important?

1. The sensation of an urge to breathe (air hunger) associated with a fixed level of hypercapnia is reduced when ventilation increases. The aim of the present study was to investigate whether pulmonary receptors are important in this mechanism. 2. Five heart-lung transplant (HLT) subjects and five control subjects were studied during periods of mechanical and spontaneous ventilation. End-tidal Pco2 (PET,CO2) was increased by altering the level of inspired CO2. Throughout, subjects rated sensations of air hunger. Air hunger was also monitored during and immediately following maximal periods of breath-holding. 3. When the level of mechanical ventilation was fixed, both groups experienced a high degree of air hunger when PET,CO2 was increased by about 10 mmHg. At similar levels of hypercapnia, both groups derived relief from approximately twofold increases in tidal volume, although relief was slightly less effective in HLT subjects. This was reversible, with decreases in the level of mechanical ventilation rapidly giving rise to increased ratings of air hunger. 4. With breath-holding, all subjects obtained some respiratory relief within 2 s of the break point; there was no significant difference between the groups. 5. The results suggest that sensations of an urge to breathe induced by hypercapnia can be modulated by changes in tidal volume in the presumed absence of afferent information from the lung.

Evidence for limbic system activation during CO2-stimulated breathing in man.

1. The role of supra-brainstem structures in the ventilatory response to inhaled CO2 is unknown. The present study uses positron emission tomography (PET), with infusion of H2(15)O, to measure changes in relative regional cerebral blood flow (rCBF) in order to identify sites of increased neuronal activation during CO2-stimulated breathing (CO2-SB) in awake man. 2. Five male volunteers were scanned during CO2-SB (mean +/- S.E.M.; end-tidal PCO2, 50.3 +/- 1.7 mmHg; respiratory frequency, 16.4 +/- 2.7 min-1; tidal volume, 1.8 +/- 0.2 l). As control, scans were performed during 'passive' isocapnic (elevated fraction of inspired CO2) positive pressure ventilation (end-tidal PCO2, 38.4 +/- 1.0 mmHg; respiratory frequency, 15.5 +/- 2.2 min-1; tidal volume, 1.6 +/- 0.2 l). With CO2-SB, all subjects reported dyspnoea. 3. The anatomical locations of the increases in relative rCBF (CO2-SB versus control) were obtained using magnetic resonance imaging. 4. Group analysis identified neuronal activation within the upper brainstem, midbrain and hypothalamus, thalamus, hippocampus and parahippocampus, fusiform gyrus, cingulate area, insula, frontal cortex, temporo-occipital cortex and parietal cortex. No neuronal activation was seen within the primary motor cortex (at sites previously shown to be associated with volitional breathing). 5. These results suggest neuronal activation within the limbic system; this activation may be important in the sensory and/or motor respiratory responses to hypercapnia in awake man.

Changes in total pulmonary resistance and PCO2 between wakefulness and sleep in normal human subjects.

We investigated the possible role of an increase in total pulmonary resistance in the sleep-related hypoventilation that occurs in healthy subjects. Eight nonsnoring volunteers were studied during quiet wakefulness and stage IV sleep. Airflow was measured via a nasal mask with a low dead space, and breathing pattern, end-tidal PCO2 (PETCO2), and a continuous estimate of total pulmonary resistance were estimated. From wakefulness to sleep, mean inspiratory resistance increased from 5.5 +/- 2.4 (SD) to 8.1 +/- 4.3 cmH2O.l-1.s, PETCO2 increase from 38.7 +/- 3.0 to 40.7 +/- 3.5 Torr, and ventilation decreased from 7.12 +/- 1.15 to 6.47 +/- 1.68 l/min. In five of the eight subjects, low levels of continuous positive airway pressure were applied during stage IV sleep to reverse any increase in resistance. In these subjects, continuous positive airway pressure reduced mean inspiratory resistance from 9.3 +/- 4.3 +/- 3.0 cmH2O.l-1.s but had little effect on mean PETCO2 (from 39.8 +/- 4.0 to 39.6 +/- 4.0 Torr) and mean ventilation (from 6.79 +/- 1.93 to 6.91 +/- 1.80 l/min). These findings suggest that in nonsnoring subjects reductions in alveolar ventilation cannot be accounted for by an increase in airway resistance.

Dose dependency of perceived breathlessness on hypoventilation during exercise in normal subjects.

To determine whether a dose-dependent relationship exists between the subjective sensation of breathlessness and hypoventilation during steady-state exercise, we measured breathlessness at six levels of volitionally suppressed ventilation. To achieve this, subjects targeted their breathing at 0, 5, 10, 15, 20, and 25% below their spontaneous exercise level. All 12 subjects were successful in hypoventilating in a graded manner. However, in general, the degree of hypoventilation achieved was less than that of the target level set; this discrepancy was greatest at the higher target levels. Volitional hypoventilation at target levels of > or = 10% caused significant decreases in ventilation and significant increases in end-tidal PCO2. All levels of volitional hypoventilation caused increased ratings of breathlessness, reaching statistical significance at a set target level of 15%. Significant increases in breathlessness intensity were associated with increases in end-tidal PCO2 of 2-3 Torr. We conclude that, during steady-state exercise, there appears to be a dose-dependent relationship between breathlessness and volitionally induced inappropriately low ventilation. The need to minimize such subjective sensations of breathlessness may play a role in the increased ventilation observed during exercise.

Neurotransmission in isolated sheep mesenteric lymphatics.

Spontaneous isometric contractions were measured in rings of sheep mesenteric lymphatics. Field stimulation at short pulse widths increased the frequency of spontaneous contractions and this response was blocked by 10(-7) M tetrodotoxin. The alpha-antagonists phentolamine, prazosin, and yohimbine failed to block the excitatory response in a dose of 10(-6) M. Exogenous noradrenaline (10(-6) M) increased the frequency and force of spontaneous contractions and this effect was blocked by a 10(-6) M phentolamine. Atropine 10(-6) M failed to block the excitatory response to field stimulation. alpha beta-methylene ATP caused an intense transient excitatory effect followed by recovery to a frequency level just above that of control but the excitatory effect of field stimulation was not blocked in these desensitized vessels. When vessels were exposed to a mixture of 10(-4) M noradrenaline and 10(-5) M phentolamine field stimulation did not further increase the frequency of spontaneous contractions. These results demonstrate that the innervation of sheep mesenteric lymphatics is different from that of bovine mesenteric lymphatics. The identity of the transmitter is as yet unknown but it does not appear to be ATP nor is it noradrenaline acting on postsynaptic alpha-receptors.

Comparison between continuous and discrete measurements of breathlessness during exercise in normal subjects using a visual analogue scale.

1. Visual analogue scaling of breathlessness made at discrete intervals during ventilatory stimulation tests can provide useful information about the intensity of this sensation. The aim of the present study was to investigate the use of continuous visual analogue scaling as a means of improving the temporal resolution of this measurement. 2. Six normal naive subjects scaled breathlessness using a visual analogue scale, during steady-state exercise. Further changes in this sensation were induced by either sustained hypercapnia or acute hypoxia; these responses were assessed either continuously or at discrete 30 s intervals and the two scaling methods were compared. 3. The continuous method of assessing breathlessness compared favourably with that of the more established discrete method, providing reproducible measurements in repeated tests equivalent in intensity to those obtained every 30 s. 4. Transient changes in the sensation of breathlessness produced by acute episodes of hypoxia were identified using the continuous scaling method but not with discrete scaling. 5. The continuous method of scaling breathlessness should aid the investigation of the neurophysiological basis of this sensation by allowing temporal relationships between changes in respiratory variables and the sensory consequences to be more carefully defined.

Mesenteric lymph flow responses to splanchnic nerve stimulation in sheep.

The main mesenteric lymph duct was cannulated in halothane-anesthetized sheep, and continuous recordings were made of lymph flow, lymphatic pressure fluctuations, and arterial pressure. Stimulation of the left greater splanchnic nerve at frequencies of 1, 4, and 10 Hz caused lymph flow to increase by 30 +/- 9, 74 +/- 19, and 80 +/- 21%, respectively. Lymphatic contraction frequency and mean arterial pressure showed graded increases in response to increasing stimulus frequencies. These responses were reduced after intravenous infusion of phentolamine, suggesting that they were mediated by alpha-adrenoceptors. Lymph protein concentration remained unchanged during stimulation, suggesting that lymph formation in the nodes was not responsible for the increased lymph flow. The lymph flow response during 20 min of stimulation was biphasic, showing an initial transient increase followed by a depression to 45% of control. It is concluded that the initial increase in flow may be explained by stimulation of the lymphatic pump by nerves and/or circulating catecholamines, while the subsequent decrease reflected a reduction in lymph formation.