Can airway function be predicted?
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Asthma↗
Biomedical subjects
P T Macklem
Publications and source records attributed to P T Macklem.
[Function of the diaphragm during exercise].
We examined the control of respiratory muscles with emphasis on the diaphragm during exercise at 30%, 60% and 90% of maximal working capacity in normal subjects. Control of the diaphragm was quantified by plotting transdiaphragmatic pressure (Pdi), its electromyographic activity (Edi) and its power (Wdi = Pdi x Dab/Ti) vs. workload and Pdi, an index of shortening velocity of diaphragmatic fibres (Dab/Ti) and Wdi vs. Edi. We observed that increase in Pdi (approximately 2-fold) from rest to heavy exercise was inadequately small comparing to increases in minute ventilation (approximately 9-fold) and Edi (approximately 4.5-fold). We hypothesized and confirmed that Wdi might increase even though Pdi decreased due to increasing Dab/Ti and expresses more closely diaphragmatic contribution to inspiratory effort during exercise than Pdi. Significantly augmented shortening velocity of the diaphragm suggests that it acts predominantly as a flow generator during exercise. It is strongly assisted in this task by abdominal muscles. The responsibility for generating inspiratory pressures falls on the inspiratory rib cage muscles. This arrangement may however impair diaphragm's performance even in healthy subjects as indicated by reduced Pdi twitch after exercise.
Adult↗
[Effect of respiratory muscle fatigue on their function during exercise].
We evaluated the effect of global inspiratory muscle fatigue (GF) on respiratory muscle control during exercise at 30%, 60%, and 90% of maximal power output in normal subjects. Fatigue was induced by breathing against a high inspiratory resistance until exhaustion. Respiratory pressures, breathing pattern, and perceived breathlessness were measured. Induction of GF had no effect on the ventilatory parameters during mild and moderate exercise. It altered, however, ventilatory response to heavy exercise by increasing breathing frequency and minute ventilation, with minor changes in tidal volume. This was accompanied by an increase in perceived breathlessness. GF significantly increased both the tonic and phasic activities of abdominal muscles that allowed 1) the diaphragm to maintain its function while developing less pressure, 2) the same tidal volume with lesser shortening of the rib cage inspiratory muscles, and 3) relaxation of the abdominal muscles to contribute to lung inflation. The increased work performed by the abdominal muscles may, however, lead to a reduction in their strength. GF may impair exercise performance in some healthy subjects that is probably not related to excessive breathlessness or other ventilatory factors. The respiratory system is remarkably adaptable in maintaining ventilation during exercise even with impaired inspiratory muscle contractility.
Abdominal Muscles↗
Control of cell volume in oocytes and eggs from Xenopus laevis.
The mechanism by which Xenopus laevis oocytes and eggs survive in hypotonic media was investigated by measuring cell volume (Vc) and intracellular pressure (P(ic)) during osmotic swelling. After 2 hr in 10 mOsm buffer, eggs remained intact, while 60.2 +/- 7.0% of oocytes had burst. Water uptake was proportional to buffer osmolarity in oocytes, but not in eggs. We did not see a regulatory volume decrease in the cells, nor was there any evidence for osmolyte efflux. Oocyte P(ic) increased from 0.27 cm H2O (range 0.14-0.61 cm H2O) to 5.92 cm H2O (range 2.52-7.18 cm H2O, P < 0.001) after 70 min in 20 mOsm buffer. Egg P(ic) in 20 mOsm buffer (0.04 cm H2O, range -0.07 to 0.014 cm H2O) was not significantly different from the value in isotonic (200 mOsm) buffer (0.14 cm H2O, range 0-0.16 cm H2O). The data indicate that Vc in oocytes and eggs is not regulated by either plasma membrane ion transport or the mechanical properties of the vitelline envelope. While oocytes appear to behave as passive osmometers, we speculate that the ability of eggs to maintain volume is determined, in part, by the cytoplasm, in particular by its gel-like nature.
Animals↗
Effects of fatigue, fiber length, and aminophylline on human diaphragm contractility.
The clinical relevance of methylxanthines as therapeutic agents for improving diaphragmatic contractility is controversial. In a double-blind, placebo-controlled trial, we investigated the effect of aminophylline on the contractility of fresh and fatigued human diaphragm at different lung volumes, and therefore as a function of fiber length. The diaphragmatic contractility of normal subjects was assessed by measurements of transdiaphragmatic pressure changes (Pdi,T) in response to single, bilateral, supramaximal phrenic-nerve shocks during relaxation from total lung capacity (TLC) to functional residual capacity (FRC). Fatigue was induced by resistive breathing. Therapeutic levels of theophylline were reached in all subjects. Under fresh (i.e., nonfatigue) conditions, aminophylline significantly increased Pdi,T at lung volumes above 75% of the inspiratory capacity (IC). Fatigue in the absence of aminophylline caused a disproportionately greater reduction of Pdi,T at high than at low lung volume (J. Appl. Physiol. 1992; 72:1064), which was rapidly reversible with rest. With aminophylline, the disproportionate decrease in diaphragmatic contractility at short fiber lengths was not observed. Aminophylline potentiates diaphragmatic contractility to a proportionately greater extent at short than at long fiber lengths, under both fresh and fatigued conditions. We explain these findings by known effects of muscle shortening, fatigue, and methylxanthines on excitation-contraction coupling mechanisms.
Adult↗
Theoretical basis of airway instability. Roger S. Mitchell Lecture.
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Asthma↗
Density dependence of pulmonary resistance: correlation with small airway pathology.
The density dependence of maximal expiratory flow is not an effective test of the site of airway narrowing in obstructive lung disease. We hypothesized that the density dependence of pulmonary resistance (DD,RL) would be more closely related to the degree of airway narrowing and peripheral airway pathology in smokers. We measured maximal expiratory flow at 50% vital capacity (V'max50) and lung resistance (RL) breathing air and 80% helium-20% oxygen, and calculated density dependence of V'max50 and RL in 40 patients who had moderate airflow obstruction and in 10 normal subjects. We compared the density dependence of RL and V'max50 with the degree of airway obstruction and bronchiolar pathology scores in 27 patients with resected lung specimens. There were no differences in DD of V'max50 or RL between normal subjects and patients, and no relationship between the degree of obstruction or the bronchiolar pathology score and the DD of these measurements. There were significant relationships between V'max50, RL and the bronchiolar pathology scores. In conclusion, lung resistance and maximal expiratory flow are related to the severity of peripheral airway pathology, but there is no relationship between the severity of obstruction or the severity of peripheral airway pathology and the density dependence of maximal expiratory flow or lung resistance.
Adult↗
Three-dimensional reconstruction of the in vivo human diaphragm shape at different lung volumes.
The ability of the diaphragm to generate pressures at different lung volumes (VLs) in humans may be determined by the following factors: 1) its in vivo three-dimensional shape, radius of curvature, and tension according to Laplace law; 2) the relative degree to which it is apposed to the rib cage (i.e., zone of apposition) and lungs (i.e., diaphragm dome); and 3) its length-force properties. To gain more insight into these factors we have reconstructed from nuclear magnetic images the three-dimensional shape of the diaphragm of four normal subjects under supine relaxed conditions at four different VLs: residual volume, functional residual capacity, functional residual capacity plus one-half of the inspiratory capacity, and total lung capacity. Under our experimental conditions the shape of the diaphragm changes substantially in the anteroposterior plane but not in the coronal one. Multivariate regression analysis indicates that the zone of apposition is dependent on both diaphragm shortening and lower rib cage widening with lung inflation, although much more on the first of these two factors. Because of the changes in anteroposterior shape and expansion of the insertional origin at the costal margin with lung inflation, the data therefore suggest that the diaphragm may be more accurately modeled by a "widening piston" (Petroll's model) than a simple "piston in a cylinder" model. A significant portion of the muscular surface is lung apposed, suggesting that diaphragmatic force has radial vectors in the dome and vectors along the body axis in the zone of apposition. The muscular surface area of the diaphragm decreased linearly by approximately 41% with VL from residual volume to total lung capacity. Diaphragmatic fibers may shorten under physiological conditions more than any other skeletal muscle. The large changes in fiber length combined with limited shape changes with lung inflation suggest that the length-twitch force properties of the diaphragm may be the most important factor for the pressure-generating function of this respiratory muscle in response to bilateral phrenic shocks at different VLs.
Diaphragm↗
Effects of fatigue on the length-tetanic force relationship of the rat diaphragm.
It has been established that the in vivo operating length of the diaphragm corresponds to a wide range of the ascending limb of its length-tetanic force relationship. To investigate the length-dependent effects of fatigue on maximum force production, we constructed length-tetanic force relationships of rat costal diaphragm strips in vitro before and after fatigue induced by repetitive supramaximal electrical field stimulations at optimal length. Two levels of fatigue were studied (i.e., force reductions of 40 and 65% at optimal length). Results indicate that fatigue, when evaluated with high-frequency stimulations, causes a proportionately larger decrease in tetanic force at short muscle lengths as seen by a smaller control force-to-fatigue force ratio and an apparent shift in the length at which active force is zero. A possible explanation for the results obtained is failure of propagation of membrane depolarization into the t-tubule system at short muscle lengths, which is aggravated by fatigue evaluated by high-frequency stimulation.
Animals↗
Lung volume changes during relatively fluent speech in stutterers.
We investigated breathing patterns in stutterers during relatively fluent speech and compared these with normal subjects for similar speech tasks. Rib cage and abdominal displacements and esophageal, gastric, and transdiaphragmatic pressures provided indexes of diaphragmatic, rib cage, and abdominal muscle contraction. We found that stutterers spoke either at substantially higher or lower lung volumes than normal subjects, confining their speech to the inspiratory capacity or expiratory reserve volume. During spontaneous speech, stutterers did not cross functional residual capacity (FRC) for most breaths. In addition, stutterers used several different motion pathways from breath to breath. At high lung volumes stutterers used the diaphragm to provide inspiratory braking. At lung volumes below FRC stutterers recruited their abdominals. This contrasted with normal subjects who spoke in the middle part of the vital capacity and who recruited inspiratory and expiratory rib cage muscles above and below FRC, respectively. Breath sizes were log-normally distributed in stutterers compared with a gaussian distribution in normal subjects (P < 0.001). During reading, stutterers tended to cross FRC (P < 0.01), used very similar initiation lung volumes from breath to breath (P < 0.001), and used similar motion pathways to achieve deflation. We conclude that stutterers sustain fluency by speaking at abnormally high or low lung volumes and that this may account for the different muscle patterns observed in stutterers compared with normal subjects.
Diaphragm↗
Effect of diaphragmatic fatigue on control of respiratory muscles and ventilation during CO2 rebreathing.
We studied the influence of diaphragmatic fatigue on the control of ventilation and respiratory muscle contribution to pressure swings in six normal seated subjects. CO2 was rebreathed before and after diaphragmatic fatigue induced by breathing against an inspiratory resistance requiring 60% maximal transdiaphragmatic pressure with each breath until exhaustion. After diaphragmatic fatigue for a given level of end-tidal PCO2, we found that tidal volume, breathing frequency, minute ventilation, duty cycle, and mean inspiratory flow did not change; esophageal pressure swings were the same, but gastric and transdiaphragmatic pressure swings were decreased; and the slope of the transpulmonary pressure-gastric pressure relationship determined at zero flow points at end expiration and end inspiration was increased. End-expiratory transpulmonary pressure progressively decreased and end-expiratory gastric pressure progressively increased with increasing end-tidal PCO2 by the same magnitude before and after diaphragmatic fatigue. We conclude that diaphragmatic fatigue induces proportionately greater contributions of inspiratory rib cage muscles than of the diaphragm, which results in the preservation of ventilatory response to CO2 despite impaired diaphragmatic contractility.
Adult↗
Effect of global inspiratory muscle fatigue on ventilatory and respiratory muscle responses to CO2.
We evaluated the effect of global inspiratory muscle fatigue on ventilation and respiratory muscle control during CO2 rebreathing in normal subjects. Fatigue was induced by breathing against a high inspiratory resistance until exhaustion. CO2 response curves were measured before and after fatigue. During CO2 rebreathing, global fatigue caused a decreased tidal volume (VT) and an increased breathing frequency but did not change minute ventilation, duty cycle, or mean inspiratory flow. Both esophageal and transdiaphragmatic pressure swings were significantly reduced after global fatigue, suggesting decreased contribution of both rib cage muscles and diaphragm to breathing. End-expiratory transpulmonary pressure for a given CO2 was lower after fatigue, indicating an additional decrease in end-expiratory lung volume due to expiratory muscle recruitment, which leads to a greater initial portion of inspiration being passive. This, combined with the reduction in VT, decreased the fraction of VT attributable to inspiratory muscle contribution; therefore the inspiratory muscle elastic work and power per breath were significantly reduced. We conclude that respiratory control mechanisms are plastic and that the respiratory centers alter their output in a manner appropriate to the contractile state of the respiratory muscles to conserve the ventilatory response to CO2.
Adult↗
Assessment of diaphragm function using mouth pressure twitches in chronic obstructive pulmonary disease patients.
The relative invasiveness of the balloon catheter technique in measuring twitch transdiaphragmatic pressure (Pdit) limits its clinical use. By phrenic stimulation we obtained swings in mouth pressure (Pmt) in six COPD patients (age 50 to 72, FEV1 18 to 48% of predicted) at relaxed FRC (rFRC) and during graded inspiratory efforts (IE; twitch occlusion, TO). At rFRC, Pmt was damped and time lagged relative to the esophageal pressure twitch (Pes(t)), as if pressure had equilibrated through an RC system. Pmt was not correlated with Pdit. Conversely, Pmt and Pes(t) were always well matched during IE [Pmt = 0.971 (SEM +/- 0.028) Pes(t), r > 0.89], possibly in relation to a decrease in upper airway compliance or more uniform pleural pressure swings. Pmt decreased with the level of voluntary diaphragmatic contraction (Pdivol) in proportion to Pdit, reflecting a progressive increase in the level of diaphragm activation. During IE, Pmt was closely related to the voluntary mouth pressure in five subjects but not in the remaining subject, indicating intersubject variability in the level of diaphragmatic recruitment relative to other inspiratory muscles. We submit that measuring Pm during inspiratory efforts upon which bilateral phrenic stimulation is superimposed offers a relatively simple method for the assessment of diaphragm activation, potentially applicable in the clinical field.
Aged↗
Effect of diaphragmatic and global inspiratory muscle fatigue on chemical control of breathing.
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Carbon Dioxide↗
Force-frequency relationships of in vivo human and in vitro rat diaphragm using paired stimuli.
Supramaximal stimuli, with time intervals of 100 ms (10 Hz) to 10 ms (100 Hz), were delivered in pairs to the phrenic nerves, bilaterally, in five seated normal subjects, while transdiaphragmatic pressure swings (Pdi,s) were recorded at relaxed end-expiratory lung volume with airways closed. In fresh diaphragms, Pdi,s increased between 10-20 Hz and reached a plateau between 20-30 Hz. Diaphragmatic fatigue decreased Pdi,s at all frequencies. Pdi,s was assumed to be the sum of two successive responses (T1+T2), T1 being constant at any frequency and equal to a single twitch, T2 being obtained by subtraction. We found that T2 amplitude, which was significantly reduced after fatigue, was fully returned to normal after 15 min rest at high, not at low, stimulation frequencies. The ratio of T2 at 10 Hz over 100 Hz (T2(10/100)) thus decreased from 1.33 +/- 0.05 before fatigue to 0.97 +/- 0.12 after fatigue, and to 0.81 +/- 0.06 after 15 min rest. Similar results were obtained in isolated rat diaphragmatic strips stimulated and fatigued in vitro, from which we found a highly linear relationship (r = 0.94, p < 0.001) between the ratio of T2(10/100) and that of tetanic force at 10 Hz over 100 Hz (P10/100). We conclude that phrenic nerve paired twitches provide similar information when obtained from phrenic tetanic stimulation in terms of diaphragmatic contractility, and the decrease in T2(10/100) ratio indicates diaphragm low frequency fatigue.
Animals↗
Effect of negative pressure ventilation in severe chronic obstructive pulmonary disease.
The hypothesis that patients with chronic obstructive pulmonary disease (COPD) have chronic inspiratory muscle fatigue was tested in an effectiveness trial in which negative pressure ventilation (NPV) was used to produce inspiratory muscle rest. In a double-blind study 184 patients with severe COPD were randomly allocated active or sham NPV treatment for a 12-week period of home use. The distance walked in a 6 min walk test was the primary outcome variable. Secondary outcome measures were cycle exercise endurance time, severity of dyspnoea, quality of life, arterial blood gas tensions, and respiratory muscle strength. The percentage reduction in amplitude of the diaphragmatic electromyographic signal multiplied by hours of NPV was used to reflect the dose of NPV so we could examine dose-response relations. Analysis was based on intention to treat. We found no evidence of a clinically or statistically significant difference in any outcome measure between active and sham groups. No dose-response relation was observed. Moreover, the intervention was poorly accepted despite substantial clinical support. We conclude that NPV as used in this study is difficult to apply and ineffective when used with the aim of resting the respiratory muscles in patients with stable COPD.
Aged↗
Induction of sleep apnoea with negative pressure ventilation in patients with chronic obstructive lung disease.
BACKGROUND: Negative pressure ventilation provides intermittent non-invasive ventilatory assistance for patients with advanced chronic obstructive lung disease. Upper airway obstruction during sleep, a reported complication of the technique, may, however, limit its clinical applicability. METHODS: The effects of nocturnal negative pressure ventilation on ventilation and on indices of sleep quality were investigated in five patients with severe chronic obstructive lung disease (mean (SE) FEV1 31% (3%) predicted) who had completed three months of nightly negative pressure ventilation. Subjects underwent overnight polysomnography on consecutive nights, the first night serving as a control and negative pressure ventilation being provided on the second night. Ventilators were adjusted to result in maximum suppression of the peak phasic electromyogram signal from the diaphragm. RESULTS: Negative pressure ventilation resulted in substantial increases in episodes of obstructive apnoea and hypopnoea (mean (SE)/h 59.3 (19.8) v 3.2 (1.3) on control nights). Most obstructive events, however, were associated with under 3% oxygen desaturation, and the lowest recorded values for overnight oxygen saturation were similar on the two study nights. Negative pressure ventilation was also associated with significant increases in the frequencies of movement arousals and changes in sleep stage. CONCLUSIONS: Negative pressure ventilation applied during sleep to patients with advanced chronic obstructive lung disease may result in the development of recurrent episodes of apnoea and hypopnoea as well as altered sleep quality, which could limit its clinical applicability.
Aged↗
Effect of fatigue on diaphragmatic function at different lung volumes.
The transdiaphragmatic pressure twitches (PdiT) in response to single maximal shocks delivered bilaterally to the phrenic nerves were recorded as a function of lung volume when the diaphragm was fresh and when fatigued. All relationships were linear and negatively sloped (all r greater than 0.85). From these relationships PdiT was found to decrease with fatigue more rapidly and to recover more quickly at high than at low lung volumes. Complete recovery of PdiT at all lung volumes was greater than 1 h. Contraction and relaxation rate constants of PdiT did not change significantly with fatigue. We conclude that fatigue affects diaphragm contractility more at high than at low lung volumes and that changes in diaphragm contractility are best reflected in the measurement of PdiT as a function of lung volume.
Adult↗