Oxygen cost of breathing during fatiguing inspiratory resistive loads

When a subject breathes against an inspiratory resistance, the inspiratory pressure, the inspiratory flow, and the lung volume at which the breathing task takes place all interact to determine the length of time the task can be sustained (Tlim). We hypothesized that the mechanism actually limiting tasks in which these parameters were varied involved the rate of energy utilization by the inspiratory muscles. To test this hypothesis, we studied four experienced normal subjects during fatiguing breathing tasks performed over a range of pressures and flows and at two different lung volumes. We assessed energy utilization by measuring the increment in the rate of whole body O2 consumption due to the breathing task (VO2 resp). Power and mean esophageal pressure correlated with Tlim but depended also on lung volume and inspiratory flow rate. In contrast, VO2 resp closely correlated with Tlim, and this relationship was not systematically altered by inspiratory flow or lung volume. The shape of the VO2 resp vs. Tlim curve was approximately hyperbolic, with high rates of VO2 resp associated with short endurance times and lower rates of VO2 resp approaching an asymptotic value at high Tlim. These findings are consistent with a mechanism whereby a critical rate of energy utilization determines the endurance of the inspiratory pump, and that rate varies with pressure, flow, and lung volume.     

Detection of inspiratory resistive loads in double-lung transplant recipients.

The afferent pathways mediating respiratory load perception are still largely unknown. To assess the role of lung vagal afferents in respiratory sensation, detection of inspiratory resistive loads was compared between 10 double-lung transplant (DLT) recipients with normal lung function and 12 healthy control (Nor) subjects. Despite a similar unloaded and loaded breathing pattern, the DLT group had a significantly higher detection threshold (2.91 +/- 0.5 vs. 1.55 +/- 0.3 cmH(2)O. l(-1). s) and Weber fraction (0.50 +/- 0.1 vs. 0.30 +/- 0.1) compared with the Nor group. These results suggest that inspiratory resistive load detection occurs in the absence of vagal afferent feedback from the lung but that lung vagal afferents contribute to inspiratory resistive load detection response in humans. Lung vagal afferents are not essential to the regulation of resting breathing and load compensation responses.     

Neuromuscular and mechanical responses to inspiratory resistive loading during sleep

The purposes of this study were 1) to characterize the immediate inspiratory muscle and ventilation responses to inspiratory resistive loading during sleep in humans and 2) to determine whether upper airway caliber was compromised in the presence of a resistive load. Ventilation variables, chest wall, and upper airway inspiratory muscle electromyograms (EMG), and upper airway resistance were measured for two breaths immediately preceding and immediately following six applications of an inspiratory resistive load of 15 cmH2O.l-1 X s during wakefulness and stage 2 sleep. During wakefulness, chest wall inspiratory peak EMG activity increased 40 +/- 15% (SE), and inspiratory time increased 20 +/- 5%. Therefore, the rate of rise of chest wall EMG increased 14 +/- 10.9% (NS). Upper airway inspiratory muscle activity changed in an inconsistent fashion with application of the load. Tidal volume decreased 16 +/- 6%, and upper airway resistance increased 141 +/- 23% above pre-load levels. During sleep, there was no significant chest wall or upper airway inspiratory muscle or timing responses to loading. Tidal volume decreased 40 +/- 7% and upper airway resistance increased 188 +/- 52%, changes greater than those observed during wakefulness. We conclude that 1) the immediate inspiratory muscle and timing responses observed during inspiratory resistive loading in wakefulness were absent during sleep, 2) there was inadequate activation of upper airway inspiratory muscle activity to compensate for the increased upper airway inspiratory subatmospheric pressure present during loading, and 3) the alteration in upper airway mechanics during resistive loading was greater during sleep than wakefulness.     

Magnitude estimation of inspiratory resistive loads by double-lung transplant recipients.

The purpose of this study was to investigate the role of afferent input from the lung and lower airways in magnitude estimation of inspiratory resistive loads (R). To assess the role of lung vagal afferents in respiratory sensation, sensations related to inspiratory R, reflected by subjects' percentage of handgrip responses (HG%), were compared between double-lung transplant (DLT) recipients with normal lung function and healthy control (Nor) subjects. Perceptual sensitivity to the external load was measured as the slope of HG% as a function of peak mouth pressure (Pm), and the slope of HG% as a function of R, after a log-log transformation. The results showed that the DLT group had a similar HG% response, as well as the slopes of log HG%-log Pm and log HG%-log R, compared with the Nor group. Furthermore, the ventilatory responses to external loads were also similar between the two groups. These results suggest that lung vagal afferents do not play a significant role in magnitude estimation of inspiratory resistive loads in humans.     

Detection threshold for inspiratory resistive loads and respiratory-related evoked potentials.

The relationship between detection threshold of inspiratory resistive loads and the peaks of the respiratory-related evoked potential (RREP) is unknown. It was hypothesized that the short-latency and long-latency peaks of the RREP would only be elicited by inspiratory loads that exceeded the detection threshold. The detection threshold for inspiratory resistive loads was measured in healthy subjects with inspiratory-interruption or onset load presentations. In a separate protocol, the RREPs were recorded with resistive loads that spanned the detection threshold. The loads were presented in stimulus attend and ignore sessions. Onset and interruption load presentations had the same resistive load detection threshold. The P(1), N(f), and N(1) peaks of the RREP were observed with loads that exceeded the detection threshold in both attend and ignore conditions. The P(300) was present with loads that exceeded the detection threshold only in the attend condition. No RREP components were elicited with subthreshold loads. The P(1), N(f), and P(300) amplitudes varied with resistive load magnitude. The results support the hypothesis that there is a resistive load threshold for eliciting the RREPs. The amplitude of the RREP peaks vary as a function of load magnitude. The cognitive P(300) RREP peak is present only for detectable loads and when the subject attends to the stimulus. The absence of the RREP with loads below the detection threshold and the presence of the RREP elicited by suprathreshold loads are consistent with the gating of these neural measures of respiratory mechanosensory information processing.     

Breathing responses to small inspiratory threshold loads in humans.

To investiage the effect of inspiratory threshold load (ITL) on breathing, all previous work studied loads that were much greater than would be encountered under pathophysiological conditions. We hypothesized that mild ITL from 2.5 to 20 cmH2O is sufficient to modify control and sensation of breathing. The study was performed in healthy subjects. The results demonstrated that with mild ITL 1) inspiratory difficulty sensation could be perceived at an ITL of 2.5 cmH2O; 2) tidal volume increased without change in breathing frequency, resulting in hyperpnea; and 3) although additional time was required for inspiratory pressure to attain the threshold before inspiratory flow was initiated, the total inspiratory muscle contraction time remained constant. This resulted in shortening of the available time for inspiratory flow, so that the tidal volume was maintained or increased by significant increase in mean inspiratory flow. On the basis of computer simulation, we conclude that the mild ITL is sufficient to increase breathing sensation and alter breathing control, presumably aiming at maintaining a certain level of ventilation but minimizing the energy consumption of the inspiratory muscles.     

Sustained isocapnic hypoxia suppresses the perception of the magnitude of inspiratory resistive loads.

The sensation of increased respiratory resistance or effort is likely to be important for the initiation of alerting or arousal responses, particularly in sleep. Hypoxia, through its central nervous system-depressant effects, may decrease the perceived magnitude of respiratory loads. To examine this, we measured the effect of isocapnic hypoxia on the ability of 10 normal, awake males (mean age = 24.0 +/- 1.8 yr) to magnitude-scale five externally applied inspiratory resistive loads (mean values from 7.5 to 54.4 cmH(2)O. l(-1). s). Each subject scaled the loads during 37 min of isocapnic hypoxia (inspired O(2) fraction = 0.09, arterial O(2) saturation of approximately 80%) and during 37 min of normoxia, using the method of open magnitude numerical scaling. Results were normalized by modulus equalization to allow between-subject comparisons. With the use of peak inspiratory pressure (PIP) as the measure of load stimulus magnitude, the perception of load magnitude (Psi) increased linearly with load and, averaged for all loaded breaths, was significantly lower during hypoxia than during normoxia (20.1 +/- 0.9 and 23.9 +/- 1.3 arbitrary units, respectively; P = 0. 048). Psi declined with time during hypoxia (P = 0.007) but not during normoxia (P = 0.361). Our result is remarkable because PIP was higher at all times during hypoxia than during normoxia, and previous studies have shown that an elevation in PIP results in increased Psi. We conclude that sustained isocapnic hypoxia causes a progressive suppression of the perception of the magnitude of inspiratory resistive loads in normal subjects and could, therefore, impair alerting or arousal responses to respiratory loading.     

Effects of inspiratory resistive load on respiratory control in hypercapnia and exercise

Eight healthy young men underwent two separate steady-state incremental exercise runs within the aerobic range on a treadmill with alternating periods of breathing with no load (NL) and with an inspiratory resistive load (IRL) of approximately 12 cmH2O.1-1.s. End-tidal PCO2 was maintained constant throughout each run at the eucapnic or a constant hypercapnic level by adding 0-5% CO2 to the inspired O2. Hypercapnia caused a steepening, as well as upward shift, relative to the corresponding eucapnic ventilation-CO2 output (VE - VCO2) relationship in NL and IRL. Compared with NL, the VE - VCO2 slope was depressed by IRL, more so in hypercapnic [-19.0 +/- 3.4 (SE) %] than in eucapnic exercise (-6.0 +/- 2.0%), despite a similar increase in the slope of the occlusion pressure at 100 ms - VCO2 (P100 - VCO2) relationship under both conditions. The steady-state hypercapnic ventilatory response at rest was markedly depressed by IRL (-22.6 +/- 7.5%), with little increase in P100 response. For a given inspiratory load, breathing pattern responses to separate or combined hypercapnia and exercise were similar. During IRL, VE was achieved by a greater tidal volume (VT) and inspiratory duty cycle (TI/TT) along with a lower mean inspiratory flow (VT/TI). The increase in TI/TT was solely because of a prolongation of inspiratory time (TI) with little change in expiratory duration for any given VT. The ventilatory and breathing pattern responses to IRL during CO2 inhalation and exercise are in favor of conservation of respiratory work.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response of normal subjects to inspiratory resistive unloading

The purpose of this study was to examine the role of the normal inspiratory resistive load in the regulation of respiratory motor output in resting conscious humans. We used a recently described device (J. Appl. Physiol. 62: 2491-2499, 1987) to make mouth pressure during inspiration positive and proportional to inspiratory flow, thus causing inspiratory resistive unloading (IRUL); the magnitude of IRUL (delta R = -3.0 cmH2O.1(-1).s) was set so as to unload most (approximately 86% of the normal inspiratory resistance. Six conscious normal humans were studied. Driving pressure (DP) was calculated according to the method of Younes et al. (J. Appl. Physiol. 51: 963-1001, 1981), which provides the equivalent of occlusion pressure at functional residual capacity throughout the breath. IRUL resulted in small but significant changes in minute ventilation (0.6 1/min) and in end-tidal CO2 concentration (-0.11%) with no significant change in tidal volume or respiratory frequency. There was a significant shortening of the duration (neural inspiratory time) of the rising phase of the DP waveform and the shape of the rising phase became more convex to the time axis. There was no change in the average rate of rise of DP or in the duration or shape of the declining phase. We conclude that 1) the normal inspiratory resistance is an important determinant of the duration and shape of the rising phase of DP and 2) the neural responses elicited by the normal inspiratory resistance are similar to those observed with added inspiratory resistive loads.     

Steady-state response of quadriplegic subjects to inspiratory resistive load

Normal subjects preserve tidal volume (VT) in the face of added inspiratory resistance by increasing maximal amplitude and duration of the rising phase of respiratory driving pressure (DP) and by changing the shape of this phase to one that is more concave to the time axis. To explore the possible role of chest wall afferents in mediating these responses, we determined averaged DP in eight quadriplegic subjects during steady-state unloaded breathing and while breathing through an inspiratory resistance (8.5 cmH2O X 1(-1) X s). As with normal subjects, quadriplegics preserved VT (loaded VT = 106% control) by utilizing all three mechanisms. However, prolongation of the inspiratory duration derived from the DP waveform (+22% vs. +42%) and shape response were significantly less in the quadriplegic subjects. Shape response was completely absent in subjects with C4 lesions. The results provide strong evidence that respiratory muscle spindles are responsible for shape response and that changes in afferent feedback from the chest wall play an important role in mediating inspiratory prolongation.     

Steady-state response of normal subjects to inspiratory resistive load

Tidal volume (VT) is usually preserved when conscious humans are made to breathe against an inspiratory resistance. To identify the neural changes responsible for VT compensation we calculated the respiratory driving pressure waveform during steady-state unloaded and loaded breathing (delta R = 8.5 cmH2O X 1(-1) X s) in eight conscious normal subjects. Driving pressure (DP) was calculated according to the method of Younes et al. (J. Appl. Physiol. 51: 963-989, 1981), which provides the equivalent of occlusion pressure at functional residual capacity throughout the breath. VT during resistance breathing was 108% of unloaded VT, as opposed to a predicted value of 82% of control in the absence of neural compensation. Compensation was accomplished through three changes in the DP waveform: 1) peak amplitude increased (+/- 23%), 2) the duration of the rising phase increased (+42%); and 3) the rising phase became more concave to the time axis. There were no changes in the relative decay rate of inspiratory pressure during expiration, in the shape of the declining phase of DP, or in end-expiratory lung volume.     

Impaired cortical processing of inspiratory loads in children with chronic respiratory defects

Background

We tested the hypothesis that maternal interleukin-1β (IL-1β) pretreatment and induction of fetal cortisol synthesis activates MAP kinases and thereby affects lung fluid absorption in preterm guinea pigs.

Methods

IL-1β was administered subcutaneously daily to timed-pregnant guinea pigs for three days. Fetuses were obtained by abdominal hysterotomy and instilled with isosmolar 5% albumin into the lungs and lung fluid movement was measured over 1 h by mass balance. MAP kinase expression was measured by western blot.

Results

Lung fluid absorption was induced at 61 days (D) gestation and stimulated at 68D gestation by IL-1β. Maternal IL-1β pretreatment upregulated ERK and upstream MEK expression at both 61 and 68D gestation, albeit being much more pronounced at 61D gestation. U0126 instillation completely blocked IL-1β-induced lung fluid absorption as well as IL-1β-induced/stimulated ERK expression. Cortisol synthesis inhibition by metyrapone attenuated ERK expression and lung fluid absorption in IL-1β-pretreated fetal lungs. JNK expression after maternal IL-1β pretreatment remained unaffected at either gestation age.

Conclusion

These data implicate the ERK MAP kinase pathway as being important for IL-1β induction/stimulation of lung fluid absorption in fetal guinea pigs.     

Effect of resistive loads on pattern of respiratory muscle recruitment during exercise.

In healthy subjects, we compared the effects of an expiratory (ERL) and an inspiratory (IRL) resistive load (6 cmH2O.l-1.s) with no added resistive load on the pattern of respiratory muscle recruitment during exercise. Fifteen male subjects performed three exercise tests at 40% of maximum O2 uptake: 1) with no-added-resistive load (control), 2) with ERL, and 3) with IRL. In all subjects, we measured breathing pattern and mouth occlusion pressure (P0.1) from the 3rd min of exercise, in 10 subjects O2 uptake (VO2), CO2 output (VCO2), and respiratory exchange ratio (R), and in 5 subjects we measured gastric (Pga), pleural (Ppl), and transdiaphragmatic (Pdi) pressures. Both ERL and IRL induced a high increase of P0.1 and a decrease of minute ventilation. ERL induced a prolongation of expiratory time with a reduction of inspiratory time (TI), mean expiratory flow, and ratio of inspiratory to total time of the respiratory cycle (TI/TT). IRL induced a prolongation of TI with a decrease of mean inspiratory flow and an increase of tidal volume and TI/TT. With ERL, in two subjects, Pga increased and Ppl decreased more during inspiration than during control suggesting that the diaphragm was the most active muscle. In one subject, the increases of Ppl and Pga were weak; thus Pdi increased very little. In the two other subjects, Ppl decreased more during inspiration but Pga also decreased, leading to a decrease of Pdi. This suggests a recruitment of abdominal muscles during expiration and of accessory and intercostal muscles during inspiration. With IRL, in all subjects, Ppl again decreased more, Pga began to decrease until 40% of TI and then increased.(ABSTRACT TRUNCATED AT 250 WORDS)