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.     

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.     

Response to inspiratory resistive loading during sleep in normal children and children with obstructive apnea.

The response to inspiratory resistance loading (IRL) of the upper airway during sleep in children is not known. We, therefore, evaluated the arousal responses to IRL during sleep in children with the obstructive sleep apnea syndrome (OSAS) compared with controls. Children with OSAS aroused at a higher load than did controls (23 +/- 8 vs. 15 +/- 7 cmH(2)O. l(-1). s; P < 0.05). Patients with OSAS had higher arousal thresholds during rapid eye movement (REM) vs. non-REM sleep (P < 0.001), whereas normal subjects had lower arousal thresholds during REM (P < 0.005). Ventilatory responses to IRL were evaluated in the controls. There was a marked decrease in tidal volume both immediately (56 +/- 17% of baseline at an IRL of 15 cmH(2)O. l(-1). min; P < 0.001) and after 3 min of IRL (67 +/- 23%, P < 0.005). The duty cycle increased. We conclude that children with OSAS have impaired arousal responses to IRL. Despite compensatory changes in respiratory timing, normal children have a decrease in minute ventilation in response to IRL during sleep. However, arousal occurs before gas-exchange abnormalities.     

Steady-state response of normal subjects to an inspiratory sinusoidal pressure load

Inspiratory duration (TI) increases during inspiratory resistive loading in conscious humans. To ascertain whether this response is related to the temporal pattern of pressure perturbation (reaching a peak in early or midinspiration and declining subsequently) we compared the response of nine normal subjects to a usual resistor (narrow tube, RES) with their response when mouth pressure was reduced in a sinusoidal fashion during inspiration (SIN). Whereas the negative pressure pattern was similar with both loads (peak negative pressure near midinspiration), there was no relation between pressure and flow in the case of sinusoidal loading. Each experiment consisted of two loading periods, 4 min each, and three unloaded periods, also 4 min each, bracketing the periods of loading. The order of RES and SIN was randomized. TI during loading was compared with the average TI of the preceding and following unloaded periods. TI increased 0.74 +/- 0.12 and 0.27 +/- 0.05 (SE) s during RES and SIN, respectively (P less than 0.01). We conclude that the temporal pattern of pressure change during resistance breathing plays a small role in mediating the TI prolongation. Coupling between flow and the pressure perturbation appears to be an important determinant of TI prolongation.     

Task failure with lack of diaphragm fatigue during inspiratory resistive loading in human subjects

McKenzie, D. K., G. M. Allen, J. E. Butler, and S. C. Gandevia. Task failure with lack of diaphragm fatigue during inspiratory resistive loading in human subjects. J. Appl. Physiol. 82(6): 2011-2019, 1997.Taskfailure during inspiratory resistive loading is thought to beaccompanied by substantial peripheral fatigue of the inspiratorymuscles. Six healthy subjects performed eight resistive breathingtrials with loads of 35, 50, 75 and 90% of maximal inspiratorypressure (MIP) with and without supplemental oxygen. MIP measuredbefore, after, and at every minute during the trial increased slightlyduring the trials, even when corrected for lung volume (e.g., for 24 trials breathing air, 12.5% increase, P < 0.05). In some trials, taskfailure occurred before 20 min (end point of trial), and in thesetrials there was an increase in end-tidalPCO₂(P < 0.01), despite the absence of peripheral muscle fatigue. In four subjects (6 trials with task failure), there was no decline in twitch amplitude with bilateral phrenic stimulation or in voluntary activation of the diaphragm, eventhough end-tidal PCO₂ rose by 1.6 ± 0.9%. These results suggest that hypoventilation,CO₂ retention, and ultimate taskfailure during resistive breathing are not simply dependent on impairedforce-generating capacity of the diaphragm or impaired voluntaryactivation of the diaphragm.

     

Model analysis of respiratory responses to inspiratory resistive loads

Based on experimental inspiratory driving pressure waveforms and active respiratory impedance data of anesthetized cats, we made model predictions of the factors that determine the immediate (first loaded breath) intrinsic (i.e., nonneural) tidal volume compensation to added inspiratory resistive loads. The time course of driving pressure (P) was given by P = atb, where a is the pressure at 1 s from onset of inspiration and represents the intensity of neuromuscular drive, t is time, and b is a dimensionless index of the shape of the driving pressure wave. For a given value of active respiratory impedance, tidal volume compensation to added resistive loads increases with increasing inspiratory duration and decreasing value of b but is independent of a. Model predictions of load compensation are compared to experimental results.     

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.     

Coronary and systemic vascular response to inspiratory resistive breathing.

To evaluate the coronary and systemic cardiovascular response to graded inspiratory resistive breathing, seven dogs were studied 2-4 wk after chronic instrumentation to measure circumflex coronary artery and ascending aortic blood flows as well as aortic and left ventricular (LV) blood pressures. The experiments were performed under chloralose anesthesia (to exclude any confounding emotional effects by dyspnea on cardiovascular variables) and hyperoxic conditions (to prevent chemoreflex activation by hypoxemia). In a randomized fashion, the dogs were subjected to graded inspiratory resistive breathing (spontaneous breathing alone and moderate and severe resistive loading, corresponding to resistances of approximately 0, 40, and 110 cmH2O.s.l-1, respectively). Each run lasted 10 min. Compared with mechanical ventilation with the respiratory muscles at rest, spontaneous breathing alone and moderate and severe inspiratory resistive loading induced pronounced and significant increases in circumflex coronary blood flow (19, 32, and 62%, respectively), which were almost exclusively accounted for by significant decrements in coronary vascular resistance and were paralleled (r = 0.88, P less than 0.0001) by significant increments (18, 31, and 57%) in heart rate transmural-aortic pressure product, an indicator of LV myocardial O2 demand. An increase in myocardial O2 consumption during resistive breathing was confirmed by analysis of coronary sinus blood samples in additional experiments (n = 3). Cardiac output significantly increased (10, 14, and 35%) because of increases in heart rate (15, 24, and 49%), with LV stroke volume and diastolic dimensions remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of inspiratory muscle fatigue on breathing pattern during inspiratory resistive loading

The purpose of this study was to determine whether induction of either inspiratory muscle fatigue (expt 1) or diaphragmatic fatigue (expt 2) would alter the breathing pattern response to large inspiratory resistive loads. In particular, we wondered whether induction of fatigue would result in rapid shallow breathing during inspiratory resistive loading. The breathing pattern during inspiratory resistive loading was measured for 5 min in the absence of fatigue (control) and immediately after induction of either inspiratory muscle fatigue or diaphragmatic fatigue. Data were separately analyzed for the 1st and 5th min of resistive loading to distinguish between immediate and sustained effects. Fatigue was achieved by having the subjects breathe against an inspiratory threshold load while generating a predetermined fraction of either the maximal mouth pressure or maximal transdiaphragmatic pressure until they could no longer reach the target pressure. Compared with control, there were no significant alterations in breathing pattern after induction of fatigue during either the 1st or 5th min of resistive loading, regardless of whether fatigue was induced in the majority of the inspiratory muscles or just in the diaphragm. We conclude that the development of inspiratory muscle fatigue does not alter the breathing pattern response to large inspiratory resistive loads.     

Chest wall distortion during resistive inspiratory loading

We studied six (1 naive and 5 experienced) subjects breathing with added inspiratory resistive loads while we recorded chest wall motion (anteroposterior rib cage, anteroposterior abdomen, and lateral rib cage) and tidal volumes. In the five experienced subjects, transdiaphragmatic and pleural pressures, and electromyographs of the sternocleidomastoid and abdominal muscles were also measured. Subjects inspired against the resistor spontaneously and then with specific instructions to reach a target pleural or transdiaphragmatic pressure or to maximize selected electromyographic activities. Depending on the instructions, a wide variety of patterns of inspiratory motion resulted. Although the forces leading to a more elliptical or circular configuration of the chest wall can be identified, it is difficult to analyze or predict the configurational results based on insertional and pressure-related contributions of a few individual respiratory muscles. Although overall chest wall respiratory motion cannot be readily inferred from the electromyographic and pressure data we recorded, it is clear that responses to loading can vary substantially within and between individuals. Undoubtedly, the underlying mechanism for the distortional changes with loading are complex and perhaps many are behavioral rather than automatic and/or compensatory.     

Effects of inspiratory flow on diaphragmatic motor output in normal subjects.

Increasing inspiratory flow (V) has been shown to shorten neural inspiratory time (TI(n)) in normal subjects breathing on a mechanical ventilator, but the effect of V on respiratory motor output before inspiratory termination has not previously been studied in humans. While breathing spontaneously on a mechanical ventilator, eight normal subjects were intermittently exposed to 200-ms-duration positive pressure pulses of different amplitudes at the onset of inspiration. Based on the increase in V above control breaths (DeltaV), trials were grouped into small, medium, and large groups (mean DeltaV: 0.51, 1.11, and 1.65 l/s, respectively). We measured TI(n), transdiaphragmatic pressure (Pdi), and electrical activity (electromyogram) of the diaphragm (EMGdi). Transient increases in V caused shortening of TI(n) from 1.34 to 1.10 (not significant), 1.55 to 1.11 (P < 0.005), and 1.58 to 1.17 s (P < 0. 005) in the small, medium, and large DeltaV groups, respectively. EMGdi measured at end TI(n) of the pulse breaths was 131 (P < 0.05), 142, and 155% (P < 0.05) of the EMGdi of the control breaths at an identical time point in the small, medium, and large trials, respectively. The latency of the excitation was 126 +/- 42 (SD) ms, consistent with a reflex effect. Increasing V had two countervailing effects on Pdi: 1) a depressant mechanical effect due primarily to the force-length (11.2 cmH(2)O/l) relation of the diaphragm, and 2) an increase in diaphragm activation. For the eight subjects, mean peak Pdi did not change significantly, but there was significant intersubject variability, reflecting variability in the strength of the excitation reflex. We conclude that increasing inspiratory V causes a graded facilitation of EMGdi, which serves to counteract the negative effect of the force-length relation on Pdi.     

Phrenic motoneuron discharge during sustained inspiratory resistive loading

Iscoe, Steve. Phrenic motoneuron discharge duringsustained inspiratory resistive loading. J. Appl.Physiol. 81(5): 2260-2266, 1996.I determinedwhether prolonged inspiratory resistive loading (IRL) affects phrenicmotoneuron discharge, independent of changes in chemical drive. Inseven decerebrate spontaneously breathing cats, the discharge patternsof eight phrenic motoneurons from filaments of one phrenic nerve weremonitored, along with the global activity of the contralateral phrenicnerve, transdiaphragmatic pressure, and fractional end-tidalCO₂ levels. Discharge patterns during hyperoxic CO₂ rebreathingand breathing against an IRL (2,500-4,000cmH₂O ^· l^{1 ·} s)were compared. During IRL, transdiaphragmatic pressure increased andthen either plateaued or decreased. At the highest fractional end-tidalCO₂ common to both runs,instantaneous discharge frequencies in six motoneurons were greaterduring sustained IRL than during rebreathing, when compared at the sametime after the onset of inspiration. These increased dischargefrequencies suggest the presence of a load-induced nonchemical drive tophrenic motoneurons from unidentified source(s).

     

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.     

Identification of respiratory vagal feedback in awake normal subjects using pseudorandom unloading.

Evidence of the Hering-Breuer reflex has been found in humans during anesthesia and sleep but not during wakefulness. Cortical influences, present during wakefulness, may mask the effects of this reflex in awake humans. We hypothesized that, if lung volume were increased in awake subjects unaware of the stimulus, vagal feedback would modulate breathing on a breath-to-breath basis. To test this hypothesis, we employed proportional assist ventilation in a pseudorandom sequence to unload the respiratory system above and below the perceptual threshold in 17 normal subjects. Tidal volume, integrated respiratory muscle pressure per breath, and inspiratory time were recorded. Both sub- and suprathreshold stimulation evoked a significant increase in tidal volume and inspiratory flow rate, but a significant decrease in inspiratory time was present only during the application of a subthreshold stimulus. We conclude that vagal feedback modulates respiratory timing on a breath-by-breath basis in awake humans, as long as there is no awareness of the stimulus.