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.     

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.     

Effect of resistive loading on inspiratory work output in anesthetized cats

In five spontaneously breathing anesthetized cats, we determined the inspiratory elastic (Wel), resistive (Wres), and total (WI) mechanical work rates (power) during control and first loaded inspirations through graded linear resistances (delta R) by "Campbell diagrams" based on measurement of esophageal pressure. WI did not change with delta R's up to 0.31 cmH2O X ml-1 X s, the concomitant decrease in Wel being balanced by an increase in Wres. The stability of WI in the face of delta R's was due to the vagally mediated prolongation of inspiration and the intrinsic properties of the respiratory system and of the contracting inspiratory muscles. To assess the separate contributions of volume-related and flow-related intrinsic mechanisms to the stability of WI, we made model predictions of the immediate effects of delta R's on inspiratory mechanical work output based on measurements of inspiratory driving pressure waves and passive and active respiratory resistance and elastance on the same five cats. The results suggest that the intrinsic stability of WI in the face of delta R's is provided primarily by the active elastance.     

Effects of Inspiratory Strength Training on the Detection of Inspiratory Loads

Pressure-threshold loads (ΔPT) are inspiratory force-related loads, which contrast with resistive loads (ΔR), are airflow-dependent loads. If detection of respiratory loads is a function of the background load, then pressure-threshold type inspiratory muscle strength training (IMST) would affect the detection of ΔPT but have less effect on detection of ΔR. ΔR and ΔPT detection and ventilatory responses were measured in healthy volunteers. IMST consisted of 4 sets of 6 breaths per day for 4 weeks, at 75% of maximal inspiratory pressure (MIP). MIP increased and a measure of inspiratory dirve, the mouth pressure generated in the initial 100 msec of an occluded inspiration (P_0.1), decreased after IMST. IMST significantly increased MIP after 4 weeks of training. IMST did not change ΔR detection threshold and ΔR-breathing pattern. IMST decreased ΔPT detection percent and ΔPT-breathing pattern. Comparing ΔR and ΔPT at the same mouth pressure-generating level, the detection percent was different. We conclude that IMST affects the detection of ΔPT, but not ΔR. These results also suggest that mouth pressure is not the primary determinant of the inspiratory load detection. The significance of these results is that inspiratory pressure generating capacity can be increased by our pressure threshold training and this increase in respiratory muscle strength increases the ability of pulmonary patients to compensate for increased respiratory load and modulates the threshold for detection of changes in pulmonary mechanics.     

Respiratory load compensation in neuromuscular disorders

First-breath ventilatory responses to graded elastic (delta E) and resistive (delta R) loads from 10 people with spinal muscular atrophy (SMA), 15 people with Duchenne muscular dystrophy (DMD), and 80 able-bodied people were compared. The SMA and DMD groups produced equal tidal volume, respiratory frequency, inspiratory duration (TI), expiratory duration, mean inspiratory airflow, and duty cycle responses to both delta E and delta R. Thus SMA (primarily a motoneuron disorder) and DMD (primarily a muscle disorder) have the same net effect on loaded breathing responses. The SMA and DMD groups failed to duplicate the normal group's short expirations during delta E, long inspirations during delta R, and thus, extended duty cycles during both delta E and delta R. The deficit in load compensation therefore was due to impaired regulation of respiratory timing (reflecting neural mechanisms) but not airflow defense (reflecting mechanical and neural mechanisms). One-fifth of the normal but none of the SMA or DMD subjects actively generated an "optimal" TI response (defined theoretically as TI greater than 160% control during large delta R and TI less than 75% control during large delta E). This lack of optimal responses, which is the same abnormality exhibited by quadriplegic people, suggests that SMA and DMD also impair human ability to discriminate between large delta R and delta E. These findings support the hypothesis that neuromuscular disorders can lead to disturbances in respiratory perception.     

Pleural pressure changes in dogs measured from suprasternal fossa movements

Movements of the suprasternal fossa during spontaneous breathing monitored with the surface inductive plethysmograph (SIP) have been shown to reflect changes of intrapleural pressure in conscious humans. Calibration of this device in anesthetized intubated dogs was accomplished by adjusting the electrical gain of its analog waveform to be equivalent to changes of airway pressure during inspiratory efforts against an occluded airway. This procedure, denoted the occlusion test, was also used to identify the site of esophageal balloon catheter placement for its recording of intrapleural pressure deflections. The validity of SIP-derived estimates of inspiratory and expiratory pulmonary resistances and lung compliance was established by finding close agreement with measurements obtained with intraesophageal pressure changes during 1) unimpeded spontaneous breathing, 2) inspiratory resistive loading, 3) bronchoprovocation with aerosolized carbachol, 4) mechanical ventilatory modalities, and 5) induced pulmonary edema. Therefore, movements of the suprasternal fossa with respiration can be reliably transformed into quantitative or semiquantitative changes of intrapleural pressure in anesthetized intubated dogs during major alterations of pulmonary mechanics.     

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.     

The effect of increased background resistance on the resistive load threshold for eliciting the respiratory-related evoked potential.

The detection threshold (DeltaR(50)) of resistive (R) loads is a function of the total background resistance (R(0)). Increased R(0) increases the DeltaR(50), but the ratio DeltaR(50)/R(0) remains constant. The respiratory-related evoked potential (RREP) is elicited only by R loads greater than the cognitive detection threshold, DeltaR(50). We hypothesized that the RREP Nf, P1, and N1 peaks will be elicited only when the added load DeltaR/R(0) is greater than the normal detection threshold, DeltaR(50)/R(0) = 0.30. We also hypothesized that when the R(0) is increased by adding extrinsic R, the RREP will not be elicited if the DeltaR/R(0) is less than the 0.30 ratio. RREPs were recorded with healthy volunteers (n = 20) respiring through a non-rebreathing valve. Three inspiratory R loads that spanned the DeltaR(50)/R(0) = 0.30 detection threshold were presented in two conditions: 1) no added R(0) (R1 < 0.30, R2 > 0.30, R3 > 0.30); and 2) increased R(0) = 13.3 cmH(2)O.l(-1).s (R1 < 0.30, R2 < 0.30, R3 > 0.30). For the control R(0), P1, Nf, and N1 peaks of the RREP were elicited by both R2 and R3, and not present with R1. The increased R(0) decreased R2/R(0) > 1.5 to R2/R(0) < 0.15. With increased R(0), the R1 and R2 loads did not elicit the RREP, but the Nf, P1, and N1 peaks were present for R3. These results demonstrate that the RREP is present if the DeltaR is above the cognitive detection threshold, and the RREP is absent if the load is below the detection threshold. When the R(0) is increased to make the DeltaR/R(0) less than the detection threshold, the DeltaR no longer elicits the RREP.     

Effects of expiratory loading on respiration in humans

We examined the effects of expiratory resistive loads of 10 and 18 cmH2O.l-1.s in healthy subjects on ventilation and occlusion pressure responses to CO2, respiratory muscle electromyogram, pattern of breathing, and thoracoabdominal movements. In addition, we compared ventilation and occlusion pressure responses to CO2 breathing elicited by breathing through an inspiratory resistive load of 10 cmH2O.l-1.s to those produced by an expiratory load of similar magnitude. Both inspiratory and expiratory loads decreased ventilatory responses to CO2 and increased the tidal volume achieved at any given level of ventilation. Depression of ventilatory responses to Co2 was greater with the larger than with the smaller expiratory load, but the decrease was in proportion to the difference in the severity of the loads. Occlusion pressure responses were increased significantly by the inspiratory resistive load but not by the smaller expiratory load. However, occlusion pressure responses to CO2 were significantly larger with the greater expiratory load than control. Increase in occlusion pressure observed could not be explained by changes in functional residual capacity or chemical drive. The larger expiratory load also produced significant increases in electrical activity measured during both inspiration and expiration. These results suggest that sufficiently severe impediments to breathing, even when they are exclusively expiratory, can enhance inspiratory muscle activity in conscious humans.     

Respiratory-related cortical potentials evoked by inspiratory occlusion in humans

It has long been recognized that humans can perceive respiratory loads. There have been several studies on the detection and psychophysical quantification of mechanical load perception. This investigation was designed to record cortical sensory neurogenic activity related to inspiratory mechanical loading in humans. Inspiration was periodically occluded in human subjects while the electroencephalographic (EEG) activity in the somatosensory region of the cerebral cortex was recorded. The onset of inspiratory mouth pressure (Pm) was used to initiate signal averaging of the EEG signals. Cortical evoked potentials elicited by inspiratory occlusions were observed when C3 and C alpha were referenced to CZ. This evoked potential was not observed with the control (unoccluded) breaths. There was considerable subject variability in the peak latencies that was related to the differences in the inspiratory drive, as measured by occlusion pressure (P0.1). The results of this study demonstrate that neurogenic activity can be recorded in the somatosensory region of the cortex that is related to inspiratory occlusions. The peak latencies are longer than analogous somatosensory evoked potentials elicited by stimulation of the hand and foot. It is hypothesized that a portion of this latency difference is related to the time required for the subject to generate sufficient inspiratory force to activate the afferents mediating the cortical response.     

Relationship of transdiaphragmatic pressure and latencies for detecting added inspiratory loads

The purpose of this investigation was to measure changes in transdiaphragmatic pressure (Pdi) developed during graded elastic (E) and resistive (R) loaded breaths and to correlate the emergence of such changes with the load-dependent alterations in latency for detection (Tdet). Five healthy adults were studied using three protocols, i.e., graded E, graded R, and graded R in the presence of elevated background R. In each protocol, loads were added for single inspirations, 10 times in random order and separated by three to five unloaded breaths. Subjects pressed a signal marker as soon as loads were detected. Inspiratory flow (VI), inspired volume (VI), mouth pressure, and Pdi of loaded breaths and the preceding unloaded breaths were recorded and computer averaged. Patterns of VI and VI were not altered prior to detection of the smallest added E and R loads but decreased with the higher loads. Group mean patterns of Pdi showed graded increases during loaded breaths. Augmentation of Pdi preceded Tdet and occurred earlier as Tdet decreased with graded E and R loads. Elevating the background R delayed both Tdet of added R and the augmentation of Pdi. Results are consistent with the hypothesis that load-induced changes in diaphragmatic tension may play a sensory role in detection of inspiratory loads.     

Effect of inspiratory resistive loading on control of ventilation during progressive exercise

Eight healthy volunteers performed gradational tests to exhaustion on a mechanically braked cycle ergometer, with and without the addition of an inspiratory resistive load. Mean slopes for linear ventilatory responses during loaded and unloaded exercise [change in minute ventilation per change in CO2 output (delta VE/delta VCO2)] measured below the anaerobic threshold were 24.1 +/- 1.3 (SE) = l/l of CO2 and 26.2 +/- 1.0 l/l of CO2, respectively (P greater than 0.10). During loaded exercise, decrements in VE, tidal volume, respiratory frequency, arterial O2 saturation, and increases in end-tidal CO2 tension were observed only when work loads exceeded 65% of the unloaded maximum. There was a significant correlation between the resting ventilatory response to hypercapnia delta VE/delta PCO2 and the ventilatory response to VCO2 during exercise (delta VE/delta VCO2; r = 0.88; P less than 0.05). The maximal inspiratory pressure generated during loading correlated with CO2 sensitivity at rest (r = 0.91; P less than 0.05) and with exercise ventilation (delta VE/delta VCO2; r = 0.83; P less than 0.05). Although resistive loading did not alter O2 uptake (VO2) or heart rate (HR) as a function of work load, maximal VO2, HR, and exercise tolerance were decreased to 90% of control values. We conclude that a modest inspiratory resistive load reduces maximum exercise capacity and that CO2 responsiveness may play a role in the control of breathing during exercise when airway resistance is artificially increased.     

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)     

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.     

Effects of PGF2 alpha on the EMG of costal and crural parts of the diaphragm of the newborn pig

We investigated the effects of PGF2 alpha on the breathing patterns and electric activity of costal and crural parts of the diaphragm in 9 anesthetized newborn pigs. The change in diaphragmatic tension was evaluated as the change in transdiaphragmatic pressure. Because PGF2 alpha induces bronchoconstriction and an increase in respiratory resistances, the changes induced by prostaglandin were evaluated as differences between bronchoconstriction after PGF2 alpha and resistive load obtained by applying gradual occlusion to the inspiratory line of the breathing circuit. Our results show that PGF2 alpha decreased respiratory frequency with lengthening of expiratory time, while the resistive load increased both respiratory phases. The changes in breathing pattern were associated with different electrical activities of the diaphragm. While resistive load did not significantly change the EMG power spectrum, PGF2 alpha recruited new motor units. Furthermore, resistive load induced synchronization of the inspiratory time discharge of the costal and crural parts of the diaphragm, while after PGF2 alpha infusion there was an early inspiratory discharge of the crural part.     

Cardiorespiratory failure in rat induced by severe inspiratory resistive loading.

The mechanisms underlying acute respiratory failure induced by respiratory loads are unclear. We hypothesized that, in contrast to a moderate inspiratory resistive load, a severe one would elicit central respiratory failure (decreased respiratory drive) before diaphragmatic injury and fatigue. We also wished to elucidate the factors that predict endurance time and peak tracheal pressure generation. Anesthetized rats breathed air against a severe load ( approximately 75% of the peak tracheal pressure generated during a 30-s occlusion) until pump failure (fall in tracheal pressure to half; mean 38 min). Hypercapnia and hypoxemia developed rapidly ( approximately 4 min), coincident with diaphragmatic fatigue (decreased ratio of transdiaphragmatic pressure to peak integrated phrenic activity) and the detection in blood of the fast isoform of skeletal troponin I (muscle injury). At approximately 23 min, respiratory frequency and then blood pressure fell, followed immediately by secondary diaphragmatic fatigue. Blood taken after termination of loading contained cardiac troponin T (myocardial injury). Contrary to our hypothesis, diaphragmatic fatigue and injury occurred early in loading before central failure, evident only as a change in the timing but not the drive component of the central respiratory pattern generator. Stepwise multiple regression analysis selected changes in mean arterial pressure and arterial Pco(2) during loading as the principal contributing factors in load endurance time, and changes in mean arterial pressure as the principal contributing factor in peak tracheal pressure generation. In conclusion, the temporal development of respiratory failure is not stereotyped but depends on load magnitude; moreover respiratory loads induce cardiorespiratory, not just respiratory, failure.     

Respiratory volume-time relationships during resistive loading in the cat.

The first-breath (neural) effects of graded resistive loads added separately during inspiration and expiration was studied in seven anesthetized cats before and after bilateral vagotomy. Additions of airflow resistance during inspiration reduced the volume inspired (VI) and increased inspiratory duration (TI). The duration of the ensuing unloaded expiration (TE) was unchanged. Vagotomy eliminated the TI modulation with inspiratory loads. Tracheal occlusion at the onset of inspiration yielded TI values similar to the fixed values observed following vagotomy. Resistive loads added during expiration produced similar results. Expired volume (VE) decreased and (TE) increased approaching the values obtained after vagotomy. Unlike the inspiratory resistive loads, loading during expiration results in an upward shift in the functional residual capacity (FRC). The FRC shift produces a time lag between the onset of diaphragmatic (EMG) activity and the initiation of airflow of the next (unloaded) inspiration. These studies suggest separate volume-time relationships for the inspiratory and expiratory phases of the breathing cycle. Both relationships are dependent upon vagally mediated volume feedback.     

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.     

Mechanism of detection of resistive loads in conscious humans.

Conscious humans easily detect loads applied to the respiratory system. Resistive loads as small as 0.5 cmH2O.l-1.s can be detected. Previous work suggested that afferent information from the chest wall served as the primary source of information for load detection, but the evidence for this was not convincing, and we recently reported that the chest wall was a relatively poor detector for applied elastic loads. Using the same setup of a loading device and body cast, we sought resistive load detection thresholds under three conditions: 1) loading of the total respiratory system, 2) loading such that the chest wall was protected from the load but airway and intrathoracic pressures experienced negative pressure in proportion to inspiratory flow, and 3) loading of the chest wall alone with no alteration of airway or intrathoracic pressure. The threshold for detection for the three types of load application in seven normal subjects was 1.17 +/- 0.33, 1.68 +/- 0.45, and 6.3 +/- 1.38 (SE) cmH2O.l-1.s for total respiratory system, chest wall protected, and chest wall alone, respectively. We conclude that the active chest wall is a less potent source of information for detection of applied resistive loads than structures affected by negative airway and intrathoracic pressure, a finding similar to that previously reported for elastic load detection.     

Decay of inspiratory muscle pressure during expiration in anesthetized cats

In six spontaneously breathing anesthetized cats (pentobarbital sodium, 35 mg/kg) we studied the antagonistic pressure developed by the inspiratory muscles during expiration (PmusI). This was accomplished in two ways: 1) with our previously reported method (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 52: 1266-1271, 1982) based on the measurement of changes in lung volume and airflow during spontaneous expiration, together with determination of the total passive respiratory system elastance and resistance; and 2) measurement of the time course of changes in tracheal/pressure after airway occlusion at end inspiration, up to the moment when the inspiratory muscles become completely relaxed. The agreement between the two methods is generally good, both in the amplitude of PmusI and in its time course. We also applied the first method to spontaneous expirations through added linear resistive loads. These did not alter the relative decay of PmusI. Thus in anesthetized cats the braking action of the inspiratory muscles does not decrease when expiratory resistive loads are added, i.e., when such braking is clearly not required.