Inspiratory Flow-resistive Loading Research Articles

Diaphragmatic fatigue in unanesthetized adult sheep.

We studied diaphragmatic muscle function during inspiratory flow resistive (IFR) loaded breathing in unanesthetized sheep. We measured the change in transdiaphragmatic pressure (dPdi) and arterial blood gas tensions and recorded diaphragmatic electromyogram (EMG) from electrodes implanted on the muscle. We found that, with IFR loads less than 150 cmH2O X l-1 X s, dPdi and the integrated EMG increased, reached a plateau, and were maintained at high levels. The centroid frequency (fc) of the EMG power spectrum did not consistently change. With IFR loads greater than 150 cmH2O X l-1 X s, O2 was administered to prevent hypoxia, cyanosis, and agitation. With these loads, dPdi increased severalfold above base line, reached a plateau, and then started to decrease. Arterial PCO2 increased sharply at the time when dPdi decreased. The integrated EMG (iEMG) and fc started to decrease gradually 10-20 min before dPdi started to decrease. We conclude that 1) the diaphragm is capable of generating large pressures for prolonged periods with no evidence of fatigue; 2) with very high IFR loads, mechanical failure of the diaphragm can occur in the unanesthetized awake sheep; 3) diaphragmatic fatigue is associated with acute hypercapnia and therefore failure of the entire respiratory pump; and 4) a decrease in iEMG and a concommitant shift in the power spectrum density towards lower frequencies precede the mechanical failure of the diaphragm.

Augmentation of CO2 drives by chlormadinone acetate, a synthetic progesterone.

We studied 10 male subjects who were administered chlormadinone acetate (CMA), a potent synthetic progesterone, to clarify the physiological basis of its respiratory effects. Arterial blood gas tension, resting ventilation, and respiratory drive assessed by ventilatory and occlusion pressure response to CO2 with and without inspiratory flow-resistive loading were measured before and 4 wk after CMA administration. In all subjects, arterial PCO2 decreased significantly by 5.7 +/- 0.6 (SE) Torr with an increase in minute ventilation by 1.8 +/- 0.6 l X min-1, whereas no significant changes were seen in O2 uptake. During unloaded conditions, both slopes of occlusion pressure and ventilatory response to CO2 increased, being statistically significant in the former but showing nonsignificant trends in the latter. Furthermore, inspiratory flow-resistive loading (16 cmH2O X l(-1) X s) increased both slopes more markedly after CMA. The magnitudes of load compensation, assessed by the ratio of loaded to unloaded slope of the occlusion pressure response curve, were increased significantly. We concluded CMA is a potent respiratory stimulant that increases the CO2 chemosensitivity and neuromechanical drives in the load-compensation mechanism.

DUPLICATION OF THE CHEST LAG IN REM SLEEP BY INSPIRATORY FLOW-RESISTIVE LOADING IN NREM SLEEP

In REM sleep relaxation of the geniohyoid and genioglossus muscles have been shown, which will result in an increase in the intrinsic resistive load of the upper airway. To determine the role of this increase in load on paradoxical chest wall movement (CWM) noted in preterm infants during REM sleep, CWM in REM was compared to CWM in NREM and CWM in NREM with external inspiratory flow resistive loading in 5 preterm infants. Abdominal wall and CWM were measured by Hg strain-gauges, sleep state evaluation included EOG and EEG and a stable load (L) of 100 cm H2O/L/sec by face-mask and one-way valve was used. Mean ± SEM BW was 1.42 ± 0.19 kg, GA was 31.8 ± 1.5 wks and post-natal age was 5.8 ± 1.53 wks. In NREM sleep, the respiratory rate was 66.6 ± 13.3 breaths/min, Ti was 0.46 secs ± 0.04 secs, Ti/Ttot was 0.50 ± 0.01 and there was a delay between abdomen and chest rise (A-C lag) of 0.21 ± 0.07 sec, which was 22.5 ± 6.4% of Ttot (% delay). In comparison to NREM, both REM and NREM + L produced significant prolongation of A-C lag and % delay. The A-C lag was 0.46 ± 0.11 sec in REM, p<0.05, and 0.33 ± 0.08 sec in NREM + L, p<0.01. The % delay was 40.7 ± 5.3 in REM, p<0.05, and 29.9 ± 6.5% in NREM + L, p<0.01. Only NREM + L increased Ti significantly to 0.63 ± 0.05 sec, p<0.05, and Ti/Ttot to 0.58 ± 0.01, p<0.05. These data indicate that raising the inspiratory flow resistive load of the upper respiratory system increases chest lag independent of other factors accompanying sleep state change.

Control of Breathing in Obstructive Sleep Apnea

We studied the responses of ventilation and occlusion pressure (P100) to hypercapnia, with and without the application of an inspiratory flow-resistive load (12 cm H2O/L/sec), in eight control subjects and in eight subjects with obstructive sleep apnea who did not retain carbon dioxide while awake. The hypercapnic response was assessed by a modification of the Read rebreathing technique. For a given endtidal carbon dioxide, ventilation in control subjects was the same with or without load, and P100 was increased with loading. In contrast, the subjects with sleep apnea decreased their ventilation during loading and did not increase their P100 in response to loading. Relationships between ventilation and P100 were similar in the two groups both with and without load. We conclude that patients with occlusive sleep apnea do not exhibit the normal increase in neural drive to compensate for inspiratory flow-resistive loading.

Impaired detection of added inspiratory resistance in patients with obstructive sleep apnea.

The ability to detect added inspiratory flow-resistive loads during wakefulness was examined in 5 men with laboratory-documented obstructive sleep apnea. The patients were eucapnic, and standard measurements of lung volumes and flow rates were within the normal range. The patients breathed through a circuit, to which each of 5 flow resistances of 0.12 to 5.5 cm H2O/L/s was added at 20- to 30-s intervals for 1 inspiration, following a cue. Each resistance was presented 10 times in random sequence, and the percentage of trials in which each load was detected by the patient was calculated. The threshold level of load detection, defined as the change in resistance that could be detected 50% of the time, was higher in the patients (2.37 +/- 0.41 cmH2O/L/s, mean +/- SE) than in 9 healthy subjects (0.65 +/- 0.08; p less than 0.001), and this difference persisted when the threshold load was corrected for background resistance (1.05 +/- 0.11 versus 0.45 +/- 0.07; p less than 0.001). In addition, the ventilatory response to hypercapnia was less in the patients (1.82 +/- 0.22 L/min/mm Hg) than in the normal subjects (3.87 +/- 0.40; p less than 0.005), and there was a significant negative correlation (r = 0.97; p less than 0.001) between the load detection threshold and the ventilatory response to CO2. The results add to the developing concept that subtle defects in respiratory control can be demonstrated even during wakefulness in eucapnic patients with obstructive sleep apnea.

Sleep Deprivation Decreases Ventilatory Response to CO2 But Not Load Compensation

Because sleep is known to reduce ventilatory drive, and sleep deprivation is a common accompaniment to ventilatory failure, we tested ventilatory response to carbon dioxide (delta V1/delta PCO2) and response to an inspiratory flow resistive load (change in delta P100/delta PCO2 with load) after both a normal night of sleep and after 24 hours of sleep deprivation in 13 healthy volunteers. Sleep deprivation was associated with a significant decrease in delta V1/delta PCO2 from 2.51 +/- .36 to 2.09 +/- .34 L/min/mm Hg (p less than 0.02). However, load compensation was preserved during sleep deprivation. Since many acutely-ill patients are sleep deprived, an associated reduction of ventilatory drive may play a role in progressive respiratory insufficiency.

An analysis of respiratory drive components during flow-resistive respiratory loading.

Inspiratory flow-resistive loading normally causes an additional respiratory drive that limits the resistance-induced decrease in minute ventilation (load compensation). Occlusion pressures (P100) were measured during CO2 rebreathing with and without added inspiratory loads in normal persons and persons with obstructive sleep apnea (OSA). At each point obtained during loaded breathing, the additional drive due to resistive loading was determined by subtracting CO2-dependent drive (estimated from the nonloaded run) from total drive. In normal subjects, the additional drive correlated with each of four different estimates of load magnitude. In OSA subjects, there was no significant increase in drive due to loading and ventilation decreased markedly during loading. The relationships among ventilation rate, load, and drive, with and without load compensation, were analyzed using a 4-quadrant feedback control diagram. The diagram enables the prediction of ventilation rate for any end-tidal CO2 in the loaded and nonloaded cases, and the flow decrement that will occur as a result of added inspiratory resistance.

Ventilatory responses to inspiratory flow-resistive loads in awake and sleeping dogs.

We studied ventilatory responses to inspiratory flow-resistive loads in six trained dogs, during quiet wakefulness and non-rapid-eye-movement (NREM) sleep. During studies dogs lay quietly in a lateral position and breathed through an endotracheal tube inserted via a chronic tracheostomy. Linear resistances of 6, 10, 19, and 31 cmH2O X l-1 X s were applied during inspiration for only a single breath to assess the immediate ventilatory response. The highest resistance was also applied for five successive breaths to assess the progressive ventilatory response. Ventilatory responses to hyperoxic progressive hypercapnia were also examined, with and without flow-resistive loading. During loading the maintenance of constant states of quiet wakefulness and NREM sleep was confirmed by electroencephalographic monitoring. Ventilation decreased on the first loaded breath and returned to control in a stepwise manner by the fifth loaded breath. No state-related differences were observed in either the immediate or progressive ventilatory responses. During CO2 rebreathing, the slope of the ventilatory response to CO2 was reduced by loading, with the reduction in slope (as percent of control) greater in the NREM state. We therefore conclude that in the dog immediate and progressive ventilatory responses to resistive loads are unaffected by NREM sleep, whereas the decrease in ventilatory response to CO2 resulting from loading tends to be greater in NREM sleep than in quiet wakefulness.

Respiratory muscle function during CO2 rebreathing with inspiratory flow-resistive loading.

We investigated the respiratory muscle contribution to inspiratory load compensation by measuring diaphragmatic and intercostal electromyograms (EMGdi and EMGic), transdiaphragmatic pressure (Pdi), and thoracoabdominal motion during CO2 rebreathing with and without 15 cmH2O X l-1 X s inspiratory flow resistance (IRL) in normal sitting volunteers. During IRL compared with control, Pdi measured during airflow and during airway occlusion increased for a given change in CO2 partial pressure and EMGdi, and there was a greater decrease in abdominal (AB) end expiratory anteroposterior dimensions with increased expiratory gastric pressure (Pga), this leading to an inspiratory decline in Pga with outward AB movement, indicating a passive component to the descent of the abdomen-diaphragm. The response of EMGic to IRL was similar to that of EMGdi, though rib cage (RC)-Pga plots did infer intercostal muscle contribution. We conclude that during CO2 rebreathing with IRL there is improved diaphragmatic neuromuscular coupling, the prolongation of inspiration promoting a force-velocity advantage, and increased AB action serving to optimize diaphragm length and configuration, as well as to provide its own passive inspiratory action. Intercostal action provides increased assistance also. Therefore, compensation for inspiratory resistive loads results from the combined and integrated effort of all respiratory muscle groups.

Inspiratory and expiratory resistive loading as a model of dyspnea in asthma.

20 ambulatory asthmatics were questioned regarding their perception of the dyspnea of acute asthmatic attacks; in particular, its relationship to the phase of respiration. 19 (95%) stated that inspiration was more difficult than expiration although 5 (25%) reported that they had been taught that the reverse was 'correct'. In order to explore further these observations, we applied psychophysical methods to determine the phase relationship of the conscious perception of resistive loads in healthy volunteers. 14 subjects of similar age and sex distribution to the asthmatics estimated numerically the magnitude of resistive loads applied in random sequence to either the inspiratory or expiratory arm of a low-resistance breathing circuit. The relationship between perceived magnitude (psi) and physical magnitude (phi) was described by Steven's law: psi = k phi n, where k and n are constants. The mean exponent (n) for inspiratory resistances was 0.69 +/- 0.28 (+/- SD) and for expiratory resistances was 0.51 +/- 0.27 (p less than 0.01 by two-tailed, paired t test). There was a positive correlation (r = 0.82) between inspiratory and expiratory exponents within individuals. In 12 of 14 subjects, the perceived magnitude of inspiratory loads was greater than the perceived magnitude of expiratory loads for all resistances greater than 10 cm H2O/l/s. At a load of 25 cm H2O/l/s, the inspiratory sensation of load exceeded the expiratory sensation in all subjects. Our findings that normal subjects scaled greater breathlessness with inspiratory versus expiratory flow resistive loads were consistent with the clinical observation that inspiratory, rather than expiratory difficulty contributed more to the dyspnea of asthma.

Brain hypoxia and control of breathing: neuromechanical control.

The effects of graded brain hypoxia on respiratory cycle timing, the lung inflation reflex, and respiratory compensation for an inspiratory flow-resistive load were studied in unanesthetized goats. Two models, inhalation and CO and acute reduction of brain blood flow (BBF) were used to produce comparable levels of brain hypoxia. The lung inflation reflex was assessed as the ratio of inspiratory time of an occluded breath to that of the preceding spontaneous breath (TIoccl/TIspont). Compensation for flow-resistive loading was assessed as the effect of the load upon the airway occlusion pressure response to rebreathing CO2 (delta P 0.1/delta PCO2). Major findings were 1) severe brain hypoxia (HbCO of 60% or BBF of 42%) caused tachypnea due to a 50% or more reduction of expiratory time but only a 20% or less reduction of inspiratory time; 2) moderate carboxyhemoglobinemia (HbCO of 25-30%) enhanced TIoccl/TIspont from 1.5 +/- 0.1 at control to 2.1 +/- 0.1, while severe brain hypoxia (HbCO of 60% and BBF of 42%) reduced the ratio to 1.0 +/- 0.2; and 3) compensation for a flow-resistive load, manifested by increases of delta P 0.1/delta PCO2 of 75-300% in the control state, was abolished at HbCO of 45-50% and BBF of 60%. The data suggest that in unanesthetized animals brain hypoxia elicits tachypnea largely by an effect on the expiratory phase of the bulbopontine timing mechanism. The observed enhancement of the lung inflation reflex and abolition of flow-resistive load compensation are best explained by hypoxic depression of higher than brain stem neural function.

Elastic and Resistive Loading in Chronic Obstructive Lung Disease

R espiratory neuromuscular output as measured by the mouth occlusion pressure increases in normal subjects when the resistance to airflow is heightened acutely. In studies conducted by Altose et al’ in patients with chronic obstructive lung disease, the compensatory response to resistive loading was found to be significantly blunted. The diminished occlusion pressure response to flow loading in patients with chronic obstructive lung disease could be due to inspiratory muscle weakness or muscle fatigue. Alternatively, abnormalities in the function of proprioceptive receptors in the muscles of the thoracic cage or in vagal mechanoreceptors in the lung or their central processing could explain the abnormal response to external flow loading. It was reasoned that defective respiratory muscle function should affect the occlusion pressure response to both types of loads equally. If impairment of sensory mechanisms accounted for the blunted P,00 response to flow loads in COPD the response to an elastic load need not be affected. To further evaluate these possibilities, we compared the effects of elastic and inspiratory flow resistive loads on ventilation and occlusion pressure in patients with COPD.

Interaction Between Chemical Ventilatory Drive and Respiratory Compensation for Flow-Resistive Loading

Normal individuals increase inspiratory effort during inspiratory flow-resistive loading. Several conditions have been shown to impair this response. These include anesthesia, brain hypoxia, sleep and chronic airways obstruction. Since all of these may be associated with blunting of chemical drive, and load compensation is tested during progressive hypercapnia, we determined whether alterations in ventilatory response to CO2, per se, could influence the respiratory compensation for flow-resistive loading. Ten goats were prepared with chronic tracheostomies and indwelling arterial and venous cannulae. Ventilatory and occlusion pressure (P10o> as an index of inspiratory drive) responses to rebreathing CO2 in O2 were assessed before and after imposition of an inspiratory flow-resistive load of 25 cm H2O/L/sec. In five goats, studies were done before and during infusion of doxapram (3 mg/min); in the other five, studies were repeated 30 min after infusion of Tris buffer (15 mM/kg).

Interaction Between Chemical Ventilatory Drive and Respiratory Compensation for Flow-Resistive Loading

Normal individuals increase inspiratory effort during inspiratory flow-resistive loading. Several conditions have been shown to impair this response. These include anesthesia, brain hypoxia, sleep and chronic airways obstruction. Since all of these may be associated with blunting of chemical drive, and load compensation is tested during progressive hypercapnia, we determined whether alterations in ventilatory response to CO2, per se, could influence the respiratory compensation for flow-resistive loading.

Respiratory neuromuscular response to CO 2 rebreathing with inspiratory flow resistance in humans

The effects of inspiratory flow resistance on mouth occlusion pressure (P 0.15) and diaphragmatic EMG (EMG di) responses to CO 2 rebreathing were studied in normal subjects. Occlusion pressures were measured 150 msec after onset of an inspiratory effort; EMG di was analyzed as a moving time average and quantified in terms of peak activity and rate of rise of activity. After a control CO 2 response was obtained in each subject, rebreathing was repeated 30 min later with either of two inspiratory flow resistive loads, 5 sm H 2O/L/sec (IR 5) and 14 cm H 2O/L/sec (IR 14). With IR 5 (6 subjects), the P 0.15 response was decreased in two subjects, unchanged in two, and increased in twol; peak EMG di was unchanged in all, while rate of rise of EMG di response decreased in 4 of the 6 subjects. With IR 14 (6 subjects, 9 runs), the P 0.15 response was not decreased in any subejct, remained unchanged in 4, and increased in 5; peak EMG di response to rebreathing in all runs was, again, unchanged by this load, but rate of rise of EMG di was decreased in 3 and unchanged in 6. The inspiratory off-switch threshold as reflected by peak diaphragmatic activity was not changed by inspiratory flow resistance, whereas inspiratory neural drive as reflected by the rat of rise of activity was decreased in some subjects. The decrease in inspiratory drive without change in inspiratory off-switch threshold resulted in prolongation of inspiration in an attempt to reflect efficient lung expansion. However, the defense of ventilation during rebreathing with both resistances appeared to mainly depend on the response of inspiratory muscle force (P 0.15), since in 7 of the 7 runs in which the P 0.15 response was significantly increased from control, the ventilatory response was not decreased.

Effects of hypercapnia and inspiratory flow-resistive loading on respiratory activity in chronic airways obstruction.

The respiratory responses to hypercapnia alone and to hypercapnia and flow-resistive loading during inspiration were studied in normal individuals and in eucapnic and hypercapnic patients with chronic airways obstruction. Responses were assessed in terms of minute ventilation and occlusion pressure (mouth pressure during airway occlusion 100 ms after the onset of inspiration). Ventilatory responses to CO2 (deltaV/deltaPCO2) were distinctly subnormal in both groups of patients with airways obstruction. The two groups of patients, however, showed different occlusion pressure responses to CO2 (deltaP100/deltaPCO2): deltaP100/deltaPCO2 was normal in the eucapnic patients but subnormal in the hypercapnic patients. Flow-resistive loading during inspiration reduced deltaV/deltaPCO2 both in normal subjects and in patients with airways obstruction. The occlusion pressure response to CO2 increased in normal subjects during flow-resistive loading but remained unchanged in both groups of patients with chronic airways obstruction. These results indicate that while chemosensitivity as determined by deltaP100/deltaPCO2 is impaired only in hypercapnic patients with chronic airways obstruction, an acute increase in flow resistance elicits a subnormal increase in respiratory efferent activity in both eucapnic and hypercapnic patients.

Effects of hypercapnia on mouth pressure during airway occlusion in conscious man.

The effects of hypercapnia and inspiratory flow-resistive loading on mouth pressure during periods of arrested airflow were studied in conscious human subjects to determine the usefulness of inspiratory muscle force in the assessment of respiratory neural efferent activity. Hypercapnia increased the peak end-inspiratory mouth pressure (Ppeak) during complete airway occlusion and the pressures at 100, 200, and 300 ms after the onset of inspiration (P100, P200, P300). During rebreathing without added mechanical loads, P100 and Ppeak increased linearly with the electrical activity of the diaphragm and changes in P100 and Ppeak during hypercapnia correlated well with ventilatory responses to PCO2 (DELTA V/DELTA PCO2) suggesting that occluded mouth pressures are reliable measures of respiratory activity. In individuals with the greatest reduction in delta V/DELTA PCO2 during inspiratory flow-resistive loading, changes in P100 and Ppeak with PCO2 increased only minimally. In contrast, there was a much greater increase in occluded mouth pressures with hypercapnia in the presence of mechanical loading when inspiratory flow-resistive loading failed to depress delta V/DELTA PCO2. In all subjects, occluded mouth pressures were greater at any given PCO2 during mechanical loading than during free breathing. Mechanical loading resulted in augmented respiratory neural efferent activity unexplained by alterations in chemical stimulation.

Effects of hypercapnia and flow-resistive loading on tracheal pressure during airway occlusion.

To determine whether the isometric force of concentration of the inspiratory muscles could be used to assess respiratory efferent neural activity, the tracheal pressure generated by the inspiratory muscles during airway occlusion (occluded tracheal pressure) was measured during progressive hypercapnia in anesthetized dogs breathing normally and breathing against added flow-resistive loads. Hypercapnia increased the peak end-inspiratory tracheal pressure and the occluded tracheal pressures generated 100, 200, and 300 ms after the onset of inspiration. The duration of the occluded inspiratory effort generally remained unchanged and the configuration of the pressure tracing was not affected. During normal breathing occluded tracheal pressures increased linearly with tidal volume and with the electrical activity of the diaphragm and the external intercostal muscles both before and after vagotomy. Inspiratory flow-resistive loading reduced the ventilatory response to CO2 but did not affect occluded tracheal pressures at any given PCO2 or the change in pressures with hypercapnia both before and after vagotomy. Similarly, expiratory flow-resistive loading failed to affect occluded tracheal pressures. These results suggest that occluded tracheal pressures measure respiratory efferent neural activity and can be used as indices of CO2 responsivity even during mechanical loading in anesthetized animals.

Relative contribution of rib cage and abdomen to ventilation during exercise.

Relative contribution of rib cage and abdomen to ventilation during exercise.