Diaphragmatic function during hypoxemia: neonatal and developmental aspects

The effect of acute hypoxemia on diaphragmatic force output was studied in five young (age 4-8 days, wt 1.3-2.2 kg) and five older (age 16-19 days, wt 2.8-3.3 kg), anesthetized, spontaneously breathing piglets. Diaphragmatic force output was assessed by analysis of the transdiaphragmatic pressure (Pdi) generated during an occluded inspiratory effort, at end-expiratory lung volume, triggered by supramaximal transvenous stimulation of both phrenic nerves at frequencies of 20, 30, 50, and 100 Hz. During pressure measurements, the piglets were fitted with a rigid plaster cast covering the abdomen and lower third of the chest to ensure a consistency in diaphragmatic shortening during phrenic nerve stimulation. Pdi was measured under base-line conditions [inspired O2 fractional concentration (FIO2) = 0.50] and after 10 min of hypoxemia induced by breathing 12-14% FIO2. Pdi was significantly less than base line during acute hypoxemia at all frequencies of stimulation in both young and older piglets. The decline in the older piglets' Pdi during hypoxemia was significantly greater than that seen in younger piglets. We conclude that acute hypoxemia impairs the capacity of the developing piglet diaphragm to generate force. Furthermore, our data suggest that the young piglet is more resistant to the depressant effects of hypoxemia when compared to its older counterpart.     

Effect of inspiratory resistive loaded breathing and hypoxemia on diaphragmatic function in the piglet.

The combined effects of inspiratory resistive loaded breathing (IRL) and hypoxemia on transdiaphragmatic pressure (Pdi) in nine 1-mo-old Yorkshire piglets were studied. IRL was adjusted to increase spontaneously generated Pdi five to six times above baseline but maintain arterial PCO2 < 70 Torr to prevent hypercapnic depression of diaphragmatic contractility. Measurements of ventilation, blood gases and pH, Pdi, diaphragmatic electromyogram, Pdi during phrenic nerve stimulation, diaphragmatic blood flow, and end-expiratory lung volume were obtained at baseline, after 2 h of IRL, and then after 1 h of hypoxemia (arterial PO2 approximately 40 Torr) combined with IRL. Diaphragmatic muscle samples were obtained after study completion and immediately frozen in liquid nitrogen for determination of tissue ATP, phosphocreatine, lactate, and glycogen levels. Ten 1-mo-old piglets were subjected to IRL alone and served as controls. IRL alone resulted in significant impairment of Pdi generation. The addition of hypoxemia for 1 h did not further compromise Pdi in comparison to control animals who were subjected to IRL alone. Blood flow to both the costal and crural segments of the diaphragm increased significantly during IRL; the addition of the hypoxemic stress resulted in further significant augmentation of blood flow to both segments of the diaphragm. No differences were noted in diaphragmatic muscle tissue ATP, phosphocreatine, or glycogen between control and IRL animals or between control and IRL plus hypoxemia animals. Muscle lactate levels increased significantly in the IRL plus hypoxemia animals only. The data from this study suggest that moderate hypoxemia during resistive-loaded breathing in the piglet does not accentuate diaphragmatic fatigue.     

Respiratory load compensation in chronic airway obstruction

To assess respiratory neuromuscular function and load compensating ability in patients with chronic airway obstruction (CAO), we studied eight stable patients with irreversible airway obstruction during hyperoxic CO2 rebreathing with and without a 17 cmH2O X l-1 X s flow-resistive inspiratory load (IRL). Minute ventilation (VE), transdiaphragmatic pressure (Pdi), and diaphragmatic electromyogram (EMGdi) were monitored. Pdi and EMGdi were obtained via a single gastroesophageal catheter with EMGdi being quantitated as the average rate of rise of inspiratory (moving average) activity. Based on the effects of IRL on the Pdi response to CO2 [delta Pdi/delta arterial CO2 tension (PaCO2)] and the change in Pdi for a given change in EMGdi (delta Pdi/delta EMGdi) during rebreathing, two groups could be clearly identified. Four patients (group A) were able to increase delta Pdi/delta PaCO2 and delta Pdi/delta EMGdi, whereas in the other four (group B) the IRL responses decreased. All group B patients were hyperinflated having significantly greater functional residual capacity (FRC) and residual volume than group A. In addition the IRL induced percent change in delta Pdi/delta PaCO2, and delta VE/delta PaCO2 was negatively correlated with lung volume so that in the hyperinflated group B the higher the FRC the greater was the decrease in Pdi response due to IRL. In both groups the greater the FRC the greater was the decrease in the ventilatory response to loading. Patients with CAO, even with severe airways obstruction, can effect load compensation by increasing diaphragmatic force output, but the presence of increased lung volume with the associated shortened diaphragm prevents such load compensation.     

Naloxone alters the early response to an inspiratory flow-resistive load

In a previous study in unanesthetized goats, we demonstrated that cerebrospinal fluid levels of beta-endorphin were significantly elevated after 2.5 h of inspiratory flow-resistive loading. Naloxone (NLX) (0.1 mg/kg) administration partially and transiently reversed the tidal volume depression seen during loading. In the current study, we tested the hypothesis that endogenous opioid elaboration results in depression of respiratory output to the diaphragm. In six studies of five unanesthetized goats, tidal volume (VT), transdiaphragmatic pressure (Pdi), diaphragmatic electromyogram (EMGdi), and arterial blood gases were monitored. A continuous NLX (0.1 mg/kg) or saline (SAL) infusion was begun 5 min before an inspiratory flow-resistive load of 120 cmH2O.l-1.s was imposed. Our data show that the depression of VT induced by the load was prevented by NLX as early as 15 min and persisted for 2 h. At 2 h, Pdi was still 294 +/- 45% of the base-line value compared with 217 +/- 35% during SAL. There was no difference in EMGdi between the groups at any time. However, the augmentation of Pdi was associated with a greater increase in end-expiratory gastric pressure in the NLX group. We conclude that the reduction in VT and Pdi associated with endogenous opioid elaboration is not mediated by a decrease in neural output to the diaphragm, but it appears to be the result of a decrease in respiratory output to the abdominal muscles.     

Diaphragmatic and ventilatory responses to alveolar hypoxia and hypercapnia in conscious kittens.

Ventilation and electromyographic (EMG) activity of the diaphragm were recorded in unanesthetized kittens 2 and 10 wk of age during normoxia, hypercapnia (2 and 4% CO2), and hypoxia (12 and 10% O2). We measured integrated diaphragmatic EMG activity at end inspiration (DIAI) and end expiration (DIAE); the difference (DIAI-E), which represents the phasic change of the diaphragmatic activity, was considered responsible for a given tidal volume (VT). During hypercapnia, the 2-wk-old kittens increased minute ventilation (V) by increases in both VT and respiratory frequency (f), whereas the 10-wk-old kittens increased V primarily by an increase in VT. At both ages, DIAI and DIAI-E increased during hypercapnia, whereas DIAE did not change significantly. During hypoxia, in the young kittens, V and VT decreased while f increased markedly; in the older kittens, V, VT, and f did not change significantly. In kittens of both ages, DIAI increased during hypoxia; because diaphragmatic activity persisted into expiration, DIAE also increased. DIAI-E, as well as VT, was decreased in the young kittens, whereas in the older ones DIAI-E was slightly increased despite an unchanged VT. Finally, the ventilatory and diaphragmatic response to hypoxia changes with maturation in contrast to the response to hypercapnia. It is concluded that 1) the hypoxia-induced reduction of VT may result from prolongation of diaphragmatic activity into expiration, inasmuch as it induces a reduction of the phasic change of the diaphragmatic activity, and 2) because DIAI-E indirectly reflects central inspiratory output, a central mechanism should be involved in the reduced VT and V in response to hypoxia in newborns.     

Effect of lung inflation on diaphragmatic shortening

The effect of lung inflation on chest wall mechanics was studied in 11 vagotomized pentobarbital sodium-anesthetized dogs. Diaphragmatic shortening (percent change from initial length at functional residual capacity, %LFRC) and transdiaphragmatic pressure swings (delta Pdi) were compared with control values over a range of positive-pressure breathing that produced a maximum increase in lung volume to 40% of inspiratory capacity. There was no change in the electromyogram of the diaphragm or parasternal intercostals during positive-pressure breathing. delta Pdi and tidal volume (VT) fell to 52 +/- 3.3 and 42.5 +/- 5% (SE) of control. This was associated with a reduction in the initial resting length of 13 +/- 1.9 and 21 +/- 2.2%LFRC (SE) in the costal and crural diaphragms, respectively. Tidal diaphragmatic shortening, however, decreased to 66 +/- 7 and 57 +/- 7 and the mean velocity decreased to 78 +/- 10 and 63 +/- 8% (SE) of control for the costal and crural diaphragms, respectively. We conclude that the reduction in diaphragmatic shortening is the main determinant of the reduced delta Pdi and VT during lung inflation and relate this to what is currently known about diaphragmatic contractile properties.     

Diaphragmatic force and substrate response to resistive loaded breathing in the piglet

Inspiratory resistive loaded (IRL) breathing results in hypoventilation and diaphragmatic fatigue in the piglet. We studied the effects of 6 h of IRL on ten 1-mo-old piglets. The load was adjusted to increase spontaneously generated transdiaphragmatic pressure five to six times baseline. Six 1-mo-old piglets acted as controls and were identically instrumented but were not subjected to IRL. Measurements of ventilation, blood gases and pH, diaphragmatic electromyogram, force-frequency curve, blood flow, and end-expiratory lung volume were obtained hourly. Diaphragmatic muscle samples were obtained after 6 h for determination of ATP, phosphocreatine, lactate, and glycogen levels. No changes occurred in the control animals. IRL resulted in a significant decrease in ventilation, an increase in diaphragmatic EMG, onset of abdominal expiratory muscle activity, and a fall in end-expiratory lung volume by 1 h. The force-frequency curve adjusted for lung volume change fell by 20% at all frequencies of stimulation at 1 h and by 40% at 6 h. Blood flow to the costal and crural diaphragm increased by 51 and 141%, respectively. No differences were noted in ATP, phosphocreatine, lactate, or glycogen between control and IRL animals. It is concluded that submaximal spontaneous contractions of the piglet diaphragm over a 6-h period cause a substantial decrease in its maximal force-generating capacity that is not related to substrate depletion.     

Mechanical role of expiratory muscles during breathing in upright dogs

To examine the mechanical effects of the abdominal and triangularis sterni expiratory recruitment that occurs when anesthetized dogs are tilted head up, we measured both before and after cervical vagotomy the end-expiratory length of the costal and crural diaphragmatic segments and the end-expiratory lung volume (FRC) in eight spontaneously breathing animals during postural changes from supine (0 degree) to 80 degrees head up. Tilting the animals from 0 degree to 80 degrees head up in both conditions was associated with a gradual decrease in end-expiratory costal and crural diaphragmatic length and with a progressive increase in FRC. All these changes, however, were considerably larger (P less than 0.005 or less) postvagotomy when the expiratory muscles were no longer recruited with tilting. Alterations in the elastic properties of the lung could not account for the effects of vagotomy on the postural changes. We conclude therefore that 1) by contracting during expiration, the canine expiratory muscles minimize the shortening of the diaphragm and the increase in FRC that the action of gravity would otherwise introduce, and 2) the end-expiratory diaphragmatic length and FRC in upright dogs are thus actively determined. The present data also indicate that by relaxing at end expiration, the expiratory muscles make a substantial contribution to tidal volume in upright dogs; in the 80 degrees head-up posture, this contribution would amount to approximately 60% of tidal volume.     

Ventilatory responses to increased blood flow and decreased lung volume in awake dogs

The effect of decreased lung volume on ventilatory responses to arteriovenous fistula-induced increased cardiac output was studied in four chronic awake dogs. Lung volume decreases were imposed by application of continuous negative-pressure breathing of -10 cmH2O to the trachea. The animals were surgically prepared with chronic tracheostomy, indwelling carotid artery catheter, and bilateral arteriovenous femoral shunts. Control arteriovenous blood flow was 0.5 l/min, and test flow level was 2.0 l/min. Arterial blood CO2 tension (PaCO2) was continuously monitored using an indwelling Teflon membrane mass spectrometer catheter, and inhaled CO2 was given to maintain isocapnia throughout. Increased fistula flow alone led to a mean 52% increase in cardiac output (CO), whereas mean systemic arterial blood pressure (Psa) fell 4% (P less than 0.01). Negative-pressure breathing alone raised Psa by 3% (P less than 0.005) without a significant change in CO. Expired minute ventilation (VE) increased by 27% (P less than 0.005) from control in both of these conditions separately. Combined increased flow and negative pressure led to a 50% increase in CO and 56% increase in VE (P less than 0.0025) without any significant change in Psa. Effects of decreased lung volume and increased CO appeared to be additive with respect to ventilation and to occur under conditions of constant PaCO2 and Psa. Because both decreased lung volume and increased CO occur during normal exercise, these results suggest that mechanisms other than chemical regulation may play an important role in the control of breathing and contribute new insights into the isocapnic exercise hyperpnea phenomenon.     

Functional adaptation of diaphragm to chronic hyperinflation in emphysematous hamsters

Costal strips of diaphragmatic muscle obtained from animals with elastase-induced emphysema generate maximum tension at significantly shorter muscle fiber lengths than muscle strips from control animals. The present study examined the consequences of alterations in the length-tension relationship assessed in vitro on the pressure generated by the diaphragm in vivo. Transdiaphragmatic pressure (Pdi) and functional residual capacity (FRC) were measured in 22 emphysematous and 22 control hamsters 4-5 mo after intratracheal injection of pancreatic elastase or saline, respectively. In 12 emphysematous and 12 control hamsters Pdi was also measured during spontaneous contractions against an occluded airway. To allow greater control over muscle excitation, Pdi was measured during bilateral tetanic (50 Hz) electrical stimulation of the phrenic nerves in 10 emphysematous and 10 control hamsters. Mean FRC in the emphysematous hamsters was 183% of the value in control hamsters (P less than 0.01). During spontaneous inspiratory efforts against a closed airway the highest Pdi generated at FRC tended to be greater in control than emphysematous hamsters. When control hamsters were inflated to a lung volume approximating the FRC of emphysematous animals, however, peak Pdi was significantly greater in emphysematous animals (70 +/- 6 and 41 +/- 8 cmH2O; P less than 0.05). With electrophrenic stimulation, the Pdi-lung volume curve was shifted toward higher lung volumes in emphysematous hamsters. Pdi at all absolute lung volumes at and above the FRC of emphysematous hamsters was significantly greater in emphysematous compared with control animals. Moreover, Pdi continued to be generated by emphysematous hamsters at levels of lung volume where Pdi of control subjects was zero.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vagal modulation of respiratory muscle activity in awake dogs during exercise and hypercapnia.

Using chronically instrumented awake tracheotomized dogs, we examined the contributions of vagal feedback to respiratory muscle activities, both electrical and mechanical, during normoxic hypercapnia (inspired CO2 fraction = 0.03, 0.04, 0.05, and 0.06) and during mild treadmill exercise (3, 4.3, and 6.4 km/h). Cooling exteriorized vagal loops eliminated both phasic and tonic mechanoreceptor input during either of these hyperpneas. At a given chemical or locomotor stimulus, vagal cooling caused a further increase in costal, crural, parasternal, and rib cage expiratory (triangularis sterni) muscles. No further change in abdominal expiratory muscle activity occurred secondary to vagal cooling during these hyperpneas. However, removal of mechanoreceptor input during hypercapnia was not associated with consistent changes in end-expiratory lung volume, as measured by the He-N2 rebreathe technique. We conclude that during these hyperpneas 1) vagal input is not essential for augmentation of expiratory muscle activity and 2) decrements in abdominal expiratory muscle activity may be offset by increments in rib cage expiratory muscle activity and contribute to the regulation of end-expiratory lung volume.     

Regulation of end-expiratory lung volume during exercise

We determined the effects of exercise on active expiration and end-expiratory lung volume (EELV) during steady-state exercise in 13 healthy subjects. We also addressed the questions of what affects active expiration during exercise. Exercise effects on EELV were determined by a He-dilution technique and verified by changes in end-expiratory esophageal pressure. We also used abdominal pressure-volume loops to determine active expiration. EELV was reduced with increasing exercise intensity. EELV was reduced significantly during even mild steady-state exercise and during heavy exercise decreased an average of 0.71 +/- 0.3 liter. Dynamic lung compliance was reduced 30-50%; EELV remained greater than closing volume. Changing the resistance to airflow (via SF6-O2 or He-O2 breathing) during steady-state exercise changed the peak gastric and esophageal pressure generation during expiration but did not alter EELV; breathing through the mouthpiece produced similar effects during exercise. EELV was significantly reduced in the supine position. With supine exercise active expiration was not elicited, and EELV remained the same as in supine rest. With CO2-driven hyperpnea (7-70 l/min), EELV remained unchanged from resting levels, whereas during exercise, at similar minute ventilation (VE) values EELV was consistently decreased. At the same VE, treadmill running caused an increase in tonic gastric pressure and greater reductions in EELV than either walking or cycling. We conclude that both the exercise stimulus and the resultant hyperpnea stimulate active expiration and a reduced FRC. This new EELV is preserved in the face of moderate changes in mechanical time constants of the lung. This reduced EELV during exercise aids inspiration by optimizing diaphragmatic length and permitting elastic recoil of the chest wall.     

Effects of separate rib cage and abdominal restriction on exercise performance in normal humans

We assessed the effects of selective restriction of movements of the rib cage (Res,rc) and abdomen (Res,ab) on ventilatory pattern, transdiaphragmatic pressure (Pdi), and electrical activity of the diaphragm (Edi) in five normal subjects exercising at a constant work rate (80% of maximum power output) on a cycle ergometer till exhaustion. Restriction of movements was achieved by an inelastic corset applied tightly around the rib cage or abdomen. Edi was recorded by an esophageal electrode, rectified, and then integrated, and peak values during inspiration were measured. Each subject exercised at the same work rate on 3 days: with Res,rc, with Res,ab, and without restriction (control). Res,rc but not Res,ab reduced exercise time (tlim). Up to tlim, minute ventilation (VE) was similar in all three conditions. At any level of VE, however, Res,rc decreased tidal volume and inspiratory and expiratory time, whereas Res,ab had no effect on the pattern of breathing. Res,ab was associated with higher inspiratory Pdi swings at any level of VE, whereas peak Edi was similar to control. Inspiratory Pdi swings were the same with Res,rc as control, but the peak Edi for a given Pdi was greater with Res,rc (P less than 0.05). During Res,rc the abdominal pressure swings in expiration were greater than with Res,ab and control. We conclude that Res,rc altered the pattern of breathing in normal subjects in high-intensity exercise, decreased diaphragmatic contractility, increased abdominal muscle recruitment in expiration, and reduced tlim. On the other hand, Res,ab had no effect on breathing pattern or tlim but was associated with increased diaphragmatic contractility.     

Relationship among EMG and contractile responses of the diaphragm elicited by hypotension

In a canine model, we investigated the effects of severe hypotension on the indexes of diaphragmatic failure. We measured 1) the transdiaphragmatic pressure obtained in response to 20- and 100-Hz stimulation of phrenic nerves (Pdi20 and Pdi100), 2) the power spectrum of diaphragmatic electromyogram (EMG), 3) the ratio of integrated diaphragmatic EMG to Pdi (Edi/Pdi), and 4) the rate of relaxation of Pdi100 and Pdi20. Arterial blood pressure (Pa) was reduced to 40-50 mmHg by a balloon inflated in the inferior vena cava and was maintained at this level until Pdi100 declined to 75% of the control value (100% shock time, ST). A recovery period of 60 min at normal Pa was allowed. During hypotension, Pdi100 and Pdi20 declined only at 100% ST [95.0 +/- 13.0 (SE) min]; however, only Pdi100 recovered within 15 min. The power spectrum shifted to low frequencies early and progressively during shock period. Edi/Pdi rose significantly at 80 and 100% ST and recovered within 15 min. The relaxation rate of Pdi20 and Pdi100 increased significantly at 100% ST only. We conclude that 1) diaphragmatic contractility is depressed during severe hypotension, 2) changes in the power spectrum occurred first in the shock state, followed by alterations in Edi/Pdi, and subsequently both changes in the frequency-pressure curve and relaxation rate occurred last.     

Changes in rate of relaxation of sniffs with diaphragmatic fatigue in humans

The rate of relaxation of the diaphragm after stimulated (4 subjects) and voluntary (8 subjects) contractions was compared in normal young men. Stimulated contractions were induced by supramaximal unilateral phrenic nerve stimulation and voluntary contractions by short, sharp sniffs of varying tensions against an occluded airway. The rate of relaxation of the diaphragm was calculated from the rate of decline of transdiaphragmatic pressure (Pdi). In both conditions the maximum relaxation rate (MRR) was proportional to the peak transdiaphragmatic pressure (Pdi), whereas the time constant (tau) of the later exponential decline in Pdi was independent of Pdi. The mean +/- SE rate constant of relaxation (MRR/Pdi) was 0.0078 +/- 0.0002 ms-1 and the mean tau was 57 +/- 3.8 ms for stimulated contractions. The rate of relaxation after sniffs was not different, and it was not affected by either the lung volume at which occluded sniffs were performed (in the range of residual volume to functional residual capacity + 1 liter) or by the relative contribution gastric pressure made to Pdi. After diaphragmatic fatigue was induced by inspiring against a high alinear resistance there was a decrease in relaxation rate. In the 1st min postfatigue MRR/Pdi decreased (0.0063 +/- 0.0003 ms-1; P less than 0.005) and tau increased (83 +/- 5 ms; P less than 0.005). Both values returned to prefatigue levels within 5 min of the end of the studies. We conclude that the sniff may prove to be clinically useful in the detection of diaphragmatic fatigue.     

Changes in lung volume and breathing pattern during exercise and CO2 inhalation in humans

Lung volume changes during CO2 inhalation and exercise were compared in seven human subjects. Expiratory reserve volume (ERV) normalized by vital capacity (VC) was used as an index of end-expiratory lung volume (EELV). Work loads tried were 30, 60, and 90 W and inspired CO2 concentrations were 3.5 and 5.0%. Exercise at 30 W led to a significant decrease in EELV, by 7% VC (P less than 0.005), with no further change at higher levels of exercise (P greater than 0.1). Both 3.5 and 5.0% CO2 inhalation resulted in an increase in EELV that was not statistically significant (3% VC, P greater than 0.1). A possible linkage of this different EELV behavior to breathing pattern was tested. The tidal volume-inspiratory duration curve shifted to a higher volume region during exercise compared with CO2 inhalation. Consequently, the volume-time threshold characteristic was better described by an end-inspiratory lung volume-inspiratory duration plot, resulting in a common relationship under these two different stimuli. These results suggest that the depth and rate of breathing in humans can be affected by not only phasic but also tonic components. A decrease in functional residual capacity or EELV was peculiar to exercise and should be associated with increased mechanical efficiency compared with CO2 inhalation. Theoretical predictions based on work of breathing optimization via a decreased EELV seemed to be capable of explaining isocapnic exercise hyperpnea in conjunction with proportional control of arterial CO2 tension.     

Interaction of fatigue and hypercapnia in the canine diaphragm

We studied 10 open-chest dogs and measured the pressure across the diaphragm (Pdi) in each period of the protocol during stimulation at frequencies of 1, 20, 50, and 80 Hz. Three ranges of arterial PCO2 (PaCO2) were examined: less than or equal to 26, 36-50, and greater than or equal to 89 Torr. The diaphragm was fatigued with repetitive phrenic stimulation (30 Hz). During the fatiguing activity, five of the animals were subjected to hypercapnia and the other five to hypocapnia. A frequency-Pdi curve was generated for each period in the protocol. The data show that 1) fatiguing to 50% of the initial Pdi value during hypercapnia was significantly more rapid than during hypocapnia; 2) both the prefatigue and postfatigue mean Pdi values over all interactions of frequency, fatigue, and PaCO2 were unaffected by the fatiguing environment (hypercapnia vs. hypocapnia); 3) the percent reduction of Pdi by hypercapnia was the same at all four frequencies; 4) hypocapnia did not alter either the pre- or postfatigue frequency-Pdi curve; and 5) one-half relaxation time, unaffected by PaCO2, was prolonged by fatigue. We conclude that the hypercapnic diaphragm has less endurance than the hypocapnic diaphragm and that although both fatigue and hypercapnia decrease Pdi, they appear to be separate entities working through different mechanisms.     

Ventilatory response to fatiguing and nonfatiguing resistive loads in awake sheep

To study the changes in ventilation induced by inspiratory flow-resistive (IFR) loads, we applied moderate and severe IFR loads in chronically instrumented and awake sheep. We measured inspired minute ventilation (VI), ventilatory pattern [inspiratory time (TI), expiratory time (TE), respiratory cycle time (TT), tidal volume (VT), mean inspiratory flow (VT/TI), and respiratory duty cycle (TI/TT)], transdiaphragmatic pressure (Pdi), functional residual capacity (FRC), blood gas tensions, and recorded diaphragmatic electromyogram. With both moderate and severe loads, Pdi, TI, and TI/TT increased, TE, TT, VT, VT/TI, and VI decreased, and hypercapnia ensued. FRC did not change significantly with moderate loads but decreased by 30-40% with severe loads. With severe loads, arterial PCO2 (PaCO2) stabilized at approximately 60 Torr within 10-15 min and rose further to levels exceeding 80 Torr when Pdi dropped. This was associated with a lengthening in TE and a decrease in breathing frequency, VI, and TI/TT. We conclude that 1) timing and volume responses to IFR loads are not sufficient to prevent alveolar hypoventilation, 2) with severe loads the considerable increase in Pdi, TI/TT, and PaCO2 may reduce respiratory muscle endurance, and 3) the changes in ventilation associated with neuromuscular fatigue occur after the drop in Pdi. We believe that these ventilatory changes are dictated by the mechanical capability of the respiratory muscles or induced by a decrease in central neural output to these muscles or both.     

Effects of loaded breathing and hypoxia on diaphragm metabolism as measured by (31)P-NMR spectroscopy.

Diaphragm fatigue may contribute to respiratory failure. (31)P-nuclear magnetic resonance spectroscopy is a useful tool to assess energetic changes within the diaphragm during fatigue, as indicated by P(i) accumulation and phosphocreatine (PCr) depletion. We hypothesized that loaded breathing during hypoxia would lead to diaphragm fatigue and inadequate aerobic metabolism. Seven piglets were anesthetized by using halothane inhalation. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at end expiration with the airway occluded. A nuclear magnetic resonance surface coil placed under the right hemidiaphragm measured P(i) and PCr during four conditions: control, inspiratory resistive breathing (IRB), IRB with hypoxia, and recovery (IRB without hypoxia). IRB alone resulted in hypercarbia (32 +/- 7 to 61 +/- 21 Torr) and respiratory acidosis but no change in diaphragm force output or aerobic metabolism. Combined IRB and hypoxia resulted in decreased force output (Pdi decreased by 40%; from 30 +/- 17 to 19 +/- 11 mmHg) and evidence of metabolic stress (ratio of P(i) to PCr increased by 290%; from 0.19 +/- 0.09 to 0.74 +/- 0.27). We conclude that diaphragm fatigue associated with inadequate aerobic oxidative metabolism occurs in the setting of loaded breathing and hypoxia. Conversely, aerobic metabolism and force output of the diaphragm remain unchanged from control during loaded normoxic or hyperoxic breathing despite the onset of respiratory failure.     

Inspiratory muscle function with restrictive chest wall loading during exercise in normal humans

The effects of selective restriction of rib cage (Res,rc) and abdominal wall (Res,ab) movements on endurance of short-term constant-load heavy exercise and on diaphragmatic function during such exercise were examined in five normal young men. An inelastic surgical corset was used to achieve Res,rc and Res,ab. Subjects exercised on a cycle ergometer at 80% of their maximum power output to exhaustion on three occasions: with Res,rc, with Res,ab, and without restriction of chest wall movements (control). Transdiaphragmatic (Pdi), esophageal, and gastric pressures were measured. Electromyogram of the diaphragm was recorded by an esophageal electrode, and the ratio of the power content of a high-frequency to low-frequency band (H/L ratio) was measured. In addition, maximum Pdi (Pdimax) pre- and immediately postexercise was recorded. Res,rc was associated with a shorter endurance time, a progressive decline of the H/L ratio, and a significant reduction of Pdimax postexercise, whereas no such changes were found with Res,ab. We conclude that diaphragmatic function was well defended with abdominal wall loading, whereas limitation of rib cage expansion reduced diaphragmatic endurance during exercise. The diaphragmatic tension-time index (TTdi) in exercise was always less than the critical value of 0.15 found by Bellemare and Grassino (J. Appl. Physiol. 53: 1190-1195, 1982) when subjects inspired against large resistive loads at normal minute ventilations. We suggest that the higher inspiratory flow rate (P less than 0.05) and breathing frequency (P less than 0.05) account for the occurrence of diaphragmatic fatigue in exercise with Res,rc when the TTdi was 0.06 +/- 0.02.