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Ventilatory pump failure can occur in the setting of severe infection. Recent in vivo studies have shown a significant decrease in diaphragm force production in rats with pneumococcal sepsis and sepsis secondary to Escherichia coli endotoxin. We hypothesized that diaphragm impairment during sepsis may be mediated by a direct effect of tumor necrosis factor-alpha (TNF) or endotoxin. To test this hypothesis we studied the mechanical characteristics of isolated rat diaphragm strips in tissue baths containing rTNF-alpha or endotoxin and compared the results with control strips. The strips were stimulated to contract isometrically in the tissue baths that were aerated with 95% O2-5% CO2. Baseline force-frequency determinations were made at 60 min. Following this, the strips were fatigued over a 4-min period (20 Hz, 0.33-s trains, 1 train/s) and force-frequency relationships determined 30 s, 10 min, and 60 min post-fatigue. There were no significant differences found between control and experimental strips in any aspect of contractile function tested, including force-frequency characteristics, fatiguability, and recovery from fatigue. Using an isolated cell line assay (L929), we found evidence of attenuated cytotoxicity of TNF at 26 degrees C compared with 37 degrees C. Therefore, we repeated the experiments studying the effects of TNF on in vitro muscle at 37 degrees C. We once again found no effect of TNF on contractile function. We conclude that the impairment of diaphragm function during sepsis is not mediated by a direct effect of TNF or endotoxin.

To determine the effect of non-REM (NREM) sleep on inspiratory muscle electromyographic (EMG) activity in asthmatic patients and the subsequent effect of such changes on FRC, 12 asthmatic patients with nocturnal worsening were monitored overnight in a horizontal volume-displacement body plethysmograph. During studies FRC was monitored using the single inspiratory occlusion technique, whereas EMG activities of the diaphragm (DI), intercostal (IC), and sternocleidomastoid (SCM) muscles were monitored using surface electrodes. FRC decreased progressively, from 3.63 +/- 0.27 L while awake prior to "lights out" to 3.15 +/- 0.27 L after 60 min of NREM sleep (p < 0.005). With awakening at the end of the study FRC increased to 4.69 +/- 0.48 L (p < 0.01). Onset of NREM sleep was also associated with significant (p < 0.05) reductions in EMG tonic activities of all three inspiratory muscles. These levels of tonic activity returned and were further augmented (p < 0.001) with awakening at the conclusion of the study. Linear relationships were demonstrated between sleep-state dependent changes in FRC and EMG tonic activity for each of the three inspiratory muscles (r = 0.98, 0.93, and 0.97 for DI, IC, and SCM, respectively, p < 0.01). NREM sleep did not significantly alter mean inspiratory phasic activities of these muscles, although there was considerable heterogeneity between individual subjects in the effects of NREM sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

The relative invasiveness of the balloon catheter technique in measuring twitch transdiaphragmatic pressure (Pdit) limits its clinical use. By phrenic stimulation we obtained swings in mouth pressure (Pmt) in six COPD patients (age 50 to 72, FEV1 18 to 48% of predicted) at relaxed FRC (rFRC) and during graded inspiratory efforts (IE; twitch occlusion, TO). At rFRC, Pmt was damped and time lagged relative to the esophageal pressure twitch (Pes(t)), as if pressure had equilibrated through an RC system. Pmt was not correlated with Pdit. Conversely, Pmt and Pes(t) were always well matched during IE [Pmt = 0.971 (SEM +/- 0.028) Pes(t), r > 0.89], possibly in relation to a decrease in upper airway compliance or more uniform pleural pressure swings. Pmt decreased with the level of voluntary diaphragmatic contraction (Pdivol) in proportion to Pdit, reflecting a progressive increase in the level of diaphragm activation. During IE, Pmt was closely related to the voluntary mouth pressure in five subjects but not in the remaining subject, indicating intersubject variability in the level of diaphragmatic recruitment relative to other inspiratory muscles. We submit that measuring Pm during inspiratory efforts upon which bilateral phrenic stimulation is superimposed offers a relatively simple method for the assessment of diaphragm activation, potentially applicable in the clinical field.

Previous work has suggested that diaphragm EMGs recorded from the lower thoracic wall yield spuriously low centroid frequencies (Fc). For this reason we compared EMGs recorded from two anterolateral thoracic wall locations with EMGs recorded simultaneously from a bipolar esophageal electrode in 11 stable quadriplegic patients. Their maximal inspiratory pressures (Pdimax) ranged from 31 to 85, averaging 55 cm H2O. Quadriplegic patients were selected to exclude EMG contamination of surface recordings by intercostal muscle activity. Recordings were made during resting breathing, voluntary hyperventilation, CO2-stimulated hyperventilation, and inspiratory resistance breathing at 50% of Pdimax. Centroid frequencies were consistently lower from surface recordings than from esophageal recordings. Centroid frequencies (Hz) recorded from the esophagus were 86.9 +/- 3.0 (SEM) resting, 93.4 +/- 3.7 during voluntary hyperventilation, 85.8 +/- 4.2 during CO2-stimulated ventilation, and 88.5 +/- 1.4 during inspiratory resistance breathing. Corresponding Fc values from simultaneous thoracic surface recordings were 62.6 +/- 3.6, 62.0 +/- 2.8, 58.6 +/- 3.1, and 58.8 +/- 2.5. On several subjects, decreases in Fc that occurred during sustained maximal inspiratory efforts were present in esophageal recordings but not in surface recordings. We conclude that thoracic surface recordings of the diaphragmatic EMG do not accurately reflect frequency information.

The relative effects of respiratory and metabolic acidosis on diaphragm function are not known. To determine these effects, we compared the effects of respiratory and lactic acidosis on the contractile properties of the diaphragm. We estimated diaphragmatic performance from the change in transdiaphragmatic pressure after supramaximal stimulation of the phrenic nerves in an open-chested, casted-abdomen dog. Similarly, we stimulated the gastrocnemius motor nerve and examined force production and relaxation rate to determine if there was a difference in the response of this skeletal muscle. There was a fall in diaphragm performance with respiratory acidosis (77.1 +/- 16.9 cm H2O versus 93.8 +/- 15.0 cm H2O baseline), but not with lactic acidosis (96.7 +/- 15.7 cm H2O versus 93.8 +/- 15.0 cm H2O baseline); and the gastrocnemius was unaffected by either acidosis. The changes with respiratory acidosis were similar to those seen with diaphragmatic fatigue and had similar relaxation rate changes, suggesting that intracellular pH may play a mechanistic role in respiratory muscle fatigue. In addition, the absence of a respiratory acidosis effect on a non-diaphragmatic skeletal muscle's function represents another physiologic difference between the diaphragm and other skeletal muscles.

We report 16 adult men (age, 41 to 75 yr) with neuralgic amyotrophy (NA) who presented with dyspnea due to involvement of the diaphragm. All patients developed breathlessness after a prodrome of acute severe neck and shoulder pain. Bilateral diaphragm paralysis (BDP) was confirmed in 12 patients and unilateral diaphragm paralysis (UDP) in four by the absence of electrical and mechanical responses to percutaneous phrenic nerve stimulation. Global expiratory muscle strength was well preserved in all patients, but inspiratory muscle strength was reduced in proportion to the extent of diaphragmatic involvement. Lung function showed low lung volumes with preservation of carbon monoxide transfer coefficient in all patients. Two BDP patients were hypoxic (PaO2 = 67 and 54 mm Hg, respectively) on daytime arterial blood gas analysis; the latter patient with pre-existing chronic obstructive pulmonary disease and marked obesity also had borderline hypercapnia (PaO2 = 49 mm Hg). Overnight sleep studies in three BDP and two UDP patients showed frequent intermittent arterial oxygen desaturations apparently caused by obstructive sleep apneas, but there was no evidence of alveolar hypoventilation. Follow-up muscle studies in five BDP and four UDP patients between 2 and 4 yr after initial referral showed complete recovery of diaphragmatic function in only two UDP patients, one of whom relapsed a year later. We postulate that NA may be an important but underrecognized cause of diaphragmatic paralysis in otherwise normal patients. Diaphragmatic strength returns very slowly, if at all.

The changes in muscle mechanical properties caused by the myopathy of chronic uremia was examined in the soleus and the diaphragm muscles of rats in which chronic uremia was produced by subtotal nephrectomy. Using an in vitro muscle preparation in two groups of rats (moderately and severely uremic), we determined that uremia had a significant detrimental effect on both muscles with respect to the force-frequency relationships. In the diaphragm it decreased by 15% in the moderate group and by 43% in the severe group. In the soleus it decreased by 20% in both groups. Twitch characteristics behaved differently in the soleus and the diaphragm muscles in that 1/2 RT and TPT increased significantly (p < 0.05) in the soleus (severely uremic group) but not in the diaphragm. Fatigability was increased in both muscles in the moderately uremic rats and in the diaphragm in the severely uremic rats; however, the fatigability of the soleus in the severely uremic group was not different from that in the control group. Our findings suggest that the myopathic changes occurring in chronic uremia affects the function of the soleus and the diaphragm in different ways. Other findings in the severely uremic group indicate that additional factors such as marked electrolyte imbalances may also affect the excitation-contraction coupling in different ways.

We evaluated the effects of sublethal Escherichia coli endotoxemia with or without concomitant administration of N-acetylcysteine, an antioxidant agent, on diaphragmatic strength, endurance, and malondialdehyde (MDA) content in rats. One hundred ninety rats were inoculated subcutaneously on 2 successive days with 0.6 and 1.2 mg/100 g body weight of E. coli lipopolysaccharide respectively (E animals, n = 100) or saline (C group, n = 90). E and C animals were divided into two groups based on administration of endotoxin or saline alone (E group, n = 55; C group, n = 47, respectively) or endotoxin or saline plus N-acetylcysteine (1 g/kg body weight/day intraperitoneally) (E-NAC group, n = 45; C-NAC group, n = 43, respectively). Diaphragmatic strength was assessed in vivo 48 h after the first endotoxin or saline administration by measuring the transdiaphragmatic pressure (Pdl) generated during electrical stimulation of the phrenic nerves at 0.5, 10, 20, 30, 50, and 100 Hz. Endurance index was calculated as the percent ratio of Pdl generated after 30 s of phrenic stimulation at 10 Hz divided by the initial force. Diaphragmatic MDA (fluorometric technique) was measured 0, 6, 18, 30, 42, and 48 h after the first dose of endotoxin or saline. Pdl for 50 and 100 Hz was significantly reduced in Group E as compared with group C. This phenomenon was associated with a reduced endurance performance as assessed by a lower diaphragmatic endurance index in E as compared with C animals (90.9 +/- 4.2 versus 114.3 +/- 4.1 respectively; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

We studied pulmonary function tests, maximal voluntary ventilation, arterial blood gases, and respiratory muscle strength and recruitment pattern in a 37-yr-old symptomatic man before and after surgical plication for a left unilateral diaphragmatic paralysis. After plication, FVC, FEV1, TLC and FRC increased, whereas residual volume remained unchanged. Arterial PO2 improved from 70 to 87 mm Hg. Diaphragmatic strength, as expressed by the maximal transdiaphragmatic pressure increased from 30 to 75 cm H2O, and maximal voluntary ventilation increased from 74 to 123 L/min. Ventilatory muscle recruitment also changed: there was a shift from a positive to a negative delta Pg/delta Ppl slope during tidal breathing. This indicates more effective diaphragmatic recruitment after the procedure. We conclude that surgical plication may be of benefit to patients with symptomatic unilateral diaphragmatic paralysis. The improvement is due to improved respiratory muscle function.

Although it is known that endotoxin can induce diaphragmatic dysfunction, the mechanism of this effect is not fully understood. However, because the effects of endotoxin on other tissues appear to be mediated in part by free radicals, the present study sought to determine if free radicals may also contribute to the diaphragmatic dysfunction induced by endotoxin administration. Studies were performed on four groups of hamsters. One group of animals received intraperitoneal injections of endotoxin on the first and second days of study (i.e., 10 and 20 mg/kg, respectively). The second group received saline rather than endotoxin, the third group received both endotoxin and a free radical scavenger, PEG-SOD (2,000 U/kg given intraperitoneally every 12 h on Days 1 and 2), and the fourth group received PEG-SOD alone. All groups were killed on the third study day (i.e., 48 h after the initial injections). Diaphragmatic contractile function was assessed in vitro using muscle strips excised from the costal diaphragms of freshly killed animals; diaphragm samples were also assayed for malondialdehyde (MDA), a commonly used index of free-radical-mediated lipid peroxidation. MDA levels were higher in diaphragms from endotoxin-treated animals than from saline-treated control animals, and the contractility of diaphragm strips from endotoxin-treated animals was reduced when compared with strips from saline-treated control animals. Administration of PEG-SOD prevented MDA formation and contractile dysfunction in endotoxin-treated animals. Diaphragm contractility and MDA levels for animals given PEG-SOD alone were similar to those for saline-treated control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the effect of blood flow on diaphragm fatigue independent of oxygen delivery, the left hemidiaphragm was vascularly isolated in 14 pentobarbital-anesthetized, mechanically ventilated dogs. Fatigue (decline in tension generation) of the left diaphragm was induced by phrenic nerve stimulation at 10 Hz, 12/min, duty cycle of 0.5 for 8 min. Two stimulation periods separated by 30 min of rest were performed in each animal. Diaphragmatic O2 delivery during the two periods was the same. In Group 1 (n = 8), the diaphragm was autoperfused from the femoral artery (high O2-low flow) during the first stimulation period. The tension generated by the diaphragm during this period declined progressively to 47.7% of initial values. In the second period in this group, the diaphragm was pump perfused with arterial blood, diluted with an equal volume of 6% dextran at a flow rate twice that of the first period (low O2-high flow). Tension in this period declined to 76% of initial tension (p less than 0.05 compared with high O2-low flow). In Group 2 (n = 6), stimulation performed while perfusing the diaphragm in the first period with diluted arterial blood at a flow rate twice that recorded during autoperfusion (low O2-high flow) produced a decline in tension to 70% of the initial values. In the second period, the diaphragm was perfused with undiluted arterial blood at a flow rate equal to 50% of that of the first period (high O2-low flow). Tension during this period declined to 56% of initial values (p less than 0.05 compared with low O2-high flow).(ABSTRACT TRUNCATED AT 250 WORDS)

Recent studies indicate that diaphragmatic contractility is adversely affected by bacterial infection. Using transdiaphragmatic pressure (Pdi) with phrenic nerve stimulation, the effect of continuous Group B Streptococcus (GBS) infusion on diaphragmatic force output was studied in seven anesthetized, spontaneously breathing 1-month old piglets. Pdi was measured under baseline condition (50% O2/50% N2) and at 1, 2, and 4 h of GBS infusion. The GBS was infused at a level that caused a doubling of the pulmonary artery pressure and a 32% decrease in cardiac output but which avoided hypotension or acidosis--both of which can decrease diaphragmatic contractility. In addition, the piglets were kept hyperoxic (PaO2 greater than 100) and no piglet with hypercapnia (PaCO2 greater than 65) was studied, as hypoxia and hypercapnia also can cause respiratory muscle dysfunction. Pdi in response to phrenic nerve stimulation did not change during GBS infusion. We conclude that GBS infusion, in the absence of hypotension, hypercapnia, hypoxia, or acidosis, has no effect on diaphragmatic force generation in the piglet.

Basic mechanisms of sleep-disordered breathing (SDB) during rapid-eye-movement sleep (REMS) have been little investigated, despite the fact that events are often more prolonged and SaO2 nadirs lower during REMS. We predicted that the mechanisms of SDB in REMS would be related to the normal phasic changes in respiratory control in that state, rather than to cyclic arousals or responses to hypoxia as postulated for non-REMS SDB. Recordings of the EMG of the diaphragm (DIA) and the sternohyoid (SH), an upper airway dilating muscle, were made in five English bulldogs during sleep. We found that, as predicted, SDB events were associated with phasic influences rather than with arousals or response to hypoxia. The onset of SDB was significantly related to suppression of drive to both the DIA (p less than 0.01) and the SH (p less than 0.01). The mean drive of the DIA was suppressed to 42% of normal and of the SH to 17% of normal; the suppression of the SH was significantly greater than that of the DIA (p less than 0.05). Events were associated with changes in respiratory muscle EMG patterns typical of phasic REMS (p less than 0.01 for each muscle). The occurrence and duration of events exhibited no clear pattern or relationship to arousal or SaO2. Rather, as would be expected of phenomena associated with phasic REMS, the onset and termination of events were unpredictable. The association of SDB in REMS with phasic REMS influences rather than arousal or hypoxia suggests new directions for therapeutic approaches.

The effects of short periods of fasting on diaphragm contractile function remain unclear. The purpose of the present study was (1) to examine the relationship between duration of acute fasting and diaphragm contractile performance, and (2) to assess the effects of fasting on diaphragm glycogen stores and the relationship between changes in diaphragm function and alterations in muscle glycogen stores. Studies were performed on four groups of Syrian hamsters (nine animals in each group). One group served as a control and was allowed to feed normally, whereas the other three groups were fasted for either 1, 2, or 3 days. Diaphragm strips from animals were studied in vitro by measuring tension during electrically induced contractions. Two strips from each animal were studied; one strip was examined with a bath glucose equal to the prevailing blood glucose, and the second was preincubated in a high glucose solution (170 mg/dl) for 20 min. Fasting resulted in reductions in body weight, blood glucose concentrations, diaphragm strength, and diaphragm endurance in strips tested at the prevailing blood glucose levels. These effects were pronounced in animals fasted for 3 days, with little or no change in diaphragm contractility observed in animals fasted for shorter periods. Diaphragm weight, thickness, and glycogen content were unchanged in the fasted animals, as was the weight of the soleus muscle. Preincubation of strips from 3-day-fasted animals in a high glucose medium resulted in a significant increase in diaphragm strip strength and endurance.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the breathing pattern during incremental exercise before and after induction of inspiratory muscle fatigue. Our aim was to determine whether induction of fatigue alters the ventilatory response to exercise and in particular whether such changes are most apparent at high levels of exercise when minute ventilation and thus inspiratory load are greatest. A group of 10 healthy subjects was studied on a cycle ergometer. Fatigue was achieved by having the subject breathe against an inspiratory threshold load that required the subject to generate 80% of the predetermined maximal mouth pressure to initiate airflow. Breathing pattern, oxygen consumption (VO2), mouth occlusion pressure (P0.1), and a visual analog scale (VAS) for respiratory effort were obtained for 3 min at rest and at 25, 50, 75, and 100% of the subject's maximal work load (Wmax) as determined by preliminary testing. Exercise was performed on two separate occasions, once immediately after induction of fatigue and the other as a control. Induction of fatigue had no effect on resting breathing and only minimal effects at the lower work loads (25 and 50% Wmax). At the higher work loads (75 and 100% Wmax) induction of fatigue significantly altered the pattern of breathing during exercise. At 75% of Wmax the respiratory frequency (f) increased from 22.5 +/- 4.4 (SD) during control to 27.0 +/- 6.7 breaths/min (p less than 0.02) following induction of fatigue; tidal volume was not significantly altered, 2.15 +/- 0.65 versus 2.24 +/- 0.74 L during control. The increase in f was due to reductions in both inspiratory and expiratory time because fractional inspiratory time remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. Inspiratory muscles may be subjected to potentially fatiguing loads during an obstructive apnea and this may be related to the termination of obstructive apnea. We have measured transdiaphragmatic pressure (Pdi) and breathing patterns in six male patients with OSA during sleep to characterize respiratory muscle function in OSA and determine whether apnea termination is consistently related to a pressure time index of the diaphragm (PTI) associated with respiratory muscle fatigue. There was a large intersubject variability in Pdi generation during apnea. No consistent level of PTI was associated with apnea termination. During prolonged apneas, the respiratory duty cycle plateaued, which is suggestive of an inhibitory reflex possibly mediated by chest wall afferents. There were intersubject differences in both inspiratory and expiratory muscle recruitment during apnea. In the majority of patients, the diaphragm appeared to be the primary inspiratory muscle during apnea, but in some it appeared to be the intercostal/accessory muscles. The majority of patients demonstrated an increase in gastric pressure and inward abdominal movement during the expiratory phases of an apnea, consistent with abdominal muscle recruitment stimulated by increased ventilatory drive.

Tracheobronchial clearance was measured in seven patients with bilateral diaphragmatic weakness using a noninvasive objective radioaerosol technique. The data were compared with those from seven healthy nonsmoking control subjects matched for physical characteristics and studied under the same experimental conditions; the control subjects were drawn from a data bank of healthy subjects and were matched to the patients for age, sex, and the initial distribution of their radioaerosol deposition. Pulmonary function indices (FEV1, FVC, PEFR, and MMFR25-75) for the patients were all significantly (p less than 0.01) reduced compared with those for the control subjects. The initial topographic distribution of the radioaerosol within the lungs of the patients and control groups was similar: alveolar deposition [mean (SD)] was 36.4 (6.7) versus 41.0 (4.0)%, and penetration index was 0.56 (0.08) versus 0.56 (0.03), respectively. Tracheobronchial clearance of deposited radioaerosol over a 6-h observation period after inhalation showed a marked reduction (p less than 0.02) in the patients: area under the clearance curve (between zero and 6 h) was 262 (80)% h for the patients and 142 (41)% h for the healthy control subjects. These data suggest that in patients with bilateral diaphragmatic weakness, mucociliary clearance is depressed, or that reduced mechanical movement of the lungs can itself impair clearance of secretions from the lungs. Impaired clearance from either cause may contribute to an increased incidence of chest infections in severe respiratory muscle weakness.

Patients with chronic airflow obstruction (CAO) frequently develop abnormal thoraco-abdominal excursion, but the patterns described are inconsistent and the factors that relate to their development remain unknown. We studied 45 stable patients with FEV1 ranging from 0.36 to 2.1 L. A pattern of ventilatory muscle recruitment (VMR) was established by simultaneously measuring gastric (Pg) and pleural (Ppl) pressures and rib cage (Vrc) and abdominal (Vab) volume displacement with inductance plethysmography. From these tracings, Pg-Ppl plots were constructed and the delta Pg/delta Ppl values were calculated. The delta Pg/delta Ppl was validated in 15 patients with simultaneous analysis of Vab-Pg plots. Pearson's test and multiple regression analyses were used to correlate delta Pg/delta Ppl to factors thought to influence respiratory muscle function such as age, sex, nutritional status (weight/height, albumin), hyperinflation, airflow obstruction, and arterial blood gases. We found a direct correlation between a more positive delta Pg/delta Ppl value and increasing hyperinflation (r = 0.69, p less than 0.0001), increasing airflow obstruction (r = -0.55, p less than 0.001), and decreasing diaphragmatic strength (r2 = 0.32, p less than 0.001). We also found that expiratory Ppl became more positive with decreasing FEV1 (r2 = 0.33, p less than 0.001). This change in VMR was independent of age, sex, nutritional status, and arterial blood gas determinations.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the effects of a sublethal Escherichia coli endotoxemia with and without concomitant administration of indomethacin on diaphragmatic strength in an in vivo rat model. Ninety-six rats were inoculated subcutaneously on two successive days with 0.3 and 0.6 mg/100 g body weight of E. coli lipopolysaccharide, respectively (E animals, n = 64), or saline (C group, n = 32). E animals were divided into two groups based on subcutaneous administration of endotoxin alone (E group, n = 32) or endotoxin plus indomethacin (2.5 mg/kg body weight/day) (EI group, n = 32). Diaphragmatic strength was evaluated in 14 animals from each group 2 days after the first endotoxin or saline administration. Diaphragmatic strength was assessed by measuring the transdiaphragmatic pressure (Pdi) during electrical stimulation of the phrenic nerves at different frequencies (0.5, 10, 20, 30, 50, and 100 Hz). Lung histologic examination and measurements of lung weights were performed 1 and 2 days after the first endotoxin or saline administration in nine animals of each group each day. A slight increase in the number of neutrophils without alveolar septal thickening and alveolar edema was observed in the lungs of endotoxin-inoculated animals. No differences in the lung weight to body weight ratio nor in the dry to wet weight ratio of the lungs were noted between C, E, and EI groups. Diaphragmatic weight was not different in the three groups, whereas the weights of the extensor digitorum longus, tibialis anterior, and soleus muscles were significantly reduced in E compared with C and EI animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was undertaken to determine the effects of 8 days of corticosteroid administration on diaphragmatic atrophy and contractile properties. One hundred sixty rats were divided into a pair-fed (PF) group (n = 80) and a steroid-treated (ST) group (n = 80). The treated rats received a single injection of Kenacort 80 retard (0.1 mg/kg intramuscularly). The experimental period was 8 days. Steroid treatment resulted in a 30% decrease in body weight in the ST group when compared with the PF group. Diaphragmatic mass in the ST group decreased in proportion to body weight (30%) as did the weight of the extensor digitorum longus (EDL). The soleus muscle was unaffected. The diaphragmatic atrophy was associated with a significant decrease (p less than 0.001) in normalized tetanic force as assessed both in vivo and in vitro. Diaphragmatic strength was determined in vivo by measuring transdiaphragmatic pressure (Pdi) during bilateral electrical stimulation of the phrenic nerves at different frequencies (0.5, 10, 20, 30, 50, and 1000 Hz). The force-frequency relationship was also studied in vitro using direct stimulation of costal diaphragmatic strips. In both preparations, twitch and low-frequency force were unaffected, whereas normalized tetanic force in the ST group was markedly reduced compared with that in the PF group (p less than 0.001). Soleus and EDL muscles were also studied in vitro. Although steroid treatment had no effect on the soleus, in the EDL, a slight (11%) decrease in normalized tetanic tension was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Diaphragmatic function and biochemical changes were studied during respiratory failure induced by incremental inspiratory threshold loading in anesthetized rabbits (1) who were unbound and spontaneously breathing, (2) during lower thoracic and abdominal binding, and (3) while bound and undergoing transvenous phrenic nerve pacing of the diaphragm. There was no evidence of contractile fatigue or alterations in glycogen or lactate concentrations in the diaphragm of unbound spontaneously breathing animals. With thoracoabdominal binding, there was a fall in maximal transdiaphragmatic pressure (Pdimax) and the ratio of diaphragmatic force divided by neural input (Pdi/Edi ratio); there was no change in diaphragm glycogen, but there was a significant rise in lactate. In the bound and phrenic-paced animals Pdimax and Pdi/Edi ratio fell, and there was significant glycogen depletion and lactate accumulation. There was a significant correlation between diaphragm function and the levels of diaphragm glycogen and lactate at the point of respiratory failure. We conclude that (1) respiratory failure induced by incremental inspiratory threshold loading was not associated with either contractile fatigue of the diaphragm or diaphragmatic biochemical changes in unbound spontaneously breathing animals, (2) when mechanisms that preserve diaphragmatic function are circumvented by phrenic pacing and/or thoracoabdominal binding, diaphragm fatigue and biochemical changes occur, and (3) there is a significant relationship between in vivo evidence of contractile fatigue of the diaphragm and diaphragmatic glycogen depletion and lactate accumulation.

The effects of upper abdominal surgery on diaphragmatic function were studied in 5 patients. During quiet tidal breathing, the volume displacement of the abdomen within the tidal volume (Vab/Vt) and the ratio of abdominal and transdiaphragmatic pressure changes (delta Pab/delta Pdi), taken as an index of the diaphragmatic contribution to the breathing process, decreased significantly on the first postoperative day (p less than 0.001); in 2 patients, a cephalad paradoxical motion of the diaphragm during inspiration was observed. Diaphragmatic dysfunction also occurred during maximal inspiratory efforts as shown by the significant fall in maximal static transdiaphragmatic pressure (Pdimax) and cephalocaudal diaphragmatic displacement on the first (p less than 0.001) and third (p less than 0.001) postoperative days. On the first postoperative day, opiate epidural analgesia did not modify Vab/VT, delta Pab/delta Pdi, and Pdimax. These parameters spontaneously returned towards control values on the seventh postoperative day. We conclude that upper abdominal surgery induces a marked diaphragmatic dysfunction lasting about 1 wk and that it is not suppressed by postoperative pain relief. The mechanism of this dysfunction remains to be determined. It may be the main cause of the postoperative pulmonary restrictive pattern.

Global respiratory muscle function and diaphragmatic strength were assessed and compared with quadriceps femoris muscle strength in 17 patients with generalized mild-to-moderate myasthenia gravis and breathlessness. Initial measurements, made 10 h after the last dose of oral anticholinesterase therapy, demonstrated reduced maximal static expiratory (52.4 +/- 26.8% predicted) and inspiratory (54.0 +/- 23.5% predicted) mouth pressures in 16 patients, and reduced quadriceps femoris muscle strength in all cases. Vital capacity (VC) (70.9 +/- 19.0% predicted) was abnormal in 12 patients. Transdiaphragmatic pressure recorded during maximal sniffs (sniff Pdl) was reduced in eight patients, whereas pressure recorded during bilateral phrenic nerve stimulation at 1 Hz (twitch Pdi) was reduced in only three. There was no relationship between the grade of myasthenia or the severity of dyspnea and any of the measurements of respiratory muscle strength. After the administration of edrophonium hydrochloride (Tensilon), there was a significant increase in maximal static expiratory and inspiratory mouth pressures in quadriceps muscle strength and in sniff Pdi. The small increase in VC was not significant, and twitch Pdi increased in only one patient. Phrenic nerve conduction time was normal before and after Tensilon. Two patients with severe long-standing myasthenia showed no improvement in any measurement after Tensilon. We conclude that expiratory and inspiratory muscle weakness was not uncommon in patients with myasthenia gravis. Respiratory muscle strength improved after Tensilon. Vital capacity was a less sensitive measure of respiratory muscle strength than were respiratory mouth pressures and sniff Pdi. Diaphragmatic involvement was not detected by twitch Pdi unless the weakness was severe.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of pharyngeal dilator muscles, such as the genioglossus, during hypoxia must be sufficient to overcome the increased subatmospheric pressure generated by the diaphragm. This is particularly important during sleep, when upper airway resistance is greater. We measured ventilatory, genioglossal (EMGgg) and diaphragmatic (EMGdi) electromyogram responses to isocapnic hypoxia during wakefulness (W), slow-wave sleep (SWS), and rapid eye movement (REM) sleep in seven chronically instrumented adult goats. We also compared the EMG responses to hypoxia to response to CO2 during W. delta EMGdi/delta SaO2 decreased progressively from W to SWS (p less than 0.05) to REM sleep (p less than 0.05 versus SWS), paralleling the corresponding ventilatory responses. EMGgg was activated only below an SaO2 threshold, similar during W (69.8 +/- 6.3%) and SWS (67.2 +/- 4.3%), beyond which there was a brisk linear increase. During REM sleep, arousal preceded activation of EMGgg in each animal, although SaO2 at arousal (61.3 +/- 4.4%) was less than the SaO2 threshold for EMGgg activation during W or SWS (p less than 0.05). Despite state-related differences in the individual muscle responses, simultaneous EMGgg and EMGdi during hypoxia or hypercapnia in W, and during hypoxia in SWS and REM sleep, were linked in a constant manner. This suggests common integration of central and peripheral chemoreceptor inputs. Furthermore, these relationships are unaffected by either SWS or REM sleep.

Our study evaluated whether a dose-response relationship exists for theophylline and diaphragmatic contractility within the usual therapeutic range for theophylline. The study, involving 16 patients with mild to moderate chronic obstructive pulmonary disease, was done in a randomized, placebo-controlled, double-blind, crossover fashion. We found no statistically significant effect of theophylline on diaphragmatic contractility at mean theophylline concentrations of 5.13, 12.07, and 18.6 micrograms/ml.

Using the weighted spirometer technique we studied chest wall compliance (Cw) in 16 nonobese patients with chronic weakness of the respiratory muscles and 20 healthy control subjects. In order to evaluate the validity of the technique, while Cw was being measured, we monitored thoracoabdominal configuration with 2 pairs of linearized magnetometers and electrical activity of the external oblique with a concentric needle electrode in 3 healthy subjects and 4 patients; in addition, we recorded in 3 subjects the electrical activity from the intercostal muscles and diaphragm throughout the procedure. The method was reproducible within 5.8% and provided Cw values that compared well with those yielded by the relaxation technique. In each subject, the weight-induced shifts in end-expiratory lung volume showed a very good linear correlation with the changes in transrespiratory pressure at end-expiration (r greater than or equal to 0.91). In addition, in none of the subjects tested did the electromyograms reveal any intercostal, diaphragmatic, or abdominal muscle activity at end-expiration, nor did the end-expiratory level ever show a significant departure from the relaxed thoracoabdominal configuration, thus suggesting adequate respiratory muscle relaxation. The reduction in inspiratory muscle force in the patients ranged from 17 to 94% of predicted (mean +/- SE, 43 +/- 6). The decrease in vital capacity, total lung capacity, and functional residual capacity averaged 59, 34, and 15% of predicted, respectively. Both the patient and the control groups showed a large interindividual variability regarding Cw. It varied from 0.117 to 0.258 L/cm H2O (mean +/- SE, 0.162 +/- 0.012) in the patients and from 0.163 to 0.366 L/cm H2O (mean +/- SE, 0.248 +/- 0.013) in the healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of aminophylline on diaphragmatic fatigue and recovery in the face of hypoxemia and hypercapnic acidosis were studied in anesthetized, spontaneously breathing, dogs. The phrenic nerves were stimulated supramaximally at 10, 20, 50, and 100 Hz during 2 s with electrodes placed around the fifth roots, and the resulting transdiaphragmatic pressure (Pdi) was measured with balloon catheters. The dogs were occluded before the stimulations at functional residual capacity. The latter was monitored by measuring the end-expiratory transpulmonary pressure, which remained constant throughout the experiment. Diaphragmatic fatigue was produced by resistive loaded breathing. At the end of the runs, which lasted 15 +/- 2 min, all the dogs were severely hypoxemic (30 +/- 5 mmHg), hypercapnic (65 +/- 4 mmHg), and acidotic (7.1 +/- 0.05). During the fatigue runs, phrenic stimulation resulted in a marked decrease in Pdi, which amounted at 20 Hz to 70 +/- 8% and 45 +/- 12% of the control values 5 min after the onset of the fatigue runs and at the end, respectively. After recovery (3 h), Pdi and arterial blood gas determinations returned to control values. Identical fatigue runs were repeated with aminophylline infusion (loading dose, 6 mg/kg in 10 min and maintenance dose, 1 mg/kg/h), leading to a plasmatic concentration of 16.4 +/- 2 mg/l. Aminophylline protected the diaphragm against fatigue, and despite the presence of hypoxemia and hypercapnic acidosis, the Pdi generated for a 20 Hz stimulation of the phrenic nerves at identical times of the preceding run amounting to 100 +/- 15% and 85 +/- 10% of control values, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilators can impose resistive and elastic loads during subject-initiated and spontaneous breaths. Such loads might worsen the chest wall distortion that is characteristic of patients with flail chest. We have tested this expectation in nine patients with flail chest and four normal subjects. All subjects breathed for 3 to 5 min on each of the following modes: assist control, intermittent mandatory ventilation (IMV), continuous positive airway pressure 5 to 10 cm H2O by demand valve and by a high flow system (CPAP-HF), and spontaneously (T-piece). Pressure at the airway opening was evaluated as a measure of ventilator loading, and magnetometric displacements of the major chest wall dimensions were evaluated to assess chest wall distortion. In contrast to the normal volunteers, patients with flail chest displayed chest wall distortion during active inspirations. The patterns of distortion were variable among patients. The degree of distortion varied among ventilator modes; generally, there was a greater degree of chest wall distortion in breaths with greater loading. For example, distortion was greater during the spontaneous breaths taken on the IMV-mode than during spontaneous breaths taken on the T-piece. The CPAP-HF mode resulted in the least distortion, reversing chest wall distortion in five patients, improving it in two, and not changing the distortion in the remaining two. The improvements may be related to positive pleural pressures and to the minimal ventilator-imposed load of the high gas flow system. The distortion imposed by ventilators increases the work of breathing in these patients and may thus contribute to difficulty in weaning.

To compensate for diaphragmatic weakness, intercostal/accessory muscles may be recruited in inspiration and/or abdominal muscles in expiration with relaxation during subsequent inspiration. As a consequence, for a given decrease in pleural pressure (Ppl) during quiet inspiration (qi), abdominal pressure (Pab) should either undergo a smaller increase than normal or, in severe cases, decrease. If so, the ratio of change in Pab to Ppl during qi (delta Pab/delta Ppl(qi], which is normally less than -1 when upright, should increase, approaching +1 in profound diaphragmatic weakness. To examine the relationship between degree of diaphragmatic weakness and delta Pab/delta Ppl(qi), we measured (erect and supine) anteroposterior rib cage and abdominal motion, Pab, Ppl, and transdiaphragmatic pressure (Pdi) during qi, maximal inspiration (Pdi(max)mi) and maximal inspiratory effort at FRC (Pdi(max)FRC) in 10 patients with bilateral and 8 with unilateral diaphragmatic weakness. Pdi(max)mi and Pdi(max)FRC were low in all patients. delta Pab/delta Ppl(qi) (erect) was increased in all patients (0.28 +/- 0.7; mean +/- SD) and correlated closely with both Pdi(max)mi (r = -0.89, p less than 0.001) and Pdi(max)FRC (r = -0.76, p less than 0.001). There was extensive overlap in the data between unilateral and bilateral diaphragmatic weakness. The ratio of delta Pdi during qi to Pdi(max)FRC was less than 0.31 in all patients. The results suggest that delta Pab/delta Ppl(qi) is a useful index of the degree of diaphragmatic weakness and that the functional consequences of unilateral and bilateral weakness are not rigidly separable.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the mechanical effectiveness of the parasternal intercostals at FRC and near TLC in 14 supine, vagotomized, and anesthetized dogs. First, we determined the relationship between parasternal intramuscular pressure (Pps), measured with Gaeltec 12 CT-mini-transducers, and parasternal EMG activity (Eps) during breathing at FRC and near TLC. Second, we examined the changes in Pps and the changes in parasternal force (Fps) generated during bilateral parasternal stimulation at FRC and near TLC with a given supramaximal stimulus. Before phrenicotomy, the inspiratory increases in Pps remained relatively constant near TLC (FRC, 50.4 +/- 16.5 versus TLC, 48.7 +/- 13.3 cm H2O, NS), whereas the Eps clearly decreased (82.9 +/- 5.5% FRC, p less than 0.01). This indicates that the gain converting electrical activity into pressure for the parasternals is greater near TLC than at FRC. A similar pattern of changes in Pps and in Eps was observed during quiet inspiration at FRC and near TLC after phrenicotomy. During bilateral parasternal stimulation the increases in Pps near TLC tended to be greater than those at FRC (140.7 +/- 28.6 versus 100 +/- 28.3 cm H2O, NS), whereas the increases in Fps were significantly greater near TLC than at FRC (277.4 +/- 60.6 versus 214.2 +/- 47.1 g, p less than 0.05). Therefore, we conclude that the mechanical effectiveness of the parasternal contraction near TLC remains relatively unchanged and is even greater in relation to that at FRC.

Studies of vocal cord function were undertaken in a quadriplegic patient requiring ventilatory assistance, and in 2 normal subjects during controlled ventilation in a tank-type respirator. When the patient and the normal subjects relaxed and made no conscious effort to assist the respirator, the vocal cords were observed to close during inspiration and a large pressure gradient (12 to 19 cm H2O) developed across the cords. When the subjects made a slight inspiratory effort ("assist" mode), the cords opened widely during inspiration. There were large increases in flow and tidal volume in the "assist" mode compared with passive ventilation. Measurements of transdiaphragmatic pressure and esophageal pressure showed that these variables did not increase with the slight assist. Thus, increase in ventilation during the "assist" mode appeared to be due to alleviation of inspiratory obstruction at the level of the vocal cords. The same phenomenon was observed in the patient during phrenic nerve pacing. A pacemaker was designed to be triggered by the electromyographic impulse from an accessory muscle of respiration. In this manner, vocal cord opening could be coordinated with the mechanical assist given by the phrenic nerve pacer.

This study evaluated whether inspiratory muscle training (IMT) could increase inspiratory muscle strength and endurance and exercise performance in 11 patients with cystic fibrosis (CF) with moderately severe airflow limitation. The IMT consisted of breathing through an inspiratory resistance (IR) for 15 min twice daily for 4 wk, preceded or followed by a 4-wk control period. After IMT, there was an increase in inspiratory muscle strength measured by maximal inspiratory mouth pressure at functional residual capacity: 74 +/- 18 cmH2O before training to 81 +/- 12 cmH2O after training, mean +/- 1 SD, p less than 0.025, and in inspiratory muscle endurance measured by the maximal IR tolerated for 10 min. Limitation of performance in the progressive exercise test was related to increased airflow limitation and possibly to poor nutrition. Mean exercise performance during progressive or submaximal exercise testing did not change after training. It is concluded that this form of IMT improved inspiratory muscle strength and endurance, but had little effect on exercise performance in patients with CF.

We studied six patients with isolated bilateral paralysis or severe weakness of the diaphragm, present for 2 to 60 months (mean = 25), to document the clinical and respiratory sequelae of the condition. Severe diaphragm dysfunction was confirmed by the demonstration of the very low maximal transdiaphragmatic pressure (Pdi) generated by either a sniff (13 +/- 6 cm H2O, normal 148 +/- 24) or a static inspiration (11 +/- 8, normal 108 +/- 30) and during bilateral phrenic nerve stimulation (0.8 +/- 2.0, normal 22 +/- 4). Resting arterial blood gases were normal (SaO2 = 95 to 97%) and no oxygen desaturation occurred during maximal exercise on a treadmill. Maximum voluntary ventilation was low and related to PImax (r = 0.89). Overnight sleep monitoring showed that time spent in rapid eye movement sleep was normal (mean 55 +/- 36 min, range 26 to 117 min). Mean maximum increment in transcutaneous CO2 was within normal limits (6 +/- 2 mm Hg, range 3 to 9 mm Hg). Three patients had occasional brief episodes of oxygen desaturation (mean maximal decrease 13 +/- 10%, range 2 to 27%); however, only two of these spent a measurable proportion of total sleep time (TST) with an SaO2 of less than 80% (1% and 3% TST, respectively). No patient has developed any symptoms of nocturnal hypoventilation or chronic respiratory failure during periods of observation of up to five yr. We conclude that bilateral paralysis or very severe weakness of the diaphragm does not of itself lead to respiratory failure unless weakness of other respiratory muscles is present.

Breathlessness is a common complaint in patients with hyperthyroidism, and respiratory failure requiring artificial ventilation, although rare, can occur. While a proximal myopathy is frequently recognized, diaphragm muscle function has not hitherto been studied in detail in thyrotoxicosis. The strength of the quadriceps femoris and respiratory muscles was therefore assessed in seven consecutive thyrotoxic patients, on presentation and during medical treatment, when euthyroid. Prior to therapy, reduced quadriceps muscle strength, vital capacity, and global expiratory and inspiratory muscle strength were found. Diaphragmatic weakness was present in one of four patients studied by measuring transdiaphragmatic pressures during maximal sniffs and during bilateral phrenic nerve stimulation at 1 Hz (twitch). After treatment, significant improvement occurred in quadriceps muscle strength, vital capacity, and global respiratory muscle strength. Sniff and twitch transdiaphragmatic pressures also increased significantly. These results indicate that respiratory muscle weakness occurs in hyperthyroidism and that such weakness is reversible with medical treatment. It is important to realize that respiratory muscles may be directly affected when assessing thyrotoxic patients with breathlessness, as severe involvement of the respiratory muscles may cause respiratory failure.

To examine the relationship between inspiratory mechanical load in asthma and the pattern of respiratory muscle recruitment, we studied lung and chest wall mechanics in 7 asymptomatic asthmatics in whom progressive bronchoconstriction was induced with inhaled aerosolized histamine. A fall in the FEV1 to 49.5 +/- 3.9% of the control value (mean +/- 1 SE) was associated with a 10.7-fold increase in the inspiratory work rate of the inspiratory muscles from 6.7 +/- 1.6 to 71.4 +/- 11.4 Joules/min. Elastic work accounted for 69% of the total work during the control period and 57% at the maximal level of bronchoconstriction studied. The net pressure-time product for the inspiratory muscles, measured over 1 min, rose fivefold from 245 +/- 33 cmH2O.s to a maximum of 1,211 +/- 107 cmH2O.s, indicating a relatively greater increase in the recruitment of the intercostal/accessory muscles of inspiration. The abdominal muscles, which were recruited during bronchoconstriction, relaxed during inspiration, and permitted outward movement of the abdominal wall with progressively smaller net increases in Pga. We concluded that during induced asthma (1) the increase in inspiratory muscle work was largely the result of hyperinflation, (2) the recruitment of the intercostal/accessory muscles exceeded that of the diaphragm, and (3) the combined action of the intercostal/accessory and abdominal muscles favored the diaphragm.

One of the more unusual respiratory manifestations of systemic lupus erythematosus is "shrinking lungs." We report a patient with this syndrome and provide evidence for this being due to diaphragm dysfunction. Significant improvement occurred after albuterol therapy, providing new possibilities in the treatment of this syndrome. This is the first report in humans supporting animal work demonstrating that beta-agonists can improve diaphragmatic performance.

Using a special gastroesophageal catheter, electromyographic measurements of the diaphragm (Edi) and transdiaphragmatic pressure (Pdi) were taken in the supine, standing, erect sitting, and leaning forward (sitting) positions in 8 normal subjects and 6 patients with severe chronic obstructive pulmonary disease (COPD) with marked hyperinflation and low fat diaphragms. Four patients had pronounced postural relief of their dyspnea from assuming the supine and/or leaning forward positions. All 8 normal subjects and 4 of the 6 patients with COPD showed substantial (2- to 5-fold) increases in delta Edi, the phasic inspiratory amplitude of Edi, on assuming the standing and erect sitting postures. In the normal subjects, delta Pdi, the phasic inspiratory increment in Pdi, was maintained in all 4 postures, whereas in all patients with COPD, it decreased significantly in the erect sitting and standing postures. In 2 of the 6 patients with COPD, the delta Edi did not increase in the erect postures. This suggested that in these patients a reflex, which normally compensates for reduced diaphragmatic efficiency because of shortened muscle fibers in the erect postures, was not operating. Although it is not clear what mechanism(s) might account for suppression of this compensatory reflex, such reflex suppression might be advantageous from the viewpoint of diaphragmatic muscle energetics. The diaphragm would be thus spared energetically wasteful attempts to accomplish a fatiguing mechanical task.

We investigated the effects of aminophylline, isoproterenol, and neostigmine on decreased diaphragmatic contractility induced by hypercapnia. With the thorax open, the animal receiving mechanical ventilation, and a plaster cast around the abdomen, constant length and geometry of the diaphragm were maintained. Contractility was assessed by analysis of transdiaphragmatic pressure (Pdi) generated during supramaximal phrenic stimulation at different frequencies. Bilateral phrenectomy was performed to prevent spontaneous diaphragm movement. Hypercapnia (PaCO2, 85 mmHg) reduced Pdi by 10% at low and high frequencies of stimulation. Subsequently, aminophylline (20 mg/kg) restored Pdi to the control value at every frequency of stimulation (p less than 0.05), whereas neostigmine (0.25 and 1.0 mg) restored Pdi at low frequencies only (p less than 0.05). Isoproterenol did not improve Pdi at any frequency. Analysis of twitch characteristics revealed that hypercapnia reduced peak twitch amplitude by 17%, this being the underlying cause of the decrease in Pdi. Low and high doses of all 3 drugs significantly reversed this effect by improving peak twitch tension to values equal with or greater than control values (p less than 0.05). In addition, aminophylline (40 mg/kg) and neostigmine (0.25 and 1.0 mg) significantly increased time to peak tension of the twitch (p less than 0.05) and isoproterenol (5 and 20 micrograms/min) significantly decreased twitch half relaxation time (p less than 0.05). We conclude that aminophylline and neostigmine improve diaphragmatic contractility during hypercapnia by virtue of their potentiating effect on twitch amplitude, whereas isoproterenol does not increase contractility because the process underlying the decrease in twitch duration masks the effect of an improved twitch amplitude.

To define the roles of mechanical loading, respiratory neuromuscular control, and sleep apnea in the pathogenesis of obesity hypoventilation, respiratory muscle drive and output, assessed by diaphragmatic electromyogram (EMGdi) and mouth occlusion pressure (P 0.15), respectively, were determined during CO2 chemostimulation in nonobese volunteers who were subjected to abdominal mass loading, and in three groups of markedly obese patients: eucapnic obese without sleep apnea (O), eucapnic obese with sleep apnea (OSA), and hypercapnic obese with sleep apnea (OH). The P0.15 responses were decreased in OSA and OH, but the EMGdi responses were not significantly different from those in control subjects. In O patients EMGdi responses were significantly greater than those in control subjects as well as those in OSA and OH patients. EMGdi and P0.15 responses increased in all nonobese subjects when they were subjected to mass loading. We conclude that both OSA and OH patients were equally unable to develop the expected increase in respiratory muscle drive and output. The presence of sleep apnea, possibly by causing nocturnal hypoxemia and/or sleep fragmentation, may result in impaired mass load compensation and predispose obese patients to develop hypercapnia.

The effect of changes in continuous positive airway pressure (CPAP) on the tidal volume generation by the diaphragm during electrical stimulation of the phrenic nerves in a quadriplegic patient is presented. Measurements of tidal volume, end-tidal PCO2, arterial PCO2, oxygen consumption, physiologic dead space to tidal volume ratio, diaphragm length, and thoracic and abdominal dimensions were made at values of CPAP from 0 to 20 cm H2O during periods of diaphragm pacing. Total respiratory compliance (TRC) was measured during controlled ventilation with incremental positive end-expiratory pressure (PEEP) from 0 to 20 cm H2O. A significant negative correlation was found between increasing CPAP and generated tidal volumes. This correlation was seen to occur even when TRC was constant at degrees of CPAP from 0 to 7.5 cm H2O. When phrenic nerve stimulation was commenced, oxygen consumption rose significantly from values obtained during controlled ventilation, but there was no significant correlation between changes in CPAP and the rise in oxygen consumption. Using inductance methods, thoracic and abdominal diameters were seen to rise as CPAP was increased. As suggested by the decrease in the length of the vertical and horizontal portions of the diaphragm in the chest roentgenogram, the conformation of the diaphragm also changed. It is suggested that the operating length and conformation of the diaphragm are principal factors affecting tidal volume generation during electrical stimulation of the phrenic nerves.

Inspiratory muscle strength in COPD could be reduced either because of mechanical disadvantage consequent to increased lung volume or because respiratory muscles share in generalized muscle weakness. To assess the relative contributions of these factors, we measured maximal inspiratory and expiratory pressures (Pimax, Pemax, cmH2O) at RV and TLC, respectively, in 32 patients with COPD. The TLC, RV, and diaphragm length index at RV (DLI, cm/cm height) were determined roentgenographically and compared with values from 22 normal subjects studied at comparable lung volume. Half the patients with COPD had normal and half had low values of Pemax, but both groups had similar values of TLC, RV, and DLI. In patients with COPD, Pimax correlated (p less than 0.001) with Pemax (r = 0.73) and DLI (r = 0.64). The slope of the Pimax-DLI relationship was essentially the same in both groups of patients with COPD as it was in the normal subjects. However, at any value of DLI, Pimax was in the normal range in patients with normal Pemax, but significantly lower in patients with low Pemax (p less than 0.001). Expressing Pimax as a combined function of Pemax and DLI yielded the highest correlation (r = 0.84, p less than 0.001), with Pemax explaining 46% and DLI explaining 35% of the variance in Plmax not explained by the other variable alone (p less than 0.001). The PaCO2 was elevated in 13 of 18 patients whose Pimax was less than 55 cm H2O, and inversely correlated with Pimax (r = -0.66, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

In order to study the relationship between sleep-induced periodic breathing and the development of occlusive sleep apneas, 6 patients with hypersomnia-sleep apnea syndrome were studied during nocturnal sleep before and approximately 1 month after therapeutic tracheostomy. Post-tracheostomy studies were performed in open and closed tracheostomy states. Sleep-induced periodic breathing resembling the pattern of Cheyne-Stokes breathing was observed in all patients before and after tracheostomy, even when tracheostomy was left open. When tracheostomy was closed all patients developed periodic hypopneas with significant oxygen desaturation, and 4 patients developed occlusive apneas at the nadir of the periodic changes. However, apnea and desaturation indexes during closed tracheostomy were significantly lower than their respective pretracheostomy values. These results indicate that sleep-induced periodic breathing, which represents an instability of respiratory control, is primary to the development of occlusive apneas, and the periodically observed is exaggerated by hypoxemia. Comparison of pre- and post-tracheostomy studies indicate a significant improvement in the underlying disorder most likely caused by the elimination of nocturnal hypoxemia and sleep fragmentation.

In 7 conscious, unsedated goats with chronically implanted diaphragm electrodes, the effect of respiratory loading on the relationship between occlusion pressure and diaphragm EMG was studied. Diaphragm electrical activity (ED) quantified by the moving average technique was measured in separate trials during progressive hyperoxic hypercapnia and progressive isocapnic hypoxia, both before and after inspiratory resistance had been increased by externally applied loads. Airway occlusion was performed during inspiration on random breaths at functional residual capacity, and the maximum negative pressure (Pmax) was measured. In all 7 goats, occlusion pressure was greater with external loads (EL) than control. The peak ED of unoccluded breaths was greater with EL than control in all animals during hypoxia but in only 3 of the animals during hypercapnia. In half of the trials, the ratio of Pmax to ED of occluded or unoccluded breaths was higher with EL than control. In the remaining studies, the ratio was the same. FRC was unaffected by EL. In the one goat in which it was measured, intercostal EMG was also greater during EL than control. These results suggest that the inspiratory muscles other than the diaphragm are recruited during EL causing the Pmax to ED ratio to rise even if neuromechanical coupling remains unchanged. It is speculated that in conscious, unsedated animals, acute increases in the resistance to air flow affect the distribution of respiratory motor activity.

This report discusses mechanisms causing the airways to open during obstructive sleep apnea (OSAS). In 4 male patients with OSAS, 92 nonrapid eye movement (NERM) sleep apnea episodes and 37 rapid eye movement (REM) sleep apnea episodes were analyzed breath by breath during a one-night study. We calculated the pressure time index of the diaphragm (the product of inspiratory time/cycle duration (Tl/Ttot) and mean transdiaphragmatic pressure swing), evaluated the sleep stages via EEG, and performed frequency spectrum analysis of the EMG of the diaphragm. It was found that with each occluded inspiratory effort the tension time index of the diaphragm (TTdi) increased progressively to reach or slightly exceed the fatigue threshold, 0.15 to 0.18 (during NREM sleep the TTdi of the last occluded breath was 0.195 +/- 0.045 and during REM sleep the TTdi of the last occluded breath was 0.153 +/- 0.037); that a close time relationship was observed as well between the onset of arousal and the opening of the airways. Our data suggest that the airways may be triggered to open by a protective reflex originating in the larynx or the inspiratory muscles upon reaching a certain degree of contraction.

Electromyograms of the parasternal intercostal muscles and of the diaphragm were obtained with surface electrodes in 20 patients with early flaccid hemiplegia due to cerebrovascular accident. In most patients, a striking reduction in activity was observed during voluntary inspirations in both the intercostal muscles and the diaphragm on the side of the paresis. These findings suggest that in most persons the respiratory muscles are innervated primarily by decussated fibers. Dysfunction of the respiratory muscles might be implicated in the respiratory tract infections of patients with early hemiplegia.