Maximal Pdi Research Articles

Acute inhibition of autophagy impairs maximal diaphragm force generation in old mice

Transdiaphragmatic pressure (Pdi) measurements are used to determine diaphragm force generation across various motor behaviors. Previous studies in the diaphragm muscle found selective age-related changes at fast-twitch fatigable motor units including increased susceptibility to neuromuscular transmission failure and denervation. Accordingly, age-related changes at diaphragm motor units predominantly impair the ability to accomplish higher force behaviors, and these aging effects are evident prior to the onset of muscle atrophy. Recent findings suggest that autophagy plays a critical role in the development of age-related neuromuscular dysfunction; however, the possible contribution of autophagy impairment to the maintenance of diaphragm force generation in old age is unknown. We hypothesized that inhibition of autophagy (using chloroquine) decreases diaphragm force-generating capacity (Pdi) in mice susceptible to age-related neuromuscular dysfunction. Adult male and female C57BL/6 mice at 16-28 months of age were randomized to receive a single intraperitoneal injection of 50 mg/kg of chloroquine or vehicle (n= 9 per treatment group) four hours before Pdi measurements, with the experimenter blinded. Pdi was measured during eupnea (room air breathing), exposure to hypoxia/hypercapnia (10% O 2 /5% CO 2 ), tracheal occlusion, spontaneous deep breaths (“sighs”) and during maximal activation elicited by bilateral phrenic nerve stimulation. Consistent with our hypothesis, there was an ~25% reduction in maximal Pdi in the chloroquine group (46 ± 12 cm H 2 O) compared to the vehicle control (61 ± 16 cm H 2 O; p < 0.05). There was no effect of chloroquine on Pdi during eupnea, hypoxia/hypercapnia, tracheal occlusion, or sigh behaviors. Acute inhibition of autophagy results in reduced maximal Pdi, consistent with that evident in old mice. Thus, we propose that autophagy impairment may be an important contributor to the reduced diaphragm force generation associated with aging. These findings help us further understand the mechanisms regulating age-related neuromuscular dysfunction and may serve as a foundation to develop novel treatments to mitigate aging effects. Support: NIH R01 AG057052. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

22. LARGE-SCALE, MULTI-ETHNIC RESOURCE OF GENE, ISOFORM, AND SPLICING REGULATION IN THE DEVELOPING HUMAN BRAIN

The diaphragm muscle (DIAm) has a large reserve capacity for force generation such that in rats, the transdiaphragmatic pressure (Pdi) generated during ventilatory behaviors is less than 50% of maximal Pdi (Pdimax) elicited by bilateral phrenic nerve stimulation. Accordingly, we hypothesized that following unilateral denervation (DNV), the ability of the contralateral DIAm to generate sufficient Pdi to accomplish ventilatory behaviors will not be compromised and normal ventilation (as determined by arterial blood gas measurements) will not be impacted, although neural drive to the DIAm increases. In contrast, we hypothesized that higher force, non-ventilatory behaviors requiring Pdi generation greater than 50% of Pdimax will be compromised following DIAm hemiparalysis, i.e., increased neural drive cannot fully compensate for lack of force generating capacity. Pdi generated during ventilatory behaviors (eupnea and hypoxia (10% O2)–hypercapnia (5% CO2)) did not change after DNV and arterial blood gases were unaffected by DNV. However, neural drive to the contralateral DIAm, assessed by the rate of rise of root mean squared (RMS) EMG at 75 ms after onset of inspiratory activity (RMS75), increased after DNV (p < 0.05). In contrast, Pdi generated during higher force, non-ventilatory behaviors was significantly reduced after DNV (p < 0.01), while RMS75 was unchanged. These findings support our hypothesis that only non-ventilatory behaviors requiring Pdi generation greater than 50% of Pdimax are impacted after DNV. Clinically, these results indicate that an evaluation of DIAm weakness requires examination of Pdi across multiple motor behaviors, not just ventilation.

Aging and TrkB Signaling Effects on Autophagy Flux in Cervical Spinal Cord

Autophagy maintains cellular homeostasis by the elimination of damaged proteins or organelles. Our overarching hypothesis is that autophagy contributes to aging-related neuromuscular dysfunction. The mechanisms regulating autophagy flux are promising therapeutic targets to mitigate the effects of neuromuscular dysfunction across conditions such as aging. In previous studies, we found that autophagy flux is reduced in early old age (18-month old mice; 90% survival), with progressive autophagosome accumulation in old age evident by increased LC3 and p62 protein expression in cervical motor neurons (24-month old mice; 75% survival). Neurotrophins acting through the tropomyosin-related kinase receptor subtype B (TrkB) are critical to the maintenance of neuromuscular function including neuromuscular transmission in the diaphragm muscle and generation of maximal transdiaphragmatic pressure (Pdi), both in young and aged mice. Specifically, inhibition of TrkB signaling impairs maximal Pdi generation whereas activation of TrkB signaling blunts failure in neuromuscular transmission. We hypothesize that inhibiting TrkB kinase activity reduces autophagy flux resulting in increased LC3 and p62 expression, like the aging effects at phrenic motor neurons. TrkBF616A mice at 18- and 24- months of age, harboring a mutation that induces susceptibility to 1NMPP1-mediated TrkB kinase inhibition, were randomized to receive 1-week treatment with vehicle or 1NMPP1 (n=6 per age and treatment group). Protein expression of the autophagy markers LC3 and p62 in cervical spinal cord (CSC) segments C2-C6 was analyzed by Western blotting. There was a significant effect on LC3 and p62 expression of age, but not of 1NMPP1 treatment, and no age*treatment interaction. LC3B expression increased by ~50% and p62 expression increased by ~30% in 24 month-old compared to 18 month-old mice. These results are consistent with previous reports that there is an aging-related impairment of autophagy and accumulation of autophagosomes; however, inhibiting TrkB kinase activity does not modulate autophagy in these age groups. Understanding the role of TrkB signaling in mediating changes in autophagy and age-related neuromuscular dysfunction will be important in advancing potential therapeutic applications of TrkB agonists.

TrkB signaling contributes to transdiaphragmatic pressure generation in aged mice.

Ventilatory deficits are common in old age and may result from neuromuscular dysfunction. Signaling via the tropomyosin-related kinase receptor B (TrkB) regulates neuromuscular transmission and, in young mice, is important for the generation of transdiaphragmatic pressure (Pdi). Loss of TrkB signaling worsened neuromuscular transmission failure and reduced maximal Pdi, and these effects are similar to those observed in old age. Administration of TrkB agonists such as 7,8-dihydroxyflavone (7,8-DHF) improves neuromuscular transmission in young and old mice (18 mo; 75% survival). We hypothesized that TrkB signaling contributes to Pdi generation in old mice, particularly during maximal force behaviors. Old male and female TrkBF616A mice, with a mutation that induces 1NMPP1-mediated TrkB kinase inhibition, were randomly assigned to systemic treatment with vehicle, 7,8-DHF, or 1NMPP1 1 h before experiments. Pdi was measured during eupneic breathing (room air), hypoxia-hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths ("sighs"), and bilateral phrenic nerve stimulation (Pdimax). There were no differences in the Pdi amplitude across treatments during ventilatory behaviors (eupnea, hypoxia-hypercapnia, occlusion, or sigh). As expected, Pdi increased from eupnea and hypoxia-hypercapnia (∼7 cm H2O) to occlusion and sighs (∼25 cm H2O), with no differences across treatments. Pdimax was ∼50 cm H2O in the vehicle and 7,8-DHF groups and ∼40 cm H2O in the 1NMPP1 group (F8,74 = 2; P = 0.02). Our results indicate that TrkB signaling is necessary for generating maximal forces by the diaphragm muscle in old mice and are consistent with aging effects of TrkB signaling on neuromuscular transmission.NEW & NOTEWORTHY TrkB signaling is necessary for generating maximal forces by the diaphragm muscle. In 19- to 21-mo-old TrkBF616A mice susceptible to 1NMPP1-induced inhibition of TrkB kinase activity, maximal Pdi generated by bilateral phrenic nerve stimulation was ∼20% lower after 1NMPP1 compared with vehicle-treated mice. Treatment with the TrkB agonist 7,8-dihydroxyflavone did not affect Pdi generation when compared with age-matched mice. Inhibition of TrkB kinase activity did not affect the forces generated during lower force behaviors in old age.

Sex differences in diaphragmatic fatigue: Effects of hypoxia during inspiratory loading.

Under normoxic conditions, both healthy female and male diaphragms fatigue at a similar degree when matched for absolute diaphragmatic work during inspiratory loading. We investigated whether similarities in diaphragm fatigability persist under acute hypoxic conditions. We found that, in acute hypoxia, fatigue of the diaphragm is greater in women compared to men, whereas the magnitude of fatigue in normoxia did not differ between sexes. When matched for maximal diaphragm strength, women and men had a similar pressor response to work-matched inspiratory loading, independent of oxygen availability. In normoxia, women and men display a comparable magnitude of diaphragmatic fatigue (DF) after work-matched inspiratory loading. Whether these sex similarities are maintained under acute hypoxic conditions is unknown. We investigated the influence of acute hypoxia during work-matched inspiratory pressure-threshold loading (PTL) on DF in healthy women (n=8) and men (n=8). Two 5min isocapnic PTL tasks targeting a transdiaphragmatic pressure (Pdi ) of 92cmH2 O in normoxia and hypoxia (8% O2 ) were performed on separate days (≥48h). DF was quantified by twitch Pdi (Pdi,tw ) via cervical magnetic stimulation post-PTL. Women and men had similar maximal Pdi (Pdi,max ; women: 171±16, men: 178±20cmH2 O) and relative target workload (women: 54±5%, men: 53±6% Pdi,max ). The absolute cumulative diaphragmatic work did not differ between sexes in normoxia (women: 12,653±1796cmH2 Os-1 , men: 13,717±1231cmH2 Os-1 ; P=0.202) or hypoxia (women: 11,624±1860cmH2 Os-1 , men: 12 722±1502cmH2 Os-1 ; P=0.189). In normoxia, the magnitude of reduction in Pdi,tw post-PTL was similar between sexes (women: -21.1±8.4%, men: -22.5±4.9 %; P=0.193); however, a higher degree of DF was observed in women compared to men following PTL in acute hypoxia (women: -27.6±7.7%, men: -23.4±9.6%, P=0.019). We conclude that the female diaphragm is more susceptible to fatigue after inspiratory loading under acute hypoxic conditions. This finding may be related to sex differences in diaphragm muscle metabolism, such as fibre type composition, contractile properties, substrate utilisation and blood perfusion.

Maintenance of spontaneous breathing at an intensity of 60%-80% may effectively prevent mechanical ventilation-induced diaphragmatic dysfunction.

Controlled mechanical ventilation (CMV) can cause diaphragmatic motionlessness to induce diaphragmatic dysfunction. Partial maintenance of spontaneous breathing (SB) can reduce ventilation-induced diaphragmatic dysfunction (VIDD). However, to what extent SB is maintained in CMV can attenuate or even prevent VIDD has been rarely reported. The current study aimed to investigate the relationship between SB intensity and VIDD and to identify what intensity of SB maintained in CMV can effectively avoid VIDD. Adult rats were randomly divided according to different SB intensities: SB (0% pressure controlled ventilation (PCV)), high-intensity SB (20% PCV), medium-intensity SB (40% PCV), medium-low intensity SB (60% PCV), low-intensity SB (80% PCV), and PCV (100% PCV). The animals underwent 24-h controlled mechanical ventilation (CMV). The transdiaphragmatic pressure (Pdi), the maximal Pdi (Pdi max) when phrenic nerves were stimulated, Pdi/Pdi max, and the diaphragmatic tonus under different frequencies of electric stimulations were determined. Calpain and caspase-3 were detected using ELISA and the cross-section areas (CSAs) of different types of muscle fibers were measured. The Pdi showed a significant decrease from 20% PCV and the Pdi max showed a significant decrease from 40% PCV (P<0.05). In vivo and vitro diaphragmatic tonus exhibited a significant decrease from 40% PCV and 20% PCV, respectively (P<0.05). From 20% PCV, the CSAs of types I, IIa, and IIb/x muscle fibers showed significant differences, which reached the lowest levels at 100% PCV. SB intensity is negatively associated with the development of VIDD. Maintenance of SB at an intensity of 60%-80% may effectively prevent the occurrence of VIDD.

Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation.

Signaling via the tropomyosin-related kinase receptor subtype B (TrkB) regulates neuromuscular transmission, and inhibition of TrkB kinase activity by 1NMPP1 in TrkBF616A mice worsens neuromuscular transmission failure (NMTF). We hypothesized that acute inhibition of TrkB kinase activity will impair the ability of the diaphragm muscle to produce maximal transdiaphragmatic pressure (Pdi) without impacting the ability to generate forces associated with ventilation, consistent with the greater susceptibility to NMTF in motor units responsible for higher-force nonventilatory behaviors. Adult male and female TrkBF616A mice were injected with 1NMPP1 (n = 8) or vehicle (DMSO; n = 8) 1 h before Pdi measurements during eupneic breathing, hypoxia/hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths ("sighs") and during maximal activation elicited by bilateral phrenic nerve stimulation. In the vehicle-treated group, Pdi increased from ~10 cmH2O during eupnea and hypoxia/hypercapnia, to ~35 cmH2O during sighs and tracheal occlusion, and to ~65 cm H2O during maximal stimulation. There was no effect of acute 1NMPP1 treatment on Pdi generated during most behaviors, except during maximal stimulation (~30% reduction; P < 0.05). This reduction in maximal Pdi is generally similar to the worsening of NMTF previously reported with TrkB kinase inhibition in rodents. Accordingly, impaired TrkB signaling limits the range of motor behaviors accomplished by the diaphragm muscle and may contribute to neuromuscular dysfunction, primarily by impacting fatigable, higher force-generating motor units.NEW & NOTEWORTHY TrkB signaling plays an important role in maintaining neuromuscular function in the diaphragm muscle and may be necessary to accomplish the various motor behaviors ranging from ventilation to expulsive, behaviors requiring near-maximal forces. This study shows that inhibition of TrkB kinase activity impairs maximal pressure generation by the diaphragm muscle, but the ability to generate the lower pressures required for ventilatory behaviors is not impacted.

Impact of aging on diaphragm muscle function in male and female Fischer 344 rats.

The diaphragm muscle (DIAm) is the primary inspiratory muscle in mammals and is active during ventilatory behaviors, but it is also involved in higher‐force behaviors such as those necessary for clearing the airway. Our laboratory has previously reported DIAm sarcopenia in rats and mice characterized by DIAm atrophy and a reduction in maximum specific force at 24 months of age. In Fischer 344 rats, these studies were limited to male animals, although in other studies, we noted a more rapid increase in body mass from 6 to 24 months of age in females (~140%) compared to males (~110%). This difference in body weight gain suggests a possible sex difference in the manifestation of sarcopenia. In mice, we previously measured transdiaphragmatic pressure (Pdi) to evaluate in vivo DIAm force generation across a range of motor behaviors, but found no evidence of sex‐related differences. The purpose of this study in Fischer 344 rats was to evaluate if there are sex‐related differences in DIAm sarcopenia, and if such differences translate to a functional impact on Pdi generation across motor behaviors and maximal Pdi (Pdimax) elicited by bilateral phrenic nerve stimulation. In both males and females, DIAm sarcopenia was apparent in 24‐month‐old rats with a ~30% reduction in both maximum specific force and the cross‐sectional area of type IIx and/or IIb fibers. Importantly, in both males and females, Pdi generated during ventilatory behaviors was unimpaired by sarcopenia, even during more forceful ventilatory efforts induced via airway occlusion. Although ventilatory behaviors were preserved with aging, there was a ~20% reduction in Pdimax, which likely impairs the ability of the DIAm to generate higher‐force expulsive airway clearance behaviors necessary to maintain airway patency.

Compensatory plasticity in diaphragm and intercostal muscle utilization in a rat model of ALS

In SOD1G93A transgenic rat model of ALS, breathing capacity is preserved until late in disease progression despite profound respiratory motor neuron (MN) cell death. To explore mechanisms preserving breathing capacity, we assessed inspiratory EMG activity in diaphragm and external intercostal T2 (EIC2) and T5 (EIC5) muscles in anesthetized SOD1G93A rats at disease end-stage (20% decrease in body mass). We hypothesized that despite significant phrenic motor neuron loss and decreased phrenic nerve activity, diaphragm electrical activity and trans-diaphragmatic pressure (Pdi) are maintained to sustain ventilation. We alternatively hypothesized that EIC activity is enhanced, compensating for impaired diaphragm function. Diaphragm, EIC2 and EIC5 muscle EMGs and Pdi were measured in urethane-anesthetized, spontaneously breathing female SOD1G93A rats versus wild-type littermates during normoxia (arterial PO2 ~90mmHg, PCO2 ~45mmHg), maximal chemoreceptor stimulation (MCS: 10.5% O2/7% CO2), spontaneous augmented breaths and sustained tracheal occlusion. Phrenic MNs were counted in C3-5; T2 and T5 ventrolateral MNs were counted. In end-stage SOD1G93A rats, 29% of phrenic MNs survived (vs. wild-type), yet integrated diaphragm EMG amplitude was normal. Nevertheless, maximal Pdi decreased ~30% vs. wild type (p<0.01) and increased esophageal to gastric pressure ratio (p<0.05), consistent with persistent diaphragm weakness. Despite major T2 and T5 MN death, integrated EIC2 (100% greater than wild type) and EIC5 (300%) EMG amplitudes were increased in mutant rats during normoxia (p<0.01), possibly compensating for decreased Pdi. Thus, despite significant phrenic MN loss, diaphragm EMG activity is maintained; in contrast, Pdi was not, suggesting diaphragm dysfunction. Presumably, increased EIC EMG activity compensated for persistent diaphragm weakness. These adjustments contribute to remarkable preservation of breathing ability despite major respiratory motor neuron death and diaphragm dysfunction.

Altered activation of the diaphragm in late-onset Pompe disease

Pompe disease is an inherited neuromuscular disorder that affects respiratory function and leads to dependence on external ventilatory support. We studied the activation of the diaphragm using bilateral phrenic magnetic stimulation and hypothesized that diaphragm compound muscle action potential (CMAP) amplitude and evoked transdiaphragmatic pressure (Twitch PDI) would correlate to disease severity. Eight patients with late onset Pompe disease (LOPD, aged 14–48 years) and four healthy control subjects completed the tests. Maximal Twitch PDI responses were progressively reduced in patients with LOPD compared to control subjects (1.4–17.1cm H2O, p<0.001) and correlated to voluntary functional tests (p<0.05). Additionally, CMAP amplitude (mA) was lower in the patients who used nighttime or fulltime ventilatory support, when compared to controls and patients who used no ventilatory support (p<0.005). However, the normalized (%peak) Twitch PDI and CMAP responses were similar between patients and controls. This suggests a loss of functional phrenic motor units in patients, with normal recruitment of remaining motor units.

Impact of unilateral denervation on transdiaphragmatic pressure

The diaphragm muscle (DIAm) has a large reserve capacity for force generation such that in rats, the transdiaphragmatic pressure (Pdi) generated during ventilatory behaviors is less than 50% of maximal Pdi (Pdimax) elicited by bilateral phrenic nerve stimulation. Accordingly, we hypothesized that following unilateral denervation (DNV), the ability of the contralateral DIAm to generate sufficient Pdi to accomplish ventilatory behaviors will not be compromised and normal ventilation (as determined by arterial blood gas measurements) will not be impacted, although neural drive to the DIAm increases. In contrast, we hypothesized that higher force, non-ventilatory behaviors requiring Pdi generation greater than 50% of Pdimax will be compromised following DIAm hemiparalysis, i.e., increased neural drive cannot fully compensate for lack of force generating capacity. Pdi generated during ventilatory behaviors (eupnea and hypoxia (10% O2)–hypercapnia (5% CO2)) did not change after DNV and arterial blood gases were unaffected by DNV. However, neural drive to the contralateral DIAm, assessed by the rate of rise of root mean squared (RMS) EMG at 75ms after onset of inspiratory activity (RMS75), increased after DNV (p<0.05). In contrast, Pdi generated during higher force, non-ventilatory behaviors was significantly reduced after DNV (p<0.01), while RMS75 was unchanged. These findings support our hypothesis that only non-ventilatory behaviors requiring Pdi generation greater than 50% of Pdimax are impacted after DNV. Clinically, these results indicate that an evaluation of DIAm weakness requires examination of Pdi across multiple motor behaviors, not just ventilation.

Unilateral diaphragm muscle paralysis minimally impacts ventilation in rodents (871.5)

Ventilatory behaviors across a range of species including humans require less than 50% of maximal force‐generating capacity by the diaphragm muscle, the main inspiratory muscle in mammals. Near maximal forces are only generated during expulsive behaviors usually associated with airway clearance. There is ongoing controversy regarding the impact of unilateral lesions (e.g., spinal cord injury, denervation) on ventilatory outcomes. We hypothesized that unilateral denervation of the diaphragm muscle in rats and mice would minimally impact ventilation. Transdiaphragmatic pressure (Pdi) measurements were used to estimate diaphragm muscle force in adult male rats and mice. Following acute, unilateral phrenic nerve transection in the neck, there was no change in Pdi during eupnea or hypoxia‐hypercapnia in rats or mice. Reduced Pdi was evident during deep breaths and tracheal occlusion (behaviors associated with ~70% of maximal Pdi elicited by bilateral phrenic nerve stimulation) in both species. These results are also consistent with the lack of changes in tidal volume or respiratory pattern during eupnea measured by whole body plethysmography in unrestrained, spontaneously breathing rats after mid‐cervical contusion or hemisection injuries. These results highlight the large reserve capacity for force generation by the diaphragm muscle in rodents and the importance of measuring multiple motor behaviors.Grant Funding Source: Supported by HL096750, AG044615, HL105355 and Mayo Center for Regenerative Medicine

Assessment of neural respiratory drive in humans

Assessment of neural respiratory drive is useful for diagnosis of dyspnea and respiratory failure with unknown causes. The purpose of the study was to compare the sensitivity of trandiaphragmatic pressure (Pdi) and diaphragm electromyogram (EMGdi) in assessment of neural respiratory drive. A combined catheter with 10 electrodes and 2 balloons was used to record EMGdi and Pdi during CO2 rebreathing. Three different inspiratory maneuvers-inspiration from functional residual capacity to total lung capacity (TLC), deep inspiration from functional residual capacity against closed airway (MIP), and short sharp inspiration through the nose (Sniff) were performed. Ten healthy subjects [male 4 and female 6; age (26 ± 4) years] were studied. Linear relationship between EMGdi and end-tidal CO2 (r = 0.83-0.98, all P < 0.01) was better than that between Pdi and end-tidal CO2 (r = 0.48-0.96, all P < 0.01) during CO2 rebreathing, Z = -2.731, P < 0.05. The slope of linear relation between EMGdi and end-tidal CO2 (16.3-32.5) was significantly higher than that between Pdi and end-tidal CO2 (0.4-11.1), Z = -3.780, P < 0.01. The maximal EMGdi derived from TLC maneuver (211 ± 48) µV was larger than those from the MIP maneuver (161 ± 48) µV and the Sniff maneuver (145 ± 37) µV, F = 5.931, P < 0.05, whereas the maximal Pdi derived from TLC maneuver (58 ± 27) cm H2O (1 cm H2O = 0.098 kPa) was significantly lower than those from the MIP maneuver (92 ± 32) cm H2O and the Sniff maneuver (95 ± 27) cm H2O, F = 5.155, P < 0.05. EMGdi is more sensitive than Pdi in the assessment of neural respiratory drive.

Optimal arrangement of magnetic coils for functional magnetic stimulation of the inspiratory muscles in dogs

In an attempt to maximize inspiratory pressure and volume, the optimal position of a single or of dual magnetic coils during functional magnetic stimulation (FMS) of the inspiratory muscles was evaluated in twenty-three dogs. Unilateral phrenic magnetic stimulation (UPMS) or bilateral phrenic magnetic stimulation (BPMS), posterior cervical magnetic stimulation (PCMS), anterior cervical magnetic stimulation (ACMS) as well as a combination of PCMS and ACMS were performed. Trans-diaphragmatic pressure (Pdi), flow, and lung volume changes with an open airway were measured. Transdiaphragmatic pressure was also measured with an occluded airway. Changes in inspiratory parameters during FMS were compared with 1) electrical stimulation of surgically exposed bilateral phrenic nerves (BPES) and 2) ventral root electrical stimulation at C5-C7 (VRES C5-C7). Relative to the Pdi generated by BPES of 36.3 +/- 4.5 cm H2O (Mean +/- SEM), occluded Pdi(s) produced by UPMS, BPMS, PCMS, ACMS, and a combined PCMS + ACMS were 51.7%, 61.5%, 22.4%, 100.3%, and 104.5% of the maximal Pdi, respectively. Pdi(s) produced by UPMS, BPMS, PCMS, ACMS, and combined ACMS + PCMS were 38.0%, 45.2%, 16.5%, 73.8%, and 76.8%, respectively, of the Pdi induced by VRES (C5-C7) (48.0 +/- 3.9 cm H2O). The maximal Pdi(s) generated during ACMS and combined PCMS + ACMS were higher than the maximal Pdi(s) generated during UPMS, BPMS, or PCMS (p < 0.05). ACMS alone induced 129.8% of the inspiratory flow (73.0 +/- 9.4 L/ min) and 77.5% of the volume (626 +/- 556 ml) induced by BPES. ACMS and combined PCMS + ACMS produce a greater inspiratory pressure than UPMS, BPMS or PCMS. ACMS can be used to generate sufficient inspiratory pressure, flow, and volume for activation of the inspiratory muscles.

Respiratory Effects of Combined Truncal and Abdominal Support in Patients With Spinal Cord Injury

Hart N, Laffont I, Perez de La Sota A, Lejaille M, Macadou G, Polkey MI, Denys P, Lofaso F. Respiratory effects of combined truncal and abdominal support in patients with spinal cord injury. Objective To determine whether a custom girdle, designed to provide truncal stability and abdominal support, will improve pulmonary function, enhance inspiratory muscle activity, and reduce the sensation of respiratory effort in patients with spinal cord injury (SCI). Design Pulmonary function, transdiaphragmatic pressure time product (PTP di), twitch (Tw Pdi) and maximal transdiaphragmatic pressures (Pdi), and perception of respiratory effort (Borg Rating of Perceived Exertion score) were measured with and without an abdominal girdle in a seated position. Setting Rehabilitation hospital. Participants Ten patients with posttrauma SCI (injury level, C5–T6). Intervention Application of the abdominal girdle. Main Outcome Measures Borg score and measures of lung volumes, dynamic abdominal compliance, and Tw Pdi and maximal Pdi. Results Wearing of the girdle was associated with a lower Borg score ( P=.002) and reduced functional residual capacity ( P=.006) but increased inspiratory capacity ( P=.02) and forced vital capacity ( P=.02). Although there was a decrease in dynamic abdominal compliance ( P<.001) and an increase in PTP di ( P=.02), this was accompanied by an increase in both Tw Pdi ( P=.02) and maximal Pdi ( P=.03). Conclusions The custom girdle reduced the sensation of respiratory effort in patients with SCI by optimizing the operating lung volumes and decreasing abdominal compliance, which enhanced diaphragm performance.

Tests of Respiratory Muscle Strength In Neonates

After completing this article, readers should be able to: 1. Describe the underlying cause of respiratory failure in about 50% of preterm infants who require intubation and mechanical ventilation. 2. Compare compliance characteristics of the chest wall in infants, older children, and adults. 3. List some of the conditions seen in neonates that can adversely affect respiratory muscle function. 4. List noninvasive tests for assessing respiratory muscle strength in neonates. Chest wall mechanics of neonates and infants play an essential role in ventilation that frequently is underappreciated. Dysfunction of the respiratory muscles can cause both a disease process and an inability of the patient to compensate for it. As an example, respiratory muscle failure may be the underlying cause in about 50% of preterm infants who have ventilatory failure. (1) In this article, we detail the current understanding of the physiology of the respiratory muscles in neonates and discuss a number of tests designed to assess their function. Mechanically, the respiratory system can be thought of as being composed of two components. The first includes the respiratory muscles, the rib cage, and the anterior abdominal wall, which together make up the “pump,” whose function is to move air in and out of the lungs. The second includes the airways and lung parenchyma through which gas exchange occurs and can be referred to as the “load” on which the pump must act. For ventilation to occur, the respiratory pump must overcome both the frictional (eg, airway resistance) and tissue elastic forces (eg, lung and chest wall compliance) that create the load. The balance between the capabilities of the pump and the magnitude of the load can influence whether respiratory “success” or “failure” occurs. The chest wall, which contains muscles and skeletal structures, undergoes dramatic maturational changes over the first several years of life. In addition …

Effects of Emphysema and Lung Volume Reduction Surgery on Transdiaphragmatic Pressure and Diaphragm Length

To determine the effect of emphysema and lung volume reduction surgery (LVRS) on diaphragm length (Ldi) and its capacity to generate transdiaphragmatic pressure (Pdi). Prospective clinical trial with a parallel group design. Laboratory investigations in normal volunteers recruited by advertisement and in emphysema outpatients being evaluated for elective LVRS. Thirteen normal subjects and 13 emphysema patients matched for age and sex. Six emphysema patients underwent LVRS. Ldi and maximal Pdi during static inspiratory efforts (PdiMax) were measured at three different lung volumes (LVs). Pdi during maximal bilateral phrenic nerve twitch stimulation (PdiTw) was measured at functional residual capacity (FRC). All measurements were repeated at 3, 6, and 12 months postoperatively. Ldi, PdiMax, and PdiTw were lower in emphysema patients than in normal subjects at their respective LVs. PdiMax and PdiTw at FRC returned within the normal range after LVRS in emphysema patients. The relationships between PdiMax and LV or Ldi were shifted respectively to higher LV and shorter Ldi in emphysema patients relative to normal subjects, both before and after LVRS. LVRS effected craniad displacement of the diaphragm but no change in rib cage dimensions. Improvements in dyspnea and quality of life after LVRS correlated with changes in LV and Ldi but not with changes in airway caliber. Adaptive mechanisms, consistent with sarcomere deletion, tend to restore diaphragm strength in emphysema patients at FRC, which are fully expressed after LVRS. Lung remodeling by LVRS may alter pleural surface pressure distribution, causing a sustained change in chest wall shape.

Physiologic Evaluation of 4 Weeks of Nocturnal Nasal Positive Pressure Ventilation in Stable Hypercapnic Patients with Chronic Obstructive Pulmonary Disease

Background: The long-term daily use of noninvasive mechanical ventilation (NIMV) to treat chronic respiratory failure in chronic obstructive pulmonary disease (COPD) patients is not widely recommended, partly because of a lack of clear clinical results and partly because the physiological mechanisms by which the daily application of NIMV would be helpful in these patients have not yet been clarified. Objectives: We designed a physiological study in order to assess the effects of supervised long-term NIMV on gas exchange, respiratory muscle function, pulmonary mechanics and to ascertain the possible effect of the treatment in responders and nonresponders. Methods: Fourteen consecutive inpatients with stable hypercapnic COPD (pH = 7.37 ± 0.01; PaCO₂ = 56.73 ± 6.48 mm Hg) underwent 4 weeks of nocturnal NIMV delivered with a bilevel ventilator ‘physiologically’ set to reduce tidal transdiaphragmatic pressure (Pdi) by at least 50% and the amount of dynamic intrinsic positive end-expiratory pressure by 70%. Various measurements were compared with those obtained in a control group of consecutive patients with comparable baseline characteristics who refused NIMV and underwent breathing exercises for the same period of time. Results: By the end of the 4 weeks NIMV had induced a slight but significant (p < 0.01) reduction in resting PaCO₂ (53.78 ± 5.64 mm Hg) associated with a decrease in the pressure time product of the diaphragm per minute (from 172 ± 60 to 136 ± 61 cm H₂O/l/s; p < 0.05). This latter value was primarily due to a significant shortening of the inspiratory duty cycle, while Pdi and lung mechanics were not modified. Eight of the 13 NIMV-treated patients (1 dropped out for nonmedical reasons) had a clear reduction in PaCO₂ (>3 mm Hg or >5% from enrollment) and were classified as responders. The acute reduction in PaCO₂ during the first trial with NIMV resulted to be a strong index of the final response. The subgroup of responders had a significantly increased maximal Pdi (from 41 ± 19 to 49 ± 23 cm H₂O, p < 0.05) and an enhanced ability of the ventilatory pump to clear CO₂ (9.7 ± 3.4 vs. 7.2 ± 2.9 cm H₂O × s/min; p < 0.01). No significant changes were observed in the control group. Conclusions: These results suggest that in a remarkable and identifyable proportion of patients with stable hypercapnic COPD, nocturnal NIMV may decrease resting PaCO₂, reraising the role of chronically supporting the respiratory pump.

Respiratory muscle function and dyspnea in patients with chronic congestive heart failure.

Patients with heart failure (HF) frequently experience exertional dyspnea. Using near-infrared spectroscopy, we have previously demonstrated accessory respiratory muscle deoxygenation during exercise in these patients by monitoring changes in light absorption at 760-800 nm. To investigate whether low-frequency respiratory muscle fatigue occurs, we performed supramaximal bilateral transcutaneous phrenic nerve stimulation before and after maximal bicycle exercise in 10 patients with HF (age, 62 +/- 10 years; ejection fraction, 18 +/- 7%) and six normal subjects (age, 50 +/- 8 years). Maximal rates of contraction and relaxation, peak twitch tension, and maximal transdiaphragmatic pressure (Pdi) were derived before and after exercise from analysis of six to 12 twitches obtained at functional residual capacity. Pdi, time in inspiration (Ti), time per breath (TTOT), respiratory gases, ratings of perceived dyspnea and fatigue, and 760-800 nm near-infrared spectroscopy absorbency changes of the serratus anterior muscle were measured throughout exercise. The tension time index (TTdi) of the diaphragm was derived. In both normal and HF subjects, all parameters of diaphragmatic function (i.e., maximal rates of contraction and relaxation, peak twitch tension, and maximal Pdi) were unchanged before and after exercise. Mean Pdi was comparable at rest (normal, 3.7 +/- 1; HF, 5.8 +/- 2.9 cm H2O; p = NS) but significantly greater in patients with HF at peak exercise (normal, 12.1 +/- 3; HF, 18.3 +/- 6.6 cm H2O; p less than 0.05). Ti/TTOT of both groups was similar at rest and throughout exercise. TTdi was significantly greater at rest (normal, 0.01 +/- 0.01; HF, 0.03 +/- 0.02; p less than 0.05) and at peak exercise (normal, 0.03 +/- 0.02; HF, 0.10 +/- 0.03; p less than 0.04) in patients with HF. Significant accessory respiration muscle deoxygenation was noted only in patients with HF (peak exercise; normal, -1 +/- 13; HF, 28 +/- 15 arbitrary units; p less than 0.01). Linear correlation analysis was performed between ratings of perceived dyspnea and parameters of pulmonary and diaphragmatic function. Significant correlations were observed between ratings of perceived dyspnea and maximal inspiratory and expiratory pressure, the TTdi of the diaphragm, near-infrared absorption changes, and forced expiratory volume in 1 second (FEV1) (all r greater than 0.5; p less than 0.05). Thus, respiratory muscle strength, work, and oxygenation were significantly correlated with the degree of dyspnea. We conclude that low-frequency diaphragmatic muscle fatigue does not occur despite accessory respiratory muscle deoxygenation during exercise in patients with HF. However, diaphragmatic work as assessed by the TTdi is dramatically increased in patients with HF and approaches levels previously shown to generate fatigue. The sensation of dyspnea appears closely related to respiratory muscle function.

Optimal diaphragmatic blood perfusion.

The intrabreath time course of phrenic artery blood perfusion (Qpha) was studied in five anesthetized dogs. The diaphragm was paced with submaximal levels of stimulation at various duty cycles (DC) to achieve tension-time index below and above the fatigue threshold (0.03-0.60). Left Qpha was measured via Doppler technique during control (inactive diaphragm) and during two submaximal levels of bilateral phrenic nerve stimulation sustained for 1 min. Measurements were done when Qpha reached steady state in each run. The frequency of pacing of each run was 10/min, and the DC ranged from 0.1 to 0.9 in 0.1 increments. Shortening of costal and crural segments was measured by sonomicrometry. It was found that Qpha during the diaphragmatic contraction phase (QphaC) was a sigmoidal function of DC and was not affected by the levels of transdiaphragmatic pressure (Pdi) explored (34-64% of maximal Pdi). Qpha during the diaphragmatic relaxation phase (QphaR) was a parabolic function of the DC, reaching an optimal value at DC of approximately 0.3 at any given Pdi. QphaR increased significantly with the preceding level of Pdi. QphaT (the sum of QphaC and QphaR) was a parabolic function of DC, reaching peak values at DC of 0.4-0.6 and then decreasing. This function was similar at two levels of Pdi. Post-pacing hyperemia was directly related to tension-time index greater than 0.20.