Diaphragm Contractile Properties Research Articles

Mucopolysaccharidosis (MPS IIIA) mice have increased lung compliance and airway resistance, decreased diaphragm strength, and no change in alveolar structure.

Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease.NEW & NOTEWORTHY Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age.

Respiratory Muscle Contraction Characteristics and Potential Mechanisms in Severely Burned Rats.

Postburn hypermetabolism remains an important clinical problem. During this phase, there is a significant loss of diaphragmatic proteins. Better understanding of respiratory muscle dynamics and potential mechanisms affecting respiratory muscle function is necessary for the development of effective therapeutic approaches. Male Wistar rats were subjected to 50% TBSA burns and sham injuries, and respiratory muscle function was assessed with 0, 1, 4, 7, and 14 days postinjury, including pulmonary function, blood gas analysis, transdiaphragmatic pressure, diaphragm ultrasonography, isolated diaphragm contractility, fatigue index, protein oxidative stress content, and ATP levels. Burned rats had significantly reduced inspiratory time, expiratory time, and tidal volume and significantly increased respiratory rate and minute ventilation. At the same time, the isolated diaphragm contractility, specific force during fatigue, and fatigue index were significantly decreased in the burned rats. Pdi, Pdimax, diaphragm thickness, diaphragm thickening fraction, and diaphragm excursion also decreased significantly postburn, whereas the Pdi/Pdimax ratio increased significantly. Finally, the content of protein carbonyls and lactic acid of burned rats was increased, and ATP levels of burned rats were decreased. The present study demonstrates the dynamic changes in diaphragm contractile properties postburn from both in vivo and in vitro perspectives, while cursorily exploring the possibility that protein oxidative stress and reduced ATP production may be the cause of diaphragm dysfunction. This understanding contributes to the development of methods to mitigate the extent of diaphragmatic function loss after severe burns.

Ultrasonographic assessment of diaphragmatic contraction and relaxation properties: correlations of diaphragmatic displacement with oesophageal and transdiaphragmatic pressure

Transdiaphragmatic (Pdi) and oesophageal pressures (Pes) are useful in understanding the pathophysiology of the respiratory system. They provide insight into respiratory drive, intrinsic positive end-expiratory pressure, diaphragmatic fatigue and weaning...

Dietary nitrate supplementation increases diaphragm peak power in old mice.

Respiratory muscle function declines with ageing, contributing to breathing complications in the elderly. Here we report greater in vitro respiratory muscle contractile function in old mice receiving supplemental NaNO3 for 14days compared with age-matched controls. Myofibrillar protein phosphorylation, which enhances contractile function, did not change in our study - a finding inconsistent with the hypothesis that this post-translational modification is a mechanism for dietary nitrate to improve muscle contractile function. Nitrate supplementation did not change the abundance of calcium-handling proteins in the diaphragm of old mice, in contrast with findings from the limb muscles of young mice in previous studies. Our findings suggest that nitrate supplementation enhances myofibrillar protein function without affecting the phosphorylation status of key myofibrillar proteins. Inspiratory muscle (diaphragm) function declines with age, contributing to ventilatory dysfunction, impaired airway clearance, and overall decreased quality of life. Diaphragm isotonic and isometric contractile properties are reduced with ageing, including maximal specific force, shortening velocity and peak power. Contractile properties of limb muscle in both humans and rodents can be improved by dietary nitrate supplementation, but effects on the diaphragm and mechanisms behind these improvements remain poorly understood. One potential explanation underlying the nitrate effects on contractile properties is increased phosphorylation of myofibrillar proteins, a downstream outcome of nitrate reduction to nitrite and nitric oxide. We hypothesized that dietary nitrate supplementation would improve diaphragm contractile properties in aged mice. To test our hypothesis, we measured the diaphragm function of old (24months) mice allocated to 1mm NaNO3 in drinking water for 14days (n=8) or untreated water (n=6). The maximal rate of isometric force development (∼30%) and peak power (40%) increased with nitrate supplementation (P<0.05). There were no differences in the phosphorylation status of key myofibrillar proteins and abundance of Ca2+-release proteins in nitrate vs. control animals. In general, our study demonstrates improved diaphragm contractile function with dietary nitrate supplementation and supports the use of this strategy to improve inspiratory function in ageing populations. Additionally, our findings suggest that dietary nitrate improves diaphragm contractile properties independent of changes in abundance of Ca2+-release proteins or phosphorylation of myofibrillar proteins.

Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles

There is a persistent, aberrant accumulation of V0/V1 versican in skeletal muscles from patients with Duchenne muscular dystrophy and in diaphragm muscles from mdx mice. Versican is a provisional matrix protein implicated in fibrosis and inflammation in various disease states, yet its role in the pathogenesis of muscular dystrophy is not known. Here, female mdx and male hdf mice (haploinsufficient for the versican allele) were bred. In the resulting F1 mdx-hdf male pups, V0/V1 versican expression in diaphragm muscles was decreased by 50% compared to mdx littermates at 20–26 weeks of age. In mdx-hdf mice, spontaneous physical activity increased by 17% and there was a concomitant decrease in total energy expenditure and whole-body glucose oxidation. Versican reduction improved the ex vivo strength and endurance of diaphragm muscle strips. These changes in diaphragm contractile properties in mdx-hdf mice were associated with decreased monocyte and macrophage infiltration and a reduction in the proportion of fibres expressing the slow type I myosin heavy chain isoform. Given the high metabolic cost of inflammation in dystrophy, an attenuated inflammatory response may contribute to the effects of versican reduction on whole-body metabolism. Altogether, versican reduction ameliorates the dystrophic pathology of mdx-hdf mice as evidenced by improved diaphragm contractile function and increased physical activity.

Sedation with midazolam worsens the diaphragm function than dexmedetomidine and propofol during mechanical ventilation in rats

BackgroundMechanical ventilation (MV) is identified as an independent contributor to diaphragmatic atrophy and contractile dysfunction. Appropriate sedation is also essential during MV, and anesthetics may have direct adverse effects on the diaphragm. However, there is a lack of research into the effects of different anesthetics on diaphragm function during MV. ObjectivesIn the present study, we aim to examine the effect of midazolam, dexmedetomidine, and propofol on diaphragm function during MV. DesignAnimal study. SettingUniversity research laboratory. SubjectsMale Wistar rats. InterventionsAnimals were experienced 12 h of MV or spontaneous breathing (SB) with continuous anesthetics infusion. Diaphragm contractile properties, cross-sectional areas, microcirculation, oxidative stress, and proteolysis were examined. Measurements and main resultsDiaphragmatic specific force was markedly reduced in the midazolam group compared with the dexmedetomidine (−60.4 ± 3.01%, p < 0.001) and propofol group (−58.3 ± 2.60%, p < 0.001) after MV. MV sedated with midazolam induced more atrophy of type II fibers compared with dexmedetomidine (−21.8 ± 2.11%, p = 0.0001) and propofol (−8.2 ± 1.53%, p = 0.003). No significant differences of these indices were found in the midazolam, dexmedetomidine, and propofol groups under SB condition (all p > 0.05, respectively). Twelve hours of MV resulted in a time dependent reduction in diaphragmatic functional capillary density (PB −25.1%, p = 0.0001; MZ −21.6%, p = 0.0003; DD −15.2%, p = 0.022; PP −24.8%, p = 0.0001, respectively), which did not occur in the gastrocnemius muscle. The diaphragmatic lipid peroxidation adducts 4-HNE and HIF-1α levels were significantly lower in dexmedetomidine group and propofol group compared to midazolam group (p < 0.05, respectively). Meanwhile, the catalase and SOD levels were also relatively lower (p < 0.05, respectively) in midazolam group compared to dexmedetomidine group and propofol group. ConclusionsTwelve hours of mechanical ventilation during midazolam sedation led to a more severe diaphragm dysfunction than dexmedetomidine and propofol, possibly caused by its relative weaker antioxidant capacity.

Diaphragm Muscle Contraction Decrease in a Mouse Model of Ovalbumin-Induced Allergic Airway Inflammation

Objective: We investigated diaphragm contractile and inflammatory properties of mice with OVA sensitization and challenge. Methods: BALB/c mice were sensitized to OVA by intraperitoneal (i.p.) injection at 0 and 7 days, and challenged with aerosolized OVA on 21, 22, and 23 days (O/O group). Budesonide/Formoterol combination was inhaled on days 21, 22, and 23 before OVA challenge on those same days (O/OC group). Control mice were sensitized and challenged with an aerosolized saline (O-group). The diaphragm contractile and inflammatory properties were measured on day 24. NOS activity in the diaphragm muscle was evaluated by NADPH diaphorase staining. IL-4 and IL-13 levels of BALF, as well as lung tissue and diaphragm muscle homogenates were measured by ELISA. Results: Force-frequency (F/f) curves of O/O and O/OC shifted downward in comparison with O- (p<0.05). NADPH diaphorase staining results of O/O and O/OC showed a significantly higher density compared with O-. The IL-4 level of diaphragm muscle homogenates increased significantly in the O/O compared with the O- and O/OC. Conclusions: OVA sensitization and challenge decreased diaphragm muscle contraction, increased NOS activity, IL-4 levels of diaphragm in a mouse model. Budesonide/Formoterol combination could protect diaphragm muscle weakness and inflammation. According to the traditional concept of the contemporary Immunology, neither autoimmune diseases nor allergic diseases can be cured completely. Nevertheless, a fortunate coincidence led me to discovery of a novel concept that eliminations of the causes of these diseases are possible. In other words, combinations of pathogenic antibodies with responsible cells, namely, cytolytic T lymphocytes in cases of autoimmune diseases and mast cells in cases of allergic diseases, can be decomposed by replacing the pathogenic antibodies with non-specific antibodies. In more detail, intradermal injections with a non-specific antigen preparation induce production of non-specific antibodies in the body of the patient. Repetitions of the injections bring about an accumulation of them. Accumulated non-specific antibodies will occupy most of the receptors on the surface of responsible cells. When the accumulation reaches the sufficient level, virtually no pathogenic antibodies would remain on the receptors. That is, no causes of the diseases remain. Naturally, where there is no cause, there is no disease. Details are demonstrated elsewhere.

Sevoflurane exposure prevents diaphragmatic oxidative stress during mechanical ventilation but reduces force and affects protein metabolism even during spontaneous breathing in a rat model.

Ventilator-induced diaphragmatic dysfunction is associated with the generation of oxidative stress, enhanced proteolysis, autophagy and reduced protein synthesis in the diaphragm. Sevoflurane is a common operating room anesthetic and can be used in the intensive care medicine as well. Besides its anesthetic properties, its use in cardiac ischemia-reperfusion models can maintain protein synthesis and inhibit generation of reactive oxygen species, if used at the beginning of heart surgery. This study has been performed on the hypothesis that sevoflurane might protect against ventilator-induced diaphragmatic dysfunction by preventing the production of oxidative stress. Four-month-old, male Sprague-Dawley rats sedated with sevoflurane (minimal alveolar concentration = 1) were either mechanically ventilated (MV) for 12 hours (n = 8) or allowed to breathe spontaneously (SB) for 12 hours (n = 8). An acutely anesthetized group was used as a control (Con) group (n = 8). After euthanization, diaphragmatic contractile properties, fiber cross-sectional areas, proteolysis (calpain-1 and caspase-3), and oxidative stress (lipid peroxidation, protein oxidation) were examined. After testing for normality, 1-way or 2-way analysis of variance with the Dunnett post hoc test was used to test for significance. The diaphragm contractile force was similarly reduced at all stimulation frequencies in the SB and MV groups compared with controls. Markers of oxidative stress and fiber cross-sectional areas were unaltered between Con and SB/MV, respectively. The calcium-dependent proteases (calpain-1 and caspase-3) were enhanced in the MV group. The p-AKT/AKT ratio and p-FoxO1/FoxO1 ratio were significantly and similarly reduced after sevoflurane exposure in the SB and MV group compared with Con group. Exposure to sevoflurane did not induce oxidative stress. It led to reduction in diaphragmatic force. In the MV group, sevoflurane led to the activation of atrophy signaling pathways. These findings are of particular importance for clinical utilization in intensive care units and question its use, especially during the phases of SB.

Effects of Long-Acting β2-Agonist and Corticosteroid Inhalation on Diaphragm Muscle in Mice

Background and Objective: Although a combination of inhaled corticosteroid (ICS) and inhaled long-acting β2- agonist (LABA) reduces exacerbation of asthma, whether these affect diaphragm muscle contraction is still unclear. Methods: We investigated the effects of ICS and LABA inhalation separately, endotoxin injection-only, and ICS or LABA inhalation plus endotoxin injection on diaphragm contractile properties and nitric oxide (NO) production during 4 h, using BALB/c mice (n=84). In this study, budesonide was used as the ICS, and formoterol fumarate dehydrate was used as the LABA. After administrations of these drugs, the diaphragm muscles were dissected, and their contractile properties, including force/frequency (F/f) curves and twitch contraction, were measured by electrical pulse stimulation in an isometric condition. A reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry was performed to assess NO production, which induces cellular damages in diaphragm muscle fibers. Results: The ICS inhalation did not significantly shift the F/f curves; but the LABA inhalation significantly shifted them upward compared with shams at 1 h (p < 0.01), 2 h (p < 0.01), and 4 h (p < 0.05) after inhalation, that is, it showed an inotropic effect. Although endotoxin injection resulted in a downward shift in F/f curves at 4 h (p < 0.01) and induced NO production, the endotoxin plus either ICS or LABA inhalation prevented downward shifts of the F/f curves and inhibited NO production. Conclusions: These results indicate that the inhalation of LABA potentiates diaphragm muscle contractility more than ICS inhalation and that both ICS and LABA inhalation inhibit NO production induced by endotoxin injection.

AT1 receptor blocker attenuates mechanical ventilation‐induced atrophy and oxidative stress in the diaphragm muscle (1102.39)

Background: Mechanical ventilation (MV) is a method of maintaining adequate gas exchange in patients who are unable to sustain adequate alveolar ventilation on their own. Recently, our lab demonstrated that Angiotensin II (Ang II) is a possible mechanism that causes MV‐induced diaphragm muscle atrophy. During MV, elevation of Ang II induces Reactive Oxygen Species (ROS) emission from mitochondria and results in activation of key proteases, calpain and caspase‐3, in the diaphragm. To determine Ang II is a required upstream signal for MV‐induced diaphragm muscle atrophy and contractile dysfunction, we used AT1 receptor blocker (Losartan) and ACE inhibitor (Enalapril), which prevent the elevation of plasma Ang II levels during MV.Methods: Adult female rats were randomly assigned to one of six experimental groups (n =12 each) (1) Spontaneous breathing (SB) with salin, (2) SB with Losartan (LOS), (3) SB with Enalapril (ENA), (4) MV with salin, (5) MV with LOS, (6) MV with ENA. Dependent measures included plasma Ang II levels, diaphragmatic muscle fiber cross‐sectional area, diaphragm contractile properties, and the activity of key proteases in the diaphragm.Results: ENA attenuates increased circulating Ang II levels during 12 hours prolonged MV but LOS does not. However, only LOS attenuated MV‐induced diaphragm muscle atrophy. As well as, LOS attenuated MV‐induced mitochondrial dysfunction, ROS production, and proteasome activity during.Therefore, Ang II does not appear to be a possible upstream mechanism to prevent MV‐induced diaphragm muscle atrophy. AT1 receptor blocker, losartan has an antioxidant effect and attenuates MV‐induced VIDD. Therefore, the results of our experiments could lead to human clinical trials using losartan as a therapeutic intervention to prevent VIDD.

Dexamethasone-induced hyposensitivity to rocuronium in rat diaphragm associated with muscle-fiber transformation

The aim of the current study was to investigate the effect of chronic dexamethasone (Dex) administration on rat diaphragm function and sensitivity to rocuronium and muscle‑fiber transformation. Adult male Sprague‑Dawley rats were randomized to receive a daily intraperitoneal injection of Dex to evaluate whether alterations in diaphragm function and susceptibility to rocuronium would be induced. In addition, diaphragm contractile properties, histopathology and isometric twitch tensions of nerve‑hemidiaphragm preparations were evaluated. Dex administration led to impaired diaphragm force generation, increased fatigue resistance and a prolonged half‑relaxation time, as well as time‑to‑peak tension. Dex treatment led to desensitization of the rat diaphragm to rocuronium, as demonstrated by a shift of the rocuronium concentration‑twitch tension curves to the right. Histochemical analysis of adenosine triphosphatase revealed that the distribution and cross‑sectional area of type II fibers were decreased in rats exposed to Dex. The present study indicates that chronic Dex treatment induced alterations in muscle function and that susceptibility to rocuronium is associated with muscle fiber‑type transformation, which may aid in directing future administration of muscle relaxants.

Negative Pressure Ventilation and Positive Pressure Ventilation Promote Comparable Levels of Ventilator-induced Diaphragmatic Dysfunction in Rats

Mechanical ventilation is a life-saving intervention for patients with respiratory failure. Unfortunately, a major complication associated with prolonged mechanical ventilation is ventilator-induced diaphragmatic atrophy and contractile dysfunction, termed ventilator-induced diaphragmatic dysfunction (VIDD). Emerging evidence suggests that positive pressure ventilation (PPV) promotes lung damage (ventilator-induced lung injury [VILI]), resulting in the release of signaling molecules that foster atrophic signaling in the diaphragm and the resultant VIDD. Although a recent report suggests that negative pressure ventilation (NPV) results in less VILI than PPV, it is unknown whether NPV can protect against VIDD. Therefore, the authors tested the hypothesis that compared with PPV, NPV will result in a lower level of VIDD. Adult rats were randomly assigned to one of three experimental groups (n = 8 each): (1) acutely anesthetized control (CON), (2) 12 h of PPV, and (3) 12 h of NPV. Dependent measures included indices of VILI, diaphragmatic muscle fiber cross-sectional area, diaphragm contractile properties, and the activity of key proteases in the diaphragm. Our results reveal that no differences existed in the degree of VILI between PPV and NPV animals as evidenced by VILI histological scores (CON = 0.082 ± 0.001; PPV = 0.22 ± 0.04; NPV = 0.25 ± 0.02; mean ± SEM). Both PPV and NPV resulted in VIDD. Importantly, no differences existed between PPV and NPV animals in diaphragmatic fiber cross-sectional area, contractile properties, and the activation of proteases. These results demonstrate that NPV and PPV result in similar levels of VILI and that NPV and PPV promote comparable levels of VIDD in rats.

Diaphragm atrophy and contractile dysfunction in a murine model of pulmonary hypertension.

Pulmonary hypertension (PH) causes loss of body weight and inspiratory (diaphragm) muscle dysfunction. A model of PH induced by drug (monocrotaline, MCT) has been extensively used in mice to examine the etiology of PH. However, it is unclear if PH induced by MCT in mice reproduces the loss of body weight and diaphragm muscle dysfunction seen in patients. This is a pre-requisite for widespread use of mice to examine mechanisms of cachexia and diaphragm abnormalities in PH. Thus, we measured body and soleus muscle weight, food intake, and diaphragm contractile properties in mice after 6–8 weeks of saline (control) or MCT (600 mg/kg) injections. Body weight progressively decreased in PH mice, while food intake was similar in both groups. PH decreased (P<0.05) diaphragm maximal isometric specific force, maximal shortening velocity, and peak power. Protein carbonyls in whole-diaphragm lysates and the abundance of select myofibrillar proteins were unchanged by PH. Our findings show diaphragm isometric and isotonic contractile abnormalities in a murine model of PH induced by MCT. Overall, the murine model of PH elicited by MCT mimics loss of body weight and diaphragm muscle weakness reported in PH patients.

Diaphragm Contractile Function Differs Among Murine Strains

Murine diaphragm fiber bundles are routinely used to study physiologic properties of skeletal muscle. Based on pilot data, we hypothesized that contractile function differs among strains in healthy mice.MethodsWe measured specific force (N/cm2) and fatigue characteristics in diaphragm fiber bundles from age‐matched male ICR, C57BL/6, and DBA‐1 mice. Fiber bundles were studied in vitro (optimal length, 37°C, n=4/group) using a standard force‐frequency protocol (1, 15, 30, 50, 80, 120, 180, 250, 300 Hz). Fatigue was induced using repeated submaximal tetanic contractions (40 Hz, 500 ms trains; 0.5 trains/s) for 5 min.ResultsAmong groups, ICR muscle generated higher maximal forces (26.4 N/cm2 ± 0.3 SE) than C57BL/6 (21.1 ± 0.3) or DBA (14.7 ± 0.2). Relative force (as % maximal) did not differ among groups at any stimulus frequency. During the fatigue protocol, force fell less in DBA muscle (5.9 to 3.0 N/cm2; −50% decrement) than ICR (8.8 to 2.7; −69%) or C57BL/6 (8.3 to 3.0; −69%).ConclusionSpecific force and fatigue characteristics differ among diaphragm fiber bundles of ICR, C57BL/6, and DBA‐1 mice.SummaryThese data suggest that diaphragm contractile properties differ among murine strains. Supported by NIH grant HL08341 (T32 training fellowship).

Inhalation of Budesonide/Formoterol Increases Diaphragm Muscle Contractility

Although budesonide/formoterol (BUD/FORM) is used clinically as a steroid/β(2)-agonist single inhaler, it has not yet been clarified whether BUD/FORM has inotropic effects on diaphragm muscles after inhalation. We examined the effects of BUD/FORM inhalation, endotoxin injection, and BUD/FORM inhalation plus endotoxin injection on diaphragm contractile properties and nitric oxide (NO) production. After these three treatments, the diaphragm muscle was dissected, and its contractile properties were measured. Histochemistry for the reduced form of nicotinamide adenine dinucleotide phosphate diaphorase was performed for each muscle to assess NO production. The force-frequency curves showed an upward shift 1 h after inhalation (p < 0.05) in the BUD/FORM inhalation only group. The force-frequency curves showed a downward shift 4 h after injection (p < 0.001) in the endotoxin injection groups. In the BUD/FORM inhalation plus endotoxin injection groups, a downward shift in the force-frequency curves at 4 h after endotoxin injection was prevented. NO production was inhibited in the BUD/FORM inhalation plus endotoxin injection group compared with that of the endotoxin injection only groups. BUD/FORM inhalation has an inotropic effect on diaphragm muscle, protects diaphragm muscle deterioration after endotoxin injection, and inhibits NO production. Increments in muscle contractility with BUD/FORM inhalation are induced through a synergistic effect of an anti-inflammatory agent and β(2)-agonist.

Reply: Combined 18F-FDG and Fluoride Approach in PET/CT Imaging: Is There a Clinical Future?

Transdiaphragmatic (Pdi) and oesophageal pressures (Pes) are useful in understanding the pathophysiology of the respiratory system. They provide insight into respiratory drive, intrinsic positive end-expiratory pressure, diaphragmatic fatigue and weaning failure. <h3>Background</h3> The use of Pdi and Pes in clinical practice is restricted due to the invasiveness of the technique and the cumbersome equipment needed. On the other hand, diaphragmatic displacement is non-invasively and easily assessed with M-mode ultrasound. <h3>Purpose</h3> We observed striking similarities in shape and magnitude between M-mode diaphragmatic displacement, Pes and Pdi pressures. The study aimed to evaluate if the information provided by these two pressures could be obtained non-invasively from the diaphragmatic displacement curve. <h3>Material and methods</h3> In 14 consecutive intubated patients undergoing a weaning trial, simultaneous recordings of Pes and Pdi pressures and the diaphragmatic displacement were assessed while breathing spontaneously and during a sniff-like manoeuvre. Moreover, the slope of the diaphragmatic displacement curve during relaxation was compared with the maximal relaxation rate (MRR) obtained from the Pdi curve. <h3>Results</h3> More than 200 breaths were analysed in pairs. Diaphragmatic displacement significantly correlated with Pdi (R²=0.33, p&lt;0.001) and Pes (R²=0.44, p&lt;0.001), and this correlation further improved during sniff (R²=0.47, p&lt;0.001) and (R²=0.64, p&lt;0.001), respectively. Additionally, a significant correlation was found between the relaxation slope derived from the diaphragmatic displacement curve and the MRR derived from the Pdi curve, both in normal breathing (R²=0.379, p&lt;0.001) and during the sniff manoeuvre (R²=0.71, p&lt;0.001). <h3>Conclusions</h3> M-mode diaphragmatic displacement parameters correlate well with the ones obtained from oesophageal pressure and Pdi, particularly during sniffing. Diaphragmatic displacement assessment possibly offers an alternative non-invasive solution for understanding and clinically monitoring the diaphragmatic contractile properties and weaning failure due to diaphragmatic fatigue.

Neural deficits contribute to respiratory insufficiency in Pompe disease

Pompe disease is a severe form of muscular dystrophy due to glycogen accumulation in all tissues, especially striated muscle. Disease severity is directly related to the deficiency of acid alpha-glucosidase (GAA), which degrades glycogen in the lysosome. Respiratory dysfunction is a hallmark of the disease, muscle weakness has been viewed as the underlying cause, and the possibility of an associated neural contribution has not been evaluated previously. Therefore, we examined behavioral and neurophysiological aspects of breathing in 2 animal models of Pompe disease--the Gaa(-/-) mouse and a transgenic line (MTP) expressing GAA only in skeletal muscle, as well as a detailed analysis of the CNS in a Pompe disease patient. Glycogen content was elevated in the Gaa(-/-) mouse cervical spinal cord. Retrograde labeling of phrenic motoneurons showed significantly greater soma size in Gaa(-/-) mice vs. isogenic controls, and glycogen was observed in Gaa(-/-) phrenic motoneurons. Ventilation, assessed via plethysmography, was attenuated during quiet breathing and hypercapnic challenge in Gaa(-/-) mice (6 to >21 months of age) vs. controls. We confirmed that MTP mice had normal diaphragmatic contractile properties; however, MTP mice had ventilation similar to the Gaa(-/-) mice during quiet breathing. Neurophysiological recordings indicated that efferent phrenic nerve inspiratory burst amplitudes were substantially lower in Gaa(-/-) and MTP mice vs. controls. In human samples, we demonstrated similar pathology in the cervical spinal cord and greater accumulation of glycogen in spinal cord compared with brain. We conclude that neural output to the diaphragm is deficient in Gaa(-/-) mice, and therapies targeting muscle alone may be ineffective in Pompe disease.

Adaptive support ventilation prevents ventilator-induced diaphragmatic dysfunction: an in vivo piglet study

Mechanical ventilation is a lifesaving supportive therapy for patients with acute respiratory failure. However, prolonged mechanical ventilation results in the complete absence of neural activation and mechanical activity of the diaphragm and has been shown to induce ventilator-induced diaphragmatic dysfunction (VIDD) [1]. Few studies have shown that maintaining spontaneous ventilation could prevent VIDD in in vitro animal studies [2]. Adaptive support ventilation (ASV) is an automatic ventilation mode that allowed pressure-controlled breaths in active patients able to trigger. The aim of our study was to compare ASV with controlled ventilation (CV) without paralysing agents on diaphragmatic contractile properties in an in vivo piglet study.

Altered diaphragmatic contractile properties after high airway pressure controlled mechanical ventilation

Altered diaphragmatic contractile properties after high airway pressure controlled mechanical ventilation

Interleukin-6 Causes Myocardial Failure and Skeletal Muscle Atrophy in Rats

The impact of interleukin (IL)-6 on skeletal muscle function remains the subject of controversy. The effects of 7-day subcutaneous administration of recombinant human IL-6 were examined at 3 doses, 50, 100, or 250 microg x kg(-1) x d(-1), in rats. Skeletal muscle mass decreased dose-dependently (with increasing dose: in the diaphragm, -10%, P=NS; -15%, P=0.0561; and -15% P<0.05; and in the gastrocnemius, -9%, P=NS; -9%, P=NS; and -18%, P<0.005) because of decreases in cross-sectional area of all fiber types without alterations in diaphragm contractile properties. Cardiovascular variables showed a dose-dependent heart dilatation (for end-diastolic volume: control, 78 microL; moderate dose, 123 microL; and high dose, 137 microL, P<0.001), reduced end-systolic pressure (control, 113 mm Hg; moderate dose, 87 mm Hg; and high dose, 90 mm Hg; P=0.037), and decreased myocardial contractility (for preload recruitable stroke work: control, 79 mm Hg; moderate dose, 67 mm Hg; and high dose, 48 mm Hg; P<0.001). Lung edema was confirmed by an increased wet-to-dry ratio (control, 4.2; moderate dose, 4.6; and high dose, 4.5; P<0.001) and microscopy findings. These cardiovascular alterations led to decreases in organ blood flow, particularly in the diaphragm (control, 0.56 mL x min(-1) x g(-1); moderate dose, 0.21 mL x min(-1) x g(-1); and high dose, 0.23 mL x min(-1) x g(-1); P=0.037). In vitro recombinant human IL-6 administration did not cause any alterations in diaphragm force or endurance capacity. IL-6 clearly caused ventilatory and peripheral skeletal muscle atrophy, even after short-term administration. Blood flow redistribution, resulting from the myocardial failure induced by IL-6, was likely responsible for this muscle atrophy, because IL-6 did not exert any direct effect on the diaphragm.