Diaphragmatic Weakness Research Articles

1238 West Nile Encephalitis with suspected diaphragmatic dysfunction leading to sleep apnea with associated hypoventilation

Currently, there are no guidelines on the management of acute sleep disordered breathing in the ICU or inpatient setting. Here, we report a case in which an acute sleep medicine evaluation was utilized to treat a patient with West Nile Encephalitis and sleep related hypoventilation with suspected diaphragmatic weakness. This is an 82 yo male who presented with lethargy and dyspnea after a recent trip to El Salvador. Physical exam was significant for shallow, rapid respirations with mild use of accessory muscles and fluctuating mental status. Patient denied any history of lung disease or OSA but became progressively more somnolent with rising pCO2 levels. This prompted a sleep medicine consult to optimize PAP therapy as patient had declined elective intubation. Due to patient’s unstable condition, a bedside trial was performed in the Step Down Unit utilizing BIPAP with settings of 18/8 cmH20, PS 4 cmh20 and 2L O2. Results showed an AHI of 72 with evidence of worsening hypoventilation based on his pCO2 of 80 (ABG). However, this study was limited due to the inability to differentiate central from obstructive events given the available equipment. Concurrently, further workup for encephalopathy revealed presence of West Nile Encephalitis based on positive IgM antibodies in CSF. Upon review of additional studies, chest imaging was concerning for diaphragmatic dysfunction. This concern was corroborated by ultrasonography which, although of poor image quality, failed to show any significant inspiratory contraction of the R diaphragm. A repeat BIPAP trial was then performed utilizing a backup rate of 12 bpm with pressure of 16/10 cmH20 and 2L O2. Results showed an AHI of 15.7 with average O2 91.6%. In the days following, his pCO2 levels improved to 50. In conclusion, WNV-induced myositis vs phrenic neuropathy leads the differential for this patient’s diaphragmatic dysfunction/hypoventilation. Further testing is needed.

The neurology of acutely failing respiratory mechanics

Forces involved in breathing-which effectively pull in air-are the diaphragmatic, intercostal, spine, and neck muscles. Equally important is the bulbar musculature maintaining the architecture of a patent airway conduit and abdominal wall and internal intercostal muscles providing cough. Acute injury along a neural trajectory from brainstem to muscle will impair the coordinated interaction between these muscle groups. Acutely failing respiratory mechanics can be caused by central and peripheral lesions. In central lesions, the key lesion is in the nucleus ambiguus innervating the dilator muscles of the soft palate, pharynx, and larynx, but abnormal respiratory mechanics rarely coincide with abnormalities of the respiratory pattern generator. In peripheral lesions, diaphragmatic weakness is a main element, but in many neuromuscular disorders mechanical upper airway obstruction from oropharyngeal weakness contributes equally to an increased respiratory load. The neurology of breathing involves changes in respiratory drive, rhythm, mechanics, and dynamics. This review focuses on the fundamentals of abnormal respiratory mechanics in acute neurologic conditions, bedside judgment, interpretation of additional laboratory tests, and initial stabilization, with practical solutions provided. Many of these respiratory signs are relevant to neurologists, who in acute situations may see these patients first. Ann Neurol 2017;81:485-494.

Hypoxic Preconditioning Improves Respiratory Muscle Function during Hypoxia by Regulating Mitochondria in COPD Mice

Diaphragm weakness has been observed in patients with chronic obstructive pulmonary disease (COPD), which may be associated with the prolonged hypoxic conditions in the disease. We found that hypoxic preconditioning (HPC) can strengthen diaphragm under hypoxic conditions in COPD mice by treating the muscle with alternating low and high O2 concentrations. In this study, we tested the hypothesis that the protective effects offered by HPC are linked with the opening of mitochondrial ATP‐sensitive potassium channel (KATP) and the closing of the mitochondrial permeability transition pore (mPTP) in COPD mice. Adult C57BL6 mice were smoked for three months to develop COPD symptoms. Following the completion of smoking, diaphragms of the mice were isolated and mounted in a contractile chamber. Each muscle strip was treated (n = 6) or non‐treated with HPC (n = 6), or pre‐incubated with a combination of KATP channel inhibitor (glibenclamide; 100 μM) and mPTP opener (carboxyatractyloside; 50 μM; n = 6) for 30 min prior to HPC. Another two groups of muscles were treated either with KATP channel activator (diazoxide; 100 μM; n = 6) or mPTP inhibitor (cyclosporine A; 100 μM; n = 6) in the absence of HPC. The muscles were then consecutively stimulated for five minutes (0.5 Hz) during a 30‐min hypoxic period. Fatigue tolerance was determined as the ratio of residual force at the end of the five‐min contraction to the initial force. Data were expressed as means ± SE, and analyzed using multi‐way ANOVA. P < 0.05 was considered statistically different. Our results show that HPC significantly improved diaphragm function during hypoxia (29 ± 2.8% for HPC vs. 6 ± 1.3% for control, p < 0.05). However, such protective effects were eliminated via the simultaneous inhibition of KATP channel and the opening of mPTP (5 ± 2.1%, p < 0.05 vs. HPC). On the other hand, either the activation of KATP channel (27 ± 2.6%) or the inhibition of mPTP (24 ± 3.6%) significantly mitigates diaphragm fatigue (p < 0.05 vs. control) to an extent similar to that of HPC. These data collectively indicate that the mechanisms of HPC protection on diaphragm under hypoxia may involve the opening of mitochondrial KATP channel and inhibition of mPTP in COPD mice.Support or Funding InformationAmerican Physiological Society (APS) 2016 S&R Foundation Ryuji Ueno Award

SEX DIFFERENCES AND PROTEOMIC PROFILING OF DIAPHRAGM WEAKNESS IN CHRONIC HEART FAILURE

Inspiratory dysfunction occurs in patients with chronic heart failure (CHF). The diaphragm is the primary inspiratory muscle, and diaphragm abnormalities likely contribute to the dyspnea and exercise intolerance that these patients experience. Animal models show that CHF causes diaphragm weakness, but it remains unclear whether disease effects and mechanisms of weakness are sex‐specific. We conducted the current study to test whether CHF effects on diaphragm function and morphology are sex‐specific and to explore putative mechanisms for diaphragm abnormalities via proteomics. We performed myocardial infarction or sham surgery on Sprague Dawley rats. We focused our efforts on animals with severe CHF, determined by 1) transmural infarct ≥ 35% of left ventricle + septal area and 2) right ventricle hypertrophy. We assessed diaphragm isometric contractile function in vitro, fiber type and cross sectional area, and global label free proteomics with mass spectrometry. CHF decreased diaphragm maximal tetanic isometric specific force (N/cm2) by ~20% in both males and females (n = 5–8 per group; P < 0.05). However, the effects on isometric twitch specific force were sex‐specific. CHF decreased twitch specific force (N/cm2) by ~30% (P < 0.05) in males, with no effect in females. There were no effects of disease on fiber type distribution or cross‐sectional area in either sex. Our preliminary proteomic results did not reveal any obvious changes in protein abundance that could explain the decrease in maximal diaphragm force in CHF. For instance, CHF (males) increased the relative quantity of myosin binding protein C fast‐type and troponin T slow isoform and decreased myosin light chain kinase‐2 and phosphorylase b kinase (P < 0.01, false‐discovery rate 1%). In females, our proteomics showed no changes in relative protein quantity with CHF. Overall, our data show that CHF effects on the diaphragm are generally similar between sexes, except for twitch specific force. Our preliminary findings from proteomics suggest that post‐translational modifications, rather than changes in relative quantity, are the main mechanisms underlying diaphragm weakness in CHF.Support or Funding InformationFunding support from NIH R01 HL130318

Valoración ecográfica de la función diafragmática y sus aplicaciones en el paciente crítico, en ventilación mecánica y en la anestesia del plexo braquial

Before diaphragm ultrasonography, assessment of diaphragm function was very difficult due to the complex nature of its exploration. The use of this new technique has shed light on diagnostic problems and treatment with an improvement in final outcomes for critically ill patients, in whom the incidence of diaphragm weakness or dysfunction has been underestimated. Better knowledge of diaphragm function enables us earlier diagnosis by quantification of diaphragm contractile activity or evaluation of functional status after delivery of plexus block anaesthesia, facilitating therapeutic decisions. It is also being used as a guide in the process of weaning from mechanical ventilation or as the safest approach for braquial plexus block. In this review we present how to perform a systematic exploration of diaphragm function and its clinical implications.

Ultrasonographic evaluation of diaphragm structure and function

Diaphragm is the principal respiratory muscle. Diaphragm dysfunction resulting from mechanical ventilation, chronic cardiopulmonary disease, medicine, cardio-thoracic surgery, septic shock and chronic malnutrition predisposes to weaning failure from mechanical ventilation and prolongs intensive care unit (ICU) stay. Traditionally, the method of assessment of diaphragm structure and function was invasive, lacking specific, and was difficult to be used bedside. A number of recent studies have been suggested that ultrasonographic evaluation has been proposed as an accurate, safe and noninvasive method of quantification of diaphragm structure and function. This article reviews the related researches of technique and the clinical applications of ultrasonography in the evaluation of diaphragmatic structure and function, which may possibly result in timely identification of patients with diaphragm dysfunction and improve the assessment of recovery from diaphragm weakness.

Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension.

Patients with pulmonary hypertension (PH) suffer from inspiratory insufficiency, which has been associated with intrinsic contractile dysfunction in diaphragm muscle. Here, we examined the role of redox stress in PH-induced diaphragm weakness by using the novel antioxidant, EUK-134. Male Wistar rats were randomly divided into control (CNT), CNT + EUK-134 (CNT + EUK), monocrotaline-induced PH (PH), and PH + EUK groups. PH was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg body weight). EUK-134 (3 mg/kg body weight/day), a cell permeable mimetic of superoxide dismutase (SOD) and catalase, was daily intraperitoneally administered starting one day after induction of PH. After four weeks, diaphragm muscles were excised for mechanical and biochemical analyses. There was a decrease in specific tetanic force in diaphragm bundles from the PH group, which was accompanied by increases in: protein expression of NADPH oxidase 2/gp91phox, SOD2, and catalase; 3-nitrotyrosine content and aggregation of actin; glutathione oxidation. Treatment with EUK-134 prevented the force decrease and the actin modifications in PH diaphragm bundles. These data show that redox stress plays a pivotal role in PH-induced diaphragm weakness. Thus, antioxidant treatment can be a promising strategy for PH patients with inspiratory failure.

Respiratory muscle contractile inactivity induced by mechanical ventilation in piglets leads to leaky ryanodine receptors and diaphragm weakness.

Respiratory muscle contractile inactivity during mechanical ventilation (MV) induces diaphragm muscle weakness, a condition referred to as ventilator-induced diaphragmatic dysfunction (VIDD). Although VIDD pathophysiological mechanisms are still not fully understood, it has been recently suggested that remodeling of the sarcoplasmic reticulum (SR) calcium release channel/ryanodine receptors (RyR1) in the diaphragm is a proximal mechanism of VIDD. Here, we used piglets, a large animal model of VIDD that is more relevant to human pathophysiology, to determine whether RyR1 alterations are observed in the presence of diaphragm weakness. In piglets, diaphragm weakness induced by 72h of respiratory muscle unloading was associated with SR RyR1 remodeling and abnormal resting SR Ca2+ leak in the diaphragm. Specifically, following controlled mechanical ventilation, diaphragm contractile function was reduced. Moreover, RyR1 macromolecular complexes were more oxidized, S-nitrosylated and phosphorylated at Ser-2844 and depleted of the stabilizing subunit calstabin1 compared with controls on adaptive support ventilation that maintains diaphragmatic contractile activity. Our study strongly supports the hypothesis that RyR1 is a potential therapeutic target in VIDD and the interest of using small molecule drugs to prevent RyR1-mediated SR Ca2+ leak induced by respiratory muscle unloading in patients who require controlled mechanical ventilation.

Global Proteome Changes in the Rat Diaphragm Induced by Endurance Exercise Training.

Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, prolonged MV results in the rapid development of diaphragmatic atrophy and weakness. Importantly, endurance exercise training results in a diaphragmatic phenotype that is protected against ventilator-induced diaphragmatic atrophy and weakness. The mechanisms responsible for this exercise-induced protection against ventilator-induced diaphragmatic atrophy remain unknown. Therefore, to investigate exercise-induced changes in diaphragm muscle proteins, we compared the diaphragmatic proteome from sedentary and exercise-trained rats. Specifically, using label-free liquid chromatography-mass spectrometry, we performed a proteomics analysis of both soluble proteins and mitochondrial proteins isolated from diaphragm muscle. The total number of diaphragm proteins profiled in the soluble protein fraction and mitochondrial protein fraction were 813 and 732, respectively. Endurance exercise training significantly (P<0.05, FDR <10%) altered the abundance of 70 proteins in the soluble diaphragm proteome and 25 proteins of the mitochondrial proteome. In particular, key cytoprotective proteins that increased in relative abundance following exercise training included mitochondrial fission process 1 (Mtfp1; MTP18), 3-mercaptopyruvate sulfurtransferase (3MPST), microsomal glutathione S-transferase 3 (Mgst3; GST-III), and heat shock protein 70 kDa protein 1A/1B (HSP70). While these proteins are known to be cytoprotective in several cell types, the cyto-protective roles of these proteins have yet to be fully elucidated in diaphragm muscle fibers. Based upon these important findings, future experiments can now determine which of these diaphragmatic proteins are sufficient and/or required to promote exercise-induced protection against inactivity-induced muscle atrophy.

Respiratory impairment in multiple sclerosis: a study of respiratory function in wheelchair-bound patients.

Respiratory disorders are a major cause of morbidity and mortality in multiple sclerosis (MS). Mainly reported in walking patients, they are poorly explored when walking is severely impaired. To characterize respiratory impairment in patients with advanced MS. From 2012 to 2015, patients with MS with an Expanded Disability Status Scale (EDSS) score of ≥7 who were referred for functional and rehabilitation evaluation underwent pulmonary function tests to study lung volumes, cough efficacy and respiratory muscle pressures. Among 73 patients with a median EDSS score of 8 [7.5; 8.5], 72.6% had impaired respiratory function with a mean vital capacity (VC) of 57.9 ± 33.5% of theoretical value. Severe impairment (VC < 50%) was found for 34 (46.6%) patients. Cough was impaired in 45 (61.6%) patients, with a mean cough peak flow of 3.14 ± 1.9 L/s and severe impairment (cough peak flow < 2.67 L/s) in 27 (37.0%) patients. Overall, the results suggested predominant expiratory muscle dysfunction and non-predominant diaphragm impairment. EDSS score was correlated with VC but not with any other clinical data. Restrictive respiratory failure is frequent in severely impaired patients with MS, predominantly involves expiratory muscles, does not involve diaphragm weakness and is associated with cough impairments.

Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients.

Intensive care unit (ICU)- and mechanical ventilation (MV)-acquired limb muscle and diaphragm dysfunction may both be associated with longer length of stay and worse outcome. Whether they are two aspects of the same entity or have a different prevalence and prognostic impact remains unclear. To quantify the prevalence and coexistence of these two forms of ICU-acquired weakness and their impact on outcome. In patients undergoing a first spontaneous breathing trial after at least 24 hours of MV, diaphragm dysfunction was evaluated using twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (a pressure <11 cm H2O defined dysfunction) and ultrasonography (thickening fraction [TFdi] and excursion). Limb muscle weakness was defined as a Medical Research Council (MRC) score less than 48. Seventy-six patients were assessed at their first spontaneous breathing trial: 63% had diaphragm dysfunction, 34% had limb muscle weakness, and 21% had both. There was a significant but weak correlation between MRC score and twitch pressure (ρ = 0.26; P = 0.03) and TFdi (ρ = 0.28; P = 0.01), respectively. Low twitch pressure (odds ratio, 0.60; 95% confidence interval, 0.45-0.79; P < 0.001) and TFdi (odds ratio, 0.84; 95% confidence interval, 0.76-0.92; P < 0.001) were independently associated with weaning failure, but the MRC score was not. Diaphragm dysfunction was associated with higher ICU and hospital mortality, and limb muscle weakness was associated with longer duration of MV and hospital stay. Diaphragm dysfunction is twice as frequent as limb muscle weakness and has a direct negative impact on weaning outcome. The two types of muscle weakness have only limited overlap.

Diaphragmatic Dysfunction after Thoracic Operations.

The perioperative management of diaphragmatic weakness and phrenic nerve dysfunction is complex, due to varied etiologies and clinical presentations. The factors leading to diaphragmatic weakness may culminate after the operation with transient or persistent respiratory failure. This review discusses diaphragmatic disorders and postoperative respiratory failure caused by unilateral or bilateral diaphragmatic impairment. The origins of neuromuscular weakness involving the diaphragm are diverse, and often lie within the domains of different medical specialties, with only a portion of the condition related to surgical intervention. Consideration of underlying etiologies for any individual patient requires thorough multidisciplinary review. The most important clinical scenarios compounding diaphragmatic weakness, including acute myasthenic states, persistent neuromuscular blockade, and surgical injury to the phrenic nerve or diaphragm, are accessible to attentive surgeons. Awareness of the signs and symptoms of undiagnosed weakness, preoperative pursuit of its diagnosis, knowledge of surgical alternatives to phrenic nerve resection, and cooperative skills in the multidisciplinary management of myasthenia all are crucial to improve patient outcomes.

Diaphragm ultrasound as a new functional and morphological index of outcome, prognosis and discontinuation from mechanical ventilation in critically ill patients and evaluating the possible protective indices against VIDD

BackgroundThere is increasing awareness that diaphragm weakness is common in patients undergoing MV and is likely a contributing cause of weaning failure. Recent studies have suggested that the ventilator is a likely cause of the decreased diaphragm force generating capacity (dFGC) seen in mechanically ventilated patients; a condition referred to as ventilator-induced diaphragmatic dysfunction (VIDD). The study was focused on using diaphragm thickness and excursion measured by ultrasound as a predictor of weaning outcome and to assess the clinical evolution and risk factors for VIDD in an adult intensive care unit (ICU) and evaluating the possible protective indices against VIDD. Patients and methodsThis study included 60 invasively mechanically ventilated patients matched with twenty healthy non-mechanically ventilated individuals as a control group. Diaphragm thickness and excursion measured daily for 14days or until extubation or death. ResultsHere was a significant decrease in the MDT, DTF and mean diaphragmatic excursion with increased length and duration of mechanical ventilation. the maximum diaphragmatic changes occurred early in the first 3days after MV. Cutoff values for diaphragmatic ultrasound predicting successful weaning were MDT >2mm, DTF >30% and DE >1.5cm. Early switch from controlled MV to assist ventilation (addition of PS and or PEEP) was associated with reversal of VIDD. ConclusionUltrasound is a sensitive accurate method for predicting weaning outcome. Maintaining mechanically ventilated at a controlled mild to moderate hypercapnia, early switch from controlled MV to PS and or addition of PEEP improve weaning outcome.

Ventilatory Support and Management of Secretions in Amyotrophic Lateral Sclerosis

The term amyotrophic lateral sclerosis (ALS) comprises a group of motor neuron diseases which are characterized by rapid disease progression and poor prognosis which is mostly due to severe respiratory muscle weakness and its sequelae. Since causative treatment options are limited it is crucial to offer comprehensive symptomatic therapies to affect patients. Symptoms of respiratory muscle weakness, sleep-disordered breathing and, subsequently, chronic hypercapnic respiratory failure are known to severely affect health-related quality of life and social functioning of patients with ALS. This review article delineates the clinical presentation of respiratory muscle weakness, diagnostic procedures to assess diaphragmatic function, and practical aspects of both mechanical ventilation and cough assistance, respectively. Various technical and electrophysiological methods allow for detection of diaphragmatic weakness and nocturnal hypoventilation. These include spiro-manometric tests of respiratory muscle strength, cardiorespiratory polygraphy and polysomnography, transcutaneous capnography, and blood gas analysis. Once the diagnosis of respiratory muscle weakness is established, non-invasive ventilation, tracheostomy-invasive ventilation (if the patient agrees to it), and management of secretions all become increasingly important in the course of the disease.

Muscle weakness in respiratory and peripheral skeletal muscles in a mouse model for nebulin-based nemaline myopathy

Nemaline myopathy is among the most common non-dystrophic congenital myopathies, and is characterized by the presence of nemaline rods in skeletal muscles fibers, general muscle weakness, and hypotonia. Although respiratory failure is the main cause of death in nemaline myopathy, only little is known regarding the contractile strength of the diaphragm, the main muscle of inspiration. To investigate diaphragm contractility, in the present study we took advantage of a mouse model for nebulin-based nemaline myopathy that we recently developed. In this mouse model, exon 55 of Neb is deleted (NebΔExon55), a mutation frequently found in patients. Diaphragm contractility was determined in permeabilized muscle fibers and was compared to the contractility of permeabilized fibers from three peripheral skeletal muscles: soleus, extensor digitorum longus, and gastrocnemius. The force generating capacity of diaphragm muscle fibers of NebΔExon55 mice was reduced to 25% of wildtype levels, indicating severe contractile weakness. The contractile weakness of diaphragm fibers was more pronounced than that observed in soleus muscle, but not more pronounced than that observed in extensor digitorum longus and gastrocnemius muscles. The reduced muscle contractility was at least partly caused by changes in cross-bridge cycling kinetics which reduced the number of bound cross-bridges. The severe diaphragm weakness likely contributes to the development of respiratory failure in NebΔExon55 mice and might explain their early, postnatal death.

Chilaiditi Sign: A Rare Incidental Finding

Chilaiditi sign is an incidental radiologic finding that presents as a crescent lucency below the right diaphragm due to malpositioned loops of the colon or small bowel. It is extremely rare, occurring in 0.025% to 0.28% of the general population. It is usually benign but can lead to various life threatening complications including obstruction, perforation, or ischemia. It is therefore important to recognize this sign and proceed with timely management. An 80 year old male with history significant for diabetes mellitus, atrial fibrillation, and hypertension presented with complaints of intermittent right-sided pleuritic chest pain and productive cough for one week. On presentation, patient was tachycardic, tachypnic, afebrile, normotensive, and on room air. Chest x-ray showed pneumonia, fractures of the right 6th and 7th ribs, and incidentally, presence of gas below the right diaphragm. Due to this alarming finding, patient was reassessed. He reported regular bowel movements without nausea or vomiting, had active bowel sounds, and no signs of acute abdomen. As this finding was inconsistent with the clinical condition, Chilaiditi was considered. CT abdomen confirmed diagnosis of Chilaiditi syndrome with hepatodiaphragmatic interposition of the colon. Patient was discharged on Levofloxacin and pain control for pneumonia and fractures respectively. Incidental findings were appropriately documented to prevent extensive retesting in the future. Our case illustrates the incidental sign of Chilaiditi. It is due to the anterior interposition of the colon to the liver and is a cause of pseudopneumoperitoneum. The absence of pain, nausea, vomiting, and abdominal distention distinguishes Chilaiditi sign from its counterpart, Chilaiditi syndrome. The exact mechanism is unknown but thought to be from a wide space between the liver and the diaphragm. This could be from liver scarring, ascites, diaphragmatic weakness, laxity of ligaments, abnormal colon mobilization, constipation, obesity, or increased intraabdominal pressure. Further imaging must be obtained if Chilaiditi sign is found. If there is evidence of ischemic bowel, volvulus, obstruction, or perforation, surgical treatment should be pursued. Chilaiditi sign occurs in 1 in 50,000 adults and therefore is not widely taught or recognized. Though it is generally benign, it can be a sign of a life-threatening condition. Prompt recognition and early therapy are quintessential to prevent fatal complications.Figure 1

Vanishing Lung

SESSION TITLE: Fellow Case Report Slide: Pulmonary Disorders SESSION TYPE: Affiliate Case Report Slide PRESENTED ON: Tuesday, October 25, 2016 at 04:30 PM - 05:30 PM INTRODUCTION: Shrinking lung syndrome (SLS) is a rare complication of systemic lupus erythematosus (SLE) with only 77 cases reported in a review published in 2009 (1). CASE PRESENTATION: A 38 year-old woman with SLE complicated by inflammatory arthropathy and proteinuria managed with mycophenolate mofetil (MMF) and hydroxychloroquine was referred to our care with history of shortness of breath associated with pleuritic chest pain for 6 months. These symptoms started after her MMF was tapered down from 4,000 mg per day to 2,000 mg per day and her prednisone tapered off. Pulmonary function testing was mostly consistent with a severe restrictive process but radiographic evaluation with plain films and chest CT did not show evidence of interstitial or pleural pathology. Supine forced vital capacity decreased by 30% from upright values and MEP was diminished, implicating diaphragmatic dysfunction as an etiology. Prednisone was restarted at 40 mg per day with the patient reporting substantial improvement in her exertional limitations 6 weeks later. DISCUSSION: Various pathological mechanisms for SLS have been proposed, including diaphragmatic weakness with abnormal diaphragmatic pressures, intercostal muscle involvement, and phrenic nerve involvement (2, 3), though the precise cause is contested. We have implicated diaphragmatic dysfunction in our patient’s case in light of significant FVC drop in the supine position. Corticosteroids are the mainstay of treatment and there are also reports addressing benefit of inhaled beta agonists and theophylline (2, 3). Interestingly, our patient did demonstrate objective improvement with inhaled beta-agonists with subjective improvement after steroids were begun. CONCLUSIONS: We present a case of SLS, demonstrating evidence of diaphragmatic dysfunction with a significant improvement with inhaled beta agonists and subjective improvement with escalation in immunosuppresive therapy - all of these features inconsistently described in prior case reports and series. With its rarity, SLS is poorly characterized with subsequent heterogeneity in proposed etiology, treatment and prognosis. Reference #1: Calderaro DC et.al Presentation and prognosis of shrinking lung syndrome in systemic lupus erythematosus: report of four cases. Rheumatol Int.2012 May;32(5):1391-6 Reference #2: Carmier D et.al. Respiratory involvement in systemic lupus erythematosus. Rev Mal Respir. 2010 Oct;27(8):e66-78. Reference #3: Warrington KJ et.al. The shrinking lungs syndrome in systemic lupus erythematosus. Mayo Clin Proc. 2000 May;75(5):467-72. DISCLOSURE: The following authors have nothing to disclose: Venkata Ravi Kumar Angirekula, Yasir Tarabichi No Product/Research Disclosure Information

P.54 - Case report: Non SMARD1 presentation of IGHMBP2 mutation with late onset diaphragmatic weakness

P.54 - Case report: Non SMARD1 presentation of IGHMBP2 mutation with late onset diaphragmatic weakness

Influence of weaning methods on the diaphragm after mechanical ventilation in a rat model.

BackgroundMechanical ventilation (MV) is associated with diaphragm weakness, a phenomenon termed ventilator-induced diaphragmatic dysfunction. Weaning should balance diaphragmatic loading as well as prevention of overload after MV. The weaning methods pressure support ventilation (PSV) and spontaneous breathing trials (SBT) lead to gradual or intermittent reloading of a weak diaphragm, respectively. This study investigated which weaning method allows more efficient restoration of diaphragm homeostasis.MethodsRats (n = 8 per group) received 12 h of MV followed by either 12 h of pressure support ventilation (PSV) or intermittent spontaneous breathing trials (SBT) and were compared to rats euthanized after 12 h MV (CMV) and to acutely euthanized rats (CON). Force generation, activity of calpain-1 and caspase-3, oxidative stress, and markers of protein synthesis (phosphorylated AKT to total AKT) were measured in the diaphragm.ResultsReduction of diaphragmatic force caused by CMV compared to CON was worsened with PSV and SBT (both p < 0.05 vs. CON and CMV). Both PSV and SBT reversed oxidative stress and calpain-1 activation caused by CMV. Reduced pAKT/AKT was observed after CMV and both weaning procedures.ConclusionsMV resulted in a loss of diaphragmatic contractility, which was aggravated in SBT and PSV despite reversal of oxidative stress and proteolysis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0285-2) contains supplementary material, which is available to authorized users.

FV 8. Sleep-disordered breathing and effects of non-invasive ventilation on sleep outcomes in adult Pompe disease

In juvenile or adult onset Pompe disease, non-invasive ventilation (NIV) is indicated if sleep-disordered breathing (SDB), daytime hypercapnia, or significant diaphragmatic weakness is present. We investigated both short-term and long-term effects of NIV on measures of sleep and nocturnal ventilation in patients with late-onset Pompe disease. Polysomnography (PSG) and transcutaneous capnography were performed in 22 adult patients with late-onset Pompe disease. If indicated, NIV was initiated the subsequent night and long-term follow-up visits were scheduled for up to 28 months including PSG and nocturnal carbon dioxide monitoring. Retrospective data analysis comprised PSG-based sleep and ventilation outcome measures. Daytime performance, subjective sleep quality, and health-related quality of life (HRQoL) were self-assessed using standard questionnaires. 22 patients (12 females) initially underwent detailed sleep studies. Enzyme replacement therapy had been initiated in 18 individuals, and 3 patients were treatment-naïve. 9 patients reported excessive daytime sleepiness (Epworth Sleepiness Scale score > 10), 8 patients had obstructive sleep apnea with an apnea hypopnea index above 5/h total sleep time, 3 patients showed daytime hypercapnia, and 4 individuals showed nocturnal increase of transcutaneous tcCO2 above 50 mmHg. In patients with SDB, HRQoL and both subjective and objective sleep quality were significantly reduced, the latter reflected by frequent sleep stage changes and decreased slow wave sleep. NIV was initiated in 15 patients and significantly increased mean and minimal oxygen saturation, shortened desaturation time, and enhanced CO2 elimination. Sleep outcomes were not significantly influenced in the first night on NIV but on first follow-up after three months nocturnal wake time was significantly decreased. During long-term follow-up sleep studies revealed stable normoxia and normocapnia in all patients receiving nighttime ventilatory support. Objective measures of sleep quality did not show deterioration over time. Alterations to ventilator settings were necessary only in few patients. NIV significantly improves objective sleep quality and respiration in the first night of treatment in adult patients with late-onset Pompe disease and SDB. NIV warrants nocturnal normoventilation without deterioration of sleep quality in the long run with only minor changes to ventilator settings.