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Background Every year, more than 2.5 million critically ill patients in the ICU are dependent on mechanical ventilation. The positive pressure in the lungs generated by the ventilator keeps the diaphragm passive, which can lead to a loss of myofibers within a short time. To prevent ventilator-induced diaphragmatic dysfunction (VIDD), phrenic nerve stimulation may be used. Objective The goal of this study is to show the feasibility of transesophageal phrenic nerve stimulation (TEPNS). We hypothesize that selective phrenic nerve stimulation can efficiently activate the diaphragm with reduced co-stimulations. Methods An in vitro study in saline solution combined with anatomical findings was performed to investigate relevant stimulation parameters such as inter-electrode spacing, range to target site, or omnidirectional vs. sectioned electrodes. Subsequently, dedicated esophageal electrodes were inserted into a pig and single stimulation pulses were delivered simultaneously with mechanical ventilation. Various stimulation sites and response parameters such as transdiaphragmatic pressure or airway flow were analyzed to establish an appropriate stimulation setting. Results Phrenic nerve stimulation with esophageal electrodes has been demonstrated. With a current amplitude of 40 mA, similar response figures of the diaphragm activation as compared to conventional stimulation with needle electrodes at 10mA were observed. Directed electrodes best aligned with the phrenic nerve resulted in up to 16.9 % higher amplitude at the target site in vitro and up to 6 cmH20 higher transdiaphragmatic pressure in vivo as compared to omnidirectional electrodes. The activation efficiency was more sensitive to the stimulation level inside the esophagus than to the inter-electrode spacing. Most effective and selective stimulation was achieved at the level of rib 1 using sectioned electrodes 40 mm apart. Conclusion Directed transesophageal phrenic nerve stimulation with single stimuli enabled diaphragm activation. In the future, this method might keep the diaphragm active during, and even support, artificial ventilation. Meanwhile, dedicated sectioned electrodes could be integrated into gastric feeding tubes.

Background: The twitch interpolation technique is a promising tool for assessing central drive to the diaphragm. It is used to quantify the degree of voluntary diaphragm activation during predefined breathing maneuvers. Objectives: This study was designed to (a) determine reference values for the level of voluntary activation of the diaphragm using the twitch occlusion technique in healthy adults and (b) explore the association between central drive to the diaphragm and volitional tests of respiratory muscle strength. Methods: Twenty-seven healthy volunteers aged 26 ± 14 years (18 male) were enrolled. Twitch transdiaphragmatic pressure (Pdi) was determined at relaxed functional residual capacity in response to cervical magnetic stimulation (CMS) of the phrenic nerves. The subjects were then instructed to gradually increase voluntary activation of the diaphragm, and the effects of superimposed magnetic stimuli on voluntary Pdi were assessed. Results: The twitch Pdi amplitude following CMS linearly decreased with increasing inspiratory effort. The resulting diaphragm voluntary activation index (DVAI) during maximal voluntary contraction was 75 ± 15% irrespective of gender or age. Twitch duration, half relaxation time, and area under the curve of superimposed Pdi deflections did not show a linear but an exponential association with increasing voluntary activation of the diaphragm. More than 2/3 of the decrease in the above values was evident after 1/3 of voluntary diaphragm contraction. Forced vital capacity (FVC) was inversely correlated with the DVAI. Conclusions: Twitch interpolation allows for assessment of central drive to the diaphragm. The maximum DVAI is independent of gender or age, and significantly related to FVC but not to maximum inspiratory pressure or Pdi as direct measures of diaphragm strength.

Abdominal exercises, such as sit ups and leg lifts, are used to enhance strength of the core muscles. An overlooked aspect of abdominal exercises is the compression the abdomen, leading to increased diaphragmatic work. We hypothesized that core exercises would produce a variety of transdiaphragmatic pressures. We also sought to determine if some of the easy exercises would produce pressures sufficient for a training stimulus to the diaphragm. We evaluated the effect of 13 different abdominal exercises, ranging in difficulty, on transdiaphragmatic pressure (Pdi), an index of diaphragmatic activity. Six healthy subjects, aged 22 to 53, participated. Each subject was instrumented with two balloon-tipped catheters to obtain gastric and esophageal pressures, from which Pdi was calculated. Prior to initiating the exercises, each subject performed a maximal inspiratory pressure (MIP) maneuver. Resting Pdi was also measured. The exercises were performed from least to most difficult, with five repetitions each. There was a significant difference between the exercises and the MIP Pdi, as well as between the exercises and resting Pdi (p < 0.001). The exercises stratified into three Pdi levels. Seven of the exercises yielded Pdi ≥ 50% of the Pdi during the MIP maneuver, which may provide a training stimulus to the diaphragm if used as a regular exercise. The Pdi measurements also provide insight into diaphragm recruitment during different core exercises, and may aid in the design of exercises to improve diaphragm strength and endurance. Key pointsPlease provide 3-5 bullet points of the study.The study examined the effect of different core exercises of varying difficulty on activation of the diaphragm.We found that the exercises yielded different pressures, some of which were greater than 50% of the pressures generated during a maximal inspiratory maneuver.The difficulty of the exercise was not always correlated with the magnitude of the pressure.Some of these exercises should be easy enough for subjects in rehabilitation programs to perform and still generate high enough pressures to help strengthen the diaphragm.

Purpose During neurally adjusted ventilatory assist (NAVA) the ventilator is driven by the patients electrical activation of the diaphragm (EAdi), detected by a special esophageal catheter. A reliable positioning of the EAdi-catheter is mandatory to trace a representative EAdi signal. We aimed to determine whether a formula that is based on the measurement from nose to ear lobe to xiphoid process of the sternum (NEX distance) modified for EAdi-catheter placement (NEX mod ) is sufficient for predicting the accurate catheter position. Methods Twenty-six patients were enrolled in this study. The optimal EAdi-catheter position (OPT) was defined by: (1) stable EAdi signal, (2) electrical activity highlighted in central leads of the catheter positioning tool, and (3) absence of p-wave in distal lead. Afterwards NEX mod was calculated and compared to the OPT finding. Results At NEX mod the EAdi signal was suitable for running NAVA in 18 out of 25 patients (72%). NEX mod was identical with OPT in four patients (16%). NAVA was possible in all patients at OPT. Median OPT position was 2 cm caudal of the NEX mod ranging from 3 cm too cranial to a position 12 cm too caudal ( P  < 0.01). In one patient excluded from further analysis EAdi-catheter placement led to the diagnosis of bilateral injury of the phrenic nerves. Conclusions EAdi-catheter placement based on the NEX mod formula allows running NAVA in about two-thirds of all patients. The additional tools provided are efficient and facilitate the correct positioning of the EAdi-catheter for neurally adjusted ventilatory assist.

Purpose Neurally adjusted ventilatory assist (NAVA) relies on the patient’s electrical activity of the diaphragm (EAdi) for actuating the ventilator. Thus a reliable positioning of the oesophageal EAdi catheter is mandatory. We aimed to evaluate the effects of body position (BP), positive end-expiratory pressure (PEEP) and intra-abdominal pressure (IAP) on catheter positioning. Methods Twenty-one patients were enrolled in this study. In six different situations [supine or 45° head of bed elevation (HBE) at PEEP 5 and 15 cmH 2 O; left lateral anti-decubitus at PEEP 5 cmH 2 O; supine at PEEP 5 cmH 2 O with abdominal surgical belt (ASB)] the catheter position was evaluated for the stability of the EAdi signal and information provided by a catheter positioning tool (highlighted electrical activity in central leads, absence of p waves in the distal lead). Results With an optimal catheter position EAdi signals were stable for all tested situations. During “45° PEEP 15” and “supine PEEP 15” absence of p waves in the distal lead revealed a difference compared with “supine PEEP 5” ( p  = 0.03), suggesting a caudal shift of the diaphragm relative to the oesophagus. The analysis of the highlighted electrical activity in the central leads supports this finding, revealing an influence of PEEP, BP and IAP on EAdi catheter position ( p  < 0.01). Conclusion PEEP, BP and IAP may affect the EAdi catheter position, although not compromising a stable signal. Additional information as provided by the catheter positioning tool is needed to ensure an optimal EAdi catheter position.

A theoretical framework is developed for mechanics of the diaphragm. The diaphragm is modeled as an anisotropic elastic material surface with activation functionality. A constitutive function is formulated that relates the stresses in the diaphragm to the surface deformation gradient, the anisotropy vector, and the muscle activation parameter. The equilibrium equations for the diaphragm are derived to determine the deformed shape of the diaphragm in the process of respiration with the associated transdiaphragmatic pressures. A numerical solution is presented, that demonstrates the capability of the model to recover the experimental observations and to predict the shape and stresses of the diaphragm.

Congenital diaphragmatic hernia (CDH) is a frequently occurring source of severe neonatal respiratory distress. It has been hypothesized that abnormal retinoid signaling contributes to the etiology of this developmental anomaly. Here, we use rodent models toward specifically understanding the role of retinoid signaling in the developing diaphragm and how its perturbation is a common mechanism in drug-induced CDH. This includes monitoring of retinoic acid (RA) response element (RARE) activation with RARE-lacZ mice, RA supplementation studies, systematic analyses of the expression profile of key elements in the RA signaling pathway within the developing diaphragm, and the in utero delivery of a RA receptor (RAR) antagonist. These data demonstrate the timing of RARE perturbation by CDH-inducing teratogens and the efficacy of RA supplementation. Furthermore, a detailed profile of retinoid binding proteins, synthetic enzymes, and retinoid receptors within primordial diaphragm cells was obtained. The expression profile of RAR-α was particularly striking in regard to its overlap with the regions of primordial diaphragm affected in multiple CDH models. Blocking of RAR signaling with the pan-RAR antagonist BMS493 induced a very high degree of CDH, with a marked left–right sidedness that depended on the timing of drug delivery. Collectively, these data demonstrate that retinoid signaling is essential for normal diaphragm development, providing further support to the hypothesis that abnormalities related to the retinoid signaling pathway cause diaphragmatic defects. This study also yielded a novel experimental model that should prove particularly useful for further studies of CDH.

Significance The neuromuscular junction (NMJ) is a synapse between the motor nerve and myotube essential for controlling skeletal muscle contraction. Motor nerve-derived glycoprotein agrin is indispensable for the formation and maintenance of NMJs, and genetic defects in agrin underlie a congenital myasthenic syndrome (CMS). Agrin’s role has been thought to be activation of the muscle-specific receptor kinase MuSK. Here, we demonstrate that forced activation of MuSK in agrin-deficient mice restored embryonic formation, but not postnatal maintenance, of NMJs, demonstrating that agrin plays an essential role distinct from MuSK activation in the postnatal maintenance of NMJs. Given that CMSs frequently show postnatal onset, this finding provides key insights not only into NMJ homeostasis but also into CMS pathology with unknown etiology. The motoneural control of skeletal muscle contraction requires the neuromuscular junction (NMJ), a midmuscle synapse between the motor nerve and myotube. The formation and maintenance of NMJs are orchestrated by the muscle-specific receptor tyrosine kinase (MuSK). Motor neuron-derived agrin activates MuSK via binding to MuSK’s coreceptor Lrp4, and genetic defects in agrin underlie a congenital myasthenic syndrome (an NMJ disorder). However, MuSK-dependent postsynaptic differentiation of NMJs occurs in the absence of a motor neuron, indicating a need for nerve/agrin-independent MuSK activation. We previously identified the muscle protein Dok-7 as an essential activator of MuSK. Although NMJ formation requires agrin under physiological conditions, it is dispensable for NMJ formation experimentally in the absence of the neurotransmitter acetylcholine, which inhibits postsynaptic specialization. Thus, it was hypothesized that MuSK needs agrin together with Lrp4 and Dok-7 to achieve sufficient activation to surmount inhibition by acetylcholine. Here, we show that forced expression of Dok-7 in muscle enhanced MuSK activation in mice lacking agrin or Lrp4 and restored midmuscle NMJ formation in agrin-deficient mice, but not in Lrp4-deficient mice, probably due to the loss of Lrp4-dependent presynaptic differentiation. However, these NMJs in agrin-deficient mice rapidly disappeared after birth, and postsynaptic specializations emerged ectopically throughout myotubes whereas exogenous Dok-7–mediated MuSK activation was maintained. These findings demonstrate that the MuSK activator agrin plays another role essential for the postnatal maintenance, but not for embryonic formation, of NMJs and also for the postnatal, but not prenatal, midmuscle localization of postsynaptic specializations, providing physiological and pathophysiological insight into NMJ homeostasis.

Adult stem cells are essential for tissue homeostasis. In skeletal muscle, muscle stem cells (MuSCs) reside in a quiescent state, but little is known about the mechanisms that control homeostatic turnover. Here we show that, in mice, the variation in MuSC activation rate among different muscles (for example, limb versus diaphragm muscles) is determined by the levels of the transcription factor Pax3. We further show that Pax3 levels are controlled by alternative polyadenylation of its transcript, which is regulated by the small nucleolar RNA U1. Isoforms of the Pax3 messenger RNA that differ in their 3′ untranslated regions are differentially susceptible to regulation by microRNA miR206, which results in varying levels of the Pax3 protein in vivo. These findings highlight a previously unrecognized mechanism of the homeostatic regulation of stem cell fate by multiple RNA species.

Mechanical ventilation (MV) is a life-saving intervention for patients in respiratory failure. However, prolonged MV causes the rapid development of diaphragm muscle atrophy, and diaphragmatic weakness may contribute to difficult weaning from MV. Therefore, developing a therapeutic countermeasure to protect against MV-induced diaphragmatic atrophy is important. MV-induced diaphragm atrophy is due, at least in part, to increased production of reactive oxygen species (ROS) from diaphragm mitochondria and the activation of key muscle proteases (i.e., calpain and caspase-3). In this regard, leakage of calcium through the ryanodine receptor (RyR1) in diaphragm muscle fibers during MV could result in increased mitochondrial ROS emission, protease activation, and diaphragm atrophy. Therefore, these experiments tested the hypothesis that a pharmacological blockade of the RyR1 in diaphragm fibers with azumolene (AZ) would prevent MV-induced increases in mitochondrial ROS production, protease activation, and diaphragmatic atrophy. Adult female Sprague-Dawley rats underwent 12 hours of full-support MV while receiving either AZ or vehicle. At the end of the experiment, mitochondrial ROS emission, protease activation, and fiber cross-sectional area were determined in diaphragm muscle fibers. Decreases in muscle force production following MV indicate that the diaphragm took up a sufficient quantity of AZ to block calcium release through the RyR1. However, our findings reveal that AZ treatment did not prevent the MV-induced increase in mitochondrial ROS emission or protease activation in the diaphragm. Importantly, AZ treatment did not prevent MV-induced diaphragm fiber atrophy. Thus, pharmacological inhibition of the RyR1 in diaphragm muscle fibers is not sufficient to prevent MV-induced diaphragm atrophy.