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Patients with acute respiratory distress syndrome (ARDS) require periods of deep sedation and mechanical ventilation, leading to diaphragm dysfunction. Our study seeks to determine whether the combination of temporary transvenous diaphragm neurostimulation (TTDN) and mechanical ventilation changes the degree of diaphragm injury and cytokines concentration in a preclinical ARDS model. Moderate ARDS was induced in pigs using oleic acid, followed by ventilation for 12 h post-injury with volume-control at 8 mL/kg, positive end-expiratory pressure (PEEP) 5 cmH 2 O, respiratory rate and [Formula: see text] set to achieve normal arterial blood gases. Two groups received TTDN: every second breath (MV + TTDN50%, n = 6) or every breath (MV + TTDN100%, n = 6). One group received ventilation only (MV, n = 6). Full-thickness diaphragm and quadricep muscle biopsies were taken at study end. Samples were fixed and stained with hematoxylin and eosin and a point-counting technique was applied to calculate abnormal muscle area fraction. Cytokine concentrations were measured in homogenized tissue using porcine-specific enzyme-linked immunosorbent assay (ELISA) and compared with serum samples. Percentage of abnormal diaphragm tissue was different between MV [8.1% (6.0-8.8)] versus MV + TTDN50% [3.4% (2.1-4.8)], P = 0.010 and MV versus MV + TTDN100% [3.1% (2.5-4.0)], P = 0.005. Percentage of abnormal quadriceps tissue was not different between groups. Cytokine concentration patterns in diaphragm samples were different between all groups ( P < 0.001) and the interaction between TTDN application and resultant cytokine concentration pattern was significant ( P = 0.025). TTDN, delivered in synchrony with mechanical ventilation, mitigated diaphragm injury, as evidenced by less abnormal tissue in the diaphragm samples, in pigs with oleic acid-induced ARDS and is an exciting tool for lung and diaphragm-protective ventilation. NEW & NOTEWORTHY This study adds to our understanding of applying transvenous diaphragm neurostimulation synchronously with mechanical ventilation by examining its effects on diaphragm muscle injury and cytokine concentration patterns in pigs with acute respiratory distress syndrome (ARDS). We observed that using this therapy for 12 h post lung injury mitigated ventilator-induced diaphragm injury and changed the pattern of cytokine concentration measured in diaphragm tissue. These findings suggest that transvenous diaphragm neurostimulation is an exciting tool for lung and diaphragm protective ventilation.

Introduction/aims: Phrenic neuropathy (PhN) impairs diaphragm muscle function, causing a spectrum of breathing disability. PhN etiologies and their natural history are ill-defined. This knowledge gap hinders informed prognosis and management decisions. This study aims to help fill this knowledge gap on PhN etiologies, outcomes, and recovery patterns, especially in the context of nonsurgical clinical practice., Methods: This was a retrospective study from two interdisciplinary clinics, physiatry and neurology based. Patients were included if PhN was identified, and other causes of hemi-diaphragm muscle dysfunction excluded. Patients were followed serially at the discretion of the neuromuscular-trained neurologist or physiatrist. Recovery was assessed using pulmonary function tests (PFTs), diaphragm muscle ultrasound (US) thickening ratio, and patient-reported outcomes in patients presenting within 2 years of PhN onset., Results: We identified 151 patients with PhN. The most common etiologies were idiopathic (27%), associated with cardiothoracic procedure (24%), and intensive care unit (17%). Of these patients, 117 (77%) were evaluated within 2 years of PhN onset. Of patients included in outcome analyses, 64% saw improvement on serial US, 50% on serial PFTs and 79% reported symptomatic improvement at an average of 15, 16, and 17 months, respectively., Discussion: A clear majority of PhN patients show improvement in diaphragm muscle function, but on average, improvements took 15-17 months depending on the assessment type. These insights are vital for developing tailored treatments and can guide physicians in prognosis and decision-making, especially if more invasive interventions are being considered., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Introduction: Pulsed-field ablation (PFA) is a novel nonthermal energy that shows unique features that can be of use beyond pulmonary vein ablation, like tissue selectivity or proximity rather than contact dependency., Methods and Results: We report three cases of right focal atrial tachycardias arising from the superior cavoatrial junction and the crista terminalis, in close relationship with the phrenic nerve, effectively ablated using a commercially available PFA catheter designed for pulmonary vein isolation without collateral damage., Conclusion: PFA can be useful for treating right atrial tachycardias involving sites near the phrenic nerve, avoiding the need for complex nerve-sparing strategies., (© 2024 Wiley Periodicals LLC.)

Respiratory deficits after C2 hemisection (C2Hx) have been well documented through single-sex investigations. Although ovarian sex hormones enable enhanced respiratory recovery observed in females 2 wk post-C2Hx, it remains unknown if sex impacts spontaneous respiratory recovery at chronic time points. We conducted a longitudinal study to provide a comprehensive sex-based characterization of respiratory neuromuscular recovery for 8 wk after C2Hx. We recorded ventilation and chronic diaphragm electromyography (EMG) output in awake, behaving animals, phrenic motor output in anesthetized animals, and performed diaphragm muscle histology in chronically injured male and female rodents. Our results show that females expressed a greater recovery of tidal volume and minute ventilation compared with males during subacute and chronic time points. Eupneic diaphragm EMG amplitude during wakefulness and phrenic motor amplitude are similar between sexes at all time points after injury. Our data also suggest that females have a greater reduction in ipsilateral diaphragm EMG amplitude during spontaneous deep breaths (e.g., sighs) compared with males. Finally, we show evidence for atrophy and remodeling of the fast, fatigable fibers ipsilateral to injury in females, but not in males. To our knowledge, the data presented here represent the first study to report sex-dependent differences in spontaneous respiratory recovery and diaphragm muscle morphology following chronic C2Hx. These data highlight the need to study both sexes to inform evidence-based therapeutic interventions in respiratory recovery after spinal cord injury (SCI). NEW & NOTEWORTHY In response to chronic C2 hemisection, female rodents display increased tidal volume during eupneic breathing compared with males. Females show a greater reduction in diaphragm electromyography (EMG) amplitude during spontaneous deep breaths (e.g., sighs) and atrophy and remodeling of fast, fatigable diaphragm fibers. Given that most rehabilitative interventions occur in the subacute to chronic stages of injury, these results highlight the importance of considering sex when developing and evaluating therapeutics after spinal cord injury.

Purpose: We aimed to quantify perioperative changes in diaphragmatic function and phrenic nerve conduction in patients undergoing routine thoracic surgery., Methods: A prospective observational study was performed in patients undergoing esophageal resection or pulmonary lobectomy. Examinations were carried out the day prior to surgery, 3 days and 10-14 days after surgery. Endpoints for diaphragmatic function included ultrasonographic measurements of diaphragmatic excursion and thickening fraction. Endpoints for phrenic nerve conduction included baseline-to-peak amplitude, peak-to-peak amplitude, and transmission delay. Measurements were assessed on both the surgical side and the non-surgical side of the thorax., Results: Forty patients were included in the study. Significant reductions in diaphragmatic excursion were seen on the surgical side of the thorax for all excursion measures (posterior part of the right hemidiaphragm, p < 0.001; hemidiaphragmatic top point, p < 0.001; change in intrathoracic area, p < 0.001). Significant changes were seen for all phrenic nerve measures (baseline-to-peak amplitude, p < 0.001; peak-to-peak amplitude, p < 0.001; transmission delay, p = 0.041) on the surgical side. However, significant changes were also seen on the non-surgical side for all phrenic nerve measures (baseline-to-peak amplitude, p < 0.001; peak-to-peak amplitude, p < 0.001; transmission delay, p = 0.022). A postoperative reduction in posterior diaphragmatic excursion of more than 50% was significantly associated with postoperative pulmonary complications (coefficient: 2.69 (95% CI [1.38, 4.01], p < 0.001)., Conclusion: Thoracic surgery caused a significant unilateral reduction in diaphragmatic excursion on the surgical side of the thorax, which was accompanied by significant changes in phrenic nerve conduction. However, phrenic nerve conduction was also significantly affected on the non-surgical side to a lesser extent, which was not mirrored in diaphragmatic excursion. Our findings suggest that phrenic nerve paresis plays a role in postoperative diaphragmatic dysfunction, which may be a contributing factor in the pathogenesis of postoperative pulmonary complications., Clinical Trials Registration Number: NCT04507594., (© 2024. The Author(s).)

Background: Late-onset Pompe disease (LOPD) patients may still need ventilation support at some point of their disease course, despite regular recombinant human alglucosidase alfa treatment. This suggest that other pathophysiological mechanisms than muscle fibre lesion can contribute to the respiratory failure process. We investigate through neurophysiology whether spinal phrenic motor neuron dysfunction could contribute to diaphragm weakness in LOPD patients., Material and Methods: A group of symptomatic LOPD patients were prospectively studied in our centre from January 2022 to April 2023. We collected both demographic and clinical data, as well as neurophysiological parameters. Phrenic nerve conduction studies and needle EMG sampling of the diaphragm were perfomed., Results: Eight treated LOPD patients (3 males, 37.5%) were investigated. Three patients (37.5%) with no respiratory involvement had normal phrenic nerve motor responses [median phrenic compound muscle action potential (CMAP) amplitude of 0.49 mV; 1st-3rd interquartile range (IQR), 0.48-0.65]. Those with respiratory failure (under nocturnal non-invasive ventilation) had abnormal phrenic nerve motor responses (median phrenic CMAP amplitude of 0 mV; 1st-3rd IQR, 0-0.15), and were then investigated with EMG. Diaphragm needle EMG revealed both myopathic and neurogenic changes in 3 (60%) and myopathic potentials in 1 patient. In the last one, no motor unit potentials could be recruited., Conclusions: Our study provide new insights regarding respiratory mechanisms in LOPD, suggesting a contribution of spinal phrenic motor neuron dysfunction for diaphragm weakness. If confirmed in further studies, our results recommend the need of new drugs crossing the blood-brain barrier., Competing Interests: Declaration of competing interest Miguel Oliveira Santos and Mamede de Carvalho received support from Sanofi. The other authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diaphragm dysfunction develops in central nervous system damage, chest injuries, complications of cardiac surgery, long-term artificial lung ventilation, respiratory diseases. Anatomical morphological features of phrenic nerves allow to effectively use electromagnetic stimulation methods for functional recovery of the diaphragm in different pathological conditions. Invasive and non-invasive, electric and magnetic methods of stimulation are used depending on the severity of manifestations of the diaphragm dysfunction and its genesis., Objective: To perform a review and comparison of modern methods of electromagnetic stimulation of the diaphragm; to determine the role of repetitive peripheral magnetic stimulation (rPMS) in the diaphragm dysfunction as a result of stroke., Material and Methods: An analysis of publications from the Pubmed and Elibrary databases for 2008-2024 years was conducted. The search was done by the following keywords: diaphragm dysfunction, repetitive peripheral magnetic stimulation of phrenic nerve, stroke, hemiparesis., Results: There is a real possibility of effective diaphragm stimulation for recovery of its function due to the innervation of the diaphragm strictly by the phrenic nerves, their large diameter, presence of myelinated fibers as well as anatomical location of the phrenic nerves. Direct electric stimulation of the phrenic nerve is usually applied in the case of long-term continuous support of respiratory function. Non-invasive techniques of electric or magnetic stimulation of the phrenic nerve or directly of the diaphragmatic muscle are used in the case of temporary respiratory support or recovery of diaphragm function. The motor neurons of the brain and peripheral nerves are activated, thus a peak strength of the variable magnetic field usually reachs 1-2 T in rPMS. Application of rPMS affects the efferent nerve fibers, causing muscle contractions, and activates sensory afferent fibers, creating a stimulating effect on the superjacent nervous structures. It is advisable to use rPMS of the phrenic nerve in the cervical segment or rPMS of one of the segments of the diaphragmatic muscle in the case of unilateral diaphragm lesion during the recovery period after stroke. It is important to consider the frequency of exposure in the 10-30 Hz range, the closest location of the coil to the stimulation area, the choice of the coil shape depending on the localization when adjusting parameters of rPMS., Conclusion: The use of rPMS of the phrenic nerve and diaphragm allows to preserve and recover motor and contractile functions of the diaphragm in different pathological conditions, including its unilateral lesion as a result of stroke. The method of rPMS of the phrenic nerves has a number of advantages over electric stimulation and repetitive transcranial magnetic stimulation, since it allows to achieve an effective motor response with less intensity of exposure, is painless and non-contact, better tolerated by patients.

Objective: To report a new patient friendly and convenient technique for phrenic nerve conduction with alternative sites of stimulation and recording., Methods: Phrenic nerve conduction was performed in forty volunteers and ten patients of peripheral neuropathy. Active recording electrode was placed in tenth intercostal space 2.5 cm away from para-spinal muscles (mid-scapular line), reference electrode in eighth intercostal space just medial to subcostal margin with ground between stimulating and recording electrode. Stimulation was done at the level of crico-thyroid space near or under the posterior margin of sternocleidomastoid muscle. This new method was compared with existing ones., Analysis: Data was analysed using SPSS 23 version. Correlation between height, weight, body mass index, age, and chest expansion was done using bi-variate correlation. Mean latency and amplitude of the study method were compared with other methods using MANNOVA test., Results: Total of forty subjects were studied. Thirty-seven were male subjects. Mean age was 28.03 ± 9.63 years, height 168.0 ± 9.60 cm and chest expansion 3.53 ± 0.64 cm. Right sided phrenic nerve mean latency was 5.99 ± 0.629 ms and amplitude 1.088 ± 0.178 mV. Left sided phrenic nerve conductions showed mean latency of 6.02 ± 1.82 ms, amplitude of 1.092 ± 0.2912 mV. These standard deviations were smaller than what were observed with other methods suggesting increased consistency of our results. There was no correlation between phrenic nerve conduction with age, height, gender or chest expansion., Conclusion: This study method gave a better as well as consistent morphology, higher amplitude and required lower amount of current strength. It was superior to previously reported methods in consistency of normative data., Competing Interests: None

The neuronal system that controls respiration creates plasticity in response to physiological changes. Chronic sustained hypoxia causes neuroplasticity that contributes to ventilatory acclimatization to hypoxia (VAH). The purpose of this study is to explain the potential roles of the VAH mechanism developing because of chronic sustained hypoxia on respiratory neuroplasticity of vascular endothelial growth factor (VEGF) receptor activation on the nucleus tractus solitarius (NTS) and phrenic nerve. In this study 24 adult male Sprague-Dawley rats were used. Subjects were separated into four groups, a moderate-sham (mSHAM), severed-sham (sSHAM), moderate chronic sustained hypoxia (mCSH), and severed chronic sustained hypoxia (sCSH). Normoxic group (mSHAM and sSHAM) rats were exposed to 21% O₂ level (7 days) in the normobaric room while hypoxia group (mCSH and sCSH) rats were exposed to 13% and 10% O₂ level (7 days). Different protocols were applied for normoxic and hypoxia groups and ventilation, respiratory frequency, and tidal volume measurements were made with whole-body plethysmography. After the test HIF-1α, erythropoietin (EPO), and VEGFR-2 expressions on the NTS region in the medulla oblongata and phrenic nerve motor neurons in spinal cord tissue were analyzed using the immunohistochemical stain method. Examinations on the medulla oblongata and spinal cord tissues revealed that HIF-1α, EPO, and VEGFR-2 expressions increased in hypoxia groups compared to normoxic groups while a similar increase was also seen when respiratory parameters were assessed. Consequently, learning about VAH-related neuroplasticity mechanisms developed as a result of chronic continuous hypoxia will contribute to developing new therapeutical approaches to various diseases causing respiratory failure using brain plasticity without recourse to medicines., (© 2021 Wiley Periodicals LLC.)

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear. Furthermore, the functional impact of AIH is enhanced by repeated/daily exposure to AIH (dAIH). Here, we explored the effects of AIH versus 2 wk of dAIH preconditioning on spontaneous and evoked phrenic responses in anesthetized, paralyzed, and mechanically ventilated rats. Evoked phrenic potentials were elicited by respiratory cycle-triggered lateral funiculus stimulation at the C2 spinal level delivered before and 60 min post-AIH (or the equivalent in time controls). Charge-balanced biphasic pulses (100 μs/phase) of progressively increasing intensity (100-700 μA) were delivered during the inspiratory and expiratory phases of the respiratory cycle. Although robust pLTF (∼60% from baseline) was observed after a single exposure to moderate AIH (3 × 5 min; 5-min intervals), there was no effect on evoked phrenic responses, contrary to our initial hypothesis. However, in rats preconditioned with dAIH, baseline phrenic nerve activity and evoked responses were increased, suggesting that repeated exposure to AIH enhances functional synaptic strength when assessed using this technique. The impact of daily AIH preconditioning on synaptic inputs to PMNs raises interesting questions that require further exploration. NEW & NOTEWORTHY Two weeks of daily acute intermittent hypoxia (dAIH) preconditioning enhanced stimulus-evoked phrenic responses to lateral funiculus stimulation (targeting respiratory bulbospinal projection to phrenic motor neurons). Furthermore, dAIH preconditioning enhanced baseline phrenic motor output responses to maximal chemoreflex activation in intact rats.

Diaphragm weakness affects up to 60% of ventilated patients leading to muscle atrophy, reduction of muscle fiber force via muscle fiber injuries and prolonged weaning from mechanical ventilation. Electromagnetic stimulation of the phrenic nerve can induce contractions of the diaphragm and potentially prevent and treat loss of muscular function. Recommended safety distance of electromagnetic coils is 1 m. The aim of this study was to investigate the magnetic flux density in a typical intensive care unit (ICU) setting. Simulation of magnetic flux density generated by a butterfly coil was performed in a Berlin ICU training center with testing of potential disturbance and heating of medical equipment. Approximate safety distances to surrounding medical ICU equipment were additionally measured in an ICU training center in Bern. Magnetic flux density declined exponentially with advancing distance from the stimulation coil. Above a coil distance of 300 mm with stimulation of 100% power the signal could not be distinguished from the surrounding magnetic background noise. Electromagnetic stimulation of the phrenic nerve for diaphragm contraction in an intensive care unit setting seems to be safe and feasible from a technical point of view with a distance above 300 mm to ICU equipment from the stimulation coil., (© 2021. The Author(s).)

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Patients with late-onset PD retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, required nocturnal ventilation at age 40, 24-h noninvasive ventilation by age 43, and passed away from respiratory failure at age 54. Diaphragm electromyography recorded using indwelling "pacing" wires showed asynchronous bursting between the left and right diaphragm during brief periods of independent breathing. The synchrony declined over a 4-yr period preceding respiratory failure. Histological assessment indicated motoneuron atrophy in the medulla and rostral spinal cord. Hypoglossal (soma size: 421 ± 159 µm 2 ) and cervical motoneurons (soma size: 487 ± 189 µm 2 ) had an atrophied, elongated appearance. In contrast, lumbar (soma size: 1,363 ± 677 µm 2 ) and sacral motoneurons (soma size: 1,411 ± 633 µm 2 ) had the ballooned morphology typical of early-onset PD. Diaphragm histology indicated loss of myofibers. These results are consistent with neuromuscular degeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle. NEW & NOTEWORTHY This case study offered a unique opportunity to investigate longitudinal changes in phrenic neurophysiology in an individual with severe, ventilator-dependent, late-onset Pompe disease. Additional diaphragm and neural tissue histology upon autopsy confirmed significant neuromuscular degeneration, and it provided novel insights regarding rostral to caudal variability in the neuropathology. These findings suggest that a successful treatment approach for ventilator-dependent Pompe disease should target the central nervous system, in addition to skeletal muscle.

Background: Diaphragm paralysis (DP) complicates the postoperative course of neonates and infants undergoing cardiac surgery. Events causing DP remain poorly understood, and preventive strategies remain elusive. This retrospective cohort analysis aims to test the hypothesis that chest tubes in contact with the phrenic nerve in the pleural apex may cause pressure palsy., Methods: In late 2018, the chest tube positioning strategy was changed so as to avoid a putative "danger zone" configuration, defined as (1) the chest tube looping apicomedially at the level of the second right intercostal space, and (2) wedging of chest tube tip against pericardium. A preintervention and postintervention analysis of 531 patients from 2012 to 2019 was performed to evaluate any association of chest tube position or duration in place with DP. Univariable and multivariable analyses were carried out, with significance set a priori at P < .05., Results: The preintervention group comprised 488 patients, of whom 32 (6.6%) had RDP. The postintervention group comprised 43 patients, none of whom had DP. Multivariable analysis of the entire cohort revealed chest tube positioning in the danger zone as the only significant association with RDP (odds ratio, 4.22; 95% confidence interval, 1.57-11.33; P < .05)., Conclusions: Chest tubes that occupy the right superior pleural space are associated with increased risk of DP., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Although cervical spinal cord injury (cSCI) disrupts bulbo-spinal serotonergic projections, partial recovery of spinal serotonergic innervation below the injury site is observed after incomplete cSCI. Since serotonin contributes to functional recovery post-injury, treatments to restore or accelerate serotonergic reinnervation are of considerable interest. Intermittent hypoxia (IH) was reported to increase serotonin innervation near respiratory motor neurons in spinal intact rats, and to improve function after cSCI. Here, we tested the hypotheses that spontaneous serotonergic reinnervation of key respiratory (phrenic and intercostal) motor nuclei: 1) is partially restored 12 weeks post C2 hemisection (C2Hx); 2) is enhanced by IH; and 3) results from sprouting of spared crossed-spinal serotonergic projections below the site of injury. Serotonin was assessed via immunofluorescence in male Sprague Dawley rats with and without C2Hx (12 wks post-injury); individual groups were exposed to 28 days of: 1) normoxia; 2) daily acute IH (dAIH28: 10, 5 min 10.5% O2 episodes per day; 5 min normoxic intervals); 3) mild chronic IH (IH28-5/5: 5 min 10.5% O2 episodes; 5 min intervals; 8 h/day); or 4) moderate chronic IH (IH28-2/2: 2 min 10.5% O2 episodes; 2 min intervals; 8 h/day), simulating IH experienced during moderate sleep apnea. After C2Hx, the number of ipsilateral serotonergic structures was decreased in both motor nuclei, regardless of IH protocol. However, serotonergic structures were larger after C2Hx in both motor nuclei, and total serotonin immunolabeling area was increased in the phrenic motor nucleus but reduced in the intercostal motor nucleus. Both chronic IH protocols increased serotonin structure size and total area in the phrenic motor nuclei of uninjured rats, but had no detectable effects after C2Hx. Although the functional implications of fewer but larger serotonergic structures are unclear, we confirm that serotonergic reinnervation is substantial following injury, but IH does not affect the extent of reinnervation., (Copyright © 2021. Published by Elsevier Inc.)

Background: Unilateral diaphragmatic paralysis (UDP) has major clinical and etiological implications and, therefore, is important to diagnose. Lung function tests and invasive transdiaphragmatic pressure (Pdi) measurements are widely used to this end but, contrary to phrenic nerve conduction study (NCS), they require volitional maneuvers and/or may be poorly tolerated by patients. The purpose of this study was to compare the diagnostic accuracy of Pdi and phrenic NCS for UDP., Methods: We retrospectively reviewed 28 patients with suspected UDP. The diagnosis established during a multidisciplinary meeting was the reference standard., Results: Phrenic NCS correlated well with Pdi (r = 0.82, P < .005), and the two tests showed good agreement (κ = 0.82, P < .005). Phrenic NCS and Pdi measurements both had 95% sensitivity, 87.5% specificity, 95% positive predictive, and 87.5% negative predictive values., Conclusions: Both tests were highly sensitive and specific. Phrenic NCS measurement is a simple, reproducible, noninvasive method whose results correlate well with Pdi and provide insight into the UDP mechanism. In the most difficult cases, combining lung function tests, respiratory muscle assessments, and phrenic NCS can help to establish the diagnosis., (© 2020 Wiley Periodicals LLC.)

Background: Diaphragm Pacing(DP) demonstrates benefits over mechanical ventilation(MV) for spinal cord injured(SCI) patients. The hypothesis of this report is that phrenic nerve conduction study(PNCS) results cannot differentiate success or failure in selection of patients for DP. Direct surgical evaluation of the diaphragm should be performed., Methods: Observational report of prospective databases of patients undergoing laparoscopic evaluation of their diaphragms to assess for ability to stimulate to cause contraction for ventilation., Results: In 50 SCI patients who could not be weaned from MV, PNCS results showed latencies in stimulated patients (n = 44) and non-stimulated(n = 6) overlapped (7.8 ± 2.5 ms vs 9.4 ± 2.8 ms) and the null hypothesis cannot be rejected (p-value>0.05). Amplitudes overlapped (0.4 ± 0.2 mV vs 0.2 ± 0.2 mV) and the null hypotheses cannot be rejected (P-value >0.05). In 125 non SCI patients with diaphragm paralysis, there were 78(62.4%) with false negative PNCS., Conclusion: PNCS are inadequate pre-operative studies. Direct laparoscopic evaluation should be offered for all SCI patients to receive the benefit of DP., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with refractory epilepsy. Centrally-mediated respiratory dysfunction has been identified as one of the principal mechanisms responsible for SUDEP. Seizures generate a surge in adenosine release. Elevated adenosine levels suppress breathing. Insufficient metabolic clearance of a seizure-induced adenosine surge might be a precipitating factor in SUDEP. In order to deliver targeted therapies to prevent SUDEP, reliable biomarkers must be identified to enable prompt intervention. Because of the integral role of the phrenic nerve in breathing, we hypothesized that suppression of phrenic nerve activity could be utilized as predictive biomarker for imminent SUDEP. We used a rat model of kainic acid-induced seizures in combination with pharmacological suppression of metabolic adenosine clearance to trigger seizure-induced death in tracheostomized rats. Recordings of EEG, blood pressure, and phrenic nerve activity were made concomitant to the seizure. We found suppression of phrenic nerve burst frequency to 58.9% of baseline (p < 0.001, one-way ANOVA) which preceded seizure-induced death; importantly, irregularities of phrenic nerve activity were partly reversible by the adenosine receptor antagonist caffeine. Suppression of phrenic nerve activity may be a useful biomarker for imminent SUDEP. The ability to reliably detect the onset of SUDEP may be instrumental in the timely administration of potentially lifesaving interventions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

High spinal cord injuries (SCI) lead to permanent respiratory insufficiency, and the search for new therapeutics to restore this function is essential. To date, the most documented preclinical model for high SCI is the rat cervical C2 hemisection. However, molecular studies with this SCI model are limited due to the poor availability of genetically modified specimens. The aim of this work was to evaluate the pathophysiology of respiratory activity following a cervical C2 injury at different times post-injury in a C57BL/6 mouse model. No significant spontaneous recovery of diaphragmatic activity was observed up to 30 days post-injury in eupneic condition. However, during a respiratory challenge, i.e. mild asphyxia, a partial restoration of the injured diaphragm was observed at 7 days post-injury, corresponding to the crossed phrenic phenomenon. Interestingly, the diaphragmatic recording between 2 respiratory bursts on the injured side showed an amplitude increase between 1-7 days post-injury, reflecting a change in phrenic motoneuronal excitability. This increase in inter-burst excitability returned to pre-injured values when the crossed phrenic phenomenon started to be effective at 7 days post-injury. Taken together, these results demonstrate the ability of the mouse respiratory system to express long-lasting plasticity following a C2 cervical hemisection and genetically modified animals can be used to study the pathophysiological effects on these plasticity phenomena., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Neuralgic amyotrophy is a poorly understood neuromuscular disorder affecting peripheral nerves mostly within the brachial plexus distribution but can also involve other sites including the phrenic nerve. In the classic form of the syndrome it causes proximal upper limb and neck pain on the affected side with subsequent muscle weakness that can be highly heterogeneous. Nocturnal noninvasive ventilation support is a first-line treatment after phrenic mononeuropathy. The regular monitoring of diaphragm function with spirometry and diaphragm ultrasound can help determine prognosis and inform decision-making., Competing Interests: Disclosure The authors have no disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Moderate acute intermittent hypoxia (AIH) elicits a persistent, serotonin-dependent increase in phrenic amplitude, known as phrenic long-term facilitation (pLTF). Although pLTF was originally demonstrated by carotid sinus nerve stimulation, AIH still elicits residual pLTF in carotid denervated (CBX) rats via a distinct, but unknown mechanism. We hypothesized that exaggerated hypoxia-induced hypotension after carotid denervation leads to greater spinal tissue hypoxia and extracellular adenosine accumulation, thereby triggering adenosine 2A receptor (A 2A )-dependent pLTF. Phrenic activity, arterial pressure and spinal tissue oxygen pressure were measured in anesthetized CBX rats. Exaggerated hypoxia-induced hypotension after CBX was prevented via intravenous phenylephrine; without the hypotension, spinal tissue hypoxia during AIH was normalized, and residual pLTF was no longer observed. Spinal A 2A (MSX-3), but not serotonin 2 receptor (5-HT 2 ) inhibition (ketanserin), abolished residual pLTF in CBX rats. Thus, pLTF regulation may be altered in conditions impairing sympathetic activity and arterial pressure regulation, such as spinal cord injury., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Central sleep apnea (CSA) is a highly common comorbidity in heart failure (HF) patients and is known to deteriorate quality of life and prognosis. Effective treatment options are scarce. Transvenous phrenic nerve stimulation (PNS) has been shown to be effective and safe in CSA treatment in HF. However, lead implantation may be difficult or fail due to anatomical or technical challenges. We report novel and innovative approaches applying different interventional techniques to enhance PNS implantation success, allowing otherwise missing CSA treatment., Methods: Twenty-seven consecutive HF patients (86% male, mean age: 69 ± 11 years; reduced left ventricular ejection fraction in 16 patients (57%)) were included in this study who were unable to tolerate or had contraindications for mask-based therapy. We evaluated PNS total implantation success, procedural characteristics, and feasibility and success rates of intravascular interventions to facilitate PNS lead implantation in otherwise ineffective procedures., Results: Seven lead implantation attempts (24%) required additional intravascular interventional action to facilitate successful implantation, mainly consisting of balloon angioplasties to allow optimal PNS lead placement. Two procedures remained unsuccessful and two patients underwent a second procedure due to stimulation side effects and lead fracture respectively. All over, no complications resulted from application of interventional techniques to achieve a 93% implantation success rate., Conclusion: Transvenous PNS lead placement for CSA treatment can be difficult and challenging. However, interventional intravascular techniques markedly increase implantation success and thereby allow application of this therapy for effective CSA treatment in most patients without additional complications.

The role of the different components of the respiratory network in the mediation of opioid-induced respiratory depression is still unclear. We investigated the contribution of the preBötzinger Complex (preBötC) and the neighbouring Bötzinger Complex (BötC) and inspiratory portion of the ventral respiratory group (iVRG) in anesthetized, vagotomized, paralyzed and artificially ventilated adult rabbits making use of bilateral microinjections (30-50 nl) of the μ-opioid receptor agonist [D-Ala 2 , N-Me-Phe 4 , Gly 5 -ol]-enkephalin (DAMGO). Dose-dependent effects were observed. In the preBötC and the BötC 0.1 mM DAMGO microinjections caused mainly reductions in peak phrenic amplitude associated with tonic phrenic activity and irregular (ataxic) patterns of breathing that were more pronounced in the preBötC. Apneic effects developed at 0.5 mM. In the iVRG DAMGO provoked decreases in amplitude and frequency of phrenic bursts at 0.1 mM and apnea at 0.5 mM. Local 5 mM naloxone reversed the apneic effects. The results imply that different components of the respiratory network may contribute to opioid-induced respiratory disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In patients with moderate-to-severe Chronic Obstructive Pulmonary Disorder (COPD), pulmonary hyperinflation can occur at rest and increase during episodes of exacerbation. Among other mechanical constraints, changes in position and configuration of the diaphragm are also induced by increased end-expiratory lung volume. Both descent and flattening of diaphragm might damage the phrenic nerves by stretching their fibers. The study aimed to investigate the phrenic nerve conduction in COPD patients in stable conditions and during COPD exacerbation. In a group of 11 COPD patients without relevant comorbidities in stable conditions and subsequently in another group of 10 COPD patients during in-hospital COPD exacerbation and recovery, measurements of functional respiratory parameters and assessment of phrenic nerves motor conduction by bilateral electric stimulation were performed concurrently. Significant increase in phrenic nerves latency ( p  < 0.05), but similar amplitude of motor compound muscle action potential (cMAP) was observed in stable COPD patients vs. matched controls ( p  < 0.05). However, in COPD patients with resting pulmonary hyperinflation as reliably detected by substantial Inspiratory Capacity reduction (<80% pred.), the mean bilateral latency was longer vs. COPD patients without pulmonary hyperinflation ( p  < 0.02). During COPD exacerbation, in contrast with mean latency, the mean amplitude of phrenic nerves cMAP improved at discharge when compared with in-hospital admission ( p  < 0.05). In stable COPD patients the velocity of phrenic nerve conduction was impaired mostly in the presence of pulmonary hyperinflation, while during COPD exacerbation where dynamic pulmonary hyperinflation abruptly occurs, the reversible decrease of cMAP amplitude does suggest a temporary, acute axonal damage of phrenic nerves, potentially contributing to diaphragmatic dysfunction in these circumstances.

Background: Lung transplantation is a complex but effective treatment of end-stage pulmonary disease. Among the post-operative complications, phrenic nerve injury, and consequent diaphragmatic dysfunction are known to occur but are hitherto poorly described. We aimed to investigate the effect of lung transplantation on diaphragmatic function with a multimodal approach., Methods: A total of 30 patients were studied at 4 time points: pre-operatively, at discharge after surgery, and after approximately 6 and subsequently 12 months post surgery. The diaphragmatic function was studied in terms of geometry (assessed by the radius of the diaphragmatic curvature delineated on chest X-ray), weakness (considering changes in forced vital capacity when the patient shifted from upright to supine position), force (maximal pressure during sniff), mobility (excursion of the dome of the diaphragm delineated by ultrasound), contractility (thickening fraction assessed by ultrasound), electrical activity (latency and area of compound muscle action potential during electrical stimulation of phrenic nerve), and kinematics (relative contribution of the abdominal compartment to tidal volume)., Results: Despite good clinical recovery (indicated by spirometry and 6 minutes walking test), a reduction of the diaphragmatic function was detected at discharge; it persisted 6 months later to recover fully 1 year after transplantation. Diaphragmatic dysfunction was demonstrated in terms of force, weakness, electrical activity, and kinematics. Our data suggest that the dysfunction was caused by phrenic nerve neurapraxia or moderate axonotmesis, potentially as a consequence of the surgical procedure (i.e., the use of ice and pericardium manipulation)., Conclusions: The occurrence of diaphragmatic dysfunction in patients with a good clinical recovery indicates that the evaluation of diaphragmatic function should be included in the post-operative assessment after lung transplantation., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Phrenic nerve injury (PNI) remains one of the most frequent complications during cryoballoon-based pulmonary vein isolation (CB-PVI). Since its introduction in 2013, the use of compound motor action potential (CMAP) for the prevention of PNI during CB-PVI is increasing; however, systematic outcome data are sparse., Methods: The CMAP technique was applied in conjunction with abdominal palpation during pacing manoeuvres (10 mV, 2 ms) from the superior vena cava for 388 consecutive patients undergoing CB-PVI between January 2015 and May 2017 at our tertiary arrhythmia centre. Cryoablation was immediately terminated when CMAP amplitude was reduced by 30%., Results: Reductions in CMAP amplitude were observed in 16 (4%) of 388 patients during isolation of the right veins. Of these, 11 (69%) patients did not manifest a reduction in diaphragmatic excursions. The drop in CMAP amplitude was observed in 10 (63%) patients during ablation of the right superior pulmonary veins (PVs) and in 7 (44%) patients during ablation of the right inferior PVs. Postprocedural persistent PNI was observed in three of four patients for a duration of 6 months, with one of these patients remaining symptomatic at the 24-month follow-up. One of the four patients was lost to long-term follow-up., Conclusions: All PNIs occurred during right-sided CB-PVI and were preceded by a reduction in CMAP amplitude. Thus, the standardized use of CMAP surveillance during CB-PVI is easily applicable, reliable and compared with other studies, results in a lower number of PNIs., Competing Interests: The authors have declared that no competing interests exist.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by deleterious mutations in the DMD gene which encodes the dystrophin protein. Skeletal muscle weakness and eventual muscle degradation due to loss of dystrophin are well-documented pathological hallmarks of DMD. In contrast, the neuropathology of this disease remains understudied despite the emerging evidence of neurological abnormalities induced by dystrophin loss. Using quantitative morphological analysis of nerve sections, we characterize axonopathies in the phrenic and hypoglossal (XII) nerves of mdx mice. We observe dysfunction in these nerves - which innervate the diaphragm and genioglossus respectively - that we propose contributes to respiratory failure, the most common cause of death in DMD. These observations highlight the importance in the further characterization of the neuropathology of DMD. Additionally, these observations underscore the necessity in correcting both the nervous system pathology in addition to skeletal muscle deficits to ameliorate this disease.

Patients with intensive care unit-acquired weakness have an increased risk of prolonged mechanical ventilation, which is a risk factor for prolonged stay and mortality. The most common cause of this problem is weakness of the diaphragm, which can derive from phrenic nerve injury associated with critical neuropathy, or with the complex multiorgan failure/systemic respiratory response syndrome causing muscle fiber lesion. Two conventional neurophysiological techniques are useful to investigate the respiratory muscles, phrenic nerve conduction, and needle electromyography of the accessory respiratory muscles and diaphragm. Phrenic nerve stimulation is a standard noninvasive technique; amplitude of the motor response can be reduced because of muscle fiber inexcitability or axonal loss. Electromyography of the diaphragm is an invasive method but is safe if performed as indicated. It can reveal neurogenic or myopathic motor units. Although these neurophysiological methods have limitations in the investigation of intensive care unit patients with severe respiratory involvement, normal phrenic nerve responses should exclude marked axonal loss and indicate a better prognosis.

Objectives: Maintaining diaphragm work using electrical stimulation during mechanical ventilation has been proposed to attenuate ventilator-induced diaphragm dysfunction. This study assessed the safety and feasibility of temporary percutaneous electrical phrenic nerve stimulation on user-specified inspiratory breaths while on mechanical ventilation., Design: Two-center, nonblinded, nonrandomized study., Setting: Hospital ICU., Patients: Twelve patients mechanically ventilated from 48 hours to an expected 7 days., Interventions: Leads were inserted to lie close to the phrenic nerve in the neck region using ultrasound guidance. Two initial patients had left-sided placement only with remaining patients undergoing bilateral lead placement. Percutaneous electrical phrenic nerve stimulation was used for six 2-hour sessions at 8-hour intervals over 48 hours., Measurements and Main Results: Data collected included lead deployment success, nerve conduction, ventilation variables, work of breathing, electrical stimulation variables, stimulation breath synchrony, and diaphragm thickness measured by ultrasound at baseline, 24, and 48 hours. Primary endpoints included ability to capture the left and/or right phrenic nerves and maintenance of work of breathing within defined limits for 80% of stimulated breaths. Lead insertion was successful in 21 of 22 attempts (95.5%). Analysis of 36,059 stimulated breaths from 10 patients with attempted bilateral lead placement demonstrated a mean inspiratory lag for phrenic nerve stimulation of 23.7 ms (p < 0.001 vs null hypothesis of <88ms). Work of breathing was maintained between 0.2 and 2.0 joules/L 96.8% of the time, exceeding the 80% target. Mean diaphragm thickness increased from baseline by 7.8% at 24 hours (p = 0.022) and 15.0% at 48 hours (p = 0.0001) for patients receiving bilateral stimulation after excluding one patient with pleural effusion. No serious device/procedure-related adverse events were reported., Conclusions: The present study demonstrated the ability to safely and successfully place percutaneous electrical phrenic nerve stimulation leads in patients on mechanical ventilation and the feasibility of using this approach to synchronize electrical stimulation with inspiration while maintaining work of breathing within defined limits.

Phrenic motor neuron (PhMN) development in early onset hypertonia is poorly understood. Respiratory disorders are one of the leading causes of morbidity and mortality in individuals with early onset hypertonia, such as cerebral palsy (CP), but they are largely overshadowed by a focus on physical function in this condition. Furthermore, while the brain is the focus of CP research, motor neurons, via the motor unit and neurotransmitter signaling, are the targets in clinical interventions for hypertonia. Furthermore, critical periods of spinal cord and motor unit development also coincide with the timing that the supposed brain injury occurs in CP. Using an animal model of early-onset spasticity ( spa mouse [B6.Cg-Glrbspa/J] with a glycine receptor mutation), we hypothesized that removal of effective glycinergic neurotransmitter inputs to PhMNs during development will result in fewer PhMNs and reduced PhMN somal size at maturity. Adult spa (Glrb-/-), and wild-type (Glrb+/+) mice underwent unilateral retrograde labeling of PhMNs via phrenic nerve dip in tetramethylrhodamine. After three days, mice were euthanized, perfused with 4% paraformaldehyde, and the spinal cord excised and processed for confocal imaging. Spa mice had ~30% fewer PhMNs ( P = 0.005), disproportionately affecting larger PhMNs. Additionally, a ~22% reduction in PhMN somal surface area ( P = 0.019), an 18% increase in primary dendrites ( P < 0.0001), and 24% decrease in dendritic surface area ( P = 0.014) were observed. Thus, there are fewer larger PhMNs in spa mice. Fewer and smaller PhMNs may contribute to impaired diaphragm neuromotor control and contribute to respiratory morbidity and mortality in conditions of early onset hypertonia. NEW & NOTEWORTHY Phrenic motor neuron (PhMN) development in early-onset hypertonia is poorly understood. Yet, respiratory disorders are a common cause of morbidity and mortality. In spa mice, an animal model of early-onset hypertonia, we found ~30% fewer PhMNs, compared with controls. This PhMN loss disproportionately affected larger PhMNs. Thus, the number and heterogeneity of the PhMN pool are decreased in spa mice, likely contributing to the hypertonia, impaired neuromotor control, and respiratory disorders.

Objective: Phrenic nerve conduction study is a marker of hypoventilation in amyotrophic lateral sclerosis. We aimed to evaluate its intra-rater reliability in healthy subjects and in a cohort of Primary Lateral Sclerosis (PLS) patients., Methods: Eighteen healthy subjects and 16 PLS patients were included. All subjects underwent three phrenic nerve conduction evaluations (time interval: 1 week for healthy controls; 1 year for PLS patients). We analyzed intra-rater reliability for five parameters of the diaphragmatic motor response: latency; negative-peak duration, area and amplitude; peak-to-peak amplitude., Results: Healthy subjects showed excellent inter-test reliability for most parameters (coefficients of variation <10%). In PLS patients coefficients of variation resulted <10% for latency and peak-to-peak amplitude, <20% for remaining parameters. Inter-test reliability was excellent for latency and peak-to-peak amplitude [intra-class correlation coefficient (ICC) > 0.9] and good for negative-peak amplitude and area (ICC 0.75 ≥ 0.9); duration was not reliable (ICC = 0.383). Negative peak and peak-to-peak amplitude had the least random error (respectively ±0.136 mV and ± 0.177 mV). All parameters showed homoscedasticity (R2 < 0.1)., Conclusions: Intra-rater reliability is high for phrenic nerve study, especially for latency, peak-to-peak and negative-peak amplitude., Significance: Phrenic nerve conduction study is a reliable method to monitor respiratory function., Competing Interests: Declaration of Competing Interest The authors report no conflict of interests., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: A significant role of the left atrial appendage (LAA) in the genesis of atrial fibrillation (AF) has been described. Left atrial appendage electrical isolation (LAAEI) confers substantial long-term clinical benefits. Nevertheless, the left phrenic nerve (LPN) is in the vicinity of the LAA and can be injured during radiofrequency ablation at the ostial level., Objective: The purpose of this study was to describe our experience mapping the LPN, its anatomic relationships to the LAA and alternative approaches to isolate this structure when the LPN is located at the LAA ostium., Methods: Patients undergoing LAAEI for nonparoxysmal AF were included in this study. We attempted to localize the LPN with high-output pacing (20 mA/2 ms). Cases were classified into 4 groups (distal, middle, proximal segment and unmappable) based on the position of the LPN in electroanatomic mapping in the posterior wall of the LAA., Results: A total of 66 cases were included in this study. The LPN was mapped in the distal segment in 27 cases (40.9%); in the middle segment in 22 (33.3%); and at the proximal segment/ostium in 3 (4.5%); the LPN was unmappable in 14 cases (21.2%). In the 3 patients in whom the LPN was at the ostial level or crossing the ostium, segmental LAAEI was attempted in 2, with successful LAAEI achieved in 1 case. There was no LPN injury., Conclusion: LPN mapping is feasible and should be routinely performed to prevent LPN injury during LAAEI., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Respiratory disturbances present in Parkinson's disease (PD) are not well understood. Thus, studies in animal models aimed to link brain dopamine (DA) deficits with respiratory impairment are needed. Adult Wistar rats were lesioned with injection of 6-hydroxydopamine (6-OHDA) into the third cerebral ventricle. Two weeks after hypoxic test was performed in whole-body plethysmography chamber, phrenic (PHR) and hypoglossal (HG) nerve activities were recorded in normoxic and hypoxic conditions in anesthetized, vagotomized, paralyzed and mechanically ventilated rats. The effects of activation and blockade of dopaminergic carotid body receptors were investigated during normoxia in anesthetized spontaneously breathing rats. 6-OHDA injection affected resting respiratory pattern in awake animals: an increase in tidal volume and a decrease in respiratory rate had no effect on minute ventilation. Hypoxia magnified the amplitude and minute activity of the PHR and HG nerve of 6-OHDA rats. The ratio of pre-inspiratory to inspiratory HG burst amplitude was reduced in normoxic breathing. Yet, the ratio of pre-inspiratory time to total time of the respiratory cycle was increased during normoxia. 6-OHDA lesion had no impact on DA and domperidone effects on the respiratory pattern, which indicate that peripheral DA receptors are not affected in this model. Analysis of monoamines confirmed substantial striatal depletion of dopamine, serotonin and noradrenaline (NA) and reduction of NA content in the brainstem. In bilateral 6-OHDA model changes in activity of both nerves: HG (linked with increased apnea episodes) and PHR are present. Demonstrated respiratory effects could be related to specific depletion of DA and NA.

Background: The objective of this study was to characterize phrenic nerve and brachial plexus variation encountered during supraclavicular decompression for neurogenic thoracic outlet syndrome and to identify associated postoperative neurologic complications., Methods: A multicenter retrospective review was performed to evaluate anatomic variation of the phrenic nerve and brachial plexus from November 2010 to July 2018. After initial characterization, the following two groups were identified: variant anatomy (VA) group and standard anatomy (SA) group. Complications were analyzed and compared between the two groups., Results: In total, 105 patients were identified, and 100 patients met inclusion criteria. Any anatomic variation of the standard course or configuration of the phrenic nerve and/or brachial plexus was encountered in 47 (47%) patients. Phrenic nerve anatomic variations were identified in 28 (28%) patients. These included 9 duplicated nerves, 6 lateral accessory nerves, 8 medial displacement, and 5 lateral displacement. Brachial plexus anatomic variation was found in 34 (34%) patients. The most common variant configuration of a fused middle and inferior trunk was identified in 25 (25%) patients. Combined phrenic nerve and brachial plexus anatomic variation was demonstrated in 15 (15%) patients. The VA and SA groups consisted of 47 and 53 patients, respectively. Transient phrenic nerve injury with postoperative elevation of the ipsilateral hemidiaphragm was documented in 3 (6.4%) patients in the VA group and 6 (11.3%) patients in the SA group (P = 0.49). Permanent phrenic nerve injury was identified in 1 (2.1%) patient in the VA group (P = 0.47) and none in the SA group. Transient brachial plexopathy was encountered in 1 (1.9%) patient in the SA group (P = 1.0) with full recovery to normal function., Conclusions: Anatomic variability of the phrenic nerve and brachial plexus are encountered more frequently than previously reported. While the incidence of nerve injury is low, surgeons operating within the thoracic aperture should be familiar with variant anatomy to reduce postoperative complications., (Published by Elsevier Inc.)

The pathophysiology of respiratory muscle weakness in myotonic dystrophy type 1 (DM1) remains incompletely understood. 21 adult patients with DM1 (11 men, 42 ± 13 years) and 21 healthy matched controls underwent spirometry, manometry, and diaphragm ultrasound. In addition, surface electromyography of the diaphragm and the obliquus abdominis muscle was performed following cortical and posterior cervical magnetic stimulation (CMS) of the phrenic nerves or magnetic stimulation of the lower thoracic nerve roots. Magnetic stimulation was combined with invasive recording of the twitch transdiaphragmatic and gastric pressure (twPdi and twPgas) in 10 subjects per group. The following parameters were reduced in DM1 patients compared to control subjects: maximum inspiratory pressure (MIP; 40.3 ± 19.2 vs. 95.8 ± 28.5 cmH 2 O, p < 0.01), diaphragm thickening ratio (DTR; 2.0 ± 0.4 vs. 2.7 ± 0.6, p < 0.01), twPdi following CMS (10.8 ± 8.3 vs. 21.4 ± 10.1 cmH2O, p = 0.03), and amplitude of diaphragm compound muscle action potentials (0.10 ± 0.25 vs. 0.46 ± 0.35 mV; p = 0.04). MIP and DTR were significantly correlated with the muscular impairment rating scale (MIRS) score. Maximum expiratory pressure (MEP) was reduced in DM1 patients compared to controls (41.3 ± 13.4 vs. 133.8 ± 28.0 cmH2O, p < 0.01) and showed negative correlation with the MIRS score. Pgas following a maximum cough was markedly lower in patients than in controls (71.9 ± 43.2 vs. 102.4 ± 35.5 cmH 2 O) but without statistical significance (p = 0.06). In DM1, respiratory muscle weakness relates to clinical disease severity and involves inspiratory and probably expiratory muscle strength. Axonal phrenic nerve pathology may contribute to diaphragm dysfunction., (Copyright © 2019 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? What are the alterations in respiratory motor activity that may underlie ventilatory dysfunctions in juvenile and adult animals exposed to postnatal chronic intermittent hypoxia? What is the main finding and its importance? Postnatal chronic intermittent hypoxia modifies the motor activity to pumping and upper airway respiratory muscles in rats, mediated by epigenetic DNA hypermethylation, enhancing resting pulmonary ventilation and predisposing to collapse of the upper airways in juvenile and adult life., Abstract: Periods of apnoea, commonly observed in prematures and newborns, are an important risk factor for the development of cardiorespiratory diseases in adulthood. In the present study, we evaluated changes in pulmonary ventilation and respiratory motor pattern in juvenile and adult rats exposed to postnatal chronic intermittent hypoxia (pCIH). Newborn male Holtzman rats (P1) were submitted to pCIH (6% O 2 for 30 s, every 9 min, 8 h a day (09.30-17.30 h)) during their first 10 days of life, while control animals were maintained under normoxic conditions (20.8% O 2 ). Thereafter, animals of both groups were maintained under normoxia until the experiments. Unanaesthetized juvenile pCIH rats (n = 27) exhibited elevated tidal volume and respiratory irregularities (P < 0.05) compared to control rats (n = 7). Decerebrate, arterially perfused in situ preparations of juvenile pCIH rats (n = 11) displayed augmented phrenic nerve (PN) burst amplitude and reduced central vagus nerve activity in comparison to controls (n = 10). At adulthood, pCIH rats (n = 5) showed enhanced tidal volume (P < 0.05) and increased respiratory variability compared to the control group (n = 5). The pCIH-induced changes in ventilation and respiratory motor outputs were prevented by treatment with the DNA methyltransferase inhibitor decitabine (1 mg kg -1 , i.p.) during the exposure to pCIH. Our data demonstrate that pCIH in rats impacts, in a persistent way, control of the respiratory pattern, increasing PN activity to the diaphragm and reducing the vagal-related activity to laryngeal muscles, which, respectively, may contribute to improve resting pulmonary ventilation and predispose to collapse of the upper airways during quiet breathing., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Objectives: To assess the prognostic value of phrenic nerve conduction (PNC) in amyotrophic lateral sclerosis (ALS)., Methods: We conducted a systematic review to identify studies reporting on PNC, and mortality and/or forced vital capacity (FVC) in patients with ALS. We searched Medline, EMBASE, and Web of Science. Two independent authors selected studies and extracted data. Risk of bias was assessed using the QUIPS tool. Hazard-ratios and correlation coefficients were pooled using a random effects generic inverse-variance model. Evidence quality was evaluated with GRADE., Results: In the pooled analysis, patients with CMAP-amplitude equal or below 0.4 mV are 2.021 more likely to die over the studied period (95%CI 1.161-3.522; I 2  = 55.9%; 338 participants). CMAP-amplitude showed a moderate positive correlation with FVC (r = 0.400, 95%CI = 0.226-0.550; I 2  = 69.77%; 381 participants). However, there was a weak negative correlation between CMAP-latency and FVC (r = -0.235; 95%CI = -0.447 to -0.024; I 2  = 15.92%; 112 participants)., Conclusions: There is moderate-quality evidence that CMAP-amplitude of the PNC is correlated with FVC. Results favour a predictive value for mortality, but the risk of bias is high., Significance: PNC is a simple test that should be considered to assess respiratory function in ALS, especially in patients with bulbar involvement or cognitive impairment., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Study Objectives: Early evidence with transvenous phrenic nerve stimulation (PNS) demonstrates improved disease severity and quality of life (QOL) in patients with central sleep apnea (CSA). The goal of this analysis is to evaluate the complete prospective experience with PNS in order to better characterize its efficacy and safety, including in patients with concomitant heart failure (HF)., Methods: Using pooled individual data from the pilot (n = 57) and pivotal (n = 151) studies of the remedē System in patients with predominant moderate to severe CSA, we evaluated 12-month safety and 6- and 12-month effectiveness based on polysomnography data, QOL, and cardiac function., Results: Among 208 combined patients (June 2010 to May 2015), a remedē device implant was successful in 197 patients (95%), 50/57 pilot study patients (88%) and 147/151 pivotal trial patients (97%). The pooled cohort included patients with CSA of various etiologies, and 141 (68%) had concomitant HF. PNS reduced apnea-hypopnea index (AHI) at 6 months by a median of -22.6 episodes/h (25th and 75th percentile; -38.6 and -8.4, respectively) (median 58% reduction from baseline, P < .001). Improvement in sleep variables was maintained through 12 months of follow-up. In patients with HF and ejection fraction ≤ 45%, PNS was associated with improvement in systolic function from 27.0% (23.3, 36.0) to 31.1% (24.0, 41.5) at 12 months (P = .003). In the entire cohort, improvement in QOL was concordant with amelioration of sleep measures., Conclusions: Transvenous PNS significantly improves CSA severity, sleep quality, ventricular function, and QOL regardless of HF status. Improvements, which are independent of patient compliance, are sustained at 1 year and are associated with acceptable safety., (© 2019 American Academy of Sleep Medicine.)

Objective: To evaluate the extent of airway improvement and voice quality in patients with bilateral vocal fold paralysis (BVFP) who underwent selective laryngeal reinnervation surgery., Methods: Seven patients with BVFP caused by thyroid surgeries were enrolled. They underwent selective laryngeal reinnervation surgery. Videostroboscopy data, voice perceptual data (grade [G]), acoustic data, laryngeal electromyography data, and pulmonary function test data were obtained preoperatively and postoperatively., Results: Videostroboscopic videos showed that six patients could achieve moderate-to-maximal abduction in the bilateral vocal folds during inspiration, whereas all patients achieved adduction in the bilateral vocal folds during phonation at 4 to 7 months postoperatively. G score was decreased significantly versus preoperative values (P < 0.05), and vocal functional parameters were improved significantly at 12 months postoperatively (P < 0.05). The aerodynamic parameter of maximum phonation time was significantly longer than the preoperative value (P < 0.05). Most parameters in pulmonary function test recovered to normal reference levels as early as 3 months postoperatively, whereas maximal inspiratory pressure (PImax) values were still slightly lower than normal levels 12 months after surgery. All of these parameters improved significantly versus preoperative values. Electromyographic data at 12 months postoperatively showed full interference potentials in bilateral posterior cricoarytenoid muscles during inspiration and full interference potentials in bilateral thyroarytenoid muscles during phonation in all patients. Moderate electric potentials were seen in left interarytenoid muscle in one failed patient., Conclusion: This new selective laryngeal reinnervation procedure can achieve physiological movements of the bilateral vocal folds in selected patients with BVFP., Level of Evidence: 4. Laryngoscope, 129:2669-2673, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

The present study was designed to evaluate the therapeutic effectiveness and mechanism of acute intermittent hypoxia on respiratory function at distinct injury stages following mid-cervical spinal contusion. In the first experiment, adult male rats received laminectomy or unilateral contusion at 3rd-4th cervical spinal cord at 9 weeks of age. The ventilatory behavior in response to mild acute intermittent hypercapnic-hypoxia (10 episodes of 5 min of hypoxia [10% O 2 , 4% CO 2 , 86% N 2 ] with 5 min of normoxia intervals) was measured by whole-body plethysmography at the acute (∼3 days), subchronic (∼2 weeks), and chronic (∼8 weeks) injury stages. The minute ventilation of contused animals is significantly enhanced following acute intermittent hypercapnic-hypoxia due to an augmentation of the tidal volume at all time-points post-injury. However, acute intermittent hypercapnia-hypoxia-induced ventilatory long-term facilitation was only observed in uninjured animals at the acute stage. During the second experiment, the effect of acute intermittent hypercapnic-hypoxia on respiration was examined in contused animals after a blockade of serotonin receptors, or adenosine 2A receptors. The results demonstrated that acute intermittent hypercapnic-hypoxia-induced enhancement of minute ventilation was attenuated by a serotonin receptor antagonist (methysergide) but enhanced by an adenosine 2A receptor antagonist (KW6002) at the subchronic and chronic injury stages. These results suggested that acute intermittent hypercapnic-hypoxia can induce respiratory recovery from acute to chronic injury stages. The therapeutic effectiveness of intermittent hypercapnic-hypoxia is dampened by the inhibition of serotonin receptors, but a blockade of adenosine 2A receptors enhanced respiratory recovery induced by intermittent hypercapnic-hypoxia.

Study Objective: To evaluate long-term efficacy and safety of phrenic nerve stimulation (PNS) in patients with moderate-to-severe central sleep apnea (CSA) through 3 years of therapy., Methods: Patients in the remedē System Pivotal Trial were observed every 3 months after implant until US Food and Drug Administration approval. At the time of approval and study closure, all patients completed 24 months of follow-up; 33 patients had not reached the 36-month visit. Sleep metrics (polysomnography) and echocardiographic parameters are reported at baseline, 12, 18, and 24 months, in addition to available 36-month sleep results from polygraphy. Safety was assessed through 36 months; however, analysis focused through 24 months and available 36-month results are provided., Results: Patients were assessed at 24 (n = 109) and 36 (n = 60) months. Baseline characteristics included mean age 64 years, 91% male, and mean apnea-hypopnea index 47 events per hour. Sleep metrics (apnea-hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation index, rapid eye movement sleep) remained improved through 24 and 36 months with continuous use of PNS therapy. At least 60% of patients in the treatment group achieved at least 50% reduction in AHI through 24 months. Serious adverse events (SAEs) related to the remedē System implant procedure, device, or therapy through 24 months were reported by 10% of patients, no unanticipated adverse device effects or deaths, and all events resolved. No additional related SAEs were reported between 24 and 36 months., Conclusion: These data suggest beneficial effects of long-term PNS in patients with CSA appear to sustain through 36 months with no new safety concerns., Trial Registration: NCT01816776., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)

Diaphragm weakness in Charcot-Marie-Tooth disease 1A (CMT1A) is usually associated with severe disease manifestation. This study comprehensively investigated phrenic nerve conductivity, inspiratory and expiratory muscle function in ambulatory CMT1A patients. Nineteen adults with CMT1A (13 females, 47 ± 12 years) underwent spiromanometry, diaphragm ultrasound, and magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots, with recording of diaphragm compound muscle action potentials (dCMAP, n = 15), transdiaphragmatic and gastric pressures (twPdi and twPgas, n = 12). Diaphragm motor evoked potentials (dMEP, n = 15) were recorded following cortical magnetic stimulation. Patients had not been selected for respiratory complaints. Disease severity was assessed using the CMT Neuropathy Scale version 2 (CMT-NSv2). Healthy control subjects were matched for age, sex, and body mass index. The following parameters were significantly lower in CMT1A patients than in controls (all P < .05): forced vital capacity (91 ± 16 vs 110 ± 15% predicted), maximum inspiratory pressure (68 ± 22 vs 88 ± 29 cmH 2 O), maximum expiratory pressure (91 ± 23 vs 123 ± 24 cmH 2 O), and peak cough flow (377 ± 135 vs 492 ± 130 L/min). In CMT1A patients, dMEP and dCMAP were delayed. Patients vs controls showed lower diaphragm excursion (5 ± 2 vs 8 ± 2 cm), diaphragm thickening ratio (DTR, 1.9 [1.6-2.2] vs 2.5 [2.1-3.1]), and twPdi (8 ± 6 vs 19 ± 7 cmH 2 O; all P < .05). DTR inversely correlated with the CMT-NSv2 score (r = -.59, P = .02). There was no group difference in twPgas following abdominal muscle stimulation. Ambulatory CMT1A patients may show phrenic nerve involvement and reduced respiratory muscle strength. Respiratory muscle weakness can be attributed to diaphragm dysfunction alone. It relates to neurological impairment and likely reflects a disease continuum., (© 2019 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.)

Background: Herpes zoster can be associated with severe neurological complications., Case Presentation: In this article, we describe the case of a 54-year-old man with herpes zoster affecting his right upper chest and neck region complicated by phrenic nerve palsy and respiratory compromise. The diagnosis of herpes zoster was made based on the classic appearance of the rash and associated neuropathic-type pain. The diagnosis of phrenic nerve palsy was made by chest x-ray and ultrasound., Conclusion: Clinicians should be aware of the possibility of phrenic nerve palsy occurring in patients who have herpes zoster affecting the region of C3,4,5 dermatomes. Although symptoms of unilateral diaphragmatic paresis are usually mild, in patients with obesity or comorbid lung disease, new onset phrenic nerve palsy can lead to significant respiratory compromise., (© 2019 Apiyo et al.)

Key Points: Intermittent reductions in respiratory neural activity, a characteristic of many ventilatory disorders, leads to inadequate ventilation and arterial hypoxia. Both intermittent reductions in respiratory neural activity and intermittent hypoxia trigger compensatory enhancements in inspiratory output when experienced separately, forms of plasticity called inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. Reductions in respiratory neural activity that lead to moderate, but not mild, arterial hypoxia occludes plasticity expression, indicating that concurrent induction of iMF and LTF impairs plasticity through cross-talk inhibition of their respective signalling pathways. Moderate hypoxia undermines iMF by enhancing NR2B-containing NMDA receptor signalling, which can be rescued by exogenous retinoic acid, a molecule necessary for iMF. These data suggest that in ventilatory disorders characterized by reduced inspiratory motor output, such as sleep apnoea, endogenous mechanisms of compensatory plasticity may be impaired, and that exogenously activating respiratory plasticity may be a novel strategy to improve breathing., Abstract: Many forms of sleep apnoea are characterized by recurrent reductions in respiratory neural activity, which leads to inadequate ventilation and arterial hypoxia. Both recurrent reductions in respiratory neural activity and hypoxia activate mechanisms of compensatory plasticity that augment inspiratory output and lower the threshold for apnoea, inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. However, despite frequent concurrence of reduced respiratory neural activity and hypoxia, mechanisms that induce and regulate iMF and LTF have only been studied separately. Here, we demonstrate that recurrent reductions in respiratory neural activity ('neural apnoea') accompanied by cessations in ventilation that result in moderate (but not mild) hypoxaemia do not elicit increased inspiratory output, suggesting that concurrent induction of iMF and LTF occludes plasticity. A key role for NMDA receptor activation in impairing plasticity following concurrent neural apnoea and hypoxia is indicated since recurrent hypoxic neural apnoeas triggered increased phrenic inspiratory output in rats in which spinal NR2B-containing NMDA receptors were inhibited. Spinal application of retinoic acid, a key molecule necessary for iMF, bypasses NMDA receptor-mediated constraints, thereby rescuing plasticity following hypoxic neural apnoeas. These studies raise the intriguing possibility that endogenous mechanisms of compensatory plasticity may be impaired in some individuals with sleep apnoea, and that exogenously activating pathways giving rise to respiratory plasticity may be a novel pharmacological strategy to improve breathing., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Introduction: Phrenic nerve (PN) injury is a well-known complication of cryoballoon ablation (CBA) for pulmonary vein (PV) isolation in patients with atrial fibrillation. However, it is still insufficient to practically predict phrenic nerve injury (PNI) before freezing. We hypothesized that phrenic nerve capture (PNC) with phrenic nerve orifice pacing (PVOP) might be a surrogate sign of the close proximity of the PN, and that might predict PNI and changes in the compound motor action potential (CMAP) amplitude., Methods: Seventy patients (60 ± 12 years, male 80%, paroxysmal 56%) underwent PVOP with a 20-electrode ring catheter before the CBA. The clinical outcome was the occurrence of transient and persistent PNI. In addition, the PV position and pacing threshold during PNC with PVOP, and changes in the CMAP amplitude were recorded. We compared these measurements between patients with and without PNC (PNC/non-PNC group) with PVOP., Results: PNC with PVOP occurred in 39 (56%) patients and was localized only to the right superior PV. Transient PNI occurred in seven (10%) patients and permanent in none. The CMAP amplitude decreased significantly more in the PNC group (PNC 33% vs non-PNC 16%, P = .027). PNC group had a higher risk of the composite outcome of transient PNI or ≥30% decrease in the CMAP amplitude (PNC 54% vs non-PNC 13%; P < .001)., Conclusions: This PVOP technique could be feasible and contribute to predicting transient PNI and CMAP amplitude reductions before cryoapplications. Further studies are necessary to elucidate the additional efficacy of PVOP over CMAP monitoring alone., (© 2019 Wiley Periodicals, Inc.)

The diaphragm is the main breathing muscle and contraction of the diaphragm is vital for ventilation so any disease that interferes with diaphragmatic innervation, contractile muscle function, or mechanical coupling to the chest wall can cause diaphragm dysfunction. Diaphragm dysfunction is associated with dyspnoea, intolerance to exercise, sleep disturbances, hypersomnia, with a potential impact on survival. Diagnosis of diaphragm dysfunction is based on static and dynamic imaging tests (especially ultrasound) and pulmonary function and phrenic nerve stimulation tests. Treatment will depend on the symptoms and causes of the disease. The management of diaphragm dysfunction may include observation in asymptomatic patients with unilateral dysfunction, surgery (i.e., plication of the diaphragm), placement of a diaphragmatic pacemaker or invasive and/or non-invasive mechanical ventilation in symptomatic patients with bilateral paralysis of the diaphragm. This type of patient should be treated in experienced centres. This review aims to provide an overview of the problem, with special emphasis on the diseases that cause diaphragmatic dysfunction and the diagnostic and therapeutic procedures most commonly employed in clinical practice. The ultimate goal is to establish a standard of care for diaphragmatic dysfunction., (Copyright © 2018 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

We examine 2 means by which the healthy respiratory system contributes to exercise limitation. These include the activation of respiratory and locomotor muscle afferent reflexes, which constrain blood flow and hasten fatigue in both sets of muscles, and the excessive increases in pulmonary vascular pressures at high cardiac outputs, which constrain O 2 transport and precipitate maladaptive right ventricular remodeling in endurance-trained subjects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess the acute success rate, periprocedural complications, and long-term outcomes in patients with atrial fibrillation (AF) and persistent left superior vena cava (PLSVC) treated with second-generation 28-mm cryoballoon (CB2)., Background: PLSVC is a cardiac anomaly associated with AF., Methods: Between July 2012 and October 2018, 8 patients from 4 German high-volume centers referred for pulmonary vein isolation (PVI) demonstrated a PLSVC. PVI and ablation within the PLSVC was performed using the CB2., Results: A total of 2,876 patients were treated with CB2-based PVI. Eight patients (0.28%; mean 65 ± 7 years of age, 2 paroxysmal, 6 with persistent AF, mean left atrial size of 44 ± 4 mm) presenting with PLSVC were evaluated. All patients underwent PVI, and 3 of 8 patients with documented triggered activity from PLSVC underwent PLSVC ablation with CB2. Electrical isolation of PLSVC was achieved in 2 of 3 patients. Mean procedure and fluoroscopy times were 120 ± 22 min and 32 ± 18 min, respectively. In 2 of 8 patients, major complications (right phrenic nerve palsy) occurred during right PV ablation. After 3 months, 1 of 2 patients recovered from right phrenic nerve palsy. Two patients underwent a redo procedure after AF recurrence, demonstrating PV reconnection but no triggers from PLSVC. Freedom from AF after 332 days of follow-up was 63%., Conclusions: CB2 ablation for AF in patients with PLSVC is feasible, with an increased risk for right phrenic nerve palsy. Electrical isolation of PLSVC can be achieved with the CB2 in most patients., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)