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A rare but important complication after lung transplantation (LTx) is postoperative phrenic nerve dysfunction (PND). Diaphragmatic plication (DP) is a well-established treatment option for PND, however, the long-term effect of PND and DP on lung function parameters and survival after LTx are currently unknown. We retrospectively reviewed 1400 LTx recipients transplanted at Medical University of Vienna between 01/2003 and 12/2022. Fluoroscopy and/or phrenic nerve conduction studies confirmed PND when chest radiographs after extubation showed a unilateral heightened diaphragm. We identified 25 patients with post-operative PND, of whom 12 underwent DP. The remaining 1,375 patients served as a control group. Median ICU-stay and hospital-stay were significantly longer in the PND groups (DP: 20 and 57 days; non-DP: 27 and 43 days; control group: 7 and 25 days; P = 0.001/ P < 0.001). PND led to consistently lower %TLC in lung function tests performed within the first three years after LTx. DP was associated with lower %FEV1.0 early after LTx but it aligned to %FEV1.0 of the other groups during follow-up. Although PND significantly affected postoperative recovery after LTx, it did not impair long-term survival outcomes.

Background Anesthesia consultation for oncologic patients who require diagnostic imaging may be necessary due to anxiety, claustrophobia, and inability to lie flat secondary to pain, physical limitations, or cardiopulmonary comorbidities. This case report highlights a patient with complex pulmonary comorbidities who successfully underwent Magnetic Resonance Imaging (MRI) with comprehensive planning directed by the anesthesia team with the use of atypical positioning strategies and a flexible MRI coil. Case presentation A 54-year-old man presented with metastatic lung adenocarcinoma complicated by phrenic nerve dysfunction and hemidiaphragmatic paresis, chronic obstructive pulmonary disease (COPD), and recurrent radiation recall pneumonitis (RRP). He also reported recent worsening orthopnea, dyspnea, and persistent cough requiring a steroid taper and daily inhaler treatments. Pulmonary function tests demonstrated severe obstruction, moderate restriction, and poor diffusion capacity. In addition, the patient reported utilizing continuous positive airway pressure (CPAP) at night for symptom relief stemming from hemidiaphragmatic paresis. Given these findings, anesthesia consultation was requested to facilitate the brain MRI, which requires supine, fully recumbent positioning. Due to the patient’s compromised pulmonary status and worsening clinical picture, he was deemed high risk for anesthetic management. After careful consideration, the case proceeded with monitored anesthesia care (MAC), with available resources to escalate anesthetic care if necessary. Initially, trials of ventilator-assisted CPAP in a semi-recumbent position failed due to patient-reported dyspnea and increased work of breathing. Eventually, lateral decubitus positioning was better tolerated and only required oxygen delivery through a simple facemask. However, the standard MRI brain coil was not suitable in this position, thus an alternative “flex” coil was adapted without significantly compromising image quality. Ultimately, this combination of strategies was successful, while avoiding the need for additional pharmacological agents or advanced hemodynamic and airway support. Conclusions This case illustrates the need for innovative, multidisciplinary strategies in non-operating room anesthesia (NORA) settings, which often carry a higher risk of anesthetic complications. In our case, avoiding sedatives and general anesthesia, while adapting patient positioning and equipment, enabled safe and effective imaging conditions. This approach highlights how individualized planning, comprehensive anesthetic considerations, and interprofessional collaboration can overcome significant clinical barriers.

Abstract Background Pulsed field ablation (PFA) is a new feasible and safe method for the ablative treatment of cardiac arrhythmias, such as atrial fibrillation (AF). Through the use of electric fields, it causes pore-like openings in the cell’s wall, leading to cell death. The most appealing characteristic of this new technique is its selectivity for cardiomyocytes and consequently its low risk of collateral damage to extracardiac tissues. We present three cases of a PFA-induced transient phrenic nerve (PN) injury documented during pulmonary vein isolation (PVI). Case summaries Three patients aged 55–81 years underwent PFA for symptomatic AF. Cases 1 and 3 were affected by paroxysmal AF without evidence of structural heart disease. Case 2 had persistent AF and ischaemic cardiomyopathy with preserved ejection fraction. We observed a transient right hemidiaphragm palsy during the delivery of impulses in the right superior pulmonary vein (Cases 1 and 2) and in the right inferior pulmonary vein (Case 3). The palsy lasted <1 min and was followed by spontaneous full recovery in all cases. Discussion Transient PN dysfunction can be observed following PFA in AF ablation. According to our initial experience, a full recovery of the PN function can be expected within seconds. We hypothesize a hyperpolarization of neuronal cells or a depletion of acetylcholine in the motoric endplate to explain this event. Further studies are required to understand the exact pathophysiological mechanism.

Phrenic nerve injury may occur after cardiac surgery; however, its cause has not been extensively investigated with electrophysiology. The purpose of this study was to determine by electrophysiologic means the importance of various possible risk factors in the development of phrenic nerve dysfunction after cardiac surgical operations. A prospective study was conducted. A tertiary teaching hospital provided the background for the study. Sixty-three cardiac surgery patients on whom surgical operations were performed by the same surgical team constituted the study group. Mean (+/-SD) age and ejection fraction were 63+/-5 years and 50+/-10%, respectively. Measurement of phrenic nerve conduction latency time after transcutaneous stimulation preoperatively and at 24 h and 7 and 30 days postoperatively. Thirteen patients had abnormal phrenic nerve function postsurgery, 12 on the left side and one bilaterally. Logistic regression analysis revealed that among the potential risk factors investigated, use of ice slush for myocardial preservation was the only independent risk factor related to phrenic nerve dysfunction (p=0.01), carrying an 8-fold higher incidence for this complication. In contrast, age, ejection fraction of the left ventricle, operative/bypass/aortic cross-clamp time, left internal mammary artery use, and diabetes mellitus were not found to be associated with phrenic neuropathy. The postoperative outcome of patients who received ice slush compared with that of those who had cold saline solution did not differ in terms of early morbidity and mortality. Among the risk factors investigated, only the use of ice slush was significantly associated with postoperative phrenic nerve dysfunction. Therefore, ice should be avoided in cardiac surgery, since it does not seem to provide additional myocardial protection.

Phrenic nerve injury may occur after cardiac surgery; however, its cause has not been extensively investigated with electrophysiology. The purpose of this study was to determine by electrophysiologic means the importance of various possible risk factors in the development of phrenic nerve dysfunction after cardiac surgical operations. A prospective study was conducted. A tertiary teaching hospital provided the background for the study. Sixty-three cardiac surgery patients on whom surgical operations were performed by the same surgical team constituted the study group. Mean (±SD) age and ejection fraction were 63 ±5 years and 50±10%, respectively. Measurement of phrenic nerve conduction latency time after transcutaneous stimulation preoperatively and at 24 h and 7 and 30 days postoperatively. Thirteen patients had abnormal phrenic nerve function postsurgery, 12 on the left side and one bilaterally. Logistic regression analysis revealed that among the potential risk factors investigated, use of ice slush for myocardial preservation was the only independent risk factor related to phrenic nerve dysfunction (p=0.01), carrying an 8-fold higher incidence for this complication. In contrast, age, ejection fraction of the left ventricle, operative/bypass/aortic cross-clamp time, left internal mammary artery use, and diabetes mellitus were not found to be associated with phrenic neuropathy. The postoperative outcome of patients who received ice slush compared with that of those who had cold saline solution did not differ in terms of early morbidity and mortality. Among the risk factors investigated, only the use of ice slush was significantly associated with postoperative phrenic nerve dysfunction. Therefore, ice should be avoided in cardiac surgery, since it does not seem to provide additional myocardial protection.

Ventilator-induced diaphragmatic dysfunction (VIDD) is characterized by diaphragmatic atrophy and contractile failure, leading to prolonged intensive care unit (ICU) stays and increases mortality. While phrenic nerve stimulation (PNS) has demonstrated efficacy in mitigating VIDD by preserving diaphragmatic activity, its underlying molecular mechanisms remain unclear. This study aimed to elucidate the role of competing endogenous RNA (ceRNA) networks in PNS-mediated protection against VIDD through integrated miRNA-Seq and RNA-Seq analyses in a rabbit model. Eleven adult male New Zealand white rabbits were divided into control (n = 4), MV (n = 3) and PNS groups (n = 4). MV and PNS groups underwent 24 h of MV, with intermittent bilateral transvenous PNS applied only to the PNS group. Differentially expressed (DE) analysis of mRNAs, miRNAs and circRNAs across pairwise group comparisons was performed via RNA-seq and miRNA-seq. Functional enrichment analyses (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) identified key pathways. Potential miRNA targets and interacting circRNAs were computationally predicted. An integrated ceRNA network was constructed using major DE RNAs to identify PNS-associated core regulators. CeRNA network was validated by quantitative real-time polymerase chain reaction (RT-qPCR) and dual-luciferase assays. High-throughput sequencing revealed significant dysregulation of miRNAs, circRNAs and mRNAs in the diaphragm following MV which was partially reversed by PNS. Bioinformatic screening identified a ceRNA network, wherein two key miRNAs emerged: miR-500-3p (targeting RAB37 , an autophagy-related gene) and miR-133b-3p (targeting L-selectin , a cell adhesion molecule regulating immune responses and fibrosis). Both miRNAs were down-regulated after MV and restored by PNS. Computational prediction also identified five circRNAs (circRNA_12437, 24673, 14127, 14942, 12463) as putative sponges for these miRNAs, although this interaction lacks experimental confirmation. Dual-luciferase assays confirmed direct binding of miR-500-3p to RAB37 and miR-133b-3p to L-selectin , functionally linking them to PNS-mediated VIDD protection. Enrichment analyses indicated that DE genes were predominantly enriched in phagosome activity and cell adhesion molecule pathways. Collectively, these findings suggest that PNS preserves diaphragmatic function by modulating ceRNA networks to suppress excessive autophagy and immune cell infiltration. This study identifies the first PNS-responsive ceRNA network in VIDD pathogenesis. Our data highlight the potential critical roles of miR-500-3p- RAB37 and miR-133b-3p- L-selectin axes in regulating autophagy and immune responses. These results provide mechanistic insights and suggest potential therapeutic targets for diaphragm dysfunction.

Aging disrupts multiple homeostatic processes, including autophagy, a cellular process for the recycling and degradation of defective cytoplasmic structures. Acute treatment with the autophagy inhibitor chloroquine blunts the maximal forces generated by the diaphragm muscle, but the mechanisms underlying neuromuscular dysfunction in old age remain poorly understood. We hypothesized that chloroquine treatment increases the presynaptic retention of the styryl dye FM 4-64 following high-frequency nerve stimulation, consistent with the accumulation of unprocessed bulk endosomes. Diaphragm-phrenic nerve preparations from 24-month-old male and female C57BL/6 × 129 J mice were incubated with FM 4-64 (5 µM) and either chloroquine (50 µM) or vehicle during 80 Hz phrenic nerve stimulation. Acute chloroquine treatment significantly decreased FM 4-64 intensity at diaphragm neuromuscular junctions following 80 Hz phrenic nerve stimulation, consistent with disrupted synaptic vesicle recycling. A similar reduction was evident in regions with the greatest FM 4-64 fluorescence intensity, which most likely surround synaptic vesicle release sites. In the absence of nerve stimulation, chloroquine treatment significantly increased FM 4-64 intensity at diaphragm neuromuscular junctions. These findings highlight the importance of autophagy in regulating presynaptic vesicle retrieval (including vesicle recycling and endosomal processing) and support the role of autophagy impairments in age-related neuromuscular dysfunction.

Background Ventilator-induced diaphragmatic dysfunction (VIDD) occurs in up to 60% of mechanically ventilated patients and prolongs ventilatory dependance. The consequences of VIDD are muscle atrophy, reduction of strength, and injury of muscle fibers. Atrophy and contractile activity of the diaphragm can be estimated by ultrasound muscle thickness and thickening fraction. Prior experience demonstrates invasive electrical stimulation of the diaphragm helps preserve muscle thickness. This is the first study on a non-invasive phrenic nerve stimulator that aims to assess its feasibility, safety, and usefulness in preserving diaphragm thickness. Methods A multi-center randomized clinical trial will be performed in four intensive care units (ICUs) in the United States of America and Canada. Inclusion criteria include patients older than 21 years, in the first 48 h of mechanical ventilation (MV) and predicted to remain on the ventilator for at least 48 h. Patients with contraindications for phrenic nerve stimulation, severe chronic pulmonary diseases, or impossibility to measure diaphragm thickness with ultrasound will be excluded. Patients enrolled will be randomized to standard care (control) or 30-min daily non-invasive phrenic nerve stimulation up to 10 days after enrollment (intervention). The primary effectiveness endpoint is the change in diaphragm thickness on day 10, extubation, or death whichever occurs first. Secondary endpoints include change in diaphragm thickness on day 4, maximal inspiratory pressure before extubation, and time-to rapid shallow breathing index (RSBI) <105. Safety objectives include the proportion of device- or procedure-related adverse events (SAE). The estimated sample size will be 40 patients (20 per group). Discussion The STIMIT ACTIVATOR trial is a randomized multi-center study powered to elucidate whether non-invasive phrenic nerve stimulation is feasible, safe, and preserves diaphragm thickness. Meeting the primary endpoint will demonstrate its applicability in clinical practice to prevent diaphragmatic atrophy in ventilated patients. Trial registration ClinicalTrials.gov: NCT05883163, August 29, 2023.

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 In the United States in 2017, there were an estimated 903,745 hospitalizations involving mechanical ventilation (MV). Complications from ventilation can result in longer hospital stays, increased risk of disability, and increased healthcare costs. It has been hypothesized that electrically pacing the diaphragm by phrenic nerve stimulation during mechanical ventilation may minimize or reverse diaphragm dysfunction, resulting in faster weaning. Methods The ReInvigorate Trial is a prospective, multicenter, randomized, controlled clinical trial evaluating the safety and efficacy of Stimdia’s pdSTIM System for facilitating weaning from MV. The pdSTIM system employs percutaneously placed multipolar electrodes to stimulate the cervical phrenic nerves and activate contraction of the diaphragm bilaterally. Patients who were on mechanical ventilation for at least 96 h and who failed at least one weaning attempt were considered for enrollment in the study. The primary efficacy endpoint was the time to successful liberation from mechanical ventilation (treatment vs. control). Secondary endpoints will include the rapid shallow breathing index and other physiological and system characteristics. Safety will be summarized for both primary and additional analyses. All endpoints will be evaluated at 30 days or at the time of removal of mechanical ventilation, whichever is first. Discussion This pivotal study is being conducted under an investigational device exception with the U.S. Food and Drug Administration. The technology being studied could provide a first-of-kind therapy for difficult-to-wean patients on mechanical ventilation in an intensive care unit setting. Trial registration Clinicaltrials.gov, NCT05998018 , registered August 2023.