Phrenic nerve stimulation prevents diaphragm atrophy in patients with respiratory failure on mechanical ventilation

Background Diaphragm atrophy and dysfunction is a major problem among critically ill patients on mechanical ventilation. Ventilator-induced diaphragmatic dysfunction is thought to play a major role, resulting in a failure of weaning. Stimulation of the phrenic nerves and resulting diaphragm contraction could potentially prevent or treat this atrophy. The subject of this study is to determine the effectiveness of diaphragm stimulation in preventing atrophy by measuring changes in its thickness. Methods A total of 12 patients in the intervention group and 10 patients in the control group were enrolled. Diaphragm thickness was measured by ultrasound in both groups at the beginning of study enrollment (hour 0), after 24 hours, and at study completion (hour 48). The obtained data were then statistically analyzed and both groups were compared. Results The results showed that the baseline diaphragm thickness in the interventional group was (1.98 ± 0.52) mm and after 48 hours of phrenic nerve stimulation increased to (2.20 ± 0.45) mm (p=0.001). The baseline diaphragm thickness of (2.00 ± 0.33) mm decreased in the control group after 48 hours of mechanical ventilation to (1.72 ± 0.20) mm (p<0.001). Conclusions Our study demonstrates that induced contraction of the diaphragm by pacing the phrenic nerve not only reduces the rate of its atrophy during mechanical ventilation but also leads to an increase in its thickness – the main determinant of the muscle strength required for spontaneous ventilation and successful ventilator weaning. Trial registration: The study was registered with ClinicalTrials.gov (18/06/2018, NCT03559933, https://clinicaltrials.gov/ct2/show/NCT03559933).

853 Severe Obstructive Sleep Apnea after Treatment with Phrenic Nerve Implant for Central Sleep Apnea: A Case for Dual Stimulation?

Introduction The remedē® system is a transvenous phrenic nerve stimulator used to treat central sleep apnea (CSA). It is a safe and effective implantable device that has demonstrated significant improvements in objective sleep and quality of life. While complex sleep apnea represents development of central sleep apnea during treatment with continuous positive airway pressure (CPAP) for obstructive sleep apnea, and has been well-described in the literature, we present a novel case of predominantly central sleep apnea treated with phrenic nerve stimulation with augmentation of obstructive events thereafter. This patient is, at the time of submission, being evaluated for hypoglossal nerve stimulation. Report of case(s) A 63-year-old male patient with a past medical history of hypertension, atrial fibrillation, asthma, chronic obstructive pulmonary disease, GERD, obesity, and prior pulmonary embolism presented to the sleep medicine clinic with complaints of difficulty initiating and maintaining sleep, snoring, multiple nocturnal awakenings, excessive daytime sleepiness, and physical fatigue. On exam, BMI was 30.4, and airway classification was Mallampati 4. Split night polysomnography revealed severe mixed sleep apnea with an overall apnea hypopnea index (AHI) of 58.6 and a central AHI of 53.8 per hour after successful PAP titration at 7 cm H2O. He underwent phrenic nerve stimulator implantation and activation without complications. Phrenic nerve stimulation titration study four months after activation showed a normal central AHI of 4.6 per hour at a therapeutic voltage of 1.6 to 1.9mA, but significantly worse OSA with obstructive AHI of 53.1. In follow up, he reported intolerance of CPAP due to significant nasal congestion as well as asthma. Presently, he is scheduled for drug induced sleep endoscopy to visualize airway obstruction and is being evaluated for Inspire hypoglossal nerve stimulation and nasal surgery. Conclusion The treatment of sleep apnea has recently evolved rapidly with the development of implantable devices to treat both central and obstructive sleep apnea. We present a novel case of the first known patient to be considered for dual nerve stimulation for sleep apnea. Further study needs to be done to determine the safety and efficacy of concurrent implantable devices for the simultaneous treatment of OSA and CSA. Support (if any):

Transvenous phrenic nerve stimulation improves central sleep apnea, sleep quality, and quality of life regardless of prior positive airway pressure treatment

Study objective Positive airway pressure (PAP) therapy for central sleep apnea (CSA) is often poorly tolerated, ineffective, or contraindicated. Transvenous phrenic nerve stimulation (TPNS) offers an alternative, although its impact on previously PAP-treated patients with CSA has not been examined. Methods TPNS responses among PAP-naïve and prior PAP-treated patients from the remedē® System Pivotal Trial were assessed. Of 151, 56 (37%) used PAP therapy before enrolling in the trial. Patients were implanted with a TPNS device and randomized to either active or deferred (control) therapy for 6 months before therapy activation. Apnea-hypopnea index (AHI) and patient-reported outcomes (PRO) were assessed at baseline, and 6 and 12 months following active therapy. Results Patients had moderate-severe CSA at baseline, which was of greater severity and more symptomatic in the PAP-treated vs. PAP-naïve group (median AHI 52/h vs. 38, central apnea index (CAI) 32/h vs. 18, Epworth Sleepiness Scale 13 vs. 10, fatigue severity scale 5.2 vs. 4.5). Twelve months of TPNS decreased AHI to <20/h and CAI to ≤2/h. Both groups showed reductions in daytime sleepiness and fatigue, improved well-being by patient global assessment, and high therapeutic acceptance with 98% and 94% of PAP-treated and PAP-naïve patients indicating they would undergo the implant again. Stimulation produced discomfort in approximately one-third of patients, yet <5% of prior PAP-treated participants discontinued therapy. Conclusion Polysomnographic and clinical responses to TPNS were comparable in PAP-naïve and prior PAP-treated CSA patients. TPNS is a viable therapy across a broad spectrum of CSA patients. Trial registration ClinicalTrials.gov Identifier NCT01816776; March 22, 2013

TrkB Signaling Contributes to Transdiaphragmatic Pressure Generation in Aged Mice

Ventilatory deficits are common in old age and may result from neuromuscular dysfunction. Signaling via the tropomyosin-related kinase receptor B (TrkB) regulates neuromuscular transmission and in young mice is important for the generation of transdiaphragmatic pressure (Pdi). Loss of TrkB signaling worsened neuromuscular transmission failure and reduced maximal Pdi, and these effects are similar to those observed in old age. Administration of TrkB agonists such as 7,8-dihydroxyflavone (7,8-DHF) improves neuromuscular transmission in young and old mice (18 months; 75% survival). We hypothesized that TrkB signaling contributes to Pdi generation in old mice, particularly during maximal force behaviors. Old male and female TrkBF616A mice, with a mutation that induces 1NMPP1-mediated TrkB kinase inhibition, were randomly assigned to systemic treatment with vehicle, 7,8-DHF, or 1NMPP1 one hour prior to experiments. Pdi was measured during eupneic breathing (room air), hypoxia-hypercapnia (10% O2/5% CO2), tracheal occlusion, spontaneous deep breaths ("sighs"), and bilateral phrenic nerve stimulation (Pdimax). There were no differences in the Pdi amplitude across treatments during ventilatory behaviors (eupnea, hypoxia-hypercapnia, occlusion or sigh). As expected, Pdi increased from eupnea and hypoxia-hypercapnia (~7 cm H2O) to occlusion and sighs (~25 cm H2O), with no differences across treatments. Pdimax was ~50 cm H2O in the vehicle and 7,8-DHF groups and ~40 cm H2O in the 1NMPP1 group (F8,74 = 2; p = 0.02). Our results indicate that TrkB signaling is necessary for generating maximal forces by the diaphragm muscle in old mice, and are consistent with aging effects of TrkB signaling on neuromuscular transmission.

Transvenous Phrenic Nerve Stimulation and Positive Airway Pressure devices for Central Sleep Apnea in Patients with Heart Failure with Reduced Ejection Fraction: A Network Meta-analysis

Purpose: Adaptive servo-ventilation (ASV) is contraindicated for central sleep apnea (CSA) treatment in patients with heart failure with reduced ejection fraction (HFrEF) limiting treatment options. Though, continuous positive airway pressure (CPAP), bi-level PAP with back-up rate (BPAP-BUR) and transvenous phrenic nerve stimulation (TPNS) are alternatives, not much is known about their comparative efficacies, which formed the basis of this network meta-analysis, in which their effects on apnea hypopnea index (AHI) and subjective daytime sleepiness (based on Epworth sleepiness score (ESS)), were analyzed.Methods: PubMed was searched for potentially includable randomized controlled trials and network meta-analysis was conducted in R program using package netmeta.Results: Network meta-analysis showed no statistically significant differences between interventions in AHI reduction. In exploring heterogeneity, sensitivity analysis elicited statistically significant differences in AHI reduction between ASV and TPNS (-18.30 [-27.8; -8.79]), with BPAP-BUR (-21.90 [-30.79; -13.01]) and CPAP (-23.10 [-29.22; -16.98]), favoring ASV. Of all the interventions, only TPNS showed a statistically significant decrease in ESS (-3.70 (-5.58; -1.82)) when compared to guideline directed medical therapy (used as a common comparator across trials), while also showing significant differences when compared with ASV (-3.20 (-5.86; -0.54)), BPAP-BUR (-4.00 (-7.33; -0.68)), and CPAP (-4.45 (-7.75; -1.14)). Hasse diagram, accounting for both AHI and ESS as outcomes for relative hierarchy showed relative superiority of both ASV and TPNS over BPAP-BUR and CPAP.Conclusions: Results indicate relative superiority of TPNS and ASV to BPAP-BUR and CPAP in their effects on AHI and ESS reduction in patients with CSA and HFrEF.