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Journal of Clinical Sleep Medicine :... Dec 2020Idiopathic central sleep apnea (ICSA) is a rare disorder diagnosed when known causes of central sleep apnea are excluded. No established treatments exist for ICSA, and...
STUDY OBJECTIVES
Idiopathic central sleep apnea (ICSA) is a rare disorder diagnosed when known causes of central sleep apnea are excluded. No established treatments exist for ICSA, and long-term studies are lacking. We assessed the long-term effectiveness and safety of transvenous phrenic nerve stimulation in patients with ICSA.
METHODS
In the remedē System Pivotal Trial, 16/151 (11%) participants with central sleep apnea were diagnosed as having ICSA. Patients were implanted and followed through 18 months of active therapy. Polysomnograms obtained at baseline and at 6, 12, and 18 months were scored by a central laboratory. Sleep metrics and patient-reported quality of life outcomes were assessed.
RESULTS
Patients experienced moderate-severe central sleep apnea. The baseline AHI, central apnea index, and arousal index were 40, 25, and 32 events/h of sleep, respectively. These metrics improved at 6, 12, and 18 months of therapy: the AHI decreased by 25, 25, and 23 events/h (P < .001 at each visit), the central apnea index by 22, 23, and 22 events/h (P < .001 at each visit), and the arousal index by 12 (P = .005), 11 (P = .035), and 13 events/h (P < .001). Quality of life instruments showed clinically meaningful improvements in daytime somnolence, fatigue, general and mental health, and social functioning. The only related serious adverse event was lead component failure in 1 patient.
CONCLUSIONS
This is the longest prospective study for the treatment of ICSA. Transvenous phrenic nerve stimulation significantly decreased sleep-disordered breathing metrics with consequent improvement in quality of life at 6 months, and all benefits were sustained through 18 months.
CLINICAL TRIAL REGISTRATION
Registry: ClinicalTrials.gov; Name: Respicardia, Inc. Pivotal Trial of the remedē System; URL: https://clinicaltrials.gov/ct2/show/NCT01816776; Identifier: NCT01816776.
Topics: Adult; Electric Stimulation Therapy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phrenic Nerve; Prospective Studies; Quality of Life; Sleep Apnea, Central; Treatment Outcome
PubMed: 32946372
DOI: 10.5664/jcsm.8802 -
The Journal of Physiological Sciences :... Mar 2020Respiratory 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 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.
Topics: Adrenergic Agents; Animals; Brain; Disease Models, Animal; Dopamine; Hypoglossal Nerve; Hypoxia; Male; Norepinephrine; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Phrenic Nerve; Rats; Rats, Wistar; Respiration
PubMed: 32160868
DOI: 10.1186/s12576-020-00743-4 -
Sleep & Breathing = Schlaf & Atmung Dec 2021Positive airway pressure (PAP) therapy for central sleep apnea (CSA) is often poorly tolerated, ineffective, or contraindicated. Transvenous phrenic nerve stimulation... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Aged; Continuous Positive Airway Pressure; Electric Stimulation Therapy; Female; Humans; Implantable Neurostimulators; Male; Middle Aged; Patient Reported Outcome Measures; Phrenic Nerve; Quality of Life; Sleep Apnea, Central; Sleep Quality
PubMed: 33745107
DOI: 10.1007/s11325-021-02335-x -
Acta Medica Okayama Dec 2018We studied phrenic nerve conduction times in 90 phrenic nerves of 45 normal subjects. The phrenic nerve was stimulated at the posterior border of the sternomastoid...
We studied phrenic nerve conduction times in 90 phrenic nerves of 45 normal subjects. The phrenic nerve was stimulated at the posterior border of the sternomastoid muscle in the supraclavicular fossa, just above the clavicle, with bipolar surface electrodes. For recording, positive and negative electrodes were placed on the xiphoid process and at the eighth intercostal bone-cartilage transition, respectively. We studied both the right and left sides to determine whether there was any difference between the two sides. The mean onset latency (± SD) of the right compound muscle action potentials (CMAPs) (5.99±0.39 msec) was significantly shorter than that of the left CMAPs (6.45±0.50 msec). The mean peak latency was significantly shorter in the right CMAPs (10.22±1.33 msec) than the left CMAPs (12.48±2.02 msec). The mean (± SD) amplitude was significantly lower in the left CMAPs (0.42±0.11 mV) than the right CMAPs (0.49±0.10 mV). The difference between the length of the nerve on the right and left sides might have affected the difference in latency between the two sides.
Topics: Adult; Humans; Male; Neural Conduction; Phrenic Nerve; Young Adult
PubMed: 30573910
DOI: 10.18926/AMO/56373 -
Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea.Sleep Oct 2019To 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.
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.
Topics: Aged; Electric Stimulation Therapy; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Middle Aged; Phrenic Nerve; Polysomnography; Prospective Studies; Quality of Life; Sleep Apnea, Central; Treatment Outcome
PubMed: 31634407
DOI: 10.1093/sleep/zsz158 -
Journal of Cardiovascular... Mar 2022Persistent phrenic nerve palsy (PNP) is an established complication of atrial fibrillation (AF) ablation, especially during cryoballoon and thoracoscopic ablation. Data...
BACKGROUND
Persistent phrenic nerve palsy (PNP) is an established complication of atrial fibrillation (AF) ablation, especially during cryoballoon and thoracoscopic ablation. Data on persistent PNP reversibility is limited because most patients recover <24 h. This study aims to investigate persistent PNP recovery, freedom of PNP-related symptoms after AF ablation and identify baseline variables associated with the occurrence and early PNP recovery in a large nationwide registry study.
METHODS
In this study, we used data from the Netherlands Heart Registration, comprising data from 9549 catheter and thoracoscopic AF ablations performed in 2016 and 2017. PNP data was available of 7433 procedures, and additional follow-up data were collected for patients who developed persistent PNP.
RESULTS
Overall, the mean age was 62 ± 10 years, and 67.7% were male. Fifty-four (0.7%) patients developed persistent PNP and follow-up was available in 44 (81.5%) patients. PNP incidence was 0.07%, 0.29%, 1.41%, and 1.25%, respectively for patients treated with conventional-RF, phased-RF, cryoballoon, and thoracoscopic ablation respectively. Seventy-one percent of the patients fully recovered, and 86% were free of PNP-related symptoms after a median follow-up of 203 (113-351) and 184 (82-359) days, respectively. Female sex, cryoballoon, and thoracoscopic ablation were associated with a higher risk to develop PNP. Patients with PNP recovering ≤180 days had a larger left atrium volume index than those with late or no recovery.
CONCLUSION
After AF ablation, persistent PNP recovers in the majority of patients, and most are free of symptoms. Female patients and patients treated with cryoballoon or thoracoscopic ablation are more prone to develop PNP.
Topics: Aged; Atrial Fibrillation; Catheter Ablation; Cryosurgery; Female; Follow-Up Studies; Humans; Male; Middle Aged; Netherlands; Paralysis; Phrenic Nerve; Pulmonary Veins; Treatment Outcome
PubMed: 35040534
DOI: 10.1111/jce.15368 -
Journal of Cardiovascular Development... Dec 2023Phrenic nerve injury is a devastating complication that results in significant morbidity and mortality. We developed a novel technique to localize the phrenic nerve and...
BACKGROUND
Phrenic nerve injury is a devastating complication that results in significant morbidity and mortality. We developed a novel technique to localize the phrenic nerve and evaluate its success.
METHODS
Two groups of children underwent repeat sternotomy for a variety of indications. Group I (69 patients, nerve stimulator) and Group II (78 patients, no nerve stimulator).
RESULTS
There was no significant difference in the mean age and weight between the two groups: (6.4 ± 6.5 years vs. 5.6 ± 6.4 years; = 0.65) and (25.2 ± 24.1 vs. 22.6 ± 22.1; = 0.69), respectively. The two groups were comparable in the following procedures: pulmonary conduit replacement, bidirectional cavopulmonary anastomosis, aortic arch repair, and Fontan, while Group I had more pulmonary arterial branch reconstruction ( = 0.009) and Group II had more heart transplant patients ( = 0.001). There was no phrenic nerve injury in Group I, while there were 13 patients who suffered phrenic nerve injury in Group II ( < 0.001). No early mortality in Group I, while five patients died prior to discharge in Group II. Eleven patients underwent diaphragm plication in Group II ( = 0.001). The mean number of hours on the ventilator was significantly higher in Group II (137.3 ± 324.9) compared to Group I (17 ± 66.9), < 0.001. Group II had a significantly longer length of ICU and hospital stays compared to Group I ( = 0.007 and = 0.006 respectively).
CONCLUSION
Phrenic nerve injury in children continues to be associated with significant morbidities and increased length of stay. The use of intraoperative phrenic nerve stimulator can be an effective way to localize the phrenic nerve and avoid its injury.
PubMed: 38248878
DOI: 10.3390/jcdd11010008 -
JACC. Heart Failure Oct 2017Most patients with heart failure (HF) have sleep-disordered breathing (SDB), with central (rather than obstructive) sleep apnea becoming the predominant form in patients... (Review)
Review
Most patients with heart failure (HF) have sleep-disordered breathing (SDB), with central (rather than obstructive) sleep apnea becoming the predominant form in patients with more severe disease. Cyclical apnea and hypopneas are associated with sleep disturbance, hypoxemia, hemodynamic changes, and sympathetic activation. These patients have a worse prognosis than those without SDB. Mask-based therapies of positive airway pressure targeted at SDB can improve measures of sleep quality and can partially normalize the sleep and respiratory physiology. However, recent randomized trials of cardiovascular outcomes in central sleep apnea in chronic HF with reduced ejection fraction have had neutral findings or suggested the possibility of harm, likely from an increased rate of sudden death. Further randomized outcome studies are required to determine whether mask-based treatment is appropriate for patients with chronic HF with reduced ejection fraction and obstructive sleep apnea, for patients with heart failure with preserved ejection fraction, and for patients with decompensated heart failure. New therapies for sleep apnea (e.g., implantable phrenic nerve stimulators) also require robust assessment. No longer can the surrogate endpoints of improvement in respiratory and sleep metrics be taken as adequate therapeutic outcome measures in patients with HF and sleep apnea.
Topics: Chronic Disease; Death, Sudden, Cardiac; Electric Stimulation Therapy; Heart Failure; Hemodynamics; Humans; Hypoxia; Phrenic Nerve; Positive-Pressure Respiration; Prognosis; Severity of Illness Index; Sleep; Sleep Apnea Syndromes; Sleep Apnea, Central; Sleep Apnea, Obstructive; Stroke Volume; Sympathetic Nervous System; Treatment Outcome
PubMed: 28888522
DOI: 10.1016/j.jchf.2017.06.016 -
ELife Jan 2020The precise pattern of motor neuron (MN) activation is essential for the execution of motor actions; however, the molecular mechanisms that give rise to specific...
The precise pattern of motor neuron (MN) activation is essential for the execution of motor actions; however, the molecular mechanisms that give rise to specific patterns of MN activity are largely unknown. Phrenic MNs integrate multiple inputs to mediate inspiratory activity during breathing and are constrained to fire in a pattern that drives efficient diaphragm contraction. We show that Hox5 transcription factors shape phrenic MN output by connecting phrenic MNs to inhibitory premotor neurons. genes establish phrenic MN organization and dendritic topography through the regulation of phrenic-specific cell adhesion programs. In the absence of genes, phrenic MN firing becomes asynchronous and erratic due to loss of phrenic MN inhibition. Strikingly, mice lacking genes in MNs exhibit abnormal respiratory behavior throughout their lifetime. Our findings support a model where MN-intrinsic transcriptional programs shape the pattern of motor output by orchestrating distinct aspects of MN connectivity.
Topics: Animals; Genes, Homeobox; Mice; Motor Neurons; Phrenic Nerve; Respiration; Transcription, Genetic
PubMed: 31944180
DOI: 10.7554/eLife.52859 -
Respiratory Physiology & Neurobiology Jun 2016Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the... (Meta-Analysis)
Meta-Analysis
Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the consistency of nerve recordings, activity is most often expressed as a percent change from baseline values. However, absolute values of nerve activity are necessary to assess the impact of neural injury or disease on phrenic motor output. To date, no systematic evaluations of the repeatability/reliability have been made among animals when phrenic recordings are performed by an experienced investigator using standardized methods. We performed a meta-analysis of studies reporting integrated phrenic nerve activity in many rat groups by the same experienced investigator; comparisons were made during baseline and maximal chemoreceptor stimulation in 14 wild-type Harlan and 14 Taconic Sprague Dawley groups, and in 3 pre-symptomatic and 11 end-stage SOD1(G93A) Taconic rat groups (an ALS model). Meta-analysis results indicate: (1) consistent measurements of integrated phrenic activity in each sub-strain of wild-type rats; (2) with bilateral nerve recordings, left-to-right integrated phrenic activity ratios are ∼1.0; and (3) consistently reduced activity in end-stage SOD1(G93A) rats. Thus, with appropriate precautions, integrated phrenic nerve activity enables robust, quantitative comparisons among nerves or experimental groups, including differences caused by neuromuscular disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Chemoreceptor Cells; Disease Models, Animal; Humans; In Vitro Techniques; Male; Microelectrodes; Phrenic Nerve; Rats, Sprague-Dawley; Rats, Transgenic; Reflex; Reproducibility of Results; Respiration; Species Specificity; Superoxide Dismutase-1
PubMed: 26724605
DOI: 10.1016/j.resp.2015.12.005