Design of the remede System Therapy (reST) study: A prospective non-randomized post-market study collecting clinical data on safety and effectiveness of the remede system for the treatment of central sleep apnea.

BACKGROUND: Central sleep apnea (CSA) is a disorder defined by lack of respiratory drive from the brain stem on breathing efforts. There is a lack of established therapies for CSA and most available therapies are limited by poor patient adherence, limited randomized controlled studies, and potentially adverse cardiovascular effects. The remede System (ZOLL Respicardia, Inc., Minnetonka, Minnesota) uses transvenous phrenic nerve stimulation to stimulate the diaphragm, thereby restoring a more normal breathing pattern throughout the sleep period. METHODS: The remede System Therapy (reST) Study is a prospective non-randomized multicenter international study evaluating long-term safety and effectiveness of the remede System in the post-market setting. Up to 500 adult patients with moderate to severe CSA will be enrolled and followed up to 5 years at approximately 50 sites in the United States and Europe. Safety objectives include evaluation of adverse events related to the implant procedure, device or delivered therapy, death, and hospitalizations. Effectiveness endpoints include assessment of changes in sleep-disordered breathing metrics from polysomnograms and home sleep tests, changes in daytime sleepiness using the Epworth Sleepiness Scale, and changes in QoL using the PROMIS-29 and Patient Global Assessment questionnaires. The subgroup of patients with heart failure will undergo additional assessments including echocardiography to assess cardiac reverse remodeling, 6-min walk distance, QoL assessment by Kansas City Cardiomyopathy Questionnaire and measurement of biomarkers. CONCLUSION: This will be the largest prospective study evaluating long-term safety and effectiveness of transvenous phrenic nerve stimulation for the treatment of moderate to severe CSA in adult patients.

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 remede® 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.

Position Paper for the Treatment of Nightmare Disorder in Adults: An American Academy of Sleep Medicine Position Paper.

INTRODUCTION: Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can significantly impair quality of life. This paper provides the American Academy of Sleep Medicine (AASM) position regarding various treatments of nightmare disorder in adults. METHODS: A literature search was performed based upon the keywords and MeSH terms from the Best Practice Guide for the Treatment of Nightmare Disorder in Adults that was published in 2010 by the AASM. The search used the date range March 2009 to August of 2017, and sought to find available evidence pertaining to the use of behavioral, psychological, and pharmacologic therapies for the treatment of nightmares. A task force developed position statements based on a thorough review of these studies and their clinical expertise. The AASM Board of Directors approved the final position statements. DETERMINATION OF POSITION: Positions of "recommended" and "not recommended" indicate that a treatment option is determined to be clearly useful or ineffective/harmful for most patients, respectively, based on a qualitative assessment of the available evidence and clinical judgement of the task force. Positions of "may be used" indicate that the evidence or expert consensus is less clear, either in favor or against the use of a treatment option. The interventions listed below are in alphabetical order within the position statements rather than clinical preference: this is not meant to be instructive of the order in which interventions should be used. POSITION STATEMENTS: The following therapy is recommended for the treatment of PTSD-associated nightmares and nightmare disorder: image rehearsal therapy. The following therapies may be used for the treatment of PTSD-associated nightmares: cognitive behavioral therapy; cognitive behavioral therapy for insomnia; eye movement desensitization and reprocessing; exposure, relaxation, and rescripting therapy; the atypical antipsychotics olanzapine, risperidone and aripiprazole; clonidine; cyproheptadine; fluvoxamine; gabapentin; nabilone; phenelzine; prazosin; topiramate; trazodone; and tricyclic antidepressants. The following therapies may be used for the treatment of nightmare disorder: cognitive behavioral therapy; exposure, relaxation, and rescripting therapy; hypnosis; lucid dreaming therapy; progressive deep muscle relaxation; sleep dynamic therapy; self-exposure therapy; systematic desensitization; testimony method; nitrazepam; prazosin; and triazolam. The following are not recommended for the treatment of nightmare disorder: clonazepam and venlafaxine. The ultimate judgment regarding propriety of any specific care must be made by the clinician, in light of the individual circumstances presented by the patient, accessible treatment options, and resources.

The use of Valeriana officinalis (Valerian) in improving sleep in patients who are undergoing treatment for cancer: a phase III randomized, placebo-controlled, double-blind study (NCCTG Trial, N01C5).

Sleep disorders are a substantial problem for cancer survivors, with prevalence estimates ranging from 23% to 61%. Although numerous prescription hypnotics are available, few are approved for long-term use or have demonstrated benefit in this circumstance. Hypnotics may have unwanted side effects and are costly, and cancer survivors often wish to avoid prescription drugs. New options with limited side effects are needed. The purpose of this trial was to evaluate the efficacy of a Valerian officinalis supplement for sleep in people with cancer who were undergoing cancer treatment. Participants were randomized to receive 450 mg of valerian-or placebo orally 1 hour before bedtime for 8 weeks. The primary end point was area under the curve (AUC) of the overall Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included the Functional Outcomes of Sleep Questionnaire, the Brief Fatigue Inventory (BFI), and the Profile of Mood States (POMS). Toxicity was evaluated with both self-reported numeric analogue scale questions and the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Questionnaires were completed at baseline and at 4 and 8 weeks. A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007, with 119 being evaluable for the primary end point. The AUC over the 8 weeks for valerian was 51.4 (SD = 16), while that for placebo was 49.7 (SD = 15), with a P value of 0.6957. A supplemental, exploratory analysis revealed that several fatigue end points, as measured by the BFI and POMS, were significantly better for those taking valerian over placebo. Participants also reported less trouble with sleep and less drowsiness on valerian than placebo. There were no significant differences in toxicities as measured by self-report or the CTCAE except for mild alkaline phosphatase increases, which were slightly more common in the placebo group. This study failed to provide data to support the hypothesis that valerian, 450 mg, at bedtime could improve sleep as measured by the PSQI. However, exploratory analyses revealed improvement in some secondary outcomes, such as fatigue. Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.

Best practice guide for the treatment of nightmare disorder in adults.

Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level A. Image Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level A. Systematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level B. Venlafaxine is not suggested for treatment of PTSD-associated nightmares. Level B. Clonidine may be considered for treatment of PTSD-associated nightmares. Level C. The following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level C. The following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level C. The following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self-Exposure Therapy. Level C No recommendation is made regarding clonazepam and individual psychotherapy because of sparse data.

Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report.

The expanding science of circadian rhythm biology and a growing literature in human clinical research on circadian rhythm sleep disorders (CRSDs) prompted the American Academy of Sleep Medicine (AASM) to convene a task force of experts to write a review of this important topic. Due to the extensive nature of the disorders covered, the review was written in two sections. The first review paper, in addition to providing a general introduction to circadian biology, addresses "exogenous" circadian rhythm sleep disorders, including shift work disorder (SWD) and jet lag disorder (JLD). The second review paper addresses the "endogenous" circadian rhythm sleep disorders, including advanced sleep phase disorder (ASPD), delayed sleep phase disorder (DSPD), irregular sleep-wake rhythm (ISWR), and the non-24-hour sleep-wake syndrome (nonentrained type) or free-running disorder (FRD). These practice parameters were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the AASM to present recommendations for the assessment and treatment of CRSDs based on the two accompanying comprehensive reviews. The main diagnostic tools considered include sleep logs, actigraphy, the Morningness-Eveningness Questionnaire (MEQ), circadian phase markers, and polysomnography. Use of a sleep log or diary is indicated in the assessment of patients with a suspected circadian rhythm sleep disorder (Guideline). Actigraphy is indicated to assist in evaluation of patients suspected of circadian rhythm disorders (strength of recommendation varies from "Option" to "Guideline," depending on the suspected CRSD). Polysomnography is not routinely indicated for the diagnosis of CRSDs, but may be indicated to rule out another primary sleep disorder (Standard). There is insufficient evidence to justify the use of MEQ for the routine clinical evaluation of CRSDs (Option). Circadian phase markers are useful to determine circadian phase and confirm the diagnosis of FRD in sighted and unsighted patients but there is insufficient evidence to recommend their routine use in the diagnosis of SWD, JLD, ASPD, DSPD, or ISWR (Option). Additionally, actigraphy is useful as an outcome measure in evaluating the response to treatment for CRSDs (Guideline). A range of therapeutic interventions were considered including planned sleep schedules, timed light exposure, timed melatonin doses, hypnotics, stimulants, and alerting agents. Planned or prescribed sleep schedules are indicated in SWD (Standard) and in JLD, DSPD, ASPD, ISWR (excluding elderly-demented/nursing home residents), and FRD (Option). Specifically dosed and timed light exposure is indicated for each of the circadian disorders with variable success (Option). Timed melatonin administration is indicated for JLD (Standard); SWD, DSPD, and FRD in unsighted persons (Guideline); and for ASPD, FRD in sighted individuals, and for ISWR in children with moderate to severe psychomotor retardation (Option). Hypnotic medications may be indicated to promote or improve daytime sleep among night shift workers (Guideline) and to treat jet lag-induced insomnia (Option). Stimulants may be indicated to improve alertness in JLD and SWD (Option) but may have risks that must be weighed prior to use. Modafinil may be indicated to improve alertness during the night shift for patients with SWD (Guideline).

Treatment of complex sleep apnea syndrome: a retrospective comparative review.

BACKGROUND AND PURPOSE: Some patients with obstructive sleep apnea syndrome (OSAS) develop problematic central apneas or Cheyne-Stokes pattern with acute application of continuous positive airway pressure (CPAP), herein called complex sleep apnea syndrome (CompSAS). This response makes it difficult to be certain that CPAP will be a successful treatment strategy. We sought to compare treatments between patients with CompSAS vs. OSAS and hypothesized that CompSAS patients would find CPAP less effective and have more problems with adherence than patients with OSAS. PATIENTS AND METHODS: We performed a retrospective review of patients studied in our sleep disorders center over 1 month. RESULTS: There were 133 patients with OSAS (mean age=57.6+/-12.2 years; males=63.9%) and 34 with CompSAS (mean age=54.4+/-16 years; males=82.35%). CPAP was prescribed in 93.7 and 87.9% of OSAS and CompSAS patients, respectively (P=0.284), with no significant difference in required CPAP pressures (P=0.112). There was no difference in prescription frequency of alternative therapies. Mean time to the first follow-up was shorter in CompSAS patients (46.2+/-47.3 vs. 53.8+/-36.8 days; P=0.022). CPAP compliance in OSAS and CompSAS patients (5.1+/-1.6 vs. 6.1+/-1.5h, P=0.156) and improvement in Epworth Sleepiness Scale (ESS) (-4.6+/-4.8 vs. -5.9+/-6.9, P=0.483) was similar. However, interface problems were more common in CompSAS patients, especially air hunger/dyspnea (0.8 vs. 8.8%) and inadvertent mask removal (2.6 vs. 17.7%) (all P<0.050). CONCLUSION: CompSAS patients have more CPAP interface problems and require more follow-up than OSAS patients but with intervention may have similar treatment results compared to patients with OSAS.