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REM) Rebound on Initial Exposure to CPAP Therapy: a Systematic Review and Meta-Analysis Gaurav Nigam1*, Macario Camacho2 and Muhammad Riaz3

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REM) Rebound on Initial Exposure to CPAP Therapy: a Systematic Review and Meta-Analysis Gaurav Nigam1*, Macario Camacho2 and Muhammad Riaz3 Nigam et al. Sleep Science and Practice (2017) 1:13 Sleep Science and Practice DOI 10.1186/s41606-017-0014-7 REVIEW Open Access Rapid Eye Movement (REM) rebound on initial exposure to CPAP therapy: a systematic review and meta-analysis Gaurav Nigam1*, Macario Camacho2 and Muhammad Riaz3 Abstract Objective: Rapid Eye Movement (REM) rebound is a polysomnographic phenomenon where a substantial increase in REM sleep is noted in patients with untreated obstructive sleep apnea (OSA) when first undergoing continuous positive airway pressure (CPAP) titration. The objectives of this study are to determine: 1) the percentage of patients experiencing REM rebound during CPAP titrations, 2) to quantify the relative increase in REM sleep duration and 3) to identify if there are patient variables associated with REM rebound. Methods: Four databases (including PubMed/Medline) were systematically searched through March 12, 2017. Results: Four hundred sixty-seven articles were screened, 58 were reviewed in full-text form and 14 studies met the criteria for inclusion in this review. Eleven of the fourteen studies noted a statistically significant increase in amount of REM sleep during the titration night, compared to baseline sleep study. Pre- and post-CPAP REM sleep duration percentage means ± standard deviations (M ± SD) in 1119 patients increased from 13.8 ± 8.2% to 20.0 ± 10.1%; random effects modeling demonstrated a mean difference of 7.86 (%) [95% CI 5.01, 10.70], p-value <0.00001, corresponding to a 57% relative increase in REM sleep duration. The standardized mean difference (SMD) is 0.90 [95% CI 0.59, 1.22], representing a large magnitude of effect. Conclusions: In studies reporting REM rebound, the REM sleep duration increased by 57% during the first CPAP titration night compared to the baseline sleep study. The prevalence of REM rebound varied between 23 and 46%. A low amount of REM sleep on the diagnostic PSG predicted REM rebound. Keywords: REM rebound, Continuous positive airway pressure, Cortical arousal, Adherence, Obstructive sleep apnea, Sleep hypnogram Background by repetitive arousals, more so than stage slow wave The hypnogram obtained during a sleep study in a sleep (Agnew et al. 1967). This might suggest that REM patient with untreated obstructive sleep apnea (OSA) sleep is more frequently abolished by untreated OSA, as has certain distinct features. The majority of them have compared to slow wave sleep. fragmented sleep architecture with limited amounts of When first exposed to continuous positive airway Rapid Eye Movement (REM) and slow wave sleep. pressure (CPAP), certain favorable changes occur in the Historically, the sleep fragmentation has been attributed sleep architecture. CPAP therapy leads to a reduction in to the preponderance of arousals that are temporally the arousal index, sleep stage shifts and non-rapid eye associated with respiratory events in patients with un- movement (NREM) stage 1 (Loredo et al. 2006). Conse- treated OSA (Remmers et al. 1978). Early experimental quently, sleep becomes more consolidated with an in- studies of selective sleep deprivation have demonstrated crease in the duration of REM sleep compared to the that stage REM sleep is highly susceptible to eradication diagnostic study. REM rebound (Brillante et al. 2012; Koo et al. 2012; Kushida et al. 2011; Yaegashi et al. 2009; * Correspondence: [email protected] Osuna et al. 2008; Drake et al. 2003; Verma et al. 2001; 1Clay County Hospital, 911 Stacy Burk Drive, Flora, IL 62839, USA Randerath et al. 2001; Parrino et al. 2000; Yamashiro and Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nigam et al. Sleep Science and Practice (2017) 1:13 Page 2 of 11 Kryger 1995; Lamphere et al. 1989; Aldrich et al. 1989; hand searches of the reference lists of relevant articles Issa and Sullivan 1986; Collard et al. 1996) is the poly- were performed in order to identify other pertinent arti- somnographic phenomenon of substantial increase in cles. Also, meticulous grey literature and Google Scholar duration of REM sleep in a patient with untreated OSA searches were performed to identify relevant publica- when first undergoing CPAP titration. Similarly, some tions that could have been missed during the electronic patients may exhibit an increase in the duration of slow database search. Search was restricted to English lan- wave sleep called slow wave sleep rebound (Brillante guage articles only. An example of a PubMed search is: et al. 2012; Osuna et al. 2008; Verma et al. 2001). ((("Continuous Positive Airway Pressure"[Mesh] AND REM rebound on the first night of CPAP use has mul- "Sleep, REM"[Mesh] OR ("Continuous Positive Airway tiple clinical implications. Clinically, patients exhibiting Pressure"[Mesh] AND "Sleep, REM"[Mesh]) AND "Sleep REM rebound have reported better sleep quality on Apnea, Obstructive"[Mesh], Increase* in REM sleep CPAP titration night than on nights with untreated OSA AND CPAP*, rapid eye movement sleep [tiab] AND (Osuna et al. 2008). In new CPAP users early CPAP CPAP [tiab]))) All articles were reviewed which adherence was found to be higher in patients exhibiting discussed REM rebound in patients with OSA. Articles significant REM rebound during CPAP titration night meeting the inclusion criteria were included in the sys- (Koo et al. 2012). Currently, there are no consensus tematic review. guidelines as to how much increase in duration of REM Inclusion criteria using PICOS were: 1) Patients: those sleep in the titration night over the baseline sleep study diagnosed with OSA, 2) Intervention: CPAP therapy, 3) (or baseline portion of a split night study) qualifies as Comparison: a) studies assessing amount of increase in REM rebound. The primary objective of this study was REM sleep during CPAP titration as compared to to determine if there is a statistically significant increase amount of REM sleep in baseline PSG, b) and/or studies in percentage of REM sleep during CPAP titration as discussing slow-wave sleep rebound in addition to REM compared to baseline polysomnogram (PSG), in patients rebound, and c) studies looking for correlation between undergoing CPAP titration after being diagnosed with sleep quality or CPAP adherence and REM rebound, 4) OSA. Secondary objectives were to quantify the relative Outcomes: the REM sleep duration differences on CPAP increase in REM sleep duration and to predict polysom- therapy during the titration night compared to the base- nographic factors associated with REM rebound. In line PSG, and 5) Study design: randomized controlled order to meet the objectives of this review, a systematic trials, prospective and retrospective cohort studies, and review of the literature was performed to identify studies case series. Exclusion criteria included: 1) Studies on reporting REM rebound on the CPAP titration night as sleep-disordered breathing (SDB) which exclusively compared to the baseline sleep study night, and the discussed slow-wave sleep rebound, 2) Home sleep quantitative data was used to determine the percent apnea studies with no electrooculography (EEG) and increase in REM sleep duration using a meta-analysis electromyography (EMG) monitoring capability, and 3) with random effects modeling. Individual case reports, editorials, review articles, and meeting abstracts. Methods The Preferred Reporting Items for Systematic Reviews Statistical analysis and Meta-Analyses (PRISMA) statement checklist was Statistical evaluation was performed using Review used to report the findings of this systematic review Manager (REVMAN) Software version 5.3. The pre- and (Fig. 1). Two authors (GN and MR) conducted a system- post-CPAP REM percentage, standard deviations (SD), atic search of electronic databases that included PubMed, mean differences (MD), 95% confidence intervals (CI) Medline, Scopus, Web of Science and Cochrane Library and p-values were calculated using the IBM Statistical from inception through March 12, 2017. Package for Social Sciences (SPSS) software. Combined mean differences and 95% CI were calculated only for Protocol studies reporting means and SD. The null hypothesis for The Tripler Army Medical Center Department of Clinical the study was that there is no difference in percentages Investigation approved the protocol for this meta-analysis of REM sleep rebound between baseline PSG versus (Protocol TAMC 16N14). titration study and in order to test this hypothesis the data was analyzed using post minus pre CPAP therapy Search strategy outcome data. A random effects modeling was utilized The search included Medical Subject Headings (MeSH) and the overall effect size estimation was performed by terms, key words, and phrases in combinations to obvi- calculating the standardized mean difference (SMD). ate missing articles due to the use of select terminology Cohen’s guidelines were used to determine the magni- in the different databases. To make the search thorough, tude of the effect size, and the SMD cutoff values were: Nigam et al. Sleep Science and Practice (2017) 1:13 Page 3 of 11 Fig. 1 Flowchart for study selection small = 0.2, medium = 0.5 and large = 0.8 (Cohen 1988). during titration night compared to baseline sleep study. Heterogeneity was defined as a REVMAN Q-statistic Most studies reported REM rebound in percentage in- value of ≤0.10 (Lau et al. 1997), and the REVMAN I2 crease in REM sleep duration when comparing titration value cutoffs for inconsistency were 25% = low inconsist- to baseline sleep study except two studies (Aldrich et al.
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