This systematic review and meta-analysis has five main findings. First, eleven of fourteen studies reported a statistically significant increase in REM sleep duration during titration night compared the baseline sleep study. While all studies report REM rebound, only a few studies define what REM rebound entails based on their statistical prediction models. Studies adopted cut-off criteria of 6%-20% increase in percentage REM sleep on titration night when compared to baseline PSG to define REM rebound. Accepting a lower REM percentage increase as the cut -off criteria for REM rebound (when comparing REM percentage in titration study to REM percentage in baseline PSG study) leads to reporting a higher prevalence of REM rebound on CPAP titration. Accordingly, based on cut-off criteria used to define REM rebound, the prevalence of REM rebound varies between 23 and 46% in all patients undergoing CPAP titration study.
Second, when the specific cut-off criteria (in terms of duration of increase in REM sleep percentage) defining REM rebound are overlooked, the majority of patients undergoing a CPAP titration experience increased duration of REM sleep compared to their baseline sleep study. The percentage increase in REM sleep duration varies between 1.5 and 14% and may depend on certain polysomnographic and demographic factors. The mean difference of 7.86% corresponds to a 57% relative percentage increase of REM sleep during the CPAP treatment night compared to the baseline study. When evaluating the effect size based on Cohen’s guidelines, the SMD is 0.90 [95% CI 0.59, 1.22], which is defined as a large effect. Interestingly, the sensitivity analysis demonstrated two sub-groups of studies that were non-heterogenous when combined, and the subgroups tended to be grouped by the year of the study publication; with the first non-heterogenous sub-group consisted of studies from 1996 to 2009 (Yaegashi et al., Drake et al., Verma et al., Randerath et al. and Collard et al.) with a Q-statistic p = 0.62 and I2 = 0%. The second non-heterogenous sub-group consisted of studies from 1986 to 1995 (Yamashiro et al., Lampere et al. and Issa et al.) with a Q-statistic p = 0.54 and I2 = 0%. It is unclear as to why these two sub-groups were non-heterogenous when grouped alone, but did cause heterogeneity and inconsistency when grouped as part of the fourteen studies.
Third, a high percentage increase in REM sleep was observed specifically during split night studies. A relatively high proportion of REM sleep during split night studies (compared to full night titration studies) could be multifactorial, associated with at least three factors: (A) the natural timing of REM sleep, (B) the rapidity of up-titrations and (C) the baseline severity of OSA. First, the PAP titration portion of split night study temporally coincides with timing for natural preponderance of REM sleep in the latter half of sleep period (Ciftci et al. 2008). Second, in contrast to dedicated, full night titration studies, during split-night studies, sleep technicians might be up-titrating the pressures relatively rapidly due to limited titration window leading to early, brief but repetitive bursts of saw tooth waves or low voltage mixed frequency REM spikes. Lastly, patients who undergo split night study typically have severe OSA. In such patients both high baseline AHI and high arousal index from sleep fragmentation, are being simultaneously resolved with PAP therapy, which may be promoting additional periods of restorative REM sleep. Immediate increased REM duration from CPAP use as early as after one night have been observed (Loredo et al. 2006; Issa and Sullivan 1986). So, it is plausible that the rebound REM increase occurs even within a few hours of initiation of CPAP, given that untreated OSA represents a state of several years of chronic partial sleep deprivation as well as sleep fragmentation.
We speculate that the quantity of REM rebound could depend upon rapidity of up- titrations as well how quickly the patient adapted to these up-titrations. In some studies, rapid CPAP up-titration may have led to early attainment of therapeutic pressure providing more time during sleep period to exhibit REM. In other studies, a more conservative and cautious approach may have lead to at least some REM sleep attained chronologically prior to attainment of therapeutic CPAP pressure leading to less REM rebound. Of note, about 5-20% patients may have experienced treatment emergent central sleep apnea or TECSA on first exposure to CPAP during these studies (Nigam et al. 2016). TECSA may have lead to increased arousal index and sleep fragmentation thereby limiting REM rebound which would be subsequently seen after several weeks of CPAP use in this cohort of CPAP users.
Fourth, certain polysomnographic and demographic factors could enhance REM rebound. Two such factors predicting enhanced Delta REM (and thereby predicting substantial REM rebound) as suggested in several studies include: 1) a lower amount of REM sleep on diagnostic PSG (strong association) and 2) a higher severity of OSA as noted by the AHI during diagnostic PSG (weak association, if any). Other possible associations include higher arousal index on baseline PSG, low oxygen saturation on baseline PSG, male gender, higher BMI and utilization of split-night PSG to study REM rebound. Additional research is needed to further evaluate the variables that predict which patients are more likely to experience REM rebound.
Fifth, almost half of the currently published studies were retrospective observational studies and prone to limitations of any retrospective study. There were differences amongst studies as to the definition of REM rebound. The sleep stage and respiratory events scoring rules have undergone considerable changes over the last few decades. Given the review includes studies conducted over last 30 years, the majority of the included studies were scored using Rechtschaffen and Kales manual for the scoring of sleep stages, while others were scored based on the American Academy of Sleep Medicine scoring manual introduced in 2007. The rules for scoring respiratory events have undergone considerable changes as well over the years, making it difficult to directly compare baseline AHIs reported by different authors; however, given that REM is defined based on the electroencephalogram, we believe that despite the differences in the AHI scoring criteria, the percentage of sleep scored for each of the sleep stages, including REM, should not change.
Limitations
We acknowledge that the expression “percentage” increase in REM sleep could arithmetically, sometimes get misconstrued as demonstrated by the following example: a doubling of REM sleep time from 5 to 10 min is not the same as a doubling of REM sleep time from 20 to 40 min. Therefore, we suggest that the percentage of relative increase in REM sleep should be interpreted cautiously in appropriate clinical and polysomnographic context. This “percentage” increase in REM sleep was chosen as they are conventional mathematical tools for data representation. Also, percentages are employed as a standard practice for reporting the proportion of the time spent in different sleep stages on a polysomnogram report. Unfortunately, as demonstrated by the above example, even a small amount of additional time spent in REM during the treatment night could translate to a significantly inflated percentage increase in REM sleep. Consistent with all systematic reviews, it is possible that we missed identifying studies that met our criteria; however, to decrease this possibility, we had two authors search independently. Additionally, our search was restricted to English-language manuscripts only, and there may have been additional studies in other languages. Lastly, as demonstrated by the funnel plot, there is a high risk of publication bias, therefore, it is possible that researchers with negative findings either never shared their findings, or those inferences may have been rejected after submission. Previous studies suggest that sleep stages (including REM stage) recovery after CPAP titration is not an instant “all-or-none phenomenon” but requires several days to weeks before complete return to normal control values (Parrino et al. 2005). This might have lead to underestimation of REM rebound as sleep reorganization is a dynamic adaptive process spanning several weeks, and our work only captured the initial phases of effective CPAP treatment. Our analysis was restricted to REM rebound in terms of duration and percentages; it did not include analysis of REM latency as this parameter was not recorded and shared by most constituent studies.