- Email: [email protected]
The effect of childhood obstructive sleep apnea on ambulatory blood pressure is modulated by the distribution of respiratory events during rapid eye movement and nonrapid eye movement sleep
Sleep Medicine 14 (2013) 1317–1322
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
The effect of childhood obstructive sleep apnea on ambulatory blood pressure is modulated by the distribution of respiratory events during rapid eye movement and nonrapid eye movement sleep Chun Ting Au a,⇑, Crover Kwok Wah Ho b, Yun Kwok Wing b, Albert Martin Li a a b
Department of Pediatrics, Prince of Wales and Shatin Hospitals, The Chinese University of Hong Kong, Shatin, Hong Kong Department of Psychiatry, Prince of Wales and Shatin Hospitals, The Chinese University of Hong Kong, Shatin, Hong Kong
a r t i c l e
i n f o
Article history: Received 7 March 2013 Received in revised form 29 August 2013 Accepted 1 September 2013 Available online 17 October 2013 Keywords: Obstructive sleep apnea Rapid eye movement REM-related OSA Blood pressure Polysomnography Children
a b s t r a c t Objective: We aimed to investigate if different childhood obstructive sleep apnea (OSA) subtypes, namely rapid eye movement (REM)-related, nonrapid eye movement (NREM)-related and stage-independent OSA would exert different effects on ambulatory blood pressure (ABP). Methods: Data from our previous school-based cross-sectional study were reanalyzed. Subjects who had an obstructive apnea–hypopnea index (OAHI) between 1 and 10 events per hour and a total REM sleep duration of >30 min were included in our analysis. REM-related and NREM-related OSA were defined as a ratio of OAHI in REM sleep (OAHIREM) to OAHI in NREM sleep (OAHINREM) of >2 and <0.5, respectively. The others were classified as stage-independent OSA. Results: A total of 162 subjects were included in the analysis. In the mild OSA (OAHI, 1–5 events/h) subgroup, no significant differences in any ABP parameters were found between OSA subtypes. On the other hand, in subjects with moderate OSA (OAHI, 5–10 events/h), the REM-related OSA subtype had a significantly lower daytime systolic blood pressure (SBP) z score ( 0.13 ± 0.90 cf 1.15 ± 0.67; P = .012) and nighttime SBP z score (0.29 ± 1.06 cf 1.48 ± 0.88, P = .039) than the stage-independent OSA subtype. Linear regression analyses revealed that OAHINREM but not OAHIREM was significantly associated with both daytime (P = .008) and nighttime SBP (P = .042) after controlling for age, gender, and body size. Conclusion: Children with obstructive events mainly in REM sleep may have less cardiovascular complications than those with stage-independent OSA. Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction In recent years, a number of studies have shown that pediatric obstructive sleep apnea (OSA) is associated with elevated blood pressure (BP) [1–4]. Our group documented that children with OSA had significantly higher daytime and nocturnal BP compared to nonsnoring control subjects. In addition, moderate to severe OSA, defined as an obstructive apnea–hypopnea index (OAHI) of >5 events per hour, was associated with a higher risk for nocturnal hypertension, whereas the effect of mild OSA was only modest [4]. It has been found that obstructive respiratory events more commonly are found in rapid eye movement (REM) sleep [6,7] in children with OSA, possibly attributed to the reduced muscle tone and blunted arousal and ventilatory responses during this sleep state [6–9]. A previous study revealed that 55% of obstructive apneas in children occurred during REM sleep [10]. Patients with obstructive respiratory events mainly during REM sleep are defined as ⇑ Corresponding author. Tel.: +852 2632 2917; fax: +852 2636 0020. E-mail address: [email protected] (C.T. Au). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.09.017
having REM-related OSA. Clinically, the diagnosis of REM-related OSA has not been standardized. For research purposes, a subject is classified as having REM-related OSA when the diagnostic criteria of OSA are fulfilled and the ratio of OAHI in REM sleep (OAHIREM) to OAHI in non-REM (NREM) sleep (OAHINREM) is >2 [11–13]. Although REM-related OSA in children is common, research in this topic is limited. There are no published data on its prevalence based on a community sample. A pediatric study [14] that involved sleep laboratory attendants showed that nearly 70% of patients had higher OAHIREM than OAHINREM. From adult studies, the prevalence of REM-related OSA is approximately 10–36% among patients with OSA [11–13,15]. The clinical significance of REM-related OSA is controversial. Some studies suggest that REM-related OSA is associated with excessive daytime sleepiness [16,11,17], and others argue that the main correlate with adverse outcomes is OAHINREM rather than OAHIREM [18–20]. There currently is no evidence to suggest differential effects on 24-h ambulatory BP (ABP) monitoring by the different OSA subtypes. Our study aimed to investigate if differences in ABP were present in children with OSA, with different
1318
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
distributions of respiratory events among REM and NREM sleep. We stratified the study population into mild (OAHI, 1–5 events/ h) and moderate OSA (OAHI, 5–10 events/h) subgroups to control for the effect of overall OSA severity on ABP. 2. Methods 2.1. Study design
The other subjects with a ratio between 0.5 and 2 were classified as stage-independent OSA. To avoid an overestimated OAHIREM in cases with inadequate total REM sleep, subjects with less than 30 min of total REM sleep were excluded. The severe OSA cases also were excluded, as there were only three subjects in each of NREM-related and the stage-independent groups. Such small sample size would provide unreliable results. Moreover, their OAHI widely varied from 11.3 events per hour to 80.9 events per hour and combining severe and moderate groups was not an option as that would distort the results by greatly increasing the variance of OAHI.
Data from our previous school-based cross-sectional study, which investigated the association between OSA and ABP, were reanalyzed [4]. The study included 306 children aged 6–13 years recruited from primary schools that were randomly selected from two local districts, Sha Tin and Tai Po. All subjects underwent anthropometric measurements, overnight polysomnography (PSG) and ABP monitoring. ABP monitoring was performed over a 24-h period during which overnight PSG also was performed. Body mass index (BMI) was converted to BMI z score according to normal reference [21]. Written informed consent and assent were obtained from parents and subjects, respectively. The study was approved by the Joint Chinese University of Hong Kong, New Territories East Cluster.
Overnight PSG was performed in a dedicated sleep laboratory with CNS 1000P polygraph (CNS, Inc., Chanhassen MN) as described in our previous publication [22]. All computerized sleep data were further manually edited by experienced PSG technologists and clinicians according to standardized criteria [23]. All studies were standardized to record the time in bed for 9.5 h ± 5 min, starting at 21:30 ± 15 min and ending at 7:00 ± 15 min the next day.
2.2. Clinical research ethics committee
2.4. ABP monitoring
Based on the PSG results, subjects were divided into four groups: (1) healthy control subjects without OSA (OAHI <1 event/ h), (2) mild OSA (OAHI, 1–5 events/h), (3) moderate OSA (OAHI, 5–10 events/h), and (4) severe OSA (OAHI, >10 events/h) [4]. In our retrospective analysis subjects within each group, except for the control group, were further stratified into different OSA subtypes, namely REM-related, NREM-related, and stage-independent OSA for comparisons. REM-related OSA and NREM-related OSA were defined as OAHIREM/OAHINREM of >2 and <0.5, respectively.
Subjects underwent 24-h ABP monitoring on the same day as overnight PSG using an oscillometric monitor (SpaceLabs 90217, SpaceLabs Medical, Redmond, Washington, USA), which has been validated for use in children [24]. Systolic BP (SBP) and diastolic BP (DBP) were measured every 60 min during the nighttime from 09:30 pm to 07:00 am and every 30 min from 07:00 am to 09:30 pm (daytime period). The exact cutoff dividing daytime and nighttime BP was individually defined according to the PSG tracings. Individual mean SBP and DBP were calculated for daytime
2.3. Polysomnography
Table 1 Anthropometric and polysomnographic data of different obstructive sleep apnea subtypes. Control (OAHI <1/h) n = 127 Age, y Male gender, n (%) Height, cm BMI, m/kg2 BMI z score REM sleep, % Stage 1, % Stage 2, % SWS, % TST, min ODI, events /h
10.4 ± 1.7 72 (56.7) 139 ± 10 17.4 ± 2.9 0.21 ± 0.98 21.0 ± 3.9 6.5 ± 3.0 49.4 ± 5.4 23.1 ± 5.4 474 ± 58 0.1 (0–0.4)
ArI, events/h Respiratory ArI, events/h SpO2 nadir in REM, % SpO2 nadir in NREM, % SpO2 nadir, % OAHITST, events /h OAHIREM, events/h
6.1 ± 2.5 0.3 (0.1–0.7)
OAHINREM, events/h
93 ± 2 93 ± 2 92 ± 2 0.3 ± 0.3 0 (0–1.0) 0 (0–0.3)
Mild OSA (OAHI 1–5/h)
Moderate OSA (OAHI 5–10/h)
REMrelated n = 90
NREMrelated n = 18
Sleep stage: independent n = 24
P value
REM-related
10.6 ± 1.6 62 (68.9) 140 ± 11 18.9 ± 3.5 0.63 ± 1.00 21.6 ± 3.6 8.2 ± 3.6 48.0 ± 5.0 22.2 ± 4.8 467 ± 59 0.4 (0.2– 0.9) 7.1 ± 2.7 1.3 (0.9– 2.3) 94 ± 2 93 ± 2
10.2 ± 1.7 12 (66.7) 138 ± 10 18.8 ± 3.4 0.69 ± 0.94 20.1 ± 3.9 7.7 ± 4.8 49.9 ± 4.9 22.3 ± 5.7 478 ± 61 0.7 (0.2– 1.2) 8.1 ± 4.9 2.0 (1.5– 2.7)⁄ 92 ± 4 92 ± 2
10.7 ± 1.6 18 (75) 141 ± 11 17.7 ± 3.8 0.11 ± 1.16 19.9 ± 4.2 8.9 ± 2.7 48.3 ± 5.7 22.9 ± 6.0 462 ± 75 0.8 (0.5–1.3)
.558 .808 .635 .336 .074 .070 .535 .355 .841 .714 .049
10.1 ± 1.7 13 (86.7) 139 ± 11 19.1 ± 3.2 0.82 ± 0.98 21.3 ± 3.4 6.6 ± 3.4 46.9 ± 6.8 25.2 ± 5.1 505 ± 53 1.4 (0.5–2.3)
8.9 ± 3.0⁄ 2.2 (1.3–3.2)⁄
.030 .005
8.8 ± 3.5 3.7 (2.2–5.0)
92 ± 2 91 ± 2⁄
.758 .011
91 ± 4 93 ± 3
92 ± 3 2.3 ± 1.1 7.0 (4.3– 9.8) 0.6 (0.3– 1.0)
91 ± 4 1.8 ± 0.7 0.2 (0–0.6)⁄
91 ± 2 2.2 ± 1.0 2.1 (1.1–2.7)⁄
.288 .291 <.001
2.0 (1.6– 3.1)⁄
2.1 (1.3–2.6)⁄
<.001
n = 15
90 ± 4 6.9 ± 1.2 23.2 (18.4– 29.6) 1.5 (1.1–2.7)
NREMrelated n=8
Sleep stage: independent n=7
P value
10.2 ± 1.8 5 (62.5) 140 ± 12 20.3 ± 2.4 1.24 ± 0.98 21.0 ± 4.8 8.3 ± 3.2 47.8 ± 6.8 22.9 ± 6.4 463 ± 44 1.2 (0.5– 4.5) 10.9 ± 2.4 6.9 (6.0– 8.7)⁄ 93 ± 2 90 ± 5
9.3 ± 1.4 5 (71.4) 138 ± 11 18.6 ± 2.6 0.87 ± 0.94 21.4 ± 7.1 10.8 ± 4.4⁄ 44.1 ± 3.4 23.8 ± 4.1 456 ± 71 3.7 (0.9–5.7)
.490 .398 .966 .503 .598 .988 .056 .489 .574 .095 .220
13.7 ± 5.0⁄ 7.2 (5.1–9.3)
.024 .004
92 ± 3 93 ± 1
.435 .109
90 ± 5 7.2 ± 1.4 1.7 (0–2.7)⁄
91 ± 2 7.9 ± 1.0 8.6 (5.2–10.0)⁄
.780 .253 <.001
8.3 (7.0– 9.4)⁄
8.1 (7.1–8.7)⁄
<.001
Abbreviations: OSA, obstructive sleep apnea; h, hour; OAHI, obstructive apnea–hypopnea index; REM, rapid eye movement; NREM, nonrapid eye movement; y, years; BMI, body mass index; SWS, slow-wave sleep; TST, total sleep time; ODI, oxygen desaturation index; ArI, arousal index; SpO2, oxygen saturation; OAHIREM, OAHI in REM sleep; OAHINREM, OAHI in NREM sleep. * Significantly different from REM-related OSA group.
1319
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322 Table 2 Daytime and nighttime ambulatory blood pressure data of different obstructive sleep apnea subtypes. Control (OAHI <1/h)
Daytime SBP, mmHg Daytime DBP, mmHg Nighttime SBP, mmHg Nighttime DBP, mmHg Nocturnal SBP dipping,% Nocturnal DBP dipping,%
Mild OSA (OAHI 1–5/h)
Moderate OSA (OAHI 5–10/h)
NREMrelated n = 18
Sleep stage: independent n = 24
P value for trend
REMrelated n = 15
NREMrelated n=8
Sleep stage: independent n=7
P value for trend
n = 127
REMrelated n = 90
111 ± 8
113 ± 8
112 ± 8
113 ± 9
.779
112 ± 7
119 ± 7
122 ± 7⁄
.003
71 ± 5
71 ± 5
71 ± 5
73 ± 6
.295
72 ± 4
75 ± 6
75 ± 2
.097
99 ± 9
102 ± 8
101 ± 9
102 ± 7
.932
101 ± 9
104 ± 7
110 ± 9
.022
58 ± 6
59 ± 5
59 ± 4
60 ± 5
.829
59 ± 6
59 ± 7
63 ± 6
.229
10.5 ± 5.3
9.5 ± 5.8
10.3 ± 6.9
9.4 ± 4.7
.928
10.3 ± 5.7
12.3 ± 4.2
9.5 ± 5.7
.892
17.5 ± 6.9
16.6 ± 6.7
16.1 ± 7.0
17.3 ± 5.1
.728
18.1 ± 6.6
21.2 ± 6.3
16.8 ± 6.9
.854
Abbreviations: OSA, obstructive sleep apnea; h, hour; OAHI, obstructive apnea–hypopnea index; REM, rapid eye movement; NREM, nonrapid eye movement; DBP, diastolic blood pressure; SBP, systolic blood pressure. * Significantly different from REM-related OSA group.
and nighttime periods. All mean BP variables were converted into BP z scores using the reference ranges relative to gender and height published by Wuhl et al. [25]. Nocturnal dipping of SBP and DBP were derived by calculating the difference between daytime and nighttime BP and expressed as a percentage of mean daytime BP. 2.5. Statistical analysis The mean ± standard deviation, median (interquartile range), and number (percentage) were presented for parametric, nonparametric, and categorical data, respectively. Data from the control group were shown for reference. Normally distributed and nonnormally distributed data were compared using one-way analysis of variance and the Kruskal–Wallis test, respectively. Two group pairwise comparisons were performed with post hoc testing of analysis of variance for normally distributed data and the Mann–Whitney U test with Bonferroni correction (significance at P < .016) for non-
normally distributed data. The v2 test or Fisher exact test with Bonferroni correction (significance at P < .016) were performed to investigate the difference in proportions between groups. Linear contrast tests were used to examine the linear trends across groups for continuous variables. Linear regression analyses were used to examine the association of OAHIREM and OAHINREM with ABP measures. All analyses were performed using the statistical software packages SPSS (version 13.0 for Windows; SPSS Inc., Chicago, Illinois, USA).
3. Results 3.1. Mild OSA subgroup In the mild OSA subgroup, one child who had less than 30 min of total REM sleep was excluded. Among the remaining 132 chil-
Fig. 1. Scatter plot of ambulatory blood pressure of different mild obstructive sleep apnea subtypes.
1320
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
Fig. 2. Scatter plot of ambulatory blood pressure of different moderate obstructive sleep apnea subtypes. P values were obtained from linear contrast tests. ⁄Significantly different from rapid eye movement sleep-related obstructive sleep apnea group. (P < .05, post hoc testing of analysis of variance).
dren, 90 subjects had REM-related OSA, 18 subjects had NREM-related OSA, and 24 subjects had stage-independent OSA. No significant differences in age, gender, and body size were found between these subtypes (Table 1). From the PSG results, the REM-related OSA group had a significantly lower arousal index (P = .031) and higher oxygen saturation nadir during NREM sleep (P = .015) than the stage-independent OSA group. However, no significant difference in overall OAHI could be found (Table 1). For ABP parameters, there were no significant differences or linear trends across different OSA subtypes (Table 2 and Fig. 1). 3.2. Moderate OSA subgroup In the moderate OSA subgroup, 15, 8, and 7 subjects were found to have REM-related, NREM-related, and stage-independent OSA, respectively. No significant differences in age, gender, and body size were found between these subtypes. The REM-related OSA group had significantly less stage 1 sleep (P = .046) and lower arousal index (P = .019) than the stage-independent OSA group (Table 1). The ABP data revealed that there were significant increasing linear trends in both daytime (P for trend = .003) and nighttime SBP (P for trend = .022) across different OSA subtypes, namely from the REM-related to NREM-related to the stage-independent group. Post hoc analyses demonstrated that the REM-related OSA group had significantly lower daytime SBP (P = .014) and a trend of lower nighttime SBP (P = .052) than the stage-independent OSA group (Table 2). These linear trends across different OSA subtypes and differences between the REM-related and stage-independent OSA subtypes remained significant, even after converting the ABP parameters into z scores (P for trend = .003 and P for trend = .015; P = .012 and P = .039, respectively) (Fig. 2). 3.3. Multivariate analysis Multiple linear regression analysis showed that OAHINREM but not OAHIREM was significantly associated with both daytime
Table 3 Results of multiple linear regression analysis showing the association of obstructive apnea–hypopnea index in rapid eye movement sleep and obstructive apnea– hypopnea index in nonrapid eye movement sleep with daytime and nighttime systolic blood pressure (n = 162). Daytime SBP b Age, y Body height, cm Male gender BMI z score OAHIREM, events/h OAHINREM, events/h
1.009 0.244 3.020 2.458 0.022 0.652
Nighttime SBP
SE
P value
0.572 0.090 1.252 0.588 0.078 0.245
.080 .008 .017 <.001 .781 .008
b 0.581 0.331 0.833 1.272 0.054 0.517
SE
P value
0.591 0.093 1.292 0.608 0.080 0.253
.327 <.001 .520 .038 .505 .042
Abbreviations: SBP, systolic blood pressure; SE, standard error; y, years; BMI, body mass index; OAHIREM, obstructive apnea–hypopnea index in rapid eye movement sleep; OAHINREM, OAHI in nonrapid eye movement sleep; h, hour.
(P = .008) and nighttime SBP (P = .042) after adjusting for age, gender, height, and BMI z score (Table 3). No two-way interaction effect between OAHIREM and BMI z score or between OAHINREM and BMI z score could be found on ABP measures. 4. Discussion To our knowledge, our study is the first to investigate ABP in children with different OSA subtypes. The main finding was that daytime and nighttime SBP were lowest in children with REM-related OSA (mean, 112 and 101 mmHg) and highest in children with stage-independent OSA (mean, 122 and 110 mmHg), despite the groups having similar overall OAHI. On the contrary, no similar differences were observed in children with mild OSA. In addition, OAHINREM but not OAHIREM was shown to be independently associated with daytime and nighttime SBP in linear regression analysis after adjusting for confounders. Each 1-unit increase in OAHINREM was associated with an increase of 0.7 mmHg in
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
daytime SBP and 0.5 mmHg in nighttime SBP. Such effect size may be clinically significant, as a previous study demonstrated that a small increase in BP in children was associated with left ventricular abnormalities [3]. Furthermore, it was suggested that elevated childhood BP, though not exceeding the threshold of hypertension, could mediate adulthood hypertension and metabolic syndrome [26]. Our results also showed that children with REM-related OSA had less respiratory event–related arousals and lower proportion of stage 1 sleep than the other two subtypes. This finding is consistent with a previous study which demonstrated that arousal threshold in response to inspiratory resistance load in REM sleep was substantially higher than that in NREM sleep [9]. This physiologic phenomenon may serve as a protective mechanism against arousal-related swings in sympathetic activity and hence BP. In addition, it was found that children with REM-related OSA tended to also have lower oxygen desaturation index, though the difference was not statistically significant. This finding may offer another explanation for the lower BP seen in the REM-related group, as intermittent hypoxia would lead to increased sympathetic activity, endothelial dysfunction, and systemic inflammation, all of which would cause elevation of BP [27]. Our findings were consistent with results from previous studies. Elevated BP was significantly correlated with OAHINREM but not with OAHIREM in children aged 5–12 years [2]. One study showed that morning awakening from stage 2 sleep was associated with greater heart rate and BP surges compared to awakening from REM sleep in young adults, indicating that awakening from REM sleep led to a lesser degree of autonomic activation [28]. Another study demonstrated that acute surges in heart rate and BP immediately after obstructive events were more pronounced during NREM compared to REM sleep in children aged 7–12 years [29]. These results and our findings suggest that disturbances in REM rather than NREM sleep maybe less harmful for cardiovascular outcomes. Interestingly, significant differences in ABP between different OSA subtypes could only be found in moderate but not mild OSA. One possible explanation is that the differences in OAHINREM between different OSA subtypes among the mild group were not as great as those found in the moderate OSA group. This finding was particularly true during the nighttime, as the frequency of ABP measurement was only taken once per hour; therefore, the chance of picking up significant postrespiratory BP surges was relatively low in the mild group compared to the moderate group. It is possible that important BP differences in the mild OSA group were underestimated. Because our study comprised a community-based cohort, most of the cases had relatively mild OSA compared to subjects recruited from hospital attendants. The use of community-based samples should make the data more applicable to the general population. However, the small sample size in the moderate OSA group limited the generalizability of the results and should be interpreted with caution. A prospective study with a larger sample size is required to confirm our findings. Nevertheless, the effect size observed in the moderate OSA group was so large that it was unlikely to be a random effect. Synchronization between ABP monitoring and PSG was not performed at the data collection stage. It would be interesting to examine if children exhibited differential BP levels in different sleep stages depending on their OSA subtype. Another limitation of our study was that ABP was intermittently measured instead of continuously. In children with REM-related OSA, obstructive respiratory events are concentrated in REM sleep, which accounts for only approximately 25% of total sleep time in school-aged children [30,31]. BP in REM sleep might be continuously elevated, due
1321
to the frequent respiratory events. However, because the hourly measurements had a higher probability to be taken during NREM sleep, the increased BP in REM sleep would be diluted and would result in a lower overall BP. Nevertheless, our results showed that children with REM-related OSA did not only have a lower nighttime BP but also a lower daytime BP, supporting the fact that it was unlikely to be a biased result. Overall OAHI is conventionally used as a marker of OSA severity in both children and adults. However, linear associations between OAHI and adverse outcome measures were only found in some studies [2–4] but not the others [5,32]. To determine a subject’s OSA severity by solely relying on OAHI is continuously being questioned. The definitions of REM-related and NREM-related OSA in our study were totally arbitrary, and our design was not powered to validate such definitions. Nevertheless, our results suggest that we may need to pay more attention to the distribution of respiratory events among REM and NREM sleep, as it may modulate the adverse effect of OSA on BP in children. Our findings have important implications as the majority of children with OSA had REM-related OSA, which did not seem to lead to significant BP abnormalities. It is possible that we have been overstating and even overtreating this problem in children. Our results will need to be replicated, and further studies examining other recognized OSA-related complications such as neurocognitive and metabolic abnormalities are needed. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.09.017.
References [1] Ng DK, Wong JC, Chan CH, Leung LC, Leung SY. Ambulatory blood pressure before and after adenotonsillectomy in children with obstructive sleep apnea. Sleep Med 2010;11:721–5. [2] Bixler EO, Vgontzas AN, Lin HM, Liao D, Calhoun S, Fedok F, et al. Blood pressure associated with sleep-disordered breathing in a population sample of children. Hypertension 2008;52:841–6. [3] Amin R, Somers VK, McConnell K, Willging P, Myer C, Sherman M, et al. Activity-adjusted 24-hour ambulatory blood pressure and cardiac remodeling in children with sleep disordered breathing. Hypertension 2008;51:84–91 [published online ahead of print December 10, 2007]. [4] Li AM, Au CT, Sung RY, Ho C, Ng PC, Fok TF, et al. Ambulatory blood pressure in children with obstructive sleep apnoea: a community based study. Thorax 2008;63:803–9 [published online ahead of print April 3, 2008]. [5] Horne RS, Yang JS, Walter LM, Richardson HL, O’Driscoll DM, Foster AM, et al. Elevated blood pressure during sleep and wake in children with sleepdisordered breathing. Pediatrics 2011;128:e85–92 [published online ahead of print June 27, 2011]. [6] Katz ES, Marcus CL, White DP. Influence of airway pressure on genioglossus activity during sleep in normal children. Am J Respir Crit Care Med 2006;173:902–9. [7] Katz ES, White DP. Genioglossus activity during sleep in normal control subjects and children with obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:553–60. [8] Marcus CL, Lutz J, Carroll JL, Bamford O. Arousal and ventilatory responses during sleep in children with obstructive sleep apnea. J Appl Physiol 1998;84:1926–36. [9] Marcus CL, Moreira GA, Bamford O, Lutz J. Response to inspiratory resistive loading during sleep in normal children and children with obstructive apnea. J Appl Physiol 1999;87:1448–54. [10] Goh DY, Galster P, Marcus CL. Sleep architecture and respiratory disturbances in children with obstructive sleep apnea. Am J Respir Crit Care Med 2000;162(2, pt. 1):682–6. [11] Haba-Rubio J, Janssens JP, Rochat T, Sforza E. Rapid eye movement-related disordered breathing: clinical and polysomnographic features. Chest 2005;128:3350–7. [12] Koo BB, Dostal J, Ioachimescu O, Budur K. The effects of gender and age on REM-related sleep-disordered breathing. Sleep Breath 2008;12:259–64. [13] Koo BB, Patel SR, Strohl K, Hoffstein V. Rapid eye movement-related sleepdisordered breathing: influence of age and gender. Chest 2008;134:1156–61.
1322
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
[14] Verginis N, Jolley D, Horne RS, Davey MJ, Nixon GM. Sleep state distribution of obstructive events in children: is obstructive sleep apnoea really a rapid eye movement sleep-related condition? J Sleep Res 2009;18:411–4. [15] Resta O, Carpanano GE, Lacedonia D, Di Gioia G, Giliberti T, Stefano A, et al. Gender difference in sleep profile of severely obese patients with obstructive sleep apnea (OSA). Respir Med 2005;99:91–6. [16] Kass JE, Akers SM, Bartter TC, Pratter MR. Rapid-eye-movement-specific sleepdisordered breathing: a possible cause of excessive daytime sleepiness. Am J Respir Crit Care Med 1996;154:167–9. [17] Conwell W, Patel B, Doeing D, Pamidi S, Knutson KL, Ghods F, et al. Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population. Sleep Breath 2012;16:519–26 [published online ahead of print May 27, 2011]. [18] Punjabi NM, Bandeen-Roche K, Marx JJ, Neubauer DN, Smith PL, Schwartz AR. The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep. Sleep 2002;25:307–14. [19] Chami HA, Baldwin CM, Silverman A, Zhang Y, Rapoport D, Punjabi NM, et al. Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. Am J Respir Crit Care Med 2010;181:997–1002 [published correction appears in Am J Respir Crit Care Med 2011;184:622] [published online ahead of print January 21, 2010]. [20] Pamidi S, Knutson KL, Ghods F, Mokhlesi B. Depressive symptoms and obesity as predictors of sleepiness and quality of life in patients with REM-related obstructive sleep apnea: cross-sectional analysis of a large clinical population. Sleep Med 2011;12:827–31 [published online ahead of print October 5, 2011]. [21] Leung SS, Cole TJ, Tse LY, Lau JT. Body mass index reference curves for Chinese children. Ann Hum Biol 1998;25:169–74. [22] Li AM, So HK, Au CT, Ho C, Lau J, Ng SK, et al. Epidemiology of obstructive sleep apnoea syndrome in Chinese children: a two-phase community study. Thorax 2010;65:991–7.
[23] American Thoracic Society. Cardiorespiratory sleep studies in children: establishment of normative data and polysomnographic predictors of morbidity. Am J Respir Crit Care Med 1999;160:1381–7. [24] Baumgart P, Kamp J. Accuracy of the SpaceLabs Medical 90217 ambulatory blood pressure monitor. Blood Press Monit 1998;3:303–7. [25] Wuhl E, Witte K, Soergel M, Mehls O, Schaefer F. German working group on pediatric hypertension. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens 2002;20:1995–2007. [26] Sun SS, Grave GD, Siervogel RM, Pickoff AA, Arslanian SS, Daniels SR. Systolic blood pressure in children predicts hypertension and metabolic syndrome later in life. Pediatrics 2007;119:237–46. [27] Baguet JP, Barone-Rochette G, Tamisier R, Levy P, Pépin JL. Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol 2012;9:679–88. [28] Goff EA, Nicholas CL, Simonds AK, Trinder J, Morrell MJ. Differential effects of waking from non-rapid eye movement versus rapid eye movement sleep on cardiovascular activity. J Sleep Res 2010;19(1, pt. 2):201–6. [29] O’Driscoll DM, Foster AM, Ng ML, Yang JS, Bashir F, Nixon GM, et al. Acute cardiovascular changes with obstructive events in children with sleep disordered breathing. Sleep 2009;32:1265–71. [30] Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographic characteristics in normal preschool and early school-aged children. Pediatrics 2006;117:741–53. [31] Uliel S, Tauman R, Greenfeld M, Sivan Y. Normal polysomnographic respiratory values in children and adolescents. Chest 2004;125:872–8. [32] Amin RS, Carroll JL, Jeffries JL, et al. Twenty-four-hour ambulatory blood pressure in children with sleep-disordered breathing. Am J Respir Crit Care Med 2004;169:950–6.
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
The effect of childhood obstructive sleep apnea on ambulatory blood pressure is modulated by the distribution of respiratory events during rapid eye movement and nonrapid eye movement sleep Chun Ting Au a,⇑, Crover Kwok Wah Ho b, Yun Kwok Wing b, Albert Martin Li a a b
Department of Pediatrics, Prince of Wales and Shatin Hospitals, The Chinese University of Hong Kong, Shatin, Hong Kong Department of Psychiatry, Prince of Wales and Shatin Hospitals, The Chinese University of Hong Kong, Shatin, Hong Kong
a r t i c l e
i n f o
Article history: Received 7 March 2013 Received in revised form 29 August 2013 Accepted 1 September 2013 Available online 17 October 2013 Keywords: Obstructive sleep apnea Rapid eye movement REM-related OSA Blood pressure Polysomnography Children
a b s t r a c t Objective: We aimed to investigate if different childhood obstructive sleep apnea (OSA) subtypes, namely rapid eye movement (REM)-related, nonrapid eye movement (NREM)-related and stage-independent OSA would exert different effects on ambulatory blood pressure (ABP). Methods: Data from our previous school-based cross-sectional study were reanalyzed. Subjects who had an obstructive apnea–hypopnea index (OAHI) between 1 and 10 events per hour and a total REM sleep duration of >30 min were included in our analysis. REM-related and NREM-related OSA were defined as a ratio of OAHI in REM sleep (OAHIREM) to OAHI in NREM sleep (OAHINREM) of >2 and <0.5, respectively. The others were classified as stage-independent OSA. Results: A total of 162 subjects were included in the analysis. In the mild OSA (OAHI, 1–5 events/h) subgroup, no significant differences in any ABP parameters were found between OSA subtypes. On the other hand, in subjects with moderate OSA (OAHI, 5–10 events/h), the REM-related OSA subtype had a significantly lower daytime systolic blood pressure (SBP) z score ( 0.13 ± 0.90 cf 1.15 ± 0.67; P = .012) and nighttime SBP z score (0.29 ± 1.06 cf 1.48 ± 0.88, P = .039) than the stage-independent OSA subtype. Linear regression analyses revealed that OAHINREM but not OAHIREM was significantly associated with both daytime (P = .008) and nighttime SBP (P = .042) after controlling for age, gender, and body size. Conclusion: Children with obstructive events mainly in REM sleep may have less cardiovascular complications than those with stage-independent OSA. Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction In recent years, a number of studies have shown that pediatric obstructive sleep apnea (OSA) is associated with elevated blood pressure (BP) [1–4]. Our group documented that children with OSA had significantly higher daytime and nocturnal BP compared to nonsnoring control subjects. In addition, moderate to severe OSA, defined as an obstructive apnea–hypopnea index (OAHI) of >5 events per hour, was associated with a higher risk for nocturnal hypertension, whereas the effect of mild OSA was only modest [4]. It has been found that obstructive respiratory events more commonly are found in rapid eye movement (REM) sleep [6,7] in children with OSA, possibly attributed to the reduced muscle tone and blunted arousal and ventilatory responses during this sleep state [6–9]. A previous study revealed that 55% of obstructive apneas in children occurred during REM sleep [10]. Patients with obstructive respiratory events mainly during REM sleep are defined as ⇑ Corresponding author. Tel.: +852 2632 2917; fax: +852 2636 0020. E-mail address: [email protected] (C.T. Au). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.09.017
having REM-related OSA. Clinically, the diagnosis of REM-related OSA has not been standardized. For research purposes, a subject is classified as having REM-related OSA when the diagnostic criteria of OSA are fulfilled and the ratio of OAHI in REM sleep (OAHIREM) to OAHI in non-REM (NREM) sleep (OAHINREM) is >2 [11–13]. Although REM-related OSA in children is common, research in this topic is limited. There are no published data on its prevalence based on a community sample. A pediatric study [14] that involved sleep laboratory attendants showed that nearly 70% of patients had higher OAHIREM than OAHINREM. From adult studies, the prevalence of REM-related OSA is approximately 10–36% among patients with OSA [11–13,15]. The clinical significance of REM-related OSA is controversial. Some studies suggest that REM-related OSA is associated with excessive daytime sleepiness [16,11,17], and others argue that the main correlate with adverse outcomes is OAHINREM rather than OAHIREM [18–20]. There currently is no evidence to suggest differential effects on 24-h ambulatory BP (ABP) monitoring by the different OSA subtypes. Our study aimed to investigate if differences in ABP were present in children with OSA, with different
1318
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
distributions of respiratory events among REM and NREM sleep. We stratified the study population into mild (OAHI, 1–5 events/ h) and moderate OSA (OAHI, 5–10 events/h) subgroups to control for the effect of overall OSA severity on ABP. 2. Methods 2.1. Study design
The other subjects with a ratio between 0.5 and 2 were classified as stage-independent OSA. To avoid an overestimated OAHIREM in cases with inadequate total REM sleep, subjects with less than 30 min of total REM sleep were excluded. The severe OSA cases also were excluded, as there were only three subjects in each of NREM-related and the stage-independent groups. Such small sample size would provide unreliable results. Moreover, their OAHI widely varied from 11.3 events per hour to 80.9 events per hour and combining severe and moderate groups was not an option as that would distort the results by greatly increasing the variance of OAHI.
Data from our previous school-based cross-sectional study, which investigated the association between OSA and ABP, were reanalyzed [4]. The study included 306 children aged 6–13 years recruited from primary schools that were randomly selected from two local districts, Sha Tin and Tai Po. All subjects underwent anthropometric measurements, overnight polysomnography (PSG) and ABP monitoring. ABP monitoring was performed over a 24-h period during which overnight PSG also was performed. Body mass index (BMI) was converted to BMI z score according to normal reference [21]. Written informed consent and assent were obtained from parents and subjects, respectively. The study was approved by the Joint Chinese University of Hong Kong, New Territories East Cluster.
Overnight PSG was performed in a dedicated sleep laboratory with CNS 1000P polygraph (CNS, Inc., Chanhassen MN) as described in our previous publication [22]. All computerized sleep data were further manually edited by experienced PSG technologists and clinicians according to standardized criteria [23]. All studies were standardized to record the time in bed for 9.5 h ± 5 min, starting at 21:30 ± 15 min and ending at 7:00 ± 15 min the next day.
2.2. Clinical research ethics committee
2.4. ABP monitoring
Based on the PSG results, subjects were divided into four groups: (1) healthy control subjects without OSA (OAHI <1 event/ h), (2) mild OSA (OAHI, 1–5 events/h), (3) moderate OSA (OAHI, 5–10 events/h), and (4) severe OSA (OAHI, >10 events/h) [4]. In our retrospective analysis subjects within each group, except for the control group, were further stratified into different OSA subtypes, namely REM-related, NREM-related, and stage-independent OSA for comparisons. REM-related OSA and NREM-related OSA were defined as OAHIREM/OAHINREM of >2 and <0.5, respectively.
Subjects underwent 24-h ABP monitoring on the same day as overnight PSG using an oscillometric monitor (SpaceLabs 90217, SpaceLabs Medical, Redmond, Washington, USA), which has been validated for use in children [24]. Systolic BP (SBP) and diastolic BP (DBP) were measured every 60 min during the nighttime from 09:30 pm to 07:00 am and every 30 min from 07:00 am to 09:30 pm (daytime period). The exact cutoff dividing daytime and nighttime BP was individually defined according to the PSG tracings. Individual mean SBP and DBP were calculated for daytime
2.3. Polysomnography
Table 1 Anthropometric and polysomnographic data of different obstructive sleep apnea subtypes. Control (OAHI <1/h) n = 127 Age, y Male gender, n (%) Height, cm BMI, m/kg2 BMI z score REM sleep, % Stage 1, % Stage 2, % SWS, % TST, min ODI, events /h
10.4 ± 1.7 72 (56.7) 139 ± 10 17.4 ± 2.9 0.21 ± 0.98 21.0 ± 3.9 6.5 ± 3.0 49.4 ± 5.4 23.1 ± 5.4 474 ± 58 0.1 (0–0.4)
ArI, events/h Respiratory ArI, events/h SpO2 nadir in REM, % SpO2 nadir in NREM, % SpO2 nadir, % OAHITST, events /h OAHIREM, events/h
6.1 ± 2.5 0.3 (0.1–0.7)
OAHINREM, events/h
93 ± 2 93 ± 2 92 ± 2 0.3 ± 0.3 0 (0–1.0) 0 (0–0.3)
Mild OSA (OAHI 1–5/h)
Moderate OSA (OAHI 5–10/h)
REMrelated n = 90
NREMrelated n = 18
Sleep stage: independent n = 24
P value
REM-related
10.6 ± 1.6 62 (68.9) 140 ± 11 18.9 ± 3.5 0.63 ± 1.00 21.6 ± 3.6 8.2 ± 3.6 48.0 ± 5.0 22.2 ± 4.8 467 ± 59 0.4 (0.2– 0.9) 7.1 ± 2.7 1.3 (0.9– 2.3) 94 ± 2 93 ± 2
10.2 ± 1.7 12 (66.7) 138 ± 10 18.8 ± 3.4 0.69 ± 0.94 20.1 ± 3.9 7.7 ± 4.8 49.9 ± 4.9 22.3 ± 5.7 478 ± 61 0.7 (0.2– 1.2) 8.1 ± 4.9 2.0 (1.5– 2.7)⁄ 92 ± 4 92 ± 2
10.7 ± 1.6 18 (75) 141 ± 11 17.7 ± 3.8 0.11 ± 1.16 19.9 ± 4.2 8.9 ± 2.7 48.3 ± 5.7 22.9 ± 6.0 462 ± 75 0.8 (0.5–1.3)
.558 .808 .635 .336 .074 .070 .535 .355 .841 .714 .049
10.1 ± 1.7 13 (86.7) 139 ± 11 19.1 ± 3.2 0.82 ± 0.98 21.3 ± 3.4 6.6 ± 3.4 46.9 ± 6.8 25.2 ± 5.1 505 ± 53 1.4 (0.5–2.3)
8.9 ± 3.0⁄ 2.2 (1.3–3.2)⁄
.030 .005
8.8 ± 3.5 3.7 (2.2–5.0)
92 ± 2 91 ± 2⁄
.758 .011
91 ± 4 93 ± 3
92 ± 3 2.3 ± 1.1 7.0 (4.3– 9.8) 0.6 (0.3– 1.0)
91 ± 4 1.8 ± 0.7 0.2 (0–0.6)⁄
91 ± 2 2.2 ± 1.0 2.1 (1.1–2.7)⁄
.288 .291 <.001
2.0 (1.6– 3.1)⁄
2.1 (1.3–2.6)⁄
<.001
n = 15
90 ± 4 6.9 ± 1.2 23.2 (18.4– 29.6) 1.5 (1.1–2.7)
NREMrelated n=8
Sleep stage: independent n=7
P value
10.2 ± 1.8 5 (62.5) 140 ± 12 20.3 ± 2.4 1.24 ± 0.98 21.0 ± 4.8 8.3 ± 3.2 47.8 ± 6.8 22.9 ± 6.4 463 ± 44 1.2 (0.5– 4.5) 10.9 ± 2.4 6.9 (6.0– 8.7)⁄ 93 ± 2 90 ± 5
9.3 ± 1.4 5 (71.4) 138 ± 11 18.6 ± 2.6 0.87 ± 0.94 21.4 ± 7.1 10.8 ± 4.4⁄ 44.1 ± 3.4 23.8 ± 4.1 456 ± 71 3.7 (0.9–5.7)
.490 .398 .966 .503 .598 .988 .056 .489 .574 .095 .220
13.7 ± 5.0⁄ 7.2 (5.1–9.3)
.024 .004
92 ± 3 93 ± 1
.435 .109
90 ± 5 7.2 ± 1.4 1.7 (0–2.7)⁄
91 ± 2 7.9 ± 1.0 8.6 (5.2–10.0)⁄
.780 .253 <.001
8.3 (7.0– 9.4)⁄
8.1 (7.1–8.7)⁄
<.001
Abbreviations: OSA, obstructive sleep apnea; h, hour; OAHI, obstructive apnea–hypopnea index; REM, rapid eye movement; NREM, nonrapid eye movement; y, years; BMI, body mass index; SWS, slow-wave sleep; TST, total sleep time; ODI, oxygen desaturation index; ArI, arousal index; SpO2, oxygen saturation; OAHIREM, OAHI in REM sleep; OAHINREM, OAHI in NREM sleep. * Significantly different from REM-related OSA group.
1319
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322 Table 2 Daytime and nighttime ambulatory blood pressure data of different obstructive sleep apnea subtypes. Control (OAHI <1/h)
Daytime SBP, mmHg Daytime DBP, mmHg Nighttime SBP, mmHg Nighttime DBP, mmHg Nocturnal SBP dipping,% Nocturnal DBP dipping,%
Mild OSA (OAHI 1–5/h)
Moderate OSA (OAHI 5–10/h)
NREMrelated n = 18
Sleep stage: independent n = 24
P value for trend
REMrelated n = 15
NREMrelated n=8
Sleep stage: independent n=7
P value for trend
n = 127
REMrelated n = 90
111 ± 8
113 ± 8
112 ± 8
113 ± 9
.779
112 ± 7
119 ± 7
122 ± 7⁄
.003
71 ± 5
71 ± 5
71 ± 5
73 ± 6
.295
72 ± 4
75 ± 6
75 ± 2
.097
99 ± 9
102 ± 8
101 ± 9
102 ± 7
.932
101 ± 9
104 ± 7
110 ± 9
.022
58 ± 6
59 ± 5
59 ± 4
60 ± 5
.829
59 ± 6
59 ± 7
63 ± 6
.229
10.5 ± 5.3
9.5 ± 5.8
10.3 ± 6.9
9.4 ± 4.7
.928
10.3 ± 5.7
12.3 ± 4.2
9.5 ± 5.7
.892
17.5 ± 6.9
16.6 ± 6.7
16.1 ± 7.0
17.3 ± 5.1
.728
18.1 ± 6.6
21.2 ± 6.3
16.8 ± 6.9
.854
Abbreviations: OSA, obstructive sleep apnea; h, hour; OAHI, obstructive apnea–hypopnea index; REM, rapid eye movement; NREM, nonrapid eye movement; DBP, diastolic blood pressure; SBP, systolic blood pressure. * Significantly different from REM-related OSA group.
and nighttime periods. All mean BP variables were converted into BP z scores using the reference ranges relative to gender and height published by Wuhl et al. [25]. Nocturnal dipping of SBP and DBP were derived by calculating the difference between daytime and nighttime BP and expressed as a percentage of mean daytime BP. 2.5. Statistical analysis The mean ± standard deviation, median (interquartile range), and number (percentage) were presented for parametric, nonparametric, and categorical data, respectively. Data from the control group were shown for reference. Normally distributed and nonnormally distributed data were compared using one-way analysis of variance and the Kruskal–Wallis test, respectively. Two group pairwise comparisons were performed with post hoc testing of analysis of variance for normally distributed data and the Mann–Whitney U test with Bonferroni correction (significance at P < .016) for non-
normally distributed data. The v2 test or Fisher exact test with Bonferroni correction (significance at P < .016) were performed to investigate the difference in proportions between groups. Linear contrast tests were used to examine the linear trends across groups for continuous variables. Linear regression analyses were used to examine the association of OAHIREM and OAHINREM with ABP measures. All analyses were performed using the statistical software packages SPSS (version 13.0 for Windows; SPSS Inc., Chicago, Illinois, USA).
3. Results 3.1. Mild OSA subgroup In the mild OSA subgroup, one child who had less than 30 min of total REM sleep was excluded. Among the remaining 132 chil-
Fig. 1. Scatter plot of ambulatory blood pressure of different mild obstructive sleep apnea subtypes.
1320
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
Fig. 2. Scatter plot of ambulatory blood pressure of different moderate obstructive sleep apnea subtypes. P values were obtained from linear contrast tests. ⁄Significantly different from rapid eye movement sleep-related obstructive sleep apnea group. (P < .05, post hoc testing of analysis of variance).
dren, 90 subjects had REM-related OSA, 18 subjects had NREM-related OSA, and 24 subjects had stage-independent OSA. No significant differences in age, gender, and body size were found between these subtypes (Table 1). From the PSG results, the REM-related OSA group had a significantly lower arousal index (P = .031) and higher oxygen saturation nadir during NREM sleep (P = .015) than the stage-independent OSA group. However, no significant difference in overall OAHI could be found (Table 1). For ABP parameters, there were no significant differences or linear trends across different OSA subtypes (Table 2 and Fig. 1). 3.2. Moderate OSA subgroup In the moderate OSA subgroup, 15, 8, and 7 subjects were found to have REM-related, NREM-related, and stage-independent OSA, respectively. No significant differences in age, gender, and body size were found between these subtypes. The REM-related OSA group had significantly less stage 1 sleep (P = .046) and lower arousal index (P = .019) than the stage-independent OSA group (Table 1). The ABP data revealed that there were significant increasing linear trends in both daytime (P for trend = .003) and nighttime SBP (P for trend = .022) across different OSA subtypes, namely from the REM-related to NREM-related to the stage-independent group. Post hoc analyses demonstrated that the REM-related OSA group had significantly lower daytime SBP (P = .014) and a trend of lower nighttime SBP (P = .052) than the stage-independent OSA group (Table 2). These linear trends across different OSA subtypes and differences between the REM-related and stage-independent OSA subtypes remained significant, even after converting the ABP parameters into z scores (P for trend = .003 and P for trend = .015; P = .012 and P = .039, respectively) (Fig. 2). 3.3. Multivariate analysis Multiple linear regression analysis showed that OAHINREM but not OAHIREM was significantly associated with both daytime
Table 3 Results of multiple linear regression analysis showing the association of obstructive apnea–hypopnea index in rapid eye movement sleep and obstructive apnea– hypopnea index in nonrapid eye movement sleep with daytime and nighttime systolic blood pressure (n = 162). Daytime SBP b Age, y Body height, cm Male gender BMI z score OAHIREM, events/h OAHINREM, events/h
1.009 0.244 3.020 2.458 0.022 0.652
Nighttime SBP
SE
P value
0.572 0.090 1.252 0.588 0.078 0.245
.080 .008 .017 <.001 .781 .008
b 0.581 0.331 0.833 1.272 0.054 0.517
SE
P value
0.591 0.093 1.292 0.608 0.080 0.253
.327 <.001 .520 .038 .505 .042
Abbreviations: SBP, systolic blood pressure; SE, standard error; y, years; BMI, body mass index; OAHIREM, obstructive apnea–hypopnea index in rapid eye movement sleep; OAHINREM, OAHI in nonrapid eye movement sleep; h, hour.
(P = .008) and nighttime SBP (P = .042) after adjusting for age, gender, height, and BMI z score (Table 3). No two-way interaction effect between OAHIREM and BMI z score or between OAHINREM and BMI z score could be found on ABP measures. 4. Discussion To our knowledge, our study is the first to investigate ABP in children with different OSA subtypes. The main finding was that daytime and nighttime SBP were lowest in children with REM-related OSA (mean, 112 and 101 mmHg) and highest in children with stage-independent OSA (mean, 122 and 110 mmHg), despite the groups having similar overall OAHI. On the contrary, no similar differences were observed in children with mild OSA. In addition, OAHINREM but not OAHIREM was shown to be independently associated with daytime and nighttime SBP in linear regression analysis after adjusting for confounders. Each 1-unit increase in OAHINREM was associated with an increase of 0.7 mmHg in
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
daytime SBP and 0.5 mmHg in nighttime SBP. Such effect size may be clinically significant, as a previous study demonstrated that a small increase in BP in children was associated with left ventricular abnormalities [3]. Furthermore, it was suggested that elevated childhood BP, though not exceeding the threshold of hypertension, could mediate adulthood hypertension and metabolic syndrome [26]. Our results also showed that children with REM-related OSA had less respiratory event–related arousals and lower proportion of stage 1 sleep than the other two subtypes. This finding is consistent with a previous study which demonstrated that arousal threshold in response to inspiratory resistance load in REM sleep was substantially higher than that in NREM sleep [9]. This physiologic phenomenon may serve as a protective mechanism against arousal-related swings in sympathetic activity and hence BP. In addition, it was found that children with REM-related OSA tended to also have lower oxygen desaturation index, though the difference was not statistically significant. This finding may offer another explanation for the lower BP seen in the REM-related group, as intermittent hypoxia would lead to increased sympathetic activity, endothelial dysfunction, and systemic inflammation, all of which would cause elevation of BP [27]. Our findings were consistent with results from previous studies. Elevated BP was significantly correlated with OAHINREM but not with OAHIREM in children aged 5–12 years [2]. One study showed that morning awakening from stage 2 sleep was associated with greater heart rate and BP surges compared to awakening from REM sleep in young adults, indicating that awakening from REM sleep led to a lesser degree of autonomic activation [28]. Another study demonstrated that acute surges in heart rate and BP immediately after obstructive events were more pronounced during NREM compared to REM sleep in children aged 7–12 years [29]. These results and our findings suggest that disturbances in REM rather than NREM sleep maybe less harmful for cardiovascular outcomes. Interestingly, significant differences in ABP between different OSA subtypes could only be found in moderate but not mild OSA. One possible explanation is that the differences in OAHINREM between different OSA subtypes among the mild group were not as great as those found in the moderate OSA group. This finding was particularly true during the nighttime, as the frequency of ABP measurement was only taken once per hour; therefore, the chance of picking up significant postrespiratory BP surges was relatively low in the mild group compared to the moderate group. It is possible that important BP differences in the mild OSA group were underestimated. Because our study comprised a community-based cohort, most of the cases had relatively mild OSA compared to subjects recruited from hospital attendants. The use of community-based samples should make the data more applicable to the general population. However, the small sample size in the moderate OSA group limited the generalizability of the results and should be interpreted with caution. A prospective study with a larger sample size is required to confirm our findings. Nevertheless, the effect size observed in the moderate OSA group was so large that it was unlikely to be a random effect. Synchronization between ABP monitoring and PSG was not performed at the data collection stage. It would be interesting to examine if children exhibited differential BP levels in different sleep stages depending on their OSA subtype. Another limitation of our study was that ABP was intermittently measured instead of continuously. In children with REM-related OSA, obstructive respiratory events are concentrated in REM sleep, which accounts for only approximately 25% of total sleep time in school-aged children [30,31]. BP in REM sleep might be continuously elevated, due
1321
to the frequent respiratory events. However, because the hourly measurements had a higher probability to be taken during NREM sleep, the increased BP in REM sleep would be diluted and would result in a lower overall BP. Nevertheless, our results showed that children with REM-related OSA did not only have a lower nighttime BP but also a lower daytime BP, supporting the fact that it was unlikely to be a biased result. Overall OAHI is conventionally used as a marker of OSA severity in both children and adults. However, linear associations between OAHI and adverse outcome measures were only found in some studies [2–4] but not the others [5,32]. To determine a subject’s OSA severity by solely relying on OAHI is continuously being questioned. The definitions of REM-related and NREM-related OSA in our study were totally arbitrary, and our design was not powered to validate such definitions. Nevertheless, our results suggest that we may need to pay more attention to the distribution of respiratory events among REM and NREM sleep, as it may modulate the adverse effect of OSA on BP in children. Our findings have important implications as the majority of children with OSA had REM-related OSA, which did not seem to lead to significant BP abnormalities. It is possible that we have been overstating and even overtreating this problem in children. Our results will need to be replicated, and further studies examining other recognized OSA-related complications such as neurocognitive and metabolic abnormalities are needed. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.09.017.
References [1] Ng DK, Wong JC, Chan CH, Leung LC, Leung SY. Ambulatory blood pressure before and after adenotonsillectomy in children with obstructive sleep apnea. Sleep Med 2010;11:721–5. [2] Bixler EO, Vgontzas AN, Lin HM, Liao D, Calhoun S, Fedok F, et al. Blood pressure associated with sleep-disordered breathing in a population sample of children. Hypertension 2008;52:841–6. [3] Amin R, Somers VK, McConnell K, Willging P, Myer C, Sherman M, et al. Activity-adjusted 24-hour ambulatory blood pressure and cardiac remodeling in children with sleep disordered breathing. Hypertension 2008;51:84–91 [published online ahead of print December 10, 2007]. [4] Li AM, Au CT, Sung RY, Ho C, Ng PC, Fok TF, et al. Ambulatory blood pressure in children with obstructive sleep apnoea: a community based study. Thorax 2008;63:803–9 [published online ahead of print April 3, 2008]. [5] Horne RS, Yang JS, Walter LM, Richardson HL, O’Driscoll DM, Foster AM, et al. Elevated blood pressure during sleep and wake in children with sleepdisordered breathing. Pediatrics 2011;128:e85–92 [published online ahead of print June 27, 2011]. [6] Katz ES, Marcus CL, White DP. Influence of airway pressure on genioglossus activity during sleep in normal children. Am J Respir Crit Care Med 2006;173:902–9. [7] Katz ES, White DP. Genioglossus activity during sleep in normal control subjects and children with obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:553–60. [8] Marcus CL, Lutz J, Carroll JL, Bamford O. Arousal and ventilatory responses during sleep in children with obstructive sleep apnea. J Appl Physiol 1998;84:1926–36. [9] Marcus CL, Moreira GA, Bamford O, Lutz J. Response to inspiratory resistive loading during sleep in normal children and children with obstructive apnea. J Appl Physiol 1999;87:1448–54. [10] Goh DY, Galster P, Marcus CL. Sleep architecture and respiratory disturbances in children with obstructive sleep apnea. Am J Respir Crit Care Med 2000;162(2, pt. 1):682–6. [11] Haba-Rubio J, Janssens JP, Rochat T, Sforza E. Rapid eye movement-related disordered breathing: clinical and polysomnographic features. Chest 2005;128:3350–7. [12] Koo BB, Dostal J, Ioachimescu O, Budur K. The effects of gender and age on REM-related sleep-disordered breathing. Sleep Breath 2008;12:259–64. [13] Koo BB, Patel SR, Strohl K, Hoffstein V. Rapid eye movement-related sleepdisordered breathing: influence of age and gender. Chest 2008;134:1156–61.
1322
C.T. Au et al. / Sleep Medicine 14 (2013) 1317–1322
[14] Verginis N, Jolley D, Horne RS, Davey MJ, Nixon GM. Sleep state distribution of obstructive events in children: is obstructive sleep apnoea really a rapid eye movement sleep-related condition? J Sleep Res 2009;18:411–4. [15] Resta O, Carpanano GE, Lacedonia D, Di Gioia G, Giliberti T, Stefano A, et al. Gender difference in sleep profile of severely obese patients with obstructive sleep apnea (OSA). Respir Med 2005;99:91–6. [16] Kass JE, Akers SM, Bartter TC, Pratter MR. Rapid-eye-movement-specific sleepdisordered breathing: a possible cause of excessive daytime sleepiness. Am J Respir Crit Care Med 1996;154:167–9. [17] Conwell W, Patel B, Doeing D, Pamidi S, Knutson KL, Ghods F, et al. Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population. Sleep Breath 2012;16:519–26 [published online ahead of print May 27, 2011]. [18] Punjabi NM, Bandeen-Roche K, Marx JJ, Neubauer DN, Smith PL, Schwartz AR. The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep. Sleep 2002;25:307–14. [19] Chami HA, Baldwin CM, Silverman A, Zhang Y, Rapoport D, Punjabi NM, et al. Sleepiness, quality of life, and sleep maintenance in REM versus non-REM sleep-disordered breathing. Am J Respir Crit Care Med 2010;181:997–1002 [published correction appears in Am J Respir Crit Care Med 2011;184:622] [published online ahead of print January 21, 2010]. [20] Pamidi S, Knutson KL, Ghods F, Mokhlesi B. Depressive symptoms and obesity as predictors of sleepiness and quality of life in patients with REM-related obstructive sleep apnea: cross-sectional analysis of a large clinical population. Sleep Med 2011;12:827–31 [published online ahead of print October 5, 2011]. [21] Leung SS, Cole TJ, Tse LY, Lau JT. Body mass index reference curves for Chinese children. Ann Hum Biol 1998;25:169–74. [22] Li AM, So HK, Au CT, Ho C, Lau J, Ng SK, et al. Epidemiology of obstructive sleep apnoea syndrome in Chinese children: a two-phase community study. Thorax 2010;65:991–7.
[23] American Thoracic Society. Cardiorespiratory sleep studies in children: establishment of normative data and polysomnographic predictors of morbidity. Am J Respir Crit Care Med 1999;160:1381–7. [24] Baumgart P, Kamp J. Accuracy of the SpaceLabs Medical 90217 ambulatory blood pressure monitor. Blood Press Monit 1998;3:303–7. [25] Wuhl E, Witte K, Soergel M, Mehls O, Schaefer F. German working group on pediatric hypertension. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens 2002;20:1995–2007. [26] Sun SS, Grave GD, Siervogel RM, Pickoff AA, Arslanian SS, Daniels SR. Systolic blood pressure in children predicts hypertension and metabolic syndrome later in life. Pediatrics 2007;119:237–46. [27] Baguet JP, Barone-Rochette G, Tamisier R, Levy P, Pépin JL. Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol 2012;9:679–88. [28] Goff EA, Nicholas CL, Simonds AK, Trinder J, Morrell MJ. Differential effects of waking from non-rapid eye movement versus rapid eye movement sleep on cardiovascular activity. J Sleep Res 2010;19(1, pt. 2):201–6. [29] O’Driscoll DM, Foster AM, Ng ML, Yang JS, Bashir F, Nixon GM, et al. Acute cardiovascular changes with obstructive events in children with sleep disordered breathing. Sleep 2009;32:1265–71. [30] Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographic characteristics in normal preschool and early school-aged children. Pediatrics 2006;117:741–53. [31] Uliel S, Tauman R, Greenfeld M, Sivan Y. Normal polysomnographic respiratory values in children and adolescents. Chest 2004;125:872–8. [32] Amin RS, Carroll JL, Jeffries JL, et al. Twenty-four-hour ambulatory blood pressure in children with sleep-disordered breathing. Am J Respir Crit Care Med 2004;169:950–6.