ELECTRONIC ARTICLE |
From the Kosair Children's Hospital Research Institute, Division of Pediatric Sleep Medicine, Department of Pediatrics, University of Louisville, Louisville, Kentucky
| ABSTRACT |
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Methods. Eighty-one children (mean age: 9.3 ± 3.7 years) underwent polysomnographic evaluations. Samples for plasma CRP level and lipid profile determinations were drawn the next morning.
Results. Because plasma CRP levels were not normally distributed in this cohort, logarithmic transformation was applied. Log plasma CRP levels were significantly higher in the SDB group (obstructive apnea/hypopnea index [AHI] of
5), compared with the mild SDB group (AHI of
1 and <5) and the control group (AHI of <1). Significant positive correlations were found between log CRP levels and AHI (r = .53) and arousal index (r = .28), whereas an inverse correlation was found between the lowest nocturnal arterial oxygen saturation and log CRP levels (r = .47). These correlations persisted after exclusion of outliers. Moreover, 94% of the children with elevated log CRP levels reported excessive daytime sleepiness and/or learning problems, compared with 62% of the children with normal log CRP levels.
Conclusions. Plasma CRP levels were increased among some children with SDB and were correlated with AHI, arterial oxygen saturation nadir, and arousal index measures. These changes were particularly prominent among children who were sleepy or presented with neurobehavioral complaints. The intermittent hypoxemia and sleep fragmentation of SDB may underlie inflammatory responses, the magnitude of which may ultimately lead to the cardiovascular, cognitive, and behavioral morbidities of SDB.
Key Words: sleep-disordered breathing C-reactive protein atherogenesis
Abbreviations: SDB, sleep-disordered breathing CRP, C-reactive protein BMI, body mass index HDL, high-density lipoprotein TST, total sleep time AHI, obstructive apnea/hypopnea index SPO2, arterial oxygen saturation
Sleep-disordered breathing (SDB) is characterized by repeated events of partial or complete upper airway obstruction during sleep, resulting in disruption of normal ventilation, hypoxemia, and sleep fragmentation. SDB is associated with neurobehavioral and cardiovascular morbidities.17 The increased prevalence of hypertension and atherogenesis among SDB patients has been ascribed to sympathetic activation810 and to endothelial dysfunction,1113 most likely resulting from initiation and propagation of inflammatory responses within the microvasculature.
C-reactive protein (CRP), an important serum marker of inflammation, has emerged as one of the most powerful independent predictors of risk for future cardiovascular morbidity.1416 In addition, recent evidence suggests that CRP may directly participate in atheromatous lesion formation through leukocyte activation and endothelial dysfunction.1720 CRP has also been found to be independently associated with insulin resistance2123 and low levels of the fat-derived cardioprotective hormone adiponectin,24 supporting the association between inflammation, atherogenesis, and insulin resistance.
Among adult patients with SDB, plasma CRP levels are elevated and are correlated with the severity of the disease.25 Moreover, plasma CRP levels are decreased after treatment with continuous positive airway pressure,26 which suggests that SDB leads to inflammatory responses that ultimately promote cardiovascular complications. Although substantial evidence of the cardiovascular morbidity of SDB among children has been accumulated in the past decade, no studies thus far have examined the levels of CRP among children with SDB. In this study, we assessed plasma CRP levels among a large cohort of children and also examined whether CRP levels were associated with some of the typical clinical complaints that usually lead to referral for evaluation of snoring.
| METHODS |
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7 years of age, was obtained. Blood for high-sensitivity assessments of plasma CRP levels was drawn the morning after each child underwent a standard polysomnographic evaluation in the sleep laboratory at the Kosair Children's Hospital. Plasma CRP levels were measured with a Flex reagent cartridge (Date Behring, Newark, DE), which is based on a particle-enhanced, turbidimetric, immunoassay technique. This method has a detection level of 0.05 mg/dL and exhibits linear behavior up to 255 mg/dL, with intraassay and interassay coefficients of variability of 9% and 18%, respectively. Serum levels of lipids, including total cholesterol, high-density lipoprotein (HDL) cholesterol, calculated low-density lipoprotein cholesterol, and triglycerides, were also assessed with Flex reagent cartridges (Date Behring).
A standard, overnight, multichannel, polysomnographic evaluation was performed in the sleep laboratory. Children were studied for up to 12 hours in a quiet darkened room with an ambient temperature of 24°C, in the company of 1 of their parents. No drugs were used to induce sleep. The following parameters were measured: chest and abdominal wall movements assessed by respiratory impedance or inductance plethysmography, heart rate assessed by electrocardiography, and air flow monitored by sidestream end-tidal capnography, which also provided breath-by-breath assessments of end-tidal carbon dioxide levels (BCI SC-300; Menomonee Falls, WI), and a thermistor. Arterial oxygen saturation (SPO2) was assessed by pulse oximetry (Nellcor N 100; Nellcor Inc, Hayward, CA), with simultaneous recording of the pulse waveform. Bilateral electroculograms, 8 channels of the electroencephalogram, chin and anterior tibial electromyograms, and analog output from a body-position sensor (Braebon Medical Corp, Ogdensburg, NY) were also monitored. All measures were digitized with a commercially available polysomnographic system (Rembrandt; MedCare Diagnostics, Amsterdam, The Netherlands). Tracheal sounds were monitored with a microphone sensor (Sleepmate, Midlothian, VA), and a digital, time-synchronized video recording was obtained.
Sleep architecture was assessed by standard techniques.27 The proportion of time spent in each sleep stage was expressed as percentage of the total sleep time (TST). Awakenings were defined as sustained arousal lasting for
15 seconds. The apnea index was defined as the number of episodes of apnea per hour of TST. Central, obstructive, and mixed apneic events were counted. Obstructive apnea was defined as the absence of airflow with continued chest wall and abdominal movements for the duration of at least 2 breaths.28,29 Hypopnea was defined as a decrease in nasal flow of
50% with a corresponding decrease in SPO2 of
4% and/or arousal.29 The obstructive apnea/hypopnea index (AHI) was defined as the number of episodes of apnea and hypopnea per hour of TST. Children with AHI values of
1 episode per hour of TST but <5 episodes per hour of TST were considered to have mild SDB, whereas children with AHI values of
5 episodes/hour of TST were considered to have SDB. Control children were defined as nonsnoring children with AHI values of <1 episode per hour of TST.
The mean SPO2, as measured by pulse oximetry in the presence of a pulse waveform signal void-of-motion artifact, and the SPO2 nadir were recorded. Because criteria for arousals have not yet been developed for children, arousals were defined as recommended by the American Sleep Disorders Association Sleep Disorders Atlas Task Force report,30 using the 3-second rule and/or the presence of movement arousal.31 Arousals were divided into 2 types, ie, spontaneous and respiratory arousals.
Height and weight were recorded for each child. Body mass index (BMI) was calculated, and data were also expressed as relative BMI using the following formula: relative BMI = (BMI/BMI of the 50th percentile for age and gender) x 100 (based on standardized percentile curves).32
Data are presented as means ± SD unless otherwise indicated. Because plasma CRP levels were not normally distributed, logarithmic transformation was applied. Comparisons of demographic data according to group assignment were made with independent t tests or analysis of variance followed by posthoc comparisons, with P values adjusted for unequal variances when appropriate (Levene's test for equality of variances), or
2 analyses with Fisher's exact test (dichotomous outcomes). Because obesity would be expected to contribute to increased CRP levels, we performed analysis of covariance with relative BMI as a covariate. Correlations of log CRP levels with arousal index, AHI, and SPO2 nadir were performed by linear regression, followed by calculation of Pearson correlation coefficients. All P values reported are 2-tailed, with statistical significance set at <.05.
| RESULTS |
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| DISCUSSION |
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CRP, an acute-phase reaction protein, is synthesized in the liver, and its expression is regulated by cytokines.34 CRP levels are usually stable during a 24-hour period35; the levels not only reflect the intensity of the inflammatory response but also have been shown to provide a reliable estimate of the risk of atherogenesis. Indeed, several large-scale, prospective, epidemiologic studies have shown that plasma levels of CRP are a strong independent predictor of risk for cardiovascular morbidity.15,16 Furthermore, although CRP is a nonspecific marker of inflammation, recent epidemiologic studies suggested that CRP may participate directly in atheromatous lesion formation through reduction of nitric oxide synthesis and induction of the expression of particular adhesion molecules in endothelial cells.36 In the present study, we observed higher plasma CRP levels among children with SDB, and levels were correlated with the severity of SDB. This association suggests that SDB elicits the activation of inflammatory processes and that the latter may be responsible in part for the morbidity associated with the disease. Our findings agree with those of a previous study of adult patients with SDB, in which similar correlations were found between the severity of disease and the degree of CRP level increases.25 We also found that CRP levels were correlated with the arousal index, indicating that elevated CRP levels may result from both the intermittent hypoxemia and the sleep fragmentation associated with SDB. Indeed, SDB-induced hypoxic stress has been shown to modulate levels of circulating inflammatory mediators and could lead to endothelial dysfunction through induction of cellular adhesion molecules in response to inflammatory cytokines. Plasma levels of tumor necrosis factor-
and interleukin-6 were significantly increased among patients with SDB.37 Elevated levels of circulating adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin were also reported and correlated with the severity of SDB.13
What are the potential clinical implications of these findings? The strong epidemiologic links between CRP levels and atherogenesis may indicate that the coincidence of SDB with higher CRP levels may increase the risk of atheroma formation among such children, thus promoting the development of cardiovascular morbidity later in life. CRP elevations in the context of SDB not only may provide a marker of the magnitude of the inflammatory response to SDB but also may be indicative of particular populations at increased risk for the development of long-term cardiovascular complications, which might be partially triggered or accelerated by the SDB disorder itself. Although these speculations obviously require prospective confirmatory studies that incorporate consideration of other factors, such as a family history of SDB or cardiovascular disease, it should be emphasized that the SDB-induced elevations of CRP levels were independent of BMI. This is particularly relevant because obesity in childhood constitutes an additional risk factor for cardiovascular morbidity.38,39 In addition, CRP levels were found to be independently associated with the independent cardiovascular risk factor of insulin resistance,2123, supporting the potential association between inflammation, insulin resistance, and atherogenesis.
The potential end-organ morbidity induced by SDB through an inflammation-mediated process is intriguingly supported by the significant differences in the frequency of excessive sleepiness and learning problems among children with elevated CRP levels, compared with children with similar AHI or arousal index values who did not develop increased CRP concentrations. Of note, the findings of sleepiness and learning problems were based on subjective parental reports, which is an obvious limitation of the current study. However, objective correlates of excessive sleepiness in children, ie, the multiple sleep latency test, are very insensitive among children.3 Although these findings need to be corroborated with more appropriate and objective methods, rather than using parental reports alone, they raise the possibility that the magnitude of the inflammatory response may underlie components of neurocognitive and vigilance deficits associated with SDB.3,6,7
No significant differences in serum lipid profiles emerged among the various SDB groups, indicating that specific alterations in lipid regulation do not seem to occur as a function of SDB severity. However, the negative correlation between HDL levels and plasma CRP levels and the positive correlation between triglyceride levels and CRP levels are in close agreement with previous reports on adults,40 suggesting that SDB may play a role in the regulation of HDL and triglycerides.
| CONCLUSIONS |
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| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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Reprint requests to (D.G.) Kosair Children's Hospital Research Institute, University of Louisville School of Medicine, 571 S Preston St, Suite 321, Louisville, KY 40202. E-mail: david.gozal{at}louisville.edu
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