PEDIATRICS
Autonomic Dysfunction in Children with Sleep-Disordered Breathing Louise M. O’Brien, PhD; David Gozal, MD Kosair Children’s Hospital Research Institute, and Division of Pediatric Sleep Medicine, Department of Pediatrics, University of Louisville, Louisville, KY
continuously monitored during immersion and 20-minute recovery periods. Signal amplitude changes were expressed as percentage change from corresponding baseline. Results: The magnitude of sympathetic discharge-induced attenuation of pulse arterial tonometry signal was significantly increased in children with sleep-disordered breathing during sigh maneuvers (74.1%±10.7% change compared with 59.2%±13.2% change in controls; P5 and children were assigned to the control group if their apnea-hypopnea index was < 1. Intervention: N/A. Measurements and Results: During quiet wakefulness, pulse arterial tonometry was used to assess changes in sympathetic activity following vital capacity sighs in 28 children with sleep-disordered breathing and 29 controls. Each child underwent a series of 3 sighs, and the average maximal pulse arterial tonometry signal attenuation was calculated. Further, a cold pressor test was conducted in a subset of 14 children with sleep-disordered breathing and 14 controls. The left hand was immersed in ice cold water for 30 seconds while right-hand pulse arterial tonometry signal was
effect of SDB on the autonomic nervous system in childhood has not been systematically investigated, it is likely that autonomic nervous system dysfunction is also present in some children, albeit to a lesser degree than in adults.10,11 A recently developed technique allowing for noninvasive moment-to-moment measurement of sympathetic tone is peripheral arterial tonometry, (PAT, Itamar Medical, Caesarea, Israel).12 PAT has been previously well described and employs a finger plethysmographic approach that eliminates venous pulsations and continuously measures the arterial pulse waveform of the digit. PAT continuously measures the pulsatile volume change using a pneumo-optic probe, which reflects the relative change of blood volume in the finger. Changes in sympathetic nervous system activity, which are mediated by alpha adrenoreceptor activation, result in episodic vasoconstriction of the digital vascular beds with corresponding attenuation of PAT signal.13,14 Thus, increases in sympathetic activity will elicit robust changes in peripheral vascular cutaneous perfusion and can be readily detected on a beatto-beat basis. In adults, PAT is exquisitely sensitive to changes in sympathetic autonomic nervous system activity.12 The purpose of this study was, therefore, to investigate dynamic responses of the sympathetic autonomic nervous system in children with and without SDB.
INTRODUCTION SLEEP-DISORDERED BREATHING (SDB) IN ADULTS IS ASSOCIATED WITH INCREASED CARDIOVASCULAR MORBIDITY AND MORTALITY, PARTICULARLY SYSTEMIC hypertension and ischemic heart disease.1-6 Although the mechanisms that mediate cardiovascular morbidity in adults with SDB are poorly understood, autonomic nervous system dysfunction is believed to play a key role.7 It is likely that both intermittent hypoxia and increased arousals mediate the elevation in sympathetic nerve activity that results in altered vasomotor tone regulation. Indeed, recurrent hypoxemia, associated with mild hypercapnia, and increased chemoreceptor firing all lead to increased muscle sympathetic nerve activity and increased blood pressure.8 In addition, arousals during sleep will directly activate the sympathetic nervous system with a resultant pressor response.9 Although the Disclosure Statement This was an industry supported study supported by Itamar Ltd. Itamar Ltd. provided an unrestricted grant and the PAT instrumentation required for the measurements. No involvement by Itamar occurred in regards to the original idea for the research project or project design. Dr. Gozal serves on the national speakers’ bureau for Merck Inc. Dr. O’Brien has indicated no financial conflict of interest. The data were analyzed and the paper was written by the authors.
METHODS Subjects were prospectively recruited from children being evaluated for potential SDB at Kosair Children’s Hospital Sleep Medicine Center. In addition, healthy children with no reports of sleep disturbance were also recruited from a community-based survey to act as controls. The study was approved by the University of Louisville Human Research Committee. Parental in-
Submitted for publication September 2004 Accepted for publication February 2005 Address correspondence to: David Gozal, MD, Kosair Children’s Hospital Research Institute, University of Louisville School of Medicine, 570 S. Preston Street Suite 204, Louisville, KY 40202; Tel: (502) 852 2323; Fax: (502) 852 2215; E-mail:
[email protected] SLEEP, Vol. 28, No. 6, 2005
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Autonomic Dysfunction in Apneic Children—O’Brien and Gozal
formed consent and child assent, in the presence of a parent, were obtained. Children were excluded if they had any chronic medical condition, received medications known to alter autonomic nervous system function, or had any psychiatric diagnoses or any genetic or craniofacial syndromes. All children underwent a standard overnight multichannel polysomnographic evaluation in the sleep laboratory to confirm the presence or absence of SDB rather than rely on parental report. No drugs were used to induce sleep. The following parameters were measured: chest and abdominal wall movement by respiratory impedance or inductance plethysmography; heart rate by electrocardiogram; air flow was monitored with a sidestream end-tidal capnograph, which also provided breathby-breath assessment of end-tidal carbon-dioxide levels (BCI SC300, Menomonee Falls, Wisc); and a thermistor. The SpO2 was assessed by pulse oximetry (Nellcor N 100; Nellcor Inc., Hayward, Calif), with simultaneous recording of the pulse waveform. The bilateral electrooculogram, 8 channels of electroencephalogram, chin and anterior tibial electromyograms, and analog output from a body position sensor (Braebon Medical Corporation, NY) were also monitored. All measures were digitized using a commercially available polysomnography system (Rembrandt, MedCare Diagnostics, Amsterdam, The Netherlands). Tracheal sound was monitored with a microphone sensor (Sleepmate, Virg), and a digital time-synchronized video recording was performed. Sleep architecture was assessed by standard techniques.15 Obstructive apnea was defined as the absence of airflow with continued chest-wall and abdominal movement for duration of at least 2 breaths.16,17 Hypopneas were defined as a decrease in nasal flow of at least 50% with a corresponding decrease in SpO2 of at least 4%, an arousal, or both a decrease in SpO2 and an arousal.17 The obstructive apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of total sleep time. Children with an AHI of 5 or more per hour of total sleep time were considered to have SDB, whereas children without a history of snoring and an AHI less than 1 were considered to be controls. 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. Since criteria for arousals have not yet been developed for children, arousals were defined as recommended by the American Sleep Disorders Association Task Force report18 using the 3-second rule, the presence of movement arousal, or both.19 Arousals were divided into 2 main subtypes: spontaneous arousals and respiratory arousals. Immediately prior to initiation of the polysomnographic recordings, PAT was used to assess changes in sympathetic activity during quiet wakefulness. The PAT probe was placed on the right hand of each child, and both raw and filtered PAT signals were digitally acquired and incorporated into the polysomnographic montage. Each child sat up on the bed with both hands resting on a table in front of him or her. Baseline PAT measurements were obtained when the child was sitting quietly and the PAT signal was steady for at least 2 minutes. Baseline values were obtained by taking the mean measurement across a 10-second period of steady, good-quality signal. Following baseline measures, each child underwent a series of 3 vital capacity sighs, each separated by at least 60 seconds of normal breathing wherein the PAT signal remained steady and artifact free. The maximal attenuation of PAT signal was measured over 10 seconds and calculated as a percentage change from baseline. Measurements were averaged over the series of sighs. Figure 1 illustrates a PAT attenuation associated with a sigh. A subgroup of children also underwent a cold pressor test 5 minutes after the series of sighs. This subgroup comprised all SLEEP, Vol. 28, No. 6, 2005
Figure 1—Peripheral arterial tonometry attenuation associated with a vital capacity sigh.
children recruited to the study following the addition of the pressor test to the challenge protocol. The left hand was immersed in ice-cold water for 30 seconds while the right hand remained still. PAT signal was continuously monitored throughout the immersion and recovery periods. Changes in signal amplitude were calculated by averaging the mean amplitude over a 10-second period before the pressor test (baseline), during the pressor test (challenge), immediately following the removal of the hand from the water (post challenge), and then at 1-minute intervals during the 20-minute recovery phase. All measures were obtained from a steady and regular artifact-free PAT signal. Amplitudes were expressed as percentage change from corresponding baseline. All maneuvers were performed at least 3 hours following ingestion of food or caffeine, since these variables may confound the results. In addition, ambient temperature remained constant throughout the assessments. Data Analysis All data were coded and analyzed blind to the subject group upon completion of recruitment. Data are presented as means ± SD and 95% confidence intervals (CI) unless otherwise indicated. Independent t tests were employed for comparisons of measures between the study groups, with the Fischer Exact Test used for dichotomous outcomes. For the cold pressor test, an analysis of variance with repeated measures was employed. All P values reported are 2 sided with statistical significance set at
