OBJECTIVE. The goal was to determine whether amelioration of sleep-disordered breathing through adenotonsillectomy would reduce middle cerebral artery velocity in parallel with improvements in cognition and behavior.
METHODS. For 19 children (mean age: 6 years) with mild sleep-disordered breathing, and 14 healthy, ethnically similar and age-similar, control subjects, parents repeated the Pediatric Sleep Questionnaire an average of 12 months after adenotonsillectomy. Children with sleep-disordered breathing underwent repeated overnight measurement of mean oxyhemoglobin saturation. Neurobehavioral tests that yielded significant group differences preoperatively were readministered. Middle cerebral artery velocity measurements were repeated with blinding to sleep study and neuropsychological results, and mixed-design analyses of variance were performed.
RESULTS. The median Pediatric Sleep Questionnaire score significantly improved postoperatively, and there was a significant increase in mean overnight oxyhemoglobin saturation. The middle cerebral artery velocity decreased in the sleep-disordered breathing group postoperatively, whereas control subjects showed a slight increase. A preoperative group difference was reduced by the postoperative assessment, which suggests normalization of middle cerebral artery velocity in those with sleep-disordered breathing. The increase in mean overnight oxyhemoglobin saturation postoperatively was associated with a reduction in middle cerebral artery velocity in a subgroup of children. A preoperative group difference in processing speed was reduced postoperatively. Similarly, a trend for a preoperative group difference in visual attention was reduced postoperatively. Executive function remained significantly worse for the children with sleep-disordered breathing, compared with control subjects, although mean postoperative scores were lower than preoperative scores.
CONCLUSIONS. Otherwise-healthy young children with apparently mild sleep-disordered breathing have potentially reversible cerebral hemodynamic and neurobehavioral changes.
- sleep-disordered breathing
- cerebral blood flow velocity
- neurocognitive function
Childhood sleep-disordered breathing (SDB) describes a spectrum of upper-airway obstruction from primary snoring, which is reported for 10% of preschool-aged children,1 to obstructive sleep apnea, with reported community prevalence rates of 0.9% to 4.3%.2,3 Obstructive sleep apnea is characterized by repetitive partial (hypopnea) or complete (apnea) collapse of the pharyngeal airway despite continued respiratory effort. Nocturnal apnea and hypopnea can result in episodic hypoxic hypercapnia, as well as repetitive arousals from sleep, which fragment sleep architecture. Disproportional adenotonsillar growth, relative to airway caliber,4 is the major causative factor in childhood, although body mass, neuromuscular control, and craniofacial anatomic features may contribute.
It is well established that obstructive sleep apnea in adults is a risk factor for cardiovascular and cerebrovascular disease and death.5 There is evidence that pediatric SDB is similarly associated with cardiovascular morbidity.6 Systemic blood pressure dysregulation,7 increased sympathetic nervous system activation,8 and decreased arterial distensibility9 have been described. Behavioral and neurocognitive deficits also are common.10 However, there has been relatively little interest in cerebrovascular health in such children, although these data might be uniquely informative for determining the relative importance of SDB.11 An association between nocturnal oxyhemoglobin desaturation and central nervous system event risk in sickle cell disease, the most-common cause of childhood stroke,12 has been documented, but it is not clear whether a similar relationship exists in asymptomatic children. We recently described significantly increased middle cerebral artery blood flow velocity (MCAV) in young children with mild SDB.13 These children were regular snorers with adenotonsillar hypertrophy deemed to require surgery on clinical grounds, and all had an apnea/hypopnea index (AHI) of <5 events per hour of sleep. Increased MCAV presented alongside reductions in processing speed and visual attention and parental reports of executive function deficits. Consistent with earlier research,14,15 we concluded that there are detrimental effects of mild SDB on cognitive and behavioral function in children and that such changes present alongside altered cerebral hemodynamic function.
In the present study, we describe follow-up MCAV, cognitive, and behavioral data obtained from our cohort of children with snoring (mild SDB), compared with longitudinal data from nonsnoring control subjects. We predicted that the postoperative amelioration of SDB would lead to normalization of MCAV, with improvements in cognition and behavior.
Ethical Approval and Consent
Ethical approval was obtained from the Southampton and South West Hampshire Research Ethics Committee. Written parental consent and child assent were obtained for all participants.
We present here longitudinal transcranial Doppler (TCD) and neuropsychological data on a subgroup of children whose baseline measures were described in detail in an earlier report.13 A total of 21 children with SDB (3–7 years of age) and 17 age-similar control subjects underwent baseline (preoperative) assessment; 19 and 14 children, respectively, returned a mean of 12 months (SD: 1.9 months) later for follow-up assessment (this assessment is termed “postoperative,” although control children did not undergo surgery). Two postoperative children and 1 control subject declined the invitation for follow-up assessment, and 2 families could not be contacted. In total, 86% of the original sample returned for follow-up assessment. The demographic characteristics of the follow-up cohort are presented in Table 1.
All 19 children with SDB were recruited from adenotonsillectomy waiting lists in the mixed urban-rural districts of Southampton and Portsmouth, England. Selection was based on a positive history of snoring with a clinical indication for adenotonsillectomy. Of the 19 children reported here, the primary indication for surgery was SDB for 7, recurrent tonsillitis for 6, and both clinical indications for the remaining 6. Although the original intention had been to identify a range of severity of obstructed breathing, the majority of cases fell within the mild range. The presence of snoring was confirmed for all case subjects by parental report with the Pediatric Sleep Questionnaire (PSQ), a validated screening tool for SDB.16 Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Overnight attended polysomnography was conducted preoperatively for clinical case subjects in a purpose-built sleep laboratory by using computerized systems (Embla system with Somnologica 3 software; Medcare Flaga, Reykjavik, Iceland), according to American Thoracic Society standards.17 A standard montage was recorded, including electroencephalography (C3/A2, O1/A2, C4/A1, and O2/A1), right and left electrooculography, bipolar submental electromyography, diaphragmatic electromyography, thoracic and abdominal excursions detected with respiratory inductance plethysmography (Xact-trace; Medcare Flaga), nasal airflow monitoring (Protech, Mukilteo, WA), finger pulse oximetry (Nonin, Plymouth, MN), electrocardiography, and synchronous video-recording. Sleep staging was scored by using standard criteria.18 Respiratory arousals were defined as changes in electroencephalographic frequency of ≥1 second after an episode of apnea or hypopnea.19 Obstructive apnea was defined as the presence of chest/abdominal wall movement in the absence or decrease of airflow by >80%, compared with the preceding breath, for ≥2 breaths. Hypopnea was classified as described for apnea but the reduction in flow was 50% to 80%, compared with the previous breath, with associated desaturation or respiratory arousal. Oxygen desaturation was classified as a ≥3% decrease in pulse oxygen saturation (Spo2) from baseline values. The AHI was defined as the number of obstructive apnea, hypopnea, and mixed apnea episodes per hour of total sleep time. Episodes of central apnea were scored separately. Testing confirmed a median AHI of 2.1 episodes per hour (range: 0.4–4.8 episodes per hour) and mean overnight Spo2 of 96.5% (range: 94.0%–98.1%), consistent with a diagnosis of mild SDB. After baseline assessment, all case subjects underwent adenoidectomy and/or tonsillectomy on clinical grounds and were asked to return for postoperative assessment. The mean age at each assessment and the time interval between assessments for each group are described in Table 1.
The parents of all children completed the PSQ preoperatively, and parents of children with SDB also completed the PSQ after surgery. This quantified baseline SDB (scores of >0.33 indicate clinical significance)16 and the extent of symptom improvement for 18 case subjects with SDB; 1 follow-up form was spoiled. By design, only nonsnoring children were recruited as control subjects, and this is reflected in their preoperative PSQ scores (median: 0.02; range: 0.00–0.28); no control child scored above the threshold for clinical significance. Postoperative clinical improvement in children with SDB was further assessed by using home overnight oximetry (MasimoSet Radical; Artemis Medical, Dartford, England). In total, 16 of 19 studies provided sufficient data for analysis.
TCD sonography was performed postoperatively by the same experienced operator (Dr Hogan) who supervised data acquisition in preoperative assessments, who was blinded to data from the sleep studies. The same protocol as for the preoperative assessments was followed. In brief, averaged mean maximal MCAV values were obtained by using a Compumedics Doppler box (El Paso, TX) system. The middle cerebral artery was tracked from shallow depths to the middle cerebral artery/anterior cerebral artery bifurcation (∼53 mm) at both the left and right temporal acoustic windows, and the highest value across both sides was recorded.20 All TCD data were obtained between the hours of 2 and 6 pm, with the child relaxed in a semireclined position. Two children refused to undergo a TCD study at either time point. Two children refused to undergo a second study, in one case because the child could not tolerate the ultrasound gel and in the other because TCD sonography was interpreted by the child as a prelude to additional surgery. The parents of a third child did not have time to stay for the TCD study, which typically was performed after the neuropsychological assessment. Finally, preoperative TCD studies were not performed for 2 of the children because of technical problems, which resulted in a lack of longitudinal data in those cases. In total, longitudinal TCD data were obtained for 12 children who underwent adenotonsillectomy and 14 control subjects.
Neuropsychological Assessments and Parent-Reported Behavior
All children underwent preoperative neuropsychological assessments, including administration of an age-appropriate IQ test (Wechsler PreSchool and Primary Scale of Intelligence-III [WPPSI-III]) and selected subtests from the Neuropsychological Test Battery (visual attention and design copy); parents completed the Behavior Rating Inventory of Executive Function (BRIEF). In postoperative assessments, only tests that yielded significant preoperative group differences were readministered, namely, the coding and symbol search subtests of the WPPSI-III, which together yield a processing speed index (mean: 100; SD: 15); the visual attention subtest of the Neuropsychological Test Battery (mean: 10; range: 1–19; SD: 3); and the parent-completed BRIEF questionnaire (global executive composite T scores are reported; clinically significant scores are >65). The processing speed tests (coding and symbol search subtests of the WPPSI-III) were administered only to children >4 years of age, in line with the WPPSI-III protocol.
Statistical analyses were conducted by using SPSS for Windows 14.0 (SPSS, Chicago, IL). Data were first explored by using the Shapiro-Wilk test of normality, which is appropriate for small samples. The results of nonparametric tests are reported when data were not normally distributed. Mixed-design analysis of variance models with repeated measures were used to determine whether children with mild SDB showed significant changes in MCAV, processing speed, visual attention, and executive function behavior. In each model, there was 1 within-subjects factor (eg, preoperative and postoperative MCAV values) and 1 between-subjects factor (control subjects versus children with SDB). Trends approaching significance (P < .09) are reported.
BMI z scores and gender were not significantly different between case subjects and control subjects at baseline. All children were white European, except for a single child with SDB whose ethnicity was Asian (Indian subcontinent). Ages were equivalent across groups at each assessment (Table 1). There was a small but statistically significant difference between groups in the interval between preoperative and postoperative assessments (mean difference: 2.3 months; SE: 0.56 months). This was attributable to difficulties involved in scheduling control children for follow-up assessments during their school vacation.
Indices of SDB (SDB Group)
Parental reports of reductions in snoring after tonsillectomy were supported by a significantly lower median score on the PSQ postoperatively, compared with preoperatively (Table 2). The majority of children (15 of 19 children) obtained significant case scores before surgery, whereas this proportion was decreased after surgery (5 of 16 children; McNemar, n = 16; P = .008); 2 preoperation and 1 postoperation ratings were missing.
Polysomnographic variables obtained preoperatively indicated that children had mild SDB (AHI: median: 2.1 events per hour; range: 0.2–4.8 events per hour; obstructive apnea index: median: 0 events per hour; range: 0–3.7 events per hour; hypopnea index: median: 1.4 events per hour; range: 0.1–4.1 events per hour; respiratory arousal index: median: 0.6 events per hour; range: 0–6.8 events per hour). Oximetry values were obtained at both assessment time points for the majority of children (n = 16) and improved postoperatively, with a significant increase in the mean overnight Spo2 (Table 2). The mean lowest recorded Spo2 increased numerically but not significantly, and there was little change in the median time spent with Spo2 of <90% (Table 2).
Middle Cerebral Artery Velocity
As revealed in Fig 1, MCAV decreased significantly in the SDB group (n = 12) between the 2 assessment times, whereas there was an increase in MCAV in control subjects (n = 14) (mean ± SD: preoperative: control: 83.8 ± 7.4 cm/seconds; SDB: 118.7 ± 14.9 cm/second; postoperative: control: 97.1 ± 8.9 cm/second; SDB: 105.8 ± 16.4 cm/second). This resulted in a significant interaction between assessment time and group (F1,24 = 35.7; P < .001). Importantly, this value remained significant when the time interval between preoperative and postoperative assessments (in months) was included in the model as a covariate (P < .001), and there was no main effect of time interval (P = .240). Although there was a significant preoperative group difference (t22.1 = 7.9; P < .001), this difference was reduced postoperatively (t16.5 = 1.6; P = .097), which suggests that MCAV in the children with mild SDB had normalized.
Cognition and Behavior
For both processing speed index and visual attention, the SDB group obtained higher postoperative scores, compared with preoperative scores, whereas control children showed a slight decrease over time (Table 3). There was a trend for a significant interaction between assessment time and group for processing speed (F1,22 = 3.79; P = .064). A significant interaction between assessment time and group was found for visual attention (F1,30 = 4.45; P = .043), but this value was attenuated with the inclusion of test-retest time interval as a covariate (P = .110). The difference in the mean time interval between the control and SDB groups was small, ∼2 months; however, this visual attention analysis of variance result should be interpreted cautiously.
Posthoc testing was conducted, and a significant preoperative group difference for processing speed index (t22 = −2.5; P = .017) was absent postoperatively (P = .624). Similarly, a trend for a significant preoperative group difference for visual attention scores (t30 = −1.85; P = .073) was reduced postoperatively (P = .362). Taken together, these results suggest that, compared with baseline data, the postoperative performance of children with SDB was more consistent with that of control subjects.
Behavior measured with the BRIEF global executive composite score remained significantly worse (higher scores) for the children with SDB (main effect of group: F1,29 = 13.01; P = .001), although numerically their mean postoperative scores were lower than their preoperative scores, which indicates some small improvement in behavior (Table 3).
Spo2 Correlate of MCAV Reduction
We investigated the extent to which increases in mean overnight Spo2 values (the difference between Spo2 values obtained in preoperative and postoperative assessments) were associated with the degree of reduction in MCAV over the same period. Only 9 children had MCAV and oximetry data for both time points; within this subset, however, children who had the greatest increase in mean overnight Spo2 after surgery also showed the greatest reduction in MCAV (n = 9, Rs = −0.916, 2-tailed; P = .001) (Fig 2).
AHI Correlate of MCAV Reduction
Postoperative AHI data were not available but correlation of preoperative AHI scores with the extent of MCAV changes suggested greater MCAV reduction in children with higher initial AHI values, although this fell short of statistical significance (n = 12, Rs = −0.457, 2-tailed; P = .135). It would be of interest to investigate this further with larger sample sizes.
We recently provided novel evidence that mild SDB was associated with cerebral hemodynamic changes in otherwise-healthy young children.13 The present study extended this finding to demonstrate that improvement in SDB after adenotonsillectomy was associated with normalization of cerebral hemodynamic features, as well as small improvements in processing speed and visual attention. Furthermore, the extent of change in MCAV was significantly correlated with postoperative improvement in overnight mean Spo2.
In a cross-sectional study, MCAV was higher in older, normally developing children,20 that is, 12 cm/seconds higher in a group of children between 6 and 9.9 years of age, compared with a group of children between 1 and 2.9 years of age, with the greatest increases occurring before the age of 6 years. During childhood, the highest MCAV is likely to be present between 6 and 8 years of age.21 Consistent with this normative evidence, over the course of follow-up monitoring we observed a mean increase of ∼13 cm/seconds in our healthy control subjects, all of whom were <7 years of age. In contrast, children with SDB showed a postoperative decrease in MCAV. Importantly, however, this placed them within the range for age-similar, healthy, control subjects.
It is possible that MCAV was initially increased in response to intermittent nocturnal hypoxia associated with upper-airway obstruction in sleep or to associated sympathetic activation, anemia, or hypercapnia.12 Reduction of MCAV with amelioration of upper-airway obstruction suggests the validity of this hypothesis but does not confirm the underlying mechanism. We found in a subgroup of children that the extent of decrease in MCAV was significantly associated with increases in mean overnight Spo2. If this finding is confirmed, then this may suggest that increased MCAV reflects a cascade of adaptive physiologic changes promoting an increase in cerebral blood flow and offering the immature brain some protection from the potentially damaging effects of SDB, including intermittent or sustained hypoxia.
Upper-airway obstruction in sleep in adults is associated with characteristic cardiovascular and cerebrovascular responses. Typically, an episode of apnea induces increases in cerebral blood flow and mean arterial pressure, followed by abrupt decreases at the termination of apnea to levels below baseline values.22 The initial increase in cerebral blood flow is driven by a combination of chemoreceptor responses to increasing Pco2 and increasing blood pressure. The latter is stimulated by sympathetic activation, which is itself a consequence of hypoxia.23,24 The abrupt significant decrease in cerebral blood flow at apnea termination, with the potential for cerebral hypoperfusion, has been postulated to be a consequence of brain arousal, because it does not parallel the slower decrease in Pco2.25 To our knowledge, there are no published studies of MCAV during apnea episodes in children, but it is possible that similar responses may occur.
In adults, there is evidence for an association between SDB, oxyhemoglobin desaturation, and carotid artery intima-media thickness diagnosed noninvasively by using ultrasonography.26 The mechanism probably involves endothelial dysfunction in relation to hypoxia and inflammation27 and reduction of circulating levels of the very potent vasodilator nitric oxide.28 Intracranial MCAV is slightly but not significantly lower in adults with SDB than control subjects,25 perhaps reflecting slightly lower cerebral blood flow distal to carotid artery narrowing. The pediatric data presented here for a neurologically normal population with SDB showed MCAV to be higher than that in control subjects (secondary to either hyperperfusion or narrowing of the intracranial vessels) and to decrease with amelioration of SDB. Interestingly, the majority of children with stroke have middle cerebral rather than carotid vessel disease,29 which suggests differences in the vessels that are vulnerable to environmental influences, such as hypoxia and infection. The control mechanisms responsible for cerebral vascular regulation operate in an age-dependent way; for example, nitric oxide contributes increasingly to the regulation of cerebral hemodynamics as a function of age, and there might be variations in vascular distribution.30 The role of the sympathetic nervous system has been studied to only a limited extent in children. Data confirmed that children with obstructive sleep apnea had elevated sympathetic nervous system tone during the day.8 Similar findings for adults with obstructive sleep apnea31 were postulated to be a consequence of the physiologic stress of exposure to repetitive hypoxic apnea.32 Furthermore, studies in adults demonstrated increased cerebral blood flow velocity in response to sympathetic nervous system stimulation.33,34 Similar studies in children would be instructive.
There is evidence for diurnal variation in cerebrovascular responses to hypercapnia in adults with obstructive sleep apnea35,36 and for rapid reversal of the diminished daytime vasodilator reserve with continuous positive airway pressure therapy.37 Similar reversible, attenuated, cerebral blood flow responses to isocapnic hypoxia have been reported. The vasodilatory response to hypoxia does not show diurnal variation35 but also improves with continuous positive airway pressure therapy.38 Of particular interest, the degree of cerebral blood flow velocity change for treated patients was associated with the severity of obstructive sleep apnea, as indicated by the AHI.38 We conducted a similar analysis of our data, correlating preoperative AHI scores with the extent of MCAV changes postoperatively and we also found greater MCAV reductions for those with higher initial AHI values, although this fell short of statistical significance.
These data are consistent with the hypothesis that an increase in steady-state MCAV during the day may be related to nocturnal intermittent hypoxia. What is striking about these data is the extent of differences between the MCAV findings, given the relatively mild hypoxia and SDB observed in the case subjects. It will be important to explore this relationship in children with more-severe SDB and to address the limitations of the methods in our preliminary study. In particular, future studies should use objective screening tools to exclude SDB assertively in the control group, because even the best screening questionnaires can yield false-negative results; for example, the PSQ is reported to have a sensitivity of 0.81 to 0.85 in detecting SDB, compared with polysomnographic diagnosis.16 Selection of appropriate control subjects also might consider the natural progression of measured variables over a similar time period in non–surgically treated children with adenotonsillar hypertrophy. This might shed light on the unique contribution of the surgical procedure and amelioration of SDB to the measured outcomes. Larger subject numbers in future studies would facilitate the study of gender-specific changes in MCAV. This is relevant because previous studies demonstrated higher MCAV in healthy prepubertal girls, compared with boys.39 Hypercapnia and anemia also might affect MCAV. Although acute increases in Pco2 are associated with relatively large rapid changes in MCAV,25 the cerebral circulation tends to adapt, and baseline end-tidal Pco2 accounted for only 5% of the variation in baseline MCAV in our previous study (C.M.H., A.M.H., D.H., and F.J.K., unpublished data, 2006). In the current study, for the 4 children for whom hemoglobin levels were measured intraoperatively, we found little evidence that this parameter accounted for the increase in MCAV.13 It would be difficult to justify postoperative measurements of hemoglobin levels in otherwise-healthy children, but studies of children with SDB and chronic anemia might be instructive.
It is not possible to infer a direct causative relationship between SDB and cerebral hemodynamic adaptation in children; rather, subtle physiologic changes are likely to result from intermittent nocturnal hypoxia and apnea. Evidence of persisting behavioral abnormalities on the BRIEF suggests that such adaptation may be imperfect. Our data are preliminary; however, the reversibility of the increased MCAV in children with mild SDB is an intriguing finding. Although these changes may initially protect the immature brain, altered autonomic tone or endothelial function, if uncorrected, may risk longer-term cardiovascular sequelae. Studies showing improvement in cognitive function with amelioration of SDB suggest some support for the “adaptive-response” interpretation of our results.40,41 Parents in our study reported improvement in executive function, although this was not statistically significant. Because the mean T score obtained from children with SDB was within the reference range at both assessments, a longer duration of follow-up monitoring or a larger sample size may be required to demonstrate significant improvement in such behavior. However, a longitudinal study indicated that significant improvement in parent-rated behavior is most likely to occur within the first 6 months after surgery.42
Although additional work on the mechanism is required, it is of interest that a postoperative decrease in MCAV paralleled an improvement in nocturnal oxyhemoglobin saturation. This finding may provide the impetus for further investigation of the mechanisms underpinning cognitive and behavioral deficits in children who snore.
This work was funded by grants to Dr Hogan (HOPE Innovation Award) and Dr Hill (Research and Development Management Committee, Southampton University Hospital Trust). Dr Kirkham is supported by the Stroke Association (grant PROG4) and the National Heart, Lung, and Blood Institute (grant 5-RO1-HL079937).
Polysomnography studies were conducted at the Wellcome Trust Clinical Research Facility, Southampton University Hospital Trust, and we gratefully acknowledge the assistance of management and nursing staff members. Patients were recruited from Portsmouth hospitals and Southampton University Hospital National Health Service Trust, which receive some of their funding from the National Health Service Executive. We are indebted to Dr Simon Dennis and Dr Kate Heathcote for assistance in recruitment and to Dr Nekki Onugha for collection of some of the preoperative TCD data.
- Accepted October 24, 2007.
- Address correspondence to Fenella J. Kirkham, FRCPCH, Neurosciences Unit, UCL Institute of Child Health, Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, England. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
Drs Hogan and Hill contributed equally to this study.
What's Known on This Subject
Children with mild sleep-disordered breathing have neuropsychological impairment and autonomic activation, and we reported increased cerebral blood flow velocity. Longer-term effects on cerebrovascular function are unclear, although adults with sleep-disordered breathing are at increased risk of stroke.
What This Study Adds
Middle cerebral artery blood flow velocity normalized in children with mild sleep-disordered breathing, when assessed an average of 10.9 months after surgery. The extent of this change was significantly correlated with improvement in mean overnight oxygen saturation.
- ↵Quan SF, Gersh BJ, National Center on Sleep Disorders Research, National Heart, Lung, and Blood Institute. Cardiovascular consequences of sleep-disordered breathing: past, present and future: report of a workshop from the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute. Circulation.2004;109 (8):951– 957
- ↵Hill CM, Hogan AM, Onugha N, et al. Increased cerebral blood flow velocity in children with mild sleep-disordered breathing: a possible association with abnormal neuropsychological function. Pediatrics.2006;118 (4). Available at: www.pediatrics.org/cgi/content/full/118/4/e1100
- ↵Rosen CL, Storfer-Isser A, Taylor HG, et al. Increased behavioral morbidity in school-aged children with sleep-disordered breathing. Pediatrics.2004;114 (6):1640– 1648
- ↵O'Brien LM, Mervis CB, Holbrook CR, et al. Neurobehavioral implications of habitual snoring in children. Pediatrics.2004;114 (1):44– 49
- ↵Rechtschaffen A, Kales A. A Manual of Standardized Terminology: Techniques and Scoring System for Sleep Stages of Human Subjects: UCLA Brain Information Service. Los Angeles, CA: Brain Research Institute;1968
- ↵Bode H, Wais U. Age dependence of flow velocities in basal cerebral arteries. Arch Dis Child.1988;63 (6):606– 611
- ↵Adams RJ, Nichols FT, Stephens S, et al. Transcranial Doppler: the influence of age and hematocrit in normal children. J Cardiovasc Ultrasonogr.1988;7 :201– 205
- ↵Leuenberger U, Jacob E, Sweer L, et al. Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia. J Appl Physiol.1995;79 (2):581– 588
- ↵Silvestrini M, Rizzato B, Placidi F, et al. Carotid artery wall thickness in patients with obstructive sleep apnea syndrome. Stroke.2002;33 (7):1782– 1785
- ↵Meadows GE, Kotajima F, Vazir A, et al. Overnight changes in the cerebral vascular response to isocapnic hypoxia and hypercapnia in healthy humans: protection against stroke. Stroke.2005;36 (11):2367– 2372
- ↵Diomedi M, Placidi F, Cupini LM, et al. Cerebral hemodynamic changes in sleep apnea syndrome and effect of continuous positive airway pressure treatment. Neurology.1998;51 (4):1051– 1056
- ↵Tontisirin N, Muangman SL, Suz P, et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics.2007;119 (3). Available at: www.pediatrics.org/cgi/content/full/119/3/e610
- Mitchell RB, Kelly J. Long-term changes in behavior after adenotonsillectomy for obstructive sleep apnea syndrome in children. Otolaryngol Head Neck Surg.2006;134 (3):374– 378
- Copyright © 2008 by the American Academy of Pediatrics