Posted by: Indonesian Children | February 7, 2010

Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing

Pediatrics. 2006 October; 118(4): e1100–e1108.

Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing

A Possible Association with Abnormal Neuropsychological Function

Catherine M. Hill, BM, MSc, MRCP, FRCPCH,a Alexandra M. Hogan, PhD,b Nwanneka Onugha, BM,a Dawn Harrison, BSc,b Sara Cooper, MSc(Med),c Victoria J. McGrigor, MBBS, DCH, FRCPCH,d Avijit Datta, BSc, MD, MRCP,e and Fenella J. Kirkham, MBBChir, FRCPCHaf

aDivision of Clinical Neurosciences, University of Southampton, Southampton, United Kingdom

bDevelopmental Brain-Behaviour Unit, University of Southampton, Southampton, United Kingdom

cChildren’s Sleep Disorders Unit, Sydney Adventist Hospital, New South Wales, Australia

dChildren’s Sleep Disorder Service, Southampton City Primary Care Trust, Southampton, United Kingdom

eInstitute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, United Kingdom

fInstitute of Child Health, University College London, London, United Kingdom

Address correspondence to Catherine M. Hill, BM, MSc, MRCP, FRCPCH, University of Southampton-Child Health, Mail Point 803, Southampton General Hospital, Southampton, Hampshire SO16 6YD, United Kingdom. Email: cmh2/at/soton.ac.uk

The authors have indicated they have no financial relationships relevant to this article to disclose.

The publisher’s final edited version of this article is available free at Pediatrics.

See commentary “Increased cerebral blood flow velocity in children with sickle cell disease: adenotonsillectomy or transfusion regimens?” in Pediatrics, volume 120 on page 235.

See other articles in PMC that cite the published article.

Abstract

Objective

Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.

Design

Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.

Results

Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation 80% of the preceding breath for ≥2 breaths. Hypopneas were classified as for apneas but where the reduction in flow was 50%-80% of the previous breath. Oxygen desaturation was classified by a 3% or more decrease in Spo2 from the baseline. The apnea/hypopnea index was defined as the number of obstructive apneas, hypopneas, and mixed apneas per hour of total sleep time. Central apneas could be confidently identified from the respiratory inductance plethysmography bands and were separately scored. There is currently no consensus for respiratory scoring criteria in children.34 These criteria were selected to discriminate obstructive respiratory events in sleep. Studies were independently scored by an experienced sleep technician (S.C.) and a pediatrician (C.M.H).

In addition to polysomnography, which is a single time point measure of SDB severity, the duration of exposure to SDB was estimated based on parental report, recorded as the number of years that the child had snored multiplied by the mean days per week of snoring during the previous year. Parents were asked 2 questions: (1) “How many years has your child snored?” and (2) “During the past year, on average how many days per week has your child snored?” There are no validated measures of snoring exposure in children, although previous studies have addressed this issue indirectly by asking how often the child snores35 or if the child snored between the ages of 2 and 6 years.36

Blood Pressure and Anthropometric Measures

Children were weighed, and height and occipitofrontal circumference were measured. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained using Dinamp technology (Dash 3000 GE Health care). To control for influence of age and height on blood pressure,37 a blood pressure index was computed as described by Amin et al.23

where BP is blood pressure. Blood pressure centiles were derived from standard published values.37

TCD

TCD was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and in the majority of controls. The operator (N.O.) was blinded to the neuropsychological, behavioral, and SDB status of the child but was aware of their patient/control status. The child remained awake but was encouraged to lie quietly. Time-averaged mean of the maximal CBFV of the left and right middle cerebral artery (henceforth simply referred to as CBFV) was measured through the temporal ultrasound “acoustic window” above the zygomatic arch and anterior to the ear. All of the studies started at a depth of 45 mm, and identification of the maximum velocity envelope in the terminal internal cerebral artery/middle cerebral artery was confirmed by following the vessel to a shallow depth of 35 to 40 mm and a deeper depth of 50 to 55 mm, the middle cerebral artery/anterior cerebral artery bifurcation. CBFV was recorded bilaterally for the middle cerebral artery,38 responsible for ≥80% of cerebral blood flow. Attempts to additionally insonate the anterior cerebral artery and basilar arteries were rarely tolerated by these young children. For 5 cases (2 controls), similar CBFV recordings were obtained by one of the principal investigators (A.M.H.) immediately after the first recording (r = 0.996; P 0.33 is considered to be abnormal (R. D. Chervin, MD, MS, written communication, 2005). None of the controls scored within the abnormal range (group mean: 0.1; SD: 0.1; t36 = 10.4; P < .001), further validating their allocation to a nonsnoring group.

Polysomnography

Polysomnography in the snoring children demonstrated that all of the children had some episodes of upper airway obstruction during sleep. The majority of these episodes were hypopneas. Mean oxygen levels were in the reference range for all of the children, although some children experienced episodic desaturations associated with obstructive events (Table 2). The duration of parental estimated exposure of snoring for those with SDB was 18.8 (SD: 8.0).

Time-Averaged Mean of the Maximum Blood Flow Velocities in the Middle Cerebral Artery

TCD recordings from ≥1 side were obtained in 18 of 21 and 17 of 17 of the mild SDB and control groups, respectively. As illustrated in Fig 1, CBFV was significantly increased in the mild SDB group compared with controls (t27.7 = 8.3; P < .001). Posthoc analyses addressed the possibility that systemic hypertension might account for the group differences in CBFV. However, the majority of children were normotensive according to age-, gender-, and height-adjusted values: systolic blood pressure index was raised in 1 SDB child (7.8) and diastolic in 1 control child (1.4). There was no significant correlation between blood pressure indices and CBFV, and the inclusion of this covariate did not alter the significant CBFV group difference (P < .001).

We were interested to know whether the variance in CBFV might be explained by specific polysomnographic variables. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean Spo2, lowest Spo2, accumulated time at Spo2 .1), the significant group differences did not remain when CBFV was entered as a covariate (analysis of covariance). This indicates that a proportion of the variance in processing speed and visual attention scores may be explained by factors associated with increased CBFV.

Parental Ratings of Executive Function Behavior

All of the executive function behaviors assessed by the BRIEF were significantly worse in mild SDB children compared with controls (see Table 4). As before, there were no direct correlations between BRIEF subscales or total score and CBFV in the mild SDB group (P > .1). For the majority of indices, analysis of covariance tests revealed a residual difference between groups when controlling for CBFV, although the significance of this difference slightly decreased suggesting that there may be some partial association between CBFV and parental report of executive function behaviors.

DISCUSSION

The finding of significant differences between otherwise healthy children with mild SDB and controls on neuropsychological and behavioral measures of executive function replicates the findings of previous studies.9,10 We also provide novel preliminary evidence of abnormal cerebral hemodynamics in a nonobese population of young children with mild SDB of a severity below the conventional treatment threshold. The fact that adjusting for CBFV reduces group differences in neuropsychological measures suggests that factors associated with cerebral hemodynamics may contribute to the relationship between SDB and neuropsychological impairment.

Children with a history of snoring obtained a mean value for CBFV (120 cm/second) that was intermediate between that obtained from healthy controls (84 cm/second) and the threshold for moderate stroke risk in children with sickle cell disease (>170 cm/second).40 Even African children, with a high prevalence of anemia secondary to iron deficiency and sickle trait, have mean CBFV values of 92 cm/second (+2 SDs = 142 cm/second)41; in comparison, 1 of the SDB children in the current series had a CBFV of 147 cm/second. The CBFV values for control children are very similar to those published previously in healthy children of similar age42 and before sleep in 5 children aged 5 to 13 years.43 There were no previous studies of CBFV in SDB children on which to base a power calculation, but in this sample of 21 with mild SDB, in 18 of whom we managed to obtain a TCD study, and 17 controls, the effect of snoring was large (d = 2.79). Raised CBFV is likely to be attributable either to increased cerebral blood flow or narrowing of the cerebral vessels or a combination of these factors. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect CBFV. We were able to study several potential confounding influences on CBF. First, there were no differences in systolic and diastolic blood pressure indices between SDB children and controls. Second, although CBFV increases with increasing partial pressure of carbon dioxide44,45 and hypoxia,46 it is unlikely that observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy with no cardiorespiratory disease, other than SDB in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during CBFV measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the SDB children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day.

Finally, there is an inverse linear relationship between CBF and hematocrit in adults,47 and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study.48 Increased CBFV might reflect increased CBF as an adaptation to anemia and reduced arterial oxygen content. Blood tests were not routinely performed on these children. However, a hemoglobin measure was obtained from 4 children immediately preoperatively and within 6 months of the TCD study after advice to the otolaryngologist that the child’s CBFV was raised. Normal hemoglobin levels (lower reference limits: 11.1g/dL at <5 years and 11.5 g/dL at 5-8 years) were found in 2 children with CBFV measures of 130 and 137 cm/second, respectively. Borderline low hemoglobin levels in 2 children (case 1 [3 years]: 10.9 g/dL; and case 2 [6 years]: 10.2 g/dL) were associated with CBFV values, respectively, of 131 and 130 cm/second.

Thus, there was no apparent relation between hemoglobin concentration and CBFV within the ethical constraints limiting blood tests to only a proportion of symptomatic children undergoing adenotonsillectomy. It will be important to explore the association between iron-deficient erythropoiesis and CBFV in future studies, because chronic anemia could, in part, explain both the observed neurocognitive deficits49-51 and increased CBFV in children with SDB.

Our data suggest a relationship between snoring, increased CBFV, and indices of cognitive (visual attention and processing speed), and perhaps behavioral (BRIEF) function, but this finding is preliminary and requires replication; a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. However, evidence obtained from young children with sickle cell disease suggests that increased CBFV may represent generalized increased CBF, as an adaptation to chronic-intermittent hypoxemia, or cerebrovascular disease.52 It is important to note that whereas the SDB group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their SDB in the past.

Despite the specific cognitive and behavioral deficits observed, there was no apparent impact on more general intellectual function (VIQ, PIQ, and FSIQ) or visuomotor integration, perhaps because of the young age of these children in whom intellectual function is still emerging. This finding is consistent with previous studies showing that intellectual deficit may not be expected in children with SDB53,54; however, it is possible that intellectual and cognitive deficit may become increasingly apparent with age and academic progression.36 The results of repeat measures in these children after adenotonsillectomy and longitudinal studies extending into adolescence will be of interest.

In this study, we found that as-yet unconfirmed factors associated with cerebral hemodynamic derangement may explain a proportion of the variance in visual attention and processing speed functions, both skills that are already known to be vulnerable to chronic-intermittent hypoxia associated with SDB in adults55 and with chronic hypoxia associated with cardiac abnormalities in children.56 Prospective studies that quantify cumulative exposure to the physiologic consequences of SDB, such as hypoxia, would be informative.

CONCLUSIONS

Noninvasive transcranial Doppler measurement of CBFV may provide an important marker of brain vulnerability in children with SDB. The relevance of these findings to clinical practice requires additional study. It will be important to establish whether increased CBFV is a transient adaptive response to SDB or is indicative of a permanent alteration of cerebral hemodynamics with implications for future health. Additional studies in larger samples may clarify whether correlations can be demonstrated with measurable alternations in the systemic vasculature, as well as with polysomnographic indices of hypoxia and sleep arousals.

Abbreviations

SDB

sleep-disordered breathing

OSA

obstructive sleep apnea

TCD

transcranial Doppler

CBFV

cerebral blood flow velocity

PSQ

pediatric sleep questionnaire

Wechsler Preschool and Primary Scale of Intelligence Version III

VIQ

visual IQ

PIQ

performance IQ

FSIQ

full-scale IQ

NEPSY

Neuropsychological Test Battery for Children

BRIEF

Behavior Rating Inventory of Executive Function

Spo2

pulse oxygen saturation

Footnotes

Drs Hill and Hogan contributed equally to this work and share first authorship.

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