Obstructive Sleep Apnea Syndrome
Conditions
Keywords
Obstructive Sleep Apnea Syndrome, Cerebral Blood Flow, Neurocognition
Brief summary
Obstructive sleep apnea syndrome (OSAS) causes hypoxemia and hypercapnia, which may impair cerebral blood flow and cause deficits in behavior. This is a case-control study designed to investigate cerebral blood flow and neurocognitive function in children with OSAS when compared to these findings from normal children. The study hypothesis is that children with OSAS have an impaired cerebral blood flow during wakefulness and sleep compared to normal controls, and that the degree of this impairment correlates with neurocognitive function.
Detailed description
OSAS is characterized by repetitive occlusion of the upper airway during sleep that results in hypoxemia, hypercapnia and arousal from sleep. Children with the obstructive sleep apnea syndrome (OSAS) have impaired behavior and cognition compared to normal controls. Previous studies in adults with OSAS have shown significant alterations of cerebral blood flow during wakefulness and sleep and our preliminary data showed blunted cerebral blood flow response to hypercapnia in children with OSAS during wakefulness. However, it is unknown whether children with OSAS also have impaired cerebral blood flow during sleep. It is also unknown whether the deficits in behavior and cognition in children are associated with cerebral blood flow dysregulation. This study will investigate whether the changes in cerebral blood flow during wakefulness and sleep elicited by hypercapneic challenge, differ in children with OSAS compared to normal controls. Additionally the study will evaluate the changes in cerebral blood flow during wakefulness and sleep elicited by hypercapneic challenge in children with OSAS before and after treatment (adenotonsillectomy, adenoidectomy, or tonsillectomy). Finally, the study will investigate whether the changes in cerebral blood flow elicited by the aforementioned testing correlate with neurocognitive outcomes. Children with OSAS aged 6-12 years will be recruited following a clinical polysomnogram. Normal age- and gender-matched controls will be recruited from the general community. The primary interventions of this study for the two groups (OSAS and controls) are: sleep studies, neurocognitive testing, measurement of cerebral blood flow by near-infrared spectroscopy during hypercapnic challenges conducted during wakefulness and sleep. In addition, OSAS subjects will be re-tested after clinical treatment of OSAS to evaluate for resolution of OSAS, and all subjects will be re-tested at two separate time points after baseline to compare changes due to the treatment of OSAS versus those occurring secondary to normal development.
Interventions
OTHERSleep Study
Overnight, video-recorded sleep study will be performed in a dedicated pediatric sleep lab. Sleep architecture, apneas and hypopneas, arterial oxygen saturation and end-tidal carbon dioxide tension will be evaluated during the sleep study. Safety measures including arterial oxygen saturation using pulse oximetry, EEG and EKG will be continuously monitored during the study.
Cognitive and behavioral measures including intelligence, attention, working memory, and processing speed will be assessed by a trained psychologist.
OTHERCBF During Wakefulness
Cerebral blood flow (CBF) will be measure using Diffuse optical and correlation spectroscopy (DOS/DCS), a non-significant risk device used to collect data for this study but not being tested as part of the protocol. Light sources and detectors which are embedded in a rubber pad will be attached to the subject's head in order to record right and left hemispheric cerebral blood flow, total hemoglobin concentration and tissue oxygen saturation. Measurements will be continuously recorded during the study and averaged for purposes of statistical analysis. With DOS/DCS in place, ventilatory response to hypercapnia will be determined using the rebreathing technique, a standard clinical test. While CBF is being measured, subjects will wear nose clips and sit comfortably breathing through a mouthpiece while the level of carbon dioxide is adjusted over a 3-4 minute period. Oxygen and carbon dioxide levels will be carefully monitored throughout the testing.
OTHERCBF During Sleep
This is the same as the CBF testing during wakefulness/daytime except that it will be done during a sleep study performed with a continuous positive airway pressure (CPAP) mask not nose clips and a mouthpiece. With DOS/DCS in place, ventilatory response to hypercapnia will be determined using the rebreathing technique. While CBF is being measured, OSAS subjects will receive an individualized positive pressure aimed at treating obstructive sleep apnea and controls will receive a standard pressure. End-tidal carbon dioxide will be measured via a port in the mask. A constant flow of carbon dioxide will be introduced to the circuit, a slowly adjusted until the patient arouses or for a maximum of 3 minutes, whichever occurs first. One trial will be attempted in each sleep stage (slow-wave sleep and rapid-eye-movement) with a minimum of 15 minute of breathing room air between challenges. Oxygen and carbon dioxide levels will be carefully monitored throughout the testing.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Children's Hospital of Philadelphia
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
6 Years to 12 Years
Healthy volunteers
Yes
Inclusion criteria
(OSAS subjects): 1. Age between 6 years and 12 years. The lower limit criterion was selected to include children who can understand and cooperate with testing. The upper limit criterion was selected to avoid overlap with the adult presentation of OSAS. 2. Absence of neurologic, cardiovascular, pulmonary, or any other chronic illness with the exception of well-controlled asthma 3. No prior surgery on the nose, palate or oropharynx including an adenotonsillectomy 4. No current drug intake that may interfere with testing such as sedatives or stimulants 5. No prior treatment of sleep-disordered breathing 6. Polysomnographic recording criteria: subjects with OSAS must have an obstructive apnea hypopnea index (AHI) ≥ 5/hour and be a candidate for clinically-indicated surgical treatment. 7. Parental/guardian permission (informed consent) and if appropriate, child assent.
Exclusion criteria
(OSAS Subjects) 1. Previous adenotonsillectomy 2. Previous use of CPAP 3. Craniofacial anomalies that can interfere with upper airway anatomy (e.g., Treacher-Collins syndrome) 4. Genetic syndromes (e.g., Trisomy 21, Prader-Willi) 5. Attention deficit hyperactivity disorder (ADHD) on medication 6. Developmental delay 7. Non-English speaking participants due to the nature of neurobehavioral testing Inclusion Criteria (Control subjects) 1. Age between 6 years and 12 years. The lower limit criterion was selected to include children who can understand and cooperate with testing. The upper limit criterion was selected to avoid overlap with the adult presentation of OSAS. 2. Absence of neurologic, cardiovascular, pulmonary, or any other chronic illness with the exception of well-controlled asthma 3. No prior surgery on the nose, palate or oropharynx including an adenotonsillectomy 4. No current drug intake that may interfere with testing such as sedatives or stimulants 5. No prior treatment of sleep-disordered breathing 6. Polysomnographic recording criteria: Normal control subjects must have an AHI ≤ 1.5/hour. 7. Parental/guardian permission (informed consent) and if appropriate, child assent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebral Blood Flow (CBF) at Baseline Between Obstructive Sleep Apnea Syndrome (OSAS) and Controls | Baseline measurements, up to 24 hours | To determine whether children with OSAS have impaired blood flow regulation elicited by hypercapneic challenge compared to normal controls at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of the Change in CBF From Baseline to Study Completion Between OSAS and Control Subjects | Up to 12 Months | Only children who completed 2 or more repeated measurements were included in the analysis. The change in CBF measurements obtained at baseline when compared at 6 and 12 months after baseline for controls and after adenotonsillectomy for OSAS subjects. The slope of the change in CBF over time is reported: Delta CBF/Delta time, units= percentage over year. Minimum values are -100, maximum values +100, positive values mean better outcome.Cerebral blood flow were measured non-invasively while the child was breathing oxygen mixed with carbon dioxide. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Association Between CBF Regulation and Severity of OSAS | Up to 12 months | Children who completed baseline measurements were included. Correlation coefficients between the obstructive apnea hypopnea index and relative change of cerebral blood flow in children with obstructive sleep apnea and Controls are reported. The Correlation Coefficient is calculated by dividing the Covariance of the apnea hypopnea index and CBF by the Standard deviation of the apnea hypopnea index and CBF. Units of the standard deviation of CBF= unit of CBF. So, in the correlation coefficient formula, units get canceled. The correlation coefficient does not have any units and can be positive or negative. In this case positive correlation coefficients signal better regulation of CBF. |
| Behavior Rating Inventory of Executive Function Global Executive Functioning T-score | baseline | Children who completed baseline measurements were included. One child in the obstructive sleep apnea arm did not complete the Behavior Rating Inventory of Executive Function testing. Behavior Rating Inventory of Executive Function (global executive functioning T score) is reported between the 2 groups. Because this measures uses a T score, a score of 50 is considered average for the population. The scale is 0-100, with higher scores signaling executive functioning impairment. T-scores of 60-64 are in the mildly elevated range, and scores equal to or exceeding 65 are considered to be significantly elevated. The typical standard deviation (SD) observed is 10. |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred between October 2016 and February 2020. Participants with obstructive sleep apnea were recruited from the Children's Hospital of Philadelphia Sleep Center. Control participants were recruited by means of advertisement.
Pre-assignment details
Screening phase based on the Adaptive Behavior Assessment System 3 (ABAS 3) and sleep study results resulted in 13 screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Obstructive Sleep Apnea Syndrome (OSAS) \- Typically developing children aged 6-12 years with no history of upper airway surgery or previous treatment of obstructive sleep apnea, with an obstructive apnea hypopnea index equal to or greater than 5 events per hour. | 18 |
| Controls \- Typically developing children aged 6-12 years with no snoring and no history of previous sleep disordered breathing, and an obstructive apnea hypopnea index ≤1.5/hour. | 14 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 9 | 8 |
Baseline characteristics
| Characteristic | Obstructive Sleep Apnea Syndrome (OSAS) | Controls | Total |
|---|---|---|---|
| Age, Continuous | 9.8 years STANDARD_DEVIATION 3.4 | 10.3 years STANDARD_DEVIATION 3 | 9.81 years STANDARD_DEVIATION 1.77 |
| Apnea hypopnea index, N/hour | 16.5 events per hour STANDARD_DEVIATION 11.9 | 0.74 events per hour STANDARD_DEVIATION 0.44 | 9.6 events per hour STANDARD_DEVIATION 11.9 |
| Body mass index z-score | 1.87 Z-score STANDARD_DEVIATION 1.57 | -0.04 Z-score STANDARD_DEVIATION 1.52 | 0.91 Z-score STANDARD_DEVIATION 1.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 12 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Oxyhemoglobin saturation nadir during sleep, % | 83.5 percentage of oxyhemoglobin STANDARD_DEVIATION 12 | 91.5 percentage of oxyhemoglobin STANDARD_DEVIATION 6 | 86.7 percentage of oxyhemoglobin STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 11 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 18 participants | 14 participants | 32 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 11 Participants | 7 Participants | 18 Participants |
| Sleep arousal | 13.08 Arousals per hour STANDARD_DEVIATION 11.91 | 7.84 Arousals per hour STANDARD_DEVIATION 3.28 | 12.9 Arousals per hour STANDARD_DEVIATION 9.2 |
| Sleep duration | 84.0 % of total sleep time STANDARD_DEVIATION 11.8 | 85.6 % of total sleep time STANDARD_DEVIATION 7.3 | 84.7 % of total sleep time STANDARD_DEVIATION 10 |
| Stage N1 | 4.81 % of total sleep time STANDARD_DEVIATION 4.62 | 1.31 % of total sleep time STANDARD_DEVIATION 3.68 | 4.5 % of total sleep time STANDARD_DEVIATION 4.9 |
| Stage N2 | 46.1 % of total sleep time STANDARD_DEVIATION 5.1 | 44.4 % of total sleep time STANDARD_DEVIATION 7.9 | 44.4 % of total sleep time STANDARD_DEVIATION 6.1 |
| Stage N3 | 29.05 % of total sleep time STANDARD_DEVIATION 9.9 | 31 % of total sleep time STANDARD_DEVIATION 5 | 31 % of total sleep time STANDARD_DEVIATION 7.6 |
| Stage Rapid Eye Movement | 18.6 % of total sleep time STANDARD_DEVIATION 8.39 | 22.7 % of total sleep time STANDARD_DEVIATION 5.17 | 20.3 % of total sleep time STANDARD_DEVIATION 5.4 |
| Time with oxyhemoglobin saturation < 90% | 1.1 % of total sleep time STANDARD_DEVIATION 1.4 | 0.02 % of total sleep time STANDARD_DEVIATION 0.06 | 0.6 % of total sleep time STANDARD_DEVIATION 1.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 14 |
| other Total, other adverse events | 0 / 18 | 0 / 14 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Change in Cerebral Blood Flow (CBF) at Baseline Between Obstructive Sleep Apnea Syndrome (OSAS) and Controls
To determine whether children with OSAS have impaired blood flow regulation elicited by hypercapneic challenge compared to normal controls at baseline.
Time frame: Baseline measurements, up to 24 hours
Population: Percentage of change from baseline of cerebral blood flow during hypercapneic challenge is reported in children with OSAS and controls. Unit is % change from baseline within the groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obstructive Sleep Apnea Syndrome (OSAS) | Change in Cerebral Blood Flow (CBF) at Baseline Between Obstructive Sleep Apnea Syndrome (OSAS) and Controls | 184 percentage of change from baseline | Standard Deviation 56 |
| Controls | Change in Cerebral Blood Flow (CBF) at Baseline Between Obstructive Sleep Apnea Syndrome (OSAS) and Controls | 209 percentage of change from baseline | Standard Deviation 109 |
Secondary
Comparison of the Change in CBF From Baseline to Study Completion Between OSAS and Control Subjects
Only children who completed 2 or more repeated measurements were included in the analysis. The change in CBF measurements obtained at baseline when compared at 6 and 12 months after baseline for controls and after adenotonsillectomy for OSAS subjects. The slope of the change in CBF over time is reported: Delta CBF/Delta time, units= percentage over year. Minimum values are -100, maximum values +100, positive values mean better outcome.Cerebral blood flow were measured non-invasively while the child was breathing oxygen mixed with carbon dioxide.
Time frame: Up to 12 Months
Population: Only children who completed 2 or more repeated measurements were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obstructive Sleep Apnea Syndrome (OSAS) | Comparison of the Change in CBF From Baseline to Study Completion Between OSAS and Control Subjects | 0.013 percentage change per year | Standard Deviation 0.04 |
| Controls | Comparison of the Change in CBF From Baseline to Study Completion Between OSAS and Control Subjects | -0.083 percentage change per year | Standard Deviation 0.17 |
Other Pre-specified
Association Between CBF Regulation and Severity of OSAS
Children who completed baseline measurements were included. Correlation coefficients between the obstructive apnea hypopnea index and relative change of cerebral blood flow in children with obstructive sleep apnea and Controls are reported. The Correlation Coefficient is calculated by dividing the Covariance of the apnea hypopnea index and CBF by the Standard deviation of the apnea hypopnea index and CBF. Units of the standard deviation of CBF= unit of CBF. So, in the correlation coefficient formula, units get canceled. The correlation coefficient does not have any units and can be positive or negative. In this case positive correlation coefficients signal better regulation of CBF.
Time frame: Up to 12 months
Population: Correlation coefficients between the obstructive apnea hypopnea index and relative change of cerebral blood flow were calculated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obstructive Sleep Apnea Syndrome (OSAS) | Association Between CBF Regulation and Severity of OSAS | -0.0018 Correlation coefficients |
| Controls | Association Between CBF Regulation and Severity of OSAS | 0.37 Correlation coefficients |
Other Pre-specified
Behavior Rating Inventory of Executive Function Global Executive Functioning T-score
Children who completed baseline measurements were included. One child in the obstructive sleep apnea arm did not complete the Behavior Rating Inventory of Executive Function testing. Behavior Rating Inventory of Executive Function (global executive functioning T score) is reported between the 2 groups. Because this measures uses a T score, a score of 50 is considered average for the population. The scale is 0-100, with higher scores signaling executive functioning impairment. T-scores of 60-64 are in the mildly elevated range, and scores equal to or exceeding 65 are considered to be significantly elevated. The typical standard deviation (SD) observed is 10.
Time frame: baseline
Population: Only children who completed the Behavior Rating Inventory of Executive Function testing were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obstructive Sleep Apnea Syndrome (OSAS) | Behavior Rating Inventory of Executive Function Global Executive Functioning T-score | 56.5 T score | Standard Deviation 14.1 |
| Controls | Behavior Rating Inventory of Executive Function Global Executive Functioning T-score | 49.7 T score | Standard Deviation 11.1 |