High Incidence of Sleep-Related Breathing Disorders in Children with Down Syndrome Referred to a High-Altitude Sleep Laboratory

Abstract

Aims:

The aim of the study was to assess the incidence of sleep-related breathing disorders (SRBD) in children with Down Syndrome (DS) living at high altitude.

Methods:

A retrospective descriptive study was conducted on 53 children with DS who underwent polysomnography (PSG) at San Ignacio University Hospital (2640 m/8660 ft above sea level) from 2009 to 2016. Data were extracted from official PSG reports and analyzed using measures of central tendency and dispersion, frequency calculation, ranges, and confidence intervals. Associations were examined using t-test, chi-square test, and analysis of variance test.

Results:

Obstructive sleep apnea (OSA) was present in 90.5% of children. Central sleep apnea was evident in 11.3%. Periodic breathing was seen in 15.1% of patients. Snoring was able to predict OSA with a sensitivity of 61.7%, a specificity of 100%, and negative predictive value of 25%.

Conclusion:

Children with DS who live at high altitude have a high incidence of SRBD. Our findings show a higher incidence of SRBD than previously reported in the population with DS. Furthermore, snoring was not sensitive enough to predict OSA. This high risk of SRBD may increase the risk of other comorbid conditions seen in the population with DS. Our results support the need for routine PSG screening independent of symptoms such as snoring status.

Introduction

Down syndrome (DS) is the most common chromosomal alteration in the world with an incidence of 1 in 700 newborns according to the Centers for Disease Control and Prevention (2017). It is characterized by variable degrees of intellectual disability and phenotypic characteristics such as midfacial hypoplasia, macroglossia, small upper airway, adenoidal and tonsillar hypertrophy, laryngomalacia, decreased muscle tone, hypothyroidism, and obesity (Dyken et al., 2003). This combination of phenotypic characteristics is thought to contribute to the high rates of sleep-related breathing disorders (SRBD) among children with DS, probably secondary to increased upper airway obstruction. SRBD include obstructive sleep apnea (OSA), central sleep apnea (CSA), and periodic breathing (PB). For instance, OSA is diagnosed more frequently in patients with DS (between 30% and 60%) than in the general pediatric population (1%–5%) (Marcus et al., 2012; Lal et al., 2015).

The increase in SRBD leads to higher morbidity, as it has been demonstrated that these pediatric patients show higher rates of pulmonary hypertension, deficits in neurocognitive performance, behavioral impairments, and decreased school performance (Kholdani et al., 2015; Trosman and Trosman, 2017). Furthermore, higher rates of SRBD have been reported in healthy children living at high altitude compared to those living at sea level (Patz et al., 2006; Hill et al., 2016b). Increased SRBD at higher altitudes may contribute to the already increased risk of neurocognitive deficits and pulmonary hypertension in children with DS.

To our knowledge, there are no studies describing SRBD in children with DS living at high altitude. In this study, we analyzed a sample of patients with DS who were referred to a high-altitude sleep laboratory. We hypothesized that children with DS who live at high altitude will have a high incidence of SRBD.

Materials and Methods

Study design

A retrospective descriptive study was conducted to determine the incidence of SRBD in children with DS. This study was approved by the Ethics Committee of the School of Medicine at Pontificia Universidad Javeriana and San Ignacio University Hospital.

Reports from polysomnography (PSG) studies performed from September 2009 to April 2016 in children with DS between the ages of 0 and 16 years were reviewed. All of the children lived in Bogota, Colombia at an altitude of 2640 m/8660 ft above sea level. Only the initial diagnostic study for each patient was included in the analysis. Charts were reviewed for demographic information and medical comorbidities such as hypothyroidism, atrial septal defect (ASD), ventricular septal defect, patent ductus arteriosus, mitral valve prolapse, bicuspid aorta, pulmonary hypertension, vocal cord paralysis, preterm birth, and cleft lip or palate.

Polysomnography

PSGs were performed at the sleep clinic at San Ignacio University Hospital. An Alice 5 Diagnostic Sleep System (Philips Respironics, Pittsburgh, PA) was used, and variables indicated by the American Association of Sleep Medicine (AASM) were recorded. The channels recorded included electroencephalogram, electrooculogram, electromyography, electrocardiogram, and snore microphone. Thoracic and abdominal movements, nasal and oral flow sensor, continuous digital pulse oximetry (Masimo, Irvine, CA), and end-tidal CO₂ were also measured. Patients with poor signal or artifacts lasting more than 10% of the total time of registration and those with low sleep efficiency as dictated by the AASM were excluded (Berry et al., 2012). For each sleep study, oxygen saturation, mean of desaturation events by hour, and mean length of these episodes in minutes were recorded. PSGs were analyzed by a single pediatric pulmonologist according to the guidelines provided by the AASM. The events were classified according to the AASM Manual for the Scoring of Sleep and Associated Events update of 2012 (Berry et al., 2012). The cutoff point for diagnosing OSA was an obstructive apnea–hypopnea index (OAHI) >2 events/h (Burg et al., 2013), with mild OSA categorized as 2–4.9 events/h, moderate OSA as 5–9.9 events/h, and severe OSA as greater than 10 events/h. CSA index >5 events/h was used to diagnose CSA (Nehme et al., 2017). PB was defined as three or more respiratory pauses lasting 3 or more seconds separated by no more than 20 seconds of normal breathing (Katz 2012).

Statistical analysis

Each variable distribution was assessed using the Shapiro–Wilk test. Variables with normal distribution were summarized using mean and standard deviation, while interquartile ranges and median variables were reported for variables with non-normal distribution. The Student's t-test for independent measures was used for continuous variables such as awake and asleep mean minimal saturation and partial pressure of carbon dioxide (PCO₂) compared between different diagnoses of SRBD.

Pearson's chi-squared test and analysis of variance test were used to determine the associations between variables. p-Values <0.05 were considered significant. All analyses were performed using Stata 14 by Stata Corp (College Station, TX).

Results

A total of 53 PSG reports from children with DS were included. The median age was 3.4 years (IQR 1.6–8.8 years), and 50.9% of the patients were male. The initial analysis resulted in 90.5% of patients diagnosed with OSA, 11.3% with CSA, 15.1% with PB, and only 7.5% of patients with normal polysomnograms. Table 1 displays the PSG findings by age group. There were no statistically significant differences in any of the respiratory events measured between age groups. The severity of OSA is shown in Table 2.

Table 1.

Polysomnographic Findings and Respiratory Events by Age Group

Respiratory measure	0–23 Months	24–84 Months	85–156 Months	>156 Months	p
Respiratory measure	n = 17	n = 18	n = 11	n = 7	p
Apnea–hypopnea index	7.3 (1.5–20.6)	8.6 (3.3–36.8)	15.2 (2.4–23.7)	20.4 (5.3–29.8)	0.08
Obstructive apnea–hypopnea index	7.0 (1.5–20.2)	8.3 (1.9–30.0)	8.4 (2.5–19.0)	13.0 (4.9–29.2)	0.16
Central apnea index	0.3 (0–1.8)	0.8 (0–5.9)	2.1 (0–9.1)	1.5 (0–7.3)	0.09

Table 2.

Severity of Obstructive Sleep Apnea

Severity of OSA	Percent of patients (n)
Mild (OAHI 2.0–4.9)	22.6% (12)
Moderate (OAHI 5.0–9.9)	32.1% (17)
Severe (OAHI >10.0)	35.8% (19)

OAHI, obstructive apnea–hypopnea index; OSA, obstructive sleep apnea.

Snoring was found in 52.9% of patients. All of the patients who snored had a diagnosis of OSA; however, 75% of patients who did not snore also had OSA. Snoring was able to predict OSA with a sensitivity of 61.7%, a specificity of 100%, and negative predictive value of 25%.

Table 3 reports awake, asleep, and minimal mean oxygen saturation for those with OSA, CSA, and no sleep-disordered breathing. Furthermore, the mean PCO₂ during sleep in patients with OSA was 37.7 mmHg, 39.3 mmHg in patients with CSA, and 37 mmHg in patients with no sleep-disordered breathing.

Table 3.

Mean Awake, Asleep, and Minimum SpO₂ in Different Sleep-Related Breathing Disorders

Sleep disordered breathing status	Awake mean	Asleep mean	Minimum mean
Sleep disordered breathing status	SpO2	SpO2	SpO2
No sleep disordered breathing	91.3	88.5	79.8
OSA	90.0	87.9	69.8
CSA	92.5	90.0	66.0

CSA, central sleep apnea; SpO₂, oxygen saturation as measured by pulse oximetry.

The incidence of comorbid conditions in the cohort of patients with SRBD was 48.9% for congenital heart disease, 19.1% for hypothyroidism, 8% for pulmonary hypertension, 4.3% for vocal cord paralysis, 8.5% for preterm birth, and 2.1% for cleft lip or palate. No statistically significant associations were found between any comorbid conditions and any of the diagnoses of SRBD.

Discussion

The present study shows a very high incidence of SRBD in children with DS living at high altitude. We report that 90.5% of our children had OAHI >2 events/h, consistent with a diagnosis of OSA and a 67.9% rate of moderate-to-severe OSA. In addition, 73.9% of patients who did not snore had OSA, indicating that snoring is not a good predictor of SRBD in patients with DS. Furthermore, 11.3% of our patients had CSA, 15.1% had PB, and only 7.5% had normal sleep breathing. The most common comorbid conditions in SRBD were congenital heart disease, hypothyroidism, and pulmonary hypertension. The incidence of comorbid conditions did not differ significantly from those reported for the general DS population (King et al., 2014; Mourato et al., 2014).

Higher rates of SRBD in children with DS compared to healthy controls have been consistently reported in the literature. Using lower diagnostic thresholds, the incidence of SRBD for children with DS can be as high as 79% (Dyken et al., 2003). Other reports that used the same metrics as our study found a prevalence of 57.1% and 64.8% (de Miguel-Díez, 2003; Maris et al., 2016). However, the rates of OSA found in our sample are consistently higher than previously reported. The same conclusion applies when analyzing exclusively moderate-to-severe OSA, defined by OAHI >5 events/h. De Miguel-Diez et al. (2003) and Fitzgerald et al. (2007) found 64.8% and 61% rates, respectively, compared to 67.9% seen in our sample. This is a relevant finding given that a recommendation issued by the European Respiratory Society Scientific Committee task force dictated that an OAHI >5 was a meaningful clinical treatment threshold to avoid long-term complications such as high blood pressure (Kaditis et al., 2016).

In this study at high altitude, the incidence of OSA and moderate-to-severe OSA in patients with DS is higher than previously reported in a high-altitude non-DS cohort (Burg et al., 2013) and in DS populations at lower altitude and at sea level (de Miguel-Díez, 2003; Fitzgerald et al., 2007). This increased incidence is seen irrespective of different diagnostic criteria used in previous studies. One possible explanation for this discrepancy is the effects of living at high altitude on sleep-related respiratory physiology. Chronic exposure to high altitude leads to increased minute ventilation, increased arousal frequency, and decreased partial pressure of carbon dioxide, arterial (PaCO₂). Since the eucapnic threshold is lower, these changes trigger sleep apneas which in turn lead to PB and desaturations (Hill et al., 2016a). Therefore, children living at high altitude with more frequent episodes of desaturation have an elevated index of hypopnea that tends to disappear with a descent to lower altitude (Patz et al., 2006; Burg et al., 2013; Duenas-Meza et al., 2015; Hill et al., 2016a). Supporting this theory, our mean obstructive apnea index is 2.2, and our mean obstructive hypopnea index is 9.1, indicating that the main contributors to an elevated OAHI are hypopneas. Hughes et al. also found a significant difference in AHI, OAHI, and central AHI when comparing PSGs performed on the same child at higher and lower altitudes. The increase in all indexes with high altitude was driven by a rise in hypopneas (Hughes et al., 2017).

Furthermore, pharyngeal collapse appears to be an overlapping pathophysiologic factor in different syndromes of SRBD. Duenas-Meza et al. (2015) studied healthy children at high altitude and they postulate that, for unclear reasons, hypoxia and a low barometric pressure led to instability of the upper airway and pharyngeal collapse, contributing to the higher occurrence of OSA in healthy children at high altitude. In addition, premature newborns with central apneas and PB can have passive pharyngeal collapse causing obstruction (Miller et al., 1988). As in premature newborns, DS patients have low muscle tone, perhaps predisposing them to increased pharyngeal collapse that contributes to obstruction. Therefore, low muscle tone combined with high altitude appears to augment the phenomenon of pharyngeal collapse causing an increase in the incidence of SRBD in patients with DS.

In line with the desaturation findings mentioned previously, our mean minimum oxygen saturation as measured by pulse oximetry (SpO₂), including both patients with and without SRBD, is 70.2%, which is markedly lower than what has been previously reported. Burg et al. (2013) found a median minimum SpO₂ of 85% in healthy children living at 1600 m, while Hill et al. (2016a) found a mean minimum oxygen saturation of 80% in healthy children living at a higher altitude of 3650 m. Although these two studies were conducted in healthy children, and the latter was performed at higher altitude, our mean minimum SpO₂ is markedly lower. A possible explanation for these desaturations is the higher rates of lung disease in DS, including aspiration injury and alveolar simplification (Dishop, 2010). These findings suggest that the combination of DS and high altitude can potentiate their effects on desaturations and explain the high rate of hypopneas and PB found in our sample.

The higher rates of SRBD and the lower oxygen saturation found in DS patients at high altitude could have particular importance in the neurocognitive and clinical long-term outcomes of this population. When addressing the neurocognitive outcomes, Hunter et al. demonstrated that SRBD have a dose–response impact on neurocognitive function. Children with higher AHI, especially those with severe OSA, had more significant impairment according to neurocognitive assessments than those with lower AHI (Hunter et al., 2016). In addition, OSA has been associated with higher rates of pulmonary hypertension, which in turn leads to increased mortality and decreased quality of life (Kholdani et al., 2015). Furthermore, congenital heart diseases which are more commonly diagnosed in children with DS also contribute to higher rates of pulmonary hypertension. Multiple studies have suggested that patients with DS have abnormal capillary morphology with vascular simplification leading to higher pulmonary vascular resistance and more vascular damage reflected in higher rates of pulmonary hypertension and Eisenmenger syndrome compared to children without DS (Chi and Krovetz, 1975; Dishop, 2010). In this study, 9 out of 11 children with both an ASD and DS had pulmonary hypertension, while only 5 out of 55 children with only an ASD had pulmonary hypertension (Chi and Krovetz, 1975). Fudge et al. also found that rates of pulmonary hypertension were higher in patients with both DS and an ASD (6.2%) than in controls with only an ASD (0.2%) (Fudge et al., 2010). Although we did not find a statistically significant association between SRBD and the comorbidities studied, we did find high rates of congenital heart disease and pulmonary hypertension. Taking these data into account, patients with DS living at high altitude and higher rates of moderate-to-severe SRBD constitute a particularly vulnerable population with a higher risk for adverse outcomes.

One of the main foci in evaluating the DS pediatric population has been the criteria for selecting individuals who would benefit from screening. The American Academy of Pediatrics (AAP) recommends that as early as age 1 month providers need to discuss symptoms related to OSA, including snoring (Bull and the Committee on Genetics, 2011). However, our study found that snoring is a specific but not sensitive predictor for SRBD in children with DS. In our analysis, snoring was 61.7% sensitive and had a 25% negative predictive value for predicting OSA in children with DS who live at high altitude. These findings are in line with other studies refuting the utility of snoring as a predictor of PSG-diagnosed OSA (Ng et al., 2006; Shott et al., 2006; Maris et al., 2016). Our findings suggest that providers should have a low threshold to perform polysomnograms in patients with DS and appear to support the recommendation by the AAP in which all children with DS should undergo PSG before 4 years of age (Bull and the Committee on Genetics, 2011).

To our knowledge, our series is the first to study SRBD in children with DS at high altitude. Our findings suggest that a combination of high altitude and characteristics of DS such as upper airway abnormalities and low muscle tone is responsible for the even higher rates of SRBD in this population. Our results encourage further studies on this population, as the literature is scarce and more research could lead to the prevention of these disorders and better care for this vulnerable population.

Limitations of our study include the following: (1) a lack of a significant number of patients without SRBD to serve as a control group to compare the significance of our findings and to increase the power necessary to detect associations; (2) a lower altitude control group could provide stronger evidence regarding whether altitude is, in fact, a contributing factor to the reported findings; and (3) restrictive ethnic diversity can limit applicability in other settings and the general population.

Conclusion

Children with DS who live at high altitude have a high incidence of SRBD likely from a combination of contributors of high altitude and characteristics of DS such as upper airway abnormalities and low muscle tone. The higher incidence of SRBD may contribute to the high incidence of neurocognitive and cardiopulmonary morbidity experienced by this population. This higher risk, along with a poor predictive capacity of symptoms such as snoring, supports the need for routine PSG screening.

Footnotes

Acknowledgment

The authors of this article thank the staff at the Sleep Clinic at San Ignacio University Hospital for their unparalleled support.

Author Disclosure Statement

No competing financial interests exist.

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