Sequelae of Pediatric Obstructive Sleep Apnea

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1		Catherine Kier	+ 2886 word(s)	2886	2022-02-23 07:22:36	\|
2	formating	Jason Zhu	+ 244 word(s)	3130	2022-03-07 04:25:41	\|

This entry is adapted from the peer-reviewed paper 10.3390/children9020261

Pediatric obstructive sleep apnea (OSA) has been shown to not only affect the quality of sleep, but also overall health in general. Untreated or inadequately treated OSA can lead to long-term sequelae involving cardiovascular, endothelial, metabolic, endocrine, neurocognitive, and psychological consequences. The physiological effects of pediatric OSA eventually become pathological. As the complex effects of pediatric OSA are discovered, they must be identified early so that healthcare providers can be better equipped to treat and even prevent them. Ultimately, adequate management of OSA improves overall quality of life.

Obstructive sleep apnea (OSA) Cardiovascular Diseases Neurocognitive

1. Introduction

Obstructive sleep apnea (OSA), part of the spectrum of sleep-disordered breathing (SDB), is characterized by frequent arousals, apneas, and hypopneas, and can be associated with reduction in blood oxygen saturation and hypoventilation during sleep in children ^[1]. The prevalence of children with OSA is around 1–5.8% but is rising due to the obesity pandemic ^[2]. First-line treatment of pediatric OSA is an adenotonsillectomy (AT), which directly addresses adenoid and tonsillar hypertrophy associated with pediatric OSA ^[3]. The success rates of adenotonsillectomy vary depending on the population studied but residual OSA rates can be as high as 40 to 75% in children ^[1]. For children who have OSA that persists into later childhood, alternate forms of treatment and management are necessary to maintain quality of life. Continuous positive airway pressure (CPAP) may be necessary for a select group of pediatric patients with OSA. Other options need to be explored and studied to prevent long term sequalae.

Pediatric obstructive sleep apnea (OSA) has adverse effects as a result of disruption of sleep and abnormal ventilation ^[4]. Behavioral and learning issues are commonly seen in younger children, which can present as attention problems, hyperactivity, irritability, and poor school performance. Long term, if untreated, pediatric OSA can lead to adverse cardiovascular, endothelial, metabolic, endocrine, neurocognitive, and psychological outcomes that affect quality of life ^[5]. The costs of treating long-term sequelae pose an additional burden on children, their families, as well as the entire health care system. By increasing awareness of the potential long-term sequelae of OSA and by adequate screening of children, OSA can be identified and treated accordingly. Ideally, early identification and treatment could potentially affect the trajectory of the disease in children.

2. Cardiovascular Diseases and Obstructive Sleep Apnea

Untreated or inadequately treated obstructive sleep apnea in children can lead to systemic and pulmonary hypertension, postural orthostatic hypertension syndrome, cardiac arrhythmias, coronary artery changes, and cerebrovascular changes ^[6].

2.1. Hypertension

Childhood OSA is an independent risk factor for adverse blood pressure outcomes ^[7]. Hypertension in pediatric OSA is due to multifactorial pathogenesis ^[8]. Recurrent hypoxemia and hypercapnia in pediatric OSA lead to activation of the sympathetic nervous system with consequent increases in catecholamine levels ^[7], which persist during the daytime and contribute to the development of hypertension.

Intermittent elevations in systemic blood pressure during sleep have been observed in children with OSA ^[9]. Children with moderate to severe OSA were found to have higher nocturnal systolic blood pressure and reduced nocturnal drop of systolic blood pressure at 10-year follow up ^[10]. Mean blood pressure variability was noted to be higher during wakefulness and during sleep in children with OSA compared to children with primary snoring ^[10]. The nocturnal dipping of the mean blood pressure was smaller in children with OSA compared to those with primary snoring ^[9].

Pulmonary hypertension has been reported in children with OSA, although it is rare in noncardiac patients. The overall prevalence of pulmonary hypertension in pediatric OSA patients is low (1.8%) ^[9].

2.2. Cardiac Arrhythmias

There have been limited studies on the relationship between OSAS and cardiac arrhythmia in children. Cardiac arrhythmias during sleep include nonsustained ventricular tachycardia (VT), sinus pause or arrest, second degree atrioventricular (AV) conduction block, and frequent premature ventricular contractions (PVCs > 2 bpm). Although cardiac arrhythmias may be seen in pediatric OSA and may be an incidental finding during an overnight polysomnography for a child being assessed for snoring or sleep apnea, the true prevalence and clinical significance of cardiac arrhythmias in pediatric OSA has not been well established. A retrospective study of 124 children diagnosed with OSA (after excluding patients with airway, cardiac, congenital, or genetic abnormalities), with a mean age of 6.7 ± years, was assessed for the presence of arrhythmias and heart rate variability. The cases were categorized based on the severity of OSA as mild, moderate, or severe. All cases demonstrated sinus arrhythmias (sinus rhythm with varying R-R intervals), but only 2.4% (only 3 cases) had occasional PAC. There were no other arrhythmias, such as PVC, AV block, VT, or SVT. Most cases (80.7%, 100 of 124 cases) had an episode of sinus bradycardia (with heart rate less than normal for age). Sinus arrhythmia is a normal variation found even in healthy children. Sinus bradycardia was common but showed no clinical significance. Standard deviation of heart rate (SD-HR), minimum heart rate (min-HR), and maximum heart rate (max-HR) values in NREM and REM stages were assessed. In NREM sleep, there were no significant differences among the mild, moderate, and severe OSA groups. In REM, however, the SD-HR and max-HR values were significantly higher in the severe OSA group. These data may be indirect evidence of increased heart rate variability in severe OSA ^[11]. Another retrospective cross-sectional study of children below 15 years of age with sleep-disordered breathing (SDB) suggested that heart rate variability was significantly increased in sleep in those with severe OSA compared to those with mild OSA ^[9].

QT dispersion and P-wave dispersion have also been studied in pediatric OSA. QT dispersion may be associated with a higher risk for ventricular arrhythmia and has been reported in children with severe OSA ^[9]. P-wave dispersion was found more in children with severe OSA in a study of 44 children at 1–12 years of age ^[12]. This implies that cardiac arrhythmias occur along a continuum and can be variable and benign except may be in severe OSA. More studies are required to determine links about the pathogenesis of arrhythmias in OSA.

2.3. Coronary Artery Changes and Atherogenesis

Elevated plasma P-selectin levels, a marker of platelet activation, was noted in children with OSA ^[13]. The activation of P-selectin is mediated by inflammatory processes linked to atherogenesis ^[13]. Additionally, hypoxemia and sleep fragmentation secondary to OSA can promote both sympathetic activity and reaction oxygen species (ROS) formation, which further cause platelet activation and upregulation of adhesion molecules, respectively. These data support the postulation that pediatric OSA can promote the onset of atherosclerosis and subsequent CAD.

2.4. Cerebrovascular Abnormalities

OSA is implicated in neuropsychological deficits and neuronal brain injury. The underlying mechanisms include reduced cerebrovascular perfusion, blood gas abnormalities, and neuronal injury secondary to long-term oxygen saturation abnormalities ^[14]. Children are especially vulnerable to changes in cerebral blood flow (CBF) compared to adults due to having a higher metabolic rate, a higher resting CBF, and a narrower range of autoregulation ^[15]^[16]. This makes children particularly vulnerable to brain injury during critical periods ^[17].

Hypoxia-induced lactate production and ROS formation can also leave brain regions vulnerable to neuronal injury. Increased prevalence of OSA was noted amongst children with arterial ischemic strokes (AIS), implying an association between OSA and cerebrovascular stroke ^[18]. This finding highlights the issue that even children may possibly be vulnerable to very significant sequelae as adults. Better screening and prompt identification and treatment of OSA can prevent such morbidity.

3. Metabolic and Endocrine Dysfunction and OSA

Evidence suggests that untreated OSA increases the risk and incidence of insulin resistance, dyslipidemia, growth hormone dysfunction, and other metabolic disorders in children ^[19]. The bidirectional association between OSA and obesity plays a role in the development of metabolic and endocrine syndromes ^[19]. OSA also leads to alterations in the hypothalamic–pituitary–adrenal axis and irregular sympathetic activation ^[20].

3.1. Insulin Resistance

There is a reported association of OSA with increasing insulin resistance when adjusted for confounding factors such as BMI and waist circumference ^[21]. Studies have even found an independent association between OSA and high fasting glucose and fasting insulin levels ^[22]. OSA leads to the development of type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance in both adults and children ^[12]^[23]. Appropriate treatment of OSA leads to improvement in insulin resistance, as demonstrated in pediatric studies ^[24].

3.2. Inflammatory Markers

It should also be noted that inflammation mediates the interplay between OSA, obesity, and metabolic dysregulation. Studies have shown that certain inflammatory markers are elevated in obese pediatric patients ^[25]. These markers include interleukin (IL) 6, IL-8, IL-10, IL-17, IL-18, IL-23, macrophage migration inhibitory factor (MIF), highly sensitive C-reactive protein (Hs CRP), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), and leptin. Strong positive correlations were found between these markers and fasting insulin levels, BMI, apnea–hypopnea index (AHI), and other metabolic parameters ^[25]. These biomarkers also are implicated in the developments of cardiovascular morbidities. Prior studies have also identified IL-17 and IL-23 as being significantly increased in children with OSA, suggesting that they may serve as diagnostic markers for pediatric OSA ^[26].

3.3. Metabolic Syndrome

The complex interplay of OSA with obesity, hypertension, dyslipidemia, and insulin resistance can contribute to metabolic syndrome and can result in elevated levels of serum insulin, increasedblood pressure, triglycerides, and lower levels of high-density lipoproteins levels ^[12]. Metabolic syndrome itself is a risk factor for cardiovascular disease. Mechanisms of the development of OSA-induced metabolic syndrome include increased sympathetic activity, increased serum cortisol secondary to activation of the hypothalamic–pituitary–adrenocortical axis, and reactive oxidative species (ROS) formation ^[27]. Obesity is likely the primary mediator between OSA and metabolic syndrome ^[12]^[28]. C-reactive protein, adiposity, leptin, and insulin resistance were found to be associated with SDB in children, even after controlling for various demographic confounders ^[29]^[30].

3.4. Growth Failure

Studies have shown that growth is affected by OSA. Older studies have established a link between failure to thrive (FTT) and pediatric OSA, as demonstrated by an improvement in weight gain following AT ^[31] For this reason, FTT and associated impairments in growth have been implicated in OSA diagnosis. A pediatric study demonstrated that biomarkers of growth, particularly insulin-like growth factor binding protein 3 (IGFBP-3), were low in children with OSA, suggesting that there was growth hormone secretion impairment ^[32]. The study also demonstrated that resolution of OSA via AT leads to improved growth, most notably in weight, marked by significant elevations in circulating insulin-like growth factor-I (IGF-I) and IGFBP-3 concentrations. These improvements were significantly greater in the OSA-treated group than in the primary snoring group ^[32].

3.5. Polycystic Ovarian Syndrome

There appears to be somewhat of a bidirectional association between OSA and polycystic ovarian syndrome (PCOS), as reported in literature. The underlying mechanisms of both PCOS and OSA include insulin resistance, changes in levels of circulating hormones, ROS formation, and sympathetic activation ^[33]^[34]. Studies have demonstrated the potential of CPAP therapy in the treatment of both OSA and PCOS phenotypes. Given that both OSA and PCOS are risk factors for worsening metabolic and cardiovascular changes, treatment of both can be preventative against further comorbidities. As the prevalence of women with both OSA and PCOS increases, further research on the association between OSA and possible onset of PCOS in adolescent population is warranted.

3.6. Testosterone Deficiency

Though pediatric studies exploring the association between OSA and testosterone are not well established, adult studies have found an association between OSA and decreased levels of testosterone ^[35]. This is due to suppression of the hypothalamic–pituitary axis. Sleep fragmentation, sleep deprivation, frequent nocturnal awakenings, oxygen desaturation, and worsening of AHI can all contribute to lower levels of testosterone in males with OSA ^[35]. In particular, a negative correlation between OSA severity and testosterone levels has been identified. Furthermore, a higher AHI score is associated with lower testosterone levels.

3.7. Thyroid Function

Literature on OSA in children has highlighted associations between SDB and thyroid function. Sleep fragmentation and sleep deprivation, which are features of OSA, have been associated with lower levels of circulating thyroid stimulating hormone. Persistent OSA or untreated OSA in childhood can lead to hypothyroidism through suppression of the hypothalamic pituitary axis ^[36]. This may be related to the idea that the thyroid gland becomes a watershed area with limited perfusion during hypoxemia secondary to OSA although this has not been confirmed.

4. Neurocognitive Abnormalities and OSA

4.1. Cortical Thinning

Untreated and unmanaged pediatric OSA has been linked with significant neurocognitive sequelae. The hypoxemia and hypercapnia ^[37] that results from airway obstruction during sleep leads to oxidative stress and neuronal injury within the brain, particularly the hippocampus and cerebral cortex ^[38]. Lesions within the frontal lobe white matter were found on MRI of the brain in children with OSA ^[39]. Analysis of the cortical thickness using T-1-weighted MRI images as well as volumetric reconstructions of the subcortical structures in children with OSA suggested generalized cortical thinning within the medial orbital sulci ^[40]. In addition, another study, albeit in adult patients with OSA, further localized the cortical thinning in OSA patients to the orbital gyri, dorsolateral or ventromedial prefrontal regions, pericentral gyri, cingulate, insula, inferior parietal lobule, uncus, and basolateral regions ^[41]. Through analysis with memory tests, a higher number of respiratory arousals were noted not only in relation to cortical thinning of the anterior cingulare and inferior parietal lobule, but also longer apnea duration was related to cortical thinning of the dorsolateral prefrontal regions, pericentral gyri, and insula ^[41]. Decreased activation in the inferior parietal lobe was also noted, and this finding appears to be associated with impaired sensory input and processing ^[42]. Executive function, attention, and memory and learning are neurocognitive functions affected by OSA changes in the brain in adults ^[43].

4.2. Problem Solving and Executive Function

OSA has been found to be associated with dysfunction in overall executive function in children. Executive function includes inhibition, problem solving, fluid reasoning, and mental flexibility ^[42]. Inhibition is an all-encompassing term referring to deterring an automatic response to a stimulus. In patients with OSA, impaired inhibition is associated with poor impulse control. In children with untreated OSA, impairment in skills such as reading comprehension and mathematics was also reported ^[43]. Fluid reasoning is the ability to analyze problems by taking information from established knowledge and forming new connections within the brain, and this is noted to be affected in children with untreated OSA. Mental flexibility is essential for the brain to shift from one cognitive strategy to another. Impairment of this function in untreated OSA leads to decreased mental sharpness. It is plausible that untreated OSA can result in deficits that could worsen in children through the critical developmental years and affect learning, long term academic potential and subsequent occupational abilities.

4.3. Attention

Impaired attention is found in OSA children. Studies assessing polysomnograms and MRIs suggest that attention and vigilance are prominent neurocognitive functions that are impaired in children with OSA ^[44]. There are three components of attention, each of which can be compromised in patients with OSA. These include sustained attention, selective attention, and divided attention ^[45]. Whether these are related to endothelial dysfunction, hypoxemia, or both is still unknown.

Sustained attention includes attention required over extended lengths of time. In children with OSA, issues with sustained attention required during school days while juggling multiple classes, subjects, and extracurricular activities have been reported. Many of these children are concurrently diagnosed with attention-deficit/hyperactivity disorder, which is a neurocognitive disorder associated with a spectrum of attention and/or behavioral issues ^[46]. In those cases of complex patients, distinguishing between attention issues caused by ADHD versus those caused by OSA are difficult to delineate. Adequate treatment of pediatric OSA with concurrent ADHD treatment leads to improvements in behavior and attention ^[43].

Selective attention refers to the ability to focus on one task for a period of time. The task of driving requires selective attention amongst other skills such as the brain receiving visuospatial information. Studies analyzing adults with OSA have shown an increased incidence in motor vehicle accidents in those affected with OSA ^[46]. Further studies on the adolescent population are needed, especially many of whom driving is a new skill.

Lastly, the third component to attention is divided attention. Divided attention refers to the ability to be attentive to more than one stimulus at a time. When divided attention is impaired, individuals become overwhelmed with the filtering and processing of information. In children with OSA, impairment in this skill was reported ^[47]. When these skills are impaired, academic and functional abilities in these children are compromised.

4.4. Memory

Memory is an important component of the learning process. Recall processes from memory allow the storage of material to be used later. In patients with OSA, particularly in children and adolescents who are in school, OSA may affect episodic memory. Episodic memory includes immediate and delayed recall of events and experiences ^[48]. Two subcategories of episodic memory include visual and verbal components, including recalling of images and factual details ^[48]. Pediatric patients with OSA are more likely to have issues with visual and verbal episodic memory in not only the short-term recall, but also the long-term recall as well. It is important to note that increased hypoxemia and hypercapnia, decreased sleep quality, and increased obesity with its consequences are all factors that can impede the ability to recall and store new and old memories in children. Aside from its impact on memory required for general academics, OSA also had an impact on overall intelligence. Sleep deprivation from poor quality of sleep from OSA may worsen these impairments. Sleep deprivation from societal expectations or comorbid insomnia may further potentiate the sequelae.

4.5. School Performance

Obstructive sleep apnea affects problem solving, attention, and memory, and this ultimately causes repercussions in school performance. The foundation of knowledge and skills learned through school relies on children and adolescents to not only have these important neurocognitive skills, but also to use these skills to the best of the students’ abilities. When these factors become compromised due to OSA, this leads to worsening of school performance.

Two treatment modalities of OSA and its subsequent effects on school performance have been reported. The first is tonsillectomy and adenoidectomy, which is the first line of treatment in the pediatric OSA population ^[49]. A meta-analysis conducted in 2017 evaluated neurocognitive effects in children with OSA post-tonsillectomy and -adenoidectomy ^[50]. Subsequent neuropsychological testing conducted within these studies found improvements in patients’ executive function, attention, and memory and learning ^[50]. This allowed the students to not only improve their academic performance and use of class-time effectively, but also to improve their relationships with their teachers. Another study assessed outcomes of tonsillectomies and adenoidectomies for twelve months in preschool-aged children. However, did not find any treatment-attributable improvement in neurocognitive function in these patients ^[51]. One limitation of generalizing isolated study is that it only evaluated patients with mild OSA. The second treatment modality of OSA is CPAP ^[52]. A meta-analysis evaluated 19 studies assessing neurocognitive function before and after CPAP management in adult OSA patients. Compared to pre-treatment patients, post-treatment patients were found to have improvement in neurocognitive domains of fluid reasoning, updating, inhibition, generativity, and shifting ^[52]. Moreover, another adult study correlated improvements in aspects of neurocognitive performance, including verbal fluency and working memory following oral appliance of consistent CPAP therapy ^[53]. The data on the effects on neurocognitive improvements with current treatment modalities in children are still lacking and will require further studies.

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Subjects: Pediatrics

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Catherine Kier

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