Obstructive sleep apnoea syndrome (OSAS) is an increasingly-recognised clinical entity affecting up to 5.7% of children, which, if left untreated, is associated with adverse effects on growth and development including deleterious cognitive and behavioural outcomes. Evidence exists also that untreated OSAS impacts on cardiovascular risk. Close attention should be paid to assessment and investigation of this relatively common condition, instigating early and appropriate treatment to children with OSAS. First-line treatment in younger children is adenotonsillectomy, although other treatment options available include continuous positive airways pressure (CPAP), anti-inflammatory therapies (nasal corticosteroids and anti-leukotrienes), airway adjuncts and orthodontic appliances.
Corresponding author: Dr Don Urquhart MD, MRCPCH, Consultant in Paediatric Respiratory and Sleep Medicine,
Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh, EH9 1LF,
tel: +441315360634, fax: +441315360669,
Sleep-disordered breathing in children incorporates disorders of breathing that relate to airway patency (obstructive sleep apnoea syndrome) and also conditions which affect respiratory drive (central sleep disorders) or cause hypoventilation, either as a direct central effect or secondary to peripheral muscle weakness. This review aims to describe the aetiology, presentation and sequelae of OSAS, as well as reviewing the diagnostic tests available. Central apnoeas and central sleep-disordered breathing will be briefly reviewed.
Events during sleep are scored using the American Academy of Sleep Medicine (AASM) manual for the scoring of sleep and associated events1.
Figure 1: Obstructive events during sleep measured using limited-channel polysomnography (Source: Sleep Laboratory, Royal Hospital for Sick Children, Edinburgh).
SpO2: Arterial oxygen saturations measured by pulse oximetry, Flow Th: Airflow measured by thermistor, RIP Thorax: Thoracic respiratory effort measured by inductance plethysmography, RIP Abdomen: Abdominal respiratory effort measured by inductance plethysmography.
A central apnoea is an event associated with absent inspiratory effort and an absence (or >90% reduction) of airflow lasting for > 20 seconds duration, or lasting for >2 missed breaths and associated with a physiological consequence (arousal, awakening, a >3% fall in SpO2 or, in infants, bradycardia)1,2. A central hypopnoea is scored when a 30% reduction in airflow associated with concurrently reduced inspiratory effort lasting >2 missed breaths occurs in association with a physiological consequence1,2. An example of a sleep study demonstrating central events is shown in Figure 2.
Figure 2: Central events during sleep measured using limited-channel polysomnography (Source: Sleep Laboratory, Royal Hospital for Sick Children, Edinburgh).
SpO2 : Arterial oxygen saturations measured by pulse oximetry, Flow Th: Airflow measured by thermistor, RIP Thorax: Thoracic respiratory effort measured by inductance plethysmography, RIP Abdomen: Abdominal respiratory effort measured by inductance plethysmography.
Obstructive sleep apnoea syndrome (OSAS) is a phenomenon of repeated, episodic reduction or cessation of airflow (hypopnoea/apnoea) as a result of upper airways obstruction. Respiratory effort is preserved or increased at times of apnoea, as the subject attempts to overcome obstruction. OSAS may occur as a result of enlarged tonsils and adenoids3,be related to airway(s) anatomy for example in those with Pierre-Robin sequence4, airway(s) tone as in children with muscular weakness5, or exogenous tissue around the airways in those with obesity6.
Presentation of OSAS
Even with those caveats, history-taking is the cornerstone of diagnosis as in any medical condition. Questions on sleep pattern at night are important, including enquiring about snoring, work of breathing (restlessness, sweatiness, and faltering growth), and mouth breathing (whether child sleeps with mouth open, and whether thirsty in the mornings) and the presence of apnoea. The question of whether a child stops breathing is a poor discriminator of apnoea, and is better phrased by asking whether a child sounds ‘strangled’ during sleep, or whether a period is noted where the child’s breathing goes quiet that is then overcome by a gasp. Those with OSAS are more likely than primary snorers to have been witnessed to have an apnoea (p=0.01), to have been noticed to be struggling to breathe (p16.
Examination findings are directed at examining the tonsils and grading their size (0-4) in accordance with the standardised tonsillar hypertrophy grading scale proposed by Brodsky18, as well as assessing the nose for mucosal inflammation, turbinate size, septal position, presence of polyps and nasal airflow. The nose may be directly auscultated with the stethoscope or a disposable mirror used to see whether it mists up in association with nasal exhalation19. Adenoid size may be assessed directly by either nasoendoscopy or by transoral mirror examination20. Mid-face hypoplasia or the “adenoidal facies” may be apparent in chronic OSAS. Pectus excavatum secondary to chronic sternal recession is rarely seen nowadays.
Investigation of OSAS in children
The undertaking of PSG requires resources in terms of time and also personnel to supervise the study. Attempts have been made to do snap-shot PSG studies during daytime sleeps, or so-called ‘nap studies’. Whilst these have an excellent positive predictive value (100%) in diagnosing OSAS, their negative predictive value is poor – 20%21. OSAS is likely to be worse during rapid-eye movement (REM) sleep, as airway tone falls in REM making obstruction manifest. REM sleep occurs later in the night – i.e. OSAS worsens as the night goes on, and may be missed in a short daytime nap.
Currently there are no universally accepted guidelines as to when children’s OSA is sufficiently severe as to warrant treatment. An AHI >1 is regarded as abnormal with treatment recommended for any child with an AHI >526. Severe childhood OSAS is defined as having an AHI >10 events per hour27. How to proceed is less clear in children with AHIs between 1 and 526. Table 1 illustrates the correlation of AHI and OSAS severity.
Many centres (our own included) undertake cardiorespiratory sleep studies with video camera, effort bands, airflow measures, heart rate and SpO2 +/- tcCO2 monitoring. This allows confident detection of apnoea, delineation between central and obstructive events, and quantification of the degree of ensuing hypoxia. An AHI can be generated from such studies, enabling one to embark on an appropriate treatment course.
Oximetry as a single-channel recording
Figure 3: Overnight oximetry findings in a child with OSAS (Source: Sleep Laboratory, Royal Hospital for Sick Children, Edinburgh).
SpO2 : Arterial oxygen saturations measured by pulse oximetry.
The utility of oximetry alone in the detection of OSA has been demonstrated to have limitations. Brouillette and colleagues showed that whilst oximetry is highly specific (98%), it has a sensitivity of only 43%29. The positive predictive value of an abnormal oximetry for diagnosing OSA was 97%, suggesting 3% cases where oximetry is abnormal are due to central apnoea. The negative predictive value (value of a negative oximetry in excluding OSA) was only 47%29, roughly the equivalent of tossing a coin.
Clinical implications of OSAS
It is during REM sleep that memory consolidation is postulated to occur31,such that the sleep fragmentation may affect cognition; whilst Growth Hormone is produced in slow wave sleep32 and its’ secretion may be interrupted by fragmented sleep. The increase in work of breathing to overcome obstruction and its’ consequent calorie demand are a further mechanism by which OSA impacts growth.
Known risk factors for cardiovascular disease in adulthood include hypertension and inflammation. The effects of desaturations and arousals are known to stimulate the sympathetic nervous system with an adrenaline surge and a transient rise in blood pressure. This is a frequent and oft-repeated insult in those with OSA and over time acts as a promoter of systemic hypertension, such that OSA has become an increasingly-recognised cause of adult hypertension35.Furthermore, OSA is pro-inflammatory with elevations in C reactive protein (CRP) reported in both adults36 and children37,with OSA, whilst an animal model of intermittent hypoxia and hypercapnia (mimicking OSA) resulted in increased levels of interleukin-6 (IL-6), a precursor of CRP production38. Levels of CRP are reported to fall with successful treatment of OSAS36,39. CRP is used by the American Heart Association to stratify risk for ischaemic heart disease40, and has also been shown to correlate with measures of radial artery stiffness and carotid artery intimal thickness in children41.In addition, endothelial dysfunction has been demonstrated to be present in a childhood OSAS population14,42 Thus, it seems plausible that childhood OSAS is a risk factor for later cardiovascular risk. In extreme cases of OSAS, right heart strain and development of cor pulmonale have been known to occur43.
Treatment of childhood OSAS
The benefit of AT on ameliorating obstruction is clear with consequential benefits on growth, behaviour and school performance7,33. For a some children however, obstruction may persist or recur and careful counselling of parents or carers is required pre-operatively as in some patients other means to alleviate airway obstruction may need to be considered. Such treatments include continuous positive airways pressure (CPAP) therapy, anti-inflammatory therapies, as well as airway adjuncts such as nasopharyngeal airways or orthodontic appliances.
The rationale for CPAP is that one applies a continuous positive airways pressure (CPAP) via a face-mask or nasal mask during sleep47, pushing upper airway tissues apart to splint the airway open, allowing relief of obstruction, whilst maintaining normal gas exchange and preserving sleep quality. CPAP is instituted in hospital with a team of nurses, play therapists, medical staff and of course parents involved; and sleep studies are undertaken to titrate CPAP pressures to the patients’ needs.
Orthodontic appliances, such as mandibular advancement splints, have also been advocated in some centres as a means of countering the effects of skeletal dysmorphology on airway anatomy.54
There is some evidence supporting rapid maxillary advancement surgery on having benefit on both signs and symptoms of OSASand also AHI55-57 in childhood populations. Tracheostomy, whilst effective, is considered a last resort because of its associated significant morbidity.
Central apnoeas represent absences of airflow that are accompanied by an absence of respiratory effort. Infrequent central apnoeas are found in normal children23,24,58-60, in particular following a sigh58.There are some cases where the number of central apnoeas and/or the gravity of associated desaturations are felt to be pathological. Such patterns may be related to immaturity of respiratory control and are associated with prematurity61 as well as certain medical conditions, such as Prader-Willi syndrome62. Finally, some children will have central apnoeas as part of a central hypoventilation disorder, causes for which may be inherited (Congenital Central hypoventilation Syndrome)63 or acquired (for example as a consequence of an Arnold-Chiari malformation64,65, brain tumour66, or spinal injury67).
In cases of central apnoea, polsomnography with capnometry is recommended68. Measures of flow, effort and SpO2 allow the number and the effect of central apnoeas to be quantified. In addition, simultaneous monitoring of CO2 (via transcutaneous or end-tidal methods) allows for assessment of hypoventilation in those with central sleep-disordered breathing.
A variety of treatments including pharmacological therapies (methylxanthines, acetazolamide), oxygen and ventilator support may be used in the treatment of childhood central apnoea. Each of these, is briefly discussed.
Figure 4: a) Response of repeated central apnoeas to oxygen treatment, b) In air, c) In oxygen at 0.25 L/minute (Source: Sleep
Laboratory, Royal Hospital for Sick Children, Edinburgh). ECG: Electrocardiogram, SpO2: Arterial oxygen saturations measured by pulse oximetry, Flow Th: Airflow measured by thermistor, RIP Thorax: Thoracic respiratory effort measured by inductance plethysmography, RIP Abdomen: Abdominal respiratory effort measured by inductance plethysmography.
In some cases of central sleep-disordered breathing, apnoea is accompanied by hypoventilation. Such cases require the institution of bi-level ventilatory support with a back-up rate in order to restore normal gas exchange during sleep. As discussed above, causes may be congenital or acquired. Figure 5 (a,b) illustrates a sleep study undertaken on a boy who had undergone cranial irradiation following resection of a posterior fossa tumour. Gas exchange was normalised following the institution of non-invasive bi-level ventilation.
Figure 5: Illustration of central hypoventilation in association with an intracerebral tumour a) Prior to commencing ventilatory support, b) On ventilation (Source: Sleep Laboratory, Royal Hospital for Sick Children, Edinburgh). ECG: Electrocardiogram,
SpO2: Arterial oxygen saturations measured by pulse oximetry, Flow Th: Airflow measured by thermistor, RIP Thorax: Thoracic respiratory effort measured by inductance plethysmography, RIP Abdomen: Abdominal respiratory effort measured by inductance plethysmography.
The short-term effects of undetected sleep-disordered breathing in children include detrimental effects on school performance, behaviour, and cognition. Effects in later life affecting cardiovascular risk are also suggested. The stakes are high, as it is the future health and behaviour of our children that we are dealing with. Successful treatments are readily available. Being mindful of sleep apnoea, taking an appropriate history, and undertaking to investigate and treat appropriately, will all serve to minimise the disease burden of this important group of conditions.
There are no conflicts of interest to declare.
1. AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications (Version 2.0), 2012.
2. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012; 8: 597-619.
3. Marcus CL, Brooks LJ, Ward SD, Draper KA, Gozal D, Halbower AC, et al. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012; 130: e714-e755.
4. Abel F, Bajaj Y, Wyatt M, Wallis C. The successful use of the nasopharyngeal airway in Pierre Robin sequence: an 11-year experience. Arch Dis Child. 2012; 97: 331-334.
5. Alves RS, Resende MB, Skomro RP, Souza FJ, Reed UC. Sleep and neuromuscular disorders in children. Sleep Med Rev. 2009; 13: 133-148.
6. Narang I, Mathew JL. Childhood obesity and obstructive sleep apnea. J Nutr Metab. 2012; 2012: 134202.
7. Gozal D. Sleep-disordered breathing and school performance in children. Pediatrics. 1998; 102: 616-620.
8. Bass JL, Corwin M, Gozal D, Moore C, Nishida H, Parker S, et al. The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence. Pediatrics. 2004; 114: 805-816.
9. Kohler MJ, Lushington K, van den Heuvel CJ, Martin J, Pamula Y, Kennedy D. Adenotonsillectomy and neurocognitive deficits in children with Sleep Disordered Breathing. PLoS One. 2009; 4: e7343.
10. Friedman BC, Hendeles-Amitai A, Kozminsky E, Leiberman A, Friger M, Tarasiuk A, et al. Adenotonsillectomy improves neurocognitive function in children with obstructive sleep apnea syndrome. Sleep. 2003; 26: 999-1005.
11. O’Brien LM, Mervis CB, Holbrook CR, Bruner JL, Klaus CJ, Rutherford J, et al. Neurobehavioral implications of habitual snoring in children. Pediatrics. 2004; 114: 44-49.
12. Suratt PM, Barth JT, Diamond R, D’Andrea L, Nikova M, Perriello VA Jr, et al. Reduced time in bed and obstructive sleep-disordered breathing in children are associated with cognitive impairment. Pediatrics. 2007; 119: 320-329.
13. Kheirandish-Gozal L, Bhattacharjee R, Gozal D. Autonomic alterations and endothelial dysfunction in pediatric obstructive sleep apnea. Sleep Med. 2010; 11: 714-720.
14. Kheirandish-Gozal L, Etzioni T, Bhattacharjee R, Tan HL, Samiei A, Molero Ramirez H, et al. Obstructive sleep apnea in children is associated with severity-dependent deterioration in overnight endothelial function. Sleep Med. 2013; 14: 526-531.
15. Schechter MS; Section on Pediatric Pulmonology, Subcommittee on Obstructive Sleep Apnea Syndrome. Technical report: diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2002; 109: e69.
16. Carroll JL, McColley SA, Marcus CL, Curtis S, Loughlin GM. Inability of clinical history to distinguish primary snoring from obstructive sleep apnea syndrome in children. Chest. 1995; 108: 610-618.
17. Chervin RD, Weatherly RA, Garetz SL, Ruzicka DL, Giordani BJ, Hodges EK, et al. Pediatric sleep questionnaire: prediction of sleep apnea and outcomes. Arch Otolaryngol Head Neck Surg. 2007; 133: 216-222.
18. Brodsky L. Modern assessment of tonsils and adenoids. Pediatr Clin North Am. 1989; 36: 1551-1569.
19. Brescovici S, Roithmann R. Modified Glatzel mirror test reproducibility in the evaluation of nasal patency. Braz J Otorhinolaryngol. 2008; 74: 215-222.
20. Chisholm EJ, Lew-Gor S, Hajioff D, Caulfield HJ. Adenoid size assessment: a comparison of palpation, nasendoscopy and mirror examination. Clin Otolaryngol. 2005; 30: 39-41.
21. Marcus CL, Keens TG, Ward SL. Comparison of nap and overnight polysomnography in children. Pediatr Pulmonol. 1992; 13: 16-21.
22. American Academy of Sleep Medicine. International classification of sleep disorders, American Academy of Sleep Medicine, Westchester, Illinois, 2006.
23. Uliel S, Tauman R, Greenfeld M, Sivan Y. Normal polysomnographic respiratory values in children and adolescents. Chest. 2004; 125: 872-878.
24. Scholle S, Wiater A, Scholle HC. Normative values of polysomnographic parameters in childhood and adolescence: Cardiorespiratory parameters. Sleep Med. 2011; 12: 988-996.
25. Bhattacharjee R, Kheirandish-Gozal L, Spruytl K, Mitchell RB, Promchiarak J, Simakajornboon N, et al. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicentre retrospective study. Am J Respir Crit Care Med. 2010; 182: 676-683.
26. Capdevila OS, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric obstructive sleep apnea: complications, management and long-term outcomes. Proc Am Thorac Soc. 2008; 5: 274-282.
27. Goldbart AD, Greenberg-Dotan S, Tal A. Montelukast for children with obstructive sleep apnea: a double-blind, pla-cebo-controlled study. Pediatrics. 2012; 130: e575-e580.
28. Rosen CL, Larkin EK, Kirchner HL, Emancipator JL, Bivins SF, Surovec SA, et al. Prevalence and risk factors for sleep-disordered breathing in 8- to11-year-old children: association with race and prematurity. J Pediatr. 2003; 142: 383-389.
29. Brouillette RT, Morielli A, Leimanis A, Waters KA, Luciano R, Ducharme FM. Nocturnal pulse oximetry as an abbreviated testing modality for pediatric obstructive sleep apnea. Pediatrics. 2000; 105: 405-412.
30. Kirk VG, Bohn SG, Flemons WW, Remmers JE. Comparison of home oximetry monitoring with laboratory polysomnography in children. Chest. 2003; 124: 1702-1708.
31. Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010; 11: 114-126.
32. Born J, Muth S, Fehm HL. The significance of sleep onset and slow wave sleep for nocturnal release of growth hormone (GH) and cortisol. Psychoneuroendocrinology 1988; 13: 233–243.
33. Chervin RD, Ruzicka DL, Giordani BJ, Weatherly RA, Dillon JE, Hodges EK, et al. Sleep-disordered breathing, behavior and cognition in children before and after adenotonsillectomy. Pediatrics. 2006; 117: e769-778.
34. Rosen CL, Storfer-Isser A, Taylor HG, Kirchner HL, Emancipator JL, Redline S. Increased behavioral morbidity in school-aged children with sleep-disordered breathing. Pediatrics. 2004; 114: 1640-1648.
35. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-disordered breathing, sleep apnea and hypertension in a large community-based study. JAMA. 2000; 283: 1829-1836.
36. Steiropoulous P, Tsara V, Nena E, Fitili C, Kataropoulou M, Froudarakis M, et al. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest. 2007; 132: 843-851.
37. Tauman R, Ivanenko A, O’Brien LM, Gozal D. Plasma C-reactive protein levels among children with sleep-disordered breathing. Pediatrics. 2004; 113: e564-e569.
38. Tam CS, Wong M, Tam K, Aouad L, Waters K. The effect of acute intermittent hypercapnic hypoxia treatment on IL-6, TNF-alpha and CRP levels in piglets. Sleep. 2007; 30: 723-727.
39. Ingram DG, Matthews CK. Effect of adenotonsillectomy on c-reactive protein levels in children with obstructive sleep apnea: a meta-analysis. Sleep Med. 2013; 14: 172-176.
40. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003; 107: 499-511.
41. Järvisalo MJ, Harmoinen A, Hakanen M, Paakkunainen U, Viikari J, Hartiala J, et al. Elevated serum C-reactive protein levels and early arterial changes in healthy children. Arterioscler Thromb Vasc Biol. 2002; 22: 1323-1328.
42. Kheirandish-Gozal L, Bhattacharjee R, Gozal D. Autonomic alterations and endothelial dysfunction in pediatric obstructive sleep apnea. Sleep Med. 2010; 11: 714-720.
43. Lee PC, Hwang B, Soong WJ, Meng CC. The specific characteristics in children with obstructive sleep apnea and cor pulmonale. ScientificWorldJournal. 2012; 2012: 757283.
44. Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG, et al. A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med. 2013; 368: 2366-2376.
45. Marcus CL, Brooks LJ, Draper KA, Gozal D, Halbower AC, Jones J, et al. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012; 130: 576-584.
46. Merrell JA, Shott SR. OSAS in Down syndrome: T&A versus T&A plus lateral pharyngoplasty. Int J Pediatr Otorhinolaryngol. 2007; 71: 1197-1203.
47. Waters KA, Everett FM, Bruderer JW, Sullivan CE. Obstructive sleep apnea: the use of nasal CPAP in 80 children. Am J Respir Crit Care Med. 1995; 152: 780-785.
48. Marcus CL, Rosen G, Davidson Ward SL, Halbower AC, Sterni L, Lutz J, et al. Adherence to and effectiveness of positive airway pressure therapy in children with obstructive sleep apnea. Pediatrics. 2006; 117: e442-e451.
49. Anzai Y, Ohya T, Yanagi K. [Treatment of sleep apnea syndrome in a Down syndrome patient with behavioral problems by noninvasive positive pressure ventilation: a successful case report]. No To Hattatsu. 2006; 38: 32-36.
50. Urquhart DS, Perry L, Gupta A, Rosenthal M. Sleep-disordered breathing in a 4-year old child with Down syndrome. BMJ. 2008; 337: a1229.
51. Kheirandish-Gozal L, Gozal D. Intranasal budesonide treatment for children with mild obstructive sleep apnoea syndrome. Pediatrics. 2008; 122: e149-e155.
52. Goldbart AD, Goldman JL, Veling MC, Gozal D. Leukotriene modifier therapy for mild sleep-disordered breathing in children. Am J Respir Crit Care Med. 2005; 172: 364-370.
53. Masters IB, Chang AB, Harris M, O’Neil MC. Modified nasopharyngeal tube for upper airway obstruction. Arch Dis Child. 1999; 80: 186-187.
54. Gilleminault C, Quo SD. Sleep-disordered breathing. A view at the beginning of the new Millennium. Dent Clin North Am. 2001; 45: 643-656.
55. Pirelli P, Saponara M, Guilleminault C. Rapid maxillary expansion in children with obstructive sleep apnea syndrome. Sleep. 2004; 27: 761-766.
56. Villa MP, Malagola C, Pagani J, Montesano M, Rizzoli A, Guilleminault C, et al. Rapid maxillary expansion in children with obstructive sleep apnea syndrome: 12-month follow-up. SleepMed. 2007; 8: 128-134.
57. Villa MP, Rizzoli A, Miano S, Malagola C. Efficacy of rapid maxillary expansion in children with obstructive sleep apnea syndrome: 36 months of follow-up. Sleep Breath. 2011; 15: 179-184.
58. Marcus CL, Omlin KJ, Basinki DJ, Bailey SL, Rachal AB, Von Pechmann WS, et al. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis. 1992; 146: 1235-1239.
59. Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographic characteristics in normal preschool and early school-aged children. Pediatrics. 2006; 117: 741-753.
60. Verhulst SL, Schrauwen N, Haentjens D, Van Gaal L, De Backer WA, Desager KN. Reference values for sleep-related respiratory variables in asymptomatic European children and adolescents. Pediatr Pulmonol. 2007; 42: 159-167.
61. Rigatto H, Brady JP. Periodic breathing and apnea in preterm infants. II. Hypoxia as a primary event. Pediatrics. 1972; 50: 219-228.
62. Urquhart DS, Gulliver T, Williams G, Harris MA, Nyunt O, Suresh S. Central sleep-disordered breathing and the effects of oxygen therapy in infants with Prader-Willi syndrome. Arch Dis Child. 2013; 98: 592-595.
63. Healy F, Marcus CL. Congenital central hypoventilation syndrome in children. Paediatr Respir Rev. 2011; 12: 253-263.
64. Murray C, Seton C, Prelog K, Fitzgerald DA. Arnold-Chiari type 1 malformation presenting with sleep disordered breathing in well children. Arch Dis Child. 2006; 91: 342-343.
65. Abel F, Kilner D, Sonnappa S. Unusual breathing in a 7 year old. BMJ. 2012; 344: e3022.
66. Rosen GM, Bendel AE, Neglia JP, Moertel CL, Mahowald M. Sleep in children with neoplasms of the central nervous system: case review of 14 children. Pediatrics. 2003; 112: e46-e54.
67. Jardine E, O’Toole M, Paton JY, Wallis C. Current status of long-term ventilation of children in the United Kingdom: questionnaire survey. BMJ. 1999; 318: 295-299.
68. Marcus CL. Sleep-disordered breathing in children. Am J Respir Crit Care Med. 2001; 164: 16-30.
69. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants. Cochrane Database Syst Rev. 2010; 12: CD000140.
70. Kirk VG, Morielli A, Gozal D, Marcus CL, Waters KA, D’Andrea LA, et al. Treatment of sleep-disordered breathing in children with myelomeningocele. Pediatr Pulmonol. 2000; 30: 445-452.
71. Hudgel DW, Thanakitcharu S. Pharmacological treatment of sleep-disordered breathing. Am J Respir Crit Care Med. 1998; 158: 691-699.
72. DeBacker WA, Verbraecken J, Willemen M, Wittesaele W, DeCock W, Van deHeyning P. Central apnea index decreases after prolonged treatment with acetazolamide. Am J Respir Crit Care Med. 1995; 151: 87-91.
73. De Backer WA. Central sleep apnoea, pathogenesis and treatment: an overview and perspective. Eur Respir J. 1995; 8: 1372-1383.
74. Chadha TS, Birch S, Sackner MA. Periodic breathing triggered by hypoxia in normal awake adults. Modification by naloxone. Chest. 1985; 88: 16-23.
75. Manning DJ, Stothers JK. Sleep stage, hypoxia and periodic breathing in the neonate. Acta Paediatr Scand. 1991; 80: 763-769.
76. Simakajornboon N, Beckerman RC, Mack C, Sharon D, Gozal D. Effect of supplemental oxygen on sleep architecture and cardiorespiratory events in preterm infants. Pediatrics. 2002; 110: 884-888.