paediatric respiratory reviews · 2019-01-18 · central sleep apnea sleep disordered breathing...

Paediatric Respiratory Reviews xxx (2018) xxx–xxx

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Paediatric Respiratory Reviews

Review

Diagnosis, management and pathophysiology of central sleep apnea inchildren

https://doi.org/10.1016/j.prrv.2018.07.0051526-0542/� 2018 Elsevier Ltd. All rights reserved.

⇑ Corresponding author at: Division of Respiratory Medicine, The Hospital forSick Children, 555 University Avenue, Toronto, ON M5G1X8, Canada.Fax: +1 4168136246.

E-mail addresses: [email protected] (A.T. McLaren), [email protected] (S. Bin-Hasan), [email protected] (I. Narang).

Please cite this article in press as: McLaren AT et al. Diagnosis, management and pathophysiology of central sleep apnea in children. Paediatr Re(2018), https://doi.org/10.1016/j.prrv.2018.07.005

Anya T. McLaren a, Saadoun Bin-Hasan b, Indra Narang a,c,⇑aDivision of Respiratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G1X8, CanadabDepartment of Pediatrics, Division of Respiratory Medicine, Farwaniya Hospital, Kuwaitc Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Educational aims

The reader will be able to:

� Identify the different types of pediatric central sleep apnea (CSA)� Describe the clinical presentation of CSA in children� Discuss the pathophysiology of CSA� Understand the evaluation of CSA in the pediatric population

a r t i c l e i n f o

Keywords:Central sleep apneaSleep disordered breathingHypoventilationChildren

s u m m a r y

Central sleep apnea (CSA) is thought to occur in about 1–5% of healthy children. CSA occurs more com-monly in children with underlying disease and the presence of CSA may influence the course of their dis-ease. CSA can be classified based on the presence or absence of hypercapnia as well as the underlyingcondition it is associated with. The management of CSA needs to be tailored to the patient and mayinclude medication, non-invasive ventilation, and surgical intervention. Screening children at high riskwill allow for earlier diagnosis and timely therapeutic interventions for this population. The review willhighlight the pathophysiology, prevalence and diagnosis of CSA in children. An algorithm for the manage-ment of CSA in healthy children and children with underlying co-morbidities will be outlined.

� 2018 Elsevier Ltd. All rights reserved.

INTRODUCTION

Central sleep apnea (CSA) is a sleep-related disorder occurringwhen there is diminished or absent respiratory effort. CSA is oftenassociated with arterial oxygen desaturation, arousals, frequentnocturnal awakenings and sleep fragmentation [1]. In the pediatricpopulation, the AASM defines a central apnea as the absence ofchest and/or abdominal movement associated with a cessation ofairflow of more than 20 s or lasting more than 2 baseline respira-tory cycles if it is associated with an arousal, an awakening or anoxygen desaturation of at least 3% [2]. In adults, CSA is considered

significant when the number of central apneas per hour (centralapnea index, CAI) is �5/h [1]. CSA can occur in the presence orabsence of hypoventilation, defined as a CO2 >50 mmHg for >25%of the total sleep time in the pediatric population [2].

The International Classification of Sleep Disorders (ICSD)-2 rec-ognizes six different forms of central sleep apnea including pri-mary CSA and CSA due to other causes such as Cheyne-Stokesbreathing (CSB), medical conditions, drugs or substances, high-altitude periodic breathing and infancy [1]. In the pediatric popu-lation, CSA occurs more commonly in association with underlyingmedical conditions. These conditions include anatomical brain andbrainstem abnormalities (such as Arnold–Chiari Malformation,foramen magnum stenosis), neurogenetic conditions such as Pra-der–Willi syndrome, upper airway abnormalities (laryngomalacia),prematurity, gastroesophageal reflux, obesity and hypothyroidism[3,4]. CSA can also occur in the context of other sleep disorderedbreathing conditions such as OSA [5,6], emerge with the treatment

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Table 1Central sleep apnea in healthy children and children with underlying conditions.

Study Patient Population Methods Findings

N Age (years) BMI (kg/m2) Underlyingcondition

Definitions OAHI CSA SpO2

Nadir (%)w/CA

CA CSA CAI Range %ReportedCSA

Marcus et al., 1992 [14] 50 9.7 ± 4.6 18.6 ± 3.2 Healthy �10 s NA 0.1 ± 0.5 NR NR NA 89Schluter et al., 2001 681 1–24 mo NA Healthy �3 s NA NR 1 mo:8.8/h

2 mo: 5.0/hNR NA NR

Uliel et al., 2004 [19] 70 8.0 ± 4.6 NR Healthy �10 s OR dec SaO2 >4% or �92% NA 0.37 (SD NR) 0.4 (SD NR) NR NA 88Traeger et al., 2005 [18] 66 6.6 ± 1.9 NR Healthy �20 s OR <20 s + dec SaO2 �3% NA 0.01 ± 0.03 0.08 ± 0.14 0–6 NA 81Montgomery et al., 2006 [16] 153 4.9 ± 0.69 16.7 ± 2.8 Healthy At least 2 breaths NA 0.03 ± 0.1 0.82 ± 0.73 0–3.6 NA NR

388 6.8 ± 0.48 17.1 ± 3.4 0.05 ± 0.11 0.45 ± 0.49 0–3.4Verhulst et al., 2007 [17] 66 11.7 ± 2.6 NR Healthy �10 s OR dec SaO2 >3% NA 0.06 ± 0.16 0.85 ± 1.06 0–5.5 NA 82Scholle et al., 2011 [15] 209 1–18 y NR Healthy At least 2 breaths NA **0.1–0.3 **0.4–2.8 0–6.9 NA NRBrockman et al., 2013 [12] 37 1 mo NA Healthy >20 s OR 2 breaths + dec SaO2 �3% or HR changes NA 0.8/h 5.5/h 0.9–44.3 NA NR

3 mo 0.8/h 4.1/h 1.2–27.3White et al., 2016 [35] 17 2.4 ± 3.6 NR Ach NR >5/h 24.61 ± 23.63 3.32 ± 4.15 0–10.4 4.2 69Waters et al., 1998 [23] 83 8.9 ± 5.6 NR ACM �20 s OR dec SaO2 �4% �5/h NR NR NR 17 NRKirk et al., 2000 [24] 73 1–>18 y NR ACM NR >5/h 17 (10.3–32.6) 16.6 (7.7–46.4) 34 67 ± 14Amin et al., 2015 (22) 68 7.3 ± 4.0 (z-score) ACM AASM �5/h 1.9 (0.7–5.7) 2.4 (0.63–8.95) NR 18 NRPatel et al., 2015 [21] 52 8.3 ± 0.9 NR ACM �10 s �5/h NR NR NR 29 NRCohen et al., 2014 [26] 44 1.9 (0.3, 15.6) (z-score) PWS AASM �5/h 4 (1.5–57) 10.6 (5–68.3) 5–68.3 14 52Khayat et al., 2017 [27] 28 0.9 (0.5–1.1) 16 (14.3–16.8) PWS AASM �5/h 0.5 (0.2–33) 6.6 (2.6–12.1) 2.6–12.1 53 NRAl-Saleh et al., 2016 [36] 21 (10.7, 0.5–17.7) (z-score) DCM AASM �5/h 1.2 (0–26) 1.1 (0–17.6) 0–17.6 24 NR

Values represented as mean ± standard deviation (where reported) or median (range or Interquartile range). All studies were retrospective. NR = not reported; NA = not applicable; dec = decreased. AASM: AASM Criteria for centralapnea; Ach = achondroplasia; ACM = Arnold–Chiari malformation; PWS = Prader–Willi syndrome; DCM = Dilated cardiomyopathy; OAHI = obstructive apnea–hypopnea index; CAI-central apnea indexA full overnight, laboratory PSG was used in all these studies except Brockman et al which used polygraphic recordings.CAI presented as mean ± SD, median (IQR) or range.** In this study, the median CAI across the different age groups is reported as a range. Please refer to the study for more detail.

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A.T. McLaren et al. / Paediatric Respiratory Reviews xxx (2018) xxx–xxx 3

of OSA [7] or hypoventilation disorders such as congenital centralhypoventilation syndrome (CCHS). CCHS is a rare genetic disorderof ventilatory control that is marked by alveolar hypoventilation[8]. CCHS is caused by a genetic defect in PHOX2B (paired-likehomeobox 2B gene). Mutations in this gene are known as polyala-nine repeat mutations (PARMs) or non-polyalanine repeat muta-tions (nPARMs) [8].

Table 2

Diagnosis of pediatric CSA

A full-night in-laboratory polysomnography is the gold stan-dard diagnostic test for central apneas [2]. A finding of �5 centralevents per hour is considered clinically significant [3]. However,the minimum number of events required to cause a specific disor-der or syndrome remains elusive and may be different in differentpatient populations. As such, there is no threshold of the number ofcentral apneas associated with disease. Normative data are dis-cussed in more detail below.

Pediatric classification of central sleep apnea, adapted from [9].

Physiologic CSASleep onsetPost-arousalPost-sighPhasic REM sleepBody movementSleep-wake transition

Idiopathic CSACSA with possible hypoventilationArnold–Chiari malformationCNS tumorsNeuromuscular disordersThoracic cage diseaseChronic renal failure and patients on dialysis

CSA with genetic conditionsAchondroplasiaCCHSLO-CCHSDown SyndromeRett SyndromeVici SyndromeSmith–Magenis syndrome

CSA with other sleep disordered breathing conditionsObstructive sleep apneaCPAP emergent CSA

CSA with heart conditionsHeart failureIdiopathic pulmonary arterial hypertension

CSA with congenital craniofacial abnormalitiesCraniosynostosisPierre–Robin Sequence

CSA with neurogenetic/neurological conditionsPrader–Willi SyndromeJoubert Syndrome

CSA with endocrine conditionsObesityHypothyroidism

CSA with upper airway abnormalitiesLaryngomalaciaChoanal atresia

CSA with other medical conditions

Epidemiology of central sleep apnea in children

Healthy childrenCentral apneas during sleep are common in the preterm, new-

born period and during infancy [10]. All preterm infants born atless than 29 weeks gestation have apnea of prematurity and upto 25% of these events are central in origin [11]. In healthy children,short duration (<20 s) central apneas in sleep are considered phys-iologic particularly in the context of a sigh, movement and/or REMsleep [10]. There is an age-related decrease in central apneas that isthought to be related to maturation of the central nervous system[10].

Specifically, polysomnographic recordings in healthy terminfants estimate the median CAI at one month of life to varybetween 5.5/h [12] and 8.8/h [13] with a duration ranging between3.1 and 20.1 s [12,13] when the definition of a CA was a centralpause lasting for greater than 3 s. [13]. Central apneas after sighswere not included in these indices but accounted for 18% of allCAs in one study [12]. A reduction in central apneas occurs bythe second and third month of life [12,13] and central apneas con-tinue to reduce in frequency in the second year of life [13]. In sub-jects beyond infancy, Marcus et al found that in otherwise healthy1–18 year olds (n = 50), the prevalence of central apneas thatlasted between 10 and 18 s was 30% and central apneas �20 s werefound to be rare in another study [14,15]. In other studies, themean CAI in healthy children older than one year is less than 1/hbut CAIs as high as 6/h have been measured [16–18].

Normative data from several studies across North America andEurope are summarized in Table 1 below. These studies show thatin healthy children, CAs are not associated with significant oxygendesaturation [16–19] and arousals caused by central apneas arerare in this population [15]. It is important to note that healthyterm infants that are born and reside at high altitude have a higherprevalence of total central indices (median of 12.4/h for 1 montholds) and a high frequency of oxygen desaturation episodes occur-ring with obstructive and central respiratory events [20].

Gastroesophageal refluxPrematurityBronchopulmonary dysplasiaEpilepsyTetralogy of Fallot

CSA with miscellaneous conditionsBehavioral hyperventilationEpilepsyHigh Altitude

SUMMARY

Based on the normative data shown, the authors recommend that aCAI greater than 5/h, with CAs occurring in non-REM sleep, associatedwith significant oxygen desaturations and of greater 10 s durationrequire further investigation

Please cite this article in press as: McLaren AT et al. Diagnosis, management a(2018), https://doi.org/10.1016/j.prrv.2018.07.005

Central sleep apnea in children with underlying disorders

The prevalence of CSA ranges between 4 and 6% in children[3,4]. Studies that have looked at CSA (using a cut-off of >5/h) inchildren with underlying conditions is summarized in Table 1.

In their retrospective chart review, Kritzinger et al. [3] reviewed969 children aged between 3 months to 13 years (median age 19months) who underwent an overnight PSG. Of these, 52/969(5.4%) patients had a CAI of >5/h. The commonest cause of CSA inpatients who were not preterm was an underlying neurologic dis-order. In another retrospective study, Felix and colleagues [4], intheir cohort of 441 patients found that 18/441 (4.1%) had a CAIof >5/h. Neurosurgical disorders particularly Arnold–Chiari malfor-mations were the most common cause of CSA in their cohort andoccurred in four of the eighteen patients. Arnold–Chiari malforma-tions are one of the most frequently reported neuroanatomicalconditions with a frequency of CSA that ranges between 17 and

nd pathophysiology of central sleep apnea in children. Paediatr Resp Rev


4 A.T. McLaren et al. / Paediatric Respiratory Reviews xxx (2018) xxx–xxx

34% [21–24]. Surgical decompression may improve the CAI in thesepatients [25]. Similarly, White and colleagues assessed sleep in 17children with achondroplasia who had an MRI study. A CAI >5/hwas found in 6/17 children. CSA is also common in infants withPWS, occurring in up to 53% in one cohort [26,27]. Central apneasoccur mostly in REM sleep and in some infants can cause markedhypoxia [28]. Beyond two years of age, CSA is less common andOSA predominates in this population [26].

In Down syndrome, the prevalences of CSA and hypoventilationare increased [29,30]. CSA correlates with very young age (0–3years) [29] and central apneas may occur in long and regularsequences showing a periodic pattern and accompanied by signif-icant oxygen desaturation in the absence of upper airway pathol-ogy [30]. In children with Down syndrome and adenotonsillarhypertrophy, adenotonsillectomy may improve the incidence ofCSA [31]. This has been found to be the same for healthy childrenthat undergo adenotonsillectomy [5,6] suggesting overlapping

Fig. 1. Schematic explanation of the different mechanisms contributing to CSA. The grayrepresent the different disorders with CSA. The central pentagonal shape represents CSventilatory defect and PaCO2 changes. CHF = Congestive heart failure, NMD = Neuromuscuonset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysreg


pathophysiologic mechanisms of OSA and CSA. In obese children,BMI may be predictive of central apnea [32,33]. CSA is also a com-plication of brain tumors and it has been reported in children withgangliomas and CNS tumors of the medulla [4,34].

Pediatric classification of CSA

In adults, CSA is commonly categorized based on wakefulnessCO2 levels into hypercapnic and non-hypercapnic CSA based onthe steady-state PaCO2 (normal range is 35–45 mmHg) being abovethe upper limit of normal or within the low range respectively [9].For the purposes of this review, pediatric CSA can be divided intophysiologic, idiopathic and CSA with specific medical conditionsas illustrated in Table 2 [9]. Physiologic CSA is considered normalsleep phenomena. This category includes central apneas that occurwith sleep onset, post-arousal, post-sigh, phasic REM sleep andbodymovement. The majority of central apneas in healthy children

central shapes with large dashed lines represent the plant system. The dashed boxesA with the three primary mechanisms leading to its occurrence; controller defect,lar disease, CCHS = Congenital central hypoventilation syndrome, ROHHAD = Rapid-ulation.




occurs after a movement or sigh and will not be scored on an over-night polysomnogram (PSG) [37]. Idiopathic central sleep apnea(ICSA) occurs when there are symptoms of sleep disorderedbreathing such as restless sleep, daytime sleepiness, frequentnight-time awakenings and daytime sleepiness and PSG featuresof CSA without Cheyne-Stokes breathing (CSB), hypoventilationor an underlying medical condition [1]. Central apneas occur aspart of a central hypoventilation syndrome which can either beinherited as in CCHS and late-onset congenital central hypoventila-tion (LO-CCHS). It can also be acquired, for example in childrenwith Arnold–Chiari malformations [9]. CSA can co-occur with othersleep disorders particularly OSA in both healthy children and chil-dren with other underlying conditions.

Clinical presentation of pediatric CSA

The clinical presentation of CSA can vary from an incidentalfinding in an asymptomatic child to frank apneas and hypersomno-lence in others [3,4]. Many children with a PSG diagnosis of CSAhave been found to be asymptomatic such as children with chronickidney disease, Arnold–Chiari malformations [ACM], achon-droplasia and Down syndrome [3,4,38]. On the contrary, in somecases, a child may present with symptoms of a sleep relatedbreathing disorder that is not supported by PSG findings. Thiswas illustrated in children with dilated cardiomyopathy thatsnored significantly more than controls but had no increased OAHIor CAHI scores or SDB frequency [36].

In children with ICSA, sleep complaints are common andinclude snoring, respiratory pauses, gasping, restless sleep, fre-quent night-time awakenings and daytime sleepiness [39]. Similarsymptoms have been reported in patients with Chiari malforma-tions [40,41] sometimes in the context of a normal neurologicalexamination [41,42].

In patients with CCHS, presentation is usually in the neonatalperiod with infants exhibiting shallow breathing, cyanosis andfrank central apneas suggestive of hypoventilation and hypoxemia[8]. Sleep disordered breathing can range in severity. In the milderpresentation, patients have hypoventilation during non-REM sleepwith adequate ventilation during wakefulness. More severe venti-latory abnormalities are complete apnea during sleep and severehypoventilation during wakefulness. In the latter case, patientstend to have longer PARMs and NPARMs [8]. The ventilatory abnor-malities in Individuals with LO-CCHS usually have a milder pheno-type and a particular genotype (PHOX2B PARM 20/24 or 20/25) [8].

Fig. 2. Schematic summary of the physiological changes in ventilation during sleep. As shfrom wakefulness. Post arousal CSA will occur if the PaCO2 crosses the apnea threshold


Patients can present either in childhood, adolescence or adulthoodwith unexplained seizures during sleep, respiratory depressionwith infections or after anesthesia and further, with unexplainedpersistent hypoxemia [8].

In summary, CSA in children cannot be reliably identified or diag-nosed on the basis of history, nor a specific set of signs and symptoms

Consequences of pediatric CSA

CSA-associated complications are not as well defined as in OSA.However, it has been suggested that the pathologic effect of multi-ple episodes of hypoxia, reoxygenation, apnea and arousals in OSAcan be extrapolated to CSA [43]. These effects include but are notlimited to sympathetic nervous system activation; oxidative stressand systemic inflammation. In adults, an important CSA-associatedcomplication is the increased risk of adverse cardiovascular out-comes likely mediated by sympathetic nervous system activationand impaired cardiac autonomic control [1]. In one study with 53otherwise healthy children, mean age of 9.4 years, O’Driscoll andcolleagues observed that movement-related central apneas wereassociated with significant changes in heart rate (HR) and bloodpressure (BP) measurements during the occurrence of centralevents in sleep. Children with OSA had increased movementrelated central apneas compared to children without OSA. In a sep-arate study in children with cardiomyopathy, (n = 21, median age10.7 years), the number of central events correlated with left ven-tricular indices but the consequence of CSA in children with co-existing heart conditions is unclear [38].

Pathophysiology of central sleep apnea

The control of breathing during wakefulness, sleep transitionand stable sleep is a highly integrated process. This process canbe simplified by the controller theory [44] (Fig. 1). As in any system(plant), there is a reference (thermostat) that determines the idealset point of the system (e.g., PaCO2), the sensor, and the centralcontroller that acts through the system’s effectors (e.g., respiratorymuscles) where the information is executed.

Chemoreceptors

During wakefulness, PaCO2, is tightly controlled by variousinputs from neural and chemical receptors to keep PaCO2 levelsnear 40 mmHg [45]. Chemoreceptors provide tonic stimulus to

own, with progression in sleep, new PaCO2 level will be established that is differentupon returning back to sleep state.




breathe in order to minimize PaCO2 fluctuation [46]. The centralchemoreceptors play an important role in adjusting ventilation inresponse to the acid–base changes within the brain. One of themajor sites of the CO2 chemoresponsiveness is the parafacial retro-trapezoid nucleus (RTN), where paired-like homeobox 2B gene(PHOX2B) is strongly expressed by glutamatergic interneurons[47]. This gene has a strong implication in the pathogenesis ofsome CSA syndromes like congenital central hypoventilation syn-drome (CCHS) [48]. This will be discussed in more detail below.

The peripheral chemoreceptors, carotid bodies and aortic bod-ies, above and below the aortic arch, are the primary sensors forchanges in the partial pressure of arterial oxygen (PaO2), and to a

Fig. 3. Algorithmic approach to management of pediatric CSA. In healthy children, diagrecommend a brain and spine MRI as the primary investigation following a PSG diagnotreatment of CSA, depending on the patients’ medical condition, symptoms, and severityto the specific underlying medical condition. Complex high-risk patients require special aWilli Syndrome, neuromuscular disease, congenital heart disease, achondroplasia, Arnography, TFT = Thyroid function test, NIPPV = Non-invasive positive pressure ventilationMaximum expiratory pressures, ECG = Electrocardiogram, EEG = Electroencephalogram, Ptilation syndrome, ROHHAD = Rapid-onset obesity with hypothalamic dysregulation, hy


lesser extent to hypercapnia and acidosis [49]. Signals from thosechemoreceptors rapidly transfer to the controller (medulla) viathe glossopharyngeal nerve resulting in a change in the minuteventilation [50].

Wakefulness drive and sleep transition

The wakefulness stimuli to breathe mainly function through theinvoluntary excitation involving the suprapontine systems [51]. Itcan influence wakefulness breathing patterns irrespective of thevarying degrees of PaCO2 values [52]. However, during sleep tran-sition difference in breathing control during wakefulness and sleep

nostic testing should be performed in a step-wise manner and the authors wouldsis of CSA. Personalized and targeted therapeutic interventions are required for theof CSA and long-term goals of care. Ancillary diagnostic testing needs to be targetedttention as they are at higher risk for developing CSA, e.g., Down Syndrome, Prader–ld–Chiari malformation and pulmonary arterial hypertension. ECHO = Echocardio-, PFT = Pulmonary function test, MIPS = Maximum inspiratory pressures, MEPS =HOX2B = Paired-like homeobox 2b, Trach = Tracheostomy, OHS = Obesity hypoven-poventilation, and autonomic dysregulation.



Fig. 3 (continued)


may result in ventilatory instability (Fig. 2). With sleep onset, thereis a loss in the behavioral and wakeful stimuli as well as metabolicregulation. As the sleep deepens and transitions into REM sleep,there is widespread muscle atonia and a reduction in upper airwaydilator muscle tone leading to instability of ventilatory controlwith further reduction in ventilatory response to hypoxia andhypercapnia [53]. This will cause a gradual rise in PaCO2 (3–8mmHg above the wake eucapnic level); establishing a new sleepspecific PaCO2 set point (�45 mmHg) [45]. Central apneas willensue if the PaCO2 falls below, which is usually 2–6 mmHg lowerthan the eucapnic sleeping level (apnea threshold) [54].Fig. 3.

Arousals

With arousal, the sleeping PaCO2 set point (�45 mmHg) rapidlyshifts to the wakefulness level (�40 mmHg) creating a state of rel-ative hypercapnia and the wakefulness drive to breathe is reintro-


duced leading to hyperventilation. Upon resumption of sleep thearousal induced-ventilatory response leads to reduced PaCO2 suchthat central apnea may ensue, if the hypocapnea is sufficient tocross the apnea threshold.

Loop gain

Is an engineering concept adopted in the early 1980s [55] todescribe a feedback system, through the plant gain (i.e., PaCO2

changes in response to ventilation) and the controller gain (i.e.,ventilatory response to PaCO2). As described by Younes et al., indi-viduals with high loop gain are more prone to ventilatory instabil-ity, hence periodic breathing [56]. To further explain the loop gainmodel, Malhotra et al. [57], used the thermostat analogy; in a roomwith an excessively sensitive thermostat, there will be a significantfluctuation in the room temperature with a minimal change in setpoint. As in humans, chemosensitivity is variable between individ-




uals and this might lead to respiratory disturbances in people withmore robust system [58].

Summary and recommendations

CSA is relatively rare in healthy children. When it does occur, itis usually in the context of an underlying medical condition, mostcommon of which are neuroanatomical abnormalities. A CAI of >5/h is a reasonable threshold to define clinically significant CSA.Because children may be asymptomatic, those at high risk forCSA should be screened. In healthy children with a PSG diagnosisof CSA, we suggest MRI evaluation to assess for neuroanatomicalabnormalities. In other children with specific underlying medicalconditions, further testing should be directed to the specificcondition.

DIRECTIONS FOR FUTURE RESEARCH

Although CSA is relatively uncommon in childhood, it is likelyunder diagnosed. Future research should be directed at identifyingrisk factors for CSA and promoting timely screening of at riskpatient populations. While there have been some studies lookingat the pathophysiology of CSA in specific conditions in children,further studies are needed to define the mechanisms of CSA.Finally, it would be important to understand the natural courseof CSA from childhood to adulthood and to identify the outcomesof treatment of CSA downstream.

REFERENCES

[1] AASM. Central Sleep Apnea Syndromes. International Classification of SleepDisorders. Darien, IL: American Academy of Sleep Medicine; 2014. pp. 69–107.

[2] Berry R, Brooks R, Garnaldo C, Hardig S, Lloyd R, Quan S, et al. The AASMmanual for the scoring of sleep and associated events: rules, terminology andtechnical specifications. 2017.

[3] Kritzinger FE, Al-Saleh S, Narang I. Descriptive analysis of central sleep apneain childhood at a single center. Pediatr Pulmonol 2011;46(10):1023–30.

[4] Felix O, Amaddeo A, Olmo Arroyo J, Zerah M, Puget S, Cormier-Daire V, et al.Central sleep apnea in children: experience at a single center. Sleep Med2016;25:24–8.

[5] Baldassari CM, Kepchar J, Bryant L, Beydoun H, Choi S. Changes in central apneaindex following pediatric adenotonsillectomy. Otolaryngology Head Neck Surg2012;146(3):487–90.

[6] Boudewyns A, Van de Heyning P, Verhulst S. Central apneas in children withobstructive sleep apnea syndrome: prevalence and effect of upper airwaysurgery. Sleep Med 2016;25:93–7.

[7] Waters KA, Everett FM, Bruderer JW, Sullivan CE. Obstructive sleep apnea: theuse of nasal CPAP in 80 children. Am J Respir Crit Care Med 1995;152(2):780–5.

[8] Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA,Trang H. An official ATS clinical policy statement: congenital centralhypoventilation syndrome: genetic basis, diagnosis, and management. Am JRespir Crit Care Med 2010;181(6):626–44.

[9] Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3(1):141–63.

[10] Carroll JL, Donnelly DF. Respiratory physiology and pathophysiology duringsleep. In: Sheldon SH, Ferber R, Kryger M, Gozal D, editors. Principles andPractice of Pediatric Sleep Medicine. Elsevier; 2014.

[11] Stokowski LA. A primer on Apnea of prematurity. Adv Neonatal Care 2005;5(3):155–70. quiz 71–74.

[12] Brockmann PE, Poets A, Poets CF. Reference values for respiratory events inovernight polygraphy from infants aged 1 and 3 months. Sleep Med 2013;14(12):1323–7.

[13] Schlüter B, Buschatz D, Trowitzsch E. Polysomnographic reference curves forthe first and second year of life. Somnologie. 2001.

[14] Marcus CL, Omlin KJ, Basinki DJ, Bailey SL, Rachal AB, Von Pechmann WS, et al.Normal polysomnographic values for children and adolescents. Am Rev RespirDis. 1992;146(5 Pt 1):1235–9.

[15] Scholle S, Wiater A, Scholle HC. Normative values of polysomnographicparameters in childhood and adolescence: cardiorespiratory parameters. SleepMed 2011;12(10):988–96.

[16] Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographiccharacteristics in normal preschool and early school-aged children. Pediatrics2006;117(3):741–53.


[17] Verhulst SL, Schrauwen N, Haentjens D, Van Gaal L, De Backer WA, Desager KN.Reference values for sleep-related respiratory variables in asymptomaticEuropean children and adolescents. Pediatr Pulmonol 2007;42(2):159–67.

[18] Traeger N, Schultz B, Pollock AN, Mason T, Marcus CL, Arens R.Polysomnographic values in children 2–9 years old: additional data andreview of the literature. Pediatr Pulmonol 2005;40(1):22–30.

[19] Uliel S, Tauman R, Greenfeld M, Sivan Y. Normal polysomnographic respiratoryvalues in children and adolescents. Chest 2004;125(3):872–8.

[20] Duenas-Meza E, Bazurto-Zapata MA, Gozal D, Gonzalez-Garcia M, Duran-Cantolla J, Torres-Duque CA. Overnight Polysomnographic Characteristics andOxygen Saturation of Healthy Infants, 1 to 18 Months of Age, Born andResiding At High Altitude (2,640 Meters). Chest 2015;148(1):120–7.

[21] Patel DM, Rocque BG, Hopson B, Arynchyna A, Bishop ER, Lozano D, et al.Sleep-disordered breathing in patients with myelomeningocele. J NeurosurgPediatr. 2015;16(1):30–5.

[22] Amin R, Sayal P, Sayal A, Massicote C, Pham R, Al-Saleh S, et al. The associationbetween sleep-disordered breathing and magnetic resonance imaging findingsin a pediatric cohort with Chiari 1 malformation. Can Respir J. 2015;22(1):31–6.

[23] Waters KA, Forbes P, Morielli A, Hum C, O’Gorman AM, Vernet O, et al. Sleep-disordered breathing in children with myelomeningocele. J Pediatr 1998;132(4):672–81.

[24] 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(6):445–52.

[25] Pomeraniec IJ, Ksendzovsky A, Yu PL, Jane Jr JA. Surgical History of Sleep Apneain Pediatric Patients with Chiari Type 1 Malformation. Neurosurg Clin N Am2015;26(4):543–53.

[26] Cohen M, Hamilton J, Narang I. Clinically important age-related differences insleep related disordered breathing in infants and children with Prader-WilliSyndrome. PLoS One 2014;9(6):e101012.

[27] Khayat A, Narang I, Bin-Hasan S, Amin R, Al-Saleh S. Longitudinal evaluation ofsleep disordered breathing in infants with Prader-Willi syndrome. Arch DisChild 2017;102(7):638–42.

[28] Urquhart DS, Gulliver T, Williams G, Harris MA, Nyunt O, Suresh S. Centralsleep-disordered breathing and the effects of oxygen therapy in infants withPrader-Willi syndrome. Arch Dis Child 2013;98(8):592–5.

[29] Fan Z, Ahn M, Roth HL, Li L, Vaughn BV. Sleep apnea and hypoventilation inpatients with down syndrome: analysis of 144 polysomnogram studies.Children (Basel) 2017;4(7).

[30] Ferri R, Curzi-Dascalova L, Del Gracco S, Elia M, Musumeci SA, Stefanini MC.Respiratory patterns during sleep in Down’s syndrome: importance of centralapnoeas. J Sleep Res 1997;6(2):134–41.

[31] Thottam PJ, Choi S, Simons JP, Kitsko DJ. Effect of Adenotonsillectomy onCentral and Obstructive Sleep Apnea in Children with Down Syndrome.Otolaryngology–head and neck surgery: official journal of American Academyof Otolaryngology-Head and Neck. Surgery. 2015;153(4):644–8.

[32] Verhulst SL, Schrauwen N, Haentjens D, Suys B, Rooman RP, Van Gaal L, et al.Sleep-disordered breathing in overweight and obese children and adolescents:prevalence, characteristics and the role of fat distribution. Arch Dis Child2007;92(3):205–8.

[33] Kohler M, Lushington K, Couper R, Martin J, van den Heuvel C, Pamula Y, et al.Obesity and risk of sleep related upper airway obstruction in Caucasianchildren. Journal of clinical sleep medicine: JCSM: official publication of theAmerican Academy of Sleep Medicine. 2008;4(2):129–36.

[34] Rosen GM, Bendel AE, Neglia JP, Moertel CL, Mahowald M. Sleep in childrenwith neoplasms of the central nervous system: case review of 14 children.Pediatrics 2003;112(1 Pt 1):e46–54.

[35] White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V. Is there a correlationbetween sleep disordered breathing and foramen magnum stenosis in childrenwith achondroplasia? Am J Med Genet A 2016;170(1):32–41.

[36] Al-Saleh S, Kantor PF, Chadha NK, Tirado Y, James AL, Narang I. Sleep-disordered breathing in children with cardiomyopathy. Annals of theAmerican Thoracic Society. 2014;11(5):770–6.

[37] O’Driscoll DM, Foster AM, Ng ML, Yang JS, Bashir F, Wong S, et al. Centralapnoeas have significant effects on blood pressure and heart rate in children. JSleep Res 2009;18(4):415–21.

[38] Amin R, Sharma N, Al-Mokali K, Sayal P, Al-Saleh S, Narang I, et al. Sleep-disordered breathing in children with chronic kidney disease. Pediatr Nephrol2015;30(12):2135–43.

[39] Gurbani N, Verhulst SL, Tan C, Simakajornboon N. Sleep Complaints and SleepArchitecture in Children With Idiopathic Central Sleep Apnea. J Clin Sleep Med2017;13(6):777–83.

[40] Keefover R, Sam M, Bodensteiner J, Nicholson A. Hypersomnolence and purecentral sleep apnea associated with the Chiari I malformation. J Child Neurol1995;10(1):65–7.

[41] Murray C, Seton C, Prelog K, Fitzgerald DA. Arnold Chiari type 1 malformationpresenting with sleep disordered breathing in well children. Arch Dis Child2006;91(4):342–3.

[42] Losurdo A, Dittoni S, Testani E, Di Blasi C, Scarano E, Mariotti P, et al. Sleepdisordered breathing in children and adolescents with Chiari malformationtype I. J Clin Sleep Med 2013;9(4):371–7.

[43] Costanzo MR, Khayat R, Ponikowski P, Augostini R, Stellbrink C, Mianulli M,et al. Mechanisms and clinical consequences of untreated central sleep apneain heart failure. J Am Coll Cardiol 2015;65(1):72–84.


http://refhub.elsevier.com/S1526-0542(18)30061-7/h0005
































































































































[44] Batzel JJ, Tran HT. Stability of the human respiratory control system. I. Analysisof a two-dimensional delay state-space model. J Math Biol 2000;41(1):45–79.

[45] Skatrud JB, Dempsey JA, Badr S, Begle RL. Effect of airway impedance on CO2retention and respiratory muscle activity during NREM sleep. J Appl Physiol1988;65(4):1676–85.

[46] Blain GM, Smith CA, Henderson KS, Dempsey JA. Contribution of the carotidbody chemoreceptors to eupneic ventilation in the intact, unanesthetized dog.J Appl Physiol 2009;106(5):1564–73.

[47] Nattie E, Li A. Central chemoreceptors: locations and functions. Compr Physiol2012.

[48] Amiel J, Laudier B, Attié-Bitach T, Trang H, de Pontual L, Gener B, et al.Polyalanine expansion and frameshift mutations of the paired-like homeoboxgene PHOX2B in congenital central hypoventilation syndrome. Nat Genet2003;33(4):459–61.

[49] Dempsey JA, Smith CA, Blain GM, Xie A, Gong Y, Teodorescu M. Role of central/peripheral chemoreceptors and their interdependence in the pathophysiologyof sleep apnea. Arterial Chemoreception: Springer; 2012. p. 343–9.

[50] Burton MD, Kazemi H. Neurotransmitters in central respiratory control. RespirPhysiol 2000;122(2):111–21.


[51] Moosavi S, Paydarfar D, Shea S. Suprapontine control of breathing. LUNGBIOLOGY IN HEALTH AND DISEASE. 2005;202:71.

[52] Fink BR. Influence of cerebral activity in wakefulness on regulation ofbreathing. J Appl Physiol 1961;16(1):15–20.

[53] Fogel RB, Trinder J, White DP, Malhotra A, Raneri J, Schory K, et al. The effect ofsleep onset on upper airway muscle activity in patients with sleep apnoeaversus controls. The Journal of physiology. 2005;564(2):549–62.

[54] Dempsey JA. Crossing the apnoeic threshold: causes and consequences. ExpPhysiol 2005;90(1):13–24.

[55] Khoo M, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing periodicbreathing in humans: a general model. J Appl Physiol 1982;53(3):644–59.

[56] Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemicalcontrol stability in patients with obstructive sleep apnea. Am J Respir Crit CareMed 2001;163(5):1181–90.

[57] Malhotra A, Owens RL. What is central sleep apnea? Respiratory care. 2010;55(9):1168–78.

[58] Weil J. Variation in human ventilatory control—genetic influence on thehypoxic ventilatory response. Respir Physiol Neurobiol 2003;135(2):239–46.








































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