Accepted Manuscript

Title: Obstructive Sleep Apnea and Pulmonary Hypertension

in Children

Authors: David G. Ingram, Alvin V. Singh, Zarmina Ehsan,

Brian F. Birnbaum

PII: S1526-0542(17)30002-7
DOI: http://dx.doi.org/doi:10.1016/j.prrv.2017.01.001
Reference: YPRRV 1192

To appear in: YPRRV

Please cite this article as: Ingram David G, Singh Alvin V, Ehsan Zarmina, Birnbaum
Brian F.Obstructive Sleep Apnea and Pulmonary Hypertension in Children.Paediatric
Respiratory Reviews http://dx.doi.org/10.1016/j.prrv.2017.01.001

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Obstructive Sleep Apnea and Pulmonary Hypertension in Children

David G Ingram, MD1, Alvin V Singh, MD1, Zarmina Ehsan, MD1, Brian F Birnbaum, MD2

Affiliations: 1Divisions of Pulmonary and Sleep Medicine and 2Cardiology, Children’s Mercy

Hospital, 2401 Gillham Road, Kansas City, MO.

Address correspondence to: David G Ingram, MD, Division of Pulmonary and Sleep Medicine,

Children’s Mercy Hospital, 2401 Gillham Road, Kansas City, MO, 64108, dgingram@cmh.edu,

phone: 816-983-6644, fax: 816-983-6626.

Running head: Pulmonary Hypertension and Obstructive Sleep Apnea.

The reader will come to appreciate:

1. The mechanisms of altered pulmonary hemodynamics in children with obstructive sleep

apnea.
2. The current evidence for the co-occurrence and treatment of obstructive sleep apnea and
pulmonary hypertension in children.
3. A set of relevant suggested actions in selected clinical scenarios when caring for children
with OSA and/or pulmonary hypertension.

Future directions for research:

1. Assess the true prevalence of pulmonary hypertension in children with obstructive sleep
apnea and vice versa.
2. Evaluate the effect of obstructive sleep apnea treatment on pulmonary hemodynamics.
3. Identify risk factors for pulmonary hypertension among children with obstructive sleep
apnea and develop cost-effective screening strategies.

1
Summary

Obstructive sleep apnea (OSA) is a common pediatric breathing disorder, affecting 1-5% of all

children. Pulmonary hypertension (PH), a severe complication of OSA, is associated with

significant morbidity and mortality. Despite this important relationship between OSA and PH,

there is sparse literature addressing this subject in children. This review will examine the

putative relationship between OSA and PH, synthesize the available literature in children, and

suggest a reasonable approach, despite limited data, for clinicians. We conclude that available

evidence suggests many children with OSA have evidence of PH (estimates ranging from 0% to

85%) and vice versa (estimates ranging from 6% to 24%). Furthermore, previous studies

demonstrate that treatment of the OSA, either with surgery or non-invasive ventilation,

ameliorates pulmonary artery pressures to the extent of cure in a substantial number of cases.

Future studies are required to better delineate the true co-occurrence of these diseases and help

predict which patients are at greater risk for this serious complication. Clinicians who maintain a

healthy vigilance for this important interaction of disease states will likely recognize

opportunities to intervene and improve prognoses in these patients.

Keywords: Pulmonary hypertension, obstructive sleep apnea, sleep-disordered breathing.

Introduction

Obstructive sleep apnea (OSA) is a relatively common disorder, affecting 1-5% of all children,

and is associated with deleterious health effects [1]. Furthermore, children with selected

2
conditions with features that predispose to OSA, such as Down syndrome or Prader Willi

syndrome, are at substantially increased risk of OSA with a prevalence up to 70-80% [2,3] and

lower surgical cure rates [4–6]. While OSA has been associated with much morbidity, including

learning/behavioral problems, growth problems, and cardiovascular complications [1], one of the

most potentially serious complications is pulmonary hypertension (PH). Untreated pulmonary

hypertension in children can lead to right heart failure with decreased cardiac output and may

contribute to increased morbidity and mortality [7]. While the precise prevalence of PH in

children is not well known, children with chronic cardiopulmonary conditions such as cystic

fibrosis, sickle cell disease, bronchopulmonary dysplasia, and congenital heart disease are at

higher risk [7]. In contrast to adults [8,9], there is a relative paucity of literature regarding OSA

and PH in children and, to the best of our knowledge, no recent reviews. Therefore, in the current

article we review the putative relationship between OSA and PH, synthesize the available

literature in children, and suggest a reasonable approach for clinicians caring for these children

in the face of limited data.

Putative Relationship between OSA and Pulmonary Hypertension

Pulmonary arterial hypertension is a chronic disorder of the pulmonary vasculature,

characterized by a progressive increase in pulmonary vascular resistance that can lead to right

heart failure and death [10]. The definition for children with pulmonary hypertension (PH) uses

the same criteria as in adults; mean pulmonary artery pressures (mPAP) 25 mmHg as measured

via cardiac catheterization at rest; furthermore, if the pulmonary artery capillary wedge pressure

is ≤ 15 mmHg and pulmonary vascular resistance (PVR) >3 Wood units, this identifies that PH

as pre-capillary in nature [11]. Patients with mPAP between 21 and 25 mmHg are at risk for

3
developing frank PH. Etiologies of PH are classified according to the Nice classification system

(Table 1) [12]. OSA is part of Group 3 PH, which primarily deals with disease of the respiratory

system. The adult literature largely supports a significant association between OSA and PH [13].

Echocardiography is one method to monitor the severity of PH, most commonly by evaluating

the tricuspid regurgitant jet velocity (TRJV) in order to estimate a pulmonary artery pressures in

children. Cardiac catheterization can be used to obtain a mean pulmonary artery pressure (the

gold standard). This requires sedation and often anesthesia, which greatly affects cardiac and

pulmonary blood flow and pressure estimates when compared to a crying and agitated child who

is undergoing echocardiography. Sometimes, TRJV can be under or over-estimated which may

affect the estimation of PAP one makes [14].

Establishing the prevalence of PH in adults with OSA is difficult due to variability in diagnostic

methods [9]. Increased prevalence of PH in adults with OSA has been described. In a group of

220 patients with OSA diagnosed by polysomnography (AHI > 20/hour), 17% had PH [as

diagnosed by mPAP ≥ 20 mmHg via right heart catheterization (RHC)]. This study did not

utilize the current threshold for PH diagnosis of mPAP 25 mmHg, but pressures of 21-24 mmHg

may be considered borderline [11]. Adults with PH also had increased lung obstruction

(decreased FEV1/FVC), increased PaCO2, decreased PaO2, decrease mean arterial overnight

oxygen saturation and increased BMI [15].

Conversely, the prevalence of sleep apnea in adults with PH has also been evaluated. One study

examined 169 patients with PH, diagnosed by RHC (with NYHA classification II and III - stable

disease), and evaluated them for sleep apnea with polysomnography. Approximately 27% of

4
these patients had an AHI > 10/hour, with 16% having OSA and 11% having central sleep apnea.

The mean AHI for this group was 20 episodes per hour [16]. Therefore, adults with PH have a

high prevalence of OSA, and adults with OSA have an increased risk of acquiring PH [9].

Physiologically, upper airway obstruction causes alveolar hypoxia, increasing pulmonary

vascular resistance and precapillary pulmonary artery pressures [8]. Pulmonary blood flow is

further increased by the negative intrathoracic pressure generated against a closed upper airway.

This increase in venous return (and subsequent right ventricular preload and stroke volume)

shifts the interventricular septum to the left, thereby reducing left ventricular compliance. This

contributes to an increase in pulmonary venous pressure [8]. In children who have smaller

airways, even small decreases in the radius of their airways can greatly increase resistance which

may have deleterious effects on their cardiopulmonary system.

On a molecular level, animal models have shown that intermittent episodes of hypoxia act on

multiple factors. The factors responsible for structural and pressure modifications within the

pulmonary vasculature include hypoxia-inducible factor-1 (HIF-1) and its secondary messengers,

erythropoietin and vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) [17]. It

has been reported that impaired function of these factors leads to endothelial dysfunction through

the presence of altered nitric oxide (NO) dependent vasodilation responses in patients with OSA.

OSA is also known to increase the formation of C reactive protein (CRP) in the liver, as well as

the formation and release of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and

tumor necrosis alpha (TNF-ɑ) and promote the release of leptin and adipokines. Circulating

monocytes are also activated which then express monocyte chemotactic protein (MCP-1) which

5
causes increased adhesion on the endothelial cell surface and reduce the expression and activity

of endothelial nitric oxide synthase (eNOS) and promote apoptosis [18]. These changes promote

endothelial dysfunction and limit the capacity of NO-induced vasodilation within the pulmonary

vasculature. These deleterious effects from OSA increase the systemic inflammatory pattern

within the body which causes a more directed effect in the cardiovascular system and the

pulmonary vasculature. Various biomarkers, particularly highly sensitive CRP (hsCRP) and IL-

6 have been implicated as possible markers in adults and children with OSA, which further

argues that OSA causes a systemic inflammatory state within the body [19]. In order to

understand the basic mechanisms that are caused by intermittent hypoxia, studies at the cellular

level with multiple cells from different systems within the body should be conducted [20].

Review of the Literature in Children

Co-occurrence of OSA and PH in Children

The co-occurrence of OSA and PH has been recognized for quite some time (see Tables 2 and 3

for the most informative studies). Dement and colleagues presented a series of patients with

sleep apnea and found an association between respiratory events and pulmonary arterial pressure

changes; the sample included two children that subsequently underwent tracheostomy [21]. A

series of 11 children with OSA and PH were reported by Hunt and Brouillette [22], and a larger

series was reported by Miman and colleagues [23].

Studies from national registries are informative in determining the prevalence of OSA among

children with PH. Data from a cardiac referral center in the Netherlands included 63 cases of PH

which were reviewed, and of those cases, 15 (24%) were found to have obstructive upper airway

6
breathing disorders. Eight of those cases (13%) had PH which was reversible after treatment of

the obstruction [24]. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension

(TOPP) multinational registry (n=362) found that 6% of children with PH had sleep-related

breathing disorder [25]. A Spanish PH registry of 225 patients found that 8.5% had OSA [26].

Despite the substantial number of children with PH who also have OSA, a recent analysis of the

TOPP registry found that only 15% of those children had undergone polysomnography [27].

Prevalence estimates of PH within OSA vary widely (Table 2). One study examined 45 children

with sleep-disordered breathing, and 13% were diagnosed with PH (defined by estimated systolic

pulmonary artery pressure >30mmHg) [28]. Likewise, a cross-sectional study in children with

clinical sleep-disordered breathing found a 22% prevalence of PH (defined by estimated mPAP

>25mmHg) [29]; that study also found daytime mouth breathing, stertor, and an adenoid-

nasopharynx ratio >0.75 to be predictors of its presence. Several studies out of Turkey examining

pulmonary artery pressures in children with sleep-disordered breathing and adenotonsillar

hypertrophy found a much higher prevalence, with over half of children having evidence of PH

(defined by estimated mPAP >20mmHg) [30–32]. It should be noted, that the current acceptable

definition of PH is a mPAP > 25 mmHg, not 20 mmHg, and the above studies used a clinical

diagnosis of sleep-disordered breathing rather than a PSG diagnosis of OSA. Conflicting results

have been found regarding any association between sleep-disordered breathing symptom severity

and pulmonary artery pressures [28,31,32]. Multiple single case reports also highlight the

relationship between OSA and PH [33–36]. One single retrospective study of 55 children with

PSG-defined OSA who underwent echocardiography preoperatively did not find any evidence of

7
PH or other cardiac disease; however, estimated pulmonary artery pressures were not reported

and no control group was included [37].

Children with Down syndrome are vulnerable to both PH and OSA. Approximately 50-75% of

children with Down syndrome have sleep apnea [38], with prevalence increasing to 97% among

those who snore [39]. The increased prevalence of OSA in this population is likely due to a

combination of factors, including relative hypotonia, macroglossia, high arched palate,

craniofacial features with midface hypoplasia, and increased prevalence of obesity [40]. In a

seminal paper by Loughlin and colleagues [41], five cases of children with Down syndrome and

co-occurring OSA and PH were presented. All five children had right ventricular hypertrophy

and PH that was thought to be out of proportion with their congenital heart disease. During sleep,

these children were observed to have multiple episodes of airway obstruction, and a subset of

these patients had elevated pulmonary artery pressures during sleep which improved upon

awakening or intubation. Four additional cases were reported shortly after, with all cases

presenting in infancy with heart failure in association with chronic upper airway obstruction

during sleep [42]. Further evidence for a direct relationship between elevated pulmonary artery

pressure and upper airway obstruction during sleep was found in three children with Down

syndrome and ventricular septal defect; in two out of three of these children, all of whom had PH

and clinical sleep-disordered breathing, pulmonary artery pressures decreased immediately with

intubation to relieve the airway obstruction [43]. There are several additional case reports

documenting co-occurring PH and OSA in this population [44–46].

Prader-Willi syndrome is a genetic disorder due to chromosomal abnormalities in 15q11-q13,

with a prevalence of about 1 in 10,000 live births. Children with Prader-Willi syndrome are at

8
high risk for obstructive sleep apnea due to obesity, craniofacial abnormalities, and hypotonia. A

recent review found that the prevalence of OSA among children with Prader-Willi across 14

studies was 79% [3]. Furthermore, about 35% were found to have narcolepsy, possibly related to

underlying hypothalamic dysfunction [3,47]. These children are known to have abnormal

ventilatory responses to hypercapnia and hypoxia, in that they are absent or reduced, even

independent of degree of obesity [47]. Importantly, untreated severe OSA may contribute to the

increased risk of sudden death following growth hormone initiation, so currently it is

recommended that all children with Prader Willi obtain a screening polysomnogram prior to

initiation of growth hormone [48]. Germaine to this review, there is a case report of an obese

child with Prader-Willi syndrome with PH associated with OSA [49]; the child improved with

non-invasive ventilation as well as low caloric diet over time. Treatment of OSA with

adenotonsillectomy has been shown to be beneficial, although rates of residual disease are higher

compared to typically developing children [3].

Co-occurring PH and OSA has been described in children with other syndromes as well. A 20-

month old child with pycnodysostosis syndrome (an inherited disorder of bone growth) was

found to have OSA on PSG, and subsequently developed PH [50]; the high rate of OSA in this

population is likely related to associated craniofacial features [51]. A case report of a two year

old ex-32 week preemie with a history of bronchopulmonary dysplasia documented PH and

OSA, requiring urgent placement of nasopharyngeal airway for stabilization and resulted in

immediate improvement in cardiac function [52]. There are multiple reports of children with

mucopolysaccharidoses developing right heart failure and PH in association with OSA [53–55],

with airway obstruction likely due to deposition of glycosaminoglycans in the upper airway.

9
Children with achondroplasia are known to be at increased risk sleep-disordered breathing for a

variety of reasons, including midface hypoplasia, reduced nasopharyngeal space, restrictive lung

disease, and foramen magnum stenosis [56]; prior studies have demonstrated effective treatment

with both surgery and positive airway pressure [57]. A 5 year old child with achondroplasia was

reported to have co-occurring PH and OSA [58]. A child with pulmonary atresia who was status

post Blalock-Taussig shunt presented with progressive cyanosis and was found to have PH and

clinical sleep-disordered breathing, both of which resolved with tonsillectomy [59]. The

mandibular hypoplasia associated with fibrodysplasia ossificans progressiva has been shown to

cause OSA with associated PH [60]. While the multiple case reports outlined above do suggested

association between PH and OSA in those populations, they do not prove causality.

Given the known high prevalence of PH in patients with sickle cell disease, one would

hypothesize that OSA may play a role in this population. Ambrusko and colleagues examined all

children with sickle cell disease who had undergone echocardiography at their institution (n=44),

and found that 29% had an elevated TRJV; there were a greater percentage of children in the

elevated TRJV group with OSA and/or tonsillar hypertrophy (45% vs 16%), although this did

not reach statistical significance [61]. A subsequent prospective study demonstrated elevated

TRJV in 46% of children with sickle cell disease, but concomitant pulmonary disease did not

predict its presence [62]; it should be noted that the authors combined OSA with asthma, reactive

airway disease, and acute chest syndrome in their analysis. Sedrak and colleagues [63]

performed a similar prospective study of children with sickle cell disease, and specifically

assessed for OSA with nap PSG if clinical history was suggestive; of 48 children, 3 had histories

suggestive of OSA, 2 had documented OSA on PSG, and none of the three had PH. An

10
additional analysis of 44 children with sickle cell disease utilized formal overnight

polysomnography and, although there was a relationship between nocturnal oxygenation and left

ventricular abnormalities, there was no relationship between sleep variables and TRJV [64].

Taken together, previous studies examining OSA and PH in children with sickle cell disease do

not consistently support an association.

Finally, one case report strikingly illustrates the potential danger of untreated OSA and PH [65].

An 18-year-old girl with congenital severe micrognathia presented in heart failure. She was

noted to snore loudly and have inspiratory stridor upon falling asleep. Although admitted and

treated with diuretics for her heart failure, she died in her sleep in hospital three days later. The

presumed cause of death was a respiratory arrest.

Effect of Treatment of OSA on PH in Children

Longitudinal studies assessing the cardiovascular outcomes of pediatric OSA are limited and the

majority of evidence on PH in the context of OSA consists of case reports and series. A series of

17 children with co-occurring OSA and PH underwent adenoidectomy and/or tonsillectomy, and

at 3 months follow-up all children had normalized pulmonary pressures [23]. In a series of 11

children with OSA and PH, all underwent surgical treatment with either adenotonsillectomy

and/or tracheostomy with subsequent resolution of PH [22]. Two larger samples of children with

clinically diagnosed sleep-disordered breathing in Turkey demonstrated improved pulmonary

arterial pressures following either adenoidectomy alone [66] or adenotonsillectomy [30]. Four

infants with Down syndrome, OSA, and PH underwent adenotonsillectomy and/or tracheostomy

with marked clinical improvement in PH reported [42]. Two children with Down syndrome, PH,

11
and clinical sleep-disordered breathing had dramatic clinical improvement with tonsillectomy

[43]. Two children, a 5 month and 15 month old, with Down syndrome and OSA with PH

improved after tracheostomy and adenotonsillectomy, respectively [45]. Tracheostomy was

curative in a child with pycnodysostosis syndrome and OSA/PH [50], and adenotonsillectomy

resolved PH in a child with achondroplasia and OSA [58]. There are also several single case

reports of PH resolving or dramatically improving with tonsillectomy [33–36,44,52,59,67].

However, not all cases had favorable outcomes following surgical treatment of OSA. One

important illustration of this is a case reported by Eipe and colleagues of an 11 year old girl with

Down syndrome, PH, and OSA [46]. Despite being on multiple medical therapies for her PH, she

continued to clinically deteriorate. Therefore, she underwent adenotonsillectomy for mild OSA

(apnea hypopnea index of 2.9 per hour with a nadir of 89%). Intraoperatively, the patient had

moderate hemodynamic instability. Six months postoperatively, although the patient had less

severe dyspnea, she had increased pulmonary artery pressure and worsened OSA (apnea

hypopnea index 6 per hour). The patient was placed on CPAP, resulting in stabilization of OSA

and PH and improvement in her exercise capacity. This case highlights the complexity of

intraoperative management of these patients and the importance of postoperative assessment for

residual disease. Furthermore, while adenotonsillectomy is generally considered first line therapy

for OSA, children with craniofacial or neuromuscular disorders may have multiple sites of

obstruction and may benefit from careful airway evaluation with sleep endoscopy. Especially in

the Down syndrome population, the success of adenotonsillectomy is fair at best. In one study of

36 children, only two had complete resolution of OSA (AHI< 1) [4].

12
Non-surgical treatment has also been found to be effective, although there are fewer reports in

the literature. A child with Prader-Willi syndrome who was treated with oxygen, non-invasive

positive pressure, and weight loss had resolution of PH [49]. The PH associated with OSA in

multiple children with mucopolysaccharidoses has been shown to respond well to CPAP [53].

Finally, a case report of a 6 year old child with fibrodysplasia ossificans progressiva

demonstrated resolution of PH after three months treatment of OSA with BiPAP [60].

Mechanisms of Altered Pulmonary Hemodynamics in Children with OSA

Several studies have also examined potential mechanisms underlying the relationship between

PH and OSA in children. Gozal and colleagues demonstrated impaired endothelial function

assessed via cuff occlusion and soluble CD40 ligand, which can be an important

pathophysiologic mechanism in PH, in children with OSA that was reversible with

adenotonsillectomy [68]. Duman and colleagues performed a case-control study comparing right

ventricular myocardial performance index (RV MPI; sum of isovolumetric contractions and

relaxation time divided by ejection time - a measure of RV function) in children with or without

adenotonsillar hypertrophy (ATH - defined by 3-4+ tonsils) [32]. The authors found the RV MPI

was significantly higher (worse) in patients with ATH compared to controls, and the RV MPI

normalized to control group levels following adenotonsillectomy. This finding was replicated by

Cincin and colleagues [69]. Among children with sleep-disordered breathing, there seems to be a

strong relationship between the ratio of tonsillar size to pharynx and estimated systolic

pulmonary artery pressure [28]. In addition, adenoid to nasopharynx ratio >0.75 has been shown

to be a predictor of PH among children with sleep-disordered breathing [29]. Among children

with OSA, both CRP levels and AHI correlate with TRJV at baseline and change concomitantly

13
with adenotonsillectomy [70]. O’Driscoll and colleagues compared autonomic responses to

respiratory events during sleep in children with Down syndrome to typically developing children

and found markedly reduced reactivity; they postulated that this impaired response may

exacerbate acute hypoxemia related to OSA and place them at greater risk for PH [71]. Children

with adenotonsillar hypertrophy have been shown to exhibit electromechanical cardiac delays,

reversible with adenotonsillectomy [72].

Suggested Approach

Pulmonary hypertension is an often feared potential complication of OSA. Although the body of

literature examining this association in children is sparse, available studies to-date provide

evidence for an increased risk of OSA among children with PH (estimates ranging from 6 to

24%), as well as increased risk of PH among children with OSA (estimates ranging from 0% to

85%). Most importantly, case reports and case series demonstrate either substantial improvement

or complete resolution of PH when OSA is treated, either surgically or with non-invasive

ventilation.

Although the above literature supports an important interaction between PH and OSA, it should

be noted that the strength of evidence is low. Previous studies examining prevalence of OSA

among children with PH, or PH among children with OSA were limited in size, with none being

population based. Published studies examining treatment outcomes were nonrandomized and

uncontrolled. Finally, there was wide variability in the diagnostic methods and criteria for both

OSA and PH, which makes comparing previous studies to each other difficult.

14
Despite the little evidence provided and limitations discussed above, clinicians are faced with

making important management decisions for patients with OSA and/or PH regularly. The current

state of literature precludes the formation of strong evidence-based recommendations, and this is

reflected by the fact that there is only a single paragraph devoted to discussion of this topic in

one of the most definitive textbooks on pediatric sleep medicine [73]. Given the lack of available

guidance, we provide practical suggestions for clinical practice (outlined in Table 4), which are

not meant to represent a formal guideline or practice parameter but rather opinions based on the

limited available data and clinical judgment.

All children with newly diagnosed PH should undergo screening PSG to evaluate for OSA.

While currently available AASM parameters recommend PSG only if there is clinical concern

for OSA [74], there is convincing evidence that history and clinical examination in the office

setting are not sufficient to predict pediatric OSA [75]. Moreover, given the high prevalence of

OSA within PH (6 to 24%) and the efficacy of OSA treatment, we feel all children with newly

diagnosed PH should undergo OSA screening with overnight in-laboratory PSG.

Second, objective evaluation for OSA in the setting of PH may be more helpful than

symptomatic assessment. This suggestion is based on the observed association between PSG

measures and TRJV at baseline and with treatment, in contrast to the inconsistent relationship

found between pulmonary artery pressures and OSA symptom severity. Subjective assessment

by the parents is quite variable, especially if the child sleeps alone upstairs with the door closed.

Multiple previous studies have also demonstrated that history and physical examination do not

distinguish primary snoring from OSA in children [76–78].

15
Thirdly, among children with known OSA of any severity and a comorbid disorder that places

them at increased risk for PH (e.g. neuromuscular disease, Down syndrome,

mucopolysaccharidoses, etc), we also recommend obtaining an echocardiogram to evaluate for

PH if not previously performed. The finding of PH in these patients should prompt more

aggressive treatment of their OSA, such as continued efforts at CPAP adherence or advanced

sleep apnea surgery in those children with residual disease status post adenotonsillectomy, as

well as careful perioperative management if surgery is planned. While one may feel that

screening for PH as suggested above seems overaggressive and result in unneeded

electrocardiograms, we would suggest that this is actually quite reasonable given the high

prevalence (0% to 85%) PH in OSA and potential associated morbidity; furthermore, there is

precedence for such screening given that annual screening for PH is currently recommended for

adult patients with connective-tissue disease, in which the estimated prevalence of PH is lower at

0.5-15% [81].

Conclusion

Current literature with regards to OSA and PH in children is sparse. The available published

literature largely supports the clinical intuition that OSA causes or worsens PH and that

treatment of the obstruction can resolve or improve PH. Clinicians who maintain a healthy

vigilance for this important interaction of disease states may recognize opportunities to intervene

and benefit their patients. There is still plenty of work to be done, as future work with larger

sample sizes and controlled interventions are required to develop more evidence based

guidelines.

16
Funding source: No funding was secured for this study.

Conflict of Interest: The authors have no conflicts of interest

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21
 Table 1. Nice Classification system.

1. Pulmonary arterial hypertension

1.1 Idiopathic PAH
1.2 Heritable PAH
1.2.1 BMPR2
1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3
1.2.3 Unknown
1.3 Drug and toxin induced
1.4 Associated with connective tissues disease, HIV infection, portal hypertension, congenital
heart diseases, schistosomiasis
1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
1’’ Persistent pulmonary hypertension of the newborn

2. Pulmonary hypertension due to left heart disease

2.1 Left ventricular systolic dysfunction
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart/inflow/outflow tract obstruction and congenital
cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary disease with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders,
splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Other: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

22
 Table 2. Estimated co-occurrence of obstructive sleep apnea and pulmonary hypertension in
children.

Study Sample PH diagnosis OSA diagnosis Prevalence, %

(n)

Yilmaz/2005 Otherwise healthy Echo mPAP Clinical 51% (27/52)

children seen in >20mmHg
ENT clinic for
adenotonsillar
hypertrophy (3 or
4+ tonsils) and
OSA symptoms

Duman/2008 Otherwise healthy Echo mPAP or Clinical Not reported

children seen in sPAP
ENT clinic for Average mPAP
adenotonsillar was 23.8 mmHg
hypertrophy (3 or and average
4+ tonsils) and sPAP was 44
OSA symptoms mmHg (n=21)

Naiboglu/2008 Otherwise healthy Echo mPAP Clinical 85% (33/39)

children seen in >20mmHg
ENT clinic for
adenotonsillar
hypertrophy (3 or
4+ tonsils) and
OSA symptoms

vanLoon/2009 Netherlands PH Cath mPAP Nocturnal 24% (15/63)

registry >25mmHg desaturations,
hypercapnia on
blood gas, and
“obstructive
upper airway
anatomy”

Granzotto/2010 Otherwise healthy Echo mPAP Clinical 13% (6/45)

children seen in >20mmHg or
ENT clinic for sPAP
OSA symptoms >30mmHg

23
Revenaugh/2011 Retrospective Not specified PSG AHI >1/hr 0% (0/55)
review of clinic-
based sample of
children who had
undergone PSG and
echocardiography
prior to T&A for
OSA

Berger/2012 TOPP Registry Cath mPAP Not reported 6% (23/362)

>25mmHg

Marin/2014 Spanish PH registry Cath mPAP Not reported 8% (19/225)

>25mmHg

Orji/2016 Otherwise healthy Echo mPAP Clinical 22% (18/79)

children seen in >25mmHg
ENT clinic for
adenotonsillar
hypertrophy and
OSA symptoms

24
Table 3. Case reports and series of co-occuring obstructive sleep apnea and pulmonary
hypertension in selected syndromes.
Condition N Reference

Down syndrome 5 [41]

Down syndrome 4 [42]

Down syndrome 3 [43]

Down syndrome 1 [44]

Down syndrome 3 [45]

Down syndrome 1 [46]

Prader Willi syndrome 1 [49]

Pycnodysostosis syndrome 1 [50]

Bronchopulmonary dysplasia 1 [52]

Mucopolysaccharidoses 1 [53]

Mucopolysaccharidoses 14 [54]

Mucopolysaccharidoses 13 [55]

Achondroplasia 1 [58]

Pulmonary atresia status post 1 [59]

Blalock-Taussig shunt

Fibrodysplasia ossificans 1 [60]

progressiva

Micrognathia 1 [65]

Table 4. Suggested clinical actions in selected clinical scenarios.

25
Clinical scenario
New diagnosis of PH
Evaluating for OSA in setting
of PH
Treating a child for OSA with
comorbid disorder that places
them at increased risk for PH
(e.g. neuromuscular disease,
Down syndrome,
mucopolysaccharidoses, etc)
Suggested action
PSG to screen for OSA
Objective, rather than
subjective, assessment with
PSG should be performed
Obtain echocardiogram to
screen for PH if not already
performed
26
Rationale
A substantial number of
children with PH (6-24%)
[24–26] have OSA, and
treatment of OSA can cure or
improve PH
There is a strong correlation
between AHI and TR [70], but
inconsistent relationship
between OSA symptoms and
estimated pulmonary artery
pressures [28,31,32]
The finding of PH in these
patients should prompt more
aggressive treatment of their
OSA as well as careful
perioperative management if
surgery is planned