Respiratory support in patients with Down syndrome: a systematic review

Abstract

Background

The population with Down syndrome (DS) makes up a significant portion of patients using short- and long-term noninvasive ventilation (NIV). However, limited data are available concerning the use and outcomes for patients with DS compared with other populations. We systematically reviewed articles providing indications, benefits, adherence and limits of long-term NIV use in the paediatric and adult population with DS.

Methods

A systematic review of the literature for articles published between January 2013 and November 2023 was conducted using a protocol registered at PROSPERO (CRD42023488712).

Results

In total, 18 studies focusing on the use of noninvasive respiratory support in patients with DS were included in this review. Obstructive sleep apnoea syndrome (OSAS), OSAS post-adenotonsillectomy, hypoventilation and nocturnal hypercapnia were the most common indications for NIV support in patients with DS. However, respiratory anatomical malformation and intellectual disabilities can affect adherence to NIV use. High-flow nasal cannula is an alternative to other noninvasive respiratory support.

Conclusion

Comprehensive and updated consensus compliant with international standards for clinical guidelines is required to significantly improve clinical practice quality, promote evidence-based recommendations and provide tailored interventions in patients with DS.

Shareable abstract

Limited data are available on the use and outcomes of long-term NIV for adults and children with Down syndrome (DS) compared with the non-DS population. This review summarises the literature in DS, identifying benefits, limits and future perspectives. https://bit.ly/3YAiko2

Introduction

Down syndrome (DS) (Trisomy 21) is the most prevalent chromosomal condition associated with intellectual disability and impacts multiple organ systems, including the respiratory system [1].

The involvement of the respiratory system displays several manifestations in patients with DS. Both the upper and lower airways may be affected, spanning from the nasopharynx and trachea to the alveolar spaces, involving vascular and lymphatic vessels [2].

Common upper and lower airway issues in DS include macroglossia, adenotonsillar hypertrophy, laryngomalacia, smaller and narrow trachea, tracheo- and bronchomalacia, tracheal–bronchus obstruction, ciliopathies, and impaired mucus production [3–6].

Moreover, oedema in the soft tissues of the upper away and altered regulatory control of pharyngeal muscles, in addition to reduced activity in the respiratory centres, increase the incidence of obstructive sleep apnoea syndrome (OSAS), interstitial lung diseases, pulmonary hypertension and lung infections in patients with DS [7–11].

Regarding lower airway alterations, children with DS could have up to a 25% decrease in the number of alveoli and in branch generation number [11, 12]. Moreover, impairment in respiratory blood vessels, such as an immature double capillary network, and lymphatic vessels predisposes patients with DS to pulmonary hypertension, pulmonary haemosiderosis, pulmonary capillaritis and lymphangiectasia [13–16]. Lastly, patients with DS have a high incidence of congenital heart diseases, such as atrioventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot and acquired valvular heart disease, further negatively impacting the pathophysiology of cardiorespiratory failure [4].

Impaired mucociliary clearance and failure to adequately clear bacteria and mucus, pulmonary hypoplasia, enlarged alveolar airspaces, and subpleural cysts have also been described and linked to lung infections, which occur frequently in individuals with DS since they are also affected by immune disorders [12].

All these features can contribute to higher morbidity and mortality for pulmonary causes in individuals with DS [2, 17]. More than 54% of hospitalisations are due to lung infections. Children (aged 2–7 years) with DS are more likely to be hospitalised for acute lower tract respiratory infections and respiratory syncytial virus-associated bronchiolitis than children without DS [18, 19]. Influenza and pneumonia, pneumonitis, and respiratory failure are the most common causes of deaths among patients with DS [17].

Accordingly, the use of continuous positive airway pressure (CPAP) and noninvasive mechanical ventilation (NIV) in life-threatening and chronic scenarios is common, as it provides a constant positive pressure in the airways, aiming to maintain airway patency, as well as supports the patient's breathing by delivering a supplemental higher positive pressure during each inspiration. Nevertheless, NIV use in patients with DS deserves particular attention and requires multidisciplinary management for optimal patient care.

This review aims to summarise the literature relevant to NIV use in children and adult patients with DS, identifying benefits, limits and future perspectives.

Materials and methods

Literature review

We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) statement [20] and including articles published between January 2013 and November 2023. We registered the protocol of our systematic review at PROSPERO (CRD42023488712).

Two reviewers (P.R. and S.M.) independently conducted searches of electronic medical literature databases, such as PubMed, Global Health and Embase. The search strategy used by each reviewer is detailed in supplementary appendix S1. Manual searches of the current literature were also performed by referring to the Web of Science, Google Scholar, BMJ Best Practice, National Institute for Health and Care Excellence, and World Health Organization. The following variations and terms were used: “Down Syndrome”, “Trisomy 21”, “Respiratory failure”, “Noninvasive respiratory support”, “Noninvasive mechanical ventilation”, “High flow nasal cannula”, “HFNC”, “Continuous positive airway pressure”, “CPAP”, “Obstructive sleep apnoea”, “OSA”, “Sleep disordered breathing”, “Child”, “Children”, “Adolescent” and “Adult”. Lastly, selected references of included articles were searched to find any other relevant documents in accordance with the inclusion criteria.

Eligibility criteria

Inclusion criteria were any language, publication in peer-reviewed journals, children, adolescents and adults who have been diagnosed with DS or Trisomy 21 and requiring respiratory support, guidelines meta-analyses, systematic reviews, reviews, original articles, case series, case reports, and letters.

Exclusion criteria were guidelines, meta-analyses, systematic reviews, reviews, original articles, case series, case reports and letters not focusing on the population with DS and requiring respiratory support.

Article review

Two independent reviewers (P.R. and S.M.) performed data extraction using standard templates to report recommendations on the use of noninvasive respiratory support in patients with DS. Articles were excluded by title, abstract or full text for irrelevance to the investigated issue.

Results

18 studies focusing on the use of noninvasive respiratory support in patients with DS were included in this review (supplementary appendix S2).

Results of the search

A total of 105 records were identified through the search strategy. After an accurate evaluation of eligibility criteria, 18 studies (reviews and cohort studies) were included in the systematic review, focusing on noninvasive respiratory support and DS in the paediatric and adult populations (figure 1).

FIGURE 1.

Flowchart of the literature search and study inclusion.

Characteristics of the included studies

The included studies were published between 2013 and 2023 (supplementary appendix S2). The characteristics of the included studies, such as authors, year of publication and type of study, are reported in supplementary appendix S2. Risk of bias is reported in supplementary appendix S3. The list of the excluded articles is reported in supplementary appendix S4.

Among the 18 articles included, two were reviews, one was a statement, eight were retrospective studies and seven were prospective studies. Specifically, five articles focused on indications for long-term NIV in children with DS, two articles focused on respiratory anatomical malformation and its impact on NIV efficacy, two articles investigated intellectual disability impact on NIV adherence, seven articles analysed factors influencing the use and lack of adherence to CPAP and NIV in children with DS, and two articles focused on high-flow nasal cannula (HFNC) use in children with DS. Overall, 779 patients with DS were analysed. Data on mean age and gender cannot be provided since healthy and DS patients, paediatric and adult patients were included in the same sample. Also, in many articles, age range and gender were not reported; thus, a “balance of probabilities” assessment was based on the reported mean age and gender.

Indications for long-term NIV in children and adults with DS

The indications for NIV support in patients with DS are OSAS, OSAS post-adenotonsillectomy, OSA with preference for nonsurgical treatment, hypoventilation or nocturnal hypercapnia, defined by a nocturnal arterial carbon dioxide tension >50 mmHg during ≥2% of nocturnal sleep time or >5 consecutive minutes [21–23].

Anatomical airway abnormalities in patients with DS significantly increase the incidence of OSAS, with a childhood prevalence ∼50–100% and nearing 100% in adulthood [10, 24–27]. In a retrospective study cohort involving 35 children, Adeleye et al. [28] aimed to 1) identify the associated conditions of patients <12 months of age who were referred for PSG studies; 2) collate PSG findings and physician interpretation; and 3) determine adherence with noninvasive PAP treatment. 38% of the enrolled population had a diagnosis of DS; agreement between the PSG-interpreting physician's recommendation and actual prescribed treatment by the referring or subjects’ physician was 85.9%; adherence with noninvasive PAP treatment was low.

For severe OSAS, adenotonsillectomy is the preferred therapeutic option [24, 29]. Nevertheless, the surgical procedure appears significantly less effective in patients with DS compared with non-DS patients [30]. Approximately 30–50% of patients with DS and treated with adenotonsillectomy continue to have either persistent or recurrent OSA. Accordingly, NIV has become a cornerstone in the long-term treatment of OSA in the population with DS [21].

On the other hand, van den Broek et al. [31], in their prospective study, reported the feasibility and the effectiveness of CPAP therapy also in treating OSA in patients with DS. Specifically, of 39 enrolled patients, 87% after 8–10 weeks and 70% at 8 months still used CPAP, of whom 74% and 77%, respectively, showed acceptable adherence. Baseline apnoea–hypopnoea (AHI) index decreased from 41.2 to 5.3 events·h⁻¹ after 8–10 weeks (p<0.001) and 4.3 events·h⁻¹ after 8 months (p<0.001) with a significant improvement also in the most restrictive reported complaint, difficulty waking up, handling behaviour, presence of irritability and sleepiness. Similar findings were reported by Hill et al. [32] that, in their pilot randomised, parallel controlled trial for 1 month, enrolling 28 adult participants, showed a significant improvement in pictorial Epworth Sleepiness Scale and disruptive, anxiety/antisocial and depressive behaviour scores. Moreover, improvement was also noted in verbal and nonverbal intelligence scores and in general health scores [32].

Table 1 lists articles focusing on indications for long-term NIV in patients with DS.

TABLE 1.

Articles focusing on indications for long-term noninvasive ventilation in patients with Down syndrome (DS)

First author [ref.]	Type of study	Patients with DS (n)	Age	Aim	Main findings
Maris [25]	Retrospective cross-sectional study	122	5.2 (2.8–10.7) years	To evaluate the prevalence of OSA in a large cohort of children with DS and to investigate which patient-related factors correlate with disease severity	An overall 66.4% prevalence of OSA was found in children with DS; even in those with a negative history for OSA, the prevalence was 53.8%; younger age was associated with more severe disease
Fitzgerald [26]#	Retrospective study	33	4.9 (0.2–19) years	To consider whether PSG should be recommended as a routine test in children with DS who snored, by reviewing their diagnostic overnight polysomnograms	97% demonstrated OSA, with an average AHI of 12.9 events·h−1 (normal=1) and an average oxygen desaturation of 4%; therefore, PSG should be a routine investigation for children with DS who snore
Trois [10]#	Observational study	16	33 (19–56) years	To investigate whether OSAS is common in adults with DS and to compare the severity of OSAS in adults with DS who are more obese	Adults with DS frequently have OSAS; the severity of OSAS correlated with obesity; OSAS is an important, but potentially treatable, cause of morbidity in adults with DS, because of the complication of untreated OSAS
Fan [27]	Retrospective study	144	7.6 (0.1–45.4) years	To study how obstructive OSA and CSA evolve with age in patients with DS and whether patients are also at risk for hypoventilation	78% of patients had SDB, with an average AHI of 10 events·h−1; hypoventilation occurred in >22% of patients; the obstructive component increased significantly with age and BMI, while the central component occurred most in the very young age group
Shete [30]#	Retrospective study	11	101 months	To determine if adenotonsillectomy in children with DS improves breathing, and sleep disruption, and to compare these results with a group of non-DS children with OSA	Adenotonsillectomy in children with DS improves some parameters of OSA (such as AHI), but not as markedly as in non-DS children
Adeleye [28]	Retrospective cohort study	35	186.0 (130.2–277.0) days (entire study population)	To identify the associated conditions of patients <12 months of age who were referred for PSG studies; to collate PSG findings and physician interpretation; to determine the correlation between the recommended treatment by the PSG-interpreting physician and actual prescribed treatment by the referring or subjects’ physician; to determine adherence with noninvasive PAP treatment	38% of the entire study population had a diagnosis of DS; median AHI was 22.5 events·h−1; agreement between the PSG-interpreting physician's recommendation and actual prescribed treatment by the referring or subjects’ physician was 85.9%; adherence with noninvasive PAP treatment is low
van den Broek [31]	Prospective study	7	Not stated	Primary end-points: CPAP adherence and clinical effects of CPAP therapy; secondary end-points: to explore other effects of CPAP therapy (based on the questionnaires) and reasons for not starting CPAP treatment despite an indication for CPAP therapy	Overall, 87% of patients after 8–10 weeks and 70% of patients at 8 months used CPAP, all with acceptable adherence; baseline AHI decreased significantly (p<0.001); a significant improvement was detected in complaint, difficulty waking up, handling behaviour, presence of irritability and sleepiness (p<0.01); CPAP use in the first 2 weeks predicted adherence at 8–10 weeks and 8 months (r=0.51, p<0.01 and r=0.69, p<0.01); the expectation that CPAP would not be tolerated was the main reason for not starting; the reasons for stopping CPAP included behavioural problems, comorbid insomnia, anxiety, discomfort or other side-effects
Hill [32]	Prospective study	28	28±9 years	To assess the effectiveness and acceptability of CPAP in adults with DS and OSAS, with reference to subjective sleepiness, behavioural and emotional function, cognitive function, and general health	Participant pESS (p=0.001) and disruptive (p<0.0001), anxiety/antisocial (p=0.024) and depressive (p=0.008) behaviour scores were reduced compared with baseline; improvement was noted in verbal (p=0.001) and nonverbal intelligence scores (p=0.011); general health scores also improved (p=0.02); at the end of the trial, 19 participants continued on treatment

OSA: obstructive sleep apnoea; PSG: polysomnography; AHI: apnoea–hypopnoea index; OSAS: obstructive sleep apnoea syndrome; CSA: central sleep apnoea; SDB: sleep disordered breathing; BMI: body mass index; PAP: positive airway pressure; CPAP: continuous positive airway pressure; pESS: pictorial Epworth Sleepiness Scale. ^#: these articles did not meet the inclusion criteria (see supplementary appendix S4), but are included in this table in order to underline and reinforce some of the concepts discussed in the main text.

Respiratory anatomical malformation and its impact on NIV efficacy

While CPAP provides a constant positive pressure in the airways aiming to maintain airway patency, bilevel ventilation in addition provides respiratory support at two different levels, thus it is possible to separately adjust a lower expiratory positive airway pressure (CPAP and positive end-expiratory pressure (PEEP)) and a higher inspiratory positive airway pressure (positive inspiratory pressure) [33].

Commonly, NIV or CPAP are started in a hospital setting and continued at the patient's home; thus, a bad experience at the beginning of therapy could lead to poor adherence to NIV/CPAP, especially in the long-term [34].

The specific anatomical features of patients with DS, such as flat nasal bridge, nuchal folds, obesity and macroglossia, are the most common reasons for discontinuing NIV use. The anatomy of the ears makes it challenging to secure the lower strap of the mask, resulting in a higher tendency to lie on the ear. Therefore, the mask's belt may be tied to reduce air leaks, causing functional retrognathism, skin injuries and worsening ventilator–patient compliance, especially in patients requiring long-term NIV use.

Moreover, midfacial and mandibular hypoplasia, glossoptosis with relative macroglossia, frequent adenotonsillar hypertrophy, muscle hypotonia, pharynx-laryngomalacia, and subglottic and/or tracheal stenosis may further impact the establishment of NIV respiratory support in patients with DS [35].

In conclusion, interface side-effects are mainly caused by pressure (skin damage, facial deformity) or by improper fitting (leaks, mucosal drying, corneal ulcers), so we recommend spending more time choosing the right interface, preferring adjustable masks or custom-made masks to conform to the DS patient's face, considering that the most frequent reason for CPAP/NIV intolerance or failure is interface issues [21].

Table 2 lists articles focusing on respiratory anatomical malformation and its impact on NIV efficacy in patients with DS.

TABLE 2.

Articles focusing on respiratory anatomical malformation and its impact on noninvasive ventilation efficacy in patients with Down syndrome (DS)

First author [ref.]	Type of study	Patients with DS (n)	Age	Aim	Main findings
Dudoignon [35 ]	Retrospective study	57	4.0 (0.2–24.7) years	To describe the management of OSA in a large cohort of children with DS	32% had prior upper airway surgery; the prevalence of OSA is high in DS, AHI was 14±16 events·h−1; 33% of patients required noninvasive respiratory support, which was associated with an improvement in nocturnal gas exchange
Zenteno [34]	Retrospective study	11	1.5 (0.6–2.2) years	To describe a 6-year experience in a paediatric prolonged mechanical ventilation unit, analysing lengths of stay and readmissions	Longer lengths of stay and more readmissions were observed in children with neurological damage and DS (p=0.004)

OSA: obstructive sleep apnoea; AHI: apnoea–hypopnoea index.

Impact of neurological, cognitive and psychiatric comorbidities on NIV adherence

Neurobehavioral and psychiatric comorbidities in children with DS range from 18% to 38%. Among behavioural comorbidities, heightened motor activity and impulsivity, tendencies toward noncompliance or tantrums, restlessness, anxiety or disruptive behaviour, repetitive movements, distinctive patterns of sensory responsiveness, neurocognitive processing that deviates from the typical, and, more rarely, a lack of interest in social interaction are described [36]. Variable degrees of developmental delay and hypotonia are consistently observed in all individuals with DS. Most of the population with DS exhibits an Intelligence Quotient indicating mild (50–70) to moderate (35–50) intellectual disability [37]. Children with DS consistently score lower in motor skills, adaptive functioning, feeding, toilet training, sleep patterns and social development. In particular, motor development in individuals with DS typically takes approximately twice as long as in the average child. Challenges in language and communication arise due to speech delay, poor articulation related to a narrow oral cavity and difficulties in language comprehension [38, 39]. Notably, an increasing number of individuals with DS are being identified with autistic traits characterised by peculiar, stereotyped behaviours, anxiety and social withdrawal [40]. Approximately 7% of individuals with DS may exhibit signs of autism as early as 2 or 3 years of age [41]. Other neurodevelopmental issues include seizures and moyamoya disease [42].

Seizures occur more frequently in patients with DS than in the age-matched general population [43, 44]. Remarkably, nearly 100% of individuals with DS display neuropathological features associated with Alzheimer's disease by the age of 40 years [45]. All the aforementioned neurological, cognitive and psychiatric comorbidities significantly impact the management of respiratory disorders, such as night-time apnoea, thus affecting adherence and compliance to NIV respiratory support [38, 39, 46]. The cognitive deficits may manifest in difficulties understanding and following treatment instructions, adjusting to the use of CPAP equipment, and maintaining consistent usage throughout the night [47]. Caregivers and healthcare providers face the challenge of addressing these cognitive barriers to ensure effective and sustained CPAP therapy for individuals with DS. Tailored interventions and support strategies are crucial in overcoming the cognitive hurdles associated with the management of night-time apnoea in this population, ultimately improving the overall quality of sleep and long-term health outcomes. Supportive interventions, educational interventions and behavioural therapy have proven their efficacy to improve CPAP compliance in adult patients with normal cognitive function [47]. Accordingly, parental noncompliance often arises from the emotional stresses associated with the recommended treatment. Starting NIV can be challenging and emotionally taxing as parents/caregivers continually strive to balance concerns about the treatment, its effectiveness and its duration [48].

Table 3 lists articles focusing on the impact of intellectual disability on NIV adherence in patients with DS.

TABLE 3.

Articles focusing on the impact of intellectual disability on noninvasive ventilation adherence in patients with Down syndrome (DS)

First author [ref.]	Type of study	Patients with DS (n)	Age	Aim	Main findings
Svensson [46]	Population-based, longitudinal study	64	27 (22–41) years	To compare patient characteristics and outcomes of CPAP treatment for patients with OSA with and without DS	OSA severity was substantially higher in patients with DS despite an increased rate of tonsil surgery (higher AHI and ESS score), but lower use of cardiovascular drugs; at follow-up after 1.3±0.9 years there were no differences in nocturnal CPAP usage time and CPAP adherence
Brooks [39]	Observational study	25	10.2 years (DS+OSA)/10.1 years (DS without OSA) (7.2–18.7 years)	To determine whether sleep and SDB contribute to the neuropsychological deficits of patients with DS, and whether treatment of SDB results in improvement in cognitive function	Clinical findings did not predict the presence of sleep apnoea; there was no difference in any of the neuropsychological tests between the children who did and did not have OSA; cardiorespiratory parameters measured on PSG were not associated with neuropsychological function; rather, measures of the quantity and quality of sleep, particularly slow-wave sleep, were better predictors of neuropsychological function

CPAP: continuous positive airway pressure; OSA: obstructive sleep apnoea; AHI: apnoea–hypopnoea index; ESS: Epworth Sleepiness Scale; SDB: sleep disordered breathing; PSG: polysomnography.

Factors influencing the use and lack of adherence to CPAP and NIV in individuals with DS

Although the minimal time to therapeutic effect has not been unanimously defined in the literature, it is a common clinical assumption to define “adherence” as the use of NIV for at least 4 h per night on 70% of nights within 1 month [49]. In particular, adherence to CPAP/NIV is a significant issue that remains unresolved, especially in patients with DS, a cluster of patients in which the literature evidence is not unanimous. In children with DS, Brooks et al. [39] have shown poor compliance to respiratory support due to their intellectual disability. MacDonagh et al. [38] showed that adherence to NIV in children with DS is satisfactory compared with non-DS children; however, children with DS with known congenital cardiac disease who underwent cardiac surgery had lower adherence compared with DS children without a history of cardiac surgery [50].

Specifically, MacDonagh et al. [38], in a retrospective cohort study involving 106 children with confirmed OSA, found satisfactory NIV adherence in children with DS (n=44) compared with the non-DS cohort (n=62). Dudoignon et al. [35] and Trucco et al. [51] found similar results. Recently, in a longitudinal study on patients initiating CPAP therapy, Svensson et al. [46] found that adherence and daytime sleepiness were comparable between patients with DS and the control group. These findings were in line with results from two recently published studies reporting no differences in terms of CPAP adherence between DS, individuals with an intellectual disability (including DS) and the control group [52, 53].

Table 4 lists articles focusing on factors influencing the use and lack of adherence to CPAP and NIV in patients with DS.

TABLE 4.

Articles focusing on factors influencing the use and lack of adherence to continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV) in patients with Down syndrome (DS)

First author [ref.]	Type of study	Patients with DS (n)	Age	Aim	Main findings
Dudoignon [35]	Retrospective study	57	4.0 (0.2–24.7) years	To describe the management of OSA in a large cohort of children with DS	32% had prior upper airway surgery; the prevalence of OSA is high in DS, AHI was 14±16 events·h−1; 33% of patients required noninvasive respiratory support, which was associated with an improvement of nocturnal gas exchange
Svensson [46 ]	Population-based, longitudinal study	64	Not stated	To compare patient characteristics and outcomes of CPAP treatment for patients with OSA with and without DS	OSA severity was substantially higher in patients with DS despite an increased rate of tonsil surgery (higher AHI and ESS score), but lower use of cardiovascular drugs; at follow-up after 1.3±0.9 years there were no differences in nocturnal CPAP usage time and CPAP adherence
Brooks [39]	Observational study	25	10.2 years (DS+OSA), 10.1 years (DS without OSA) (7.2–18.7 years)	To determine whether sleep and SDB contribute to the neuropsychological deficits of patients with DS, and whether treatment of SDB results in improvement in cognitive function	Clinical findings did not predict the presence of sleep apnoea; there was no difference in any of the neuropsychological tests between the children who did and did not have OSA; cardiorespiratory parameters measured on PSG were not associated with neuropsychological function; rather, measures of the quantity and quality of sleep, particularly slow-wave sleep, were better predictors of neuropsychological function
Landete [53]	Observational study	114	35.7±10 years	To determine the prevalence of OSA in a large sample of adults with DS, and its relationship with determinants including BMI, the severity of the disease and its response to CPAP treatment	All 114 patients with DS were diagnosed with OSA, with a predominance of obstructive and hypopnoea events; CPAP tolerance was considered good in 75%, with a high compliance resulting in a symptomatic improvement in 58.7%; treatment with CPAP in DS is feasible, and with higher adherence than in adults with normal cognitive functioning
MacDonagh [38]	Retrospective study	44	4.76±7.92 years	To measure adherence and efficiency of NIV delivery in children with DS	Significantly greater NIV usage was observed in the DS cohort, with an increased percentage of days used relative to their non-DS counterparts; however, the DS cohort had poorer clinical outcomes in the form of increased AHI and excessive system leak at the machine–patient interface
Trucco [51]	Retrospective, cohort study	60	1.5 (0.7–5.3) years	To characterise other forms of SDB (not only OSA) in children with DS and to assess the effectiveness and adherence to respiratory support	There is a high prevalence of OSAS in children with DS; other forms of SDB are central apnoeas and nocturnal hypoventilation; a significant number also have low baseline saturations, central apnoea and nocturnal hypoventilation, which correlates with pulmonary hypertension; contrary to popular belief, more than half of children with DS had satisfactory adherence to respiratory support
Luijks [52]	Retrospective study	3	40±14 years (entire study population)	To evaluate the feasibility of CPAP therapy in adults with different intellectual disabilities, by comparing to age- and sex-matched adults with normal cognitive functioning	Using an intensive training protocol, it is very well feasible to apply CPAP therapy in OSA patients with any degree of intellectual disability; CPAP adherence in intellectual disability patients was comparable to the control patients

OSA: obstructive sleep apnoea; AHI: apnoea–hypopnoea index; ESS: Epworth Sleepiness Scale; SDB: sleep disordered breathing; PSG: polysomnography; BMI: body mass index; OSAS: obstructive sleep apnoea syndrome.

HFNC as an alternative respiratory support

HFNC was first used in clinical settings in the early 2000s as an alternative to CPAP for treating apnoea in premature neonates [54]. Due to its feasibility and safety, HFNC has quickly gained popularity as a respiratory support modality in paediatric care. HFNC delivers a constant oxygen concentration, producing PEEP [55], reducing breathing work and eliminating the nasopharyngeal dead space [56]. Regarding the population with DS, there is a lack of randomised controlled trials comparing HFNC with NIV and CPAP, so this respiratory support remains a second-choice treatment.

Sparse case reports have shown that HFNC oxygen therapy with a standard CPAP device or a nasal RAM Cannula (Neotech) interface with a NIV device can be used successfully for children with DS who cannot tolerate noninvasive respiratory support [57–59].

During the coronavirus disease 2019 (COVID-19) pandemic, HFNC, CPAP and NIV have been life-saving supports even in patients with DS, a population well known for developing severe infection by severe acute respiratory syndrome coronavirus 2 due to their clinical characteristics and immune dysregulation [60–66]. Accordingly, HFNC, NIV and CPAP helmet ventilation were commonly performed in patients with DS with severe COVID-19 pneumonia [60–66].

Table 5 lists articles focusing on HFNC use in patients with DS.

TABLE 5.

Articles focusing on high-flow nasal cannula (HFNC) use in patients with Down syndrome (DS)

First author [ref.]	Type of study	Patients with DS (n)	Age	Aim	Main findings
Amaddeo [57]	Prospective study	6	8.9±6.2 years (entire study population)	To evaluate the compliance (hours of use per night) and the improvement of OSA on respiratory polygraphy with HFNC after 1 month of use in children not compliant with home CPAP therapy	HFNC may be used as a rescue therapy for children not compliant with CPAP
Overbergh [58]	Prospective study	2	5 and 9 years	To evaluate the use of the HFNC attached to a regular CPAP device in the setting of chronic CPAP use	Use of CPAP with the HFNC interface resulted in a significant decrease in obstructive AHI, total AHI and a trend for an increase in SaO2 nadir

OSA: obstructive sleep apnoea; AHI: apnoea–hypopnoea index; CPAP: continuous positive airway pressure; S_aO2: arterial oxygen saturation.

Limitations of the review

The most prominent limitation of this systematic review is the type of the individual studies, which were mainly retrospective and observational. Therefore, although this review provides a summary of current evidence, it cannot provide any recommendations. Also, the heterogeneity of the subject groups and limited outcome data precluded meta-analysis.

Conclusions

Patients with DS represent a sizeable group requiring NIV. Despite this, there are limited data on the use and outcomes of this technology in patients with DS. Moreover, risk of bias due to study design, confounding variables, differences in type of respiratory support, limited consideration of adherence to NIV and loss of patients to follow-up is high.

Overall, it is clear how the complexity of patients with DS requires special attention. This need is not only due to their predisposition to have more cardiorespiratory diseases and recurrent respiratory infections but also to anatomical characteristics that can make the application of mechanical ventilation devices challenging. The necessity of a multidisciplinary approach involving careful screening programmes, especially regarding intellectual disabilities, ear, nose and throat examination, assessment of OSA and nocturnal hypoventilation, as well as a cardiac evaluation, is crucial for effectively managing this condition. The availability of more advanced equipment, a shift in perspective toward home care and growing acceptance of noninvasive respiratory support as a valid treatment alternative are all potential factors contributing to a rise in the use of these noninvasive respiratory supports. Moreover, investment in understanding factors that may impact adherence early in the process of initiation and prospective studies of outcomes are needed to reduce the challenges and optimise NIV use in patients with DS.

Additional work is urgently required to understand potential challenges around establishing NIV use in children and adults with DS.

Points for clinical practice

• A satisfactory NIV adherence is achievable in patients with DS with the help of cognitive support by assistive technology.

Supplementary material

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