CPAP & NIV in children with complex genetic disorders

Alessandro Amaddeo, Brigitte FaurouxPediatric noninvasive ventilation and sleep unit

Research unit INSERM U 955Necker university Hospital, Paris, France

InsermInstitut nationalde la santé et de la recherche médicale

CPAP & NIV in children with complex genetic disorders

• The respiratory balance• Genetic disorders that may affect the

respiratory balance• Deciphering the respiratory involvement

of genetic disorders• Benefits of CPAP/NIV• Conclusion

The normal respiratory balance

Desequilibrium of the respiratory balance

Physiological changesduring sleep

Sleep

Ventilatorydrive

Respiratorymuscles

Respiratorymechanics

central drive chemoreceptor

sensitivity

preservation of activity of the diaphragm

intercostal muscles upper airway muscle

tone

V/Q mismatch airway resistance

FRC

CPAP & NIV in children with complex genetic disorders

• The respiratory balance• Genetic disorders that may affect the

respiratory balance• Deciphering the respiratory involvement

of genetic disorders• Benefits of CPAP/NIV• Conclusion

Genetic disorders that mayaffect the respiratory balance

Primary abnormality Respiratoryconsequences Diseases

Abnormal ventilatorycontrol

Central apneas Rett syndrome, ROHHADNET syndromePrader Willi syndromeAchondroplasiaStorage diseases: mucopolysaccharidosis

Upper airway obstruction

Obstructive sleep apnea Craniofacial malformationsLaryngotracheal abnormalitiesStorage diseases: mucopolysaccharidosis

Chest deformity Restrictive lung disease Jeune asphyxiating thoracic dystrophyDistal arthrogryposisFibrodysplasia ossificans progressivaOsteogenesis imperfecta,

NeurofibromatosisParenchymal lung disease

Restrictive lung disease Interstitial lung diseases

Central apneas - Necker experience13 patients seen over a one year period

Case Sex Age (years)

Medical conditions CAI AHI MeanSpO2%

Min SpO2%

Mean PtcCO2(mmHg)

Max PtcCO2 (mmHg)

ODI(n/h)

1 F 3.55 Prader Willi 43 44 96 91 39 44 11

2 F 3.95 Prader Willi 19 20 97 87 N/A N/A 20

3 F 11.38 Prader Willi 44 46 96 87 38 42 18

4 M 2.31 ACM 34 36 93 80 37 38 38

5 M 5.16 ACM 12 12 98 87 38 42 6

6 F 5.25 ACM 6 9 95 87 N/A N/A 14

7 M 5.04 CNS tumor 146 160 97 85 37 40 79

8 F 6.47 CNS tumor 11 24 96 84 44 47 23

9 M 10.95 CNS tumor 50 104 96 84 48 53 98

10 M 1.58 Hypothyroidism 13 17 94 84 43 49 27

11 F 4.21 Achondroplasia 11 14 96 80 37 42 8

12 M 1.38 Polymalformative syndrome

21 33 97 82 39 41 31

13 M 15.60 Down syndrome 5 27 94 80 53 62 22

Mean (±SD)

5.914.24

3238

4243

9626

8523

4318

4820

3431

ROHHADNET syndrome

• Rapid-onset obesity• Hypothalamic dysfunction• Hypoventilation• Autonomic dysregulation • Neuroendocrine tumor

Leissa, 12 yrs, ROHHADNET sd

• Weight 110 kg, height 136 cm• PSG

– AHI 26/h– mean SpO2 93%, min SpO2 88%, % of time with

SpO2 < 90% 1%– mean PtcCO2 46 mmHg, max PtcCO2 52 mmHg

• OSAS with alveolar hypoventilation correctedwith bilevel ventilation with volume guarantee

Spontaneous breathing

With noninvasive ventilation

OSAS and congenital anomalies• Analysis of OSAS cases in Washington

state between 1987 and 2003 (CIM-9)• 1203 OSAS cases matched with cases

without OSAS (1/5)• OSAS is associated with

– any cranio-facial anomaly RR 38– facial cleft RR 40– Down syndrome RR 51– any other malformation RR 4.1

Lam et al. Laryngoscope 2010;120:2098

Upper airway obstruction (OSA)• Craniofaciostenosis: Crouzon, Pfeiffer,

Apert• Facial cleft (Pierre Robin, Treacher

Collins (TCOF1), Goldenhar sd• (Hemi)facial microsomia• Macroglossia: Down sd, Beckwith

Wiedemann• Mucopolysaccharidosis

Down syndrome

CPAP (n = 15)CPAP level (cmH₂O) 8 ± 1

NIV (n = 4)Inspiratory pressure level (cmH₂O)Expiratory pressure level (cmH₂O)

13 ± 27 ± 1

InterfacesNasal mask (n)Nasobuccal mask (n)

172

CPAP/NIV adherenceAge at initiation (years)Duration of CPAP/NIV treatment (years)Average use per night (h:min)Number of patient using CPAP/NIV > 4h/night (n)*Failure of long term CPAP/NIV (n)Successful weaning of CPAP/NIV (n)

7 ± 72 ± 1

8h46 ± 3h599/11 (82%)*

53

NIV was initiated in 19/57 (33%) children

OSAS in children withcraniofacial anomalies

• 44 children (Crouzon, Apert, Goldenhar, Treacher Collins, Pierre Robin), mean age 5 yrs

• Pediatric Sleep Questionnaire– symptoms of airway obstruction 82%

• snoring 64%• apneas 33%

• Polygraphy• mild OSAS 20%• moderate OSAS 9%• severe OSAS 15%

Luna-Paredes et al. Int J Pediatr Otorhinolaryngol 2012:76:1767

OSAS in Treacher Collinssyndrome

Akre et al. Eur Arch Otorhinolaryngol 2012;269:331

PSGChildren

n=8Adultsn=11

Normal PSGMild OSAS (AHI 1-5/5-15)

Moderate OSAS (AHI 5-10/15-30) Severe OSAS (AHI >10/>30)

1 (12.5%)4 (50%2 (25%)

1 (12.5%)

0 (0%)3 (27%)4 (36%)4 (36%)

No corrélation between phenotypic severity, symptoms (snoring) and the AHI patients with Treacher Collins syndrome MUST undergo a PSG

Norwegian National Register

MacLean et al. Arch Dis Child 2012

Neonates hospitalizedn=37

No clinical UAOn=17

Clinical UAOn=20

Severe clinical UAOn=9

Immediate CPAP in the NICU

Moderate clinical UAOn=11

Sleep study with gas exchange

Tracheotomyn=4

CPAPn=5

Abnormal sleep studyCPAP, n=4

Normal sleep studyn=7

Moderate UAO group

Severe UAO group

Mild UAO group

No UAO group

Neonates seen as outpatientsn=7

Neonates with PRS evaluated over one yearn=44

No UAO group

Amaddeo et al. Plastic and Reconstructive Surgery, 2016;137:609

Genetic diseases associatedwith thoracic deformity

• Jeune asphyxiating thoracic dystrophy– genetically heterogeneous, ≥ 9 genes identified, all encoding

ciliary proteins • Distal arthrogryposis

– characterised by multiple congenital contractures– DA type 2A (Freeman-Sheldon syndrome = most severe form) is

caused by mutations in MYH3• Fibrodysplasia ossificans progressiva

– mutations in ACVR1 gene• Osteogenesis imperfecta• Achondroplasia, mucopolysaccharidosis,

neurofibromatosis

Jeune asphyxiating

thoracicdystrophy

NIV often can’t prevent a tracheotomy

Fibrodysplasia ossificansprogressiva

Osteogenesis imperfecta

Sleep hypoventilation in2 patients with OI

I, 17 years N, 10 years

Mean SaO2 (%) 95 ± 4 97 ± 1

Minimal SaO2 (%) 91 94

Mean PtcCO2 awake 36 ± 3 35 ± 1

Mean PtcCO2 during sleep 49 ± 4 49 ± 3

Maximal PtcCO2 during sleep 58 64

% sleep time with PtcCO2 > 50 mmHg 19% 25%

Apnea index 2 1

Hypopnea index 4 2

Patient with NIV

CPAP & NIV in children with complex genetic disorders

• The respiratory balance• Genetic disorders that may affect the

respiratory balance• Deciphering the respiratory involvement

of genetic disorders• Benefits of CPAP/NIV• Conclusion

« If you can not measure it, you can not improve it »

William Thomson (1824 - 1907) or « Lord Kelvin »

physician, founder of the thermodynamics

How can we decipher the respiratory involvement in a non

respiratory genetic disease ?

• Sleep study +++• Lung function tests• Respiratory muscle tests• Chest X-ray & CT scan & specific

radiology

Information from a sleep study• Respiratory events: central or obstructive

apneas/hypopneas• Nocturnal gas exchange: hypoxemia, hypercapnia• Sleep architecture and quality: sleep stages, sleep

efficiency, arousals• Additional information +++

– breathing pattern, respiratory rate– simultaneous decrease in airflow and thoracic and abdominal

movements accompanied or not by a change in gas exchange, suggestive of a decrease in central drive or global inspiratory muscle weakness

– paradoxical breathing with opposition phase on the thoracic and abdominal belts, suggestive of diaphragmatic dysfunction or weakness of the intercostal muscles

Age (months)

Weight(kg)

Height (cm) PICU admission Associated clinical features Final diagnosis Outcome

3 5 56 Respiratory distressPeripheral muscle weakness,

swallowing dysfunctionNemaline rod myopathy

Therapeutic abstention

4 5 40 Respiratory distress Peripheral muscle weakness Nemaline rod myopathy NIV

24 19 84 Life threatening eventsGeneralized muscle weakness and fatigability, swallowing dysfunction

Congenital myasthenia NIV

3 6 62 Respiratory distressAxial hypotonia, swallowing

dysfunctionCongenital myasthenia NIV

14 8 75 Respiratory distress Generalized inflammatory disorderDiaphragmatic

dysfunctionNIV

2 4 60 Life threatening eventsSwallowing dysfunction, bradycardia,

axial hypotonia, acute obstructive events

Brainstem dysfunction NIV

4 6 55 Life threatening eventsSwallowing dysfunction, bradycardia,

axialhypotoniaBrainstem dysfunction

Therapeuticabstention

1 3 50 Life threatening eventsSwallowing dysfunction, bradycardia,

axial hypotoniaBrainstem dysfunction cafeine

2 5 57 Respiratory distressSwallowing dysfunction, bradycardia,

axial hypotoniaBrainstem dysfunction NIV

6 5 60 Respiratory distress Acute obstructive eventsSCID T-B-NK+ and

laryngomalaciaCPAP

3 4 45 Respiratory distress Acute obstructive events Laryngomalacia CPAP

2 6 59 Life threatening eventsAcute obstructive events with

bradycardiaPharyngomalacia Lost for follow up

21 15 80 Respiratory distressRecurrent episodes of

respiratory failureCCHS

Invasive ventilation on tracheotomy

Diagnostic value of a polygraphy for infants admittedin the ICU for unexplained respiratory failure

Griffon et al. J Crit Care, in press

Plethysmography

Heart rate

Pulse oximetry

Noise

Airflow

Thoracic belt

Abdominal belt

Figure 1 Online

OSAS in patient withSCID T-B-NK+ and laryngomalacia

Information from lung function tests

• Airway obstruction– airway resistance– spirometry– functional residual volume by helium

dilution or plethysmography• Restrictive lung disease: lung volumes• Daytime gas exchange• Exercise test

Information fromrespiratory muscle tests

• Inspiratory muscles strength– Maximal static inspiratory pressure– Sniff nasal inspiratory pressure– Indirect: vital capacity

• Expiratory muscle strength– Maximal static expiratory pressure– Peak expiratory flow / peak cough flow

Information fromechocardiography

• Cardiac function• Arterial pulmonary hypertension

Information from imaging

• Chest X ray, chest computed tomography• Specific imaging

– spine X ray – brain magnetic resonance imaging

CPAP & NIV in children with complex genetic disorders

• The respiratory balance• Genetic disorders that may affect the

respiratory balance• Deciphering the respiratory involvement

of genetic disorders• Benefits of CPAP/NIV• Conclusion

Primaryabnormality

Respiratory consequences Management

Abnormalventilatory control

Central apneasFalse passages

Neurosurgery (decompression)Ventilatory support• Noninvasive ventilation• Invasive ventilation

Upper airway obstruction

Obstructive sleep apnea

Upper airway surgeryVentilatory support• Noninvasive ventilation• Invasive ventilation

Chest deformity Restrictive lung disease

Ventilatory support• Noninvasive ventilation• Invasive ventilation

Parenchymal lung disease

Restrictive lung disease, respiratory failure

No specific treatmentSymptomatic treatment : oxygen therapyCPAP if associated OSAS ?

Necker experience

Disorders in children treated withCPAP in the USA

Marcus et al. AJRCM 2012;185:998

Acute groupn=15

Subacute groupn=18

Chronic groupn=43

Age, years 1.2±3.4 6.4±7.2 5.9±7.1

Female/male 7/8 8/10 22/21

Diagnosis Pierre Robin syndromeLaryngomalaciaPolymalformative sdKabuki syndromeCystic fibrosisBPDNeuromuscular disorder

6321111

LaryngomalaciaPrader Willi syndromePierre Robin syndromeBDPCraniostenosisTreacher Collins sdVocal cord palsyDown syndromeMucopolysaccaridosisDuchenne MDLaryngeal massCraniofacial malform.Generalised dystonia AchondroplasiaTracheomalacia

411111111111111

Pierre Robin syndromeDown syndromeMucopolysaccaridosisCharge syndromeLaryngomalaciaNeuromuscular disordersPolymalformative syndromeTreacher Collins syndromeAchondroplasiaPrader Willi syndromeBPDMyhre syndromeSpinal muscular atrophyRett syndromeGoldenhar syndromeIdiopathic OSASHanhart syndromeBeckwith Wiedemann sdLoeys Dietz syndromeOssificant fibrodysplasia

55433332222111111111

76 children started on NIV (Necker 2013-2014)

• Respiratory problems are common in genetic diseases in children and associated with a high morbidity and mortality because these problems are often underestimated and underdiagnosed and thus undertreated

• A respiratory evaluation by a pediatrician having an expertise in the different respiratory problems that may occur in these children is thus mandatory

Conclusion - 1

Conclusion - 2• Non respiratory genetic diseases can have

multifactorial effects on the respiratory system– → deciphering the different components

• Variable association of :– obstructive (upper airway malformation)– restrictive (chest wall anomalies)– central (cervico-occipital compression) disorders

• Challenging situations: requirement of– a multidisciplinary team– an expertise in sleep and NIV