CPAP & NIV in children with complex genetic disorders

Alessandro Amaddeo, Brigitte Fauroux Pediatric noninvasive ventilation and sleep unit Research unit INSERM U 955 Necker university Hospital, Paris, France

Inserm

Institut national de 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

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Physiological changes during sleep Sleep

Ventilatory Respiratory Respiratory drive muscles mechanics

 central drive preservation of activity of V/Q mismatch  chemoreceptor the diaphragm  airway resistance sensitivity  intercostal muscles  FRC  upper airway muscle tone 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 may affect the respiratory balance Respiratory Primary abnormality Diseases consequences Abnormal ventilatory Central apneas Rett syndrome, ROHHADNET syndrome control Prader Willi syndrome Achondroplasia Storage diseases: mucopolysaccharidosis Upper airway Obstructive sleep apnea Craniofacial malformations obstruction Laryngotracheal abnormalities Storage diseases: mucopolysaccharidosis

Chest deformity Restrictive lung disease Jeune asphyxiating thoracic dystrophy Distal arthrogryposis Fibrodysplasia ossificans progressiva Osteogenesis imperfecta, Neurofibromatosis Parenchymal lung Restrictive lung disease Interstitial lung diseases disease Central apneas - Necker experience 13 patients seen over a one year period

Case Sex Age Medical conditions CAI AHI Mean Min Mean PtcCO2 Max PtcCO2 ODI (years) SpO2% SpO2% (mmHg) (mmHg) (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 21 33 97 82 39 41 31 syndrome 13 M 15.60 Down syndrome 5 27 94 80 53 62 22 Mean 5.91 32 42 96 85 43 48 34 (±SD) 4.24 38 43 26 23 18 20 31 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 corrected with 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

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

CPAP (n = 15) CPAP level (cmH O) 8 ± 1 NIV (n = 4) ₂ Inspiratory pressure level (cmH O) 13 ± 2 Expiratory pressure level (cmH O) 7 ± 1 ₂ Interfaces ₂ Nasal mask (n) 17 Nasobuccal mask (n) 2 CPAP/NIV adherence Age at initiation (years) 7 ± 7 Duration of CPAP/NIV treatment (years) 2 ± 1 Average use per night (h:min) 8h46 ± 3h59 Number of patient using CPAP/NIV > 4h/night (n)* 9/11 (82%)* Failure of long term CPAP/NIV (n) 5 Successful weaning of CPAP/NIV (n) 3 OSAS in children with craniofacial 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 Collins syndrome

Norwegian National Register

Children Adults PSG n=8 n=11 Normal PSG 1 (12.5%) 0 (0%) Mild OSAS (AHI 1-5/5-15) 4 (50% 3 (27%) Moderate OSAS (AHI 5-10/15-30) 2 (25%) 4 (36%) Severe OSAS (AHI >10/>30) 1 (12.5%) 4 (36%)

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

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

Neonates with PRS evaluated over one year n=44

Neonates seen as outpatients Neonates hospitalized n=7 n=37

No UAO group

No clinical UAO Clinical UAO n=17 n=20 No UAO group

Severe clinical UAO Moderate clinical UAO n=9 n=11

Immediate CPAP in the NICU Severe UAO group Sleep study with gas exchange

Tracheotomy CPAP Abnormal sleep study Normal sleep study n=4 n=5 CPAP, n=4 n=7

Moderate UAO group Mild UAO group Amaddeo et al. Plastic and Reconstructive Surgery, 2016;137:609 Genetic diseases associated with 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 thoracic dystrophy

 NIV often can’t prevent a tracheotomy Fibrodysplasia ossificans progressiva Osteogenesis imperfecta Sleep hypoventilation in 2 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 Diagnostic value of a polygraphy for infants admitted in the ICU for unexplained respiratory failure

Age Weight Height PICU admission Associated clinical features Final diagnosis Outcome (months) (kg) (cm) Peripheral muscle weakness, Therapeutic 3 5 56 Respiratory distress Nemaline rod myopathy swallowing dysfunction abstention 4 5 40 Respiratory distress Peripheral muscle weakness Nemaline rod myopathy NIV Generalized muscle weakness and 24 19 84 Life threatening events Congenital myasthenia NIV fatigability, swallowing dysfunction Axial hypotonia, swallowing 3 6 62 Respiratory distress Congenital myasthenia NIV dysfunction Diaphragmatic 14 8 75 Respiratory distress Generalized inflammatory disorder NIV dysfunction Swallowing dysfunction, bradycardia, 2 4 60 Life threatening events axial hypotonia, acute obstructive Brainstem dysfunction NIV events Swallowing dysfunction, bradycardia, Therapeutic 4 6 55 Life threatening events Brainstem dysfunction axialhypotonia abstention Swallowing dysfunction, bradycardia, 1 3 50 Life threatening events Brainstem dysfunction cafeine axial hypotonia Swallowing dysfunction, bradycardia, 2 5 57 Respiratory distress Brainstem dysfunction NIV axial hypotonia SCID T-B-NK+ and 6 5 60 Respiratory distress Acute obstructive events CPAP laryngomalacia 3 4 45 Respiratory distress Acute obstructive events Laryngomalacia CPAP Acute obstructive events with 2 6 59 Life threatening events Pharyngomalacia Lost for follow up bradycardia Recurrent episodes of Invasive ventilation 21 15 80 Respiratory distress CCHS respiratory failure on tracheotomy Griffon et al. J Crit Care, in press Figure 1 Online OSAS in patient with SCID T-B-NK+ and laryngomalacia Plethysmography

Heart rate

Pulse oximetry

Noise

Airflow

Thoracic belt

Abdominal belt 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 from respiratory 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 from echocardiography

• 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 Primary Respiratory Management abnormality consequences Abnormal Central apneas Neurosurgery (decompression) ventilatory control False passages Ventilatory support • Noninvasive ventilation • Invasive ventilation Upper airway Obstructive sleep Upper airway surgery obstruction apnea Ventilatory support • Noninvasive ventilation • Invasive ventilation Chest deformity Restrictive lung Ventilatory support disease • Noninvasive ventilation • Invasive ventilation Parenchymal lung Restrictive lung No specific treatment disease disease, respiratory Symptomatic treatment : oxygen failure therapy CPAP if associated OSAS ? Necker experience Disorders in children treated with CPAP in the USA

Marcus et al. AJRCM 2012;185:998

76 children started on NIV (Necker 2013-2014)

Acute group Subacute group Chronic group n=15 n=18 n=43

Age, years 1.2±3.4 6.4±7.2 5.9±7.1

Female/male 7/8 8/10 22/21 Pierre Robin syndrome 6 Laryngomalacia 4 Pierre Robin syndrome 5 Diagnosis Laryngomalacia 3 Prader Willi syndrome 1 Down syndrome 5 Polymalformative sd 2 Pierre Robin syndrome 1 Mucopolysaccaridosis 4 Kabuki syndrome 1 BDP 1 Charge syndrome 3 Cystic fibrosis 1 Craniostenosis 1 Laryngomalacia 3 BPD 1 Treacher Collins sd 1 Neuromuscular disorders 3 Neuromuscular disorder 1 Vocal cord palsy 1 Polymalformative syndrome 3 Down syndrome 1 Treacher Collins syndrome 2 Mucopolysaccaridosis 1 Achondroplasia 2 Duchenne MD 1 Prader Willi syndrome 2 Laryngeal mass 1 BPD 2 Craniofacial malform. 1 Myhre syndrome 1 Generalised dystonia 1 Spinal muscular atrophy 1 Achondroplasia 1 Rett syndrome 1 Tracheomalacia 1 Goldenhar syndrome 1 Idiopathic OSAS 1 Hanhart syndrome 1 Beckwith Wiedemann sd 1 Loeys Dietz syndrome 1 Ossificant fibrodysplasia 1 Conclusion - 1

• 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 - 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