Post on 23-Aug-2020
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