Sas In Prader Willi
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Sindromul de apnee în somnîn Prader Willi
dr. Ştefan MihăicuţăUMF V. Babeş TimişoaraClinica de Pneumologie
Timisoara 25 aprilie 2009
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Obstructive Sleep ApneaObstructive Sleep Apnea……and on the box sat a fat and red faced boy, in the state of and on the box sat a fat and red faced boy, in the state of
somnolency.somnolency.
Charles Dickens, “The Pickwick Papers”, 1836Charles Dickens, “The Pickwick Papers”, 1836
Definition:Definition: Repetitive partial or complete upper airway Repetitive partial or complete upper airway
obstruction during sleepobstruction during sleep associated with associated with persistent persistent respiratory effort respiratory effort causing:causing:
• apneaapnea – – airflow cessation for at least 10 secondsairflow cessation for at least 10 seconds• hypopnea hypopnea – – 30% to 50% airflow reduction for at least 10 seconds 30% to 50% airflow reduction for at least 10 seconds
and oxygen desaturation of at least 2% to 4%and oxygen desaturation of at least 2% to 4%
Excessive daytime sleepinessExcessive daytime sleepiness Impaired cognitive functionImpaired cognitive function Increased cardiovascular riskIncreased cardiovascular risk
Classification Classification ((AHI = nr.of apneas + hypopneas/h of sleepAHI = nr.of apneas + hypopneas/h of sleep):): MildMild: 5 – 15: 5 – 15 ModerateModerate: 15 – 30: 15 – 30 SevereSevere: > 30: > 30
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PWS
• Hipotonie severă, tulburări de alimentaţie• Obezitate morbidă prin alimentare
necontrolată. • Tulburări motorii, de limbaj, cognitive.• Fenotip comportamental: încăpăţânare,
manipulare, compulsiv-obsesive . • Hipogonadism, hipoplazie genitală.• Statură mică, facies tipic, strabism, scolioză,
diabet NID.
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Prader-Willi SyndromeSec XVII
Dona Eugenia Martinez Vallejo (1680), 6 ani
1956
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Somn normal şi cu SAS
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Simptome - PSG
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Physiological Characteristics• Hypotonia - Weak Muscle
Tone• Abnormal Growth (short
stature, small hands & feet)• Problems with Strength,
Balance, • Hyperphagia - Dysfunctional
Appetite Regulating System• Respiratory Issues• Gastrointerological Issues–• Hyper- & Hypothermia -• Incomplete Sexual
Development• Hypopigmentation• High Pain Threshold, Bruise
Easily
• Disordered Sleep
• Cognitive Limitations
• Speech and Language Issues (Dyspraxia & Apraxia)
• Dental Problems (decreased saliva production can cause severe problems)
• Skin Scratching and Picking
• Temperament and Behavior Issues
• Social / Psychological / Psychiatric Problems
• Other common characteristics may include: scoliosis, eye abnormalities (strabismus), medication sensitivity, orthopedic problems
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DiagnosticMajor criteria - 7
• Onset of rapid weight gain between ages 12 months and six years, causing central obesity
• Characteristic facial features: narrow bifrontal diameter, almond-shaped palpebral fissures, down-turned mouth
Gunay-Aygun et al 2001
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Minor criteria - 11
• Sleep disturbance/sleep apnea
• ≤3 years: 5 criteria, 4 majors
• > 3 years: 8 criteria, 5 majors
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MANIFESTARI CLINICE ALE SAS
ZIUA
Somnolenţă excesivăScăderea performanţei de lucru / şcolareCefalee matinalăDeteriorare intelectuală: tulburări de atenţie afectarea capacităţii de concentrare afectarea memorieiDepresieDureri precordiale
HTA
NOAPTEA
SforăitApnei raportateSomn agitatInsomniiTresăriri nocturneMicrotreziri repetateNicturieEnurezisScăderea libidouluiImpotenţă TranspiraţiiAritmii cardiace
Sex masculinVârstă: > 40 de ani
Obezitate cu dispoziţie tronculară
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Somnografia cardio-respiratorie
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Polisomnografia
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Stare de veghe – tranzitie N1
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Evenimente respiratorii înregistrate
• Apnei: – Obstructive
– Centrale
– Mixte
• Hipopnei;
• Microtreziri cauzate de evenimente respiratorii;
• Evenimente respiratorii neîncadrabile;
• Cauze de alterare a arhitecturii somnului.
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Apnea obstructivă• Oprirea fluxului de aer peste 10 sec, cu
prezenţa efortului abdominal/thoracic. Poate fi urmată de microtrezire şi/sau asociată cu o desaturare.
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Apnea centrală
• Oprirea fluxului de aer peste 10 secunde, cu abolirea efortului respirator thoracic/abdominal
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Apnea mixtă
• Combinatie
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Hipopnea• Este o reducere cu cel puţin 50% a fluxului de
aer, cu o durată de peste 10 secunde.
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Mortalitate
• Children: respiratory and other febrile illnesses
• Adults: obesity - related cardiovascular problems and gastric causes or sleep apnea - most frequent in adults
Schrander-Stumpfel 2004, Stevenson et al 2004
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GH therapy and mortalityrecommendation
• to perform polysomnography and ENT
• examination before and 6-8 weeks after
starting of GH therapy;
• adenoidectomy + tonsillectomy
before or during GH administration
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Dutch Prader-Willi Parents Association, 18+ -sleep problems
Sleep related problems:– Sleep well at night– 31% sleepy during the daySleep apnea (p=0.02):
• 18-29: 22%• 30-39: 58%• 40+: 10%
Only 4 / 14 diagnosed by physicians2 persons with narcolepsia
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Indicatie
• Disturbed sleep in children and adults should prompt a sleep study, as treatment may be available.
• Treatment depends on the cause and may include tonsillectomy and adenoidectomy and/or CPAP, as in the general population
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SAS - polisomnografie
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Hipoxia/Reoxigenarea - OSAInfecţia, Inflamaţia, Ox-LDL
Activarea factorilor de transcripţie (HIF-1, NFkB, AP-1)
Monocite, Limfocite
Aderare
Deteriorare
Citokine proinflamatorii: IL-1, IL-6, IL-8, TNF-α
Activarea
ROSROS
Disfuncţia endotelială
Celule endoteliale
Lavie L, Sleep 2004; 27(1): 123-8
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Hipoxie/Reoxigenare - OSA
ROSROS
Disfuncţie endotelială
Morbiditate cardiovasculară ~ 50
20 - 30
Mortalitate
Vârsta
Lavie L, Sleep 2004; 27(1): 123-8
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Celule inflamatorii activatePMN –apoptoză întârziată
Dyukovskaya, Am J Resp Crit Care Med, april 2008
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MecanismeActivarea sistem RAADisfuncţia cardiovasculară
•Activarea simpatetică•Disfuncţia endotelială•Stresul oxidativ•Inflamaţia•Activarea trombocitelor
Activarea genei apoptozeiObezitate / leptină
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HTA mascată: Holter 24 h
Disfuncţie endotelială: PAT
Hipertrofie carotidiană: Grosimea intimei mediei
Rigiditate arterială: unda de velocitate a pulsului
Disfuncţie diastolică: eco- cardiografie
Markeri subclinici: predictori pentru apariţia
evenimentelor cardiovasculare?
Expunere la factori de riscŞi SAS
BCV
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Placa - structură ecogenică care depăşeşte lumenul vasului cu o arie distinctă şi care are un IMT cu mai
mult de 50% decât la cei învecinaţi
CC
IMT
Hipertrofia peretelui carotidei: IMT> 0.8 mm
Factor de prognoză independent pentru riscul cardio-vascular
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Activarea simpatetică• Activitatea nervoasă
musculară simpatetică crescută în OSA
• Catecolamine crescute în plasmă şi aparatul urinar în OSA
• În timpul nopţii şi în general
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SurveillanceMonitor height, weight, and BMI:
– Monthly in infancy
– Every six months in the first decade of life
– At least annually thereafter
Obtain history of any sleep disturbance; if present, perform a sleep study: snoring with apneas, excessive daytime sleepiness
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Ateroscleroză
+ OSA
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Tratamentul implică:Îmbunătăţirea simptomelor
Normalizarea evenimentelor respiratorii din timpul somnului
Ameliorarea calităţii vieţii
Consecinţele SASO:Hipersomnia din timpul zilei
Asocerea morbidităţii cardiovasculare Diferite modalităţi de tratament
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Management - multidisciplinar
• Geneticist
• Endocrinologist
• Pulmonologist
• Feeding Specialist
• Ophthalmologist
• Dentist
• RC Case Workers
• Behaviorist, Psychologist, Psychiatrist
• Neurologist
• Urologist (boys)
• Gastroenterologist
• Nutritionist
• Orthopedist
• Attorney
• PT, OT, ST, Social Skills Therapists
• Residential Staff
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Management
Increased height and growth rate
Increased hand & foot size to normal proportions; more “normalized” facial characteristics
Decrease in body fat and body mass index (BMI)
Increase in muscle development
Improved respiratory function
Improved physical performance
Increase in resting energy expenditure
Improved cholesterol levels
Increase in bone mineral density
Improved cognitive functioning
Increased self-esteem
Diagnostic precoce– testare genetică
Hormon de crestere – efecte pozitive:
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Management • Educatia permanenta a familiei
• Terapie fizica, ocupatională, logoterapie,
• Igiena orală pentru ameliorarea simptomele de gură uscată
• Managementul greutăţii
• Exerciţii fizice regulate
• Controlul consecintelor fizice: SAS, boli cardiovasculare, diabet zaharat
37
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Managementul opţiunilor în SASOformă severă
1. CPAP- opţiune de elecţie.
2. Altele – nonresponderi la CPAP, când nu este tolerat: scădere ponderală, poziţie non-supin.
3. Măsurile de a avansa mandibula:(i) dispozitive orale(ii) Osteotomia maxilomandibulară – f rar...
Doar la pacienţii tineri, slabi şi foarte motivaţi.
4. Intervenţia chirurgicală asupra căilor aeriene superioare (UPPP) şi ablaţia prin radiofrecvenţă - nu în cazurile severe.
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Cine e tratat?
Dovezi puternice pentru propunerea tratamentului în:
SASO cu IAH foarte crescut şi simptome specifice
SASO cu IAH scăzut şi simptome specifice sau asociate cu morbiditatea cardiovasculară.
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Dispozitive
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CPAP: impactul asupra activităţii din timpul zilei
Engleman HM et al, Lancet 1994;343:572–575
Engleman HM et al, Thorax 1998;53:341–345
Redline S et al, AJRCCM 1998;57:858–865
Jenkinson C et al, Lancet 1999;353:2100–2105
, B a lle s t e r E e t a l AJRCCM 1 9 9 9 ;1 5 9 :4 9 5 – 5 0 1 , , 2 0 0 1 , 1 6 4 :6 0 8 -1 3M o n t s e r r a t e t a l A J R C C M
nCPAP aduce îmbunătăţiri semnificative
pe somnolenţă şi calitatea vieţii la pacienţii
cu simptome de SAS moderată sau severă
, , 2 0 0 0 , 1 6 1 :1 7 7 5 -8R D a v ie s a n d J S t r a d lin g A J R C C M
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Morbiditate cardiovasculară
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Dispozitive orale: eficienţă
Eficienţa a fost demonstrată,...
dar,
numai la formele uşoare
chiar şi la acestea, răspuns mai bun cu CPAP8 săpt. de CPAP Vs 8 săpt. de OA
Engleman AJRCCM 2002
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Managementul opţiunilor în formele de SAS uşoare şi moderate
1. Complianţa la CPAP e de 50% la 5 ani.
2. Scăderea ponderală- f utilă în SASO, dar este dificil de realizat.
3. Evitarea poziţiei supin din timpul somnului.
4. Dispozitivele orale - alternative rezonabile la CPAP în cazurile uşoare, şi posibil în UARS.
5. Chirurgia (UPPP) - la pacienţi selectaţi cu SASO formă uşoară, dar e mai potrivită pacienţilor cu sforăit nonapneic.
6. Diferiţi agenţi farmacologici au fost evaluaţi în OSAS, cu rezultate în general nesatisfăcătoare.
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UPPP- f rar azi
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Corelaţie IAH - HTA E. S p OR 95,0% C.I. pt RR
Minim Maxim
IAH2 0,000
IAH normal 1(ref)
IAH1 0,357 0,149 ,597 ,296 1,203
IAH2 0,335 0,239 1,484 ,769 2,865
IAH3 0,308 0,000 3,062 1,675 5,597
IAH pe 4 niveluri (normal, st I, II, III) cu referinţă st II, este extrem de semnificativ crescut (p<0.001) la cei cu HTA. Doar formele severe de SAS ating prag de semnificaţie important(p<0.001, RR 3,062, CI 1,675-5,597), cu un OR>3, deci predictor puternic.
Mihaicuta et al, Pneumologia 2008
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BCV şi SAS- HTA
– Prevalenţa crescută a HTA la cei cu SAS
– SAS – cauză de HTA secundară
– SAS – cauză de rezistenţă la terapie a HTA
Mihaicuta et al, Obesity and daytime somnolence in patients with obstructive sleep apnoea and systemic hypertension”, European Respiratory Journal, vol 12, suppl, Sept 2002, 5s.
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HTA nocturnă- nondiper
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Cauze de HTA secundară– Sindromul de apnee în somn
– HTA indusă de medicamente sau droguri
– Nefropatiile cronice
– Hiperaldosteronismul primar
– Boala renovasculară
– Corticoterapia cronică şi sindromul Cushing
– Feocromocitomul
– Coarctaţia de aortă
– Afecţiunile tiroidiene sau paratiroidiene
(The Seventh Report of the Joint National Comittee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The JNC Report). JAMA 2003; 289: 2560-2572.
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HTA şi SAS
Norm Persist
nocturn
Diurna Resistenta
Normalizare TA cu terapie SASO
Interm nocturn
MalignaNon- dippe
r
Timp
Timp
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Hipertensiunea creşte mortalitatea
Days of Survival0 500 1000 1500 2000 2500 3000 3500 4000
Cu
mu
lativ
e s
urvi
val (
%)
0
10
20
30
40
50
60
70
80
90
100
without hypertension
with hypertension
Noda et al, J Clin Neuroscience, 1998, 52,79
N=148
Zile de supravieţuire
Sup
ravi
eţui
rea
cum
ulat
ivă
(%) fără hipertensiune
cu hipertensiune
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CPAP şi frecvenţa cardiacă
HR,BPM
30507090110130150170190
SpO2,%
50
60
70
80
90
100
Stage
S4
S3
S2
S1
REM
MVT
WK
CA,sec
0
10
20
OA,sec
0
10
20
MA,sec
0
10
20
HYPO,sec
0
10
20
Night Hypnogram
9:27:43 PM 11 PM 12 AM 1 AM 2 AM 3 AM 4 AM 5 AM 6 AM
HR,BPM
30507090110130150170190
SpO2,%
5060708090100
Stage
S4S3S2S1REMMVTWK
CA,sec
01020
OA,sec
01020
MA,sec
01020
HYPO,sec
01020
CPAP,cmH2O
0
5
10
15
20
25
30
Night Hypnogram
9:53:27 PM 11 PM 12 AM 1 AM 2 AM 3 AM 4 AM 5 AM 6 AM
Înainte de CPAP După CPAP
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BCV şi SAS - Insuficienţa cardiacă
–Comună în SAS
–SAS agravează IC –Beta- blocantele ar reduce apneile
centrale
Mihăicuţă, et al. Chest e-letter february, 2007
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BCV şi SAS- Mortalitatea
– Crescută în SAS şi sforăit
– În special în timpul nopţii
– SAS creşterea mortalitatea datorită BCV
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Somers et al, NEJM 2005
Moarte subită
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Dovezi pentru reducerea risculuiBCV prin tratamentul SAS
• CPAP
• Intermediari, BP, CVD, CHD, moarte
• Managementul obezităţii
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Mortalitatea crescută la pacienţii care nu primesc CPAP
Doherty LS Chest. 2005;127:2076-2084Long-term Effects of Nasal Continuous Positive Airway Pressure Therapy on Cardiovascular Outcomes in Sleep Apnea Syndrome*
Chest. 2005;128:624-633.Mortality in Obstructive Sleep Apnea-Hypopnea Patients Treated With Positive Airway Pressure* Francisco Campos-Rodriguez,
Marti, S, Sampol, G, Muñoz, X, et al Mortality in severe sleep apnoea/hypopnoea syndrome patients: impact of treatment. Eur Respir J 2002;20,1511-1518
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Cum să folosim aceste informaţii în clinică
• Riscuri standard de BCV– Evaluare şi tratament – Obezitate, fumat, diabet, BP, colesterol, SAS
• SAS standard– Tratament – CPAP: laborator de somn
• SAS asimptomatic– Evaluarea riscului BCV : cardiologie– Evaluarea severităţii SAS: laborator de somn
Investigarea rezistenţei hipertensiunii în SASConsideraţii asupra cauzelor secundare / hiperaldosteron referitor la
complianţa la CPAP şi rezistenţa la BP
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Concluzii
Modificarea riscurilor cardiovasculare: Obezitate, fumat, diabet, BP, colesterol
Tratarea SAS concomitent
Încercarea cu CPAP în OSA sever dacă există un risc înalt de CVD
HTA rezistentă: SAS asociat?
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