Transcript Folie 1

DGPK Guideline
Pulmonary Arterial Hypertension (PAH)
in Infancy and Adolescence
Siegrun Mebus (DHM, TU München)
Christian Apitz (UKGM, Giessen)
Gerhard-Paul Diller (UKM, Münster; RBH London, GB)
Marius M. Hoeper (MHH, Hannover)
Oliver Miera (DHZB, Berlin)
Matthias Gorenflo (Universitätsklinikum Heidelberg)
Conflicts of Interests
Leitlinienkoordinator:
Leitlinie:
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Prof. Dr. med. Jochen Weil
Pulmonary arterial hypertension (PAH) in infancy and adolescence
Berater- bzw. Gutachtertätigkeit oder bezahlte Mitarbeit in einem
wissenschaftlichen Beirat eines Unternehmens der
Gesundheitswirtschaft (z.B. Arzneimittelindustrie,
Medizinproduktindustrie), eines kommerziell orientierten
Auftragsinstituts oder einer Versicherung
Honorare für Vortrags- und Schulungstätigkeiten oder bezahlte
Autoren- oder Co-Autorenschaften im Auftrag eines Unternehmens
der Gesundheitswirtschaft, eines kommerziell orientierten
Auftragsinstituts oder einer Versicherung
Finanzielle Zuwendungen (Drittmittel) für Forschungsvorhaben oder
direkte Finanzierung von Mitarbeitern der Einrichtung von Seiten
eines Unternehmens der Gesundheitswirtschaft, eines kommerziell
orientierten Auftragsinstituts oder einer Versicherung
Eigentümerinteresse an Arzneimitteln/Medizinprodukten
(z. B. Patent, Urheberrecht, Verkaufslizenz)
Besitz von Geschäftsanteilen, Aktien, Fonds mit Beteiligung von
Unternehmen der Gesundheitswirtschaft
Persönliche Beziehungen zu einem Vertretungsberechtigten
eines Unternehmens Gesundheitswirtschaft
Mitglied von in Zusammenhang mit der Leitlinienentwicklung
relevanten Fachgesellschaften/Berufsverbänden,
Mandatsträger im Rahmen der Leitlinienentwicklung
S. Mebus
C. Apitz
G.-P. Diller M.M. Hoeper O. Miera
M. Gorenflo
Actelion
Actelion
Actelion
Actelion,
Bayer, Gilead,
GSK, Lilly,
Pfizer,
Novartis
Actelion
Pfizer
Actelion
Actelion
Pfizer
GSK
Actelion
Pfizer
Actelion GB
Actelion,
Bayer, Gilead,
GSK, Lilly,
Pfizer, Novartis
Actelion
Pfizer
Actelion
Bayer
Schering
Pfizer
Ø
Actelion GB
Pfizer GB
Actelion
Bayer
Pfizer Novartis
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
Ø
DGPK
DGKJ
AEPC
KN-AHF
DGPK
DGKJ
AEPC
keine
relevanten
DGK
ERS
ESC
Ø
DGPK
DGK
DGKJ
GNPI
AEPC
Ø
keine
relevanten
Ø
Ø
Ø
UKGM
Giessen
RBP, London
UKM
MHH
DHZB
UK Heidelberg
ZU Leuven
Politische, akademische (z.B. Zugehörigkeit zu bestimmten „Schulen“), Ø
wissenschaftliche oder persönliche Interessen,
die mögliche Konflikte begründen könnten
DHM, TUM
Gegenwärtiger Arbeitgeber, relevante frühere Arbeitgeber
der letzten 3 Jahre
Definition PAH
Dana Point (2008)
• resting mean pulmonary arterial pressure
mPAP ≥ 25 mmHg
• pulmonary arterial wedge pressure ≤ 15 mmHg
Definition PAH
Dana Point (2008)
• resting mean pulmonary arterial pressure
mPAP ≥ 25 mmHg
• pulmonary arterial wedge pressure ≤ 15 mmHg
• no threshold value for
pulmonary vascular resistance (PVR)
even though:
PVRI > 3 Wood units (U*m2) pathological increased
Classification PAH
Idiopathic PAH
(IPAH)
Heritable PAH
(HPAH)
APAH-CHD
Simonneau JACC 2009
Classification PAH
Idiopathic PAH
(IPAH)
Heritable PAH
(HPAH)
APAH-CHD
Simonneau JACC 2009
General Issues
General Issues
• Epidemiology
incidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
General Issues
• Epidemiology
incidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
• Survival Period
General Issues
• Epidemiology
incidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
• Survival Period
• Pathophysiology
• Histopathology
Rabinovitch 1997
Rabinovitch 1996
Rabinovitch
2008
General Issues
• Epidemiology
incidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
• Survival Period
• Pathophysiology
• Histopathology
Rabinovitch 1997
Rabinovitch 1996
• Genetic Aspects
BMPR2
50-70% HPAH
10-40% sporadic IPAH
Rabinovitch
2008
Symptoms
UNSPECIFIC !
Varying Clinical Findings
• cor: cardiac murmur
• lungs: obstructive pulmonary disease
• advanced stages:
signs of right heart insufficiency
symptoms at rest
• APAH-CHD: Eisenmenger´s Syndrome
signs of chronical cyanosis
Diagnostic Investigation
Aims
To
• confirm the diagnosis
• evaluate severity of PAH
• identify right ventricular function
• find out causation of PAH
• evaluate pulmonary vasoreagibility
Diagnostic Tools
Useful Diagnostics
in individual cases
Diagnostic Tools
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echocardiography
ECG
pulse oximetry
chest-X-ray
pulmonary function test
CPX
6-MWT
laboratory assessment
cardiac catheterisation incl.
acute pulmonary vasodilator
testing
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spiral CT scan
MRI angiography
V/Q-Scan
sleep laboratory/
polysomnography
• genetic analysis
Procedures:
pediatric cardiologist
experienced pediatric
cardiologic center
ECG
• normal ECG doesn´t exclude PAH!
• right heart strain?
• rhythm disturbances?
• Eisenmenger patients:
cardiac arrhythmia (Holter-ECG)
is associated with a poor prognosis
Echocardiography
• most significant non-invasive screening method
• detection/ exclusion of characteristic
morphological and functional signs of PAH
• useful for follow-up (e.g. therapeutic effects?)
• estimation of intracardiac and pulmonary pressure levels
• exclusion of
structural cardiac disease
postcapillary PAH
Echocardiography
Laboratory assessment
Diagnostic and prognostic marker
Cardiac catheterisation
incl. acute pulmonary vasodilator testing
• gold standard
(accurate differential diagnosis)
• quantitation of
pulmonary arterial pressures
• pulmonary vasoreactivity
Cardiac catheterisation
incl. acute pulmonary vasodilator testing
• spontaneous breathing (anesthetic risk)
• baseline hemodynamics
• testing of acute
pulmonary vascular reactivity
with iNO, O2, inh. Iloprost,
combinations thereof
http://www.kompetenznetz-ahf.de/
forschung/klinische-studien/leitlinien
Cardiac catheterisation
present pulmonary vascular reactivity
• decrease of Rp/Rs ≥ 20%
• IPAH/HPAH:
response to medical treatment
with CCB likely
• CAVE:
follow-up
early invasive re-evaluation
 to detect decrease in
pulmonary vascular reactivity
Cardiac catheterisation
APAH-CHD
• Rp/Rs < 0,2
 OP
• Rp/Rs 0,2-0,3
 increased OP-risk
• Rp/Rs > 0,3
 individual treatment plan
special surgical methods necessary
e.g. fenestration
Therapy
PAH = fatal, not-curable disease
Therapy
PAH = fatal, not-curable disease
general therapeutic goals
• delay of disease progression
• improvement of symptoms
• improvement of quality of life
Therapy & Indication
PAH = fatal, not-curable disease
general therapeutic goals
• delay of disease progression
• improvement of symptoms
• improvement of quality of life
IPAH/HPAH
• no causal therapeutic options
• related to rapid progression
 early treatment
APAH-CHD
• OP in time
• post-OP persistent high Rp
 pulmonary vasodilatators
• Eisenmenger NYHA II/III
 pulmonary vasodilatators
Therapeutic Options
PAH = fatal, not-curable disease
general therapeutic goals
• delay of disease progression
• improvement of symptoms
• improvement of quality of life
General Measures
Interventional
Procedures
Drug Therapy
Surgical Aspects
General Measures
General Measures
• general measures/
specific treatment strategies
– physical training, school sport
– avoid situation, which aggravate PH
(pyrexia, situations which increase intrathoracic pressure
–obstipation, diving, trumped–)
– minimize risk of infections –complete vaccination status?
– surgical procedures  high risk  experienced centers
Drug Therapy
Interventional
Procedures
Surgical Aspects
General Measures
General Measures
• general measures/
specific treatment strategies
– physical training, school sport
– avoid situation, which aggravate PH
(pyrexia, situations which increase intrathoracic pressure
–obstipation, diving, trumped–)
– minimize risk of infections –complete vaccination status?
– surgical procedures  high risk  experienced centers
Drug Therapy
Interventional
Procedures
Surgical Aspects
• travel at high altitude/ flying
– quality of life!
– right heart failure: height of 1200-1400 m above sea level uncomplicated
– air pressure in plane cabins corresponds to air pressure at a height of
1800-2400 m above sea level  individual discussions
General Measures
General Measures
• phlebotomy
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only in symptomatic erythocytoses with hyperviscosity symptoms
iron deficiency
iron replacement? close laboratory controls
defiency of folic acid, vitamin-B12?
Drug Therapy
Interventional
Procedures
Surgical Aspects
General Measures
General Measures
• phlebotomy
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only in symptomatic erythocytoses with hyperviscosity symptoms
iron deficiency
iron replacement? close laboratory controls
defiency of folic acid, vitamin-B12?
Drug Therapy
Interventional
Procedures
Surgical Aspects
• contraception
– adequate contracaption in time
– consulting service with pediatric cardiologist and experienced gynecologist
– CAVE: interactions with some drugs (e.g. ERA)
General Measures
General Measures
• oxygen
– APAH-CHD: controversial, at the discretion of physician
– others: SpO2 < 90%, PaO2 < 60 mmHg, subjective benefit
Drug Therapy
Interventional
Procedures
Surgical Aspects
General Measures
General Measures
• oxygen
– APAH-CHD: controversial, at the discretion of physician
– others: SpO2 < 90%, PaO2 < 60 mmHg, subjective benefit
• oral anticoagulation
– IPAH/HPAH, thromboembolic PH:
Ø hempotysis  OAK
(class of recommendation IIa; INR 2,0-3,0)
– APAH-CHD:
only in particular cases (e.g. rhythm disturbances, thromboembolie)
Drug Therapy
Interventional
Procedures
Surgical Aspects
Drug Therapy
General Measures
• according to rareness of disease
 sparse literature available for
medical treatment in children
Drug Therapy
Interventional
Procedures
Surgical Aspects
• children: case reports, small case series
• drug application in children  adults
• approved drugs for children: Bosentan &
Sildenafil
Calcium Channel Blockers
In children off label-use.
IPAH/HPAH
responder
positive experiences
in adults
Approved fields of application:
NOT in APAH-CHD
Primary arterial hypertension.
Symptomatic coronary heart disease.
Chronic stable, instable and vasospastic angina pectoris.
Amlodipin
Diltiazem
Nifedipin
children:
adults:
children:
adults:
children:
adults:
0,2-0,5 mg/kg/d in 1-2 doses p.o.
max. 10 mg/d in 1 dose p.o.
1,5-3,5 mg/kg/d in 3-4 doses p.o.
max. 360 mg/d in 1-3 doses p.o.
1-2 mg/kg/d in 1 dose p.o.
40-max. 120 mg in 1-2 doses p.o.
General Measures
Drug Therapy
Interventional
Procedures
Surgical Aspects
Endothelin-Receptor-Antagonists
General Measures
Bosentan
Approval: age ≥ 2 years
Drug Therapy
Approved fields of application:
„Verbesserungen des Krankheitsbildes bei Patienten mit PAH
der funktionellen NYHA-Klasse II & III. Wirksamkeit nachgewiesen bei
- primärer (idiopathischer und erblicher) PAH
- Sek. PAH in Assoziation mit Sklerodermie ohne signifikante interstitielle Lungenerkrankung.
- PAH in Assoziation mit kongenitalen Herzfehlern und Eisenmenger-Physiologie
Reduzierung der Anzahl neuer digitaler Ulzerationen bei Patienten mit systemischer Sklerose,
die an digitalen Ulzerationen leiden.“
Interventional
Procedures
Surgical Aspects
children: 4 mg/kg/d in 2 doses p.o. (target dose)
adults:
62,5 mg BID p.o. (initial dose for 4 weeks),
125 mg BID p.o. (target dose)
Ambrisentan
children:
adults:
no approval
5 - 10 mg qd p.o.
side effects:
liver toxicity
drug interactions
Phosphodiesterase-5-Inhibitors
Sildenafil
General Measures
Approval: age ≥ 1 year
Approved fields of application:
„PAH der WHO-Funktionsklasse II & III
Wirksamkeit nachgewiesen bei primärer PAH und pulmonaler Hypertonie in Verbindung mit einer
Bindegewebskrankheit bei Kindern zudem bei pulmonaler Hypertonie in Verbindung mit AHF.“
children: dosing recommendation as EMA approved:
BW
8 kg < x ≤ 20 kg, age ≥ 1 year: 10 mg tid p.o.
BW
> 20 kg:
20 mg tid p.o.
pediatric PH-experts:
1-4 mg/kg/d in 3-4 doses p.o.
adults:
Drug Therapy
Interventional
Procedures
Surgical Aspects
20 mg tid oral (as per expert information)
experts consent (Kölner Konsensus Konferenz):
prn increase of doses to max. 80 mg tid p.o. (off-label-use)
Tadalafil
children: no approval
adults:
40 mg qd p.o.
10/2011:
“Rote-Hand-Brief”
Prostanoids
Combination Therapy
General Measures
Prostanoids
Drug Therapy
In children and adolescense off label-use.
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small case series
application many times daily
side effects (bronchial obstruction, cough)
 limited compliance in children
use on a regular basis  improvement for a period of years
Combination therapy
Insufficient data  indication only in expert centers
Interventional
Procedures
Surgical Aspects
Interventional Procedures
General Measures
Drug Therapy
Atrial septostomy / Stent
Interventional
Procedures
• in case of failing medical therapy
• palliation
in decompensated pts
with RV failure
• high risk
Surgical Aspects
Surgery
General Measures
• failing medical/ interventional treatment
Drug Therapy
Interventional
Procedures
• thoracic organ transplantation
Surgical Aspects
LTX, HLTX
• CAVE: survival rates
children with PAH: bil. LTX
- mean survival 45 months (2-123 months)
- 5.8 years
• experimental: Pott´s shunt
Follow-up
regular, in cooperation with specialized PAH-centers
• medical history, physical examination, clinical status (BW, .... )
• symptoms
• 6-MWT, pulmonary function test, CPX, pulse oxymetry
throughout life !
• special functional parameters
- echocardiography
- blood tests: blood gases, blood cell count,
kidney-/ liver-parameters, (NT-pro)BNP
progress of PAH  therapeutic escalation
• catheterization
Prevention
APAH-CHD
• OP in time
IPAH/HPAH
• no specific prevention
• chance: genetic counselling
DGPK Guideline
Pulmonary Arterial Hypertension (PAH)
in Infancy and Adolescence
www.kinderkardiologie.org/dgpkLeitlinien.shtml