Upload
rebekka-naumann
View
118
Download
2
Embed Size (px)
Citation preview
DGPK GuidelinePulmonary 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)
C. ApitzS. Mebus M.M. HoeperG.-P. Diller M. GorenfloO. Miera
Conflicts of Interests
Leitlinienkoordinator: Prof. Dr. med. Jochen WeilLeitlinie: Pulmonary arterial hypertension (PAH) in infancy and adolescence
1 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
Actelion
2 Honorare für Vortrags- und Schulungstätigkeiten oder bezahlte Autoren- oder Co-Autorenschaften im Auftrag eines Unternehmensder Gesundheitswirtschaft, eines kommerziell orientierten Auftragsinstituts oder einer Versicherung
ActelionPfizerGSK
3 Finanzielle Zuwendungen (Drittmittel) für Forschungsvorhaben oder direkte Finanzierung von Mitarbeitern der Einrichtung von Seiteneines Unternehmens der Gesundheitswirtschaft, eines kommerziell orientierten Auftragsinstituts oder einer Versicherung
Pfizer
4 Eigentümerinteresse an Arzneimitteln/Medizinprodukten(z. B. Patent, Urheberrecht, Verkaufslizenz)
Ø
5 Besitz von Geschäftsanteilen, Aktien, Fonds mit Beteiligung von Unternehmen der Gesundheitswirtschaft
6 Persönliche Beziehungen zu einem Vertretungsberechtigteneines Unternehmens Gesundheitswirtschaft
Ø
7 Mitglied von in Zusammenhang mit der Leitlinienentwicklung relevanten Fachgesellschaften/Berufsverbänden,Mandatsträger im Rahmen der Leitlinienentwicklung
DGPKDGKJAEPCKN-AHF
8 Politische, akademische (z.B. Zugehörigkeit zu bestimmten „Schulen“), wissenschaftliche oder persönliche Interessen,die mögliche Konflikte begründen könnten
Ø
9 Gegenwärtiger Arbeitgeber, relevante frühere Arbeitgeberder letzten 3 Jahre
DHM, TUM
Ø
Actelion
ActelionPfizer
Ø
Ø
Ø
DGPKDGKJAEPC
Ø
UKGMGiessen
Ø
Actelion
Actelion GB
Actelion GBPfizer GB
Ø
Ø
keine relevanten
keine relevanten
RBP, LondonUKM
Ø
ActelionPfizer
ActelionPfizer
Ø
Ø
Ø
Ø
Ø
DHZB
Ø
Actelion
ActelionBayer Schering
Ø
Ø
Ø
DGPKDGKDGKJGNPIAEPC
Ø
UK HeidelbergZU Leuven
Ø
Actelion,Bayer, Gilead, GSK, Lilly,Pfizer,Novartis
Actelion,Bayer, Gilead, GSK, Lilly,Pfizer, Novartis
ActelionBayerPfizer Novartis
Ø
Ø
DGKERSESC
Ø
MHH
Ø
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 forpulmonary 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
• Epidemiologyincidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
General Issues
• Epidemiologyincidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
• Survival Period
General Issues
Rabinovitch 1997Rabinovitch 1996
• Epidemiologyincidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
• Survival Period
• Pathophysiology
• Histopathology
Rabinovitch2008
General Issues
Rabinovitch 1997Rabinovitch 1996
• Epidemiologyincidence: 0,48/1 M children/year
prevalence: IPAH/HPAH 2,07/1 M children
f:m = 1,7:1
• Survival Period
• Pathophysiology
• Histopathology
• Genetic AspectsBMPR2
50-70% HPAH
10-40% sporadic IPAH
Rabinovitch2008
Symptoms
UNSPECIFIC !
Varying Clinical Findings• cor: cardiac murmur• lungs: obstructive pulmonary disease• advanced stages:
signs of right heart insufficiencysymptoms at rest
• APAH-CHD: Eisenmenger´s Syndromesigns 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
• echocardiography• ECG• pulse oximetry• chest-X-ray• pulmonary function test• CPX• 6-MWT• laboratory assessment• cardiac catheterisation incl.
acute pulmonary vasodilatortesting
Useful Diagnosticsin individual cases
• spiral CT scan• MRI angiography• V/Q-Scan• sleep laboratory/
polysomnography• genetic analysis
Diagnostic Tools
Procedures:pediatric cardiologist
experienced pediatriccardiologic 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 characteristicmorphological and functional signs of PAH
• useful for follow-up (e.g. therapeutic effects?)• estimation of intracardiac and pulmonary pressure levels• exclusion of
structural cardiac diseasepostcapillary PAH
Echocardiography
Laboratory assessment
Diagnostic and prognostic marker
Cardiac catheterisation
incl. acute pulmonary vasodilator testing
• gold standard(accurate differential diagnosis)
• quantitation ofpulmonary arterial pressures
• pulmonary vasoreactivity
Cardiac catheterisation
incl. acute pulmonary vasodilator testing
• spontaneous breathing (anesthetic risk)
• baseline hemodynamics• testing of acute
pulmonary vascular reactivitywith 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 treatmentwith CCB likely
• CAVE:follow-upearly invasive re-evaluation to detect decrease inpulmonary 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
Drug Therapy
Interventional Procedures
Surgical Aspects
General Measures
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
• 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
General Measures
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
• 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
• 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
Drug Therapy
Interventional Procedures
Surgical Aspects
• phlebotomy– only in symptomatic erythocytoses with hyperviscosity symptoms– iron deficiency– iron replacement? close laboratory controls– defiency of folic acid, vitamin-B12?
General Measures
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
• phlebotomy– only in symptomatic erythocytoses with hyperviscosity symptoms– iron deficiency– iron replacement? close laboratory controls– defiency of folic acid, vitamin-B12?
• contraception– adequate contracaption in time– consulting service with pediatric cardiologist and experienced gynecologist– CAVE: interactions with some drugs (e.g. ERA)
General Measures
• oxygen– APAH-CHD: controversial, at the discretion of physician
– others: SpO2 < 90%, PaO2 < 60 mmHg, subjective benefit
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
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)
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
Drug Therapy
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
• according to rareness of disease sparse literature available formedical treatment in children
• 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.
Approved fields of application:
Primary arterial hypertension.
Symptomatic coronary heart disease.
Chronic stable, instable and vasospastic angina pectoris.
Amlodipin children: 0,2-0,5 mg/kg/d in 1-2 doses p.o.
adults: max. 10 mg/d in 1 dose p.o.
Diltiazem children: 1,5-3,5 mg/kg/d in 3-4 doses p.o.
adults: max. 360 mg/d in 1-3 doses p.o.
Nifedipin children: 1-2 mg/kg/d in 1 dose p.o.
adults: 40-max. 120 mg in 1-2 doses p.o.
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
IPAH/HPAHresponder
positive experiences in adults
NOT in APAH-CHD
Endothelin-Receptor-Antagonists
Bosentan Approval: age ≥ 2 years
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.“
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)
Ambrisentanchildren: no approval
adults: 5 - 10 mg qd p.o.
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
side effects:liver toxicity
drug interactions
Phosphodiesterase-5-Inhibitors
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
Sildenafil 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: 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)
Tadalafilchildren: no approval
adults: 40 mg qd p.o.
10/2011: “Rote-Hand-Brief”
ProstanoidsCombination Therapy
Prostanoids
In children and adolescense off label-use.• 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 therapyInsufficient data indication only in expert centers
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
Interventional Procedures
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
Atrial septostomy / Stent
• in case of failing medical therapy
• palliation in decompensated ptswith RV failure
• high risk
Surgery
General Measures
Drug Therapy
Interventional Procedures
Surgical Aspects
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
• special functional parameters
- echocardiography
- blood tests: blood gases, blood cell count,
kidney-/ liver-parameters, (NT-pro)BNP
progress of PAH therapeutic escalation
• catheterization
throughout life !
Prevention
APAH-CHD
• OP in time
IPAH/HPAH
• no specific prevention
• chance: genetic counselling
DGPK GuidelinePulmonary Arterial Hypertension (PAH)
in Infancy and Adolescence
www.kinderkardiologie.org/dgpkLeitlinien.shtml