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DGPK Guideline Pulmonary Arterial Hypertension (PAH) in Infancy and Adolescence Siegrun Mebus (DHM, TU München) Christian Apitz (UKGM, Giessen) Gerhard-Paul.

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Präsentation zum Thema: "DGPK Guideline Pulmonary Arterial Hypertension (PAH) in Infancy and Adolescence Siegrun Mebus (DHM, TU München) Christian Apitz (UKGM, Giessen) Gerhard-Paul."—  Präsentation transkript:

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)

2 C. ApitzS. MebusM.M. HoeperG.-P. DillerM. GorenfloO. Miera Conflicts of Interests Leitlinienkoordinator:Prof. Dr. med. Jochen Weil Leitlinie:Pulmonary arterial hypertension (PAH) in infancy and adolescence 1Berater- 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 2Honorare für Vortrags- und Schulungstätigkeiten oder bezahlte Autoren- oder Co-Autorenschaften im Auftrag eines Unternehmens der Gesundheitswirtschaft, eines kommerziell orientierten Auftragsinstituts oder einer Versicherung Actelion Pfizer GSK 3Finanzielle Zuwendungen (Drittmittel) für Forschungsvorhaben oder direkte Finanzierung von Mitarbeitern der Einrichtung von Seiten eines Unternehmens der Gesundheitswirtschaft, eines kommerziell orientierten Auftragsinstituts oder einer Versicherung Pfizer 4Eigentümerinteresse an Arzneimitteln/Medizinprodukten (z. B. Patent, Urheberrecht, Verkaufslizenz) Ø 5Besitz von Geschäftsanteilen, Aktien, Fonds mit Beteiligung von Unternehmen der Gesundheitswirtschaft 6Persönliche Beziehungen zu einem Vertretungsberechtigten eines Unternehmens Gesundheitswirtschaft Ø 7Mitglied von in Zusammenhang mit der Leitlinienentwicklung relevanten Fachgesellschaften/Berufsverbänden, Mandatsträger im Rahmen der Leitlinienentwicklung DGPK DGKJ AEPC KN-AHF 8Politische, akademische (z.B. Zugehörigkeit zu bestimmten Schulen), wissenschaftliche oder persönliche Interessen, die mögliche Konflikte begründen könnten Ø 9Gegenwärtiger Arbeitgeber, relevante frühere Arbeitgeber der letzten 3 Jahre DHM, TUM Ø Actelion Pfizer Ø Ø Ø DGPK DGKJ AEPC Ø UKGM Giessen Ø Actelion Actelion GB Pfizer GB Ø Ø keine relevanten RBP, London UKM Ø Actelion Pfizer Actelion Pfizer Ø Ø Ø Ø Ø DHZB Ø Actelion Bayer Schering Ø Ø Ø DGPK DGK DGKJ GNPI AEPC Ø UK Heidelberg ZU Leuven Ø Actelion, Bayer, Gilead, GSK, Lilly, Pfizer, Novartis Actelion, Bayer, Gilead, GSK, Lilly, Pfizer, Novartis Actelion Bayer Pfizer Novartis Ø Ø DGK ERS ESC Ø MHH Ø

3 Definition PAH Dana Point (2008) resting mean pulmonary arterial pressure mPAP 25 mmHg pulmonary arterial wedge pressure 15 mmHg

4 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*m 2 ) pathological increased

5 Classification PAH Idiopathic PAH (IPAH) Heritable PAH (HPAH) APAH-CHD Simonneau JACC 2009

6 Classification PAH Idiopathic PAH (IPAH) Heritable PAH (HPAH) APAH-CHD Simonneau JACC 2009

7 General Issues

8 Epidemiology incidence: 0,48/1 M children/year prevalence: IPAH/HPAH 2,07/1 M children f:m = 1,7:1

9 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

10 General Issues Rabinovitch 1997 Rabinovitch 1996 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 2008

11 General Issues Rabinovitch 1997 Rabinovitch 1996 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 Genetic Aspects BMPR % HPAH 10-40% sporadic IPAH Rabinovitch 2008

12 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

13 Diagnostic Investigation Aims To confirm the diagnosis evaluate severity of PAH identify right ventricular function find out causation of PAH evaluate pulmonary vasoreagibility

14 Diagnostic Tools echocardiography ECG pulse oximetry chest-X-ray pulmonary function test CPX 6-MWT laboratory assessment cardiac catheterisation incl. acute pulmonary vasodilator testing Useful Diagnostics in individual cases spiral CT scan MRI angiography V/Q-Scan sleep laboratory/ polysomnography genetic analysis Diagnostic Tools Procedures: pediatric cardiologist experienced pediatric cardiologic center

15 ECG normal ECG doesn´t exclude PAH! right heart strain? rhythm disturbances? Eisenmenger patients: cardiac arrhythmia (Holter-ECG) is associated with a poor prognosis

16 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

17 Echocardiography

18 Laboratory assessment Diagnostic and prognostic marker

19 Cardiac catheterisation incl. acute pulmonary vasodilator testing gold standard (accurate differential diagnosis) quantitation of pulmonary arterial pressures pulmonary vasoreactivity

20 Cardiac catheterisation incl. acute pulmonary vasodilator testing spontaneous breathing (anesthetic risk) baseline hemodynamics testing of acute pulmonary vascular reactivity with iNO, O 2, inh. Iloprost, combinations thereof forschung/klinische-studien/leitlinien

21 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

22 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

23 Therapy PAH = fatal, not-curable disease

24 Therapy PAH = fatal, not-curable disease general therapeutic goals delay of disease progression improvement of symptoms improvement of quality of life

25 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

26 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

27 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

28 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 m above sea level uncomplicated –air pressure in plane cabins corresponds to air pressure at a height of m above sea level individual discussions

29 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?

30 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)

31 General Measures oxygen –APAH-CHD: controversial, at the discretion of physician –others: SpO 2 < 90%, PaO 2 < 60 mmHg, subjective benefit General Measures Drug Therapy Interventional Procedures Surgical Aspects

32 General Measures oxygen –APAH-CHD: controversial, at the discretion of physician –others: SpO 2 < 90%, PaO 2 < 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

33 Drug Therapy General Measures Drug Therapy Interventional Procedures Surgical Aspects according to rareness of disease sparse literature available for medical treatment in children children: case reports, small case series drug application in children adults approved drugs for children: Bosentan & Sildenafil

34 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. Amlodipinchildren: 0,2-0,5 mg/kg/d in 1-2 doses p.o. adults:max. 10 mg/d in 1 dose p.o. Diltiazemchildren: 1,5-3,5 mg/kg/d in 3-4 doses p.o. adults:max. 360 mg/d in 1-3 doses p.o. Nifedipinchildren: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/HPAH responder positive experiences in adults NOT in APAH-CHD

35 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) Ambrisentan children: no approval adults: mg qd p.o. General Measures Drug Therapy Interventional Procedures Surgical Aspects side effects: liver toxicity drug interactions

36 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: BW8 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) Tadalafil children:no approval adults:40 mg qd p.o. 10/2011: Rote-Hand-Brief

37 Prostanoids Combination 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 therapy Insufficient data indication only in expert centers General Measures Drug Therapy Interventional Procedures Surgical Aspects

38 Interventional Procedures General Measures Drug Therapy Interventional Procedures Surgical Aspects Atrial septostomy / Stent in case of failing medical therapy palliation in decompensated pts with RV failure high risk

39 Surgery General Measures Drug Therapy Interventional Procedures Surgical Aspects failing medical/ interventional treatment thoracic organ transplantation LTX, HLTX CAVE: survival rates children with PAH: bil. LTX - mean survival 45 months (2-123 months) years experimental: Pott´s shunt

40 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 !

41 Prevention APAH-CHD OP in time IPAH/HPAH no specific prevention chance: genetic counselling

42 DGPK Guideline Pulmonary Arterial Hypertension (PAH) in Infancy and Adolescence


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