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

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)

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

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  1. 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)

  2. Conflicts of Interests Leitlinienkoordinator: Prof. Dr. med. Jochen Weil Leitlinie: Pulmonary arterial hypertension (PAH) in infancy and adolescence S. Mebus C. Apitz G.-P. Diller M.M. Hoeper O. Miera M. Gorenflo 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 Actelion Actelion Actelion, Bayer, Gilead, GSK, Lilly, Pfizer, Novartis Actelion Pfizer Actelion 2 Honorare 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 Actelion Pfizer Actelion GB Actelion, Bayer, Gilead, GSK, Lilly, Pfizer, Novartis Actelion Pfizer Actelion Bayer Schering 3 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 Pfizer Ø Actelion GB Pfizer GB Actelion Bayer Pfizer Novartis Ø Ø 4 Eigentümerinteresse an Arzneimitteln/Medizinprodukten (z. B. Patent, Urheberrecht, Verkaufslizenz) Ø Ø Ø Ø Ø Ø 5 Besitz von Geschäftsanteilen, Aktien, Fonds mit Beteiligung von Unternehmen der Gesundheitswirtschaft Ø Ø Ø Ø Ø Ø 6 Persönliche Beziehungen zu einem Vertretungsberechtigten eines Unternehmens Gesundheitswirtschaft Ø Ø Ø Ø Ø Ø 7 Mitglied von in Zusammenhang mit der Leitlinienentwicklung relevanten Fachgesellschaften/Berufsverbänden, Mandatsträger im Rahmen der Leitlinienentwicklung DGPK DGKJ AEPC KN-AHF DGPK DGKJ AEPC keine relevanten DGK ERS ESC Ø DGPK DGK DGKJ GNPI AEPC 8 Politische, akademische (z.B. Zugehörigkeit zu bestimmten „Schulen“), wissenschaftliche oder persönliche Interessen, die mögliche Konflikte begründen könnten Ø Ø keine relevanten Ø Ø Ø 9 Gegenwärtiger Arbeitgeber, relevante frühere Arbeitgeber der letzten 3 Jahre DHM, TUM UKGM Giessen RBP, London UKM MHH DHZB UK Heidelberg ZU Leuven

  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 forpulmonary vascular resistance (PVR) even though:PVRI > 3 Wood units (U*m2) 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. General Issues • 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 • 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 2008 Rabinovitch 1996

  11. General Issues • Epidemiology incidence: 0,48/1 M children/year prevalence: IPAH/HPAH 2,07/1 M children f:m = 1,7:1 • SurvivalPeriod • Pathophysiology • Histopathology • GeneticAspects BMPR2 50-70% HPAH 10-40% sporadic IPAH Rabinovitch 1997 Rabinovitch 2008 Rabinovitch 1996

  12. 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

  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 Diagnostic Tools Useful Diagnosticsin individual cases spiral CT scan MRI angiography V/Q-Scan sleeplaboratory/polysomnography geneticanalysis • echocardiography • ECG • pulse oximetry • chest-X-ray • pulmonary function test • CPX • 6-MWT • laboratory assessment • cardiac catheterisation incl. acute pulmonary vasodilatortesting 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 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 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 ofpulmonary arterial pressures • pulmonary vasoreactivity

  20. 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

  21. Cardiac catheterisation • present pulmonary vascular reactivity • decrease of Rp/Rs ≥ 20% • IPAH/HPAH: response to medical treatmentwith 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 APAH-CHD no causal therapeutic options related to rapid progression early treatment 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 Interventional Procedures Drug Therapy Surgical Aspects

  27. 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

  28. 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 • 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 Drug Therapy Interventional Procedures Surgical Aspects

  29. General Measures General Measures • phlebotomy • 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

  30. General Measures General Measures • 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) Drug Therapy Interventional Procedures Surgical Aspects

  31. 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

  32. 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

  33. Drug Therapy General Measures • 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 Drug Therapy Interventional Procedures Surgical Aspects

  34. Calcium Channel Blockers IPAH/HPAH responder positive experiences in adults NOT in APAH-CHD General Measures 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. Drug Therapy Interventional Procedures Surgical Aspects

  35. Endothelin-Receptor-Antagonists General Measures BosentanApproval: 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: 5 - 10 mg qd p.o. Drug Therapy Interventional Procedures Surgical Aspects side effects: liver toxicity drug interactions

  36. Phosphodiesterase-5-Inhibitors General Measures SildenafilApproval: 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) Tadalafil children: no approval adults: 40 mg qd p.o. Drug Therapy Interventional Procedures Surgical Aspects 10/2011: “Rote-Hand-Brief”

  37. ProstanoidsCombination Therapy General Measures 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 Drug Therapy Interventional Procedures Surgical Aspects

  38. Interventional Procedures General Measures • Atrial septostomy / Stent • in case of failing medical therapy • palliation in decompensated ptswith RV failure • high risk Drug Therapy Interventional Procedures SurgicalAspects

  39. Surgery General Measures • failingmedical/ interventionaltreatment • thoracicorgantransplantationLTX, HLTX • CAVE: survivalrateschildrenwith PAH: bil. LTX - meansurvival 45 months (2-123 months) • - 5.8 years • experimental: Pott´sshunt Drug Therapy Interventional Procedures Surgical Aspects

  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 GuidelinePulmonary Arterial Hypertension (PAH)in Infancy and Adolescence www.kinderkardiologie.org/dgpkLeitlinien.shtml

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