dgpk guideline pulmonary arterial hypertension (pah) in infancy and adolescence siegrun mebus (dhm,...

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

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



f:m = 1,7:1

• Survival Period

General Issues

Rabinovitch 1997Rabinovitch 1996



f:m = 1,7:1

• Survival Period

• Pathophysiology

• Histopathology

Rabinovitch2008

General Issues

Rabinovitch 1997Rabinovitch 1996



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


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


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


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


general therapeutic goals• delay of disease progression• improvement of symptoms• improvement of quality of life

Therapy & Indication



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



General Measures

Drug Therapy

Interventional Procedures

Surgical Aspects

General Measures

General Measures

Drug Therapy


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


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


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


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


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


Surgical Aspects

Drug Therapy

General Measures

Drug Therapy


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


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


Surgical Aspects

side effects:liver toxicity

drug interactions

Phosphodiesterase-5-Inhibitors

General Measures

Drug Therapy


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


Surgical Aspects


General Measures

Drug Therapy


Surgical Aspects

Atrial septostomy / Stent

• in case of failing medical therapy

• palliation in decompensated ptswith RV failure

• high risk

Surgery

General Measures

Drug Therapy


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

dgpk guideline pulmonary arterial hypertension (pah) in infancy and adolescence siegrun mebus (dhm,...

Documents