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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 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

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)


Conflicts of interests
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


Definition pah
Definition PAH

Dana Point (2008)

  • resting mean pulmonary arterial pressure mPAP ≥ 25 mmHg

  • pulmonary arterial wedge pressure ≤ 15 mmHg


Definition pah1
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
Classification PAH

Idiopathic PAH

(IPAH)

Heritable PAH

(HPAH)

APAH-CHD

Simonneau JACC 2009


Classification pah1
Classification PAH

Idiopathic PAH

(IPAH)

Heritable PAH

(HPAH)

APAH-CHD

Simonneau JACC 2009



General issues1
General Issues

  • Epidemiology

    incidence: 0,48/1 M children/year

    prevalence: IPAH/HPAH 2,07/1 M children

    f:m = 1,7:1


General issues2
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 issues3
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


General issues4
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


Symptoms
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
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
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


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
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



Laboratory assessment
Laboratory assessment

Diagnostic and prognostic marker


Cardiac catheterisation
Cardiac catheterisation

  • incl. acute pulmonary vasodilator testing

  • gold standard(accurate differential diagnosis)

  • quantitation ofpulmonary arterial pressures

  • pulmonary vasoreactivity


Cardiac catheterisation1
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 catheterisation2
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


Cardiac catheterisation3
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
Therapy

PAH = fatal, not-curable disease


Therapy1
Therapy

  • PAH = fatal, not-curable disease

  • general therapeutic goals

  • delay of disease progression

  • improvement of symptoms

  • improvement of quality of life


Therapy indication
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


Therapeutic options
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

  • 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 measures1
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


General measures2
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


General measures3
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


General measures4
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 measures5
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
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


Calcium channel blockers
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


Endothelin receptor antagonists
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


Phosphodiesterase 5 inhibitors
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”


Prostanoids combination therapy
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


Interventional procedures
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


Surgery
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


Follow up
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
Prevention

APAH-CHD

OP in time

IPAH/HPAH

no specific prevention

chance: genetic counselling


Dgpk guideline pulmonary arterial hypertension pah in infancy and adolescence1

DGPK GuidelinePulmonary Arterial Hypertension (PAH)in Infancy and Adolescence

www.kinderkardiologie.org/dgpkLeitlinien.shtml


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