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

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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)

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Conflicts of Interests
Leitlinienkoordinator Prof. Dr. med. Jochen
Weil Leitlinie Pulmonary arterial hypertension
(PAH) in infancy and adolescence
C. Apitz
S. Mebus
M.M. Hoeper
G.-P. Diller
M. Gorenflo
O. Miera
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Berater- bzw. Gutachtertätigkeit oder bezahlte
Mitarbeit in einem wissenschaftlichen Beirat
eines Unternehmens der Gesundheitswirtschaft
(z.B. Arzneimittelindustrie, Medizinproduktindustr
ie), eines kommerziell orientierten
Auftragsinstituts oder einer Versicherung
Actelion
Actelion
Actelion
Actelion Pfizer
Actelion, Bayer, Gilead, GSK, Lilly, Pfizer, Novar
tis
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Honorare für Vortrags- und Schulungstätigkeiten
oder bezahlte Autoren- oder Co-Autorenschaften im
Auftrag eines Unternehmens der Gesundheitswirtscha
ft, eines kommerziell orientierten
Auftragsinstituts oder einer Versicherung
Actelion Pfizer GSK
Actelion Pfizer
Actelion GB
Actelion Pfizer
Actelion, Bayer, Gilead, GSK, Lilly, Pfizer,
Novartis
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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
Ø
Actelion Bayer Pfizer Novartis
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Eigentümerinteresse an Arzneimitteln/Medizinproduk
ten (z. B. Patent, Urheberrecht, Verkaufslizenz)
Ø
Ø
Ø
Ø
Ø
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Besitz von Geschäftsanteilen, Aktien, Fonds mit
Beteiligung von Unternehmen der
Gesundheitswirtschaft
Ø
Ø
Ø
Ø
Ø
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Persönliche Beziehungen zu einem
Vertretungsberechtigten eines Unternehmens
Gesundheitswirtschaft
Ø
Ø
Ø
Ø
Ø
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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
Ø
DGK ERS ESC
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Politische, akademische (z.B. Zugehörigkeit zu
bestimmten Schulen), wissenschaftliche oder
persönliche Interessen, die mögliche Konflikte
begründen könnten
Ø
Ø
keine relevanten
Ø
Ø
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Gegenwärtiger Arbeitgeber, relevante frühere
Arbeitgeber der letzten 3 Jahre
DHM, TUM
UKGM Giessen
RBP, London UKM
DHZB
MHH
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Definition PAH

• Dana Point (2008)
• resting mean pulmonary arterial pressure mPAP
  25 mmHg
• pulmonary arterial wedge pressure 15 mmHg

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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 thoughPVRI gt 3 Wood units (Um2)
  pathological increased

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

• Epidemiology
• incidence 0,48/1 M children/year
• prevalence IPAH/HPAH 2,07/1 M children
• fm 1,71

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General Issues

• Epidemiology
• incidence 0,48/1 M children/year
• prevalence IPAH/HPAH 2,07/1 M children
• fm 1,71
• Survival Period

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General Issues

• Epidemiology
• incidence 0,48/1 M children/year
• prevalence IPAH/HPAH 2,07/1 M children
• fm 1,71
• Survival Period
• Pathophysiology
• Histopathology

Rabinovitch 2008
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General Issues

• Epidemiology
• incidence 0,48/1 M children/year
• prevalence IPAH/HPAH 2,07/1 M children
• fm 1,71
• Survival Period
• Pathophysiology
• Histopathology
• Genetic Aspects
• BMPR2
• 50-70 HPAH
• 10-40 sporadic IPAH

Rabinovitch 2008
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Symptoms

• UNSPECIFIC !
• Varying Clinical Findings
• cor cardiac murmur
• lungs obstructive pulmonary disease
• advanced stagessigns of right heart
  insufficiencysymptoms at rest
• APAH-CHD Eisenmengers Syndromesigns of
  chronical cyanosis

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Diagnostic Investigation

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

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Diagnostic Tools

• Diagnostic Tools

• Useful Diagnosticsin individual cases

• echocardiography
• ECG
• pulse oximetry
• chest-X-ray
• pulmonary function test
• CPX
• 6-MWT
• laboratory assessment
• cardiac catheterisation incl. acute pulmonary
  vasodilatortesting

• spiral CT scan
• MRI angiography
• V/Q-Scan
• sleep laboratory/polysomnography
• genetic analysis

Procedures pediatric cardiologist experienced
pediatric cardiologic center
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ECG

• normal ECG doesnt exclude PAH!
• right heart strain?
• rhythm disturbances?
• Eisenmenger patientscardiac arrhythmia
  (Holter-ECG) is associated with a poor prognosis
  

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Echocardiography

• most significant non-invasive screening method
• detection/ exclusion of characteristicmorphologic
  al 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

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Echocardiography
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Laboratory assessment
Diagnostic and prognostic marker
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Cardiac catheterisation

• incl. acute pulmonary vasodilator testing
• gold standard(accurate differential diagnosis)
• quantitation ofpulmonary arterial pressures
• pulmonary vasoreactivity

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Cardiac catheterisation

• incl. acute pulmonary vasodilator testing
• spontaneous breathing (anesthetic risk)
• baseline hemodynamics
• testing of acute pulmonary vascular
  reactivitywith iNO, O2, inh. Iloprost,combinatio
  ns thereof
• http//www.kompetenznetz-ahf.de/
• forschung/klinische-studien/leitlinien

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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

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Cardiac catheterisation

• APAH-CHD
• Rp/Rs lt 0,2 ? OP
• Rp/Rs 0,2-0,3 ? increased OP-risk
• Rp/Rs gt 0,3 ? individual treatment plan
  special surgical methods necessary e.g.
  fenestration

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Therapy
PAH fatal, not-curable disease
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Therapy

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

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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

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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
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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
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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
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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
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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
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General Measures
General Measures

• oxygen
• APAH-CHD controversial, at the discretion of
  physician
• others SpO2 lt 90, PaO2 lt 60 mmHg, subjective
  benefit

Drug Therapy
Interventional Procedures
Surgical Aspects
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General Measures
General Measures

• oxygen
• APAH-CHD controversial, at the discretion of
  physician
• others SpO2 lt 90, PaO2 lt 60 mmHg, subjective
  benefit
• oral anticoagulation
• IPAH/HPAH, thromboembolic PHØ hempotysis ?
  OAK(class of recommendation IIa INR 2,0-3,0)
• APAH-CHDonly in particular cases (e.g. rhythm
  disturbances, thromboembolie)

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

• 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
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Endothelin-Receptor-Antagonists
General Measures

• 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 5 - 10 mg qd p.o.

Drug Therapy
Interventional Procedures
Surgical Aspects
side effects liver toxicity drug interactions
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Phosphodiesterase-5-Inhibitors
General Measures

• 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 lt x 20 kg, age 1 year 10 mg tid
  p.o.
• BW gt 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
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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
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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
Surgical Aspects
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Surgery
General Measures

• failing medical/ interventional treatment
• thoracic organ transplantationLTX, HLTX
• CAVE survival rateschildren with PAH bil. LTX
  - mean survival 45 months (2-123 months)
• - 5.8 years
• experimental Potts shunt

Drug Therapy
Interventional Procedures
Surgical Aspects
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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 !
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Prevention

• APAH-CHD
• OP in time
• IPAH/HPAH
• no specific prevention
• chance genetic counselling

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