Pulmonale Hypertensie: Inleiding
Refereeravond IC 2014
Dr Yvonne Heijdra
longarts
JACC december 2013 supplement D
Task Force definition PAH and diagnosis
!
!
• PH: mPAP > 25 mmHg in rust tijdens catheterisatie
• pre en post capillaire PH
• PAH: subpopulatie
•
•
•
Precappilaire
Pulmonary Capillary Wedge Pressure (of LVEDP) < 15 mm Hg
Pulmonale vaatweerstand > 3 Woods units mmHg/ l*min
!
Hart catheterisatie noodzakelijk voor onderscheid
!
• Geen plaats voor borderline PAH 21-24 mm Hg
• Geen inclusie inspannings PAH
Specific taskforce: update clinical classification
!
!
•
•
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•
•
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Zelfde classificatie volwassenen en kinderen
Afzonderlijke categorie persisterende PH bij neonaten
Toevoegen genetische oorzaken
Hemolytische anemie van 1 naar 5
Nieuwe medicatie die PH kan induceren
Groep 2, 3 en 4 onveranderd
Pathology and pathobiology task Force
• Meer herkenning veno occlusive disease
!
• Pan vasculopathie
•
•
•
•
Metabole veranderingen
Inflammatie
Dysregulatie
Groeifactoren
!
• Prognose bepaald door RVF
Task force on Pathophysiology
Maladaptive and adaptive right ventricle
Gevolgen vasculaire veranderingen
• Toename vasculaire weerstand
• Toename druk A pulmonalis
• Overload Re Ventrikel met uiteindelijk Re ventrikel falen
10
Updated treatment algorithm
• 1: algemene maatregelen, supportive therapie, verwijzing,
vasoreactiviteits testen, Ca blockers
!
• 2: PAH drugs
!
• 3: Combinatie therapie, arterial septostomie, longtransplantatie
!
!
• Titreren op outcome measurements: aggressiever!!
Genetics and Genomics Task Force
Task Force on left heart disease and pulmonary disease
Treatment Algorithm of Pulmonary Arterial Hypertension
Journal club 22 januari 2014
!
!
!
• “To date, no guidelines or consensus statement on the management
of pulmonary hypertension in critically ill patients exists. Although
several reviews have been published, the management of
pulmonary hypertension in the specific setting of the ICU is mainly
based on expert opinion.”
Gayat E, et al. Pulmonary hypertension in the critical care. Curr Opinion Crit Care 17:439-448
Simmonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol
2004;43:Suppl S:5S-12S
Pathophysiological features
Humbert M, et al. N Engl J Med 2004;351:1425-36
Pulmonary arterial hypertension: survival
!
• Survival 1981-1985
!
• 1 year: 68%
!
• 3 year: 48%
!
• 5 year: 34%
D’Alonzo et al. Survival in patients with primairy pulmonary hypertension. Results from a national
prospective registry. Ann Intern Med. 1991 sep 1;115(5):343-9
Pulmonary arterial hypertension: survival
Benza L, et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial
hypertension from the REVEAL registry. Chest 2012;142(2):448-456
World Symposium on Pulmonary Hypertension
• 1998:
• Epoprostanol
• 2003:
• Prostanoids (3)
• Endothelin receptor antagonists (1)
• Phosphodiesterase type 5 inhibitors (1)
• 2008:
• Prostanoids (4)
• Endothelin receptor antagonists (2)
• Phosphodiesterase type 5 inhibitors (2)
Therapeutic strategies
• Basic therapy
•
•
•
•
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Exercise
Oxygen
Diuretic therapy
Cardiac glycosides
Pregnancy
Anticoagulantia
Calcium-channel blockers
Weinstein AA, Chin LMK, Keyser RE, et al. Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension. Respir Med
2013;107:778-84.
Chan L, Chin LM, Kennedy M, et al. Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertnsion.
Chest 2013;143:333-43
Rubin LJ, Rich S. Medical management. In: Rubin L, Rich S, eds. Primary pulmonary hypertension. New York: Marcel Dekker,1997:271-86
Rich S, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest 1998;114:787-92
Jais X, Olsson KM, Barbera JA, et al. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. Eur Respir J 2012;40:881-5
Sitbon O, et al. Who benefits from long-term calcium-channel blocker therapy in primairy pulmonary hypertension? Am J Respir Crit Care Med 2003;167:A440
Endothelin pathway
• Ambrisentan, selective endothelin-A receptor
antagonist
!
•
•
•
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ARIES 1 and 2 study
Randomized, double-blind, placebo-controlled, multicentre
WHO-FC II/III, 202 resp 192 patients with PAH
Primairy outcome: 6MWD
Secundairy outcome: Clinical worsening, WHO-FC
!
•
•
Results: significant improvement in 6MWD. Efficacy on symptoms,
exercise capacity, hemodynamics and time to clinical worsening
Approved for PAH treatment
Galie N, Olschewski H, Oudiz RJ et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the Ambrisentan in
pulmonary arterial hypertension. Randomized, double-blind placebo controlled, multicenter efficay (ARIES) study 1 and 2. Circulation
2008;117:3010-9
Endothelin pathway
• Bosentan, dual endothelin A and B receptor
antagonist
!
•
•
•
5 RCT’s, 32-213 patients
Improvement in exercise capacity, functional class, hemodynamics and
time to clinical worsening
Reversible, dose-dependent liver function abnormalities
Channick RN, Simmonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist Bosentan in patients with pulmonary hypertension: a randomised placebocontrolled study. Lancet 2001;358:1119-23
Galie N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arteial hypertension with Bosentan (EARLY study): a double-blind, randomised
controlled trial. Lancet 2008;371:2093-100
Rubin LJ, Badesch DB, Barst RJ , et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903
Humbert M, et al. Combination of Bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-9
Galie N, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled tudy. Circulation 2006;114:48-54
Endothelin pathway
• Macitentan, dual endothelin A and B receptor
antagonist
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•
SERAPHIN trial
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•
742 patients
!
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Macitentan 3mg-10mg versus placebo
!
•
Results: reduction in mortality, morbidity, increased exercise capacity
Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med
2013;369:809-18
!
Riociguat for the treatment of pulmonary arterial hypertension
Patient selection
• Symptomatic PAH
!
• PVR > 300 dyn.sec.cm-5
!
• mPAP >25mmHg
!
• 6MWD 150-450m
!
• No treatment for PAH or an ERA/Prostanoids
Ghofrani HA, et al Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-340
Study procedure
• 3 study arms:
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•
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Placebo
Oral Riocyguat 2,5mg 3dd
Oral Riocyguat 1,5mg 3dd
Randomization 2:4:1
• 12 weeks follow-up
• Patients who completed the 12 week study, long-term follow-up
(PATENT-2 study)
• Primairy endpoint:
•
6MWD
• Secundairy endpoint:
•
PVR, NT-proBNP, WHO-FC, Time to clinical worsening, Borg dyspnoe
score
Results
Results
Discussion
!
• Riociguat significantly improve exercise
capacity and hemodynamic parameters
!
• Large proportion had a WHO-FC I/II
!
• Patients who received treatment with
phosphodiesterase type 5 inhibitors or iv
prostanoids were excluded
Nitric oxide pathway
• Sildenafil, PDE-5: inhibition of cGMP degrading
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•
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•
!
PACES trial, double-blind, placebo-controlled,
multicenter
267 patients
Combination therapy Epoprostenol and Sildenafil
(20mg 3dd) versus epoprostenol
Results: improvement in 6MWD and time to clinical
worsening
Simmonneau G, et al Addition of sildenafil to long-term epoprostenol therapy in patients with
pulmonary hypertension. Ann Intern Med 2008;149:521-30.
Nitric oxide pathway
• Sildenafil, PDE-5: inhibition of cGMP degrading
•
•
•
•
!
Super-1 trial
!
278 patients, double-blind, placebo-controlled study
!
Sildenafil 20mg, 40mg and 80mg versus placebo, 12
weeks follow-up.
!
Results: improvement of exercise capacity, WHO
functional class and hemodynamics
Galie N, et al Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57
Nitric oxide pathway
!
• Tadalafil, selective PDE-5i, increases cGMP
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Double-blind, placebo-controlled study, 405 patients
Placebo versus Tadalafil (2,5-5-10-20-40mg 1dd)
16 weeks follow-up
Results:
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Improved time to clinical worsening
Improved health-related quality of life
Improved symptoms and hemodynamics
No changes in WHO functional class
Galie N, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-903
Prostacyclin pathway
• Beraprost, oral active prostacyclin analogue
!
•
ALPHABET trial, RCT 130 patients,
• Improvement in exercise capacity and symptoms
• No effect on hemodynamics or WHO-FC
!
•
BARST trial, RCT 118 patients
• Improvement in exercise capacity, less disease progression, no effect
on hemodynamic
• No significant effect after 9-12 months
Galie N, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulomonary arterial hypertension: a
randomised, double-blind placebo-controlled trial. J Am Coll Cardiol 2002;39:1496-502
Bart RJ, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2125
Prostacyclin
pathway
!
!
• Epoprostanol
!
• 3 unblinded RCT’s
• 23-111 patients
• 12 weeks follow-up
• Improvement in exercise capacity (6MWD), symptoms
and hemodynamics
• Meta-analysis: total mortality relative risk reduction
70%
Rubin LJ, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin. Results
of randomized trial. Ann Intern Med 1990;112:485-91)
Bart RJ, et al. Primary pulmonary Hypertension Study Group. A comparison of continuous interavenous
epoprostenol with conventional therapy for primairy pulmonary hypertension. N Engl J Med 1996;334:296-302
Badesch DB, et al Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma
spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132:425-34
Prostacyclin pathway
• Iloprost
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•
1
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•
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RCT, Aerosilized Iloprost Radomized study
203 patients
6-9 times 2,5-5 µg/inhalation versus placebo
Results:
• Increase in exercise capacity
• Improvement in symptoms
• PVR↓
2 RCT’s, combination of bosentan and iliprost
Olschewski H, et al. Inhaled iloprost in severe pulmonary hypertension. N Engl J med 2002;347:322-9
Prostacyclin pathway
• Treprostinil (Remoduline)
•
•
Tricyclic benzidine analogue of epoprostanol
• Administration: iv, sc and oral
TRIUMPH trial (inhalation)
• 235 patients, NYHA III/IV
• Inhalation of treprostinil versus placebo (Bosentan/Sildenafil)
• 12 weeks follow-up
• Improvement in 6MWD and quality of life measures
• No improvement in time to clinical worsening, NYHA functional
class and PAH signs and symptoms
!
!
Mc Laughin V, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a
randomized controlled clinical trial. J Am Coll Cardiol 2010;55:1915-22
Prostacyclin pathway
!
• Treprostinil (Remoduline)
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•
•
RCT, 349 patients
Mono therapy (oral) versus placebo (no ERA/PDI)
Results:
• Improvement in 6MWD after 12 weeks.
• No improvement in WHO-FC, symptoms, time to clinical worsening
!
Jing ZC, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial
hypertension: a randomized, controlled trial. Circulation 2013;127:624-33
Prostacyclin pathway
• Treprostinil (Remoduline)
•
FREEDOM study
• Multicenter, double-blind, randomized, placebo-controlled study
• 310 patients
• Oral treprostinil versus placebo (ERA/PDE-5 or both)
• 16 weeks follow up
• No improvement in exercise, WHO-FC and signs and symtpoms of
PAH and clinical worsening
!
Tapson VF, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor
antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest 2013;142:1363-4
Combination therapy
• Meta-analysis: 6 RCT’s, 858 patients
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•
•
•
!
Reduction of the risk of clinical worsening
!
Increases the 6MWD
!
Reduction in mPAP, RAP and PVR
!
Incidence of mortality NS
Galie N, et al. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial metaanalyses. Eur Heart J 2010;31:2080-6
Interventional procedures
Treatment algoritm
• Diagnosis PAH?
• Start basic therapy
• Initiate supportive therapy
• Referral to an expert center
• Acute vasoreactivity testing: start CCB’s
• Non-responders/ WHO-FC II: start an oral
compound
• No evidence-based firstline treatment can be
proposed
• In WHO-FC IV patients: start with epoprostenol iv as
first choice
• In case of clinical inadequate response: double or
triple therapy
• In case of inadequate clinical response: consider
lungtransplantation or BAS
Future targets for therapeutics
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Vasodilators: Nitric oxide
Beta-blockers
RAAS system
Vascular remodeling
• Dichloro-acetete
• Ranolazine
Anti-inflammatory agents
• Rho-kinase inhibitors
• Rituximab
• Vasoactive intestinal peptide
Tyrosine kinase inhibitors
Stem cells
Gene therapy
Cell therapy
Devices
Pulmonale hypertensie bij chronische longziekten
Chronische longziekten
!
!
• COPD
!
• Idiopathische pulmonale fibrose (IPF) en
diffuse parenchymateuze longziekte (DPLD)
!
• Gecombineerde pulmonale fibrose en emfyseem (CPFE)
!
!
• Dyspnoe disproportioneel aan longfunctie, lage DLCO,
snelle daling PaO2 bij inspanning
Epidemiologie en klinische relevantie
!
• COPD
!
•
•
•
•
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Prevalentie hangt af v ernst COPD
GOLD IV 90% mPAP >20 mmHg
Morfologische aanwezigheid vasulaire laesies correleert met ernst PH
Matige inspanning > snelle stijging mPAP
Wijst op verlies longvasculaire elasticiteit en/of vaatrecruitment
mogelijkheden
PH progressie is traag bij COPD (<1 mmHg/jaar)
Aanwezigheid PH > sterkte voorspeller mortaliteit
5 jaar 36% bij mPAP >25 mmHg
• Idiopathische pulmonale fibrose (IPF) en
diffuse parenchymateuze longziekte (DPLD)
!
• Overleving an sich 2.5-3.5 jaar, mPAP >25 mmHg bij 8.1-14.9% initieel
Indien gevorderde ziekte 30-50% / eindstadium >60%, 9% >40 mmHg
• Weinig correlatie ernst PH en longfunctiebeperking/CT-fibrose-score
• mPAP >17 mmHg geassocieerd met lagere overleving
• mPAP en FVC onafhankelijke voorspeller overleving
• Snelle progressie PH in late stadia
• Gecombineerde pulmonale fibrose en emfyseem (CPFE)
!
•
•
•
30-50% PH
Ernstige PH / verminderde DLCO met nl longvolume en zonder obstructie
mPAP >35 mmHg 68% en >40 mmHg 48%
PH lijdt tot functiebeperking en slechte overleving
CI prognostische factor
Definitie
• “In” en “out of proportion”
!
!
1. COPD, IPF, CPFE zonder PH
2. PH-COPD, PH-IPF, PH-CPFE
3. Ernstige PH-COPD, PH-IPF, PH-CPFE
!
mPAP <25 mmHg
mPAP ≥25 mmHg
mPAP ≥35 mmHg of
mPAP ≥25 mmHg + CI <2.0
Circulatoire beperking van inspanningscapaciteit veroorzaakt door
obstructieve/restrictieve pulmonale beperking
!
!
!
DD groep 1 en 3
Behandeling
!
!
• Vasoactieve therapie in PH-COPD
!
•
!
Vasodilatatie > gaswisseling ↓ tgv lage ventilatie/perfusie ratio gebieden
1) Inhalatie prostanoiden > mPAP ↓ en PVR ↓ mbv gaswisseling
PLos One
2012;7:e52248
- geen lange-termijn studies
!
2) Bosentan
- kleine randomized controlled trial: gaswisseling ↓ zonder
toename inspanningtolerantie/kwaliteit Eur Respir J 2008;32:619-28
- kleine trial: ↑inspanningscapaciteit Adv Respir Dis 2009;3:15-21
> geen harde data pulmonale hemodynamiek / inspanning
!
• Vasoactieve therapie in longfibrose
!
•
•
Vasodilatatie > verslechtering gasuitwisseling ivm opheffen hypoxische
vasoconstrictie in meer aangedane gebieden
Inhalatie > in beter geventileerde en geoxygeneerde gebieden
iloprost/treprostinil/NO
> toename normoxische vasodilatatie
sildenafil (fosfodiesterase-5-inhibitor)
!
1) Prostanoiden
- geen lange-termijn studies PH-IPF
!
2) Niet-selectieve-endothelinereceptor antagonist vb bosentan
- trials negatief ikv progressie ziekte bij IPF
Am J Respir Crit Care2011;184:92-9, Ann Intern Med
2013;158:641-69
- PH-IPF bosentan B-PHIT NCT00637065
!
3) Sildenafil
- kleine open-label studie PH-IPF verbetering 6MWD Chest 2007;131:897-9
- controlled trial vergevorderd IPF: 6MWD (-), PaO2, DLCO, dyspnoe,
levenskwaliteit ↑ N Engl J Med 2010;363:620-8
- NCT00625079 PH-IPF volgt
!
4) Directe stimulatoren en activatoren van guanylaat cyclase
- fase II riociguat PH-DPLD: geen PAP ↓, wel PVR en systemische
vaatweerstand ↓ + 6MWD en CO ↑ Eur Respir J 2013;41:853-60
- randomized controlled trial PH-DPLD volgt
• Vasoactieve therapie in PH-CPFE
!
•
Wel case-reports, geen randomized controlled trial
Aanbeveling
Lange-termijn randomized controlled trials PH bij COPD/restrictieve longziekten
!
Milde obstructieve / restrictieve longziekte + PH
DD PH groep 1 of 3?
!
IPF met FVC <70% / COPD met FEV1 <60% / CPFE + PH 25-35 mmHg
!
Geen bewijs PAH medicatie
Meer ventilatoir dan hemodynamisch bepaalde problematiek
IPF met FVC <70% / COPD met FEV1 <60% / CPFE + PH >35 mmHg
Individuele zorg, PAH medicatie
Gaswisseling ↓ tgv ↓hypoxische vasocontrictie
Gaswisseling ↑ tgv ↑normoxische vasodilatatie en ↑ SvO2 tgv CI ↑
Randomized controlled trial / compassionate use / prospectieve registratie
Eindstadium obstructieve/restrictieve longziekte of combi
Levensverwachting stijgt ivm ECMO als bridge-to-transplantation en
(non-invasieve (nachtelijke)) thuisbeademing
!
PAH medicatie > inspanningscapaciteit, kwaliteit, tijd tot klinische
verslechtering, overleving, bridge-to-transplantation???????
Pediatric pulmonary hypertension
Journalclub 22 januari 2014
Anneliese Nusmeier
Intensive
Intensive Care
Care
Pediatric PH
• Distribution of etiologies children ≠ adults
!
• Diagnosis: ‘Standaard diagnostiek en behandeling PH bij kinderen
2013’
!
• Definition children = adults:
•
mean PAP > 25 mmHg and left atrium pressure at rest < 15 mmHg
!
• Predominance:
Idiopathic pulmonary artery hypertension (IPAH)
(0,7/million children/year)
PAH associated with congenital heart disease (APAH-CHD)
(2,2/million children/year)
Intensive Care
Pediatric PH survival
Circulation. 2012;125:113-122
Intensive Care
Pediatric PH classification
NICE classification 2013
1. Pulmonary arterial hypertension
I. Idiopathic (IPAH)
II. Heritable (HPAH)
III. Associated congenital heart disease
(APAH-CHD)
IV. Persistent PH of newborn (PPHN)
2. PH due to left heart disease
I. Congenital in-/out- flow tract
obstruction/cardiomyopathies
3. PH due to lung disease / hypoxia
I. Bronchopulmonary dysplasia (BPD)
II. Congenital diaphragmatic hernia
4. Chronic thromboembolic PH
5. PH with unclear multifactorial
mechanisms
Intensive Care
Pediatric PH classification
Intensive Care
Pediatric PH etiology
Pulm Circ. 2011; 1(2): 286–298
Intensive Care
Pediatric PH BPD
Curr Opin Pediatr 2013, 25:329–337
Pediatric Pulmonology 2014; 49:49–59
Intensive Care
Pediatric PH
Total
number
PH
Netherlands 3263
J Pediatr 2009;155:176-82
PAH
Transient
PAH
2845
82%
Progressi Lung
Tris 21
ve PAH
disease
/
hypoxi
a
5%
8%
58% PPHN
42% CHD
72% CHD
23% IPAH
12%
Intensive Care
Pediatric PH
• Treatment goals not well defined in children
!
• Indications repeated follow-up heart catheterisation:
•
•
•
•
•
Clinical deterioration
Assessment treatment effect
Detection early disease progression
Listing lung transplant
Prediction prognosis (loss of vasoreactivity)
Intensive Care
Pediatric PH treatment
• New therapeutic agents, agressive treatment strategies
• Lack of pediatric clinical trials
• Treatment strategy determined by risk stratification
Intensive Care
Pediatric PH treatment
JACC 2013; 62 (25 Suppl):117-26
Intensive Care
Pediatric PH
Early Human Develop.2013; 89: 865–874
Intensive Care
Pediatric PH
• Low risk
•
Monotherapy
• Endothelin receptor antagonist (bosentan, ambrisentan)
• Phosphodiesterase (PDE) 5 inhibitor (sildenafil, tadalafil)
!
• Low risk, deterioration
•
Addition of inhaled prostacyclin (iloprost, treprostinil)
!
• High risk
•
•
•
Initiation intravenous epoprostenol or treprostinil
Nb subcutaneous treprostinil available
Early consideration atrial septostomy, palliative Potts shunts, lung
transplant
Intensive Care
STARTS-1 & 2 study
• Barst RJ, et al. Circulation. 2012;125:324-334
!
• RCT, placebo controlled, dose ranging study of oral Sildenafil in
children with pulmonary arterial hypertension
!
• International study, 1-17 years, ≥ 8 kg, duration 16 weeks
!
• Goal:
safety and optimal pediatric dosing sildenafil in PAH
• End point: % change peak VO2
!
• Dosage regime;
3 dd low (10 mg), medium (10-40 mg), high (20-80mg),
placebo
Intensive Care
STARTS-1 & 2 study
Intensive Care
STARTS-1 & 2 study
Hazard ratio mortality H vs L 3,95 (95% CI 1,46-10,65)
Europ Heart 2012; 33 Suppl 1:979
Intensive Care
STARTS-1 & 2 study
• FDA and (European Medicines Agency) EMA recommendations:
!
•
FDA
• Warning against (chronic) use of sildenafil for children with PAH
!
•
EMA
• Dose approval sildenafil < 20kg 3dd 10mg and > 20kg 3 dd 20 mg
• Avoidance high doses
Am J Respir Crit Care Med 2013:187(6):572–575
Intensive Care
Pediatric PH summary
• Distribution and etiologies not comparable with adults
!
• Multifactorial causes and complex underlying diseases need
thorough diagnostic proces and individualised treatment
!
• Emphasize on continuous repeat evaluation for progression of
disease and therapeutic response
!
• Need of future clinical trials designed specifically for pediatric
patients with PH to optimize therapeutic guidelines
Intensive Care
Pulmonale HT tgv hartfalen
Refereeravond IC jan 2014
Pathofysiologie
•
Passieve retrograde druk verhoging in pulmonale systeem
•
Secundair vasculaire veranderingen
•
Pulmonale vaatafwijkingen, PH, RV falen
Oude definitie
•
•
•
mPAP ≥ 25 mmHg
PAWP > 15 mmHg
CO N - ↓
!
•
Te simpel/onnauwkeurig (mn bij keuze therapie)
Mogelijke presentaties
• Verhoogde PAWP, geen pulmonale vaatafwijkingen (PVD)
• Verhoogde PAWP, wel PVD
• Aanvankelijk verhoogde PAWP, inmiddels normaal (ontwateren), wel
PVD
!
• Diagnose PVD? (precapillaire remodeling)
•
Pulmonale vaatweerstand
•
Transpulmonary gradient (TPG) = mPAP-PAWP
•
Diastolic pressure difference (DPD) = dPAP-PAWP
Pulmonale vaatweerstand
• Pulmonale vaatweerstand (PVR)
•
•
PVR = 80 x (mPAP-PAWP)/CO dyn·s·cm−5
PVR = (mPAP-PAWP)/CO mm Hg/l.min (Woods units)
!
• Nadeel
•
•
flow en druk geen onafhankelijke variabelen
weinig gevoelig in rust
Transpulmonale gradient
•
TPG = mPAP-PAWP
•
Toename PAWP ook toename sPpa en mPpa
•
Effect groter bij hoger SV
•
Effect van PAWP op dPpa minder
•
TPG ≤ 12 mmHg: passieve PHT
•
TPG > 12 of 16 mmHg: out-of-proportion
!
Diastolic pressure difference
•
DPD = dPAP-PAWP
•
Nl DPD = 1-3 mmHg
•
PHT tgv hartziekte: DPD > 5-7 mmHg: betere voorspeller van out-of-proportion PHT
Gerges, Chest 2013
Nieuwe definitie
•
•
Geisoleerde postcapillaire PH
•
mPAP ≥ 25 mmHg
•
PAWP > 15 mmHg en DPD < 7 mmHG
Gecombineerde pre- en postcapillaire PH (out of proportion)
•
mPAP ≥ 25 mmHg
•
PAWP > 15 mmHg en DPD ≥ 7 mmHG
Progressie naar rechter kamer falen
• RE kamer afterload:
•
•
PVR
Pulmonale arteriele compliantie
• (Ca = PAPs-PAPd/SV)
• Sterkste voorspeller van slechte uitkomst
Pellegrini, Chest 2014
Behandeling
•
Behandeling van onderliggende hartziekte
•
Herstel klepfunctie
•
Herstel ischemische lesies
•
Optimaliseren volume status
•
Hartfalen medicatie
!
•
Behandeling/preventie van andere ziektes
•
COPD
•
Slaap-apnoe
•
longembolie
Behandeling
•
Gebruik van PAH therapie
• Indien tekenen van PVD
• Cave bijwerkingen
!
•
3
•
•
•
pathofysiologische pathways
Endotheline pathway
Prostanoids
NO pathway
Endotheline antagonisten
•
ET-1: positief inotroop en lusitroop
•
5 trials: negatief
•
Systolisch hartfalen
•
Optimalisatie volume status
•
Geen patiënten geincludeerd met kleplijden
Prostanoiden
• Geen effect bij systolisch hartfalen
PDE5 remmers
•
•
Sildenafil bij systolisch hartfalen
• Verlaging PVR
• Verbetering CO
• Betere inspanningstolerantie
Sildenalfil bij diastolisch falen: effectiviteit onduidelijk
!
•
Cave:
• Single centre
• Hoge dosis sildenafil (25-75 mg 3 dd)
!
•
2 trials onderweg
• Sildenafil
• Tadalafil
Guanylate cyclase stimulatie (sGC)
• Riociguat
Riociguat bij systolisch hartfalen: LEPHT
•
RCT, phase IIb, 202 patienten
•
Doel: Hd en klinische effecten, safety, tolerantie chronisch sGC
•
Populatie: volw, LVEF ≤ 40% en mPAP ≥ 25 mmHg (RCT), symptomatisch
•
Randomisatie 2:1:1:2 = placebo, riociguat 0.5-1-2 mg (3dd)
•
Prim uitkomst: verandering mPAP na 16 wkn
Bonderman, Circulation 2013
•
Primaire eindpunt negatief
•
Hoogste dosering betere
CI, PVR, SVR en QOL
•
Goed verdragen
Bonderman, Circulation 2013
Noradrenaline of dopamine?
Dopamine vaker aritmieen (AF)
De Backer et al, NEJM 2010
Dobutamine/noradrenaline of adrenaline?
Levy et al, CCM 2011
Noradrenaline of vasopressine?
How et al, Trans Res 2010
Dobutamine of levosimendan?
Unversagt et al, Cochrane 2014
Conclusie
• Nauwkeurige diagnostiek
•
•
Juiste behandelindicaties
Prognose vorming
!
• Behandelmogelijkheden beperkt
•
•
5PDE5 remmers
sGC