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Pediatric pulmonary hypertension

Maurice Beghetti Pediatric Cardiology Unit Children’s University Hospital, HUG, Geneva, Switzerland


Beghetti Maurice

Disclosures

l 

Consultant

Actelion, Bayer Schering, Novartis, GSK, Pfizer, Mondobiotech, Elilly

l 

Speakers Bureau

Actelion, Schering, Pfizer

l 

Grant Support

Bayer Schering, Actelion


PAH: Diagnostic classification (Dana Point 2008) 1. Pulmonary arterial hypertension (PAH) Idiopathic PAH Heritable Drugs and toxin induced Associated with – Connective tissue diseases – HIV infection – Portal hypertension – Schistosomiasis – CHD (shunts) – Chronic hemolytic anaemia PPHN 1’. Pulmonary veno occlusive disease 2. PH due to left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease

3. PH with lung diseases/hypoxia COPD Interstitial lung disease Other diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to altitude Developmental abnormalities 4. Chronic thromboembolic PH (CTEPH) 5. PH with unclear and or multifactorial mechanisms Haematologic disorders Systemic disorders: Sarcoidosis, neurofibromatosis… Metabolic disorders: Glycogen storage, Gaucher, … Other: Tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

Simonneau G, et al. J Am Coll Cardiol 2009; 54 (Suppl 1):S43-S54.


Pediatric classification….. l 

Pediatric patients present frequently with associated conditions and syndromes •  Van Loon et al J Pediatrics 2009

l 

Associated conditions may not always explain PH

l 

IPAH like conditions….. – Ie. Small septal defect (congenital heart disease)


Barst Ivy Beghetti ERJ2011

Paediatric Pulmonary Arterial Hypertension (PAH) Diagnostic Work-up Algorithm Suspect Diagnosis of PAH Electrocardiogram, CXR and Echocardiogram normal?

Yes PH unlikely

No Echocardiogram indicates left heart aetiology of PH?

Yes

Evaluate for left heart and valvular disease

No

Evaluate for airway, parenchymal lung disease, connective tissue disease, neuromuscular disease, or chest wall/restrictive disease

No Yes, but clinical suspicion of nocturnal disordered breathing Polysomnography

Yes

Pulmonary function test* normal aside from low DLCO? Chest CT normal? Yes Ventilation-perfusion scan normal or low probability Yes

Serologies to rule out connective tissue disease, hypercoagulability, HIV, liver disease, and sickle cell disease

Cardiac catheterization with acute vasodilator testing prior to initiation of targeted treatment

6-minute walk test and Cardiopulmonary exercise test**

*If unable to obtain a reliable test in a young child and there is a high index of suspicion for underlying lung disease, the patient may require further lung imaging. **Children older than 7 years of age can usually perform reliably to assess exercise tolerance and capacity in conjunction with diagnostic work-up.


Incidence and prevalence l 

l 

l 

France PAH excluding CHD Ø 

Prevalence Overall 4.2 per million

Ø 

Prevalence IPAH 2.4 per million

UK only IPAH Ø 

Incidence 0.48 per million

Ø 

Prevalence 2.07 per million

Netherlands PH Ø 

IAPH incidence 0.7 and prevalence 4.4 per MIo

Ø 

CHD-PAH incidence 2.2 and prevalence 15.6


Epidemiology: Current Knowledge Fasnacht

Beghetti

Van Loon

Fraisse

Rosenzweig

Haworth

Swiss Med wkly 2007

Pediatr Res 2008

J Ped 2009

Arch Cardiovasc Dis 2010

JACC 2005

Heart 2010

23

146

63

50

86

216

3.5

2 to 11

5.8

8.9

5

NA

52

48.6

62

48

57

62/52+

Group 1 PAH (%) Idiopathic PAH (%) Heritable (%)

20 (87%)

131 (90%)

54 (86%)

50 (100%)

8 (35%)

59 (40%)

29 (46%)

30 (60%)

CHD (%)

12 (52%)

Number of patients Age (median in years) Female (%)

173 (80%)

36 (42%)

60 (28%)

48 (56%)

104 (48%) ยง

2 (2%)

9 (4%)

5 (10%) 66 (45%)

23 (37%)

CTD (%)

4 (2.8%)

2 (3%)

Portopulmonary (%) HIV(%)

1 (0.7%)

Group 3: lung disease (%) Other (%)

86 (100%)

3(13%)

2 (1%)

8 (12%)

13 (9%)

1 (2%)

12(24%)*

NI

29 (14%)

7

14 (7%)


Functional Class: Current Knowledge NYHA 1

NYHA 2

NYHA 3

NYHA 4

Van Loon et al

2

27

47

24

Fraisse et a

17

54

26

2

Fasnacht et al

0

16

76

8

Beghetti et al

6

28

51

10

Rosenzweig et al

8

43

41

8

Badesch et al

21

52

24

3

Haworth et al

0

19

53

28

NYHA; New York Heart Association Results are in % For Beghetti, 5% were not classified Van Loon J Ped 2009, Fraisse Arch Cardiovasc Dis 2010, Fasnacht Swiss Med Wkly 2007, Beghetti Pediatr Res 2008, Rosenzweig JACC 2005, Badesch Chest 2010, Haworth Heart 2010

8


TOPP Registry l 

First international registry in pediatric pulmonary hypertension (PePH)

l 

22 Countries participating: Ø 

Australia, Austria, Belgium, Brazil, Canada, China, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Mexico, Netherlands, Norway, Poland, Portugal, Switzerland, Turkey, UK, USA

l 

38 Sites registered for participation

l 

Analysis is ongoing

l 

Result expected for march 2010

l 

Ongoing recruitment for incident patients


563 patients enrolled by December 2011 600

500

400

Total

300

Incident

200

Prevalent

100

Nov

Sep

Jul

May

Mar

2011

Nov

Sep

Jul

May

Mar

2010

Nov

Sep

Jul

May

Mar

2009

Nov

Sep

Jul

May

Mar

2008

0


Geographic distribution

Berger , Beghetti et al Lancet in Press


Clinical symptomsat diagnosis l 

Dyspnea with exertion: 65%

l 

Fatigue: 41%

l 

Syncope: 20%

l 

Cyanosis with exertion: 18%

l 

Cyanosis with rest: 12%

l 

Dyspnea with rest: 11%

l 

Chest pain: 11% Berger , Beghetti et al Lancet in Press


Abstracts AEPC and SPR 2011

Demographics PH confirmed patients All Incident Prevalent Patients, n (%) 362 (79) 102 (28) 260 (72) Female 214 (59) 58 (57) 156 (60) Pre-term 47 (13) 16 (16) 31 (12) Age at Dx (yrs) 7.5 (7.0, 8.1) 8.5 (7.5, 9.5) 7.2 (6.5, 7.8) Time from onset of symptoms to PH Dx (mos) Mean (95% CI) 17 (14, 20) 24 (16, 31) 15 (12, 18) Median (range) 6 (0 – 146) 6 (0 – 129) 5 (0 -146)

Berger , Beghetti et al Lancet in Press


Abstracts AEPC and SPR 2011

PH classification

Group 1 PH (PAH)

PH confirmed patients All Incident Prevalent 317 (88) 88 (86) 229 (88)

IPAH/FPAH

182 (57)

55 (63)

127 (55)

APAH-CHD

115 (36)

26 (30)

89 (39)

APAH-Other

20 (7)

7 (7)

17 (6)

42 (11) 3 (1)

13 (13) 1 (1)

29 (11) 2 (1)

Group 3 PH Group 4/5 PH

Berger , Beghetti et al Lancet in Press


Functional class at diagnosis PH confirmed patients All

Incident

Prevalent

I

45 (12)

11 (11)

34 (13)

II

185 (51)

52 (51)

133 (51)

III

108 (30)

28 (27)

80 (31)

IV

24 (7)

11 (11)

13 (5)

Berger , Beghetti et al Lancet in Press


Learning points l 

Children are frequently severely ill at presentation

l 

Cardiac ouput seems to be preserved in a large proportions of children

l 

Syncope is frequent

l 

CHD may not have a better survival in children


Revised “responder” criteria Drop of mPAP > 10 mmHg from baseline to < 40 mmHg in the presence of a normal CO l 

Less than 10% of adult IPAH pts are long-term responders to calcium channel blocker treatment

l 

In children there may be 20-30% responders, Problem of definition ?????

l 

Adult „Responders“ are exceptionally rare among pts with other forms of PH/PAH

l 

Avoid use of calcium channel blockers without previous vasoreactivity testing


Responders (CCB) versus non responders

Barst et al Circulation 1999;99:1197

Yung et al Circulation 2004;110:660


Pathobiology Increased Endothelin Endothelial cells

Pre-proendothelin

Decreased Nitric Oxide

Decreased Prostacyclin Arachidonic acid

Proendothelin L-arginine

L-citrulline

Endothelin-1

Endothelin receptor A

Endothelin receptor B

Prostacyclin

Prostacyclin Nitric Oxide cGMP

Vasoconstriction and proliferation

IPDE5

cAMP

Vasodilation and antiproliferation

Vasodilation and antiproliferation

Smooth muscle cells

Smooth muscle cells

1. Galiè et al. Eur Heart J 2009; 30: 2493–537; Figure adapted from Humbert et al. N Engl J Med 2004; 351: 1425–36.


Epoprostenol studies in the paediatric population l 

Efficacy data Ø  Ø 

l 

PAH-CHD / IPAH (total n=20) Improved long-term haemodynamics and functional status after 12 months1

Survival data Ø  Ø 

3 cohort studies (total n=105) 94-100%, 79-88% and 81% KM estimates of survival at 1, 3 and 5 years2–4

1. Rosenzweig EB, et al. Circulation 1999; 99:1858-65. 2. Yung D, et al. Circulation 2004; 110:660-5. 3. Lammers AE, et al. Heart 2007; 93:739-43. 4. Nakayama T, et al. Circ J 2007; 71:1785-90.


Inhaled iloprost therapy in children WHO IV

600 25

Patient Number

6-MWD (m)

500 400 300 200

WHO II

20 15 10

100

5

0

0

Pre-lloprost Post-lloprost

WHO III

Baseline

• 

Acute haemodynamic effect equivalent to inhaled nitric oxide

• 

No significant improvement in 6-MWD or WHO functional class

• 

Marked deterioration in 27%

• 

Acute wheeze in some children

n = 22

6 Months

Ivy DD, et al. J Am Coll Cardiol 2008; 51:161-9.


Sildenafil paediatric development programme lď Źâ&#x20AC;Ż

Paediatric indication is underpinned by two main studies: Study STARTS-1 (A1481131)

STARTS-2 (A1481156)

Description Randomised, double-blind, placebo-controlled study of sildenafil in children with PAH Long-term extension of A1481131 evaluating safety of sildenafil in children with PAH


Primary endpoint: improvement in exercise capacity 3.81

Low (n=24)

11.33

Medium (n=26)

7.98

High (n=27)

7.71

Low/Med/High (n=77)

-10

-5

0

5

p=0.056

10

15

20

25

Peak VO2 (% change from baseline to week 16) vs placebo (n=29) with 95% CIs


Effects of sildenafil on PVRI in children: Proportional Comparison

0.982

Low (n=37)

0.819

Medium (n=51)

0.727

High (n=68)

0.836

L/M/H (n=156) 0.4

0.6

0.8

1.0

1.2

Ratio Comparison to Placebo (n=52) with 95% CIs

1.4


Long-Term Outcomes in Children With Pulmonary Arterial Hypertension Treated With Bosentan in Real-World Clinical Settings Ivy et al Am J Cardiol 2010

Kaplan-Meier estimates of survival at 1 year and 2, 3, and 4 years for patients with IPAH/HPAH were 100%, 88%, 88%, and 85% and those for patients with PAH-CHD were 96%, 91%, 87%, and 87%, respectively. 

Kaplan-Meier estimates of survival (vs mean baseline pulmonary vascular resistance index [PVRI] of 20 Wood units × m2) at 1 year and 2, 3, and 4 years for patients with a pulmonary vascular resistance index >20 Wood units × m2 were 96%, 83%, 78%, and 74% and those for patients with a pulmonary vascular resistance index ≤20 Wood units × m2 were 100%, 94%, 94%, and 94%, respectively.


Personal suggested approach Conventional treatment Yes

Acute vasodilator response

No Non Responder

Responder

Bosentan (oral)* Iloprost (inhaled) Calcium Channel Sildenafil (oral) Blocker Tadalafil (oral) Incomplete response Treprostinil (sc,inh) Incomplete response Combination of drugs Incomplete response IV prostanoids (Epoprostenol, Treprostinil, Iloprost) Incomplete response Atrial septostomy Potts shunt Incomplete response Transplantation

* Listed in alphabetical order

No

Right heart failure

Yes

Beghetti M, et al. Eur Respir Dis.


Improved Survival in Children 2008 Van Loon

100%

2004 Yung 1999 Barst

90%

2010 Ivy

80%

2006 Bosentan 2009 Haworth IPAH

2010 Fraisse

2010 Barst

70%

Survival

2010 Modeina 2010 Berger

60%

2009 Haworth APAH

1991 Dâ&#x20AC;&#x2122;Alonzo

50%

2008 VanLoon 1995 Sandoval

40%

1999 Barst

1999 Barst Historical Controls

30%

1999 Van Loon

20% 10%

Off-label use of drugs approved for adult PAH

1993 Houde

0% 0

1

2

3

4

Years 1, 3, 5 year survival: ~ 85 - 95%, ~ 70 - 95%, ~50 - 95%, respectively vs prior to therapies: ~ 40 - 65%, ~ 45%, ~ 30%, respectively

5

6


Conclusions l 

Significant progress in chronic pediatric PH in the last 15 years

l 

Mortality seems to have significantly decreased from the 50% mortality at 10 months

l 

Stil a lot to do on: Ø 

Epidemiology

Ø 

Treatment specific to children

Ø 

Follow-up parameters


CICU Management of acute pulmonary hypertension Maurice Beghetti Pediatric Cardiology Unit Childrenâ&#x20AC;&#x2122;s University Hospital Geneva Switzerland


Post cardiac surgery: Incidence l 

Pre iNO era: Ø 

1980-84: 31%

Ø 

1990-94: 6.8% •  Bando et al JTCS 1996

l 

Current era 2% of PHT and 0.75% of crisis •  Lindberg et al JTCS 2002

l 

But mortality remains 20%

l 

Major contributor to length of stay and prolonged ventilation •  Schulze Neick et al JTCS 2001


Other potential etiologies l 

Decompensated chronic PH

l 

Acute lung injury/ARDS

l 

PPHN

l 

Other rare forms Ø 

Post liver transplant, Oncology, pulmonary emboli etc….

l 

Lack of epidemiologic data in our ICU

l 

Study in CH…..


Postoperative PHT l 

Immediately after surgery or in the first 48 hours

l 

Mortality

l 

Ø 

30% in 80-84, 6.8 % 90-94, < 3% after 2000

Ø 

Improvement in surgery and post op care

Causes Ø 

CPB (endothelial dysfunction), hypoxia, agitation, catecholamines


Pulmonary hypertension PVR = mean PAP-LAP / Qp Mean PAP = Flow x Resistance + LAP l 

Flow-associated pulmonary hypertension (hyperkinetic) Ø 

l 

Increased pulmonary vascular resistance Ø 

l 

congenital heart defects Left to right shunts pulmonary arteriopathy (pulmonary vascular disease)

Pulmonary venous congestion


PAH-CHD pathophysiology Left-to-right shunt Increased pulmonary blood flow (shear stress) Proliferation of smooth muscle cells Increase in extracellular matrix Intravascular thrombosis

Endothelial dysfunction Increase in pulmonary vascular resistance Inverted shunt: right-to-left Cyanosis (Eisenmengerâ&#x20AC;&#x2122;s)


Pulmonary Hypertension LV dysfunction

Residual shunt Pulmonary vasoconstriction

PAP = LAP + Qp x Rp Inodilatator Intervention

OP/ Cath. iNO / Prostanoids/ sildenafil


RV vicious circle Increased RV pressure Increased afterload

RV dysfunction Increased RV volume

Decreased coronary perfusion

Ischemia

Low cardiac output

LV diastolic dysfunction Tricuspid regurge

Decreased RV output


Therapeutic approach ENCOURAGE Anatomic investigations

AVOID Residual anatomic disease

Opportunities fro right to left shunt as pop Intact atrial septum in right heart failure off Sedation/Anesthesia

Agitation/ pain

Moderate hyperventilation

Respiratory acidosis

Moderate alkalosis

Metabolic acidosis

Adequate inspired oxygen

Alveolar hypoxia

Normal lung volumes

Atelectasis or overdistention

Optimal hematocrit

Excessive hematocrit

Inotropic support

Low output and low coronary perfusion

Vasodilators

Vasoconstrictors/increased afterload

Wessel in Pulmonar y arterial hypertension related to congenital heart disease. Beghetti Elsevier 2006


Endothelial dysfunction:Postoperatively Etiology Preoperative endothelial dysfunction CPB induced endothelial dysfunction Inbalance vasoconstrictors/vasodilatators

Nitric Oxide Prostacyclin

Endothelin Thromboxanes


Pathobiology Increased Endothelin Endothelial cells

Pre-proendothelin

Decreased Nitric Oxide

Decreased Prostacyclin Arachidonic acid

Proendothelin L-arginine

L-citrulline

Endothelin-1

Endothelin receptor A

Endothelin receptor B

Prostacyclin

Prostacyclin Nitric Oxide cGMP

Vasoconstriction and proliferation

IPDE5

cAMP

Vasodilation and antiproliferation

Vasodilation and antiproliferation

Smooth muscle cells

Smooth muscle cells

1. Galiè et al. Eur Heart J 2009; 30: 2493–537; Figure adapted from Humbert et al. N Engl J Med 2004; 351: 1425–36.


Successful surgical repair decreases ET levels in patients with PAH caused by CHD

Plasma endothelin levels (pg/ml)

8

p < 0.001

p < 0.001

6

4

2 (n = 11)

(n = 6) 0 Control

Before surgery

After surgery

Ishikawa S, et al. J Thorac Cardiovasc Surg 1995; 110:271-3.


Endothelin (pg/ml)

Time course of endothelin after CPB in CHD patients

(CPB = cardiopulmonary bypass; LF = low pulmonary blood flow; m-PH = mild pulmonary hypertension; s-PH = severe pulmonary hypertension.) Hiramatsu T, et al. Ann Thorac Surg 1997; 63:648-52.


100 75 50 25 0 -25 -50

ANOVA p < 0.05

300 250 200 150 100 50 0 -50

10

10

30 60 120

ANOVA p < 0.005

B

ANOVA p < 0.05

B

100 75 50 25 0 -25 -50

30 60 120

PVR (% change)

SVR (% change)

B

mPAP (% change)

mPAP (% change)

Role of endogenous ET in acute pulmonary hypertension after CPB

300 250 200 150 100 50 0 -50

10

30 60 120

ANOVA p < 0.005 Control

Bosentan B

10

30 60 120

Carteaux et al. Eur J Cardiothorac Surg 1999; 15:346.


Mean pulmonary arterial pressure (mmHg.min.kg.ml-1)

Pulmonary vascular resistance (mmHg.min.kg.ml-1)

Role of ET in post-CPB pulmonary hypertension in lambs with increased pulmonary blood flow

Reddy VM, et al. Circulation 1997, 95:1054-61.


Mechanisms of action: iNO and PGI2

ALVEOLI Protein kinase

PGI2

NO

cAMP RELAXATION cGMP adenylate cyclase

vascular lumen

guanylate cyclase


Individual response in pulmonary to systemic resistance ratio (Rp/Rs)! 0.7"

* p < 0.001 vs baseline 1 + 2!

0.6"

*!

Rp/Rs!

0.5"

*!

0.4"

*!

0.3" 0.2" 0.1" 0" Baseline!

iNO!

Baseline!

iloprost!

iNO+iloprost!


Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery Stocker et al ICM 2003 Pulmonary and systemic haemodynamics at baseline (0 min) and following each intervention, for infants receiving first nitric oxide with the addition of sildenafil at 20 min (triangle); and for infants receiving first sildenafil with the addition of nitric oxide at 20 min (square). Both

agents independently reduced pulmonary vascular resistance but, for both groups, sildenafil resulted in a fall in systemic blood pressure and vascular resistance Parameters of oxygenation and ventilation at baseline (0 min) and following each intervention, for infants receiving first nitric oxide with the addition of sildenafil at 20 min (triangle); and for infants receiving first sildenafil with the addition of nitric oxide at 20 min (square). Nitric

oxide improved oxygenation index and alveolar-arterial gradient when given alone; but for both groups, sildenafil produced significant deterioration in all measurements


Sildenafil iNO rebound

Shekerdemian et al ARCCM 2006


Levosimendan l 

Calcium sensitizer

l 

Enhances myocardial contractility by sensitizing troponin C to calcium

l 

Has also shown some pulmonary vasodilator properties in the presence of pulmonary hypertension

l 

It it improves RV contractility and decrease RV afterload it should be ideal to improve RV-PA coupling!!


Conclusions l 

Treatment Ø 

Exclude lesions requiring surgery or cath

Ø 

Optimize preload

Ø 

Optimize ventilation

Ø 

Sternum open

Ø 

Decrease afterload (inhaled vasodilators/sildenafil)

Ø 

Augment coronary perfusion and RV/LV function – Inotropes (Noradrenaline, milrinone) – New therapies???

Ø 

ECMO or RVAD


Presentation 17 - Beghetti