morsolini marco torino 13° convegno patologia immune e malattie orfane 21 23 gennaio 2010

Andrea M D’Armini, MD, FCCPMarco Morsolini, MD, PhD

PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE

UNIVERSITY OF PAVIA SCHOOL OF MEDICINE - ST. MATTEO HOSPITAL - PAVIA - ITALY

Division of Cardiac SurgeryUniversity of Pavia School of MedicineSt. Matteo HospitalPavia - Italy


INTRODUCTION

• Chronic thromboembolic pulmonary hypertension (CTEPH)represents the only type of pulmonary hypertension surgically treatable, in the majority of cases, without transplant


• This life-saving conservative surgery is called pulmonary endarterectomy (PEA)


INTRODUCTION

• Elective surgery, non donor-dependent

• No “transplant window” to be considered

• Age is not a contraindication

• Lower post-operative complications

PEA vs. LTx


• Lower post-operative complications– early (acute graft failure, acute rejection, infections)

– late (BOS, neoplasms, infections)

• Outcome– post-operative long term survival

– quality of life (back to normal)

– steady functional improvement


EPIDEMIOLOGY

• Epidemiologic data: in Italy ≈ 65.000 cases / yearof acute symptomatic pulmonary embolism (PE)

• Prevalence of CTEPHin pts surviving an acute PE(≈ 80 %) is calculated between 0.5% – 3.8%

→ up to 2.000 new cases / year


→ up to 2.000 new cases / year

• Considering asymptomatic pulmonary embolism and misdiagnosed pulmonary embolism, the true incidence of CTEPH may be even greater

• Jamieson SW, Kapelanski DP. Pulmonary endarterectomy. Curr Probl Surg2000; 37:165-252

• Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med2001; 345:1465-72

• Pengo V, Lensing AV, Prins MH, Marchiori A, Davidson BL, Tiozzo F et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med2004; 350:2257-64


CURRENT SITUATION

• CTEPH is still under-diagnosedand nowadays only few physicians are aware of the surgical procedurecalled PEA


• For all these reasons about 6000 PEAhave been performed worldwide so far with ≈ 40 %of all cases carried out by the San Diego Group


NATURAL HISTORY

• Pulmonary embolism (symptomatic / asymptomatic)

• “Honeymoon” period: months / years

• Hypertensive remodeling of the patent pulmonary vascular bed (Eisenmenger-like)


vascular bed (Eisenmenger-like)

• Right ventricle hypertrophy with progressive right heart deterioration → right failure

• Left ventricle compression with left heart functional impairment


GENERAL CONDITIONS

• Low cardiac output with dyspnea, cough, cyanosis, hepatomegaly, ascites, lower limb edema, syncope, hemoptysis andinterscapular olosystolic murmur


• Hypoxemia with exercise, sometimes at rest also

• Frequent positive anamnesis for deep venous thrombosis and / or coagulative and immunologic disorders


COAGULATIVE DISORDERSOF LAST 185 PEAs

DISORDER % PTS MEAN ± SD RANGE

HYPERHOMOCYSTEINEMIA (µmol/L) 72.6 % 21.7 ± 8.3 14.1 – 63.2

EXCESS FACTOR VIII ANTIGEN (%) 78.2 % 206.7 ± 33.9 161.1 – 392.9

EXCESS FACTOR VIII RISTOCETIN (%) 47.6 % 182.1 ± 46.6 150.0 – 334.0


EXCESS FACTOR VIII RISTOCETIN (%) 47.6 % 182.1 ± 46.6 150.0 – 334.0

EXCESS FACTOR VIII (%) 27.4 % 179.3 ± 25.8 153.4 – 220.0

PAI EXCESS (U/ml) 53.2 % 5.1 ± 1.2 3.6 – 7.9

FACTOR V LEIDEN 15.3 % 1.34 ± 0.55 0.50 – 1.99


IMMUNOLOGIC DISORDERSOF LAST 185 PEAs

DISORDER % PTS MEAN ± SD RANGE

Anti-Nuclear Antibodies (ANA) 23.4 % – –

Lupus Anticoagulans (LAC) 19.4 % – –

Anti-Cardiolipin Antibodies (ACA) IgG 20.2 % 56.3 ± 40.3 10.3 – 121.0


Anti-Cardiolipin Antibodies (ACA) IgG 20.2 % 56.3 ± 40.3 10.3 – 121.0

Anti-Cardiolipin Antibodies (ACA) IgM 13.7 % 30.8 ± 30.5 7.3 – 101.0

Anti-Phospholipid Antibodies (APA) IgG 14.5 % 63.2 ± 36.5 8.4 – 121.0

Anti-Phospholipid Antibodies (APA) IgM 12.9 % 28.0 ± 23.5 10.1 – 91.3

Positive Direct Coombs’ Test 8.9 % – –


GENETIC MUTATIONSOF LAST 185 PEAs

MUTATION % PTS

C677T MTHFR (HOMOCYSTEINEMIA) HETEROZYGOSIS 50.8 %

HOMOZYGOSIS 19.4 %

TOTAL 70.2 %


A1298C MTHFR (HOMOCYSTEINEMIA) HETEROZYGOSIS 44.4 %

HOMOZYGOSIS 9.7 %

TOTAL 54.1 %

G20210A PROTHROMBIN (FACTOR II) 8.1 %

G1691A FACTOR V (FACTOR V LEIDEN) 5.6 %


INDICATIONS FOR SURGERY

• The indications for the surgical treatmentof these patients are based on

CLINICHEMODYNAMIC


• The indications for the type of surgeryare based on

ANATOMY


CLINIC

• Patients must be in NYHA functional class III or IV

• Full anticoagulation for at least 3 months

• Some Authors (we too) recently have performed PEA


• Some Authors (we too) recently have performed PEA even in NYHA class IIpatients, given the natural history of the disease


HEMODYNAMIC

• Pulmonary hypertension (mPAP > 25 mmHg)

• Causing low cardiac output


• Resulting in calculated pulmonary vascular resistances (PVR) > 300 dyne*sec*cm-5


ANATOMY

• The surgical treatment depends on the localization of the lesions in the pulmonary arterial branches


• Lesions can be classified as PROXIMALDISTAL


PROXIMAL LESIONS



M.B. – 62 yrs M – Jul 2001 – PEA #64

Perfusion and ventilation scan


Pulmonary angiogram

Hemodynamic

mPAP 67CI 1.6PVR 1766


DISTAL LESIONS



S.S. – 31 yrs M – Sep 2002

Perfusion and ventilation scan


Pulmonary angiogram

Hemodynamic

mPAP 50CI 1.8PVR 1120

• National referral program

• Begin: April 1994


OUR PROGRAM


• Begin: April 1994

• To date: 266 PEAs performed

4079

103

12

1412

19 26

4

Pts coming from outside Italy- Greece 1- Uganda 1

2


PATIENTS’ REFERRALOF 266 PEAs

Pavia


6

164

11 101

5

11

1

≤ 10 pts

11 – 20 pts

≥ 21 pts


PATIENTS’ AMOUNT

• Apr ‘94 → Jan ‘10

• 266 PEAs(5 redo: 26, 40, 56, 86 and 174 months after the first PEA)

• In the majority of

40

50

60

Pa

tient

s

54 PEAs in 1 yr


• In the majority of pts (250/266) an ICF was placed before PEA

• Lifelong anticoagulation therapy was prescribed 0

10

20

30

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Pa

tient

s

54 PEAs in 7 yrs


PAVIA CTEPH PROGRAMJanuary, 1st - December, 31st 2004 →→→→ 130 pts

EVALUATION (54 pts) FOLLOW-UP (72 pts) DLTx (4 pts)

CONFIRMED (34 pts - 63%) OTHER DIAGNOSIS (20 pts - 37%)

• RECENT EMBOLIZATION (3 pts)- 2 medical therapy- 1 surgical embolectomy

• PROXIMAL LESIONS (25 pts)- 22 PEAs- 2 pts refused


- 1 surgical embolectomy

• TUMORS (5 pts)- 3 pulmonary angiosarcoma- 1 adenocarcinoma with pulmonary artery thrombosis- 1 intestinal tumor with liver metastases

• MISCELLANEOUS (12 pts)

OPERABILITY RATE 74 %

- 2 pts refused- 1 pt died on evaluation

• DISTAL LESIONS (7 pts)- 5 DLTx waiting-list- 2 medical therapy (too old for DLTx)

• ASSOCIATION WITH SEVERE EMPHYSEMA (2 pts)- 2 DLTx waiting-list


PAVIA CTEPH PROGRAMJanuary, 1st - December, 31st 2009 →→→→ 121 pts

NEW EVALUATIONS (78 pts) PEAs FOLLOW-UP (43 pts)

CONFIRMED (70 pts - 90%) OTHER DIAGNOSIS (8 pts - 10%)

• PROXIMAL LESIONS (62 pts)- 54 PEAs- 1 pt waiting for PEA

• RECENT EMBOLIZATION (4 pts)

• MINIMAL CTE LESIONS WITHOUT PH (4 pts)- 4 medical therapy


OPERABILITY RATE 89 %

- 1 pt waiting for PEA- 4 pts refused PEA- 2 pts with “too old” lesions (pulmonary artery

retraction)- 1 pt general condition too compromised

• DISTAL LESIONS (8 pts)- 8 medical therapy: 5 too old for DLTx

3 too early for DLTx

• RECENT EMBOLIZATION (4 pts)- 3 medical therapy- 1 surgical embolectomy

CHEST STUDIES: THE PAVIA EXPERIENCE

MAIN WORLD PEA CENTERS

Bad Nauheim, Germany≈60 PEAs / year

MORE THAN ONE PROGRAM

Cambridge, UK≈80 PEAs / year

NATIONAL REFERRAL PROGRAM BY LAW


San Diego, California, USA≈120 PEAs / year

NATIONAL REFERRAL PROGRAM FOR EXCELLENCE Paris, France

≈100 PEAs / yearNATIONAL REFERRAL PROGRAM

FOR EXCELLENCE

Pavia, Italy≈50 PEAs / year

MORE THAN ONE PROGRAM


PEA POPULATIONOF 266 PEAs

Age 56 ± 16 (11 − 84) years

Gender 134 M – 132 F

NYHA class 15 II – 122 III – 129 IV


NYHA class 15 II – 122 III – 129 IV

Length III / IV 19 ± 23 months

Urgent / Emergent 64 / 266

Oxygen therapy 131 / 266


RIGHT HEART CATHETERIZATIONOF 266 PEAs

Mean ± SD Range

mPAP 47 ± 13 17 − 88 mmHg


CI 1.9 ± 0.6 1.1 − 4.1 l/min/m2

PVR 1149 ± 535 191 − 3938 dynes*sec*cm-5


ECHOCARDIOGRAPHY



CARDIAC MAGNETIC RESONANCE



ARTERIAL BLOOD GASESOF 266 PEAs

Mean ± SD Range

Pa O2 65 ± 10 43 − 97 mmHg


Pa CO2 31 ± 7 24 − 43 mmHg

O2-sat 93 ± 3 84 − 98 %


MODIFIED BRUCE TESTOF 266 PEAs

Steps Walking distance

No (Pa O2 < 60) 36.9% 103 ± 160 (0 – 852) meters

Step 0 - ½ 56.8%


Step 0 - ½ 56.8%

Step 1 - 2 4.5%

Step 3 - 4 1.8%

Peak exercise

No (∆ECG, advanced NYHA IV, other) 16.3%

Watts ≤25 12.0%


CARDIOPULMONARY EXERCISE TESTINGOF 157 PEAs


Watts ≤25 12.0%

Watts >25 / ≤50 50.0%

Watts >50 / ≤75 15.2%

Watts >75 6.5%


CARDIOPULMONARY EXERCISE TESTINGOF 157 PEAs

Mean ± SD Range

Peak-DP 16037 ± 4822 5600 − 30600 mmHg*FC


Peak-VO2 9.9 ± 3.6 3.0 − 29.4 ml/min/kg

Peak-Exe 50 ± 22 15 − 160 watt


PULMONARY ENDARTERECTOMY



TYPICAL SURGICAL SPECIMENS


E.L. – 38 yrs M – Dec 1999 – PEA #42mPAP 43 →→→→ 20 (-53%)CO 3.3 →→→→ 6.9 (+109%)PVR 994 →→→→ 220 (-78%)

P.A. – 66 yrs M – Jun 2001 – PEA #60mPAP 50 →→→→ 25 (-50%)CO 2.6 →→→→ 4.4 (+69%)PVR 1385 →→→→ 364 (-74%)


JAMIESON TYPE I vs. TYPE II vs. TYPE III


L.M.E.L. - 65 yrs M - Oct 2004 - PEA #119mPAP 39 →→→→ 19 (-51%)CO 4.4 →→→→ 5.4 (+23%)PVR 665 →→→→ 222 (-66%)

G.A.C. - 52 yrs F - Jul 2003 - PEA #96mPAP 48 →→→→ 27 (-44%)CO 2.1 →→→→ 4.2 (+100%)PVR 1638 →→→→ 381 (-77%)

S.F. - 48 yrs F - Mar 2009 - PEA #221mPAP 44 →→→→ 29 (-34%)CO 2.9 →→→→ 3.5 (+21%)PVR 1131 →→→→ 549 (-51%)


JAMIESON TYPE III


B.A. - 43 yrs F - May 2009 - PEA #233mPAP 49 →→→→ 19 (-61%)CO 3.3 →→→→ 5.0 (+52%)RVEF 16 →→→→ 35 (+119%)PVR 1067 →→→→ 224 (-79%)

Pre-operative Pulmonary Angiogram


JAMIESON TYPE III



Pre-operative 64-HRCT

F.C. - 33 yrs F - Apr 2009 - PEA #225mPAP 52 →→→→ 20 (-62%)CO 4.6 →→→→ 4.7 (+2%)RVEF 32 →→→→ 41 (+28%)PVR 870 →→→→ 255 (-71%)


OUT OF PROPORTION PH ?





B.R.A. - 72 yrs FmPAP 44CO 2.9RVEF 28PVR 1159


JAMIESON TYPE III





B.R.A. - 72 yrs F - Mar 2009 - PEA #222mPAP 44 →→→→ 33 (-25%)CO 2.9 →→→→ 4.9 (+69%)RVEF 28 →→→→ 34 (+21%)PVR 1159 →→→→ 457 (-61%)

B.R.A. - 72 yrs FmPAP 44CO 2.9RVEF 28PVR 1159



OUT OF PROPORTION PH ?




G.G. - 62 yrs FmPAP 51CO 2.6RVEF 19PVR 1415


JAMIESON TYPE III





G.G. - 62 yrs F - Sep 2009 - PEA #240mPAP 51 →→→→ 27 (-47%)CO 2.6 →→→→ 4.0 (+54%)RVEF 19 →→→→ 24 (+26%)PVR 1415 →→→→ 460 (-68%)

G.G. - 62 yrs FmPAP 51CO 2.6RVEF 19PVR 1415

60%

70%

80%

90%

100%

Per

cent

age


CUMULATIVE PROPORTION SURVIVINGOF 266 PEAs

187 144 125 108 91 71 54 42 33 30 22 14 7 3 2

89.2±1.987.1±2.2

86.5±2.2 85.6±2.484.5±2.6

83.1±2.981.6±3.2

79.2±3.9 79.2±3.9


0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

Months after PEA

0%

10%

20%

30%

40%

50%

Per

cent

age

Operative mortalityGlobal 24/266 (9.0%)NYHA II 0/15 (0.0%)NYHA III 5/122 (4.1%)NYHA IV 19/129 (14.7%)

Jan 08 - Jan 10 5/92 (5.4%)

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Per

cent

age

133

86 .8±2.6

84.7±2.8

83.8±2.9 83.8±2.9 83.8±2.9 83.8±2.9

113 93 54 34 14


CUMULATIVE PROPORTION SURVIVINGSURGERY vs. MEDICAL THERAPY


0 12 24 36 48 60 72 84 96 108 120 132 144 156

Months after PEA

0.0

0.1

0.2

0.3

Riedel M. Chest 1982;81(2):151-8.

D’Armini A.M. Ital Heart J 2005;6(10):861-8.


FOLLOW -UP

• Very few data are available in the literature on mid and long term cardiopulmonary function, particularly on exertion, and on clinical benefits after PEA


D’Armini AM, Zanotti G, Ghio S, Magrini G, Pozzi M, Scelsi L, Meloni G, Klersy C, Viganò M. Reverse right ventricular remodelingafter pulmonary endarterectomy. J Thorac Cardiovasc Surg2007; 133:162-8

Corsico AG, D’Armini AM, Cerveri I, Klersy C, Ansaldo E, Niniano R, Gatto E, Monterosso C, Morsolini M, Nicolardi S, Tramontin C, Pozzi E, Viganò M. Long-term outcome after pulmonary endarterectomy. Am J Respir Crit Care Med2008;178(4):419-24


FOLLOW -UP TIMING

• All pts underwent follow-up evaluation at:– discharge (at this interval NYHA class, lung function, and exercise

tolerance are excluded because pts are to close to the surgical


tolerance are excluded because pts are to close to the surgical procedure)

– 3th month

– yearly for 5 years

– 7th, 10th and 15th year (10 controls)


FOLLOW -UP DATA

• Eleven of 240 pts (4.6%) refused to participate to the study since the beginning (2/4 pts referred from outside Italy) or at various intervals

• For these pts we obtained only data on survival and NYHA


• For these pts we obtained only data on survival and NYHA class on a phone-call basis

• All the other pts (95.4%) have actively participated to the FUP study


NYHA FUNCTIONAL CLASS

NYHA Functional Class

60

70

80

90

100

% patients

I-II


0

10

20

30

40

50

Pre-op 3 mesi 1 anno 3 anni 5 anni 7 anni 10 anni

Follow-up

% patients

I-II

III-IV

Pre-op 3m 1y 3y 5y 7y 10y

pp < 0.01< 0.01


mean PULMONARY ARTERY PRESSURE

mean Pulmonary Arterial Pressure

40

50

60

mmHg


0

10

20

30

Pre-op Dimiss 3 mesi 1 anno 3 anni 5 anni 7 anni 10 anni

Follow-up

mmHg

pp < 0.01< 0.01

Pre-op disch 3m 1y 3y 5y 7y 10y


PULMONARY VASCULAR RESISTANCES

Pulmonary Vascular Resistances

800

1000

1200

dyne*sec*cm-5


0

200

400

600

Pre-op Dimiss 3 mesi 1 anno 3 anni 5 anni 7 anni 10 anni

Follow-up

dyne*sec*cm-5

pp < 0.01< 0.01

Pre-op disch 3m 1y 3y 5y 7y 10y


ECHOCARDIOGRAPHYBefore



ECHOCARDOGRAPHYFirst control – POD #9



ECHOCARDIOGRAPHYThree-month control



CARDIAC MAGNETIC RESONANCEBefore First control – POD #6



CARDIAC MAGNETIC RESONANCEFirst control – POD #6 Four-year control


PULMONARY ENDARTERECTOMY: REVERSE RIGHT VENTRICULAR REMODELING

REVERSE RIGHT VENTRICULAR REMODELING



BRAIN-TYPE NATRIURETIC PEPTIDEBNP TIME COURSE AFTER PEA

Livelli plasmatici di BNP

350.0

400.0

450.0

SERUM BNP LEVELS


0.0

50.0

100.0

150.0

200.0

250.0

300.0

PRE-OP DIMISSIONE 3 MESI 1 ANNO 2 ANNI

pg/m

l

PRE-OP DISCHARGE 3 MONTHS 1 YEAR 2 YEARS


ARTERIAL OXYGEN PARTIAL PRESSURE

Arterial Oxygen Partial Pressure

60

70

80

90

100

mmHg


0

10

20

30

40

50


Follow-up

mmHg

pp < 0.01< 0.01



MODIFIED BRUCE TEST

Modified Bruce Test

600

700

800

900

1000

meters


0

100

200

300

400

500

600


Follow-up

meters

pp < 0.01< 0.01



RESULTS

• In expert Centers mortality ranges between 5% and 12% and technical failure is below 8%


• Early hemodynamic results are known to be excellent in case of successful operation


RESULTS• The majority of pts experienced dramatic improvement in

pulmonary hemodynamics after PEA

• After PEA the decrease in pulmonary artery pressure is immediate (in O.R.)and associated with complete recovery of RV morphology (at discharge)


RV morphology (at discharge)

• The functional results also show a progressive good recovery over a longer time (about years)


REFERENCE


• April 1994 – October 2008

• 204 PEAs performed

• 184 patients received a complete pre-operative


REFERENCE


• 184 patients received a complete pre-operative screening for thrombofilia

• Group A (HAPT– high titre > 10 U/ml) 28 pts

• Group B (LAPT– low titre > 10 U/ml) 156 pts


REFERENCE



PATIENTS’ MANAGEMENT

• Accurate NIRS monitoring during circulatory arrests

• Attention even to minor neurological dysfunctions

• Careful anticoagulation with higher target INR


• Careful anticoagulation with higher target INR

• Inferior vena cava filter positioning

• Accurate post-operative follow-up

RESULTS OF PULMONARY ENDARTERECTOMY: THE PAVIA EXPE RIENCE

PAVIA PULMONARY ENDARTERECTOMY GROUP

• Cardiac Surgery M Viganò, AM D’Armini, C Monterosso, G Silvaggio,

S Nicolardi, M Morsolini, D Berwick, G Mattiucci

• Anestesiology M Maurelli, T Bianchi, R Veronesi, M Toscani

MA Villani, E Milanesi, B Lusona, M Gerletti

• Cri tical Care A Braschi, V Emmi, G Rodi, G Sala Gallini

F Capra Marzani, F Mojoli

• Cardiology L Oltrona Visconti, S Ghio, A Raisaro, L Scelsi, C Raineri

• Respiratory Disease E Pozzi, I Cerveri, A Corsico


• Radiology I R Dore

• Radiology II F Zappoli Thyrion, P Quaretti, A Azzaretti, G Rodolico

• Nuclear Medicine C Aprile

• Reumatology C Montecucco, R Caporali

• Thromboembolism F Piovella, M Barone, C Beltrametti

• Pathology U Magrini, E Arbustini, M Grasso

• General Rehabilitation E Dalla Toffola, L Petrucci

• Pulmonary Rehabilitation C Fracchia, G Callegari

• Biostatistics C Klersy

morsolini marco torino 13° convegno patologia immune e malattie orfane 21 23 gennaio 2010

Health & Medicine

matteo hospital pavia

pavia experience indications

pavia experience andrea

type of pulmonary hypertension

excess factor

factor v leiden15

acute pe

type of surgery