PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE

UNIVERSITY OF PAVIA SCHOOL OF MEDICINE - SAN MATTEO HOSPITAL - PAVIA - ITALY

Andrea M D’Armini, MD, FCCP

Division of Cardiac SurgeryUniversity of Pavia School of MedicineFoundation I.R.C.C.S. San Matteo HospitalPavia - Italy

PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE



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

– 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

PEA vs. LTx



EPIDEMIOLOGY

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

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

→ 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 Surg 2000; 37:165-252• Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 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 Med 2004; 350:2257-64



CURRENT SITUATION

• CTEPH is still under-diagnosed and nowadays only few physicians are aware of the surgical procedure called PEA

• For all these reasons about 8000 PEA have been performed worldwide so far with ≈ 30 % 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)

• 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 and interscapular olosystolic murmur

• Hypoxemia with exercise, sometimes at rest also

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


• A PERMANENT INFERIOR VENA CAVA FILTER was placed before PEA in the majority (376/410) of patients

• Lifelong oral anticoagulation was prescribed after PEA


MARKED THROMBOPHILIA



REFERENCE



INDICATIONS FOR SURGERY

• The indications for the surgical treatment of these patients are based on

CLINIC

HEMODYNAMIC

• The indications for the type of surgery are 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 even in NYHA class II patients, 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



HEMODYNAMIC

• In some cases this calculation [PVR = (mPAP – Wedge) / CO * 80] could result in a value < 300 dynes*sec*cm-5 due to a partially maintained CO ( 3.5 L/min) or for a inaccurate measurement of wedge pressure (high value for extensive collateral bronchial arteries flow)

• In these cases the leading variable is the degree of pulmonary hypertension (mPAP 25 mmHg at rest)



ANATOMY

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

• Lesions can be classified asPROXIMAL

DISTAL



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


• Growing single surgeon’s experience due to learning curve


OPERABILITY ASSESSMENT

Which lesions have to be considered as inoperable?

• Different operability assessments from different Centers



BACKGROUND

• PEA is the treatment of choice for patients with CTEPH• About only 10-15 Centers worldwide are performing PEA

on a routine basis• In expert hands, mortality ranges between 5% and 12%

and technical failure is below 8%• Early hemodynamic results

are known to be excellent incase of successful operation



REFERENCE


• National referral program

• Begin: April 1994

• To date: 410 PEAs performed


OUR PROGRAM


62113

128

22

2119

30

8

57

245

20 193

6

19

Pts coming from outside Italy- Greece 1- Kosovo 1- U.S.A. 1- Uganda 1

2

3

Pavia

≤ 15 pts

16 – 30 pts

≥ 31 pts


PATIENTS’ REFERRALOF 410 PEAs



NUMBER OF PEAs / YEAROF 410 PEAs



AMOUNT OF PATIENTSOF 410 PEAs

2009-2011: 60 PEAs / yr



AMOUNT OF PATIENTSOF 410 PEAs

1994-2007 (14 yrs): 174 PEAs

2008-2011 (4 yrs): 211 PEAs



AMOUNT OF PATIENTSNEW EVALUATIONS

54

108

0

20

40

60

80

100

120

2004 2010

Pat

ien

ts

+ 100%



AMOUNT OF PATIENTSDIAGNOSTIC ACCURACY

34

82

20 260

10

20

30

40

50

60

70

80

90

2004 2010

Pat

ien

ts

IPCTE

Other

63%

76%

+ 13%



AMOUNT OF PATIENTSOPERABILITY RATE

25

73

9 90

10

20

30

40

50

60

70

80

2004 2010

Pat

ien

ts

Operable

Inoperable

74%

89%

+ 15%



AMOUNT OF PATIENTSPEAs PERFORMED

22

65

0

10

20

30

40

50

60

70

2004 2010

PE

As

+ 195 %



PEA EXPERT CENTER



MAIN WORLD PEA CENTERS

Paris, France≈100 PEAs / year

NATIONAL REFERRAL PROGRAM FOR EXCELLENCE

Cambridge, UK≈80 PEAs / year

NATIONAL REFERRAL PROGRAM BY LAW

Pavia, Italy≈60 PEAs / year

MORE THAN ONE PROGRAM

Bad Nauheim, Germany≈50 PEAs / year

MORE THAN ONE PROGRAM

San Diego, California, USA≈130 PEAs / year

NATIONAL REFERRAL PROGRAM FOR EXCELLENCE



PEA POPULATIONOF 410 PEAs

Age 58 16 (11 84) years

Gender 195 M – 215 F

NYHA class 43 II – 188 III – 179 IV

Length III / IV 19 23 months

Urgent / Emergent 81 / 410

Oxygen therapy 194 / 410



ECHOCARDIOGRAPHY



CARDIAC MAGNETIC RESONANCE



MODIFIED BRUCE TESTOF 410 PEAs

Steps Walking distance

No (Pa O2 < 60) 42.6% 183 ± 160 (8 – 852) meters

Step 0 - ½ 47.5%

Step 1 - 2 8.2%

Step 3 - 4 1.6%


• Median sternotomy• Cardio Pulmonary Bypass• Moderate hypotermia (24

°C)

• Circulatory arrest (7 min)• Reperfusion period (5 min)• Bilateral

J Thorac Cardiovasc Surg 1993;106:116-27


PULMONARY ENDARTERECTOMY


• Intra-wall dissection• Peripheral extension• Explore all branches

J Thorac Cardiovasc Surg 1993;106:116-27





SURGICAL TIPS

• Deep-moderate hypothermic circulatory arrest- meticulous dissection into a bloodless field (for optimal hemodynamic result)

• Unclamped aorta- avoidance of aortic manipulation (reduction of cerebral events)

• Hypothermic cardiac protection- ventricular fibrillation induced by hypothermia- ventricular fibrillation induced by device (fibrillator) - avoidance of cardioplegia administration


• Changing features of CTEPH patients

- population is rapidly aging, and an increasing number of elderly patients are referred for PEA

- due to the continuous surgeon’s learning curve, the crucial border between operable and inoperable patients has been pushed more and more distally over time

CTEPH patients are getting more frail and complex


SURGICAL TIPS



CPB MANAGEMENT• Original San Diego technique

- a single (20 min) deep hypothermic (18° C) total circulatory arrest for each side

• Recent advances

- short periods (5 – 7 min) of intermittent moderate hypothermic (24 ° C) circulatory arrest

- followed by short periods of reperfusion ( 5 min)

- with cerebral near-infrared spectroscopy (NIRS) monitoring



CEREBRAL PROTECTION STRATEGYNIRS MONITORING

Near-InfraRed Spectroscopy

0

20

40

60

80

100

9.03

.15

9.20

.53

9.39

.01

9.56

.48

10.1

4.55

10.3

3.14

10.5

1.24

11.0

9.32

11.2

9.10

11.4

7.13

12.0

5.15

12.2

3.17

12.4

1.20

12.5

9.23

13.1

7.26

13.3

5.30

13.5

3.34

14.1

1.37

14.2

9.39

14.4

7.42

15.0

5.45

15.2

3.48

15.4

1.52

15.5

9.54

16.1

8.27

16.3

6.26

16.5

4.23

17.1

2.20

Time

SrO

2

Right channel

Left channel

CPB start

Patient’s cooling

Pre-HCA baseline

HCA maximum drop

Reperfusion

Changing PEA side

End of PEA



CPB MANAGEMENT• 1st step

- short periods (10 – 15 min) of intermittent deep hypothermic (18 ° C) circulatory arrest followed by short periods of reperfusion ( 5 min) with cerebral near-infrared spectroscopy (NIRS) monitoring

• 2nd step

- moderate (24 ° C) instead of deep hypothermic circulatory arrest

• 3rd step

- shorter periods (5 – 7 min) of intermittent circulatory arrest

• to reduce invasiveness• to get more time to perform PEA in a bloodless surgical

field



CPB MANAGEMENTOF 410 PEAs

• Group A (83 pts)

- original San Diego technique (but unclamped aorta)

• Group B (70 pts)- short periods (10 – 15 min) of intermittent deep hypothermic (18 ° C)

circulatory arrest followed by short periods of reperfusion ( 5 min) with cerebral near-infrared spectroscopy (NIRS) monitoring

• Group C (91 pts)

- moderate (24 ° C) instead of deep hypothermic circulatory arrest

• Group D (166 pts)

- shorter periods (5 – 7 min) of intermittent circulatory arrest



CPB MANAGEMENT



CPB MANAGEMENT

Postoperative respiratory function and outcome



CPB MANAGEMENT

Despite

- patients are getting older

- PEA surgery has become more complex due to Jamieson type III lesions

- moderate (24° C) instead of deep (18° C) hypothermia

- longer total circulatory arrest time

Intermittent circulatory arrest under NIRS monitoring

seems to enhance cerebral protection during PEA

allowing for safe prolonged total circulatory arrest time

and improving postoperative outcomes



SURGICAL INSTRUMENT


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


TYPICAL SURGICAL SPECIMENS

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



DISTAL LESIONSJAMIESON TYPE IIILEARNING CURVE



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%)

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


0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228

Months

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0C

umul

ativ

e P

ropo

rtio

n S

urvi

val


CUMULATIVE PROPORTION SURVIVINGOF 410 PEAs

Hospital mortality

Global 39/410 (9.5%)WHO II 0/43 (0.0%)WHO III 12/186 (6.5%)WHO IV 27/181 (14.9%)

Jan 08 – May 12 18/236 (7.6%)Jan 11 – May 12 6/82 (7.3%)

296 238 182 140 119 103 88 68 50 42 32 31 24 18 9 3 3 2

90.0%88.3%

87.1% 86.4%84.8%

83.0%81.1%

79.5% 77.6% 74.7%



FOLLOW-UP

In literature few data are reported on mid- and long- term cardiopulmonary function, particularly on exertion, and on clinical outcomes after PEA



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 procedure)

– 3th month– yearly for 5 years– 7th, 10th and 15th year (10 controls)



FOLLOW-UP DATA

• Seventeen of 368 pts (4.6%) do not participate to the long-term follow-up study since the beginning (2/4 pts referred from outside Italy) or at various intervals

• For these pts we obtain data on survival and WHO functional class annually by scheduled phone-calls

• All the other pts (95.4%) actively participate to the study



NYHA FUNCTIONAL CLASS

NYHA Functional Class

0

10

20

30

40

50

60

70

80

90

100

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

Follow-up

% p

ati

ents

I -I I

I I I -IV

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

p < 0.01



mean PULMONARY ARTERY PRESSURE

mean Pulmonary Arterial Pressure

0

10

20

30

40

50

60

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

Follow-up

mm

Hg

p < 0.01

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



PULMONARY VASCULAR RESISTANCES

Pulmonary Vascular Resistances

0

200

400

600

800

1000

1200

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

Follow-up

dyne*se

c*cm

-5

p < 0.01

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



ECHOCARDIOGRAPHYBefore PEA



ECHOCARDOGRAPHYFirst echo after PEA – POD #9



ECHOCARDIOGRAPHY3-months FUP after PEA



CARDIAC MAGNETIC RESONANCEBefore PEA First CMR after PEA – POD #6



CARDIAC MAGNETIC RESONANCE4-years FUP after PEAFirst CMR after PEA – POD #6



REVERSE RIGHT VENTRICULAR REMODELING


PULMONARY ENDARTERECTOMY: REVERSE RIGHT VENTRICULAR REMODELING

REVERSE RIGHT VENTRICULAR REMODELING



ARTERIAL OXYGEN PARTIAL PRESSURE

Arterial Oxygen Partial Pressure

0

10

20

30

40

50

60

70

80

90

100


Follow-up

mm

Hg

p < 0.01




MODIFIED BRUCE TEST

Modified Bruce Test

0

100

200

300

400

500

600

700

800

900

1000


Follow-up

met

ers

p < 0.01




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)

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



RESULTS

• About 5% of our pts failed to showed a decrease > 20% in PVR compared to pre-operative value

• About 8-10% of our pts showed a new increase in pulmonary pressure after PEA over time

• The reason could be a secondary small vessel arteriopathy (Eisenmenger-type syndrome) in the non-obstructed segments of the lungs already present at the time of PEA



CONCLUSION

• Poor survival rate of untreated pts (10% 5-yrs survival if mPAP 50 mmHg), low mortality rate after PEA and good mid- and long- term results confirm PEA as the procedure of choice for operable CTEPH pts

• The improvement of functional capacity strictly depends on the hemodynamic changes after PEA

• When CTEPH is diagnosed, given the natural history of the disease, patients should be referred for surgery even when in NYHA functional class II



PULMONARY ENDARTERECTOMYIN THE ELDERLY

EXTENSION OFSURGICAL CRITERIA



AGE

Patients older than 70 years

• Apr 1994 – Dec 2002 → 10.8 % (9/83)

• Jan 2003 – May 2012 → 32.1% (105/327)



AGE

0%

20%

40%

60%

80%

100%

1994-1998 1999-2003 2004-2008 2009-2011

>= 70 yrs

< 70 yrs



STUDY POPULATION

Two distinct populations were therefore identified according to age (<70 yrs or ≥70 yrs) and described by

– pre-operative variables

– operative and post-operative variables

Apr 1994 – May 2012 → 410 PEAs

296 (72.2%) PEAs performed in patients < 70 years old

114 (27.8%) PEAs performed in patients ≥ 70 years old



CUMULATIVE PROPORTION SURVIVING

OF 296 vs. 114 PEAs

< 70 yrs >= 70 yrs0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

Months after PEA

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0P

erc

en

tag

e126 112 101 87 69 53 42 34 30 23 15 9 4 4 2

29 19 15 10 6 4 4 2 2 2 2 1 1

90.92.2

86.93.088.52.689.32.5

85.03.5 85.03.581.25.7

78.06.3 78.06.3


• Age did not affect the efficacy of PEA: PVR dramatically and equally decreased in both groups

• We never considered age as a contraindication to PEA

• However, operative mortality and perioperative morbidity were higher in patients age 70 and older: Gram negative infections and reperfusion edema were more severe in the elderly


CONCLUSIONS


• Compared to young subjects, elderly patients had a higher prevalence of major preoperative comorbidities, were sicker at the time of operation and had a reduced functional reserve of their vital organs

• However, this has to be expected in such patients:– age is a well identified independent risk factor in cardiac surgery– in elderly patients the immune system response is less effective– antibiotic therapy may lead to renal and hepatic impairment,

increasing morbility and mortality


CONCLUSIONS


New surgical strategies have been adopted in order to reduce invasiveness in the frail elderly:

– prefer moderate (24-26 °C) to deep (16-18 °C) hypothermia

– perform shorter circulatory arrests (7-9 min vs. 20 min)

– effective prophylaxis of infections (intra-operative BAL)

– refer elderly patients to a rehabilitation Center before PEA to improve their vital organs functional reserve and to gain a better functional status at the time of operation (notably for COPD)


CONCLUSIONS



PULMONARY ENDARTERECTOMYIN WHO FUNCTIONAL CLASS II

EXTENSION OFSURGICAL CRITERIA



WHO FUNCTIONAL CLASS II

Population

43 PEAs out of 410 (10.5 %) from Apr 1994 to May 2012

Hospital mortality 0 %

Main patients’ features

“couch potatoes” “sportsmen” 53.5 % (23/43) 46.5 % (20/43)




Population

Wide spectrum of clinical presentations




Results

Postoperative outcome


• Given the natural history of the disease we perform PEA even in NYHA functional class II patients

• Once CTEPH is diagnosed, there is no reason to delay surgery:

– CTEPH is associated with a progressive vascularremodeling of the unobstructed branches

(Eisenmenger)

– outcome after PEA in NYHA II patients is excellent



Results

PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE

Health & Medicine

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