DIAGNOSTIC AND TREATMENT DIAGNOSTIC AND TREATMENT APPROACHES TO PAH DUE TO RECURRENT APPROACHES TO PAH DUE TO RECURRENT

PULMONARY THROMBOEMBOLISMPULMONARY THROMBOEMBOLISM

SURGICAL TREATMENTSURGICAL TREATMENT

Rıza Doğan, M.D.Professor of Surgery, Department of Thoracic and

Cardiovascular SurgeryHacettepe University, Faculty of Medicine

Turkish Thoracic Society 11th Annual Congress April 23rd-17th, 2008, Belek, Antalya, TURKEY

SURGICALLY CORRECTABLE SURGICALLY CORRECTABLE HYPERTENSIONHYPERTENSION

1- Coartation of the aorta2- Renovascular hypertension3- Cathecolamine secreting tumour 4- Pulmonary hypertension

- Thromboendarterectomy- Lung transplantation

CAUSES OF PULMONARY CAUSES OF PULMONARY HYPERTENSIONHYPERTENSION

1- Idiopathic pulmonary arterial hypertension2- Congenital cardiac malformations with

- Left to Right shunt- Pulmonary venous obstruction

3- Chronic mitral and / or aortic valve pathologies4- Chronic pulmonary thromboembolism5- Vasculitis (small vessel arteriopathy)6- Tumoral invasion

Major Risk Factors for Venous Thromboembolism Major Risk Factors for Venous Thromboembolism

Genetic predisposition,- Factor V Leiden-activated protein C resistance - Protrombin G 20210 A mutation- High levels of Factor VIII- Hyperhomocysteinemia- Thrombomodulin, Protein C and S, Antithrombin III deficiency

Acquired thrombotic factors- Pregnancy- Puerperium- Oral contraception- Hormon replacement therapy- Malign tumors- Antiphospholipid syndrome

Enviromental risk factors- Surgical trauma- Neurologic disorders or paraplegia- Transvenous interventions- Long lasting flight

Major Risk Factors for Venous Major Risk Factors for Venous ThromboembolismThromboembolism

Previous history of venous thromboembolism

Major knee and hip surgery

Recent major surgical intervention

Congestive heart failure Pelvic, limb and hip

fracture

High dose eostrogen therapy

Age > 40 Bed rest > 7 days Malignancy Paralysis Multiple trauma

Approximately 5 %-10% of patients have a defined coagulation abnormality such as

- Anticardiolipin antibody - Lupus anticoagulant

- Protein C deficiency- Antithrombin III deficiency- Heparine –induced platelet antibody the vast majority of cases of thromboembolic pulmonary

hypertension (CTEPH) are due to “SPONTANEOUS” thromboembolism

Auger WR. Am Rev Respir Dis 1991

Venous thromboembolism is the third most common cardiovascular disorder after coronary artery disease and stroke (The incidence of acute pulmonary embolism in the USA has been estimated at between 300.000 and 650.000 symptomatic events per year)

Complete resolution occur in 48 % of patients after acute thrombotic occlusion. In case of appropriate treatment with thrombolytic agents, anticoagulants , vasodilator agents and ACE inhibitors, chronic thromboembolic endovascular changes were seen in 13 % of cases

Recurrent PE is estimated to occur in 4-23 % of patients

Dunning J, McNeil K . Thorax 1999:54:775

Although it was belived that 0.1 % to 0.5 % of patients surviving acute pulmonary embolism develop chronic thromboembolic pulmonary artery obstruction due to unresolved embolic material or recurrent emboli or both, the true incidence of CTEPH appears to be much higher

In a prospective study of 223 patients with acute pulmonary embolism symptomatic CTEPH occured in 3.8 % of the patients at 2 years after the acute episode

Jamieson SW.Curr.Probl.Surg 2000:37;165-252Moser KM. Circulation 1990:81;1735-43

Pengo V, et al. N Engl J Med 2004;350:2257-64

Pulmonary ThromboembolismPulmonary Thromboembolism Approximately 600.000 individuals each year, in U.S.alone,

have an acute pulmonary embolic event Of these patients, 90 % survive the acute episode In the vast majority the emboli are resolved rapidly In a subgroup with extensive embolization the emboli fail to

resolve and chronic PH develops. This sequel may develop in 0.1 % to 0.2 of survivors (in another experience 0.5-4%)

In another words pulmonary thromboendarterectomy seem to be indicated in ~ 540 to 1080 patients per year or 2.500 – 20.000 patients who suffer a PTE will develop CTEPH.

Jamieson SW. J Thorac Cardiovasc Surg 1993;106:116-27Daily PO. J Thorac Cardiovasc Surg 1987;93:221-33

İntimal fibrosis, medial hypertrophy, plexiform lesions, signs of the pulmonary endothelial injury are seen in most of the patients

CTEPH develops when more than 40-60 % of major pulmonary artery branches are obstructed and is worsened by a secondary vasculopathy in the unaffected pulmonary vessel due to increased pressure and flow persistent increase pulmonary vasculary resistance (PVR) is leading to progressive RV dysfunction and failure Shure D. Ann Thorac Surg.1996;62:1253-4

A consistent pathologic feature seen in lung of patients with PH from PTE is hyperplasia of the media of pulmonary arteriolesLung specimens from 35 patients underwent pulmonary thromboendarterectomy demonstrated up-regulation of angiopoietin-I, a gene responsible for the formation of the media of blood vessels at the m-RNA level.Degree of angiopoietin-I transcription was directly proportional to the preop.PVR and medial wall hyperplasia / hypertrophy in each patient. No detectable expression of this gene at the m-RNA or protein levels was seen in patients without PH

Thistlethwaite PA. J Thorac Cardiovasc Surg 2001;122:65-73.

CHRONIC PULMONARY CHRONIC PULMONARY THROMBOEMBOLİSM THERAPYTHROMBOEMBOLİSM THERAPY

Mean PAP 30mmHg – 5 year survey 30 %

Mean PAP 50mmHg – 5 year survey 10 %

EndarterectomyTHERAPY = SURGERY

Transplantation ?

MEDICAL surgery if not applicable

PULMONERY THROMBOEMBOLISM PULMONERY THROMBOEMBOLISM SURGICAL APPROACHSURGICAL APPROACH

1908 Trendelenburg: Pulmonary embolectomy 1956 Idea of pulmonary endarterectomy: Hollister and

Cull 1957 First pulmonary endarterectomy (inflow

occlusion and hypothermia): Hurwitt et al.. 1958 Embolectomy in chronic embolism with inflow occlusion Allison et al. 1963 Endarterectomy via right thoracotomy Snyder et al. 1964 First pulmonary endarterectomy with cardiopulmonary bypass: Castleman et al.

PULMONARY PULMONARY THROMBOENDARTERECTOMY THROMBOENDARTERECTOMY

INDICATIONSINDICATIONS1- NYHA Class III – IV2- Preoperative pulmonary vascular resistance ≥ 300 dyne.sec.cm-5 3- Surgically removable main lobar or segmental pulmonary arterial

thrombus4- Absence of severe comorbidities

≥ 50% obstruction in lobar or more proximal pulmonary arteries in pulmonary arteriography

No resolution detected by pulmonary angiography within 6 months in case of appropriate anticoagulation

PULMONARYPULMONARY THROMBOENDARTERECTOMY THROMBOENDARTERECTOMY

CONTRAINDICATIONSCONTRAINDICATIONS1- Underlying severe chronic pulmonary disease

(obstructive or restrictive)

2- Life threatening comorbidity or neurological disorder

3- < 60% of expected upstream resistance in pulmonary arterial occlusion study or small vessel disease

4- Severe left ventricular failure

Type 1: Fresh thrombus in main lobar arteriesType 2: Organized thrombus and intimal thickening proximal to segmental arteriesType 3: Intimal thickening-fibrosis in distal segmental arteriesType 4: Distal arteriolar vasculopathy Thistlethwaite PA. J. Thorac. Cardiovasc Surg. 2002;124:1203-11

Hagl C.Eur.J.Cardiothorac.Surg.2003;23:776-81

Hagl C.Eur.J.Cardiothorac.Surg.2003;23:776-81

PULMONARY PULMONARY THROMBOENDARTERECTOMY THROMBOENDARTERECTOMY

COMPLICATIONSCOMPLICATIONS Pulmonary reperfusion response (10 %-15%) Persistent PH (mean PAP>25mmHg) (10%) Arteriotomy rupture Rethrombosis of endarterectomized area Intrapulmonary bleeding (0.5%-1 %) Transient delirium (11,4 - 77 %): directly proportional with

– Deep hypothermia– Total circulatory arrest time

Permenant neurological sequela – > 60 years of age– Total circulatory arrest time > 60 minutes

Phrenic nerve paresis or paralysis (12-24 %)

• Edema

• Hemorrhage

Surgical mortality Surgical mortality

ranges between 4.4 – 20 %

Risk Factors Affecting Operative Risk Factors Affecting Operative MortalityMortality

Distal thromboembolic disease (Type 3-4) Preop PVR > 1100 dyne.sn.cm-5

Mean PAP > 50 mmHg Wrong diagnosis, other causes of PAH Incomplete endarterectomy Fulminant reperfusion pulmonary edema

PULMONARY PULMONARY THROMBOENDARTERECTOMY THROMBOENDARTERECTOMY LATE RESULTS LATE RESULTS (Univ. San Diego. CA)(Univ. San Diego. CA)

- - 6 year survey 75 % (420 cases)- - 62 % of preoperative unworking patients returned to work - - 10 % of patients need intermittant 02 therapy- - 93 % of patients are NYHA Class I or II- - Hospital admittance due to disease itself < 10 %- - 10 % of patients have permenant PAH

Arcibald CJ. Am J Respir Crit Care Med 1999:160:523-8Doughty N. Int J Nurs Pract 2003:9:60-5

PULMONARY THROMBOENDARTERECTOMY PULMONARY THROMBOENDARTERECTOMY COMBINED WITH OTHER OPEN-HEART COMBINED WITH OTHER OPEN-HEART

PROCEDURES (1)PROCEDURES (1)

During warming stage of cardiopulmonary bypass CABG, tricuspid or mitral valve repair, MVR and/or AVR can be performed

Patients with combined procedures are older than only endarterectomy cases (68 vs 50 p<0.0001)

Preoperative LV functions are worser (CO 3.1 vs 4.4 L/min p < 0.0001)

Hospital stay is longer (14 vs 9 days p<0.0001)

No statistical signifance for aortic clamp time, postop TI and LV systolic functions

Perioperative survey 93.3 % (84 / 90 cases), 94.2 % in isolated pulmonary thrombendarterectomy (1034 / 1100 cases)

Thistlethwaite PA. Ann Thorac Surg 2001:72:13-9

PULMONARY THROMBOENDARTERECTOMY PULMONARY THROMBOENDARTERECTOMY COMBINED WITH OTHER OPEN-HEART COMBINED WITH OTHER OPEN-HEART

PROCEDURES (2)PROCEDURES (2)

RE-PULMONARY RE-PULMONARY THROMBOENDARTERECTOMYTHROMBOENDARTERECTOMY

Identifiable Risk Factors:- Coagulation abnormalities- Suboptimal anticoagulation- Occluded or malpositioned IVC filter- Previous unilateral pulmonary thromboendarterectomy

- Incomplete pulmonary thromboendarterectomy Mc Gregor CGA. Ann Thorac Surg 1999

Reoperated patients- Postop arrhytmia incidence (31 % vs.13 % p< 0.05)- Reperfusion pulmonary edema incidence (46 % vs. 33 % p>0.05)- Intubation time (9.8 vs 12.1 days p>0.05)- Intensive care unit stay (11 vs. 6.6 days p >0.05)

Operative mortality 1 / 13 cases (7.7 %) Decrease in postoperative PAP and PVR is lower than first

operationMakoto M. Ann Thorac Surg 1999:68:1770-7

OUR PULMONARY THROMBOENDARTERECTOMY OUR PULMONARY THROMBOENDARTERECTOMY EXPERIENCE EXPERIENCE

1st January 2002- 29th March 20071st January 2002- 29th March 2007

Total number of cases 14Medical files of first two patients are not accesibleAge 4 -77 (mean 46.6±23.0)Sex 7 male (% 58.3) 5 female (% 41.7)Localization Bilateral 6 patients (50 %)

Right PA 5 patients (41.6 %) Left PA 1 patient (8.3 %)

Etiology DVT 10 patients (83.3 %) Malignity 3 patients (25 %) Thrombophilia 3 patients (25 %)

Etiology:

Familial Factor VIII + DVT 1 patientHepatic cyst hydatic opened to IVC + 1 patientIVC thrombosisDVT + Breast cancer (CT+RT) 1 patientDVT + Lung cancer (1 had 2 patientthrombophilia + COPD)CAD + DVT+ Factor VIII + 1 patientProtein C and S deficiencyDVT (isolated) 4 patientDiarrhea + metabolic acidosis 1 patientPrimary PH + PTE 1 patient

Preoperative Values:

PAB 45-135 mmHg (mean 79.1± 26.6mmHg) median 72.0

TI (EKO) (2+)- (4+) (mean 3.08 ± 0.5 + ) median 3.0

NYHA class 1 patient class II1 patient class III10 patient class IV

Swann-Ganz catheter measurementsSwann-Ganz catheter measurementsBasal ıv ilomedin p

C0 3.5 ± 0.2 3.6 ± 0.2 0.065

CI 2.1 ± 0.1 2.2 ± 0.1 0.348

SVR 1391.2 ± 280.6 1208.8 ± 244.1 0.131

PVR 935.6 ± 178.5 774.8 ± 247.0 0.004

PAP 84.0 ± 25.3 72.0 ± 21.7 0.003

PCWP 17.4 ± 1.3 13.0 ± 2.5 0.051

Surgery

T° 18-26°C (mean 19.2 ± 2.5)CX 51-137 min (mean 86.1 ± 28.1)TCA 34-75 min (mean 56.7 ± 15.2)

ilomedin 1-6 ngr/kg/dak (mean 3.0 ± 1.5)4 patients received Sildenafil (50 mg from NG catheter).

In early postoperative period systolic hypotension was avoided.

↑ RVEDP leads to ↓ RV coronary perfusion

Why we used postoperative ilomedin?

Incomplete endarterectomy Operative trauma + CPB Pulmonary vascular effects due to operative trauma and

PTE itself To inhibit trombus formation on endarterectomized area

and to ↓ Tromboxane A2

To inhibit pulmonary hypertensive crisis

ResultsPAP Preop 79.1 ± 26.6 mmHg decreased to 61.2 ± 35.1 mmHg postoperatively.5 patients died

RV failure 2 (1st and 7th days)Necrotizing enterocolitis 1 (7th day)Renal failure 1 (4th day)

Reperfusion pulmonary edema 1 (1st day)Survey 26.2 ± 17.7 months follow-up 63 % (7-56 months)Final PAP 35.7 ± 22.0 (20-85mmHg)Final TI 0.3 ± 0.8 (0 +2)

Preop PAP 79.1 ± 26.6ICU PAP 61.2 ± 35.1 Final PAP 35.7 ± 22.0Preop TI 3.08 ± 0.5Final TI 0.3 ± 0.8

One patient still on ilomedin therapy

All recieving coumadin ( PT-INR > 2.5)

P=0.117

p<0.05p<0.05

p=0.001

İ.C.U.12 yaş.AT: 10.12.2002

İ.C.U.12 yaş.AT: 10.12.2002

E.K.53 yaş.AT: 31.01.2005

F.N.68 yaş.AT: 17.03.2006

A.Ö. 44 yaş.AT: 24.12.2002

F.B.49 yaş.AT: 16.12.2004

H.K. 48 yaş.AT: 06.03.2006