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DIAGNOSTIC AND TREATMENT APPROACHES TO PAH DUE TO RECURRENT PULMONARY THROMBOEMBOLISM SURGICAL TREATMENT. Rıza Doğan, M.D. Professor of Surgery, Department of Thoracic and Cardiovascular Surgery Hacettepe University, Faculty of Medicine Turkish Thoracic Society 11th Annual Congress
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DIAGNOSTIC AND TREATMENT APPROACHES TO PAH DUE TO RECURRENT PULMONARY THROMBOEMBOLISMSURGICAL TREATMENT Rıza Doğan, M.D. Professor of Surgery, Department of Thoracic and Cardiovascular Surgery Hacettepe University, Faculty of Medicine Turkish Thoracic Society 11th Annual Congress April 23rd-17th, 2008, Belek, Antalya, TURKEY
SURGICALLY CORRECTABLE HYPERTENSION 1- Coartation of the aorta 2- Renovascular hypertension 3- Cathecolamine secreting tumour 4- Pulmonary hypertension - Thromboendarterectomy - Lung transplantation
CAUSES OF PULMONARY HYPERTENSION 1- Idiopathic pulmonary arterial hypertension 2- Congenital cardiac malformations with - Left to Right shunt - Pulmonary venous obstruction 3- Chronic mitral and / or aortic valve pathologies 4- Chronic pulmonary thromboembolism 5- Vasculitis (small vessel arteriopathy) 6- Tumoral invasion
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
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 Major Risk Factors for Venous Thromboembolism
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;165-252 Moser KM. Circulation 1990:81;1735-43 Pengo V, et al. N Engl J Med 2004;350:2257-64
Pulmonary 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;106:116-27 Daily 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 arterioles Lung 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 THROMBOEMBOLİSM THERAPY Mean PAP 30mmHg – 5 year survey 30 % Mean PAP 50mmHg – 5 year survey 10 % Endarterectomy THERAPY = SURGERY Transplantation ? MEDICAL surgery if not applicable
PULMONERY THROMBOEMBOLISM SURGICAL APPROACH • 1908 Trendelenburg:Pulmonary embolectomy • 1956 Idea of pulmonary endarterectomy:HollisterandCull • 1957 First pulmonary endarterectomy (inflow occlusion and hypothermia):Hurwitt et al.. • 1958 Embolectomy in chronic embolism with inflow occlusion Allisonet al. • 1963 Endarterectomy via right thoracotomy Snyder et al. • 1964 First pulmonary endarterectomy with cardiopulmonary bypass:Castlemanet al.
PULMONARY THROMBOENDARTERECTOMY INDICATIONS 1- NYHA Class III – IV 2- Preoperative pulmonary vascular resistance ≥ 300 dyne.sec.cm-5 3- Surgically removable main lobar or segmental pulmonary arterial thrombus 4- 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
PULMONARYTHROMBOENDARTERECTOMY CONTRAINDICATIONS 1- 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 arteries Type 2: Organized thrombus and intimal thickening proximal to segmental arteries Type 3: Intimal thickening-fibrosis in distal segmental arteries Type 4: Distal arteriolar vasculopathy Thistlethwaite PA. J. Thorac. Cardiovasc Surg. 2002;124:1203-11
PULMONARY THROMBOENDARTERECTOMY COMPLICATIONS • Edema • Hemorrhage • 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 %)
Surgical mortality ranges between 4.4 – 20 %
Risk Factors Affecting Operative Mortality • 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 THROMBOENDARTERECTOMY LATE RESULTS (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 1999:160:523-8 Doughty N. Int J Nurs Pract 2003:9:60-5
PULMONARY THROMBOENDARTERECTOMY COMBINED WITH OTHER OPEN-HEART 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)
PULMONARY THROMBOENDARTERECTOMY COMBINED WITH OTHER OPEN-HEART PROCEDURES (2) • 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
RE-PULMONARY THROMBOENDARTERECTOMY • 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 operation Makoto M. Ann Thorac Surg 1999:68:1770-7
OUR PULMONARY THROMBOENDARTERECTOMY EXPERIENCE 1st January 2002- 29th March 2007 Total number of cases 14 Medical files of first two patients are not accesible Age 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 patient Hepatic cyst hydatic opened to IVC + 1 patient IVC thrombosis DVT + Breast cancer (CT+RT) 1 patient DVT + Lung cancer (1 had 2 patient thrombophilia + COPD) CAD + DVT+ Factor VIII + 1 patient Protein C and S deficiency DVT (isolated) 4 patient Diarrhea + metabolic acidosis 1 patient Primary 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 II 1 patient class III 10 patient class IV
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
Results PAP 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)
P=0.117 p<0.05 p<0.05 Preop PAP 79.1 ± 26.6 ICU PAP 61.2 ± 35.1 Final PAP 35.7 ± 22.0 Preop TI 3.08 ± 0.5 Final TI 0.3 ± 0.8 One patient still on ilomedin therapy All recieving coumadin ( PT-INR > 2.5) p=0.001