Acute Pulmonary Thrombo- embolism Dr. M. Dinaker M.D.Director, Division of Internal Medicine & MICU MediCiti Hospitals, Hyderabad. CME MIMS, 23 Oct 2011
Case Study• 26 y F, recently married, presented at EMD, 3 a.m., with SOB since 2 days, episodic. No fever, cough, hemoptysis. H/O marital stress+• Anxious, HR 120/min; RR 30/min; afebrile• No cyanosis, No wheeze. Spo2 95% (r.a.).• CXR, ECG unremarkable.• Managed as ‘anxiety hyperventilation syndrome’ and sent home.
Case study …..cont’d• Came back next day (9am) with worsening SOB. No orthopnea.• RR = 40/min; HR 130/min; BP 100/70.• Sp02 92%; ABG: Pao2 70. PaCo2 28. pH 7.23. A-ao2 gradient 17 mmHg.• DIAGNOSIS: Acute PTE• (additional point in Hx: On progesterone containing OCP).
Will Cover…. Epidemiology Pathophysiology and hemodynamics Risk factors Clinical features & “pearls” Diagnosis Natural History Management (incl prevention).• Will NOT cover DVT.
Introduction• Pulmonary thromboembolism (PTE) is a major cause of mortality and morbidity in any ICU. (despite the use of prophylactic anticoagulant therapy).• PTE may be masked by other life-threatening disease. Acute PE should always be considered in the differential diagnosis of the deteriorating critically ill patient.• Diagnosis in the ICU is usually hampered by difficulties of moving patients and restrictions in the use of invasive techniques. Non invasive bedside tests are frequently relied upon in the context of high clinical suspicion.• Majority of preventable deaths due to PTE is due to an ‘initial missed diagnosis’ rather ‘failed therapies
Epidemiology• Majority of patients in the ICU have one or more risk factors for PTE.Incidence varies from 5 – 33 %. Cook et al, J Crit Care Med 2000.• 50% of patients with proximal lower limb DVT and 20% with upper limb DVT have asymptomatic PTE at presentation.• PTE was undiagnosed during life and confirmed at autopsy in 20% cases. Twigg et al Intensive care medicine 2001• Overall, the incidence of DVT in ICU pts NOT receiving prophylaxis is ~ 30%, with a 15% incidence of PTE, of which 5% may be fatal.
Epidemiology….cont’d.,• SPECTRUM: - Acute PE: with normal BP + preserved RV function. - Sub-massive PE: Normotensive with RV dysfunction. - Massive PE: RV dysfunction + Hypotension.• Mortality in ‘massive PTE’ with hemodynamic instability approaches 30 – 40%. (Overall mortality for all cases of PE is 15% in 3 months)
Dear lungs, With lots of clots, From , Your legs.
Gross PathologyTapson V. N Engl J Med 2008;358:1037-1052
PTE – Haemodynamic consequence • Depends on size of embolus, co existing cardiopulmonary disease and neurohumoral effects.Haemodynamic decompensationoccurs due to:- physical obstruction to bloodflow.- Release of humoral factors: eg5HT from platelets, thrombinfrom plasma and histamine (Bernstein effect)from tissues. Goldhaber, Circulation 2003
Risk factors• PTE is a multifactorial disease. ‘Virchow’s Triad’ (1st described in 1856) of endothelial damage, abnormal blood flow and altered blood composition is still valid.• “Economy class syndrome” relatively uncommon but continues to hold public fascination.
Risk Factors ……cont’d.,• Trauma and surgical pts: invariably have endothelial damage triggering coagulation.• Immobilization: is common in ICU pts due to disease severity, sedation and MV. Venous stasis may be further exacerbated due to hypotension, raised intra-abdominal pressure, vasodilatation, use of femoral catheters and elevated venous pressure secondary to right heart failure.• Presence of a previously known genetic risk factor increases the relative risk of thrombosis by up to 10- fold.
PTE- Risk score / predictive value SIMPLIFIED “WELLS” SCORING REVISED GENEVA SCORING SYSTEM• Clinical sg / sympt of DVT / PE - 3.0• No alternative diagnosis likely - 3.0• HR > 100 bpm - 1.5• Immobilty or recent surgery - 1.5• Previous H/O DVT / PE - 1.5• Hemoptysis - 1.0• Cancer actively treated in the last 6 mo 1.0 - Low prob <2 (1.3%) Moderate prob < 2-6 ( 16.2%) High prob >6 (37.5%) LOW 0 – 3 (8%) Moderate 4 – 10 (28%) High >/= 11 (74%)
“Think PE as a possibility first”!• Appropriate clinical setting. Focused history and physical examination. (unexplained tachycardia, unilateral wheeze, loud P2).• CXR / EKG : for rapid identification of an alternative diagnosis. (eg : MI, pneumonia).• ABG : hypoxia has to be present. Look for increased A – a o2 gradient. Rule out severe acidosis as a cause of increased R.R.• 2D – ECHO : may reveal RA / RV dilatation. (Hypoxia due to any cause can cause PAH). Look for a TR jet which was not previously present. WNL implies “ We Never Looked”!
PTE- Other “Clinical Pearls”• Young pts “look” remarkably well! Hemodynamic instability may set in very late.• Always elicit H/O OC-P ingestion in an young female who presents to the EMD with unexplained SOB for the first time.• Think twice ( or maybe more often!) before making a diagnosis of “late onset” bronchial asthma.• In any pt in the ICU who has unexplained tachycardia OR acute onset unprovoked atrial fibrillation, make a diligent search for acute PE and rule it out . NAD implies “Nothing attempted or done!”
“d – DIMER”……What is its place?• Fibrinogen specific degradation product; detects cross linked fibrin formed within vascular tree. It is a marker of endogenous “ineffective” fibrinolysis (activated by plasmin).• Assay ideally should check ratio of fibrinogen (decreased) to d-Dimer (increased).• Assay is more valuable as a test with ‘HIGH NEGATIVE’ predictive value. (99.6%).- ‘Rule out’ test. -Dunn et al (J Am Coll Card 2002) ; n = 1109 ; Out of the 547 pts who had normal d-Dimer levels, only 2 pts developed DVT in the 3 – month follow up.
Cardiac Bio-markers• Troponin I Circulation May 2007• N terminal pro BNP.• Elevated values indicate RV dysfunction and infarction;• Correlates with hemodynamic instability; may guide initiation of ‘lytic’ therapy.
Hyponatremia & outcomes in acute PE ajrccm , Oct 2010• 13,728, 185 hospitals; 2001-02. Hyponatremia is a marker of neurohumoral activation; present in 21% of pts.• 30 day mortality of 28.5% in pts with Na <130.• Odds ratio for readmission was 1.44.AT A GLANCE COMMENTARY : Scientific Knowledge on the Subject. Although associated with adverse outcomes in heart failure, pneumonia, andpulmonary hypertension, the prognostic value of hyponatremia, a marker ofneurohormonal activation, in patients with acute pulmonaryembolism (PE) isunknown.What This Study Adds to the Field: In patients with acute PE, hyponatremia at presentation is common, and isassociated with a higher risk of 30-day mortality and readmission.
Ventilation Perfusion Scan• Valuable tool when results are definitive. “Normal” V/Q scan essential rules out PTE.• “High probability” scan is strongly associated with presence of PTE. Problem area: “low” and “intermediate” scans.• ‘PIOPED Study’ (JAMA 1990): 87% of pts (103 of 118) in high probability scan had PE confirmation on angio.• In the absence of availability of ‘ventilation scan’, one can perform only a perfusion scan. (Normal CXR implies normal ventilation).
LUNG PERFUSION SCAN• 1st line investig in pregnancy, contrast allergy, renal failure.• A NORMAL Chest x-ray implies a ‘normal’ ventilation scan
MR-Pulmonary Angiography• Indications:- C/I for CTPA.- ‘Indeterminate’ V/Q scan.• Limitations:- High cost.- Breath holding, of 10-30s (maybe a limiting factor).- Cardiac pulsation artifact.- Limitation in evaluation of segmental and subsegmental pulmonary arteries.
Natural History: “Treated PE”Prognosis in relation to initial severity• (A) Shock at presentation: ~ 10% rapidly fatal. 2% first diagnosed at autopsy. 5 – 10% have shock at presentation and is associated with 25- 30% mortality.• (B) RV dysfunction without shock: n > 700 (Int’l Co-op PE Registry). Hazard ratio for death at 3 months was 2.2. Poor prognostic factors included age > 70 years, Ca, CHF, COPD, Hypotension and tachycardia.• (C) Long Term mortality: ~ ¼ die within 1 yr, of which only 20% is due to PE recurrence. (rest succumb to Ca, COPD, CHF etc).
Heparin• Discovered by Mclean 1916. Sulfated glycosaminoglycan; acts by initial binding to AT III and induces conformational changes that accelerates the rate at which AT III inhibits coagulation enzymes.• Extensive protein binding (hence therapeutic limitations).• 20,000 units in 500ml is equal to 40 units / ml. Always administer UFH as “infusion”.
Always remember……• Heparin anticoagulation should be begun while pursuing the diagnostic workup.• Advantage of IV heparin infusion is its short t1/2 (30-45 min); which is important if pt goes onto require ‘thrombolytic’ therapy or an ‘embolectomy’. - Circulation, Dec 2003, Goldhaber• In C/O “HIT”: - rapid shift to oral anticoagulation. - Use Hirudin analogues (direct thrombin inhibitors).
N = 1021, 1 /3 developed PE during the study period. RCT:LMWH Vs adjusted dose UFH. Outcome studied over 12 wks.
Oral anticoagulation…..cont’d.,• Two classes of drugs: Dicoumarol (Warfarin*). Inandiaone (Acitrom*)• Always should be started after at least 3 – 5 days of initial heparin therapy. Should be overlapped with heparin for 2 -3 days, (as it takes time to neutralize the circulating factors and deplete the hepatic stores.• Usual target therapeutic INR (for pts with PE) is 2.0 – 3.0.
Newer anticoagulants……..(A) Direct “thrombin inhibitors” Argatroban (Lewis, Circulation 2001,103:1838(B) Hirudin analogues Lepirudin (Grienacher, Circulation 1999).(C) Fondiparinux: (Arixtra*) Anti –Xa agent; synthetic pentasaccharide 7.5 mg s/c od; atleast as effective as IV heparin. (The matisse Investigators, NEJM 2003). Oral form : Rivoraxaban.(D) Ximelegatran: Oral direct thrombin inhibitor, b.d dosing. (Thrive investigators, Erickson, J. Thromb Hemos, 2003).(E) Role of antiplatelets: Can attenuate the pulmonary vasoconstriction, bronchospasm and hypoxia associated with PE.
Thrombolytic Therapy• Paucity of RCTs.• Classical indication: Massive PE with moderate to severe RV dysfunction with preserved systemic BP.• “WINDOW PERIOD”: Hours to weeks.• RT-Pa: 100mg over 2h.(without heparin).• Other agents:- Streptokinase: 1.5 Lac units IV over 45 min followed by 1Lac units / hr for 24-36h.- Urokinase: 4400 U/ kg IV bolus, followed by 4400U/ Kg/ H over 24 -36 h.- Tenecteplase*• “Catheter directed thrombolysis”
Thrombolytic Therapies….cont’d.,• RCTs:-(1) Goldhaber, Lancet 1993 N = 101, t-PA Vs iv heparin; At 14 d, no recurrence in tPA Vs 5 in heparin group. Probably, related to rapid reduction in RV end diastolic area.-(2) MAPPET 3 trial, ( NEJM, 2002;347). N = 256, RV dysfunction without hypotension: rt-PA + heparin Vs heparin alone. Primary end point: death +/- escalation of Rx; 25% in heparin alone arm Vs 10% in combined Rx arm. (p = 0.006).• IC – Bleed risk : (ICOPER, Goldhaber, Lancet 1999); N = 2454; was ~ 3% of the 304 pts who received thrombolysis.
“IVC – Filter”…..cont’d.,Absolute Indications:• C/I for anticoagulation therapy. (eg: Perioperative period). May use retrievable filter.• Recurrent PE despite extended and therapeutic level anticoagulation.• In critically ill hemodynamically unstable pts, IVC filter may be inserted bedside under USG- guidance.• 14 different types approved; no proven superiority of one over the other.Disadvantages:• Nidus for recurrent VTE. 2.6 fold increase in risk for re-hospitalization within 1 y of filter placement. - Arch Int Med 2000.
Embolectomy (Cath Vs Surgical)INDICATION:- C/I for ‘thrombolytic therapy’. - Need for CPR. - Arterial hypotension ( < 90 / 40 ). - A-a O2 gradient > 50 mm Hg.• Catheter: Clot fragmentation Rheolytic thrombectomy using high velocity saline solution jet to create a venturi effect and clot aspiration with a large syringe using a coronary guiding or a Greenfield embolectomy catheter. Goldhaber (Chest, 1998).
Combined Therapy• (A) anticoagulation + IVC filter. - Severe cardiopulmonary disease in which recurrent PE maybe fatal. - Pt with a large free floating iliocaval thrombus.• (B) Lytic therapy + clot fragmentation. Lytic therapy softens occlusive thrombus, thereby facilitating fragmentation of the clot. Fragmentation (by catheter) exposes larger surface of the thrombus to lytic therapy. Eg : Saddle thrombus of MPA with hemodynamic instability.
Prevention• There are very few disorders in medicine in which preventive measures are so highly cost effective as DVT / PTE.• “Knowledge of specific risk factors in patient groups or individual patients forms the basis for the appropriate use of prophylaxis” – Geerts et al, Chest 2001• Intensity of prophylaxis should be matched to the level of risk.
Frequency of PTE/DVT without thromboprophylaxisClinical setting DVT(%) PE(%) FATAL PEStroke 56 - -THR 51 4 1.65Trauma ortho surg - 7 -Polytrauma 50 -TKR 47 -Spinal cord injury 35 -Gen surg 25 1.6 0.87Neurosurg 22 - Joseph et al -Seminars in hematology, 2001.
PTE –Risk assessment modelSTEP 1: Exposing risk factors associated with clinical setting• Assign 1 2 factors 3 factors 5 factors FactorMinor Surg .Major Surg* .MI . Elective . POP immob . CHF LL arthr . Med/ Surg . Sepsis . Hip/pelvic # in bed > 72h . Stroke . CVP access . Polytrauma . Ac spine(* OP in which dissection imp or > 45 min) injury
PTE –Risk assessment model cont’dSTEP 2 : Predisposing risk factors associated withpatient CLINICAL SET INHERITED ACQUIRED Age (40-60) 1 f Factor V Leiden/ Lupus anticoagulant(3 APCR (3 factors) factors) Age > 60 2 f AT III defic (3 factors) APLA (3 factors) H/O DVT /PE Protein C & S defic (3 Myeloproliferative 3f Factors) disorders ( 3 factors) Postpartum/Pregnanc Dysfibrinogenemia Disorders of plasmin y (3 factors) ( 3 factors) Malignancy 2f Homocysteinemia (3 H.I.T ( 3 factors) factors) Varicose veins 20210A prothrombin Hyperviscosity mutaton (3 factors) syndromes( 3 factors) Obesity Homocysteinemia (3 IBD factors) Combined OCP/HRT
PTE –Risk assessment model cont’d Step 3: Total risk factors (exposing + prediposing): __ Step 4: Recommended prophylactic regimens for each risk group.Low risk (1 factor) Moderate risk (2 High risk (3-4 Highest risk (5 or factors) factors) more factors)No specific LDUFH (every 12 LDUFH (every 8 LMWH, oralmeasures h), LMWH, IPC h), LMWH and anticoagulants, and GCS# IPC IPC (+ LDUFH or LMWH), GCS # (+ LDUFH or LMWH)Early ambulation GCS# (+LDUFH Adjusted-dose or LMWH) heparinLDUFH = Low dose unfractionated heparinLMWH = Low molecular weight heparinGCS = Graduated compression stockings. (gradient ~ 20mmHg).IPC = Intermittent pneumatic compression
(Circulation Aug 17 2004)• RCT, N = 3706,• Dalteparin 5000 IU S/C Vs placebo for 14d.• Follow up for 90 d.• Primary end point : VTE.• RESULTS: Incidence of VTE decreased from 4.96% to 2.77%. Relative risk reduction of 45% (p = 0.0015). Observed benefit maintained at 90 d. Overall bleeding risk low. Circulation Aug 2004
Case 1• 68 y M, C/O 4 months H/ O fatigue, atypical chest pain & DOE. SpO2 95%.• Had intermittent wheeze ; treated as adult onset asthma, no relief with ‘inhalers’.• CAG normal.• UGI’scopy : mild GERD.
Case 1, cont’d.,V/Q scan interpreted as“indeterminate” scan.Selective pulmonary angio
Carry Home Message…….• Do NOT ignore subtle CXR abnormalities.• All that wheezes is not asthma.• Re-evaluate the pt once the CAG is reported normal !• Findings on V/Q scan could help guide catheter for selective pulmonary angio.
Summary• PTE is not an uncommon complication in any ICU setting. Strong clinical suspicion is essential and key to an early diagnosis.• Most in-hospital deaths (due to PTE) is due to an ‘initial missed diagnosis’ rather than ‘treatment failures’.• Objective risk assessment models should be used on day 0 of hospitalization and during preop work up.• Appropriate prophylaxis significantly reduces events and mortality.
Summary…..cont’d.,• In patients with strong clinical suspicion, the initial investigation of choice is spiral CT pulmonary angiography. D-DIMER is a negative predictive value (‘rule out) test. Be aware of the pitfalls in interpretation of V/Q scans.• Heparin remains the initial choice of Rx. Consider thrombolytic Rx in subset with ECHO e/o RV dysfunction with elevated cardiac biomarkers.• Duration of treatment after the initial therapy is controversial, but trend is towards longer and in selected cases indefinite.• Newer drugs hold great promise (out-patient Rx).