Acute Pulmonary Thromboembolism

IntroductionPulmonary 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

EpidemiologyMajority 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.

Pathophysiology

Tapson V. N Engl J Med 2008;358:1037-1052Gross Pathology

PTE Haemodynamic consequenceDepends on size of embolus, co existing cardiopulmonary disease and neurohumoral effects.Haemodynamic decompensationoccurs due to:

- physical obstruction to blood flow.

- Release of humoral factors: eg 5HT from platelets, thrombin from plasma and histamine from tissues.Goldhaber, Circulation 2003(Bernstein effect)

PTE- Risk score / predictive valueSIMPLIFIED WELLS SCORING SYSTEMAnn Intern Med.2006;144(3):165-171.

PTE- Risk score / predictive valueREVISED GENEVA SCORINGAnn Intern Med.2006;144(3):165-171.

PTE- Diagnosis

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 PearlsYoung 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!

The great masqueraderDifferential Diagnosis

Investigating PTE

Plain Chest RadiographCardiomegaly (new onset).Normal in ~ 25%.Other abnormalities are non-specific.Pleural effusionAtelectasisHge/ edemaElevated hemidgmPromin pulmon artery

Role of ECG Abrupt rightward shift in QRS axis.

Most common abnormality is Sinus tachycardia.

S1Q3T3 pattern seen in < 25%.

Dia

d DIMERWhat 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-markersTroponin IN terminal pro BNP.

Elevated values indicate RV dysfunction and infarction; Correlates with hemodynamic instability; may guide initiation of lytic therapy.Circulation May 2007

Ajrccm, Nov 2009N = 570

AT A GLANCE COMMENTARY : Scientific Knowledge on the Subject. Although associated withadverse outcomes in heart failure, pneumonia, and pulmonaryhypertension, the prognostic value of hyponatremia, a markerof neurohormonal activation, in patients with acute pulmonaryembolism (PE) is unknown.What This Study Adds to the Field: Inpatients with acute PE, hyponatremia at presentation is common,and is associated with a higher risk of 30-day mortality andreadmission. Hyponatremia & outcomes in acute PE ajrccm , Oct 201013,728, 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

CT PULMONOLOGY ANGIO

Ventilation Perfusion ScanValuable 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 AngiographyIndications:- 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.

PULMONARY ANGIOGRAPHY- THE GOLD STANDARD

Natural History

Natural History: Treated PEPrognosis 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 (Intl 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: ~ die within 1 yr, of which only 20% is due to PE recurrence. (rest succumb to Ca, COPD, CHF etc).

Management

HeparinDiscovered 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.

Heparin- Dosing schedule

Always rememberHeparin 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).

Low molecular weight heparin

(NEJM, SEP 1997)

N = 1021, 1 /3 developed PE during the study period. RCT: LMWH Vs adjusted dose UFH. Outcome studied over 12 wks.

Oral anticoagulation..contd.,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.

(Circulation, Aug 2004)

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 TherapyPaucity 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.contd.,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.

11 trials, N= 748

(Contd.,)

IVC Filter..contd.,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.

IVC Filter in-situ

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 fragmentationRheolytic 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.

PreventionThere 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 2001Intensity of prophylaxis should be matched to the level of risk.

Frequency of PTE/DVT without thromboprophylaxis

PTE Risk assessment modelSTEP 1: Exposing risk factors associated with clinical setting

PTE Risk assessment model contd STEP 2 : Predisposing risk factors associated with patient

PTE Risk assessment model contdStep 3: Total risk factors (exposing + prediposing): __Step 4: Recommended prophylactic regimens for each risk group. LDUFH = Low dose unfractionated heparinLMWH = Low molecular weight heparinGCS = Graduated compression stockings. (gradient ~ 20mmHg). IPC = Intermittent pneumatic compression

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 17 2004)Circulation Aug 2004

Lancet 2009Phase 3, N = 3148.

Circulation , Jan 2007

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.

SummaryPTE 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..contd.,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).

Thank you for your attention!