1. Acute Pulmonary Thrombo-
embolism
Dr. M. Dinaker M.D.
Director, Division of Internal Medicine & MICU
MediCiti Hospitals, Hyderabad.
CME MIMS, 23 Oct 2011

3. 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.

4. 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).

5. Will Cover….
 Epidemiology
 Pathophysiology and hemodynamics
 Risk factors
 Clinical features & “pearls”
 Diagnosis
 Natural History
 Management (incl prevention).
• Will NOT cover DVT.

6. 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

7. 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.

8. 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)

9. PTE- Pathophysiology

10. Dear lungs,
With lots of clots,
From ,
Your legs.

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

12. PTE – Haemodynamic consequence
• Depends on size of embolus, co existing
cardiopulmonary disease and neurohumoral effects.
Haemodynamic decompensation
occurs due to:
- physical obstruction to blood
flow.
- Release of humoral factors: eg
5HT from platelets, thrombin
from plasma and histamine (Bernstein effect)
from tissues.
Goldhaber, Circulation 2003

13. 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.

14. 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.

15. 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%)

16. PTE-DIAGNOSIS

17. “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”!

18. 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!”

19. Differential Diagnosis
“The great masquerader”

20. How to investigate?

21. Plain Chest Radiograph
• Cardiomegaly (new
onset).
• Normal in ~ 25%.
• Other abnormalities
are non-specific.
Atelectasis Hge/ edema

22. Role of ECG
- Abrupt rightward shift in QRS axis.
-Most common abnormality is Sinus tachycardia.
- S1Q3T3 pattern seen in < 25%.

23. Dia

24. “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.

25. 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.

26. Ajrccm, Nov 2009
N = 570

27. 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, and
pulmonary hypertension, the prognostic value of hyponatremia, a marker of
neurohormonal activation, in patients with acute pulmonaryembolism (PE) is
unknown.
What This Study Adds to the Field:
In patients with acute PE, hyponatremia at presentation is common, and is
associated with a higher risk of 30-day mortality and readmission.

29. CT – PULMONOLOGY ANGIO

31. 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).

32. LUNG PERFUSION SCAN
• 1st line investig in pregnancy, contrast allergy, renal failure.
• A NORMAL Chest x-ray implies a ‘normal’ ventilation scan

33. 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.

34. PULMONARY ANGIOGRAPHY- “THE GOLD STANDARD”

36. Natural History

37. 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).

38. Management

39. 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”.

40. Heparin- Dosing schedule

41. 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).

42. Low molecular weight heparin

44. (NEJM, SEP 1997)

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

46. 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.

47. (Circulation, Aug 2004)

48. 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.

49. 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”

50. 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.

51. 11 trials, N= 748

52. (Cont’d.,)

53. “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.

54. ‘IVC – Filter’ in-situ

55. 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).

56. 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.

59. 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.

60. Frequency of PTE/DVT without
thromboprophylaxis
Clinical setting DVT(%) PE(%) FATAL PE
Stroke 56 - -
THR 51 4 1.65
Trauma ortho surg - 7 -
Polytrauma 50 -
TKR 47 -
Spinal cord injury 35 -
Gen surg 25 1.6 0.87
Neurosurg 22 -
Joseph et al -Seminars in hematology, 2001.

61. PTE –Risk assessment model
STEP 1: Exposing risk factors associated with clinical setting
• Assign 1 2 factors 3 factors 5 factors
Factor
Minor 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

62. PTE –Risk assessment model cont’d
STEP 2 : Predisposing risk factors associated with
patient
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

63. 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, oral
measures 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) heparin
LDUFH = Low dose unfractionated heparin
LMWH = Low molecular weight heparin
GCS = Graduated compression stockings. (gradient ~ 20mmHg).
IPC = Intermittent pneumatic compression

64. (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

65. Lancet 2009
Phase 3, N = 3148.

66. Circulation , Jan 2007

67. 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.

68. Case 1, cont’d.,
V/Q scan interpreted as
“indeterminate” scan.
Selective pulmonary angio

69. 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.

70. 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.

71. 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).

72. Thank you for your
attention……!