Acute Pulmonary

Thromboembolism

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.

Pathophysiology

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

Gross Pathology

PTE Haemodynamic
consequence
Depends on size of embolus, co existing
cardiopulmonary disease and neurohumoral
effects. decompensation
Haemodynamic
occurs 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 value

SIMPLIFIED WELLS SCORING
SYSTEM

Ann Intern Med. 2006;144(3):165-171.

PTE- Risk score / predictive value

REVISED GENEVA SCORING

Ann 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 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
PEimplies
and rule
it outattempted
.
NAD
Nothing
or done!

Differential Diagnosis

The great masquerader

Investigating PTE

Plain Chest Radiograph

Cardiomegaly
(new onset).
Normal in ~ 25%.
Other abnormalities
are non-specific.

Atelectasis

Hge/ edema

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-markers
Troponin I
N 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 2009

N = 570

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.

CT PULMONOLOGY ANGIO

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 1030s (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 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 (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

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.

Heparin- Dosing schedule

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).

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 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.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 rehospitalization 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 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

thromboprophylaxis

PTE Risk assessment

model

STEP 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

contd
Step 3: Total risk factors (exposing + prediposing): __
Step 4: Recommended prophylactic regimens for each risk group.

LDUFH = Low dose unfractionated heparin

LMWH = Low molecular weight heparin
GCS = 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

Lancet 2009

Phase 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.

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..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!