Chapter 27

Pulmonary embolism
(the most under-diagnosed cause of death)

Ross Klingsberg, MD

Clinical Vignette 1
A 62-year-old woman underwent
bilateral knee replacement and was
discharged without complications on
postoperative day two. Nine days after
surgery she develops severe respiratory
distress and dies suddenly in the
emergency department. Postmortem
examination of her pulmonary artery
reveals the pathology seen in the image:

What medical condition could predispose to a

similar pathology as observed in this patient?

A. Aspiration
B. Factor V
deficiency
C. Factor VIII
deficiency
D. Protein C
deficiency
E. Thrombocytope
nia

Clinical Vignette 2
A 68-year-old obese man presented to
the emergency department with
lightheadedness progressing to nearsyncope and progressive shortness of
breath of three days duration.

 His symptoms started a week ago

when he first experiences pleuritic
chest pain that radiated to his right
side

 He had undergone sinus surgery 3 weeks

prior to presentation
His past medical history was significant for
hypertension, obstructive sleep apnea, and
diastolic heart failure
A deep vein thrombosis (DVT) following
knee surgery had occurred 15 years
previously
He quit smoking 20 years ago and did not
report alcohol use

 Physical exam revealed tachypnea,

sinus tachycardia at a HR = 118
beats/min, BP 98/62 mm Hg, and Sao2
= 90% while on 6 L/min of
supplemental inspired O2
Auscultation of the chest showed
scattered wheezes and left basilar
crackles
No calf tenderness was present

 Given the high clinical suspicion for

acute PE, a CT angiogram of the
chest was performed that revealed
multiple filling defects
The patient was thereafter
anticoagulated with low-molecular
weight heparin (LMWH)

Learning objectives
Describe the clinical symptoms and sign of
patients presenting with pulmonary embolism
Define the pathophysiology of PE and the risk
stratification of patients diagnosed with
thromboembolism
Evaluate shock and right ventricular dysfunction
as a discriminator of outcome during or after PE
Provide a stepwise approach to the treatment of
patients diagnosed with acute PE

Important points to
remember
Pulmonary embolism (PE)
Venous Thrombo-Embolism (VTE)
Deep Vein thrombosis (DVT)

Pathophysiology
V/Q mismatch leads to hypoxemia
Occlusion of the vascular bed leads
to right ventricular failure

Important points
Diagnosis and therapy reduces
morbidity/mortality
Virchows triad: endothelial
injury/decreased venous
flow/hypercoagulable state
Greatest risk of embolization in the
first seven days after formation of a
DVT

Questions for discussion

What materials can become emboli
to the lungs?
What are the physiological events
that predispose to the development
of VTE?
What are examples of strong,
moderate, and weak risk factors for
VTE?
What are the hereditary risk factors
for VTE?

Nonthrombotic pulmonary
emboli
Fat embolism
24-48 hour delay
Dyspnea, petechiae and mental confusion

Amniotic fluid embolism

Air embolism
Trendelenberg/left lateral decubitus position

Schistosomiasis
Septic emboli
Other emboli

Risk factors for venous

thromboembolism
Strong
Hip, pelvis, or leg fracture
Knee or hip replacement surgery
Major trauma
Spinal cord injury
Antiphospholipid antibody syndrome (APLAS)

Moderate
Prior VTE
Postpartum period
Malignancy
Estrogen therapy, oral contraceptives

Weak risk factors for venous

thromboembolism

Advanced age >60 years

Obesity
Antipartum period
Varicose veins
Stroke
Respiratory failure
Indwelling central venous catheter
Arthroscopic knee surgery

Hereditary risk factors for venous

thromboembolism

Factor V Leiden mutation

Protein C or S deficiency
Hyperhomocysteinemia
Prothrombin gene mutation 20210A
Antithrombin III deficiency

Clinical presentation
Prevalence
Causes 10% of all in-hospital deaths
Biggest cause of maternal deaths associated
with live births
10.7% probability by age 80
Most fatal PE are unrecognized and undiagnosed

Decision rules (Wells criteria) help in the

diagnostic process
PE cannot be ruled in or out by history and
physical

Acute pulmonary embolism

symptoms
All patients
(N=383)(%)

No previous
cardiopulmonary
disease (N=117)
(%)

Dyspnea

78

73

Pleuritic chest pain

59

66

Cough

43

37

Leg Pain

27

26

Hemoptysis

16

13

Palpitations

13

10

Wheezing

14

Angina-like pain

Symptom

PIOPED 1990

Differential diagnosis
Pneumonia

Pneumothorax

Pleural effusion

Pulmonary edema

Asthma exacerbation

COPD exacerbation

Myocardial infarction

Congestive heart
failure

Acute pericarditis

Esophageal
dysmotility

Gastroesophageal
reflux disease

Pre-test probability of PE
(Wells criteria)
Clinical characteristic

Score

Active cancer (treatment within 6 months or

palliative

Surgery or bedridden for 3 days for past 4 weeks

1.5

History of deep venous thrombosis or pulmonary

embolism

1.5

Hemoptysis

Heart rate >100 beats/min

1.5

Pulmonary embolism judged to be the most likely

diagnosis
Probability of PE

Clinical
signs and symptoms compatible with DVT
Low

Total Score
3
4

Moderate

4.5-6

High

>6
Wells PS et al 2000

D-dimer
Cross-linked fibrin derivative
>500 mcg/L: 98% sensitive; 39%
specific
If low D-dimer, RR<20, and pO2>80
mmHg PE is essentially ruled out
Low Wells score and negative DDimer: no further testing needed
If high clinical suspicion of VTE, Ddimer should not affect clinical
decisions

Cardiac biomarkers
Cardiac troponin T and troponin I
both elevated in acute PE
BNP may be elevated (e.g. 300-700)
in acute PE (caution: do not
misdiagnose CHF)

Arterial blood gas analysis

Hypoxemia
PIOPED: A-a difference increased by
more than 20 in 76 of 88 (86%)
pCO2 usually low, but high pCO2 does
not rule out PE
A-a difference may be normal in
otherwise healthy persons

Chest radiograph
PIOPED: abnormal in 98 of 117 (84%)
Atelectasis and/or parenchymal abnormalities
(79 of 117 (68%)
Pleural effusion, infiltrates, elevation of
hemidiaphragm
Juxtapleural wedge-shaped opacity at
costophrenic angle (Hamptons hump)
Decreased vascularity (Westermarks sign)
Symptoms + no bronchospasm, no evidence of
anatomical cardiac shunt, and normal CXR
suggest PE

Electrocardiography
PIOPED: 44 of 89 patients (49%)
T-wave changes, ST-segment
abnormalities, left or right axis
deviation
S1Q3T3 pattern, RBBB, P-wave
pulmonale, right axis deviation
occurred in 26%

Ventilation-perfusion (V/Q) scanning

and pulmonary arteriography
PIOPED V/Q scans
12% of low probability scans had PE
33% of intermediate probability scans had PE

With high clinical suspicion, PE found in

96% of high probability scans
66% of intermediate probability scans
40% of low probability scans

If indeterminate, consider angiography

and lower extremity ultrasound

Spiral (helical) CT scan

angiography
Requires contrast bolus
PIOPED II showed CT preferred over
V/Q
Less optimal for sub-segmental PE
Consider lower extremity U/S if high
suspicion

Better than V/Q at diagnosing other

conditions

Spiral CT for diagnosis of

acute PE
Advantages
Availability
Sensitivity and
specificity for central
emboli
Relative rapidity
Diagnosis of other
conditions
Multiplanar
reformation
Safety

Limitations
IV contrast required
Reader expertise
required
Not portable
Morbid obesity may
prevent
Relative
contraindications
Renal insufficiency
Contrast allergy

Echocardiography
May suggest PE
Clot may be directly observed

Treatment
Acute PE
Unfractionated heparin
Low-molecular weight heparin
Thrombolytics
Inferior vena cava filters

Chronic PE
Warfarin
Surgical/IR thrombectomy (usually for
chronic)

Unfractionated heparin
(UFH)
80 units/kg followed by 18
units/kg/hr
Significant bleeding in 7-30%
Warfarin may be started in first 1-2
days at 5-7.5 mg (10 mg in obese
patients) and overlap for 2 days with
INR at goal (2-3)
Reverse with 1mg protamine sulfate
per 100 units UFH
Long term use may cause

Heparin-induced thrombocytopenia
(HIT)
3.5% incidence with UFH
0.6% incidence with LMWH
50% reduction in platelets after 5
days or absolute reduction of
100,000 per mm
If present, then treat with argatroban or
hirudin

Thrombolytics
Streptokinase
Urokinase
Recombinant tissue plasminogen activator
(rt-PA)
Usually used in PE with shock
Evidence for use with large PE without shock
2% risk of intracranial hemorrhage
Mechanical thrombectomy sometimes
performed

Vena cava interruption (IVC

filter)

When anticoagulation is contraindicated

When LE clot burden is large
When bleeding occurs on anticoagulation
Removable filters are novel
Risks
insertion-related complications
filter migration
direct thrombus extension through the filter
IVC thrombosis

Surgical thrombectomy
Usually for chronic PE
May be considered for acute PE when
anticoagulation is problematic
Being replaced by interventional
radiology mechanical thrombectomy
Only performed a specialized centers

Case studies
A 59-year-old man undergoes total knee
replacement for severe degenerative joint
disease. Two days after surgery, he
develops acute onset shortness of breath
and right-sided pleuritic chest pain. He is
now in moderate respiratory distress with
a respiratory f = 28 breaths/min, HR =
120 beats/min (sinus rhythm), and
systemic BP = 110/70 mm Hg. His S ao2 =
90% by pulse oximetry on room air

 His lung exam is normal and his cardiac

exam reveals sinus tachycardia but is
otherwise unremarkable
The right lower extremity is postsurgical,
healing well, with 2+ pitting edema, calf
tenderness, erythema, and warmth
The left leg is normal
Laboratory workup reveals a serum
creatinine of 1.6 mg/dL

What is the most appropriate next

diagnostic step?
A. V/Q scan
B. CT angiogram of the chest
C. Pulmonary angiogram
D. Duplex venous ultrasonography of the
lower extremities with Doppler flow
E. No additinoal test, given high pre-test
probability of PE

A 52-year-old obese woman who is

recovering from a viral illness presents
with acute onset shortness of breath of
3 hours duration. She rpoet symptoms
of ocugh and is very anxious as she
noticed blood in her sputum,
approximately 1-2 teasopoonfuls in
quantity. At the time of presentation
her initial BP = 90/50 mm Hg and then
increaseds to 110/65 mm Hg after IV

Her ECG reveals sinus rhythm with

normal PR and QRS intervals, however
the medical student points out the S1,
QIII, and TIII pattern. A helical CT scan
with a PE protocol is obtained with
findings of bilateral filling defects in
the interlobar pulmonary arteries.

Which of the following is the most appropriate

next treatment for this patient?
A. Arrange for IVC filter
placement
B. Begin warfarin therapy
C. Initiate unfractionated
heparin to achieve a
therapeutic aPTT
D. Obtain a pulmonary
angiogram to confirm a
diagnosis of PE
E. Place a central venous
line and begin
thrombolytic therapy

High or moderate clinical

Suspicion of
PE
Stable ICU
probability patients Low

clinical probability
Follow the same
algorithm but STOP after
a negative spiral CT or
low-prob V/Q

Start
anticoagulation if
no contraindications
Spiral CT
or V/Q
scan

Positive CT or
high prob V/Q

Negative
CT or low
prob V/Q

Inadequate CT
or nondiagnostic V/Q

Treat for
PE

U/S of
legs and
upper
body if
CVC

U/S of
legs and
upper
body if
CVC

Treat for
PE

Stop
anticoagulation

Treat for
PE

Pulmonar
y
angiogra
m

Treat for
PE

Stop
anticoagulat
ion

Suspicion of PE
Unstable ICU
patients

Start anticoagulation if no
contraindications

U/S of legs and upper

body if CVC

+
Continue anticoagulation

Echocardiogram

RV dilation, dysfunction,
or clot

Consider
thromboly
sis

Normal RV

Consider bedside angiography

or perfusion scan

+
Continue
anticoagulation

Stop anticoagulation

Chapter 28

ACUTE LUNG INJURY AND THE ACUTE

RESPIRATORY DISTRESS SYNDROME

Key concepts
ARDS vs ALI
Cardiogenic vs non-cardiac
pulmonary edema
Lung protective strategy
PEEP
Alveolar recruitment

ARDS Problem-based Learning Case

Presentation

Learning objectives
Students will be able to:
Correctly diagnose ARDS using the consensus
definition of the syndrome and differentiate it from
volume overload and cardiogenic pulmonary edema
Define, list, and explain the pathophysiological
events during the acute proliferative and the
fibrosing-alveolitis stages of ARDS
Define and explain the physiologic rationale of PEEP
and the hazards of using positive pressure ventilation
Perform a basic interpretation of an arterial blood gas
Explain the effect of increased intrathoracic pressure
on left ventricular filling (preload) and blood pressure

Relevant terms
ARDS acute (adult) respiratory distress syndrome (aka,
shock lung, non-cardiogenic pulmonary edema)
ABG arterial blood gas
pCO2 partial pressure of carbon dioxide in blood
pO2 partial pressure of oxygen in blood
Ppeak peak airway pressure (on ventilator)
Pplat plateau airway pressure (on ventilator)
V/Q ventilation (inspired air)/perfusion (blood)
PEEP positive end expiratory pressure
VILI ventilator-induced lung injury
SpO2 - oxygen saturation of hemoglobin by pulse
oximetry

Case presentation
A 35-year-old previously healthy
woman is brought to the ER with a
close-range gunshot wound to the
abdomen. Thirty minutes after
arriving, her blood pressure is 40/0,
pulse 140/ minute, and respirations
are 30/minute.

Case (continued)
She quickly receives 1.5 liters of
colloid and 2 liters of normal saline.
Her blood pressure rises to 80/40
mmHg. During five hours of surgery,
the spleen is removed, her stomach,
diaphragm and liver are repaired,
and she receives a total of 21 units
(250 ml each) of blood and 700 mL of
IV fluids.

Case (continued)
Later in the day, her breathing becomes
more difficult and labored. She is breathing
rapid shallow breaths at 40 per minute. An
arterial blood gas at that time shows
pH of 7.4/pCO2, 30 mmHg/pO2,42 mmHg
breathing ambient air.

What is the most important next step in

management?
Give oxygen

Question for discussion

Since she is breathing rapidly
(hyperventilating) and her pCO2 is 30 mm
Hg (normal 35-45) why is the pH 7.4?
We would expect alkalemia, with pH >7.40, due
to the low pCO2
Normal pH is probably due to an underlying
metabolic acidosis, with respiratory
compensation
In the setting of hemorrhagic shock, the most
likely type of metabolic acidosis is lactic acidosis

Hospital course (continued)

50% 02 (FiO2 0.5) is administered by a
venturi face mask, and the pO2 rises to 60
mm Hg.

Physical Examination
Gen: well-oriented, but ill-appearing
Chest: anterior and posterior
crackles, without rubs, and no
dullness to percussion
Heart: no displacement of PMI, no
gallops, rubs, or murmurs, normal
JVD
Abd: post-surgical
Ext: diffusely decreased deep-tendon
reflexes

Arterial blood gas

The next day, on 50% oxygen, her
ABG shows:
pH, 7.48/pCO2, 28 mm Hg/pO2 40 mm Hg

What is the next step in management?

Increase oxygen to 100% (FiO2 1.0)
non-rebreather mask

Clinical course (continued)

ABG
pH, 7.46/pCO2, 32 mm Hg/pO2, 50 mm Hg

Blood pressure
120/60
She continues to have rapid shallow labored
breathing. What is the next best step?
Intubate and initiate mechanical ventilation

Course (continued)
She is intubated and mechanical
ventilation is initiated
Tidal volume, 600 ml
Rate, 20 breaths per minute
FIO2, 1.0 (100% oxygen)
Peak airway pressure is recorded at 48 cm
H2O (normal is <30)

ABG
pH 7.35/pCO2 40 mmHg/pO2 65 mmHg

Findings
Echocardiogram: normal right and left
ventricular function
Tidal volume (Vt) decreased to 350 mL
based upon her predicted body weight
of 59 kg.
ABG
pH 7.3, pCO2 65, and pO2 53 mmHg

Peak inspiratory pressure decreased to

26 cmH2O

Questions for discussion

What is the diagnosis for her respiratory
condition?
Acute respiratory distress syndrome (ARDS)
What are the criteria to make this diagnosis?
1. Acute onset respiratory failure (less than 7
days) after a precipitating event
2. Bilateral pulmonary opacities
3. PaO2/FiO2 ratio (<300)
4. Not fully explained by congestive heart failure
or fluid overload

What pathophysiological abnormalities are found in

ARDS?

Stiff (non-compliant) lungs are harder to inflate

Damaged alveoli filled with proteinaceous fluid,
cellular debris, and hyaline membranes, which
lowers the V/Q ratio
Increased shunting of blood through the lungs
without oxygenation or ventilation (R to L
shunt)
Increased pulmonary vascular resistance due to
hypoxic pulmonary vasoconstriction
Increased dead space:tidal volume ratio
Reduced functional residual capacity leads to
atelectasis (collapse of alveoli) (see next figure)

Effect of positive pressure

on FRC

Questions for discussion

Why does the patient have ARDS and not
cardiogenic pulmonary edema?
The echocardiogram was normal; no evidence
of congestive heart failure
A diagnosis of ARDS implies no clinical
evidence of elevated left atrial pressure, or a
pulmonary capillary pressure 18 mmHg
Pulmonary edema usually begins when pulmonary
capillary pressure is > 21 mmHg assuming normal
oncotic pressure and integrity of lung capillaries

The 3 safety factors that prevent

alveolar (airspace) flooding
Dilutional interstitial
oncotic pressure
Perivascular cuffing
Removal through
lymphatics
Thus, it takes about 21
mmHg or greater of
pulmonary capillary
pressure for healthy
adults to develop
airspace edema
Alveolar edema occurs
when interstitial
volume increases by
about 40%
Annals of Internal Medicine, 21 September 2004. Vol. 141 (6) pp. 460-470

Hospital Course
In spite of this therapy, forty-eight
hours later, the pO2 had again fallen
to 48 mmHg while breathing 100%
O2 (FiO2 1.0). Because of this, the
positive end-expiratory pressure
(PEEP) was increased to 12 cm H2O.

Questions
Why didnt 100% oxygen raise her arterial pO 2 more?
Right to left shunting of blood through flooded alveoli

Can you give an estimate of her lung compliance with

the tidal volume 350 mL and inspiratory pressure
(plateau pressure PEEP) 16 cm H 2O?
Compliance = volume/ pressure (nl, 80-100 ml/cm H 2O)
volume = Tidal volume
pressure = (Pplateau PEEP)

350/16 = 21.9

Why is plateau pressure and not peak pressure used

to calculate the compliance?

Single mechanically ventilated

alveolus

Pressures during mechanical ventilation

Peak pressure (Ppeak)

pressure (Pplat)

Plateau

Ppeak Pplat = airway flow resistance

Marino 2nd ed

Hospital course (continued)

Increasing the PEEP raised her pO2 to
70 mmHg. At this point her peak
inspiratory pressure (Ppeak) was 32
cmH2O and plateau pressure (Pplat)
was 28 cmH2O. Her blood pressure
fell to 80/50.
Why did her blood pressure fall after
increasing the PEEP?

Increasing intrathoracic airway pressure decreases venous return and LV

preload (particularly in the presence of decreased intravascular volume
status)

Hospital course (continued)

What is the next step to address her
low blood pressure?
Give IV fluids
A 500 mL bolus of 0.9% saline
solution raised her blood pressure to
95/63 mmHg

Question
What does PEEP do?
PEEP reopens alveoli that are collapsed
but still can be recruited with positive
airway pressure
PEEP keeps the collapsing alveoli from
continuous opening and closing with each
respiratory cycle
PEEP keeps the respiratory cycle on the
most favorable portion of the
volume/pressure curve (see graph of
volume/pressure relationship)

Compliance = vol/
pressure =
=Tidal volume/(Pplat- PEEP)
Normal = 80-100 ml/cm
H 2O

Amato et al. AJRCCM

1995.

The right amount of PEEP improves areas of low

Va/Q and decreases shunt

*Why is Blood Flow Distribution to the ARDS alveoli on

the left diagram lower than blood flow to the ARDS alveoli
on the right diagram?

The flooded alveoli causes hypoxic pulmonary

What is the risk of excessively high airway

pressures?
Barotrauma from over-distention and damage to
healthy alveoli
Capillary leak from pressure-damaged alveoli
Decreased venous return (preload) to the left
ventricle
If local alveolar pressure exceeds capillary
pressure, then blood redistributes to less
compliant damaged areas and worsens gas
exchange

Increased airway pressure via

mechanical ventilation

The goal of positive pressure ventilation is to

recruit collapsed alveoli without overstretching the
healthy alveoli
Marini-Wheeler 2nd ed.

Hazard of
positive
pressure
mechanical
ventilation
MV x 8 weeks,
Ppeak 50-70
mmHg
FiO2 80-100%

VILI - Ventilator-induced lung

Hospital course (contd)

The patient subsequently improved. After
several days of mechanical ventilation, her
pO2 rose and her chest radiograph showed
some clearing. The FiO2 needed to maintain a
pO2 greater than 60 mm Hg on ABG and SpO2
on pulse oximetry to greater than 92%
decreased to 0.35.
What are the events that led to clearing of
her lungs and improved respiratory status?

Mechanisms in the resolution of

ARDS
Proliferation and differentiation of alveolar
type II pneumocytes
Resorption of alveolar edema via energy
dependent sodium pumps on type II
pneumocytes and movement of water
through aquaporins on type I pneumocytes
Removal of cellular debris by alveolar
macrophages
Gradual remodeling and resolution of
intraalveolar and interstitial granulation
tissue and fibrosis

Follow-up questions
What caused the damage to her lungs
after her initial surgery?
Likely shock, multiple transfusions and
probable sepsis
Damage to the lungs can be direct (i.e.
pneumonia, aspiration of gastric content) or
indirect (i.e. sepsis, severe
trauma/shock/multiple transfusions)

In this case it appears more indirect, unless

the patient had also aspiration during
intubation prior to emergent surgery

Follow-up questions
What physiologic changes caused her to
hyperventilate after surgery?
Hypoxemia
Sepsis
Can cause lactic acidosis (when severe) and
hyperventilation (even to the point of
overcompensation and induction of respiratory
alkalosis)

Increased dead space:tidal volume ratio makes

the lungs inefficient at removing CO 2
Increased areas of low V/Q and right to left shunt

Follow-up questions
Can shunt be overcome with increased FiO2?
No, shunt cannot be overcome by increased oxygen administration
because there is no alveolar ventilation

What determines pCO2?

The rate of CO2 removal from the blood is determined by alveolar
ventilation

Why is rapid shallow breathing less efficient than slow deep

breathing?
Increased dead space:tidal volume ratio increase the amount of
ventilation required to keep pCO2 constant

Why would oxygen requirement increase in a situation of poor

lung compliance like ARDS?
The work of breathing is increased due increased dead space:tidal
volume ratio and increased effort to expand the lungs

Follow-up questions
Does hydrostatic pressure play a role in
worsening of the alveolar filling process in
ARDS? Oncotic pressure?
Yes, hydrostatic pressure can play an
important role, especially if there are
damaged, leaky capillaries
Oncotic pressure also plays a role, especially
when coexisting health problems exist like
malnutrition, nephrotic syndrome, and/or liver
cirrhosis which will all lower the serum
albumin

Fluid leaks out of vessels more easily

in ARDS (even more so if serum
albumin is low)

The end
Coming next:
Chapter 28, Pathophysiology and Diseases
of the Pleural Space,
Chapter 29, Principles and Goals of
Mechanical Ventilation