Pulmonary Embolism in

In t en si ve C are U n it
a, a b
Michael Baram, MD *, Bharat Awsare, MD , Geno Merli, MD

KEYWORDS
 Pulmonary embolism (PE)  Intensive care unit  Mortality  Critical care (ICU)
 Massive pulmonary emboli  Submassive pulmonary emboli
 Pulmonary embolism response team (PERT)

KEY POINTS
 Pulmonary embolism continues to have significant morbidity and mortality.
 The management of pulmonary embolism has become more complex due to a prolifera-
tion of therapeutic options, requiring communication between multiple specialties in the
hospital setting.
 The invention of multidisciplinary teams that are activated helps improve communication,
standardize care, and mobilize local resources to manage pulmonary embolism.

INTRODUCTION

Pulmonary embolism (PE) can be a lethal diagnosis, which is often made postmor-
tem.1–4 The precise morbidity and mortality, however, are difficult to determine due to
a variety of presentations, which can vary from prehospital sudden death, death within
24 hours, or death over 1-year follow-up.1,2,5–7 The mortality from PE is due to acute or
progressive right ventricular (RV) failure and may be affected by underlying comorbid-
ities and unintended complications of therapy.8 Patients are more likely to die of their
coexisting cancer, congestive heart failure, or chronic lung disease rather than directly
from the PE.8 The focus of this article is to review the epidemiology, pathophysiology,
and natural evolution of disease; the role of the intensive care unit (ICU) in management;
and factors that have led to the adoption of PE response teams (PERTs).

EPIDEMIOLOGY OF PULMONARY EMBOLISM

Approximately 1 million to 2 million people in the United States have venous thrombo-
embolisms (VTEs) a year.2,9,10 The incidence reported by the Centers for Disease

a
Department of Medicine, Division of Pulmonary and Critical Care, Jefferson University Hos-
pital, Korman Lung Institute, 834 Walnut Street, Suite 650, Philadelphia, PA 19107, USA;
b
Department of Medicine and Surgery, Division of Vascular Medicine, Jefferson University
Hospital, 111 South 11th Street Suite 6210, Philadelphia, PA 19107, USA
* Corresponding author.
E-mail address: Michael.Baram@jefferson.edu

Crit Care Clin - (2020) -–-

https://doi.org/10.1016/j.ccc.2020.02.001 criticalcare.theclinics.com
0749-0704/20/ª 2020 Elsevier Inc. All rights reserved.
2 Baram et al

Control and Prevention is 1 to 2 per 1000 persons per year.6 The incidence is signifi-
cantly affected by age, with the rate 1:100,000 in young people and 1:100 in people
older than age 80 years.1,6,10 The rate of new VTE cases increases each decade but
accelerates most rapidly during the sixth decade of life.9–11 It is a disease that affects
all races, ethnicities, ages, and genders.6 PE potentially accounts directly for 3% of all
US deaths and indirectly contributes to another 6%.1 Fig. 1 displays the scope of VTE
problem. Of patients with deep venous thrombosis (DVT), 25% have a progression to
symptomatic PE, thus generating a US occurrence rate of 500,000 new PE cases per
year.2,6,12 Based on nationwide hospital admission databases, there are approxi-
mately 200,000 annual hospital admissions for PE.13 An Australian study suggests
that PEs causing ICU admission occur in 11 cases per million people per year.15
Approximately 5% of admitted ICU patients die in the hospital.13 Of all symptomatic
PEs, 20% die prehospital and 5% in hospital, with total of 30% of acute PE patients
dying of all-cause mortality within 30 days.2,8,13 Based on autopsy and extrapolation
of databases, approximately 11% of PE deaths occur within the first hour, creating the
concept of the golden hour in PE.1,16 The greatest risk of death occurs within the first
3 months after PE.8,13 In 2008, the US Surgeon General called attention to the 100,000
to 180,000 US yearly deaths from/with VTE.9,17 Improved treatment has resulted in
lower PE-associated mortality; however, all-cause hospital mortality has increased.
This discrepancy is explained by the US national trends to manage some PE patients
as outpatients; thus, only higher-acuity patients are admitted.13 In addition, advances
in imaging techniques have diagnosed smaller incidental PEs with low risk stratifica-
tion, which also contribute to overall lower mortality numbers.2,12,15
With an increased effort in DVT prevention, the incidence of ICU-acquired PE has
been reported at 1.9%.9,18,19 The mean time to hospital-acquired PE was 8 days,
with hypotension and respiratory distress the 2 most frequent triggers for PE work-
up.19,20 This number may be biased by the 10% of patients who may have presented
and admitted to the hospital with undiagnosed PE.20 In brief, patients who have evi-
dence of shock or are at risk of hemodynamic decompensation or massive versus
submassive PE frequently are admitted to ICUs.2,21 Patients at highest risk of deteri-
oration, such as those with moderate to severe RV dysfunction, acute cor pulmonale,

Fig. 1. Yearly incidence of VTEs per year of this decade. (Data from Refs.1,2,6,8,9,12–14)
 Intensive Care Unit 3

and clot in transit within the heart, also drive ICU admission.2 Patients admitted with
shock carry a mortality risk of 25% to 50%.21,22 Patients admitted post–cardiac arrest
have a significantly higher mortality of greater than 70%.23
The cost of a single PE treatment ranges from $14,000 to $44,000, with the cost of
ICU-related PE care presumably higher.9 The yearly cost of PE treatment is estimated
at $2 billion to $10 billion.6 Preventable VTE could contribute to overall US health care
costs of more than $4.5 billion per year.9 Patients who had VTE either with or without
PE had an 80% higher risk of having a disability affecting employment.24 On average,
each first VTE event was associated with an 11-day loss of work.9 There has been a
concerted effort to reduce hospital-acquired VTE to reduce immediate-term and
long-term costs from VTE.18

PATHOPHYSIOLOGY

PE can be the result of a variety of emboli to the pulmonary artery vasculature from
VTEs to air, tumor, amniotic fluid, fat, or foreign bodies, such as coils.25 Unless
mentioned otherwise, the term PE generally refers to VTE. VTE was first reported
in thirteenth century reports which documented a probable DVT in the leg of a
20-year-old man with unilateral lower extremity swelling.10 Theories of why unilat-
eral leg swelling can occur have varied from retention of “evil humors” associated
with pregnancy to the accumulation of milk causing thrombosis (“milk leg”).10,26
Rudolf Virchow in 1856 showed that the triad of hypercoagulability, venous stasis,
and blood vessel injury predisposed individuals to thrombosis.2,10,27 There also are
environmental/situational, genetic, and modifiable factors that contribute to VTE
risk.6,11,28,29 Table 1 summarizes some of the more common factors associated
with VTE. Adenocarcinoma is the highest risk factor associated with PE.2 Ramot
and colleagues28 published an extensive review of the literature showing the com-
plex interaction between drugs and their physiologic targets and sometimes unin-
tended consequence of affecting both systemic and venous circulation. Drug
effects on VTE can be categorized by their resultant endothelial damage, platelet
adhesion or aggregation, white blood cell adhesion, effects on coagulation
cascade, and effects on blood flow.28 Of PE survivors, there is resultant endothelial
damage and deconditioning with reduced oxygen consumption that can persist.30
Approximately 5% of patients are left with residual pulmonary hypertension
90 days postevent.25,32
The physiologic effects of a PE remain complex and not fully understood. The clot
burden produces mechanical strain by the obstruction, causing increased pulmonary
vascular resistance that the thin-walled RV must overcome.25 Assessment of RV
dysfunction is important due to is impact on patient outcome. Clot burden alone, how-
ever, does not explain the increased pulmonary vascular resistance and increased RV
afterload. For example, there is a significant release of thromboxane A2 and serotonin
as a result of the embolic load, which contributes to the vasoconstriction.25,33 These
potent inflammatory mediators have direct local effects and are potential targets of
supportive therapy. In addition, the PE causes redistribution of blood flow that can
cause ventilation-perfusion (V/Q) mismatch, resulting in regional hypoxia and resulting
in further pulmonary vascular vasoconstriction.34 The resultant RV dilation can cause
increased RV wall tension and increased oxygen uptake. When combined with a
decreased perfusion pressure, RV ischemia ensues and further decreases RV output
and left ventricular (LV) preload. The enlarged RV also can impede LV filling due to ven-
tricular interdependence. The result is a cascade of events leading to RV failure also
known as the “right ventricular spiral of death.”25,35
4 Baram et al

Table 1
Risk factor venous thromboembolisms

Genetic Environmental/Situational Lifestyle

Factor V Leiden
Prothrombin G20210A
Protein C or protein S deficiency
Antithrombin deficiency
Sickle cell
Trauma Tobacco
Orthopedic surgery Obesity
Hospitalization (surgery, Sedentary lifestyle
cancer, congestive Injection drug abuse
heart failure, COPD) Long flights
Medication
(contraception,
hormone replacement)
Obstetrics
Indwelling catheters
Antiphospholipid syndrome
Human immunodeficiency virus
Nephrotic syndrome

Data from Refs.17,30,31

ROLE OF THE INTENSIVE CARE UNIT

The ICU is the optimal venue for the monitoring and support of patients with high-risk
PE.15,19,22 There are medical conditions, however, unique to the ICU that make PE
management difficult.36 Diagnostic testing is only positive in 10% to 15% of
cases.36,37 This low yield reflects the nonspecific indications for PE testing (tachy-
cardia and hypoxemia), which are common to the ICU population, as well as the cur-
rent high testing rates. The positive predictive value of the testing increases as clinical
suspicion rises.25,31,38–40 Intensivists often must function in a model of diagnostic di-
lemmas while working to stabilize hemodynamics and while trying to confirm a diag-
nosis—in the paradigm of the golden hour: diagnostic plans and treatment must be
succinct.16,41
Critical care management of PE includes hemodynamic and oxygen management.
Understanding the association of hypoxia, RV afterload, RV failure, and potentially
resultant cardiovascular collapse is part of the fundamentals of PE care. The presence
of shock and/or cardiac arrest dramatically worsens survival.16 A more compressive
understanding of this high mortality should include the comorbidities associated
with or causing PE, the complex interaction of the RV, hypoxia due to V/Q mismatch,
and the physiologic reserve.16,35 Supportive therapies of the RV failure include after-
load reduction, inotropic augmentation supported by vasopressors, and fluid manage-
ment.16,22 It is essential for intensivists to understand the complex interplay of
cardiovascular support and oxygenation support by positive pressure.42,43 Supportive
interventions may be as simple as oxygen supplementation to the extreme of extracor-
poreal membranous oxygenation (ECMO).25,44–46 Mortality of mechanically ventilated
patients approaches 40%.15 Patients receiving cardiopulmonary resuscitation have a
65% mortality.15,47

THE INTENSIVE CARE UNIT AND MULTIORGAN FAILURE

ICU patients may have multiorgan failure prior to diagnosis of PE, which presents chal-
lenges to diagnosis and management of PE, requiring the intensivist to make frequent
risk/benefit decisions to treat these patients. Sometimes a diagnosis of VTE is made inci-
dentally, and VTE is not the condition making the patient critically ill.48 The following is a
sample of some unique issues in an ICU that increase the challenges in treating PE.
 Intensive Care Unit 5

Central nervous system49

 Delirium: inability to cooperate for imaging
 Intracranial hemorrhage or subdural hematoma from trauma complicating ther-
apy for PE
Endocrinopathy50
 Tachycardia may mimic PE
 Iodine for computed tomography scan could exacerbate thyroid toxicosis
Pulmonary51
 Underlying chronic obstructive pulmonary disease (COPD), asthma, and intersti-
tial lung disease may mimic PE or magnify the effects of PE
 Mechanical ventilation may worsen hemodynamics due to increased RV afterload
 Severe hypoxemia may increase risk of transport for diagnostic imaging
Cardiovascular40,52
 Underlying cardiomyopathy, chronic VTE, sleep apnea, and pulmonary hyperten-
sion can magnify the effects of PE
 Hemodynamic instability may increase risk of transport for diagnostic imaging
 McConnell sign is not specific for PE and can be found in other causes of RV failure
seen in the ICU (RV infarct, acute RV, and dysfunction of mechanical ventilation)
 Antiplatelet agents increase risk of bleeding
 Inferior vena cava filters affect ability to cannulate femoral vein for ECMO
Gastrointestinal53
 Gastrointestinal bleeding occurring or recurring with anticoagulation
 Safety of esophagogastroduodenoscopy in setting of PE and gastrointestinal
bleeding51
Liver failure54,55
 Pharmacokinetics of clearance of warfarin or other novel oral anticoagulants
 Persistent state of disseminated intravascular coagulation
 Often with misbalance of coagulation factors, making prothrombin time less reli-
able as a marker of bleeding risk
 Coagulation factor deficiency due to decreased production
 Chronic liver disease and coagulopathy from malnutrition (vitamin K deficiency)
 Potential for life-threatening variceal bleeding
 Dysfibrinogenemia
Renal failure56
 Use of intravenous dye may be limited for diagnostic testing
 Renal clearance of drugs (direct oral anticoagulant, heparin, and low-molecular-
weight heparin)
Hematologic
 Risk of bleeding with thrombocytopenia
 Risk of heparin-induced thrombocytopenia
 Severe anemia can reduce effectiveness of fibrin deposition to stop bleeding
 Antiphospholipid syndrome
 Hypercoagulable states associated with malignancy
Postoperative patients/trauma patients
 Increased bleeding risk

PULMONARY EMBOLISM RESPONSE TEAMS

Over the past decade, there have been increasing options for acute PE care. These
include novel anticoagulants; catheter-directed therapies; RV support systems,
such as venoarterial ECMO and RV assist devices; alternate dosing of systemic
6 Baram et al

thrombolytics; and a renewed interest in surgical embolectomy.22 In response to this,

PERTs have formed to facilitate decision making.2,16,57 Some of the common constit-
uents of a PERT team include pulmonary/critical care, vascular medicine, interven-
tional radiology, hematology, cardiology, emergency medicine, and cardiothoracic
surgery.58 Each institution has different resources and varying levels of expertise
that necessitate unique institutional algorithms of care.
Similar to how tumor boards have improved the standardization and quality of can-
cer care, the PERT model hopes to achieve the same goals with PE.59 The PERT can
conference at the bedside or virtually using modern communication technology. Data,
such as imaging, risk stratification, and availability of interventions, can be shared
among team members.59 Team decision making can help reduce errors and may sup-
port interventions that are more aggressive yet potentially beneficial.57,60 Literature
suggests that there is an underutilization of PE interventions, such as systemic throm-
bolytics in massive PE, despite growing evidence.60 PERT teams that have published
their data have shown increase utilization of various reperfusion techniques over time
without increase in bleeding complication.57

SUMMARY

With the increasing complexity of health care delivery, the ICU will continue to play a
pivotal role of PE management. Fortunately, the formation of PERT teams has
increased the resources available to care for these critically ill patients. The remainder
of the issue elaborates on the diagnostics, therapeutic, and multidisciplinary manage-
ment topics raised in this introduction and provides intensivists a greater knowledge of
the principles necessary in the management of high-risk PE.

DISCLOSURE

All authors have nothing to disclose.

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