Venous Thromboembolic Disease

in the Intensive Care Unit

Chee M. Chan, M.D.1,2 and Andrew F. Shorr, M.D., M.P.H.1,2

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ABSTRACT

Critically ill patients are at increased risk of developing venous thromboemboli

(VTE). Risk factors that predispose them to acquiring VTE encompass factors that usually
afflict the general medical population as well as factors attained in the intensive care unit
(ICU) (e.g., sedation, mechanical ventilation). The poor cardiopulmonary reserve of this
patient population is intolerant of even small pulmonary emboli (PE), which emphasizes
the importance of preventing VTE from ever occurring. Indeed, the complications
associated with hospital-acquired VTE increase morbidity, mortality, hospital length of
stay, and costs. Without thromboprophylaxis, the incidence of VTE in the ICU ranges
from 15 to 60%. Systematic implementation of VTE prophylaxis significantly reduces this
rate and as a consequence, morbidity and mortality. In fact, prevention of VTE is so
important that the American College of Chest Physicians (ACCP) developed guidelines
on the use of routine VTE prophylaxis in critically ill patients. Therefore, upon admission,
all ICU patients should be evaluated for and immediately prescribed the appropriate
thromboprophylaxis therapy.
KEYWORDS: Venous thromboembolism, intensive care unit, prevention

Critically ill patients face an increased risk for

patients, 95% of DVTs are clinically silent.7 More

importantly, most critically ill patients may not tolerate
a VTE because of their already limited physiological
reserve. Concurrently, many subjects in the ICU are not
necessarily good candidates for full-strength anticoagulation because they may be either at an increased risk for
bleeding or unlikely to tolerate bleeding should it occur.
These two factors underscore the need for effective
preventive strategies in this setting.
The high prevalence and incidence of VTE in the
ICU population has led the ACCP to develop prevention guidelines to minimize VTE risk. Indeed, these
guidelines emphasize the importance of prevention
while highlighting the need to weigh the risk:benefit
ratio of thromboprophylaxis in this high-risk group.
However, to truly understand the scope of this disease

Pulmonary and Critical Care Medicine, Washington Hospital Center,

Washington, DC; 2Department of Medicine, Georgetown University
Medical Center, Washington, DC.
Address for correspondence and reprint requests: Chee M. Chan,
M.D., Washington Hospital Center, 110 Irving St., NW #2B-39,
Washington, DC 20010 (e-mail: chee.m.chan@medstar.net).

Outcomes in the ICU; Guest Editor, Andrew F. Shorr, M.D., M.P.H.

Semin Respir Crit Care Med 2010;31:3946. Copyright # 2010
by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
NY 10001, USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0029-1246283.
ISSN 1069-3424.

venous thromboemboli (VTE). Because of their impaired cardiopulmonary reserve, these VTEs may result
in significant morbidity and mortality. The risks of VTE
vary depending on the reason for critical illness. For
instance, the incidence of deep venous thrombosis
(DVT) ranges from 28 to 32% in the general medicalsurgical intensive care unit (ICU) population,1,2 but can
be as high as 60% in trauma patients3 or even 70% in
patients with acute ischemic strokes.46 In those with
hemiplegia, 1 to 2% suffer a fatal pulmonary embolism
(PE).4,5 Although the diagnosis of VTE remains generally challenging, this is particularly so in ICU patients.
Their clinical status (intubation, sedation, altered mental
status) often masks some of the common symptoms that
may suggest VTE. Confirming this, in critically ill
1

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SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 31, NUMBER 1

in the ICU, one must understand (1) new health care

policies regarding VTE prophylaxis, (2) the epidemiology of VTE, (3) the health care costs associated with
VTE, (4) the risk factors associated with developing
VTE, and (5) treatment options for VTE in the ICU.

HEALTH CARE POLICY REGARDING VTE

PROPHYLAXIS
Underscoring the evidence and need to appreciate the
issues related to VTE prevention, in the United States,
the Centers for Medicare and Medicaid Services (CMS)
recently updated its payment policies. In a continuing
effort to financially incentivize hospitals to improve
quality of care, CMS is no longer reimbursing for the
care of patients who develop a hospital-acquired VTE.
In other words, the proposed policy and rate change,
under the hospital inpatient prospective payment system
(IPPS), includes making hospitals assume the increased
costs of managing conditions acquired during hospitalization that are deemed reasonably preventable through
adherence to evidence based guidelines. These efforts
were built on earlier CMS quality measures in surgery
where CMS now audits the use of peri- and postoperative DVT prevention as part of the Surgical Care
Improvement Program (SCIP). These new rules are a
logical extension of the SCIP effort and are being
extended to the ICU patient. Additionally, CMS is
requiring hospitals to report quality measures, such as
the use of VTE prophylaxis after surgery or in the ICU,
contraindications to patient receiving VTE prophylaxis,
and incidence of VTE. Failure to comply with these
enhanced reporting requirements will lead to reductions
in reimbursements. Therefore, vigilance in the prevention of VTE in hospitalized patients is ever more
important because cumulative costs associated with
VTE can be quite high. Hopefully, if the direct complications of VTE and the potential for mortality related to
PE fail to motivate change in practice, the financial
ramifications will motivate both institutional and provider behavior to change. Again, this evolution in
financial systems underscores the need for all to be
familiar with the most recent guidelines for VTE prevention.

EPIDEMIOLOGY OF VTE IN THE ICU

When discussing VTE prophylaxis in the ICU, the
predominant presentation is that of DVT. However, as
part of a larger spectrum of disease, namely VTE, the
close relationship between DVT and PE necessitates a
systematic approach to prevent its occurrence. Incapable
of tolerating a PE due to poor cardiopulmonary reserve,
the 10% of PE that develop as a consequence of DVT
must be thwarted.8 Further illustrating this close relationship, in the general medical population,
40 to 50%

2010

of patients with a symptomatic proximal DVT also have

an asymptomatic PE on screening examination.9,10
Few small studies have assessed the incidence of
VTE in critically ill patients. In 1981, Moser et al11
performed a prospective observational study involving 34
patients admitted to a respiratory ICU. Twenty-three
patients had radiofibrinogen leg scans performed within
the first week; 13% were found to have abnormal scan
results indicating the presence of DVT. Similarly, in a
recent larger prospective observational cohort consisting
of 261 critically ill medical surgical patients,8 screening
bilateral lower extremity compression ultrasound imaging performed within 48 hours of admission found DVT
in 2.7% of patients. The presence of DVT on admission
illustrates the hypercoagulability of this patient population. Furthermore, performance of serial screening lower
extremity Doppler ultrasounds found that
30% of
patients develop DVT during the course of their ICU
stay.1 The majority of these thrombi occur within the
first week of hospitalization in the ICU. In one study,
24% of incidence cases occurred within the first week,8
thereby demonstrating the importance of assessing the
need for and expeditiously administering thromboprophylaxis in critically ill patients.
While assessing the incidence of DVT in the
ICU, Ibrahim et al12 also evaluated the incidence of
PE in those diagnosed with DVT. In a prospective
cohort study consisting of 110 ventilated medical ICU
patients, 23.6% developed DVT despite 100% employment of DVT prophylaxis for study subjects. All patients
were mechanically ventilated for more than 7 days and
had screening Doppler ultrasonography performed to
diagnose DVT. Of those diagnosed with DVT, 11.5%
had a subsequent PE compared with 0% when DVT was
not diagnosed (p 0.012).
In general, the incidence of PE in the ICU is
difficult to assess. The diagnostic challenges associated
with PE in the ICU complicate our understanding of its
epidemiology. The inability of intubated patients to
make a conscious inspiratory effort limits the use of
ventilation perfusion scintigraphy (VQ scan) in the ICU,
whereas the increased risk of contrast nephropathy from
computed tomography (CT) of the chest with PE
protocol in patients who already have impaired renal
function due to critical illness precludes screening ICU
patients for PE. Given the complexities with diagnosing
VTE, autopsy studies provide a different perspective on
the prevalence of VTE. As with observational trials,
autopsy studies are limited because of issues related to
selection bias. Postmortem studies indicate that around 7
to 27% of autopsies performed on ICU patients have
incidental PE; an estimated 1 to 3% of these PE are fatal
and are the cause of the patients demise.11,1317 Among
critically ill patients, only
6 to 8% of the cohort will
ever have an autopsy performed.18 Without knowing the
cause of death in the entire ICU patient population, the

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40

true mortality attributable to PE will be inaccurate. In

general, autopsies are performed predominantly when
the cause of death is uncertain. The 20 to 45% discrepancy rate between premortem and postmortem diagnoses
among ICU patients raises concerns regarding the diagnostic accuracy of critically ill patients.16,19,20 Among the
three major diagnoses that were most frequently missed
was PE,16,18,19 which emphasizes the need to constantly
consider and prevent VTE from occurring.
Because many in the ICU are incapacitated from
their medical disease (e.g., altered mental status, sedated,
intubated), the diagnosis of VTE may often be overlooked. Additionally, risk stratification screening tools
and diagnostic tests, such as a D-dimer biomarker, are
not reliable in this population.21 Thus, clinicians must
remain vigilant in looking for signs of VTE and constantly consider this disease during evaluation. Surely,
the best means of addressing VTE in the ICU is through
prevention.

HEALTH CARE COSTS OF VTE

To fully comprehend the magnitude of this health care
burden, one must understand the costs associated with
VTE. Estimates suggest that the cost of developing an
inpatient DVT or PE adds $8000 and $14,000, respectively, in general medical patients to the entire hospital
bill. In those who simultaneously develop both a DVT
and PE the additional cumulative costs are even more
significant at approximately $28,000 per case.22
Yet these figures are misleading. These estimates
only reflect the short-term inpatient costs of VTE in
general medical patients and are not comprehensive.
Treatment of VTE is associated with potentially hidden costs. For example, these costs do not account for
the 5% of patients who are readmitted to the hospital
within 1 year after the initial event.22 Some of these
patients suffer from bleeding complications due to
anticoagulant therapy, recurrent VTE, or potential
sequelae from the initial thromboembolic event (e.g.,
persistent pulmonary hypertension, postthrombotic
syndrome, chronic venous stasis). Often, the costs
associated with these readmissions can be higher than
the costs for the initial event: $11,862 for DVT and
$14,722 for PE.22 Furthermore, these figures are estimated costs for VTE in general medical patients but
not for VTEs acquired in the sicker ICU patient
population. Hence, these costs are an underestimate
of costs associated with VTE in the critically ill.
It is well documented that patients with critical
illness who develop VTE have longer ICU and hospital
lengths of stay which contribute significantly to hospital
costs, morbidity, and mortality. Illustrating this, patients
who develop a VTE after major orthopedic surgery (total
hip replacement, total knee replacement, or hip fracture
repair) remain in the ICU longer than their counterparts

who do not develop a VTE. Comparatively, once a VTE

occurs, the average length of ICU stay increases by 1 to 4
more days. The hospital costs associated with these extra
days are significantly higher than for the general medical
population; those who develop a DVT incur further
costs of $17,114 and $18,521 for PE.23
Increased length of hospital stay is well documented among patients who develop VTE in the ICU.
For example, in a retrospective cohort study, patients
diagnosed with DVT had a median ICU length of stay
of 7 days and 5 days for those diagnosed with a PE.24
Similarly, in another prospective observation study, the
length of ICU stay and hospital stay both concomitantly
increased when patients were diagnosed with VTE.8
Compared with those who did not develop DVT who
spent 9 days in the ICU, those who experienced an inhospital DVT spent 15.5 in the ICU (p 0.005). Hospital stay also doubled from 23 to 51 days (p < 0.001) in
the presence of a DVT. Hence VTE in critical care
patients can result in significant morbidity and mortality
as well as hospital costs.
Hospital-acquired VTE is a substantial drain on
resources. Current cost estimates do not account for
pharmacy costs that can exceed $3000, or outpatient
pharmacy costs, which are substantial. Clearly, given
these direct and indirect costs, any systematic strategy
to prevent the occurrence of VTE will be cost effective if
not cost saving.

RISK FACTORS FOR VTE IN THE ICU

Given these various diagnostic challenges, awareness of
the risk factors associated with VTE will increase the
likelihood of diagnosis. Virchows triad describes three
fundamental principles that predispose individuals to
clot formation: injury to the vascular endothelium, an
alternation in the constitution of the blood or a hypercoagulable state, and a disturbance to normal blood flow
or stasis (Table 1).9

Table 1 Virchows Triad and Risk of Venous

Thromboembolism in the Intensive Care Unit
Hypercoagulability

Stasis

Vessel
Injury

Major surgery

Trauma

Acute myocardial
infarction

Congestive

heart failure
Stroke

Burns

Sepsis

Catheter

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Risk factors known to increase the risk for

hospital-acquired VTE include age >75 years, immobilization, the performance of procedures, and the presence of certain comorbid conditions, such as congestive
heart failure, acute infection, or malignancy. According
to multiple pharmacological prevention trials, hospitalized patients suffer from more than one risk factor for
thrombosis formation, and these factors have an additive
effect. For example, in the Prophylaxis in Medical
Patients with Enoxaparin (MEDENOX)25 study, which
enrolled over 1100 subjects, factors independently associated with increased risk for development of in-hospital
VTE included age >75 years, the presence of an active
infection, the presence of a malignancy, and a prior
history of VTE. On average, patients enrolled in MEDENOX had two or more risk factors. Additionally,
these findings were subsequently confirmed in two
other randomized, placebo-controlled trials of pharmacological thromboprophylaxis in medical patients,
the Prospective Evaluation of Dalteparin Efficacy for
Prevention of VTE in Immobilized Patients Trial
(PREVENT)26 and the Arixtra for Thromboembolism Prevention in a Medical Indications Study
(ARTEMIS).27
Not only do critically ill patients possess multiple
VTE risk factors similar to those of the general medical
population, they also have ICU-acquired risk factors
(Table 2).28 Prolonged immobilization from mechanical
ventilation, sedation, and hemodynamic compromise,
which almost uniformly affects all ICU admissions, is
an independent risk factor for VTE. In conjunction, the
need to perform invasive tests and procedures, such as
placing central venous catheters,12 to administer lifesustaining measures adds further risks for the development of VTE. Furthermore, other risk factors that
increase the susceptibility of thrombus formation include
the use of vasopressors,8 the presence of sepsis (because it
activates the coagulation cascade), or an acute myocardial infarction or stroke.9
Compounded together, the existence of multiple
risk factors in this patient population places these patients at exceedingly high risk for VTE development.
Table 2 Intensive Care Unit Acquired Risk Factors
General Medical Risk Factors

ICU Acquired Risk Factors

Advanced age

Immobilization

Malignancy

Stroke

Recent surgery

Trauma

Prior venous thromboemboli

Mechanical ventilation

Pregnancy

Invasive procedures/tests

Obesity

Central venous catheters

Oral contraceptives
Nephrotic syndrome

Sepsis
Heart failure

Inherited or acquired hemophilia

Vasopressor use

Inflammatory bowel disease

Cardiopulmonary failure

2010

Knowledge of these variables should prompt physicians

always to assess the risk profile of the ICU patient
because thrombus formation is preventable with the
use of thromboprophylaxis. The high incidence of
DVT can be significantly decreased with conscientious
effort and consideration.

THROMBOPROPHYLAXIS
RECOMMENDATIONS
Unlike the extensive body of literature that is available in
the surgical population, data supporting the use of
thromboprophylaxis in critically ill patients are extremely
limited. The heterogeneity in this patient population in
regard to their risk for VTE and an accompanying
increased risk of bleeding as a complication of chemical
prophylaxis poses a challenge and must be carefully
weighed. Two general forms of VTE prophylaxis are
available: chemical or mechanical. Mechanical DVT
prophylaxis is recommended for critical care patients
who are at high risk for developing VTE but have a
contraindication for chemical prophylaxis. These include
individuals who are actively bleeding, are considered too
high risk for bleeding, or have profound thrombocytopenia. Unfortunately, no formal risk stratification tools
exist to better quantify the risk for bleeding or the
patients ability to tolerate such a risk. Thus it behooves
the physician to carefully weigh the benefits vs the risks
of chemical DVT prophylaxis before its implementation.
Nevertheless, given the high risk of VTE in this population, transition to pharmacological thromboprophylaxis from mechanical modalities should be expedited
when contraindications to its use have resolved. This is
particularly important in critically ill patients because
data are limited regarding the efficacy of mechanical
thromboprophylaxis in the ICU.
There are few prospective, randomized, controlled trials (RCTs) to guide clinicians in this area.
Only five RCTs have evaluated the utility of mechanical
DVT prophylaxis in the critical care population; four of
the five studies were performed in trauma patients,
whereas the last involved patients with acute myocardial
infarctions.2933 Thus, due to limited availability of data,
the use of mechanical DVT prophylaxis in the general
critical care population is extrapolated from studies
performed on critically ill trauma patients. In a pooled
analysis of these five studies,34 a total of 811 patients
were randomized to either mechanical thromboprophylaxis or an alternative prophylaxis group, which varied
from placebo to another mechanical prophylaxis device
to a chemical agent, low molecular weight heparin
(LMWH). As a result of these varying comparison
groups, only two studies were pooled for a meta-analysis.
In the study where cardiac patients (n 80) were
randomized to graduated compression stockings
(GCS) versus placebo, the incidence of DVT was 0%

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42

compared with 10% (p 0.003),29 respectively, whereas

patients randomized to one of two different mechanical
devices did not differ in terms of the incidence of
DVT.30,31 In combining the subjects from the two
remaining studies where individuals were randomized
to intermittent pneumatic compression (IPC) devices
versus LMWH, 562 patients were pooled.34 The combined odds ratio was 2.37 [95% confidence interval (CI),
0.579.9] in favor of LMWH. Consequently, the scarcity of existing evidence for mechanical DVT prophylaxis in the ICU patient relegates its use to those at risk
for DVT formation but with contraindications to chemical thromboprophylaxis. Undoubtedly, when contraindications subside (e.g., when the risk for bleeding
decreases or when active bleeding or thrombocytopenia
resolves), pharmacological prophylaxis should be initiated in addition to, or instead of, mechanical prophylaxis.
Effective pharmacological agents include unfractionated heparin (UFH) and LMWHs, such as dalteparin or enoxaparin, for critical care patients. Although
anti-Xa agents such as fondaparinux are available for the
general medical population, there are currently no data
regarding its use in the ICU population. Thus far, only
two RCTs have been performed to assess the efficacy and
safety of chemical thromboprophylaxis in critically ill
patients. In the first study, 119 critically ill patients were
randomized to UFH 5000 U twice daily versus placebo.1
To evaluate the incidence of DVT, all patients had 125
I labeled fibrinogen leg scanning performed daily. The
use of UFH decreased the incidence of DVT from 29 to
13% compared with placebo with a relative risk reduction of 55% (p < 0.05). The investigators of this study
also concurrently enrolled 131 general medical patients
and found that only 10% of these patients developed
DVT during the course of their hospitalization when
thromboprophylaxis was not provided. Thus, the ICU
population is at least three times as likely as the general
medical population to develop DVT while hospitalized.
In the second RCT, Fraisse et al2 randomized 223
mechanically ventilated patients with chronic obstructive
pulmonary disease (COPD) to an LMWH, nadoparin,
versus placebo. LMWH is a short-chained polysaccharide produced by fractionation or depolymerization of
UFH. It has multiple anticoagulant properties, most
notable of which is its anti-factor Xa activity. Doppler
ultrasonography was performed upon enrollment in the
study, weekly, and when there was clinical suspicion for
DVT. Also, every patient had a venography study at
completion, after early discontinuation from the study,
or as a confirmatory test to a positive or indeterminate
Doppler ultrasound result. The primary outcome measure was the incidence of DVT, whereas the secondary
outcome measure was the rate of adverse events (i.e.,
major bleeding, minor bleeding, and thrombocytopenia)
associated with DVT prophylaxis. Compared with

placebo, the use of nadoparin for DVT prophylaxis

significantly decreased the incidence of DVT from 28.2
to 15.5% (p 0.045). There was no difference in rate of
adverse events: 46.3% for nadoparin versus 39.8% for
placebo (p 0.33). Therefore, this study demonstrates
the efficacy and safety of LMWH in the critically ill.
Although few RCTs have been performed on this
topic, various prospective observational trials elucidate
how the development of VTE in the ICU affects patient
outcomes. Of note, Cook et al8 enrolled 261 medical
surgical critical care patients in a prospective study where
over 98% of patients received some form of DVT
prophylaxis (92.8% received UFH 5000 U twice daily,
7.2% received mechanical prophylaxis). Screening for
DVT was done using lower extremity Doppler ultrasonography within 48 hours of admission to the ICU,
then twice weekly thereafter or when clinically indicated
(i.e., the physician was concerned about DVT based on
signs and symptoms). The incidence of DVT in these
patients was 9.6% (95% CI, 6.3 to 13.8) despite the use
of thromboprophylaxis, and of these cases, 9.4% developed symptomatic PE. The duration of days requiring
mechanical ventilation increased significantly (9 vs
6 days, p 0.03) when VTE occurred. Despite the
thoroughness of this study, it has certain limitations.
As a prospective observational study, lack of a comparison group limits the ability to assess the efficacy of DVT
prophylaxis in this cohort. The high incidence of DVT
despite thromboprophylaxis raises the question of
whether this finding is due to prophylaxis failure versus
patient selection, particularly given the mixed medicalsurgical population included. Furthermore, the accuracy
of Doppler ultrasonography has not been studied in
critically ill patients, and the incidence of DVT may be
either over- or underestimated in this study.35 Increased
peripheral edema may hamper the diagnostic capacity of
this test.
Another concern with screening for DVT in the
ICU is the uncertainty of the clinical significance of the
DVT found. In a retrospective analysis of symptomatic
VTE found in the ICU, the incidence of DVT was 1.0%
(95% CI, 0.8 to 1.2%), whereas the incidence PE rate
was 0.5% (95% CI, 0.4 to 0.6%).24 These incidence rates
are significantly lower compared with the incidence of
asymptomatic VTE diagnosed with the use of screening
tests. Thus VTE are definitely underdiagnosed in the
ICU patient population. This also demonstrates the
limited ability of this group of patients from manifesting
signs of VTE. Irrespective of this, because the morbidity
and mortality associated with in-hospital development
of VTE are unacceptably high, thromboprophylaxis is
paramount in the critically ill.
One concern that frequently arises with the use of
pharmacological agents in the ICU relates to their
metabolism, particularly when medication is renally
metabolized. Those in the ICU often have impaired

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renal function, either because of age, from comorbid

conditions (e.g., hypertension, diabetes), or because of
the acute disease process requiring ICU level of care
(e.g., sepsis, acute myocardial infarction). Until recently,
no prospective data have described the effect of renal
dysfunction on the metabolism of LMWHs in the ICU.
Emerging data suggest that pharmacological prophylaxis
with LWMHs in this environment is generally safe and
does not necessarily elevate the risk for bleeding. Specifically, in the Dalteparins Influence on the Renally
Compromised: Anti-Xa (DIRECT) study,36 156 critically ill patients with severe renal insufficiency, defined
as a creatinine clearance of <30 mL/min based on the
Cockcroft Gault formula, received dalteparin 5000 IU
once daily for DVT prophylaxis. The aim of this analysis
was to assess if LMWH contributes significantly to
bleeding. To gauge the bioaccumulation (excess anticoagulation effect) of dalteparin, serial trough anti-Xa
levels were drawn twice weekly. A priori, the definition
for bioaccumulation was set at least one trough anti-Xa
level >0.40 IU/mL. The authors selected this threshold
because prior studies found an increased risk of bleeding
with levels >0.40 IU/mL; whereas a trough between
0.10 and 0.40 IU/mL is considered a safe level of
anticoagulation. The rate of major bleeding served as
the primary outcome measure. This was defined as one
or more of the following: (1) a decrease in hemoglobin
level of 2 g/dL or greater; (2) need for transfusion of
2 units of red cells or more without an increase in
hemoglobin level; (3) a spontaneous decrease in systolic
blood pressure of 20 mm Hg or greater or an increase in
heart rate of 20 beats/min or greater or a decrease in
systolic blood pressure of 10 mm Hg or greater while the
patient was upright in the absence of another cause of
hypotension; (4) bleeding at a critical site, such as
intracranial bleeding; or (5) bleeding at a wound site
that required an intervention. The mean creatinine
clearance in the cohort was 18.9 mL/min, and the peak
anti-Xa levels were between 0.29 and 0.34 IU/mL. In
99% of the measurements, trough anti-Xa levels were
undetectable (<0.10 IU/mL) or minimal (0.10 to
0.20 IU/mL). Ten patients (7.2%; 95% CI, 4.0 to
12.8%) had major bleeding, but there was no association
between major bleeding and anti-Xa levels. To confirm
the efficacy of dalteparin as an effective pharmacological
prophylaxis agent, serial bilateral lower limb venous
ultrasonography was performed within 48 hours of ICU
admission and twice weekly thereafter. Akin to prior
studies, the incidence of DVT was only 5.1% (95% CI,
2.5 to 10.2%). Based on this study, the use of LMWH for
DVT prophylaxis is safe and does not significantly
influence bleeding risk in critically ill patients who have
severely impaired renal function.
More significantly, the data from DIRECT indicate that current dosing regimens for some anticoagulants might be inadequate to protect against DVT in the

2010

ICU. In a prospective observational study consisting of

45 patients (15 ICU patients on pressors, 15 ICU
patients not on pressors, and 15 general surgical patients)
who received nadoparin 2850 IU/day, the anti-Xa levels
of those in the ICU on pressors were significantly lower
than those in the other groups.37 Likewise, in a similar
study comparing anti-Xa levels in 13 ward patients
versus 15 ICU patients who received enoxaparin 40 mg
once daily for thromboprophylaxis, anti-Xa levels were
significantly lower in the group of ICU patients.38 There
is uncertainty as to whether the use of vasopressors and/
or the presence of generalized edema is altering drug
absorption.3941 Both of these factors can affect absorption due to decreased subcutaneous perfusion. The
impact of these observations on the effectiveness
of chemical thromboprophylaxis is speculative and inconclusive. Further studies on the effects of decreased
anti-Xa levels and efficacy of thromboprophylaxis will be
required before changing the dosage of anticoagulants as
used for DVT prophylaxis.
Current ACCP recommendations for DVT prevention in the ICU include the use of either UFH or
LMWH. Unfortunately, there are currently no studies
that directly compare UFH versus LMWH to protect
against VTE in critical care patients. The Prophylaxis of
Thromboembolism in Critical Care Trial (PROTECT)
is currently conducting a multicenter, randomized clinical trial to evaluate the efficacy and safety of these agents
in patients with critical illness. Hopefully, this study will
clarify the role of anticoagulants and their use to prevent
VTE in the ICU.
Until then, ACCP guidelines strongly recommend the use of VTE prophylaxis in critically ill
patients. Based on strength of evidence, the use of
chemical prophylaxis is graded 1A per the guidelines,
signifying its importance as high-quality evidence exists
to support this strong recommendation. The use of
mechanical prophylaxis, however, received a grade of
1C because its use is strongly recommended when
chemical thromboprophylaxis is not an option, but the
evidence of its efficacy is low.28,42 On occasion, dual
thromboprophylaxis, which employs both mechanical
and chemical modalities, is prescribed. Although there
is no evidence as to the benefits of this strategy, the risks
of this concomitant regimen are minimal. More importantly, when the risks of bleeding are minimal, pharmacological thromboprophylaxis should be initiated with or
without the simultaneous use of mechanical modalities.
Given these recommendations and the burden of illness
of VTE in the ICU, all patients should be assessed for
and prescribed DVT prophylaxis as soon as possible.

VTE Prophylaxis in Trauma Patients

Trauma patients are at significant risk for VTE where
the incidence ranges from 25 to 65%.3 Only one

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VENOUS THROMBOEMBOLIC DISEASE IN THE INTENSIVE CARE UNIT/CHAN, SHORR

VTE Prophylaxis in Ischemic Stroke

The occurrence of VTE patients afflicted with an ischemic stroke [i.e., cerebral vascular accidents (CVAs)] is
exceedingly high and may approach 70%.46 In a metaanalysis of 3 studies, totaling 2028 CVA patients,
LMWH significantly reduced VTE occurrence compared with UFH (odds ratio, 0.54; 95% CI, 0.41 to
0.70; p < 0.001).44 Among the three studies, intracranial
hemorrhage was rare, occurring with a frequency of 0 to
0.8%. Between groups, there was no difference in intracranial hemorrhage (OR with LMWH, 0.75; 95% CI,
0.21 to 1.91; p 0.567), major bleeding (OR with
LMWH, 1.75; 95% CI, 0.73 to 4.20; p 0.551), or
overall mortality (OR with LMWH, 0.97; 95% CI,
0.69 to 1.33; p 0.633).
Few studies have been done comparing LMWH
and UFH for patients with acute ischemic stroke. Based
on this meta-analysis, LMWH was superior to UFH in
preventing DVT without increasing the risk for intracranial hemorrhage or major bleeding. However, there
was no difference in mortality with the use of either
agent.

CONCLUSION
Critically ill patients clearly face an increased risk for
developing VTE. Upon admission, all critical care patients should be immediately assessed for and prescribed
VTE prophylaxis because it can significantly reduce
VTE occurrence, its potential sequelae, and costs asso-

ciated with VTE treatment. The ACCP (8th edition)

guidelines recommend the use of LMWH or UFH to
prevent VTE in critical care patients. When chemical
thromboprophylaxis is contraindicated, mechanical prophylaxis should be utilized until any potential contraindications resolve, at which point chemical prophylaxis
should be initiated. The importance of this health care
issue should motivate hospital administration and physicians to systematically initiate thromboprophylaxis in all
ICU patients.

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