the diagnosis of deep venous thrombosis and pulmonary embolism in medical-surgical intensive care...
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The diagnosis of deep venous thrombosis and pulmonaryembolism in medical-surgical intensive care unit patients
Deborah Cook MDa,b, James Douketis MDa,*, Mark A. Crowther MDa,David R. Anderson MDc, for the VTE in the ICU Workshop Participants
aDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 4A6bDepartment of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada L8N 4A6cDepartment of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
Received 22 July 2005; revised 2 September 2005; accepted 8 September 2005
1. Introduction 2. Diagnosis of DVT in critically ill patients
The diagnosis of deep venous thrombosis (DVT) and
pulmonary embolism (PE) is problematic in critically ill
patients who are in an intensive care unit (ICU) because of
several factors specific to this patient population. Intensive
care unit patients are typically immobile and may have
decreased ability to communicate and, consequently, may
be unable to convey symptoms of DVT or PE as they
occur in ambulatory, less ill patients. Diagnostic testing in
such patients may be limited because of mechanical
ventilation, which precluded ventilation-perfusion lung
scanning, or impaired renal function, which may preclude
intravenous contrast-based testing such as venography or
chest computed tomographic angiography. The objective of
this review is to assess and compare the currently available
diagnostic tests for DVT and PE in critically ill patients
(Table 1) and to provide reasonable diagnostic algorithms
for such patients who have suspected DVT (Fig. 1) or
suspected PE (Fig. 2).
0883-9441/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcrc.2005.09.003
T Corresponding author. Department of Medicine, St Joseph’s Hospital,
Hamilton, Ontario, Canada. Tel.: +1 905 521 6178; fax: +1 905 521 6068.
E-mail address: [email protected] (J. Douketis).
Although DVT has potentially serious consequences, it is
often unrecognized among ICU patients. Concern about
undiagnosed venous thromboembolism (VTE) in the med-
ical-surgical ICU setting is underscored by studies showing
that 10% [1] to 100% [2,3] of DVTs found by compression
ultrasound (CUS) screening were not detected on physical
examination. Clinically unsuspected PE is also a problem in
this setting. Mechanically ventilated patients with sudden
episodes of hypotension, tachycardia, or hypoxemia may
have undetected PE [4]. Pulmonary embolism may also
contribute to difficulty in weaning patients from a ventilator
[2]. Among critically ill patients with DVT who had no
symptoms of PE, 13 (38%) of 34 were diagnosed with PE
by ventilation-perfusion scans [5]. Pulmonary embolism
was unsuspected clinically but detected by echocardiogra-
phy in 9 (36%) of 25 consecutive patients with cardiac arrest
due to pulseless electrical activity [6]. In one 25-year
autopsy study, 9% of patients had PE at autopsy, and in
84%, the antemortem diagnosis was missed [7].
A helpful constellation of signs and symptoms in
a mathematically derived and validated clinical mod-
el can usefully predict DVT in communicative inpa-
tients and outpatients [8]. However, diagnosing DVT in the
ICU is more challenging. Symptoms are rarely elicited
Journal of Critical Care (2005) 20, 314–319
Table 1 Comparison of diagnostic tests for DVT and PE in critically ill patients
Diagnostic test Criterion
Clinical indication Imaging strengths Imaging limitations Adverse effects
Venous ultrasound Suspected DVT of the
upper or lower
extremities
Good sensitivity and
specificity for lower
extremity proximal
DVT
Does not image distal
(calf) veins
None known
Decreased sensitivity
for asymptomatic
DVT
Ascending
venography
Suspected DVT of the
upper or lower
extremities
Reference standard
for DVT
Technically difficult
or not feasible in
patients with limb
edema
Contrast-associated
nephrotoxicity
Spiral computed chest
tomography
Suspected PE
Suspected intra-
abdominal or
intrapelvic DVT
Good sensitivity and
specificity for PE in
non-ICU patients
Also identifies
nonvascular disease
May not visualize
smaller PEs
Contrast-associated
nephrotoxicity
Ventilation-perfusion
lung scan
Suspected PE Good sensitivity and
specificity for PE
non-ICU patients
Not feasible in
mechanically
ventilated patients
None known
Computed
tomography/angiography/
venography
Suspected DVT or PE Can image lungs and
legs at same time
Not widely studied
with few clinical
management studies
Contrast-associated
nephrotoxicity
Diagnosis of DVT and PE in medical-surgical ICU patients 315
from mechanically ventilated patients, most of whom
receive sedation and analgesia, rendering the notion of
bsymptomaticQ DVT unhelpful in this setting. Compounding
the problem is the fact that physical examination of the lower
extremities may be devalued in the high-technology ICU
environment, compared with cardiopulmonary monitoring,
making it unlikely that bsignsQ of DVT will be detected. In a
recent survey of Canadian ICU Directors, respondents stated
that physical examination did not yield information that was
helpful in the diagnosis of DVT [9], yet, no studies in the
ICU setting have confirmed or refuted this hypothesis.
The reference standard for DVT from a research
perspective remains lower limb venography. Adequately
performed venography is able to detect all clinically
important forms of DVT, including calf thrombosis,
thrombosis in the pelvis, and inferior vena cava, none of
which are reliably detected by ultrasonography. Despite its
utility, venography is rarely performed in practice in the
ICU setting. In a Canadian ICU Directors’ survey, the use of
venography to detect DVT was reported rarely (56%) or
never reported (9%) [9]. Concern about transporting
potentially unstable patients to the Radiology Department
[10], the invasive nature of the test, and the risk of contrast
dye-induced nephropathy [11] may contribute to the
aversion to venography in this setting. Studies conducted
2 decades ago cite contrast nephropathy as the third leading
cause of new-onset renal failure in hospitalized patients
[12]. Although currently used nonionic contrast media are
associated with a lower rate of nephrotoxicity than ionic
contrast media [13], the volume of contrast remains an
independent predictor of nephrotoxicity [14]. Additional
risk factors for acquired renal insufficiency in ICU patients
are common and include sepsis, volume depletion, mechan-
ical ventilation, and surgery [15]. Acetylcysteine may be a
risk modifier in this population because it reduced contrast-
induced nephropathy in a recent randomized trial in the
setting of angiography [16]. Overall, venography may be
considered in selected patients with a negative initial CUS,
in whom there is a high clinical suspicion for DVT and there
is a need to reliably and rapidly determine whether DVT is
present or absent. This scenario may arise in patients in
whom empirical anticoagulant therapy confers an unaccept-
ably high risk for bleeding complications.
Although lower limb CUS is the principal method of
detecting DVT in the ICU setting in practice, the test
properties of CUS in medical-surgical ICU patients have
not been determined. A recent metaanalysis reported a pooled
sensitivity of CUS for proximal DVT of 97% (95% CI,
96%-98%) and 62% (95%CI, 53%-71%) in symptomatic and
asymptomatic patients, respectively [17]. Compression ul-
trasound is less sensitive for distal DVT (pooled sensitivity
for symptomatic patients, 73% [95% CI, 54%-93%] and
asymptomatic patients, 53% [95% CI 32%-74%]). Symp-
tomatic outpatients with suspected DVT who have serially
negative CUS testing over a 7- to 10-day period have a 1%
likelihood of subsequently developing a DVT or PE,
suggesting that this management approach safely and
effectively rule out clinically important DVT [18-20].
However, it is unclear to what extent serially negative CUS
testing in medical-surgical ICU patients is indicative of the
Fig. 1 Diagnosis of DVT in critically ill patients.
D. Cook et al.316
absence of DVT. Finally, ultrasound will also inaccurately
diagnose some patients with DVTwho do not have DVT by
venogram, highlighting the false-positive rate of CUS. Thus,
Robinson et al [21] performed CUS and venography in a large
group of asymptomatic patients at high risk of VTE at the
time of hospital discharge; in this study, 6 of 19 positive CUSs
were not confirmed by venography. Overall, it must be
acknowledged that despite the obvious advantages of using
CUS to diagnose DVT in the ICU, it is associated with a false-
positive and a false-negative rate, which are not yet clearly
established in the ICU setting.
An emerging diagnostic modality for the detection of VTE
involves combining computed tomographic (CT) imaging of
the legs and lungs. This imaging approach involves both
indirect CT venography of the lower extremities and pelvic
veins and CT angiography of the pulmonary arteries. In a
single-center study involving 26 patients with suspected PE,
this combined diagnostic approach identified PE in 12
patients and identified DVT in 19 patients [22]. By
comparison, CUS of the lower extremities detected DVT in
17 of the 19 patients in whom DVT was diagnosed by CT
venography. The 2 thrombi missed by CUS were 1 case of
isolated iliac vein thrombosis, which is not surprising
because abdominopelvic veins are not adequately imaged
by CUS, and 1 case of isolated superficial femoral DVT,
which may have been missed because CUS protocols do not
always scan the entire length of the deep venous system.
Although combined CT venography and CT angiography
hold promise as a more comprehensive method to evaluate
both DVT and PE, they are largely a research tool at present
and requires further study.
Lower limb CUS remains the most widely used
diagnostic test for DVT in medical-surgical ICU studies
[1,5,23] and according to a survey of radiologists in the
United Kingdom [24]. A recent state-of-the-art review
referred to CUS as the imaging procedure of choice for
the diagnosis of DVT [25]. Bilateral lower limb CUS is also
the most feasible diagnostic test for DVT in the ICU because
it can be done at the bedside and is noninvasive.
3. Diagnosis of PE in critically ill patients
The diagnosis of PE in critically ill patients, as with the
diagnosis if DVT, is challenging because patients may not
present with typical clinical manifestation, in part because of
Fig. 2 Diagnosis of PE in critically ill patients.
Diagnosis of DVT and PE in medical-surgical ICU patients 317
limited communication with caregivers. There are no
studies, to our knowledge, that have assessed which clinical
signs and symptoms are associated with PE in critically ill
patients. Furthermore, clinical prediction rules for patients
with suspected PE have not been assessed in critically ill
patients [26].
For many years, ventilation-perfusion lung scanning was
the principal test, outside pulmonary angiography, to
diagnose PE. Although lung scanning has been widely
investigated in non–critically ill patients [26], its use in the
ICU setting is problematic. Performing the ventilation
component of the scan may be difficult in mechanically
ventilated patients. Furthermore, because of the high propor-
tion of critically ill patients with concomitant pulmonary
disease, this impairs the interpretation of ventilation-perfu-
sion scanning, often resulting in an bindeterminateQ or bnon-diagnosticQ test result. Finally, transporting critically ill
patients to a nuclear medicine department for scanning,
which can take up to 1 hour, places additional strain on the
health care team. There is only 1 study, to our knowledge, that
assessed diagnostic tests for PE in the ICU setting. In this
prospective cohort study, the reliability of ventilation-
perfusion lung scanning was compared in 220 critically ill
patients, 88 of whom were receiving mechanical ventilation,
and 627 non–critically ill patients [27]. There was no
difference between the critically ill ventilated and non–
critically ill nonventilated patients in regards to the sensitivity
(33% vs 38%) and specificity (100% vs 96%) of lung
scanning for PE. However, the generalizability of this study
to the ICU setting is questionable because most patients were
not ventilated, and additional studies to confirm the accuracy
findings are required before definitive conclusions can
be made.
In view of the lack of ICU-specific studies assessing
diagnostic strategies for PE, some extrapolation from studies
in non–critically ill patients is inevitable [28-30]. In recent
years, spiral CT has supplanted pulmonary angiography and
ventilation-perfusion scanning in many clinical centers as
the principal method to assess patients with suspected PE.
Spiral CT has a sensitivity and specificity for PE that varies
from 53% to 100% and 81% to 100%, respectively, in non–
critically ill patients [31]. The variability in accuracy across
studies likely reflects the emergence of newer and more
accurate higher-resolution CT technologies [32] and differ-
ences in patient populations studied. The main drawback of
spiral CT scanning is the considerable intravenous contrast
load required for imaging, which may preclude its use in
patients with moderately to severely impaired renal function.
D. Cook et al.318
The other concern with spiral CT in critically ill patients is
whether a normal spiral CT scan reliably excludes PE
[28-30] particularly because smaller emboli may be associ-
ated with adverse clinical outcomes in patients with impaired
cardiorespiratory reserve who may be receiving ventilatory
or inotropic support [33]. In patients without evidence of PE
on spiral CT, it is reasonable to perform bilateral CUS testing
to provide additional evidence to exclude VTE, as what is
done in patients with indeterminate lung scans [26]. A recent
metaanalysis of 15 studies using spiral CT to rule out PE
generated an overall negative likelihood ratio (NLR) of VTE,
based on VTE events that were subsequently objectively
confirmed by additional imaging, despite an initial negative
or inconclusive CT scan [34]. The NLR of a VTE after a
negative single slice spiral CT scan for PE was 0.08 (95% CI,
0.05-0.13), whereas the NLR for PE after a multidetector-
row spiral CT was 0.15 (95% CI, 0.05-0.43). The overall
NLR of mortality attributable to PE was 0.01 (95% CI,
0.01-0.02) and the overall negative predictive value was
99.4% (95% CI, 98.7-99.9). However, as the authors state, it
is likely that many patients in these studies had smaller
peripheral emboli that were not detected; if they were, these
emboli did not seem to cause harm during the follow-up
period of these studies. The inability to detect smaller emboli
may limit the generalizability of the findings from this meta-
analysis to critically ill patients. It is biologically plausible
that smaller emboli will have important adverse consequen-
ces in critically ill patients, many of whom have poor
cardiopulmonary reserve. Smaller peripheral emboli may be
more likely to result in inability to wean patients from a
ventilator, may cause recurrent episodes of desaturation and
associated dysrhythmia or transient cardiac ischemia during
ventilation, and may result in ongoing dyspnea and
hypoxemia after extubation. Furthermore, post-test proba-
bilities of PE are always dependent on the prevalence of VTE
in the target population. Because it is established that ICU
patients have a higher overall propensity for VTE than
outpatients or patients in a general medical ward, the latter of
whom were overrepresented in this meta-analysis, the
negative predictive value of spiral CT for PE in critically
ill patients is likely lower, although determining the actual
value would require ICU-specific studies.
Noninvasive or indirect diagnostic tests in patients with
suspected PE may include ventilation-perfusion lung scan-
ning, which has been discussed above, venous CUS testing
of the upper or lower extremities, echocardiography, and
d-dimer blood testing. In patients with suspected PE and no
symptoms of DVT, bilateral lower limb CUS will detect
DVT in 50% of patients with a high-probability lung scan but
in only 5% of patients with a nondiagnostic lung scan [26].
Consequently, CUS may be reasonable to undertake in
patients with suspected PE in whom lung scanning or spiral
CT cannot be performed because it is noninvasive and can be
done at the bedside. The diagnostic yield of CUS may be
higher in patients who have prior or ongoing central vein
catheterization of the lower or upper extremities because this
would provide a nidus for DVT and embolization. However,
CUS is an indirect test for PE, and the presence of an
asymptomatic DVT does provide confirmatory evidence of
PE, and direct tests that image the pulmonary vessels and/or
right ventricle should be sought whenever possible in
patients in whom the diagnosis of PE is crucial (eg, in
patients with massive PE in whom thrombolytic therapy is
being considered).
Echocardiography may directly visualize large emboli
in the main pulmonary artery; it may also identify right
ventricular wall dilatation, paradoxical septal wall motion,
tricuspid insufficiency, and elevated pulmonary artery
pressures, all of which occur with massive PE [35,36].
However, the lack of diagnostic accuracy studies with
echocardiography in patients with suspected PE and the
inability of this test to reliably exclude PE have limited its
utility. Finally, d-dimer blood testing, which is used
primarily to exclude DVT and PE in ambulatory patients,
has no utility in critically ill patients. In one prospective
cohort study involving 40 patients in a medical-surgical
ICU who underwent serial d-dimer testing during their
ICU stay, the d-dimer assay was abnormally elevated
(N0.5 lg/mL) in 77% of 111 measurements, likely because
critically ill patients have multiple comorbid conditions,
such as sepsis or surgical trauma, that cause an abnormal
d-dimer in the absence of PE [37]. Another study
involving 57 medical-surgical ICU patients found mean
levels of d-dimer of 2.3 F 1.9 lg/mL in medical patients
and 2.2 F 2.1 lg/mL in surgical patients, which suggests
that most patients had abnormally elevated levels [38].
Finally, we have recently demonstrated in a cohort of 261
critically ill patients that none of 6 commercial d-dimer
assays were able to reliably predict DVT developing in
critically ill patients undergoing serial monitoring with
compression ultrasonography [39].
4. Summary
There is no diagnostic test for DVT that is both highly
accurate and feasible in medical-surgical ICU patients.
Diagnostic testing for PE in such patients poses an even
greater challenge. Despite a lack of studies of CUS in
critically ill patients, it is the most widely used and accepted
DVT diagnostic test in such patients. Because the likelihood
of PE from undiagnosed, untreated proximal DVT is high,
strategies that screen for proximal DVT in critically ill
patients, therefore, have the potential to reduce the risk of
PE and its cardiopulmonary consequences through early
treatment. However, systematic screening for DVT with
CUS cannot be recommended currently; this requires a
randomized trial to evaluate whether this approach does
more good than harm. In critically ill patients with suspected
PE, spiral CT scanning is the principal method to diagnose
PE although may not reliably exclude PE. Emerging clinical
management studies that involve spiral CT in patients with
Diagnosis of DVT and PE in medical-surgical ICU patients 319
suspected PE should inform clinical practice and would be
relevant also to critically ill patients.
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