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Deep Vein Thrombosis and Its Prevention in Critically Ill Adults
John Attia, MD, PhD;
Joel G. Ray, MD;
Deborah J. Cook, MD, MSc;
James Douketis, MD;
Jeffrey S. Ginsberg, MD;
William H. Geerts, MD
Arch Intern Med. 2001;161:1268-1279.
ABSTRACT
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Background Our objective was to systematically review the incidence of deep vein
thrombosis (DVT) and the efficacy of thromboprophylaxis in critically ill
adults, including patients admitted to intensive care units and following
trauma, neurosurgery, or spinal cord injury.
Methods Two authors independently searched MEDLINE, EMBASE, abstract databases,
and the Cochrane database. Data were extracted independently in triplicate.
Results Ten percent to 30% of medical and surgical intensive care unit patients
develop DVT within the first week of intensive care unit admission. The use
of subcutaneous low-dose heparin reduced the rate by 50% compared with no
prophylaxis. Approximately 60% of trauma patients developed DVT within the
first 2 weeks of admission. Use of unfractionated heparin appears to decrease
the incidence of DVT by only 20%, whereas low-molecular-weight heparin decreases
the incidence by a further 30%. The estimated prevalence of DVT in neurosurgical
patients not given prophylaxis is 22% to 35%. Mechanical prophylaxis is efficacious,
with a pooled odds ratio in 5 randomized trials of 0.28. Use of low-molecular-weight
heparin has been investigated as an adjunct to mechanical prophylaxis with
a pooled odds ratio of 0.59 compared with graduated compression stockings
alone. The incidence of DVT without prophylaxis in acute spinal cord injury
patients is likely in excess of 50% to 80%. Studies of prophylaxis in these
patients are too sparse to come to any definitive conclusion.
Conclusions Critically ill patients commonly develop DVT, with rates that vary from
22% to almost 80%, depending on patient characteristics. Methods of prophylaxis
proven in one group do not necessarily generalize to other critically ill
patient groups. More potent prophylactic regimens other than unfractionated
or low-molecular-weight heparins alone may be needed with higher-risk groups.
INTRODUCTION
PULMONARY embolism (PE) is a common and preventable cause of death among
hospitalized adults.1 Up to 95% of cases of
PE originate from clots in the deep venous system of the lower limbs, and
are often asymptomatic.2-4
Since screening methods are unlikely to be helpful in high-risk patients,5-6 emphasis has shifted to routine prophylaxis
in these individuals.
Cross-sectional studies of medical7 and
surgical8 intensive care unit (ICU) patients
have shown that approximately 10% have proximal deep vein thrombosis (DVT)
on admission to the ICU. Patients are further predisposed to DVT during their
ICU stay due to prolonged immobilization, sepsis, and vascular injury from
indwelling central venous catheters or other invasive interventions. Similarly,
venous thromboembolism (VTE) is an important cause of mortality in patients
with spinal cord injury9 or following neurosurgery10-11 or major trauma.12-13
Anticoagulant or mechanical prophylaxis against lower limb DVT is generally
recommended for these high-risk populations.1, 14-15
However, the Fifth American College of Chest Physicians Consensus Conference
on antithrombotic therapy contained no specific section on the treatment and
prevention of VTE in critically ill patients.1, 16
Herein, we systematically review the evidence for DVT risk and the efficacy
of thromboprophylaxis in adults admitted to a medical-surgical ICU, or following
major trauma, neurosurgery, or acute spinal cord injury.
METHODS
LITERATURE SEARCH
We systematically searched MEDLINE between January 1966 and August 1998;
EMBASE, Conferences Papers Index, and Inside Conferences from 1980 to 1998;
and the Cochrane Library's Clinical Trials Registry, Database of Systematic
Reviews, and the Database of Abstracts of Reviews. Our personal files and
the bibliographies of relevant articles were also examined for additional
citations. The following medical subject headings (MeSH) and text words were
used: "thromboembolism," "thrombophlebitis," "deep-vein thrombosis," "deep
vein thrombosis," "venous thrombosis," "thrombosis," "pulmonary embolus,"
"pulmonary embolism," or "venous thromboembolism." According to the population
of interest, these terms were cross-referenced with "intensive care," "critical
care," "trauma," "brain injury," "head injury," "head trauma," "neurosurgery,"
"neurosurgical," or "spinal cord injury." The search was limited to studies
of adult human subjects published in the English language.
STUDY SELECTION
The computer search, study selection, and examination of full-text articles
was performed independently by 2 authors (J.A. and J.G.R.). We applied the
following inclusion criteria to select the studies: (1) Study design: published
prospective cohort studies or randomized clinical trials of DVT prophylaxis.
(2) Population: critically ill adults admitted to a medical-surgical ICU or
those who sustained major trauma or acute spinal cord injury or underwent
neurosurgery. (3) Sample size: enrolled at least 10 patients. (4) Outcome:
used objective test method(s) to screen for lower limb DVT (fibrinogen I 125
leg scanning, impedance plethysmography, venous ultrasonography [US], or venography).
We excluded abstracts from meetings that were not later published in
full form, studies that focused on central venous catheter-related thrombosis,
and those with insufficient reporting of DVT rates.
DATA EXTRACTION
Three authors (J.A., W.H.G., and either J.G.R. or D.J.C.) independently
extracted data from each study. Disagreements were resolved through consensus.
We extracted information on study design; population; DVT screening method(s);
use of thromboprophylactic measures; DVT event rates; and study validity,
which was assessed using the 5 following quality criteria: (1) study design
(randomized clinical trial vs prospective cohort study); (2) whether patients
were enrolled in a consecutive manner; (3) completeness of follow-up; (4)
use of confirmatory venography after a positive noninvasive test result, as
the accepted reference standard5; and (5) blinding
of outcome assessment. In the absence of an accepted scoring system, validity
criteria were presented in tabular form.
DATA ANALYSIS
We calculated DVT rates for each study. For studies that compared DVT
events with and without prophylaxis, results were expressed as the relative
risk reduction (RRR). When appropriate, data were pooled using the Mantel-Haenszel  2 statistic to obtain a summary odds ratio (OR) and its 95% confidence
interval (CI). Heterogeneity testing was performed using the Breslow-Day method.17 Both calculations were performed using the OR 2 x
2 statistical software (J. Julian, PhD, McMaster University, Hamilton, Ontario,
1995). Finally, we summarized our findings using the levels of evidence system
developed for the American College of Chest Physicians Antithrombotic Consensus
Conference.18 Our primary aim was to summarize
the literature, not to generate recommendations.
RESULTS
MEDICAL-SURGICAL ICU PATIENTS
Three prospective cohort studies19-21
and 1 randomized clinical trial22 were included
(Table 1). Two studies were excluded
because screening for DVT was performed only on ICU admission.6-7
Among the studies included, more than 70% of patients required mechanical
ventilation, and most had an expected ICU stay greater than 48 hours. Two
of 3 prospective cohort studies enrolled consecutive patients,20-21
but none used venography either to screen for or to confirm the presence of
DVT.
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Table 1. Methodological Description of Studies of Deep Vein Thrombosis
(DVT) Among General Medical and Surgical Intensive Care Unit (ICU) Patients*
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The rates of DVT are listed in Table
2. In 2 of the 3 cohort studies, DVT prophylaxis was left to the
discretion of the caregivers, although most patients received some form of
prophylaxis.20-21 In the study
by Moser et al,19 fibrinogen I 125 leg scanning
was used for up to 7 days in 34 patients who did not receive prophylaxis;
DVT was diagnosed in 9% (95% CI, 2%-20%) of patients. Using serial Doppler
US, Hirsch et al20 diagnosed upper or lower
limb DVT in 32% (95% CI, 16%-48%) of patients who did not receive prophylaxis,
40% (95% CI, 25%-55%) who received subcutaneous heparin, and 33% (95% CI,
11%-55%) who received mechanical prophylaxis. In total, 48% of all DVT cases
were proximal. In the study by Marik et al,21
102 medical and surgical patients were screened using a single Doppler US,
and DVT was detected in 25% (95% CI, 0%-55%) of patients receiving no prophylaxis,
7% (95% CI, 0%-26%) receiving heparin, and 19% (95% CI, 4%-34%) receiving
mechanical prophylaxis.
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Table 2. Results of Studies of Deep Vein Thrombosis Prophylaxis Among
General Medical and Surgical Intensive Care Unit Patients*
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In the double-blind clinical trial by Cade,22
119 critically ill patients were randomized to receive subcutaneous unfractionated
heparin at a dose of 5000 U twice daily or placebo injection. Using serial
fibrinogen I 125 leg scanning for 5 days, the rates of DVT were 13% in the
heparin group and 29% in the placebo group (RRR, 0.65; 95% CI not calculable).
Bleeding complications were not evaluated in any of these 4 studies
nor was there any systematic screening process for PE. Marik et al21 performed ventilation-perfusion lung scans on patients
whose US results were positive; 4 of 12 patients had high probability scans.
Moser et al19 documented PE in 2 of 10 patients
who received autopsies, while Hirsch et al20
noted only 1 symptomatic PE in their group of 100 patients.
TRAUMA PATIENTS
Four randomized clinical trials23-26
and 11 cohort studies27-37
met our inclusion criteria (Table 3
and Table 4). Although 3 studies
were identified as randomized,32-33,35
the patients were assigned to different arms of the study at the physician's
discretion and others were randomized; hence, we have considered these as
cohort designs. Six studies were excluded due to insufficient reporting of
details relating to the primary end points.38-43
A seventh study used technetium-labeled albumin for screening, a modality
that has not been validated for the detection of DVT.44
Redundant reporting led to the exclusion of another study,45
and a ninth study used handheld Doppler flow,46
which did not meet our inclusion criteria.
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Table 3. Methodological Description of Studies of Deep Vein Thrombosis
(DVT) in Trauma Patients*
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Table 4. Results of Studies of Deep Vein Thrombosis (DVT) Prophylaxis
in Trauma Patients*
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Three studies reported the incidence of DVT in trauma patients using
routine venography. In 1 prospective cohort study, Geerts et al33
obtained 349 adequate venograms from 716 major trauma patients who did not
receive prophylaxis. A total of 201 patients (58%; 95% CI, 52%-63%) were diagnosed
as having DVT between days 14 and 21, of which one third of cases were proximal.
Nearly all events were silent, with the exception of 3 patients who had symptomatic
DVT. An additional 3 patients had fatal PE while under surveillance. In a
smaller study, comprising 39 trauma patients who were immobilized for at least
10 days, the incidence of venographically identified DVT was 63% (95% CI,
47%-77%), of which half were proximal.29 Once
again, almost all events were silent, with only 1 of 24 patients displaying
clinical signs of DVT.
In the earliest study, routine venography was used; the incidence of
DVT was 35% (95% CI, 27%-43%).27 However, this
study is not generalizable to most trauma patients because all patients were
immobilized for at least 3 weeks, 56% had hip fracture as their only injury,
and many with lower extremity fractures had their surgery delayed. In addition,
deaths and dropouts were not reported, and superficial thrombi were included
as outcomes.
Differences in the incidence of DVT across studies is probably due to
the fact that US is less sensitive than venography as a screening test for
DVT.47 Studies using US in trauma patients
tended to document a lower incidence of DVT, ranging from 6% to 30% in the
absence of prophylaxis,23, 28, 32, 34, 36
while studies using venography had DVT rates between 28% and 63%.24, 29, 33 Other sources of
variability included different frequencies of screening and the heterogeneity
of patients (ie, single-system vs multisystem trauma).
In most trauma studies, the incidence of PE was poorly described, and
systematic screening was not performed. In patient groups who did not receive
prophylaxis, the rate of symptomatic PE ranged from 0.7% to 2%, while those
who received some type of prophylaxis had a PE rate of 0% to 1.4%.24-25,29-36
In the only study to use systematic screening for PE, Fisher et al23 noted an incidence of 9 (6%) of 159 cases in the
control group compared with 6 (4%) of 145 cases in the mechanical prophylaxis
group.
Several studies examined the use of anticoagulant prophylaxis in trauma
patients. The most rigorous study, a double-blind trial, used routine screening
venography.24 There were 344 major trauma patients
included who were randomized to receive unfractionated heparin, 5000 U subcutaneously
twice daily, or enoxaparin sodium, 30 mg subcutaneously twice daily. Venography
was performed between days 10 and 14 and was interpretable in 265 patients.
Sixty (44%) of 136 patients who received unfractionated heparin experienced
DVT (compared with an expected 54% rate if the patients had not received prophylaxis,
based on a predictive equation derived in their previous cohort study). Knudson
et al32 reported a DVT rate of 3% in patients
who received heparin compared with 7% in those who did not receive prophylaxis.
However, this study assigned patients to heparin therapy at the discretion
of the attending physician.
Cohort studies of anticoagulant prophylaxis in trauma patients show
variable results. Napolitano et al34 demonstrated
a DVT rate of 12% with a pneumatic compression device (PCD) or no prophylaxis
and 9% with low-dose heparin. Another study found no benefit with heparin
compared with no prophylaxis, but only 44 patients were compared.36
As described previously, Geerts et al24
evaluated enoxaparin and unfractionated heparin in a randomized clinical trial.
Forty (31%) of 129 trauma patients randomized to enoxaparin developed DVT
compared with 60 (44%) of 136 patients in the heparin group (RRR, 30%; P = .01). The RRR for proximal DVT was 58% (P = .01), suggesting a greater benefit with low-molecular-weight heparin
(LMWH) in preventing proximal DVT. There was a nonsignificant trend toward
greater bleeding in the LMWH group (5 patients) than in the heparin group
(1 patient) (P = .12).
Haentjens et al25 randomized 215 patients
with orthopedic trauma to fixed- or adjusted-dose nadroparin calcium combined
with graduated compression stockings (GCS). When the 144 patients with hip
fracture are removed, the incidence of DVT, using duplex screening US at day
10, was similar in both groups (0 of 70 and 0 of 69, respectively). Five patients
in each group had major hemorrhage, with no fatal outcomes. In 3 separate
studies, Knudson et al31-32,35
compared either unfractionated heparin or LMWH with mechanical prophylaxis
(ie, GCS, PCD, or foot pump). Using these data, and collapsing the results
into a heparin-LMWH arm compared with a mechanical device arm, yielded a pooled
OR of 0.46 (95% CI, 0.16-1.29) favoring anticoagulants, with no evidence of
heterogeneity across studies (P = .88). This is equivalent
to a relative risk of 0.68 or an RRR of 32%.
Among the various methods of mechanical prophylaxis, no study has directly
compared GCS with PCDs. Two studies suggest that foot pumps may not be as
effective as GCS or PCDs, although these differences do not reach statistical
significance.26, 35 Two studies32, 34 compared mechanical prophylaxis with
no prophylaxis and found no difference.
NEUROSURGICAL PATIENTS
Thirteen randomized clinical trials48-60
and 5 cohort studies61-65
met our inclusion criteria (Table 5
and Table 6). Several others failed
to meet our inclusion criteria.60, 66-72
Among studies that were included, most patients began receiving mechanical
prophylaxis intraoperatively, while anticogulant prophylaxis was generally
commenced after surgery for at least 7 days. In 3 cohort studies61-62,64
that screened a total of 169 patients with fibrinogen I 125 leg scanning,
the pooled DVT event rate was 35% (95% CI, 28%-43%) in the absence of prophylaxis.
In 7 randomized clinical trials that included a nonprophylaxis arm,48-53,56
the pooled incidence of DVT was 22% (95% CI, 18%-26%). Studies that used confirmatory
venography indicated that 35% to 50% of the DVT events were proximal. The
incidence of symptomatic PE was 0% to 2%.
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Table 5. Methodological Description of Studies of Deep Vein Thrombosis
(DVT) in Neurosurgical Patients*
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Table 6. Results of Studies of Deep Vein Thrombosis (DVT) Prophylaxis
Among Neurosurgery Patients*
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Only 1 study compared unfractionated heparin with placebo. Cerrato et
al49 randomized 100 patients, most of whom
underwent craniotomy, to either heparin, 5000 U subcutaneously every 8 hours,
or no prophylaxis. Deep vein thrombosis developed in 6% of patients taking
heparin and 34% of control group patients (RRR, 82%; P
= .005). Bleeding was infrequent in both groups: 2 patients in the heparin
group and 1 patient in the control group had postoperative hematomas.
The majority of studies that evaluated mechanical prophylaxis devices
included GCS and/or PCDs. Turpie et al48 reported
a reduction in DVT during 5 days of postoperative screening from 12 (19%)
of 63 among controls to 1 (1.5%) of 65 in the patients who received PCD (P = .001). When follow-up was extended to 2 weeks,51 the incidence of DVT was 20 (21%) of 96 cases in
the control group and 8 (8%) of 103 cases among PCD recipients (RRR, 61%; P = .01). The proportion of proximal DVT in the first study
was 15%48 and 39% in the second study.51 In a third trial, Turpie et al56
reported that GCS alone or in combination with PCD were comparable, reducing
the incidence of DVT from 20% in controls to 9% in patients who received GCS
or combined therapy (RRR, 55%; P = .03). In this
study, noncompliance was greater with the combined regimen (13%) than with
GCS alone (3%). A smaller study55 also failed
to observe any difference between GCS and PCD for DVT prevention.
Pooling data from 5 randomized clinical trials that compared mechanical
devices to no prophylaxis48, 50-51,53, 56
yields an OR of 0.28 (95% CI, 0.17-0.46) in favor of mechanical prophylaxis,
with no evidence of heterogeneity across studies (Breslow-Day 2 = 3.4; P = .49). This translates into an relative
risk of 0.43 or an RRR of 57%. Three clinical trials have evaluated the combination
of LMWH and mechanical prophylaxis.58-60
In 1 study,59 screening venography was used
to detect DVT in patients who primarily had surgery for intracranial or spinal
neoplasms. Patients assigned to GCS had a DVT rate of 33%, while those assigned
to GCS plus enoxaparin at a dose of 40 mg subcutaneously once daily had a
DVT rate of 17% (RRR, 48%; P = .004). The rates of
proximal DVT were 13% and 5%, respectively, (P =
.04). Four major hemorrhagic events were detected in each group (3%), of which
7 were intracranial. These results were supported by a study of predominantly
patients who received craniotomies,58 who were
randomized to receive either GCS (DVT rate, 26%) or GCS plus nadroparin, 3075
anti-Xa units subcutaneously once daily (DVT rate, 19%) (RRR, 29%; P = .047). The proximal DVT rates were 12% and 7%, respectively, (P = .06). There were significantly more bleeding events
in the patients who received LMWH (4% vs 1%); intracranial bleeding was seen
in 6 patients who received combined therapy and 1 patient who received GCS
alone.
In a third, unmasked clinical trial, Dickinson et al60
randomized 66 patients to receive PCD; enoxaparin, 30 mg subcutaneously twice
daily; or PCD plus enoxaparin. Enoxaparin therapy was started immediately
before surgery. Five of 38 patients who received LMWH had major intracranial
bleeding, whereas this outcome was not encountered in the 19 patients in the
PCD group. The higher proportion of intracranial hemorrhages could be attributable
to the relatively high dose of enoxaparin used in this study and the administration
of a preoperative dose.
Pooling these 3 trials formally yields an OR of 0.59 (95% CI, 0.40-0.85),
with no evidence of heterogeneity across studies (Breslow-Day 2 = 6.1; P = .19), favoring the combination
of LMWH and mechanical prophylaxis over mechanical prophylaxis alone. This
figure is equivalent to a relative risk of 0.74 or an RRR of 26%.The rates
of intracranial bleeding in the mechanical and combined mechanical-LMWH arms
of these trials were 5 (1.2%) of 417 cases (95% CI, 0.4%-2.5%) and 14 (3.2%)
of 432 cases (95% CI, 1.8%-5.1%).
ACUTE SPINAL CORD INJURY PATIENTS
Ten studies met the inclusion criteria, of which 4 were randomized clinical
trials72-75
and 6 were cohort studies33, 76-80
(Table 7 and Table 8). Six additional studies failed to meet our inclusion criteria.81-86
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Table 7. Methodological Description of Studies of Deep Vein Thrombosis
(DVT) in Acute Spinal Cord Injury Patients
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Table 8. Results of Studies of Deep Vein Thrombosis (DVT) Prophylaxis
Among Acute Spinal Cord Injury Patients*
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Five studies evaluated the rate of DVT in the absence of prophylaxis.33, 72, 76-78
The only study to use screening venography was by Geerts et al,33
who documented a DVT incidence of 81% (95% CI, 66%-96%) in a subgroup of trauma
patients with acute spinal cord injury. The 4 remaining studies,72, 76-78
which used either fibrinogen I 125 leg scanning or impedance plethysmography
to screen for DVT, observed rates between 39% and 90%. Merli et al78 enrolled 87 patients within 2 weeks of injury and
found that 39% had DVT at initial screening. Among those who did not receive
active prophylaxis, 47% were subsequently diagnosed as having DVT.
In a small study by Frisbie and Sasahara,72
there was no difference between low-dose subcutaneous heparin and no prophylaxis
groups. In a cohort study by Merli et al,79
patients who received the combination of low-dose heparin, GCS, and PCD had
a DVT rate of 5% (95% CI, 0%-15%).
Green et al74 compared fixed low-dose
subcutaneous heparin with adjusted-dose heparin (target activated partial
thromboplastin time, 1.5 times control). Adjusted-dose heparin reduced the
rate of DVT from 21% to 7% (RRR, 67%; P = .25). Seven
patients (24%) in the adjusted-dose heparin arm experienced major bleeding
complications, none of which were intracranial or fatal, compared with no
bleeding events in the low-dose heparin arm.
Only 1 study compared LMWH (tinzaparin sodium, 3500 U subcutaneously
once daily) with low-dose unfractioned heparin taken subcutaneously 3 times
a day.75 In this randomized trial of only 35
patients, tinzaparin reduced the rate of DVT from 16% to 0%. This difference
only reached statistical significance when all adverse events (ie, DVT and
major bleeding) were combined (P = .02). However,
a subsequent prospective cohort study by Green et al80
did not confirm these findings, as the DVT rate with LMWH prophylaxis was
13%. In considering both of these studies together, only 1 of 80 patients
assigned to receive tinzaparin had major bleeding.
COMMENT
Major limitations to the interpretation of this literature are the variability
in the types of patients; variability in the timing, frequency, and choice
of the screening tests; and the lack of blinding of the outcome assessment.
The absence of a reference standard, contrast venography, for the diagnosis
of DVT in the majority of these studies adds the greatest uncertainty about
the true frequency of DVT in critically ill patients. Investigators may believe
that venography in the ICU setting is impractical and dangerous, and that
the risk of nephrotoxicity is too high. There may be the assumption that the
larger, and perhaps most significant thrombi, will be detected by noninvasive
means. This tenuous assumption has not been supported in the ICU populations
described herein. Meta-analyses in asymptomatic orthopedic patients have demonstrated
that the sensitivities of fibrinogen I 125 leg scanning, impedance plethysmography,
and US are low for all DVT: 45%, 15%, and 47%, respectively.47, 87
For proximal DVT, the sensitivity of US in asymptomatic patients is only 62%.
Hence, the studies described herein yield limited prevalence data and likely
underestimate the true rate of DVT. Venography remains the reference standard
and is indeed feasible in some critically ill patients, eg, trauma patients.24, 33
Another limitation is the paucity of truly randomized studies in these
patient groups. Given surgeons' reluctance to use heparin prophylaxis in patients
with traumatic injuries or undergoing neurosurgery, there are few studies
that are truly randomized, with most being observational or quasi-randomized
in which patients are assigned to 1 of 2 arms at the discretion of the attending
physician, resulting in bias.
Others have also pointed out these methodological concerns. Heffner
and colleagues88 recommended that greater methodological
rigor be used in diagnostic studies within the disciplines of respirology
and thrombosis medicine. They cited several inadequacies in these areas, including
lack of suitable reference standards, as well as insufficient assessment of
both test reproducibility and novel approaches to dealing with indeterminate
test results. Trends suggest that methodological standards for diagnostic
tests are improving89 and that generation of
likelihood ratios, for example, could aid intensivists in their interpretation
of abnormal test results.90
A number of suggestions for future research can be made: (1) patients
who cannot be (or refuse to be) randomized should be included in a parallel
observation arm; (2) a double-blind design should be used; (3) the use of
screening venography to assess efficacy should be encouraged; (4) the use
of clinically important outcomes, including symptomatic VTE, proximal DVT,
and hemorrhage, should be used to assess effectiveness; and (5) follow-up
periods should be sufficiently long. The enrollment of large heterogeneous
cohorts of critically ill patients would enable investigators to determine
risk factors that predict VTE rates. Once these risk factors are determined,
they can be used in subsequent trials to target prophylaxis to high-risk critically
ill patients. Stratification of bleeding risk may also be addressed to better
evaluate the risk-benefit ratio. Study designs that tailor the prophylaxis
to individual patients are also needed.
With respect to content, there are a number of gaps in the literature.
No truly randomized study has directly compared heparin with mechanical prophylaxis.
In addition, no trial, whether using venography or other noninvasive means,
has compared elastic stockings directly with PCDs; hence, the choice between
these 2 mechanical prophylaxis methods remains unclear. Various combinations
of pharmacological and mechanical prophylaxis also remain to be investigated,
and certain methods have been ignored in certain populations; for example,
there is a lack of data regarding mechanical prophylaxis in medical-surgical
ICU patients. The commencement and duration of prophylaxis, eg, intraoperative
initiation vs postoperative and ICU only vs extended until discharge, are
issues that also require additional study.
Even when clear research findings are available to guide thromboprophylaxis,
there are a number of barriers to implementation. Utilization surveys document
heparin prophylaxis rates ranging from 33% in a medical-surgical ICU,91 to 65%,92 to at most
86%.93 Strategies to increase prophylaxis use
in critical care include the development of written policies, incorporation
into ICU admission orders, inclusion in daily review of each patient, periodic
reviews of compliance, interactive education with periodic reminders, and
audit and feedback. Although the majority of critically ill patients will
be able to receive prophylaxis, some will have contraindications to anticoagulants,
and, perhaps, even mechanical methods. For these patients, a strategy of screening
for large deep venous thrombi may provide additional safety.
A second concern, especially for the mechanical prophylaxis modalities,
is poor patient compliance when these devices are assessed in routine clinical
use compared with the optimal circumstances of a research trial. For example,
Comerota et al94 noted that prescribed PCDs
were properly applied and functioning in only 78% of ICU visits and only 48%
of ward visits. Likewise, Anglen et al26 found
that foot pumps were in place and functioning in 48% of ward visits and in
68% of ICU visits.
CONCLUSIONS
The great range in study designs, interventions, and populations render
an overall quantitative summary of these studies impossible. However, we have
generated summaries of the literature qualitatively and statistically pooled
results of subgroups of studies when appropriate. These summaries are presented
below, with the accompanying levels of evidence. For recommendations on practice,
we refer readers to the Sixth American College of Chest Physicians Consensus
conference, which will be published shortly.
MEDICAL-SURGICAL ICU PATIENTS
1. The incidence of DVT without prophylaxis in this population has been
estimated at about 30%. This is based on limited screening with imperfect
diagnostic tests and no reference standard. The true incidence is likely higher
(level III and IV evidence).
2. Low-dose heparin prophylaxis is effective, reducing the DVT rate
by approximately 50%. This is based on 1 double-blind randomized clinical
trial. Observational studies generally support the effectiveness of heparin
(level I evidence).
3. Other means of prophylaxis, including LMWH, GCS, and intermittent
PCDs have not been adequately studied.
TRAUMA PATIENTS
1. The incidence of DVT in multisystem trauma patients, particularly
those with orthopedic trauma, head injury, or spinal trauma, appears to be
in the range of 50% to 65% (level I evidence). Studies using noninvasive methods
of screening yield a lower incidence, ie, 25% to 35%, in keeping with the
approximately 50% sensitivity of these methods in asymptomatic patients. A
number of risk factors for VTE in trauma emerge: spinal cord injury, lower
extremity fracture, major head injury, central venous repair or cannulation,
and prolonged bed rest. Injury severity is not a reliable predictor of thrombosis
risk.
2. Approximately one third to one half of these DVT events are proximal,
and therefore have high potential to embolize (level I evidence).
3. Based mainly on nonrandomized studies, unfractionated heparin prophylaxis
appears to decrease the incidence of DVT by approximately 20% compared with
placebo (level II and III evidence).
4. Low-molecular-weight heparin decreases the incidence of DVT by a
further 30% over unfractionated heparin (level I evidence).
5. Pooling all heparin trials yields an OR of 0.46 (95% CI, 0.16-1.29)
compared with mechanical prophylaxis. This is equivalent to a relative risk
of 0.68 or an RRR of 32%.
6. Concerns about excessive bleeding with heparin prophylaxis in patients
who have achieved primary hemostasis appear unwarranted. Major bleeding occurs
in 0.5% of patients treated with heparin, with few needing surgical intervention
and none having a fatal outcome (level II evidence).
7. There is insufficient evidence to state whether mechanical means
of prophylaxis (GCS, PCD, or foot pumps) are more efficacious than placebo.
NEUROSURGICAL PATIENTS
1. The incidence of DVT ranges from 20% to 30% in mixed neurosurgical
patients and ranges from 34% to 50% in higher-risk groups undergoing craniotomy
for tumors or with lower extremity paresis. These values are based on noninvasive
methods and likely underestimate the true rate of DVT (level II evidence).
2. Mechanical prophylaxis reduces the incidence of DVT by approximately
57% (OR, 0.28; 95% CI, 0.17-0.46; equivalent to a relative risk of approximately
0.43), with GCS and boots appearing to have similar efficacy (level II evidence).
3. Heparin appears to be at least as efficacious as mechanical prophylaxis,
decreasing the risk of DVT by 82% in a single study (level II evidence).
4. Low-molecular-weight heparin further reduces the risk of DVT by approximately
26% when added to GCS (OR, 0.59; 95% CI, 0.40-0.85, which translates into
a relative risk of 0.74) (level I evidence).
5. Intracranial bleeding occurs in approximately 3% of patients when
taking heparin, although fatalities have not been reported. Too few patients
have been studied to be certain that this rate is significantly greater than
in patients not receiving anticoagulant prophylaxis (level II evidence).
ACUTE SPINAL CORD INJURY PATIENTS
1. The incidence of DVT without prophylaxis is approximately 80%. This
is based on 1 small venographic study but is supported by estimates from noninvasive
methods (level II and III evidence).
2. Low-dose unfractionated heparin does not appear to provide significant
protection (level II evidence).
3. Heparin appears to be more effective in prevention of DVT when combined
with compression boots and GCS, or when given in adjusted doses, although
the latter causes more bleeding complications (level II evidence).
4. There is conflicting evidence as to whether LMWH is equivalent to
or more efficacious than unfractionated heparin (level II and IV evidence).
5. There is insufficient information to make recommendations regarding
mechanical methods of DVT prophylaxis in these patients.
During the submission and review of this manuscript, 2 other relevant
articles were published. Fraisse et al95 performed
a randomized controlled trial of nadroparin (3800 or 5700 IU subcutaneously,
once daily) compared with placebo in 223 patients mechanically ventilated
for decompensated chronic obstructive pulmonary disease. The incidence of
DVT was 15.5% in the nadroparin group and 28.2% in the placebo group, giving
an RRR of about 45%. This study confirms the estimates given in this review
and represents the only use of venography in the medical ICU population. Elliott
et al96 compared calf-thigh sequential PCDs
and foot pumps for DVT prophylaxis in 149 major trauma patients without lower
extremity injuries. The DVT rates, using compression US, were 6.5% and 21%,
respectively. This trial further supports other observations that foot pumps
provide less protection than other mechanical methods, at least in trauma
patients.
AUTHOR INFORMATION
Accepted for publication January 9, 2001.
Other research by Drs Ginsberg and Geerts is supported in part by pharmaceutical
manufacturers of anticoagulant agents (AstraZeneca, Mississauga, Ontario).
Dr Cook is an investigator with the Canadian Institutes of Health Research.
Dr Ginsberg is a career scientist of the Heart and Stroke Foundation of Ontario.
Dr Douketis holds a research scholarship from the Heart and Stroke Foundation
of Ontario and the Canadian Institutes of Health Research.
Corresponding author and reprints: John Attia, MD, PhD, Centre for
Clinical Epidemiology and Biostatistics, Level 3, David Maddison Bldg, Royal
Newcastle Hospital, Newcastle 2300, Australia.
From the Departments of Medicine (Drs Attia, Ray, Cook, Douketis, and
Ginsberg) and Clinical Epidemiology and Biostatistics (Drs Attia, Ray, and
Cook), McMaster University, Hamilton, Ontario; and Departments of Medicine
and Health Administration, University of Toronto, Toronto, Ontario (Dr Geerts).
Dr Attia is now with the Centre for Clinical Epidemiology and Biostatistics,
University of Newcastle, Newcastle, Australia.
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4. Saeger W, Genzkow M. Venous thromboses and pulmonary embolisms in post-mortem series: probable
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