By Paauw, James D Borders, Heather; Ingalls, Nichole; Boomstra, Sarah;
Lambke, Susan; Fedeson, Brian; Goldsmith, Austin; Davis, Alan T
The placement of a peripherally inserted central catheter (PICC) for
central venous access came into common usage in the mid 1970s and has
expanded dramatically since then.1-3 However, no recent survey data
are available on the volume of PICC placement nationwide. Because of
the variable success rate and relatively high malposition rate (25%)
associated with “blind” bedside PICC insertion,4 ultrasound-guided
PICC insertion services have been established at many institutions,
further enhancing the popularity of PICC usage. This popularity has
come at the expense of other central venous catheter (CVC) techniques,
such as subclavian or jugular and tunneled centrally inserted central
catheters (CICC), due to the perceived advantages of PICCs. These
advantages include ease of placement, greater cost-effectiveness, and
safety.3-6
With regard to safety, however, there is some controversy. While
virtually eliminating the risk of pneumothorax associated with CICCs,
the use of PICCs has raised the question of associated incidences of
venous thrombosis. The clinical significance of PICC- related upper
extremity venous thrombosis (PRUEVT) is manifested by the risk of
pulmonary embolism associated with CVC-related upper extremity venous
thrombosis, which may be about 12%-17%.7 The incidence of PRUEVT has
been reported to be anywhere between 0% and 56%.8-11 The wide variance
in reported incidences is likely impacted by the heterogeneity of
study conditions, including diagnostic technique, prospectivity, and
whether assaying for clinically symptomatic or “silent” PRUEVT.
Another question related to PRUEVT is the preventability of this
entity. Few studies have assessed the efficacy of prophylactic
anticoagulant therapy on the prevention of PRUEVT. In a retrospective
study, prophylactic use of unfractionated heparin or low molecular
weight heparin did not significantly reduce the incidence of venous
thrombosis in patients with either PICCs or CICCs.12 Conversely, a
meta-analysis has found that the use of prophylactic low-dose heparin
results in a significant reduction in CICC-related and arterial
catheter- related upper extremity venous thrombosis.13 In this light,
we conducted a prospective study of the incidence of silent PRUEVT and
the efficacy of prophylactic anticoagulant therapy in the prevention
of PRUEVT in patients with ultrasound-guided PICC placement.
Prophylactic anticoagulant therapy, as used in this study, does not
refer to routine line maintenance, such as flushing with heparin or
the use of positive- pressure needleless adapters.
This prospective, observational cohort study was performed at Spectrum
Health Butterworth Campus, Grand Rapids, MI. Written informed consent,
approved by the local institutional review board, was obtained from
all subjects prior to entry into the study. In- patients who required
PICC lines for central venous access were selected for inclusion in
the study. The PICC lines were used to deliver parenteral nutrition
and/or antibiotics. Any patients with known coagulopathies were
excluded.
Insertion of the catheter followed the protocol for PICC insertion per
the Interventional Radiology Department of our institution. AU PICC
lines were 5 Fr double lumen. Subjects were evaluated by ultrasound
for the presence of associated venous thrombosis at 5-7 days and again
at 12-14 days after PICC placement. A GE ultrasound machine (Logiq 9;
GE Healthcare, Wauwatosa, Wis) and an 8 MHz linear probe were used.
The vessel containing the PICC was evaluated, as were the axillary and
lateral subclavian veins, using graded compression ultrasound and
color flow Doppler imaging when necessary. A number of patients were
found to have only a small rim of thrombus around the insertion site
with no anterograde propagation of the thrombus or luminal compromise.
These thrombi were classified as insertional trauma, and the patients
were counted as thrombus-negative for study purposes. Only those
patients with thrombus extending antegrade from the insertion site for
at least 2 cm were counted as positive for study purposes. Clinical
signs and symptoms of thrombosis were also documented when present.
Patients were evaluated for the type of anticoagulation used, if any,
as well as for other clinical parameters such as smoking, ambulation,
and previous surgery. The incidence of PRUEVT (%) was then determined
for the study sample as a whole, as well as for specific subgroups of
patients.
Evaluable data were obtained for 56 subjects. The data are described
in Table 1 . With regard to the demographic and clinical descriptors,
there were no statistically significant differences between the 2
groups. There were 21 patients (37.5%) with a PICC line who had
thrombus. All PICCs were in the basilic vein, and all catheter-related
thrombi began at or immediately adjacent to the vessel insertion site
and propagated centrally. A statistically significant increase in the
incidence of PRUEVT was noted for the patients with no
anticoagulation, relative to those subjects receiving some form of
anticoagulation. No significantly increased incidence of PRUEVT was
associated with any of the other clinical or demographic variables. At
least 1 patient with PICC-associated thrombus developed a pulmonary
embolus, which was shown to be PICCrelated by 4-extremity Doppler
ultrasound and the presence of an inferior vena cava filter.
Venous thrombosis is a well-known complication of CVC placement, but
the actual incidence is not well defined. Reported incidences vary
greatly depending on a number of factors, including venous location,
length of dwell time, type of patient, and method of assay. In a
review of studies of long-term, mostly tunneled CVCs in cancer
patients, the reported incidence of clinically overt upper extremity
deep vein thrombosis (DVT) varied between 0.3% and 28.3%. When studied
by venography, the reported incidence rose to between 27% and 66%,
most of which were asymptomatic.14 Reported incidences of venous
thrombosis related to short-term, nontunneled CVCs also vary widely.
In a study of 142 single lumen catheters using Doppler ultrasound or
venography in patients with clinically suspected venous thrombosis,
none was detected.15 However, in another study of single lumen and
double lumen short-term CVCs using routine digital subtraction
angiography on the seventh catheter day, the incidence of central
venous thrombosis was found to be 40%, despite use of subcutaneous
heparin at a daily dose of 5000 units.16 In this report, the number of
lumens did not affect the development of thrombosis. Short-term
catheterization of the internal jugular vein seems to carry one of the
highest risks for venous thrombosis. Despite prophylactic
anticoagulation, Doppler ultrasound demonstrated a 56% incidence of
thrombus by day 4 in cardiac surgery patients.17 In a similar study of
63 consecutive critical care patients with internal jugular CVCs, all
receiving either low-dose or therapeutic heparin, 40 patients (63.5%)
were found to have venous thrombosis.18
Table 1 . Patient Data(a) It is generally accepted that PICCs, because
they are placed in a smaller caliber vessel than CICCs, are more
thrombogenic due to altered flow dynamics. In general, venous
catheters cause the release of thromboplastic substances from
catheter-associated intimai damage. These substances, in turn,
activate the coagulation cascade, which leads to intraluminal thrombus
formation. There are a number of suggested causative factors in
catheterrelated thrombosis. These include vessel wall insertional
trauma,19 endothelial abrasion due to IV catheter movement,20 and
venous flow occlusion due to large catheter size relative to lumen
size.20 One study using multivariate analysis directly linked PICC
diameter to thrombosis rate.21 Symptoms of venous thrombosis,
including localized redness, swelling, and pain, should prompt
clinicians to initiate diagnostic studies to evaluate for PRUEVT.
However, as was the case in this study, the majority of upper
extremity PICC-related thrombi remain asymptomatic, delaying diagnosis
of this entity. The true incidence of PRUEVT remains elusive, as many
studies to date have evaluated only symptomatic patients with imaging
or have used a retrospective method. These approaches lead to an
underreporting of the incidence of PRUEVT. As a result, reported
incidence varies widely by institution and by medical and clinical
patient parameter 1-3,6,8-10,22 The higher incidence of PRUEVT in more
recent retrospective studies is likely due to the liberal use of
duplex Doppler ultrasound scanning as a result of increased awareness
of the entity. The variance in reported incidence of PRUEVT led us to
undertake a prospective survey approach in order to determine more
accurately the actual incidence of PRUEVT in a hospital patient
population.
The gold standard for evaluating PRUEVT is venography, which is
invasive, costly, and involves the risk of IV contrast as well as a
measure of physical discomfort. As a consequence, ultrasound is
currently the more accepted technique for diagnosis of PRUEVT. The
main criteria used in Doppler ultrasound for PRUEVT are mural thrombi
or incompressibility of the vein, absence of spontaneous flow or
presence of turbulent flow, lack of transmission of cardiac
pulsatility, and observation of increased venous collaterals.14 The
accepted standard to exclude the presence of thrombosis is 2 negative-
compression ultrasound studies 1 week apart, as was used in the
present study.1,23,24
Previously, use of minidose warfarin has been shown to reduce the
incidence of CVC-related thrombosis in patients with hematological
malignancies.2,26 In the former study, upper li mb DVT was reduced
from 37.5% to 9.5%. In a prospective study, daily daltoparin 2500
units for 30 days reduced the incidence of venography-confirmed upper
limb DVT from 62% in controls to 6% in the treatment group in cancer
patients.27 A meta-analysis of randomized, controlled trials in CVC
patients showed an overall efficacy by heparin in prevention of
thromboembolic complications.28 Studies from this analysis included
the use of various doses of subcutaneous heparin, heparin added to
parenteral nutrition, and heparin bonding of catheters. In a
comparison of minidose warfarin and low molecular weight heparin
(nadroparin) in cancer patients, 28.6% of the nadroparin group and
16.7% of the warfarin group had venography-confirmed CVC-related DVT
at 90 days.29 A systematic review of studies of thrombosis prophylaxis
in CVC patients showed warfarin and dalteparin did reduce this risk in
cancer patients, while the addition of heparin to parenteral nutrition
did not significantly decrease thrombosis risk from CVCs.30 The
studies included in this review focused on CVCs of subclavian,
jugular, and femoral insertion sites, but not PICCs.
The current study found that prophylactic anticoagulation served to
significantly decrease the incidence of PRUEVT, and thus the
associated potential secondary complications. Complications of
prophylactic anticoagulation, such as bleeding or heparin-induced
thrombocytopenia (HIT) were not seen in any of the patients in this
study. The study is unique in that it prospectively evaluated all
patients with PICCs, thereby reflecting a more accurate PRUEVT
incidence rate than previous retrospective or symptomatic-only
studies. In addition, most previous studies of catheter-related venous
thrombosis focused on a significantly longer dwell time than the
current study. To date, there has been little suggestion in the
literature of a significant incidence of PRUEVT at the early time
period noted in this study.
This study has demonstrated that the true incidence of PRUEVT is
considerably higher than has been previously reported.1-3,6,8-10,22
Routine ultrasound surveillance allowed for a more accurate measure of
the actual extent of thrombotic disease associated with the use of
PICCs. Another unforeseen finding in this study was a higher than
expected incidence of PRUEVT in patients receiving prophylactic
anticoagulation. Routine prophylactic anticoagulation of hospital
patients is considerably more effective at preventing DVT of the lower
extremities than it is in preventing PRUEVT.6,8,11-13 For example, the
Medenox study of prophylaxis of venous thromboembolism in medical
patients showed that the administration of daily enoxaparin reduced
asymptomatic DVT from 14.5% to 5.5%,31 while in the PREVENT study, the
incidence of DVT was reduced to 2.77% (from 4.96%) by 5000 units of
dalteparin.32 The relatively weaker efficacy of prophylaxis in
preventing PRUEVT relates to at least 3 factors involved in promoting
PRUEVT. The first has been mentioned earlier, in that PICC placement
causes catheter-related intimai damage, which is not usually a factor
in the development of DVT in the lower extremities. The second, also
previously alluded to, is the smaller vessel lumen diameter in the
arm, with different flow mechanics than the larger vessels of the leg.
Finally, the presence of an indwelling catheter not only compromises
the volume of the vessel but presents a nidus for propagation of a
clot.
The correlation between the high incidence of Doppler-proven PRUEVT
reported here and its more serious potential sequelae, such as
pulmonary embolism (PE), infected thrombus and associated sepsis, and
postphlebitic syndrome, cannot be determined from the current study.
The incidence of clinically observable PE associated with upper
extremity venous thrombosis is estimated at about 12%,8,33,34 and is
likely between 15% and 25% in cancer patients. 3,36 The incidence of
PE was found to be greater from catheter-related upper extremity DVT
(17%) than from primary DVT of the upper extremity (6%).36 This risk
is lower than the accepted 50% risk of PE from lower extremity DVT for
reasons reviewed elsewhere.36 It nonetheless represents a significant
clinical risk, given the increasing number of hospital patients
receiving PICCs and the high risk of early PRUEVT reported in this
study.
Aside from the acute risk of thrombosis, there is a more chronic
complication associated with PRUEVT known as postphlebitic syndrome.
This syndrome is caused by valvular injury and outflow obstruction, is
characterized by pain, chronic limb edema, functional impairment of
the limb, and skin ulcerations. In 1 prospective study, 4 out of 1 5
patients followed for 2 years after diagnosis of upper extremity
venous thrombosis demonstrated the presence of moderate to severe
postphlebitic syndrome.7 Further investigation is needed to elucidate
the actual risk of this entity and other serious sequelae from PRUEVT.
Anecdotally, while only one patient in this study was documented to
have a PE, that patient was 1 of 3 patients of whom the authors were
made aware during the course of the study who developed PRUEVT-
related PE. The other patients had not been entered into the study.
Each patient had an inferior vena cava filter in place, and PRUEVT-
related PE was established by 4-extremity ultrasound.
Although the sample size is relatively small, this study suggests that
the use of prophylactic anticoagulation to reduce the risks associated
with PRUEVT outweighs the risks associated with the use of these
therapies. We feel that given the unexpectedly high incidence of early
PRUEVT in nonprophylaxed patients in this study, along with the proven
efficacy of prophylactic anticoagulation to reduce this incidence, in
the absence of contraindications, patients with PICCs should be
considered for such therapy. In patients in whom anticoagulation is
contraindicated or who are at higher risk than the general population
for thromboembolic disease, consideration should be given to placement
of subclavian CVCs instead of PICCs. Moreover, the 23.5% incidence of
PRUEVT in the face of prophylactic anticoagulation should lead
clinicians to have a low threshold for the use of Doppler ultrasound
in patients with PICCs with even early signs of thrombosis.
3. Ng PK, Ault MJ, Ellrodt AG, Maldonado L. PICCs in general medicine.
Mayo Clin Proc. 1997;72:225-233.
4. Cardella JF, Cardella K, Bacci N, Fox PS, Post JH. Cumulative
experience with 1273 peripherally inserted central catheters at a
single institution. J Vasc Interv Radiol. 1996;7:5-13.
5. Loughran SC, Borzatta M. PICCs: a report of 2506 catheter days.
JPEN J Parenteral Enteral Nutr. 1995;19:1330-1336.
6. Miller KD, Dietrick CL. Experience with PICC at a university
medical center. J Intraven Nurs. 1997;20:141-147.
7. Pradoni P, Polistene P, Bernardi E, et al. Upper-extremity deep
vein thrombosis: risk lactors, diagnosis, and complications. Arch
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8. Paz-Famagalli R, Miller YA, Russell BA, Crain MR, Beres RA, M
ewissen MW. Impact of peripherally inserted central catheters on
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11 . Chemaly RF, de Parres JB, Rehm SJ, et al. Venous thrombos is
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18. Karnik R, Valentin A, Winkler W-B, Donath P, Slany J. Duplex
sonographic detection of internal jugular venous thrombosis after
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25. Bern HM, Lokich JJ, Wallach SR, et al. Very low dose of warfarin
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central venous and pulmonary artery catheters: a metaanalysis of
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29. Mismetti P, Mille D, Laporte S, et al. Low-molecular-weight
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34. Marie I, Levesque H, Cailleaux N, et al. Deep vein thrombosis of
the upper limbs: apropos of 49 cases. Rev Med Interne.
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35. Monreal M, Raventos A, Lerma R, et al. Pulmonary embolism in
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36. Kooi JD, vander Zant FM, van Beek EJ, Reekers JA. Pulmonary
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James D. Paauw, MD, PhD1; Heather Borders, MD2; Nichole Ingalls, MD3;
Sarah Boomstra1; Susan Lambke4; Brian Fedeson, MD2,4; Austin
Goldsmith, MD3; and Alan T. Davis, PhD3,5,6
From 1 Spectrum Health Metabolic Nutrition Support Service, 2
GBMERC/MSU Radiology Residency, 3 GRMERC/MSU General Surgery
Residency, 4 Spectrum Health Interventional Radiology Service, 5
Departments of Surgery, Michigan State University and Spectrum Health,
and 6 GRMERC Department of Research, Grand Rapids, MI.
Address correspondence to: Alan T. Davis, PhD, Michigan State
University, GRMERC, 1000 Monroe NW, Grand Rapids, MI 49503; e-mail:
davisa@msu.edu.
Oct 1, 2008, 5:59 am Oct 1, 2008, 5:57 am Oct 1, 2008, 5:50 am Oct 1,
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