By Paauw, James D Borders, Heather; Ingalls, Nichole; Boomstra, Sarah; Lambke, Susan; Fedeson, Brian; Goldsmith, Austin; Davis, Alan T
Background: Indications for peripherally inserted central catheters (PICC) for long-term venous access have grown dur- ing the last several years. There are various complications associated with PICC lines, a common one being venous thrombosis. This study’s purpose was to determine the inci- dence of venous thrombosis associated with PICCs with and without prophylactic anticoagulants. Methods: In this observa- tional, prospective, cohort study, patients with PICC lines were evaluated using Doppler ultrasound for the presence of PICC-associated venous thrombosis at 5-7 days and again at 12-14 days after line placement. When present, clinical signs and symptoms of thrombosis were documented. Fifty-six patients were evaluated for the type of anticoagulation used, if any, and other clinical parameters such as smoking, ambula- tion, and previous surgery. The incidence of thrombus was then calculated for the entire population as well as for specific patient subgroups. Results: Patient age was 55.7 +- 2.6 (mean +- SEM) years, and BMI was 28.2 +- 1.2 (n = 56). There were 38 (67.9%) nonambulatory subjects, 15 (26.8%) smokers, 4 (7.1%) coagulopathic subjects, 2 (3.6%) patients receiving estrogen-containing medications, 25 (44.6%) who had undergone surgery within the past 6 months, and 5 (8.9%) cancer patients. There were 21/56 patients (37.5%) with thrombus. Patients who received anticoagulation had a 22.9% (8/35) incidence of thrombosis, which was significantly less (P
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.
Summary statistics for quantitative data are described as the mean +- SEM, while nominal data are expressed as a percentage. The t test was used to determine differences for quantitative variables, while the chi^sup 2^ test was used to determine differences for the nominal variables. Significance was determined at P
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.
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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
Financial disclosure: none declared.
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.
Received for publication June 11, 2007; accepted for publication January 25, 2008.
Address correspondence to: Alan T. Davis, PhD, Michigan State University, GRMERC, 1000 Monroe NW, Grand Rapids, MI 49503; e-mail: [email protected]
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