Rachel P. Rosovsky
David J. Kuter
Central venous catheters (CVCs) have become an integral part of treating patients both in and out of the hospital. They allow for easy administration of medications and uncomplicated withdrawal of blood samples. In cancer patients, who often require long-term chemotherapy, these devices have become the standard of care, and their use is increasing steadily every year. Unfortunately, these instruments are also associated with adverse events, most commonly, mechanical, infectious, and thrombotic complications. Recent research has focused on identifying the risk factors for and incidence, prevention, and treatment of these complications. Several studies have shown, for example, that antimicrobial-impregnated catheters can lower the risk of infection and decrease medical costs.1, 2, 3 Unfortunately, only a few randomized or controlled studies involving CVCs and thrombosis exist, and results from these studies are often inconsistent and controversial.4, 5, 6, 7, 8, 9, 10 Additional studies are clearly needed to help guide the optimal management of these complications.
This chapter reviews central venous catheters. We briefly mention the types of instruments available as well as the major indications for their usage. The majority of the review will focus on the complications of CVCs, most notably infectious and thrombotic. We will discuss the risk factors, the strategies for prevention, the current options for treatment, and new developments.
The history of the central venous catheter dates back to 1656 when Christopher Wren (1632–1723) administered wine and ale to living dogs via an intravenous cannula. He describes in his writings how the animals became somnolent or vomited after being injected with alcoholic substances, opiates, or purgatives.11,12, 13, 14, 15, 16 Wren's colleagues performed subsequent experiments with venous catheters involving the transfusion of blood products between animals and humans.17 Unfortunately, some of these studies resulted in the death of either the animal or human. This outcome halted interest in and further investigation of venous cannulae for a number of centuries.
It was not until 1952, when Aubaniac described cannulating the subclavian vein of a wounded soldier for the purpose of resuscitation, that interest in the clinical uses of CVCs was renewed.18, 19, 20 Fortunately, this attention led to the development of better technology, and over the past 30 years a number of devices for the semipermanent cannulation of the central venous system have been introduced. In 1973, Broviac developed the first long-term CVC for parenteral nutrition.21 This was followed by the Hickman catheter in 1979, the first permanent venous-access device used for cancer chemotherapy.22 Totally implantable venous access devices (Fig. 23.1), ones that are placed subcutaneously and contain their own ports attached to a centrally placed catheter, became available in the early 1980s.23 The most recent advancement has been the peripherally implanted central catheter (PICC).24
Figure 23.1 Cutaway photo of Port-a-Cath implantable port showing the injection site, reservoir, and attached catheter. (Courtesy of Smith Medical MD, Inc. St. Paul, Minnesota.)
A wide variety of CVCs are currently available (Table 23.1). There are a number of short-term devices, including percutaneous lines and peripherally inserted central catheters (PICCs), that are usually employed for less than one month's duration. Alternatively, long-term catheters can remain in place for months to years; these include the surgically tunneled catheters described above (the Broviac and the Hickman, as well as, more recently, the Groshong and the Quinton) and the totally implanted venous access devices that contain their own port (the Mediport, the Infuse-a-Port, and the Port-a-Cath) (Figure 23.1). There are several standard techniques presently practiced for the insertion of a CVC.25 The choice of catheter and the insertion strategy depend on a number of variables, most importantly the indication for its usage. However, patient characteristics, including any history of failed attempts, previous surgeries, comorbidities, skeletal deformities, and scarring, also need to be accessed.26
Central venous catheters have become essential for the management of cancer patients. In the United States, more than 5 million CVCs are inserted every year.27 They not only allow for intravenous administration of drugs, antibiotics, blood products, fluids, and nutrition but also facilitate easy drawing of blood samples to monitor for potential complications of treatments and disease. Eliminating frequent venipunctures clearly increases a patient's level of comfort. Whether the use of CVCs translates into extending life or improving quality of life is currently being investigated.28
TABLE 23.1 TYPES OF CENTRAL VENOUS CATHETERS
TABLE 23.2 INCIDENCE OF COMPLICATIONS OF CENTRAL VENOUS CATHETERS
Unfortunately, CVCs are associated with a number of early and late complications (Table 23.2), which can be both harmful to the patient and costly to treat. Most of the mechanical complications occur during the insertion process, although many of the infectious and thrombotic complications occur after the catheter has remained in place for some time. The reported incidence of catheter-related complications varies greatly among different studies, largely due to the different study designs, diagnostic protocols, and patient population.
Types of Early Complications
Arrhythmias occur in up to 13% of patients and are one of the most common complications that happen during or immediately after the insertion process; however, they are usually self-limiting and rarely cause hemodynamic instability. Most of the other early adverse events are mechanical in nature, with an incidence range of 1 to 20%.17, 27 The most commonly reported ones are a venous tear, arterial puncture, or cannulation, which can then cause a hematoma or dissection, or a lung or pleural laceration, which can result in a pneumothorax (Figure 23.2) or hemothorax.18, 26, 29 Injury to adjacent nerves or anatomic structures can also occur during the insertion process. Catheter malposition or breakage can occur early or late, as can a rare but potentially lethal complication, an air embolus.18, 25, 27 The incidence of failed attempts has been reported to be as high as 5%. Lastly, there are a few case reports of the serious and occasionally fatal complication of cardiac tamponade.30 Postinsertion care must include a chest x-ray to confirm the correct position of the catheter and the absence of injury to the vessels, lung, and pericardium.
Figure 23.2 Pneumothorax, a potential early complication of CVC. (Courtesy of the Interventional Radiology Department, Brigham and Women's Hospital, Boston, MA.)
Risks for Early Complications
The risk factors for the early mechanical complications are directly related to the site of CVC insertion as well as patient and catheter-related factors.18, 29 For the percutaneous devices, the frequency of mechanical complications such as hematoma or infection is higher with a femoral approach than with a subclavian or internal jugular approach.18, 29 However, if one only looks at the serious complications, the femoral and subclavian rates are similar.27, 29
The type of material used for catheters and the time of their insertion also confer certain risks. Stiff CVCs are easier to insert but have a higher rate of mechanical complications.18 When the insertion procedure for short-term percutaneous catheters is performed after hours, the complication rate is higher.29,31 Lastly, thrombocytopenia, altered local anatomy, prior catheterization, recent myocardial infarction, severe obesity, and atherosclerosis are a few of the patient-related factors that can also increase the risk of adverse events.18
Prevention of Early Complications
There are a number of strategies one can utilize to reduce the risks of early complications. Perhaps the most important one is to know the patient and to determine the best insertion technique based on that patient's anatomy, comorbidities, and other characteristics. Prior surgeries or radiotherapy in the clavicular region, for example, may cause an alteration in the anatomy or surface landmarks used to locate a vein. Therefore, the contralateral side should be the preferred location in these patients.
Another preventive approach includes the use of ultrasound to aid in localizing the vessel to be cannulated. Ultrasonography decreases the risks associated with an internal jugular vein catheterization but does not clearly benefit the subclavian vein approach.32 Obviously, the more experienced the physician, the less risk of a complication. One study showed that after three attempts, the incidence of mechanical complications increased to six times the rate after one attempt.26, 33
As important as these pre-procedure strategies is the ability to recognize and treat complications. For example, an air embolus can usually be prevented by placing the patient in Trendelenburg's position during the insertion process and occluding the catheter hub at all times. However, if an air embolus is suspected or occurs, immediately placing the patient in this position and administering 100% oxygen can facilitate the resorption of air and prevent a potentially fatal outcome.27
LATE COMPLICATIONS: GENERAL
Types, Risks, and Prevention of General Late Complications
Infection and thrombosis are the most common late complications associated with CVCs, and they will be discussed separately. The other late complications occur at a rate of 3 to 8%.17 CVC breakage can develop if defective material is used or if excessive manipulation is applied during the insertion process. CVCs also break due to a phenomenon associated with subclavian catheters termed the “pinch-off syndrome.” Because the subclavian catheter is situated between the clavicle and the first rib, over time repeated compression can cause the catheter to fracture, resulting in extravasation of fluids, catheter breakage, and catheter embolization.18, 25 Extravasation of fluid also develops with CVC dislocation, malposition, or damage. Several other late complications also sometimes occur, though infrequently; these include arteriovenous fistulas, cerebrovascular accidents, cardiac aneurysms, and intracardiac abscesses.18 Lastly, there are additional difficulties associated with CVC removal, but these are beyond the scope of this review.
The strategies to reduce the risks of late complications are similar to the ones presented in the section on early complications. One specific strategy to prevent the pinch-off syndrome is important to mention, however. Utilizing a more lateral approach or an alternative insertion site is recommended, especially in patients with known narrow thoracic inlet syndrome.25
LATE COMPLICATIONS: THROMBOSIS
Types of Thrombosis
Fibrin Sheath Formation
Several types of thrombi can occur with CVCs. Fibrin sheaths, or sleeve thrombi, form on the outside of catheters. They are ubiquitous, according to both autopsy and imaging studies, but rarely cause any difficulties unless they occlude the tip of the catheter.34, 35, 36, 37
Although the time of formation of the fibrin sheath has not been adequately studied, data from several studies suggest that the sheath develops within 24 hours of catheter insertion.35 Furthermore, electron microscopy and quantitative microbiologic testing of these fibrin sheaths show that they are always colonized by cocci.38, 39, 40
The presence of a sheath, however, does not predict subsequent deep venous thrombosis (DVT) of the vessel in which the catheter is placed. In one study, only 1 of 16 patients with a fibrin sheath developed thrombosis over a median of 12.5 months.34 Furthermore, embolization of the fibrin sheath is uncommon and rarely symptomatic because of the small volume of the embolus.41
A very common and underreported event is the development of clotting within the lumen of the catheter.42, 43, 44 This event is often uncovered when the catheter fails to allow blood to be withdrawn or fails to allow infusion through a port. The frequency of catheter clotting varies widely among different studies. Anderson et al. reported 40 of 43 patients (93%) had this complication. In a large study by Schwarz et al, 122 out of 923 patients (13.2%) had this problem, for a frequency of 0.81 events per 1,000 catheter days, a rate comparable to the 0.6 per 1,000 catheter days reported by Ray.42, 44, 45 These intraluminal thrombi can be lysed in most situations (80 to 95%) with local infusion of fibrinolytic agents such as urokinase, streptokinase, or tissue plasminogen activator.46, 47
The inability to withdraw blood (“ball valve effect”) does not, however, correlate with the presence of intraluminal thrombosis. In a study by Gould et al., 57% of thrombosed CVCs versus 27% of nonthrombosed CVCs failed to allow withdrawal of blood.48 When the CVCs that had problems with blood withdrawal were analyzed by venography, 58% were thrombosed but 42% were not,49 leading to the conclusion that nonthrombotic mechanical problems commonly prevented blood flow.
Central Venous Catheter-Related Blood Vessel Thrombosis (Deep Venous Thrombosis)
Catheter-related DVT is the most challenging thrombotic complication associated with long-term CVCs. These mural thrombi may partially or completely block the blood vessel, and their reported incidence from several prospective and a limited number of retrospective studies ranges from 5 to 75%.17, 50 The wide variability is due, in part, to the variation in the catheter type, the position, the duration of insertion, and the underlying disease. In addition, there is a lack of uniform standards in defining, identifying, and reporting this sort of information.
When diagnostic tests are used to evaluate patients who present with symptoms such as erythema or numbness of the extremity, swelling or pain in the arm, neck, or head, phlegmasia, or venous distension, the reported incidence of CVC-related DVT varies from 5 to 41% (Figure 23.3).17, 50 When surveillance venography or ultrasound are used to evaluate the patient, irrespective of symptoms, the rate of CVC-related DVT ranges from 12 to 75%.17, 50
The time of onset of CVC-related DVT has been studied longitudinally in only a small number of individuals. In the most extensive study, by De Cicco et al., serial venography was done, on average, 8, 30, and 105 days after insertion of a CVC.41 Of the DVTs that ultimately developed, 64% occurred by day 8 and 98% by day 30. In another study, 98% of all DVTs occurred in the first 8 days, and in a third study, 68% occurred within the first 30 days.41, 51, 52 Further analysis of the time course of thrombus formation is essential for helping to guide future studies addressing the timing and duration of anticoagulation prophylaxis to prevent CVC-related DVT (see “Prevention and Prophylaxis of Central Venous Catheter-Related Deep Venous Thrombosis” later in the chapter).
Figure 23.3 Venous distention and swelling of the arm. (Courtesy of Rachel Rosovsky, MD.)
Risk of Central Venous Catheter-Related Thrombosis
Patient-Related Risk Factors
Several observational and prospective studies have tried to elucidate the potential risk factors that may be important in the development of DVTs in CVCs. Both patient-related and catheter-related risks exist. The mere presence of malignancy is perhaps the most important patient-related risk factor, and there is a suggestion that some types of malignancy, such as adenocarcinoma of the lung, have higher rates of catheter-related DVTs than others, such as head and neck cancer.44 This may be related to the activation of the coagulation system in these different malignancies, tumor-related changes in blood flow in the upper torso, or levels of tissue factor or tissue factor pathway inhibitor. It is probably related to the general increased risk of thrombosis that occurs in oncology patients, as has been discussed elsewhere.53, 54, 55, 56.
The type of chemotherapy also appears to influence the rate of CVC-related thrombosis. Clotting occurred in 6 of 11 catheters (55%) through which sclerosing chemotherapy was infused but in only 9 of 29 (31%) infused with nonsclerosing chemotherapy.4
Controversy exists as to whether inherited thrombophilia is a risk factor. One study suggests that low levels of antithrombin III are associated with a greater risk of thrombosis.57 Another study found that 32% of patients who had CVC-related thrombosis had a diagnosis of a hypercoagulable state; most had an elevated anticardiolipin antibody but no increase in prothrombin 20210A mutation, factor V Leiden, protein C deficiency, or protein S deficiency.58 Other studies evaluating factor V Leiden have yielded inconsistent results. Although there is a positive correlation of thrombosis with factor V Leiden in pediatric patients who have acute lymphoblastic leukemia, there are conflicting results involving adults.58, 59, 60
In addition to thrombophilic molecular abnormalities, there are acquired forms of thrombophilia that contribute to the development of clots. Venous stasis caused by an indwelling CVC and vessel damage caused by chemotherapy or by injury during the insertion process are two components of Virchow's triad that are additional contributors to this multifactorial process. The role of an elevated platelet count, however, remains controversial.4, 61
Catheter-Related Risk Factors
Catheters have undergone major design changes to reduce catheter-related complications. Polyvinylchloride and polyethylene CVCs, for example, have been replaced by the less thrombogenic silicone and polyurethane CVCs.62 In addition to the catheter material, several other features of CVCs affect their thrombotic risk. Triple-lumen catheters have been shown to carry a higher risk of thrombosis than single- or double-lumen catheters.62 Catheters inserted on the left side clot more frequently than those inserted in the right.41 Finally, the position of the catheter tip needs to be at the junction of the superior vena cava (SVC) and the right atrium.63 Placement of the catheter tip at a distal or high position in the SVC results in a higher rate of thrombosis than placement more centrally or lower in the SVC.64
Overall, CVCs are a “stress test” of the coagulation system in cancer patients and can precipitate thrombosis due to multiple mechanisms related to the host and/or to the device itself.
Complications of Central Venous Catheter-Related Deep Venous Thrombosis
A number of sequelae can potentially develop in patients with CVC-related DVT. Catheter dysfunction may be the first sign of a partially or completely occluded vessel and requires either flushing or removal and replacement of the device. This management can be expensive and can cause discomfort and anxiety for the patient. Postphlebitic syndrome occurs in 15 to 35% of patients with CVC-related DVT and can also cause discomfort for the patient in the form of chronic pain, edema, and functional impairment of the limb.17, 65
The relationship between CVC-related DVT and pulmonary emboli has been examined in a few small studies, and these reveal an incidence of pulmonary emboli in up to 25% of CVC-related DVT (Figure 23.4). These are usually asymptomatic and small and fortunately rarely fatal.66, 67, 68
Patients with CVC-related DVT are also at risk for infections. This association has been proven in a number of studies and is discussed in “Late Complications: Infection” later in this chapter.
Figure 23.4 Pulmonary embolus. (Courtesy of Samual Goldhaber, MD, Brigham and Women's Hospital, Boston, MA.)
Pathological effects of CVCs on blood vessels have also been identified, largely through autopsy studies. Hemorrhage, thrombosis, calcification, ulceration, and inflammation are found in a greater number of cannulated blood vessels than in those that are not cannulated.69
Diagnosis of Central Venous Catheter-Related Deep Venous Thrombosis
Although contrast venography is considered the “gold standard” for diagnosing CVC-related DVT, it is expensive and invasive and requires contrast agents. Consequently, ultrasound with Doppler and color imaging is often used instead. The criteria used to diagnose a DVT by ultrasound include the absence of spontaneous flow or the presence of turbulent flow, abnormal waveforms peripheral to an occluded segment that do not vary with respirations or cardiac pulsations, and visualization of a thrombus or inability to compress the vein.
Studies evaluating the efficacy of ultrasound in the diagnosis of suspected upper-extremity DVTs report sensitivities of 54 to 100% and specificities of 94 to 100%.70 It is unfortunate that there are only a limited number of studies that directly address the accuracy of ultrasound in diagnosing suspected CVC-related DVT. Koksoy et al. studied 44 patients with CVC-related DVT and found that color Doppler ultrasound had a sensitivity and specificity of 94% and 96%, respectively.71 Of importance, the sensitivity of duplex ultrasound decreases significantly when used in the asymptomatic patient.
Two factors that influence the sensitivity of ultrasound are the location of the clot and the presence of the catheter. Clots located in the jugular, axillary, or subclavian veins are picked up more frequently than those located in the innominate or superior vena caval veins.72 In addition, the presence of a catheter can alter not only the venous tone but also the venous flow, making it more difficult to interpret findings visualized on ultrasound.
Newer diagnostic tools currently being investigated include magnetic resonance venography and spiral computed tomography. Preliminary studies show promising results with these newer modalities; however, randomized trials are necessary to compare them with the current standard of venography.73, 74
In practice, color Doppler ultrasound is the first tool to use in diagnosing suspected CVC-related thrombosis. If a negative result is obtained and the clinical suspicion is high, however, additional testing with serial ultrasounds or venography is warranted. Diagnosing asymptomatic clots remains a challenge and has uncertain importance clinically.
Treatment of Central Venous Catheter-Related Deep Venous Thrombosis
Due to the lack of prospective or comparative studies, there are currently no standard guidelines for the treatment of CVC-related DVT. Consequently, patients with this complication are treated in a manner similar to those patients with lower-extremity DVT. Unfractionated heparin (UFH) or low molecular weight heparin (LMWH) is given for 5 to 7 days, and then patients are continued on Coumadin. Recent studies favor LMWH because it seems to be as effective as UFH and can be given as an outpatient treatment.75 In addition, cancer patients may derive greater benefit from LMWH than from warfarin.76 Pentasaccharides and oral direct thrombin inhibitors have not yet been studied in this situation. The optimal duration of anticoagulation is unknown. Most studies show that 6 months is effective; however, patients with active cancer may benefit from indefinite use. Please refer to Table 23.3 for the authors' approach to the treatment of CVC-related thrombosis.
Two other more aggressive options—systemic thrombolysis and thrombectomy—have not been studied in a randomized fashion and, as a result, are not practiced routinely. In addition, the issue of whether to remove a functional but partially clotted catheter has not been extensively studied and remains controversial. Inserting another catheter is costly and associated with increased morbidity.
If a patient has a contraindication to anticoagulation therapy, then a superior caval vein filter can be placed. This filter has the potential to prevent subsequent complications with CVC-related DVT, such as a pulmonary embolus or superior vena cava syndrome.77 The long-term consequences, however, must be taken into account when considering the use of such devices. The authors believe that their use is rarely indicated.
If the thrombus is located at the tip of the catheter or within its lumen, then local measures are effective. Low-dose thrombolytic therapy—for example, low doses of alteplase, urokinase, or streptokinase given locally as a bolus or infusion—has been shown to restore patency in most patients.78 Occasionally, patients will need repeated boluses to achieve flow.
The optimal way to treat CVC-related DVT is to try to prevent it from occurring in the first place. Much controversy exists as to the best way to accomplish this, and there are ongoing studies addressing this issue.
TABLE 23.3 TREATMENT OF CENTRAL VENOUS CATHETER–RELATED DEEP VENOUS THROMBOSIS
Prevention and Prophylaxis of Central Venous Catheter-Related Deep Venous Thrombosis
The complications associated with CVC-related thrombosis may cause significant morbidity and occasional mortality in patients, and as a result there have been major efforts to identify mechanisms to decrease this risk. Not only are biomaterials (polymers and plasticizers) of low thrombogenicity currently being used, but there are ongoing studies to evaluate the benefit of impregnating catheters with antithrombotic substances such as heparin–antithrombin III.79 Early attempts to impregnate catheters with UFH resulted in rapid leaching from the catheter surface. Recent attempts, however, use a more successful bonding procedure. In addition, catheter designs have been developed to optimize blood flow around the catheter.
The most common procedure used to reduce CVC-related thrombosis is the routine flushing of catheter ports with UFH or other substances. Flushing occurs routinely, from once weekly to thrice weekly. Studies have shown that a 50-unit UFH flush is as effective as a 1,000-unit UFH flush.80 Surprisingly, recent studies show that a simple saline flush is as effective as a 100-unit UFH flush in preventing thrombi.81
The most controversial strategy for decreasing the thrombotic risk associated with CVCs in cancer patients is to use low-dose warfarin, LMWH, or UFH for the purpose of systemic prophylactic anticoagulation. Most of the early studies suggested that low-dose warfarin or LMWH was effective in preventing CVC-related DVTs, whereas the majority of the later studies have suggested the opposite.
Early Prophylactic Anticoagulation Studies
The first study to demonstrate efficacy with low-dose warfarin was a randomized, open-labeled, prospective trial in 1990. Bern et al. compared 1 mg of warfarin given to 42 cancer patients and placebo given to another 40 cancer patients. They evaluated all patients with venography at either 90 days or before if symptoms developed. Total catheter-related DVT rates were 9.5% in patients who received warfarin versus 37.5% in those who received placebo.4
The next study to show a benefit from systemic anticoagulation was performed in 1996 by Monreal et al. Similar to the Bern study, it was a randomized, open-label, prospective study of 29 cancer patients and required mandatory venography at 90 days or prior if symptoms developed. The researchers found that only 1 of 16 (6%) of the patients who received dalteparin (2,500 U daily) developed a DVT, as compared with 8 of 13 (62%) of the patients who received no treatment.9 Because of the highly statistically significant difference in outcome (P = .02), accrual to this study was closed early.
A third study, performed by Boraks et al., obtained similar results regarding the efficacy of anticoagulation prophylaxis. This nonrandomized study compared 108 patients with hematological malignancies who received 1mg of warfarin prophylactically to a historical control group. Unlike the Bern and Monreal studies, patients were evaluated with venography only if symptoms suspicious for DVT developed. Symptomatic DVTs were discovered in 5% of the treatment group as compared with 13% of the control group. Interestingly, the time to clot development also differed in the two groups. DVTs appeared in the treated group after an average of 72 days versus 16 days in the patients who were not treated.5
Subsequently, a number of other studies have been performed to assess the utility of low-dose warfarin prophylaxis. Three have shown a probable benefit but of borderline statistical significance, due to the small number of patients studied. In a prospective, nonrandomized study, 1 mg of warfarin resulted in no CVC-related DVTs in 52 patients (0%), versus 4 of 65 CVC-related DVTs (6%) in patients not receiving warfarin (P = .06).82 In a retrospective, nonrandomized study, symptomatic CVC-related DVTs developed in 4 of 96 patients (4%) treated with 1 mg of warfarin but in 24 out of 209 patients (11%) who received no warfarin (P = .04).83 Of 949 patients with Quinton-type catheters who received 1 mg warfarin per day, the clinical DVT rate was 5.1%, and clinical complications were not apparent.10
Old Guidelines and Barriers to Prophylactic Anticoagulation
Based on the earlier positive studies, detailed above, guidelines from the Sixth American College of Chest Physicians (ACCP) Conference on Antithrombotic Therapy in 2000 stated that warfarin (1mg/day) and LMWH (administered once a day) are valid prophylactic options for CVCs.84–86 Despite these recommendations, less than 10% of patients with CVCs received systemic prophylaxis.82 There are multiple reasons for this infrequent use of anticoagulation, including a lack of appreciation of the problem among health care providers; the absence of large, randomized, placebo-controlled trials; and concerns regarding the safety of anticoagulation use.
The early studies evaluating the efficacy of systemic prophylaxis suffered from several limitations: they included small numbers of patients studied, they had high dropout rates, most failed to use venographic endpoints, and most were not placebo-controlled.
A genuine concern about the bleeding risk of systemic anticoagulation in potentially thrombocytopenic or anorectic chemotherapy patients was another reason for the lack of routine systemic prophylaxis for CVCs. Ten percent of the patients in the study by Bern4 developed a prothrombin time greater than 15 seconds and required holding of their warfarin; 5% of the patients in the study by Boraks5 developed a prothrombin time greater than 20 seconds and required holding of their warfarin.
The heparins also have some disadvantages that possibly contributed to their low rate of usage. There is the major inconvenience of daily subcutaneous injection of UFH or LMWH, as well as the high cost of the latter. Also in the asthenic or elderly cancer patient with reduced glomerular filtration rate, even low prophylactic doses of LMWH may accumulate and cause bleeding. This adverse effect of LMWH is amplified in patients with reduced renal function due to disease or chemotherapy.
Lastly, concerns regarding the safety of systemic anticoagulation in cancer patients with CVCs likely contribute to the low compliance rate. Considerable recent data, for example, have brought into question the safety of low-dose warfarin in patients receiving 5-flurouracil–based chemotherapy. Magagnoli et al. demonstrated an increased likelihood of an elevated INR (international normalized ratio) and possible bleeding when low-dose warfarin is used in patients with 5-flurouracil–based chemotherapy regimens.87, 88 In patients on full-dose warfarin who then receive 5-flurouracil, the average warfarin dose to maintain a therapeutic INR declines by nearly half and requires careful weekly monitoring.89 Similar effects have been noted with capecitabine, the prodrug of 5-flurouracil.90, 91
Recent Prophylactic Anticoagulation Studies
Questions about the design and outcome of the early positive anticoagulation studies prompted a number of confirmatory studies to be performed to assess the utility of prophylactic anticoagulation in patients with CVCs. The majority of these studies have revealed no benefit in preventing or decreasing the rate of CVC-related DVT.
In a nonrandomized study of 160 patients with melanoma or renal cell cancer being treated with interleukin-2, warfarin (1 mg/day) did not reduce the CVC-related DVT rate.92 In a nonblinded study of patients with hematological malignancies, Heaton et al. randomized 88 patients with double-lumen subclavian Hickman CVCs to warfarin (1 mg/day) or no therapy.93 After 90 days, there was no difference in the rate of clinically significant thrombi for those treated with warfarin; 8 of 45 patients (18%) treated with warfarin had clinically evident thrombi, versus 5 of 43 patients (12%) not treated.
Similar studies done with LMWH also have failed to show any difference in CVC-related DVT. Pucheu et al. prospectively compared patients given 2,500 anti-Xa units of dalteparin subcutaneously daily with untreated historical controls using ultrasonography at 1, 3, and 12 months to screen for DVT.94 Documented DVT occurred in only 3 of 46 patients (6.5%) who received dalteparin, and all were without symptoms. In the historical control group, 11 of 72 patients(15%) developed documented DVT, which was not a statistically significant difference. In the largest randomized, blinded, placebo-controlled study ever performed to evaluate CVC prophylaxis in cancer patients, 194 patients received placebo injections and 294 received dalteparin (5,000 IU subcutaneously daily) for 16 weeks.95 Clinical DVT occurred in 5.3% of placebo and in 5.8% of dalteparin-treated patients, which was not a statistically significant difference. The low rate of DVT in the placebo group was among the lowest seen in any CVC prophylaxis study and may reflect improvements in catheter design and placement, local care, or patient selection. There was no difference in infection rate.
Current Guidelines on Prophylactic Anticoagulation
Many of the recent prophylactic anticoagulation studies, which are both large and placebo-controlled, fail to show any reduction in the rate of CVC-related DVT. These newer studies prompted the American College of Chest Physicians (ACCP) to change their guidelines in 2004. The recently published guidelines from the Seventh ACCP Conference on Antithrombotic Therapy state that the routine use of low-dose warfarin or LMWH to try to prevent thrombosis related to long-term indwelling CVCs in cancer patients is not warranted.96 In addition to the lack of benefit, concerns regarding the safety of low-dose warfarin in cancer patients are being raised.
Future Possibilities in Thrombosis Prevention
Given the recent data on low-dose warfarin and LMWH in preventing CVC-related DVT, larger, placebo-controlled studies of these drugs could be considered in the future; however, it may be more fruitful, instead, to consider newer antithrombotic agents. The two newest anticoagulants are the direct thrombin inhibitors (DTIs), such as ximelegatran, and the factor Xa inhibitors, such as the pentasaccharides fondaparinux and idraparinux. DTIs have some advantages over warfarin in that they are not affected by diet, antibiotics, or inhibitors of the CYP-450 system, such as 5-flurouracil and capecitabine.97, 98, 99, 100 The factor Xa inhibitors have recently been approved for prophylaxis and treatment of venous thromboembolism and are superior to LMWH in terms of efficacy and bleeding rates.101, 102, 103 Large, randomized, placebo-controlled trials are needed to determine if these newer agents will reduce the DVT rate in cancer patients with CVCs. However, as recent reports suggest, the rates of thrombosis in untreated patients95 appear to be decreasing and may make even an effective anticoagulant of limited importance in this setting.
LATE COMPLICATIONS: INFECTION
Types of Central Venous Catheter-Related Infection
The incidence and mortality associated with catheter-related infections (CRIs) are difficult to ascertain because of the lack of consensus on definitions. The incidence ranges from 2 to 43%,26, 29 and the mortality, in bacteremic patients, can be as high as 35%.104
Several types of vascular CRI exist; these include catheter colonization, phlebitis, exit-site infection, tunnel infection, pocket infection, and bloodstream infection.105, 106 The ability to identify each type has important therapeutic implications. A less serious infection, such as an infection at the exit-site, may require only intravenous antibiotics, whereas a more serious one, such as a tunnel infection, may warrant removal and replacement of the catheter.
The seriousness of an infection and the risks associated with it also depend on the type of organism present. Coagulase-negative Staphylococcus species are the most common cause of catheter-related infections and the least virulent. Staphylococcus aureus, Gram-negative bacilli, and Candida species are the next most common and have the potential to be extremely virulent and cause serious complications.105, 107
The clinical performance of the patient also has important implications for management decisions and outcome. Immunocompromised or critically ill patients are at significant risk for morbidity and mortality and commonly require removal of their catheter.105, 107
Risks of Central Venous Catheter-Related Infection
There are many patient- and catheter-related risks factors associated with the development of CRIs. Malignancy, AIDS, and neutropenia are a few of the host factors that predispose patients to an increased risk.106 As discussed in previous sections, the composition of the catheter and the site of insertion confer certain risks. For percutaneous devices, a subclavian approach is thought to be associated with less risk.29, 108 Occlusive plastic dressings, frequent manipulations, and nonsterile techniques are associated with increased infection risk.
One important identifiable risk factor for CRIs is the presence of thrombosis. This association was first suggested in the early 1980s when a higher rate of bacteremia was discovered in patients with documented CVC thromboses as compared with those without clots.109 Further studies have confirmed this correlation.69, 92, 110 This finding is not surprising given that, as mentioned earlier, almost all catheters develop a fibrin sheath and almost all fibrin sheaths become colonized with cocci.34, 35, 36 To date, none of the anticoagulation studies have shown any reduction in the rate of infection.
Diagnosis of Central Venous Catheter-Related Infection
Techniques for diagnosing CRIs can be divided into those that require catheter removal and those that allow it to remain in place. The “role plate, sonification, and flushing” methods require removal of the catheter, while the newer approach, the “differential time to positivity” (DTP), involves drawing blood cultures from the central line and peripheral veins simultaneously and does not require removal.106, 107 Once a CRI has been identified, it is important to determine if the infection is confined to the catheter or present in the bloodstream. Catheter-related bloodstream infections (CRBIs) often require further workup to detect the seeding of other tissues, along with the possible development of endocarditis, osteomyelitis, or septic thrombophlebitis.106, 107
Prevention of Central Venous Catheter-Related Infection
The simplest way to prevent infection is to practice meticulous sterile techniques, not only during the insertion process but also during the maintenance period. Aggressive handwashing by medical personnel is an absolute necessity. Using adhesive anchoring devices instead of sutures for catheter securement has dramatically decreased CRBIs. Recognizing the signs and symptoms of localized, systemic, or metastatic infections can help prevent progression. Removing the catheters as soon as they are no longer needed is important because the risk of developing a CRBI increases with time. In addition, poor functioning of a catheter may be a sign of occlusion, and it should be removed if the problem cannot be resolved by simple measures.
Besides the patient's skin, another common source of infection is the catheter hub. Disinfecting the hub each time it is accessed can decrease infection risk. New aseptic hub attachments have recently been developed, but their effectiveness needs to be evaluated in future randomized controlled trials.27, 111, 112
Although the use of combined antimicrobial and antiseptic flushes has been shown to decrease the rate of CRBIs,110 there is great concern that flushing will promote the development of antibiotic-resistant organisms, such as vancomycin-resistant enterococci and/or fungal species. As a result, the prophylactic use of antibiotic locks or flushes is not currently recommended.113, 114
The use of antimicrobial-impregnated catheters, however, is a routine and encouraged practice. Over the past few decades, several randomized trials have consistently shown a decrease in catheter colonization and CRBI. Presently, catheters are impregnated with either chlorhexidine and silver sulfadiazine or minocycline and rifampin; both types have been well studied and both show benefit.2, 3, 115, 116 Although a recent analysis raised questions about the methodology and benefits of these trials,117 the Guidelines for the Prevention of Intravascular Catheter-Related Infections recommend their use in catheters expected to remain in place for more than 5 days.115 Future developments to decrease infection risk include using silver iontophoretic devices, electrically charged catheters, and techniques to limit bacterial adhesion.18, 104
Treatment of Central Venous Catheter-Related Infection
The most important decision to make when managing CRIs is whether or not to remove the catheter. This assessment depends on the patient, the organism, the extent of the infection, and the type of catheter. Patients who are critically ill, suffer from persistent bacteremia, or have metastatic seeding of their infection should have their catheter removed. Tunnel or port infections warrant catheter removal. In addition, infections caused by difficult- to-treat organisms (e.g., S. aureus), virulent Gram-negative infections, and fungal infections carry a high risk of mortality if the catheter is not removed. Prompt recognition of a CRI and administration of antibiotics can help decrease morbidity and mortality, especially in critically ill patients.
CVC-related complications are a common clinical problem that may affect nearly half of all cancer patients with CVCs. The mechanical, thrombotic, and infectious complications can result in clinical symptoms, loss of catheter function, postphlebitic syndrome of the upper extremity, pulmonary embolus, increased cost, high morbidity, and even high mortality. Numerous risk factors, both patient- and catheter-related, have been identified and are currently being modified to reduce the rates and types of complications.
Given their common occurrence, further efforts to understand and prevent CVC-related complications are of importance. Efforts should include not only studies of modalities for earlier diagnosis of complications and assessment of anticoagulant and antibiotic efficacies but also studies to determine additional risk factors for CVC-related thrombosis and infection, the timing of onset of these complications, the exploration and implementation of newer preventative agents, the optimal duration and types of treatments, and the natural history of these CVC-related complications.
1. Darouiche RO, Raad, II, Heard SO, et al. A comparison of two antimicrobial-impregnated central venous catheters. Catheter Study Group. N Engl J Med 1999;340:1–8.
2. Raad I, Darouiche R, Dupuis J, et al. Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections: a randomized, double-blind trial. The Texas Medical Center Catheter Study Group. Ann Intern Med 1997;127:267–274.
3. Maki DG, Stolz SM, Wheeler S, et al. Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter: a randomized, controlled trial. Ann Intern Med 1997;127:257–266.
4. Bern MM, Lokich JJ, Wallach SR, et al. Very low doses of warfarin can prevent thrombosis in central venous catheters: a randomized prospective trial. Ann Intern Med 1990;112:423–428.
5. Boraks P, Seale J, Price J, et al. Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies. Br J Haematol 1998; 101:483–486.
6. Bozzetti F, Terno G, Bonfanti G, et al. Prevention and treatment of central venous catheter sepsis by exchange via a guidewire: a prospective controlled trial. Ann Surg 1983;198:48–52.
7. Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and Coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109:85–92.
8. Mismetti P, Mille D, Laporte S, et al. Low-molecular-weight heparin (nadroparin) and very low doses of warfarin in the prevention of upper extremity thrombosis in cancer patients with indwelling long-term central venous catheters: a pilot randomized trial. Haematologica 2003;88:67–73.
9. Monreal M, Alastrue A, Rull M, et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices: prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996;75:251–253.
10. Nightingale CE, Norman A, Cunningham D, et al. A prospective analysis of 949 long-term central venous access catheters for ambulatory chemotherapy in patients with gastrointestinal malignancy. Eur J Cancer 1997;33:398–403.
11. Bennett JA. A study of Parentalia, with two unpublished letters of Sir Christopher Wren. Ann Sci 1973;30:129–147.
12. Bennett JA. A note on theories of respiration and muscular action in England c. 1660 (Christopher Wren). Med Hist 1976; 20:59–69.
13. Bergman NA. Early intravenous anesthesia: an eyewitness account. Anesthesiology 1990;72:185–186.
14. Buess H. [Christopher Wren and the discovery of intravenous injections]. Z Krankenpfl 1973;66:274–275.
15. Kenney CA. A historical review of the illustrations of the circle of Willis from antiquity to 1664. J Biocommun 1998;25:26–31.
16. Keys TE. Historical vignettes. Sir Christopher Wren. Anesth Analg 1974;53:853.
17. Kuter DJ. Thrombotic complications of central venous catheters in cancer patients. Oncologist 2004;9:207–216.
18. Polderman KH, Girbes AR. Central venous catheter use, II: infectious complications. Intensive Care Med 2002;28:18–28.
19. Aubaniac R. Subclavian intravenous injection: advantages and technic. Presse Med 1952;60:1456.
20. Aubaniac R. Subclavian intravenous transfusion: advantages and technic. Afr Francaise Chir 1952;8:131–135.
21. Broviac JW, Cole JJ, Scribner BH. A silicone rubber atrial catheter for prolonged parenteral alimentation. Surg Gynecol Obstet 1973;136:602–606.
22. Hickman RO, Buckner CD, Clift RA, et al. A modified right atrial catheter for access to the venous system in marrow transplant recipients. Surg Gynecol Obstet 1979;148:871–875.
23. Niederhuber JE, Ensminger W, Gyves JW, et al. Totally implanted venous and arterial access system to replace external catheters in cancer treatment. Surgery 1982;92:706–712.
24. Bregenzer T, Conen D, Sakmann P, et al. Is routine replacement of peripheral intravenous catheters necessary? Arch Intern Med 1998;158:151–156.
25. Galloway S, Bodenham A. Long-term central venous access. Br J Anaesth 2004;92:722–734.
26. Mansfield PF, Hohn DC, Fornage BD, et al. Complications and failures of subclavian-vein catheterization. N Engl J Med 1994; 331:1735–1738.
27. McGee DC, Gould MK. Preventing complications of central venous catheterization. N Engl J Med 2003;348:1123–1133.
28. Cadman A, Lawrance JA, Fitzsimmons L, et al. To clot or not to clot? That is the question in central venous catheters. Clin Radiol 2004;59:349–355.
29. Merrer J, De Jonghe B, Golliot F, et al. Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. JAMA 2001;286: 700–707.
30. Booth SA, Norton B, Mulvey DA. Central venous catheterization and fatal cardiac tamponade. Br J Anaesth 2001;87:298–302.
31. Martin MJ, Husain FA, Piesman M, et al. Is routine ultrasound guidance for central line placement beneficial? A prospective analysis. Curr Surg 2004;61:71–74.
32. Randolph AG, Cook DJ, Gonzales CA, et al. Ultrasound guidance for placement of central venous catheters: a meta-analysis of the literature. Crit Care Med 1996;24:2053–2058.
33. Sznajder JI, Zveibil FR, Bitterman H, et al. Central vein catheterization: failure and complication rates by three percutaneous approaches. Arch Intern Med 1986;146:259–261.
34. Starkhammar H, Bengtsson M, Morales O. Fibrin sleeve formation after long term brachial catheterisation with an implantable port device: a prospective venographic study. Eur J Surg 1992; 158:481–484.
35. Hoshal VL Jr, Ause RG, Hoskins PA. Fibrin sleeve formation on indwelling subclavian central venous catheters. Arch Surg 1971;102:253–258.
36. Bona RD. Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Hemost 1999;25:147–155.
37. Balestreri L, De Cicco M, Matovic M, et al. Central venous catheter-related thrombosis in clinically asymptomatic oncologic patients: a phlebographic study. Eur J Radiol 1995;20: 108–111.
38. Tenney J, Moody M, Newman K, et al. Adherent microorganisms on luminal surfaces of long-term intravenous catheters: importance of Staphylococcus epidermidis in patients with cancer. Arch Intern Med 1986;146:1949–1954.
39. Raad I, Costerton W, Sabharwal U, et al. Ultrastructural analysis of indwelling vascular catheters: a quantitative relationship between luminal colonization and duration of placement. J Infect Dis 1993;168:400–407.
40. Raad, II, Hohn DC, Gilbreath BJ, et al. Prevention of central venous catheter-related infections by using maximal sterile barrier precautions during insertion. Infect Control Hosp Epidemiol 1994;15:231–238.
41. De Cicco M, Matovic M, Balestreri L, et al. Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term Silastic catheter: a prospective study. Thromb Res 1997;86:101–113.
42. Ray S, Stacey R, Imrie M, et al. A review of 560 Hickman catheter insertions. Anaesthesia 1996;51:981–985.
43. Schwarz RE, Coit DG, Groeger JS. Transcutaneously tunneled central venous lines in cancer patients: an analysis of device-related morbidity factors based on prospective data collection. Ann Surg Oncol 2000;7:441–449.
44. Anderson AJ, Krasnow SH, Boyer MW, et al. Thrombosis: the major Hickman catheter complication in patients with solid tumor. Chest 1989;95:71–75.
45. Schwarz R, Coit D, Groeger J. Transcutaneously tunneled central venous lines in cancer patients: an analysis of device-related morbidity factors based on prospective data collection. Ann Surg Oncol 2000;7:441–449.
46. Lawson M, Bottino J, Hurtibise M. The use of urokinase to restore patency of occluded central venous catheters. Ann J Intraven Ther Clin Nutr 1982;9:29–32.
47. Hurtibise M, Bottino J, Lawson M. Restoring patency of occluded central venous catheters. Arch Surg 1980;115:212–213.
48. Gould J, Carloss H, Skinner W. Groshong catheter-associated subclavian venous thrombosis. Am J Med 1993;95:419–423.
49. Stephens L, Haire W, Kotulak G. Are clinical signs accurate indictors of the cause of central venous catheter occlusion? JPEN J Parenter Enteral Nutr 1995;19:75–79.
50. Verso M, Agnelli G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 2003;21:3665–3675.
51. Curelaru I, Bylock A, Gustavsson B, et al. Dynamics of thrombophlebitis in central venous catheterization via basilic and cephalic veins. Acta Chir Scand 1984;150:285–293.
52. Lokich JJ, Becker B. Subclavian vein thrombosis in patients treated with infusion chemotherapy for advanced malignancy. Cancer 1983;52:1586–1589.
53. Durica SS. Venous thromboembolism in the cancer patient. Curr Opin Hematol 1997;4:306–311.
54. Letai A, Kuter DJ. Cancer, coagulation, and anticoagulation. Oncologist 1999;4:443–449.
55. Prandoni P, Piccioli A, Girolami A. Cancer and venous thromboembolism: an overview. Haematologica 1999;84:437–445.
56. Valente M, Ponte E. Thrombosis and cancer. Minerva Cardioangiol 2000;48:117–127.
57. De Cicco M, Matovic M, Balestreri L, et al. Antithrombin III deficiency as a risk factor for catheter-related central vein thrombosis in cancer patients. Thromb Res 1995;78:127–137.
58. Leebeck F, Stadhouders N, van Stein D, al e. Hypercoagulability states in upper-extremity deep venous thrombosis. Ann J Hematol 2001;67:15–19.
59. Fijnheer R, Paijmans B, Verdonck LF, et al. Factor V Leiden in central venous catheter-associated thrombosis. Br J Haematol 2002;118:267–270.
60. Wermes C, von Depka Prondzinski M, et al. Clinical relevance of genetic risk factors for thrombosis in paediatric oncology patients with central venous catheters. Eur J Pediatr 1999;158 (Suppl 3):S143–146.
61. Haire WD, Lieberman RP, Edney J, et al. Hickman catheter-induced thoracic vein thrombosis: frequency and long-term sequelae in patients receiving high-dose chemotherapy and marrow transplantation. Cancer 1990;66:900–908.
62. Borow M, Crowley JG. Evaluation of central venous catheter thrombogenicity. Acta Anaesthesiol Scand Suppl 1985;81: 59–64.
63. Luciani A, Clement O, Halimi P, et al. Catheter-related upper extremity deep venous thrombosis in cancer patients: a prospective study based on Doppler US. Radiology 2001;220: 655–660.
64. Puel V, Caudry M, Le Metayer P, et al. Superior vena cava thrombosis related to catheter malposition in cancer chemotherapy given through implanted ports. Cancer 1993;72:2248–2252.
65. Prandoni P. Antithrombotic strategies in patients with cancer. Thromb Haemost 1997;78:141–144.
66. Monreal M, Davant E. Thrombotic complications of central venous catheters in cancer patients. Acta Haematol 2001;106: 69–72.
67. Monreal M, Lafoz E, Ruiz J, et al. Upper-extremity deep venous thrombosis and pulmonary embolism: a prospective study. Chest 1991;99:280–283.
68. Monreal M, Raventos A, Lerma R, et al. Pulmonary embolism in patients with upper extremity DVT associated to venous central lines: a prospective study. Thromb Haemost 1994;72: 548–550.
69. Raad, II, Luna M, Khalil SA, et al. The relationship between the thrombotic and infectious complications of central venous catheters. JAMA 1994;271:1014–1016.
70. Mustafa B, Rathbun S, Whitsett T, et al. Sensitivity and specificity of ultrasonography in the diagnosis of upper extremity deep vein thrombosis: a systemic review. Arch Intern Med 2002;162: 401–404.
71. Koksoy C, Kuzu A, Kutlay J, et al. The diagnostic value of colour Doppler ultrasound in central venous catheter related thrombosis. Clin Radiol 1995;50:687–689.
72. Chait P, Dinyari M, Massicotte P. The sensitivity and specificity of lineograms and ultrasound compared with venography for the diagnosis of central venous line related thrombosis in symptomatic children: the LUV study. Thromb Haemost 2001;86 (Suppl) abstract p697.
73. Forneris G, Quarello F, Pozzato M, et al. [Spiral x-ray computed tomography in the diagnosis of central venous catheterization complications. Nephrologie 2001;22:495–499.
74. Haire W, Lynch T, Lund G, et al. Limitations of magnetic resonance imaging and ultrasound-directed (duplex) scanning in the diagnosis of subclavian vein thrombosis. J Vasc Surg 1991; 13:391–397.
75. Savage K, Wells P, Schultz V, et al. Outpatient use of low molecular weight heparin (dalteparin) for the treatment of deep vein thrombosis of the upper extremity. Thromb Haemost 1999; 82:1008–1010.
76. Lee A, Levine M, Baker R, et al. Low-molecular weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146–153.
77. Spence L, Gironta M, Malde H, et al. Acute upper extremity deep venous thrombosis: safety and effectiveness of superior vena cava filters. Radiology 1999;210:53–58.
78. Ponec D, Irwin D, Haire W, et al. Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial. The Cardiovascular Thrombolytic to Open Occluded Lines (COOL) efficacy trial. J Vasc Interv Radiol 2001;12:951–955.
79. Chan A, Du Y, Berry L, et al. Covalent antithrombin-heparin complex coated catheter prevents thrombosis in a rabbit central venous catheter model. Thromb Haemost 2001;86(Suppl 1):310S.
80. Brown-Smith JK, Stoner MH, Barley ZA. Tunneled catheter thrombosis: factors related to incidence. Oncol Nurs Forum 1990;17:543–549.
81. Stephens L, Haire W, Tarantolo S, et al. Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC). Transfus Sci 1997;18:187–193.
82. Carr KM, Rabinowitz I. Physician compliance with warfarin prophylaxis for central venous catheters in patients with solid tumors. J Clin Oncol 2000;18:3665–3667.
83. Minassian VA, Sood AK, Lowe P, et al. Long-term central venous access in gynecologic cancer patients. J Am Coll Surg 2000;191: 403–409.
84. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001;119(Suppl 1):132S–175S.
85. Guyatt G, Schunemann H, Cook D, et al. Grades of recommendation for antithrombotic agents. Chest 2001;119(Suppl 1): 3S–7S.
86. Hirsh J, Dalen J, Guyatt G. The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis. American College of Chest Physicians. Chest 2001;119 (Suppl 1):1S–2S.
87. Masci G, Magagnoli M, Zucali P, et al. Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy? J Clin Oncol 2003;21:736–739.
88. Magagnoli M, Masci G, Carnaghi C, et al. Minidose warfarin is associated with a high incidence of international normalized ratio elevation during chemotherapy with FOLFOX regimen. Ann Oncol 2003;14:959–960.
89. Kolesar J, Johnson C, Freeberg B, et al. Warfarin-5-FU interaction: a consecutive case series. Pharmacology 1999;19:1445–1449.
90. Copur M, Ledakis P, Boulton M, et al. An adverse interaction between warfarin and capecitabine: a case report and review of the literature. Clin Colorectal Cancer 2001;1:182–184.
91. Reigner B, Blesch K, Weidekamm E. Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 2001;40:85–104.
92. Eastman ME, Khorsand M, Maki DG, et al. Central venous device-related infection and thrombosis in patients treated with moderate dose continuous-infusion interleukin-2. Cancer 2001; 91:806–814.
93. Heaton DC, Han DY, Inder A. Minidose (1 mg) warfarin as prophylaxis for central vein catheter thrombosis. Intern Med J 2002;32:84–88.
94. Pucheu A, Leduc B, Sillet-Bach I, et al. Experimental prevention of deep venous thrombosis with low-molecular-weight heparin using implantable infusion devices. Ann Cardiol Angeiol (Paris) 1996;45:59–63.
95. Reichardt P, Kretzschmar A, Biakhov M, et al. A phase III randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of daily low-molecular-weight heparin (dalteparin sodium, Fragmin) in preventing catheter-related complications (CRCs) in cancer patients with central venous catheter (CVCs). Proc ASCO 2002;21:369a.
96. Geerts W, Pineo G, Heit J, et al. Prevention of venous thromboembolism. Chest 2004;126:3385–4005.
97. Colwell CW Jr, Berkowitz SD, Davidson BL, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement: a randomized, double-blind study. J Thromb Haemost 2003;1:2119–2130.
98. Gustafsson D. Oral direct thrombin inhibitors in clinical development. J Intern Med 2003;254:322–334.
99. Eriksson H, Wahlander K, Gustafsson D, et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis. THRIVE I. J Thromb Haemost 2003;1:41–47.
100. de Moerloose P, Boehlen F. Two new antithrombotic agents (fondaparinux and ximelagatran) and their implications in anesthesia. Can J Anaesth 2002;49(6):S5–10.
101. Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345:1305–1310.
102. Eriksson BI, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003;163:1337–1342.
103. Turpie AG, Bauer KA, Eriksson BI, et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833–1840.
104. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients: excess length of stay, extra costs, and attributable mortality. JAMA 1994;271:1598–1601.
105. Hall K, Farr B. Diagnosis and management of long-term central venous catheter infections. J Vasc Interv Radiol 2004;15: 327–334.
106. Fatkenheuer G, Cornely O, Seifert H. Clinical management of catheter-related infections. Clin Microbiol Infect 2002;8: 545–550.
107. Raad, II, Hanna HA. Intravascular catheter-related infections: new horizons and recent advances. Arch Intern Med 2002;162: 871–878.
108. Lam S, Scannell R, Roessler D, et al. Peripherally inserted central catheters in an acute-care hospital. Arch Intern Med 1994;154: 1833–1837.
109. Press O, Ramsey P, Larson E, et al. Hickman catheter infections in patients with malignancies. Medicine 1984;63:189–200.
110. Henrickson KJ, Axtell RA, Hoover SM, et al. Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ ciprofloxacin/heparin flush solution: a randomized, multicenter, double-blind trial. J Clin Oncol 2000;18:1269–1278.
111. Sequra M, Alvarez-Lerma F, Tellado J, et al. Advances in surgical technique: a clinical trial on the prevention of catheter-related sepsis using a new hub model. Ann Surg 1996;223:363–369.
112. Luna L, Masdeu G, Perez M, et al. Clinical trial evaluating a new hub device designed to prevent catheter-related sepsis. Eur J Clin Microbiol Infect Dis 2000;19:655–662.
113. O'Grady N, Alexander M, Dellinger P, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 2002;35:1281–1307.
114. Spafford P, Sinkin R, Cox C, et al. Recommendations for preventing the spread of vancomycin resistance: recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR 1994;44:1–13.
115. O'Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. The Hospital Infection Control Practices Advisory Committee, Center for Disease Control and Prevention. US Pediatrics 2002;110(5):e51.
116. Brun-Buisson C, Doyon F, Sollet JP, et al. Prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial. Intensive Care Med 2004;30:837–843.
117. McConnell SA, Gubbins PO, Anaissie EJ. Do antimicrobial-impregnated central venous catheters prevent catheter-related bloodstream infection? Clin Infect Dis 2003;37:65–72.