Cancer Chemotherapy & Biotherapy: Principles & Practices, 4th Edition

Central Venous Catheters: Care and Complications

Rachel P. Rosovsky

David J. Kuter

INTRODUCTION

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.

HISTORICAL PERSPECTIVE

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.)

 

CURRENT DEVICES

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

CURRENT USES

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

Short-term devices (1–14 days)
   Percutaneous internal jugular, subclavian, femoral lines
   Peripherally inserted central catheters (PICC)
Long-term devices (months to years)
   Surgically tunneled catheters (Hickman, Broviac, Groshong, Quinton)
   Totally implanted venous access devices (Mediport, Infus-a-Port, Port-a-Cath)

TABLE 23.2 INCIDENCE OF COMPLICATIONS OF CENTRAL VENOUS CATHETERS

Early
   Arrhythmia: 13%
   Arterial puncture: 2.8–3.8%
   Malposition of reservoir: 2%
   Pneumothorax: 1–1.8%
   Wound dehiscence: 1.5%
   Hemorrhage: 1.1–1.2 %
   Failure of insertion: 1.2%
Late
   Infection: 4–38%
   Catheter fracture and embolization: 3%
   Migration of catheter tip: 7.4%
   Thrombosis: ~41% (range 12–74%)
      Asymptomatic: ~29% (range: 5–62%)
      Symptomatic: ~12% (range: 5–41%)
Sequelae of CVC-related thrombosis
   Postphlebitic syndrome: 15–35%
   Pulmonary embolization: ~11% (range: 7–31%)
      Symptomatic: ~6% (range: 3–14%)
      Asymptomatic: ~5% (range: 3–15%)

COMPLICATIONS

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.

EARLY COMPLICATIONS

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

Intraluminal Thrombosis

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

1. If the CVC is nonfunctional, then it is removed and replaced as necessary in another vascular bed. If it is functional, then the CVC is kept in place if still needed.

2. All patients with adequate renal clearance receive dalteparin (150 IU/kg SQ daily) or enoxaparin (1.5 mg/kg SQ daily).

3. In the absence of active malignancy, all are then converted to warfarin (international normalized ratio [INR] 2–3) and treated for 3 to 6 months. In the presence of active malignancy, all are kept on the LMWH for at least 3 to 6 months.

4. Patients with heparin-induced thrombocytopenia are treated with fondaparinux (5 mg SQ daily).

5. Patients with reduced renal function are treated initially with unfractionated heparin, followed by warfarin.

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.

CONCLUSION

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.

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