Catheter-related infection and thrombosis of the internal jugular vein in hematologic-oncologic patients undergoing chemotherapy

A prospective comparison of silver-coated and uncoated catheters

Abstract

BACKGROUND

Catheter-related venous thrombosis is one of the most frequent complications of central venous catheters (CVCs). This complication occurs in 4– 40% of patients with hematologic malignancies receiving conventional chemotherapy after placement of CVCs.

METHODS

The objective of this prospective study was to assess whether a silver-coated CVC poses an additional risk in the development of catheter-related thrombosis in hematologic-oncologic patients. Patients were randomized to receive either silver-coated polyurethane catheters (BactiGuard; Metacot, Stockholm, Sweden) or uncoated standard polyurethane catheters (Cavatheter, Fresenius AG, Bad Homburg, Germany) for central venous access. Silver-coated catheters (n = 120) and standard catheters (n = 113) were inserted into the jugular vein in 233 consecutive patients. Variables that may be significant for the development of thrombosis were comparable in the two groups. After removal of the CVC, the patency of both jugularian veins internal as well as external was assessed with real-time ultrasound (Sonolayer-SAL-35A; Toshiba, Tokyo, Japan).

RESULTS

Four of 233 patients (1.5%) were found to have venous thrombosis. Incomplete occlusion of the internal jugular vein occurred in 2 patients (0.75%, parietal thrombosis), and complete thrombosis, although clinically silent, was found in 2 patients (0.75%). There was no difference between patients with silver-coated and uncoated CVCs.

CONCLUSIONS

The authors concluded that this novel silver-coated CVC does not cause a higher rate of central venous thrombosis compared with standard CVCs. The low overall incidence of central venous thrombosis might be attributed to the routine application of low-dose heparin in our patients during chemotherapeutic treatment. Cancer 2002;94:245–51. © 2002 American Cancer Society.

Central venous access is essential for the intensive care of patients with hematologic malignancies. An estimated 5 million central venous catheters (CVCs) are used in the United States alone each year, a figure likely to increase as patient care becomes more specialized and intensive.1 Complications of catheterization include those associated with catheter insertion (pneumothorax, arterial and nerve injuries) and those associated with long catheter use (thrombosis and infection).2–4

Central venous catheters may account for approximately 40% of all deep venous thromboses of the upper extremities.5 Pulmonary embolism occurs in 12% of patients with venous thromboses of the subclavian or axillary vein.5 The finding that many subclavian vein thromboses remain asymptomatic may be because of several factors, including 1) the presence of extensive venous collaterals in the upper extremity that minimize the hemodynamic effect of an intramural thrombus and 2) that hydrostatic forces favor venous drainage from the upper extremity to a much greater extent than from the lower extremity.6 A prospective study of adult cancer patients with long-term indwelling venous catheters has been reported by Haire et al.7 Their study of 168 patients undergoing bone marrow transplantation and 49 other patients receiving high-dose chemotherapy for a variety of hematologic malignancies resulted in a 12.9% thrombosis rate after placement of two Hickman catheters and was significantly more likely to be associated with thrombosis than placement of one catheter. Using linear regression analysis, they identified a higher platelet count as a factor predisposing to thrombosis.7 Factors not associated with catheter-related venous thrombosis are age, gender, history of a previous venous catheter, and placement technique.8 In contrast, studies of allogeneic and syngeneic bone marrow transplantation have shown this to be a rare complication.9–11 Another common problem after vein catherization in patients receiving standard chemotherapy or autologous blood stem cell transplantation (ABSCT) is catheter-related infection. Recent studies have demonstrated the efficacy of antiseptic-impregnated catheters in reducing bacterial colonization and infection.5, 12–15 Silver-impregnated CVCs show a reduction in bacterial colonization16 and reduce catheter-related infections in high-risk patients.17 However, it is not known whether silver-impregnated catheters might induce a higher rate of thrombosis. In our study, we investigated whether polyurethane catheters coated with a silver alloy might be associated with a higher rate of catheter-related thrombosis among oncologic patients undergoing chemotherapy.

PATIENTS AND METHODS

In a controlled comparative clinical study a polyurethane CVC with a novel silver impregnation of the external surface (BactiGuard, Metacot, Sweden) was used and thrombotic complications assessed. The study was designed mainly as an evaluation of silver coating for its impact on catheter-related infections. Commercially available polyurethane catheters with no antimicrobial activity (Cavatheter, Fresenius AG, Germany) were used as controls. The study was performed at the Department of Internal Medicine V, University of Heidelberg, a 76-bed teaching tertiary hospital serving hematologic, oncologic, and rheumatologic patients. Adult patients with hematologic-oncologic disease admitted to the hospital who required CVCs for treatment purposes were offered the opportunity to participate in the study. Patients were checked for compliance with the enrollment protocol.

Exclusion criteria were catheterization for less than 48 hours, second central venous access, existing severe infection, current catheter-related infection, pregnancy and age younger than 18 years.

All participants gave informed written consent. Patients were randomly assigned to receive either silver-coated or uncoated catheters (Table 1). When patients required a second (n = 29), third (n = 9), fourth (n = 1), or fifth (n = 2) catheter, each catheterization procedure was recorded as a separate event. To prevent consecutive placement of catheters of the same category, we alternated subsequent catheters in the same patient between silver-coated and standard catheter. The study protocol was approved by the Institutional Review Board of the University of Heidelberg.

Table 1. Duration of Catheterization, Condition of Entry Site, Reasons for Catheter Removal, and Incidence of Thrombosis

Factor	Standard catheter (n = 113)	Silver-coated catheter (n = 120)
SD: standard deviation.
Duration of catheterization (days)
3–5	58	77
6–10	42	31
11–15	11	7
16–20	1	4
> 20	1	1
Duration of catherisation (days)
Mean ± SD	13.3 ± 9.0	12.8 ± 8.3
Range	3–55	3–61
Condition of entry site
Erythema ≤ 3 mm	54	57
4–6 mm	32	34
> 6 mm	22	24
Edema/purulence	5	5
Reason for catheter removal
End of treatment	103	114
Malfunction	0	1
Catheter-associated infection	1	0
Catheter-related thrombosis	3	1
Other	1	0

Standardized data collection forms were completed for all patients. Data included demographic characteristics, catheter insertion and removal dates, diagnosis, chemotherapy, supportive care, and prophylactic and therapeutic antibiotics. Veins were examined by ultrasonography just before or less than 24 hours after catheter removal. Criteria considered to show the presence of catheter-related thrombosis included visualization of thrombus (T), absence of spontaneous flow (F), dilatation of the vein by the Valsalva maneuvre (V), and compressibility of the jugular vein (C) (Table 2). Suspected risk factors of catheter-related central vein thrombosis such as age older than 60 years, duration of catheterization, underlying disease, and numbers of insertions per patient were recorded. Additional data recorded were days of leukopenia (< 1.0 × 10⁹ leukocytes per liter), days of fever (< 38.5 °C), platelet count, coagulation parameters, blood pressure, and pulse rate twice daily.

Central Venous Catheters

Central venous catheterization was performed with uncoated (standard) and silver-coated 30-cm, 5-F single-lumen polyurethane catheters (Cavatheter, Fresenius AG, Germany). The impregnated catheters (BactiGuard, Metacot, Sweden) were coated externally with an antimicrobial silver alloy.

Catheter Insertion and Care

After ultrasound imaging (Sonolayer SSA-250 A; Toshiba), catheters were inserted percutaneously into the internal jugular vein by experienced physicians under aseptic conditions. The physicians wore masks, caps, sterile gloves, and surgical gowns and used large sterile drapes (“maximum barrier precautions”). Study catheters were not exchanged over guidewires. At the time of catheter insertion, the skin insertion site was disinfected with 70% alcohol (Poly-Alcohol Haut; Antiseptica GmbH, Pulheim, Germany), which was applied by scrubbing for at least 30 seconds. The Seldinger technique was used to place the catheters. The insertion sites were covered with a 7.2 × 5–cm sterile dressing (Hansapor steril; Beiersdorf AG, Hamburg, Germany). Catheter care included daily changing of the dressing under aseptic conditions. Insertion sites were examined daily for edema, tenderness, purulence, and signs of thrombosis, including arm or neck pain, localized erythema, arm swelling, dilated superficial collateral veins, and failure to aspirate blood or introduce fluid into an indwelling CVC by specialist nurses. The results of the daily examinations were recorded. Compliance with the site care regimen was monitored daily by the study team. The catheters were used for inpatient treatment. One hundred twenty-eight patients were treated in intensive care units, 53 in normal wards, and 52 in day-care units (181 inpatients and 52 outpatients). For prevention of deep venous thrombosis all inpatients received 10,000 international unit (IE) heparin i.v./die.

METHODS

Microbiologic Methods

Specimens from the skin at the insertion site (an area of approximately 4 cm²) were obtained for culture with a moistened sterile swab. The catheter hub samples were taken by repeatedly rubbing the inner surface of the hub with a sterile cotton swab. All samples were sent to the laboratory in transport medium and were plated onto blood agar plates. The outer surfaces of the catheter tips were cultured by the roll-plate technique.22 The inner surface of the catheter tip was cultured by a modified quantitative method.29 Skin and catheter hub cultures were considered positive when more than 15 colony-forming units (CFUs) were isolated. The criteria for positivity of the catheter tip culture were counts of more than 15 CFUs by the roll-plate method. Blood cultures were taken from a peripheral vein. Blood aliquots were cultured with aerobic and anaerobic BACTEC Plus/F media (Becton Dickinson Europe, Meylan Cedex, France). Aliquots of the bottles were subcultured onto adequate media. All microorganisms were identified by standard microbiologic procedures using the Api system (BioMerieux, Marcy l'Etoile, France). Definitions concerning catheter colonization, catheter-related bacteremia, catheter-related septicemia and local infection are shown in Table 3.

Table 2. Frequency of Catheter-Related Thrombosis Examined by Ultrasound

Factor	Standard catheter (n = 113)	Silver-coated catheter (n = 120)
Visualization of thrombus	3	1
Absence of spontaneous flow	2	0
Dilatation of the vein by the Valsalva maneuvre	111	120
Compressibility of the jugular vein	111	120
Total no. of catheter-related thromboses	3	1

Table 3. Definitions Concerning Catheter Colonization, Catheter-Related Bacteremia, Catheter-Related Septicemia, and Local Infection

Infections with a clinically apparent focus other than exit site or catheter (one patient with urosepsis) were excluded.
Catheter colonization	Growth of more than 15 colony-forming-units (CFUs) of an organism on semiquantitative culture of catheter in the absence of signs of local or systemic infection.
Catheter-related bacteremia	Isolation of the same organism from catheter (more than 15 CFUs) and blood culture without clinical signs of infection.
Catheter-related septicemia	Isolation of the same organism from catheter (more than 15 CFUs) and blood culture with clinical signs of infection.
Local infection	Growth of more than 15 CFUs of an organism on semiquantitative culture of the intradermal or catheter tip segment and/or local signs of infection. Sterile blood cultures.

Table 4. Risk Factors for Development of Catheter-Related Thrombosis

Factor	CRT (n = 4)	CRT/total (n = 4/233)
CRT: catheter-related thrombosis.
Age (yrs)
< 60	3
> 60	1
Gender
Female	4	4/135
Male	0	0/98
Duration of catheterization (wks)
< 1	3	3/135
> 1	1	1/98
Catheter-related infection
Presence	1	1/36
Absence	3	3/197
Underlying disease
Acute leukemia	0	0/25
Hodgkin disease	0	0/24
Non-Hodgkin lymphoma	1	1/62
Multiple myeloma	2	2/65
Breast carcinoma	1	1/16
Other	0	0/41
Catheter type
Standard central venous catheter	3	3/113
Silver-coated central venous catheter	1	1/120
No. of insertions per patient
1	0	0/134
2	2	2/29
3	0	0/9
4	1	1/1
5	1	1/2

Ultrasound

After removal of the CVC, an ultrasound examination (Sonolayer SSA-250 A; Toshiba) of the left and right internal jugular veins was conducted and documented by a Polaroid print (Fig. 1). Criteria considered to show the presence of catheter-related thrombosis included visualization of thrombus (T), absence of spontaneous flow (F), dilatation of the vein by the Valsalva maneuvre (V), and compressibility of the jugular vein (C).

Figure 1. Polaroid print of a jugular vein thrombosis after catheter replacement.

Statistical Analysis

Variables between catheter groups were compared by an uncorrected chi-square test or, when appropriate, Fisher exact test for categoric variables and the Mann–Whitney U test for continuous variables. Because randomization produced two groups of patients with comparable baseline characteristics, no indication of positive or negative confounding needed to be controlled for with multivariate Cox models. Statistical significance was established at an alpha value of 0.05. All P values are two-tailed. Multivariate analysis was performed to identify the influence of catheter type, age, gender, diagnosis, number of insertions, duration of catheterization, and catheter-associated infection for the development of a catheter-related thrombosis.

RESULTS

Over a 17-month period, 266 patients with CVCs were included in this study (Table 4). Thirty-three patients were excluded from evaluation for the following reasons: catherization within 48 hours before randomization (5 patients), failure to notify the study team when a catheter was removed (15 patients), and violations of microbiologic test requirements (> 24 hours between removal and microbiologic examination, 13 patients). Twenty patients in the standard group and 13 in the silver catheter group were excluded. Of the patients, 135 were female and 98 male. A total of 128 patients were treated in intensive care units, 53 in normal wards and 52 in a day-care unit. The distribution of standard versus silver-coated catheters was homogeneous (chi-square = 0.148; P = 0.93), and the training and experience of physicians inserting the catheters and the care of insertion site were equal in both groups. On randomization, 132 patients received standard catheters and 134 received silver-coated CVCs. In all, 233 CVCs were evaluated in the study, of which 113 were standard and 120 silver-coated. The main reason for removal of the CVC was end of therapy (93.13%). One silver-coated CVC was withdrawn because of a malfunction (occlusion). Differences between standard and silver-coated catheters concerning the gender of the patients (female: 56.6% vs. 61.7% and male 43.4% vs. 38.3%) were not significant (chi-square = 0.610; P = 0.44). Age, clinical diagnosis, rates of leukopenia, fever, and infection unrelated to the catheter were not significantly different in the two groups. The prophylactic antibiotic and antithrombotic treatment was equal in the two groups.

Catheter-related infection occurred in 21.2% of the catheters inserted in patients of the control group and in 10.2% in the silver-coated catheter group (P = 0.011). Catheter-related septicemia was observed in 5% of patients with the silver-coated catheter versus 8.8% of patients with standard catheters. No death was attributable to catheter-related infections in either group. The organisms that caused catheter colonization were coagulase negative staphylococci (n = 97), Streptococcus aureus (n = 4), Bacillus spp. (n = 3), Micrococcus spp. (n = 1), Corynebacterium spp. (n = 1), and Pseudomonas aeruginosa (n = 1).

Catheter-related internal jugular vein thrombosis occurred in 1.5% of all cases. Partial occlusion was found in 0.75% and complete occlusion in 0.75% of the cases (Fig. 2). There was no significant difference in the incidence of an internal jugular vein thrombosis between the silver-coated catheter and the standard catheter group (1 of 120 vs. 3 of 113). These patients, all of them women, were between 40 and 64 years old. There was no difference between the development of catheter-related thrombosis and the underlying disease (two cases of multiple myeloma, one case of breast carcinoma, and one case of non-Hodgkin lymphoma), the number of insertions, or the duration of catherization (median, 10.25 days). Of note, catheter-related thrombosis was not found in 134 instances of first insertion. Simultaneous infection and thrombosis was found in only one patient).

Figure 2. Polaroid print of a jugular vein without thrombosis after catheter replacement.

DISCUSSION

The incidence of symptomatic catheter-related central venous thrombosis varies between zero and 4.9%.20 In studies using radiologic assessment as well as autopsy findings, catheter-related venous thrombosis has been reported to occur in 4–40% of patients.2, 3, 21, 22 The following reasons might be responsible for the wide range in incidence of catheter-related venous thrombosis: diverse types of catheters, various underlying diseases, and various sensitivity of the examination procedures.

The current randomized, prospective trial included patients undergoing chemotherapy for hematologic malignancies, among whom 36% received high-dose chemotherapy with autologous stem cell transplantation. We used ultrasound for detection and evaluation of thrombotic complications after removal of CVCs.23 In our evaluation, two forms of thrombosis were found: incomplete thrombosis in 2 patients (0.75%) and complete thrombosis, although clinically silent, in 2 patients (0.75%). There were no significant differences between patients with silver-coated and uncoated CVCs. Our study demonstrates that silver-coated CVCs do not represent a risk factor for a catheter-related thrombosis. We conclude that fibrin coating of the CVCs is a frequent event, even if there is no clinical evidence of flow obstruction. Variables that may be significant for the development of thrombosis, e.g., catheter type, age, gender, underlying disease, number of vein punctures, duration of catheterizations, and coexisting catheter-related infection, were analyzed. Four of 233 patients (1.5%) were found to have venous thrombosis. The low rate of thrombosis may be attributed to the use of small diameter catheters (5-French) and the routine administration of low dose heparin in our patients during chemotherapeutic treatment (inpatients received 10,000 IE heparin i.v./day for prevention of deep venous thrombosis). Another reason for the low incidence of catheter-related thrombosis of the jugular vein may be the short duration of catheterisation (median, 10.25 days). Incidences of intravascular catheter-related infections are reported in 0.1– 25%.24–26 In this study, the incidence of catheter-related infections in the standard group (21.2%) was similar to those previously reported for high-risk patients.26 We found that the frequency of catheter colonization was similar in the standard catheter group and in the silver catheter group. However, catheter-related infections were significantly (P = 0.011) less in the silver catheter group. Most of the isolates were identified as coagulase negative staphylococci, which is in agreement with the general consensus in literature. No significant difference in the spectrum of colonizing bacteria could be found between both catheter groups. In our study, despite comparable colonization rates in both catheter groups, a reduction of catheter-related infection could be achieved by the application of the novel silver alloy coating with a mean catheterization period of 12.8 days. We hypothesize that the reduction of infection rates is because of a suppressed local multiplication of microorganisms colonizing the catheter surface.

Several factors play a role in the development of central venous thrombosis in cancer patients with long-term CVCs. Initially, insertion of the catheter itself induced an injury to the intima, predisposing to platelet aggregation and thrombus formation in the punctured vein. Texture and coating of the catheter is another important factor for platelet aggregation and thrombus formation. Polyvinylchloride, for example, is associated with an higher risk for development of catheter-related thrombosis than silicone or polyurethane.27, 28 Neutropenic patients, in particular, may be at higher risk of developing catheter-related infection and catheter-related thrombosis. The presence of a local fibrin sheath promotes the adherence of pathogenic microorganisms, i.e., staphylococci.29 Colonized mural thrombi also offer an ideal nutrient substrate for bacteria, resulting in persistent and disseminated bloodstream infections.30 The hypercoagulable state associated with some tumors is another predisposing factor.2 In rare cases, endothelial lesions also can be produced by tumor compression or infiltration. Two different conditions for development of catheter-related thrombosis can be distinguished: fibrin or thrombin sheath thrombosis and vascular mural thrombosis. The fibrin sheath thrombosis is a frequent but almost clinically inapparent event after catheter insertion.31 Chastre et al. demonstrated that slightly greater than 60% of critically ill patients with indwelling pulmonary artery catheters inserted through the internal jugular vein developed asymptomatic venous thromboses within 6 days of catheterization, suggesting that the actual incidence in patients with long-term indwelling venous catheters may be higher than reported.32

Lokich and Becker, in a combined retrospective and prospective study of 42 cancer patients receiving chemotherapy for advanced malignancy, found a 42% incidence of subclavian vein thrombosis.2 The manifestation of thrombosis and the time to onset after catheter insertion was highly variable. Thromboses were detected from 5 to 270 days after catheter insertion (mean, 30 days). Predisposing factors for the development of thrombosis include coagulation factors, e.g., decreased antithrombin III levels, protein C deficiency33 and hemostatic disorders,7 mediastinal tumors with possible venous flow abnormalities, and suboptimal routine catheter care. Of note, patients with an adenocarcinoma of the lung had a significantly higher rate of thrombosis than patients with squamous cell carcinomas of the lung and other sites. This indicated that certain tumors might represent risk factors for the development of thrombosis.3

In summary, our study showed a low incidence of catheter-related thrombosis in patients with central venous access for chemotherapy. A silver alloy coating does not seem to be an additional risk factor for central venous thrombosis.

Acknowledgements

The authors thank the nursing staff of the Department of Internal Medicine for their excellent care of these patients. They are also grateful to Martin Wallmeier for expert statistical work.