Post-Transplant Events

Factors influencing catheter-related infections in the Dutch multicenter study on high-dose chemotherapy followed by peripheral SCT in high-risk breast cancer patients

Abstract

Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1–141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P=<0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.

Introduction

High-dose chemotherapy followed by autologous SCT is increasingly being used in the treatment of patients with hematological diseases and has in the past two decades also been used in the treatment of solid tumor patients. Large phase III studies have mostly been executed in the adjuvant setting in breast cancer patients. The precise place of high-dose chemotherapy is unresolved.1 In selected patients however, high-dose chemotherapy results in improved disease-free survival and probably also in overall survival.2, 3, 4, 5, 6 High-dose chemotherapy-related mortality, originally reported to be around 20%,7 is consistently below 1% in more recent studies. This improvement is mostly due to advances in supportive care, the introduction of peripheral stem-cell reinfusion instead of BM reinfusion, the choice of cytostatic agents used for the high-dose chemotherapy regimen, the use of hematopoietic growth factors and the growing experience with the procedure.

It is common practice to insert a large-bore central venous catheter at some time prior to the high-dose chemotherapy regimen. This catheter facilitates the administration of the high-dose chemotherapy, reinfusion of stem cells, the drawing of blood samples and the infusion of drugs, blood products and total parenteral nutrition (TPN). The catheter can also be used for the apheresis of peripheral stem cells, prior to the high-dose regimen. Catheter-related complications, especially infections, result however in considerable morbidity and may even be fatal. Relatively little is known concerning risk factors of catheter-related infections. It is important to have insight into the complications of central venous catheters, the pros and cons, preferably in a large group of uniformly treated cancer patients. This could result in changes in the use of central venous catheters during high-dose chemotherapy.

In the present study we analyzed the complication rate of central venous catheters and evaluated risk factors associated with infectious complications in a large group of breast cancer patients receiving high-dose chemotherapy followed by peripheral SCT.

Patients and methods

Patients

All patients included in this study participated in a Dutch national randomized adjuvant breast cancer study of which the clinical results have been published.3, 5 Patients were treated in 10 centers in the Netherlands. The study was approved by all medical ethics committees; all patients gave informed consent. Chemotherapy-naive breast cancer patients with four or more tumor-involved axillary lymph nodes (stage II and III), <56 years of age with negative chest X-ray, liver ultrasound and bone scan were randomly assigned to treatment with five courses of standard chemotherapy (FEC; 5-fluorouracil, 500 mg/m2; epirubicin, 90 mg/m2 and CY, 500 mg/m2) and four courses of FEC followed by high-dose chemotherapy (CTC; carboplatin, 1600 mg/m2; thiotepa, 480 mg/m2 and CY, 6000 mg/m2 delivered over 4 days) followed by peripheral SCT. Peripheral stem cells were mobilized following a course of FEC with daily subcutaneous recombinant human G-CSF after which stem-cell apheresis was performed. Stem cells were reinfused 3 days after completion of high-dose chemotherapy.

Supportive care

All patients received selective bowel decontamination consisting of oral drugs to prevent infections with Gram-negative bacteria and fungal infections. Centers were allowed to select these drugs according to their local protocol. In three centers, in addition amphotericin B was routinely administered intravenously. In eight centers Gram-positive prophylaxis, mostly penicillin, was administered. In case of fever, patients with neutropenia were either treated based on previous positive surveillance cultures or were empirically treated with a broad-spectrum antibiotic, until definitive culture results were obtained. Centers were allowed to select these antibiotics according to their local protocol.

Catheters and (infectious) complications

For this retrospective study, all medical records of the patients randomly assigned to the high-dose arm were reviewed with a standard checklist. We also retrieved data from the available case record forms of the prospective clinical study.5 We collected information on the following: patient demographics, type of central venous catheter, catheter dwell time, use of TPN, results of blood cultures, grade of mucositis, duration of fever and neutropenia, catheter-related infectious complications, reasons for removal and mortality.

Mucositis and other nonhematological toxicities were graded according to the World Health Organization criteria.8 Fever was defined as an axillary temperature of 38.5 °C or higher, neutropenia was defined as an absolute neutrophil count <500 cells/mm3. All positive results of blood cultures were deemed significant, unless it was clearly documented in the medical record that a culture was thought to be contaminated and no change in antibiotic treatment was made. Criteria for the diagnosis of a catheter-related infection were defined as follows: ‘documented’: (1) a clinical infection with positive blood cultures from the catheter with or without positive peripheral blood cultures; (2) a positive catheter tip culture after removal of the catheter for suspicion of a catheter-related infection; ‘suspected’: a clinical infection with no other apparent focus and clinical improvement after removal of the central venous catheter or after appropriate antimicrobial therapy directed at usual organisms responsible for catheter-related infections. Patients were followed from insertion of the central venous catheter until it was removed.

Statistics

Differences in distributions of categorical variables between groups were tested using χ2-tests. Differences between groups in distributions of continuous variables were tested using t-tests or Mann–Whitney U-tests, as appropriate.

Factors influencing catheter-related infections were tested using χ2-tests and Kaplan–Meier survival curves and tested with log-rank tests. Analyses were performed and time to event (infection) was calculated from the first day of high-dose chemotherapy. All removals of the catheter for other reasons than infection were censored in the analysis.

Variables that were significantly associated with catheter-related infection in the KM analyses (neutropenia, use of catheter for both apheresis and high-dose chemotherapy, and use of TPN) were selected for the multivariate Cox regression analysis, taking type of catheter (non-tunneled vs Hickman) into account, as the latter is a potentially confounding factor as described in the literature.9

The independent associations of duration of neutropenia, use of catheter for both stem-cell apheresis and high-dose chemotherapy, type of central venous catheter and use of TPN with catheter-related infections were estimated using Cox regression analysis.

P-values <0.05 were considered significant. SPSS for Windows 12.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analysis.

Results

Patients

Between August 1993 and July 1999, 885 patients were included in the Dutch national randomized study,3, 5 of which 442 were assigned to receive high-dose chemotherapy. No patient assigned to the standard arm received the high-dose arm. In two patients data were lacking on infectious complications and in three patients data were lacking on bacterial cultures. In 99% of patients (437 patients) sufficient data could be retrieved from the medical records and case record forms. Ultimately, 392 patients actually received high-dose chemotherapy. Reasons not to proceed with the high-dose regimen were an infected central venous catheter prior to high-dose chemotherapy in three patients, venous access problems in one patient and catheter-unrelated in the remaining patients.5 Median age at start of high-dose chemotherapy was 45 years (range 23–55).

High-dose chemotherapy and peripheral SCT

The mean duration of neutropenia induced by the high-dose chemotherapy was 10 days (range 1–28). The median number of days with fever was 4 (range 0–23). A total of 295 patients (75%) were treated with broad-spectrum antibiotics for suspected or documented infections. The maximal mucositis grade was 0–1 in 56.3% and 2 in 43.7%. In 108 patients (29.3%), TPN was given on 1 or more days through the central venous catheter, mostly because of significant weight loss. The median number of RBC transfusions was 4 units (range 0–59), the median number of platelet transfusions was 3 units (range 0–48). Life-threatening hemorrhagic complications were not observed.

Central venous catheters

All patients received a central venous catheter. Among them 36.1% received a non-tunneled central venous catheter (subclavian catheter mostly), 62.8% of patients received a tunneled central venous catheter (Hickman catheter mostly), in 1.1% of patients the type of central venous catheter used was limited documented. The median number of days the catheter stayed in situ (catheter dwell time) was 25 (range 1–141). All patients received high-dose chemotherapy, stem cells and therapeutic support such as antiemetics, fluids, antibiotics and platelets and RBC transfusions through the catheter.

In 20.4% of the patients a documented catheter-related infection was encountered, corresponding to eight infections per 1000 catheter-days and in another 7.9% of the patients a suspected catheter-related infection (three infections per 1000 catheter-days) was seen. Total catheter-related infection rate was 28.3% (11 infections per 1000 catheter-days). In 101 patients (25.8%), the catheter was prematurely removed as a consequence of documented or suspected infection. Other reasons for removal of the catheter were thrombosis (45 catheters), accidental (2 catheters), malfunction (9 catheters) and death (2 catheters). In 233 patients the catheter was removed at the end of therapy/study. The most common pathogen found was coagulase-negative staphylococcus, present in 104 (56%) of 186 positive blood cultures (113 patients). No systemic fungal infection was observed. One out of the total of four deaths within 100 days after the reinfusion of stem cells was possibly partly due to a catheter-related infection (catheter-related sepsis with staphylococcus simulans).

Factors predicting catheter-related infection

The results of the Kaplan–Meier survival analysis of variables affecting catheter-related infections are shown in Figures 1, 2 and 3. Duration of neutropenia was a predictive factor for the occurrence of catheter-related infections with less catheter-related infectious complications when the duration of neutropenia was 10 days (Figure 1; P=0.004). In 62 patients (16.8%), the central venous catheter was inserted prior to the procedure of stem-cell apheresis and intended to remain in situ for the high-dose chemotherapy period. In this subgroup the median catheter dwell time was 71 vs 22 days when the catheter was used only for the high-dose chemotherapy (P<0.001) and catheter-related infection rate was 41.9 vs 25.5% when the catheter was not used for the stem-cell apheresis (P=0.009). In 37.1% of these patients, the catheter had to be removed (several before start of high-dose chemotherapy) for catheter-related infectious complications vs 23.5% when the catheter was not used for the stem-cell apheresis (P=0.007). The use of the catheter for both stem-cell apheresis and high-dose chemotherapy was significantly associated with higher catheter-related infection rate (Figure 2; P=0.007). The use of a Hickman catheter resulted in nonsignificant less catheter-related infections vs a non-tunneled catheter (Figure 3; P=0.15). Delivery of TPN, maximum mucositis grade, age, number of reinfused CD34+ cells, experience with the procedure of high-dose chemotherapy (first half of patients randomly assigned vs second half of patients randomly assigned to the study), Gram-positive prophylaxis, number of platelets and RBC transfusions were not factors predicting infection of the central venous catheter.

Figure 1
figure1

Proportion of catheters without infection over time for patients with duration of neutropenia 10 days vs >10 days (shown for first 50 days following first day of infusion of high-dose chemotherapy; day 0, first day of high-dose chemotherapy).

Figure 2
figure2

Proportion of catheters without infection over time for patients with catheters used for both stem-cell apheresis and high-dose chemotherapy vs catheters used for high-dose chemotherapy only (shown for first 50 days following first day of infusion of high-dose chemotherapy; day 0, first day of high-dose chemotherapy).

Figure 3
figure3

Proportion of catheters without infection over time for patients with Hickman catheters vs non-tunneled catheters (shown for first 50 days following first day of infusion of high-dose chemotherapy; day 0, first day of high-dose chemotherapy).

Multivariate analysis of variables influencing catheter-related infection

To investigate independent factors with respect to catheter-related infection rate, a Cox regression analysis was performed. Duration of neutropenia >10 days was a significant independent predictor for catheter-related infections (hazards ratio (HR)=1.74, 95% confidence interval (CI)=1.04–2.90, P=0.04). Use of the catheter for both apheresis and high-dose chemotherapy (HR=3.09, 95% CI=2.06–4.65, P=<0.01) and use of TPN (HR=1.81, 95% CI=1.02–3.19, P=0.04) were also significant predictors for catheter-related infections (Table 1).

Table 1 Cox proportional hazard ratios of factors influencing catheter-related infections (n=392)

Discussion

In this large study of 392 breast cancer patients, randomly assigned to high-dose chemotherapy followed by autologous peripheral SCT, systematically studying catheter-related infections, we found a high incidence of catheter-related infections. Documented catheter-related infections were seen in 20.4%, corresponding to eight infections per 1000 catheter-days, and suspected catheter-related infections were encountered in another 7.9% of the patients (three infections per 1000 catheter-days). No systemic fungal infections occurred. Factors predictive for catheter-related infection were duration of neutropenia >10 days, use of catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN.

Currently, central venous catheters represent the most frequently used intravenous line for patients treated with high-dose chemotherapy. Multiple blood tests, infusions and transfusions are easily administered through a large-bore catheter, also allowing high flow and easy removal in case of complications. However, the price that has to be paid is the high complication rate, with infections observed in 13–24% (1–8 infections per 1000 catheter-days).9, 10, 11, 12 We found a relatively high incidence (28.3%, 11 infections per 1000 catheter-days) of catheter-related infections compared to other studies. This may be partly explained by a more clinical and practical definition of a catheter-related infection. Using this definition, we included as a catheter-related infection a suspected infection for which the catheter was removed, but blood cultures were negative or unavailable. Van der Wall et al.13 used an identical high-dose regimen during which neutropenic fever occurred in 27 of 28 patients (96%). In four patients in their study, fever was accompanied by positive blood cultures. In 13 patients (46%), cultures drawn from the Hickman catheter yielded Gram-positive organisms. Blood cultures with Gram-negative or fungal organisms were not encountered.

We found a relationship between catheter-related infections and duration of neutropenia >10 days, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Neutropenia has been described in hematological, pediatric and mixed populations of patients as an independent risk factor for catheter-related infections,14, 15, 16, 17 but to our knowledge not in a uniformly treated population of solid tumor patients as in our study. The infectious complication rate if the catheter was used for stem-cell apheresis and stayed in place for the high-dose regimen (n=62) was very high (41.9 vs 25.5% of patients). There are some studies, mostly performed in children, studying complications of a single catheter used for both stem-cell apheresis and high-dose chemotherapy, but comparative studies are not available.18, 19, 20, 21, 22, 23 Most of these studies indicate that use of a single catheter is safe and effective, but sometimes as few as 31% of patients are able to complete the whole procedure with only one catheter.18 In our study the catheter for dual purpose had to be removed before the end of the procedure because of infectious complications in 37.1% of patients. Tunneled catheters have less infectious complications than non-tunneled catheters, as shown in a recent systematic review.9 This could not be confirmed in the present study. We showed however that use of TPN increases the likelihood of catheter-related infections, confirming data from other studies.24, 25

In our study population, the central venous line was intended to be used for stem-cell apheresis, delivery of chemotherapy, TPN and blood products, drawing of blood samples, delivery of large amounts of fluids in case of dehydration and intravenous amphotericin. Many of these indications are probably not absolute, giving the opportunity to diminish the number of catheters inserted and infectious complications associated.

The use of one catheter for both stem-cell apheresis and high-dose chemotherapy can be potentially avoided. In four centers that performed the stem-cell apheresis through peripheral veins, this could be done successfully in 119 of 164 patients (73%). When peripheral veins are not suitable for stem-cell apheresis, a double-lumen internal jugular vein catheter or a femoral catheter can be inserted as a bedside procedure, to be immediately removed after enough stem cells have been collected.

As in general anthracyclines, which are known irritants for veins, are not the part of high-dose regimens, it seems possible to deliver chemotherapy through peripheral veins. An alternative would be to deliver the high-dose chemotherapy on a central venous catheter, to be immediately removed after the high-dose chemotherapy has been delivered.

SCT patients often have poor food intake during and after high-dose chemotherapy for about 2–3 weeks. In many transplantation centers it has been standard policy to administer TPN in all patients or in patients losing more than 10% of body weight. Roberts et al.25 showed that in 55 breast cancer or hematopoietic cell transplantation patients, prophylactic TPN did result in a higher body mass post transplant, but did not impact length of stay or survival when compared with oral diet. They observed however a trend for more infections in the TPN group. This could be confirmed in the present study.

The central catheter is also used for the delivery of blood products. In the future, the threshold for RBC transfusions and platelet transfusions could probably be set lower. Ballen et al.26 showed in 26 Jehovah's witnesses that autologous SCT could be safely performed without the use of blood products but with the use of G-CSF, erythropoietin and IL-11. In addition, most transfusions can also be administered on peripheral veins.

Drawing of blood samples is easily performed by a central catheter. However, nearly all routine blood values (hematological values, kidney and liver functions) can be performed—if necessary—on capillary blood samples, thus diminishing the necessity of the catheter for drawing blood samples.

There are also other methods to diminish the risk of catheter-related infections. Aseptic techniques for handling the catheters,27 skin disinfection,28 impregnating catheters with antibiotics or the use of anticoagulation29, 30, 31, 32, 33 have been proven of value. A study of 356 non-tunneled catheters in cancer patients showed that impregnation of central venous catheters with minocycline and rifampicin was efficacious (3 vs 14 infections in impregnated vs nonimpregnated catheters) and safe in reducing catheter-related infections.34 Catheter-related infections may be caused by fibrin deposition associated with these catheters and interventions to decrease fibrin deposition could reduce infections. In a recent study in 208 patients33 the use of low-dose unfractionated heparin resulted in significant less catheter-related infections (6.8 vs 16.6%). Another alternative is a peripherally inserted catheter or a totally implanted venous access port (VAP). In a study of 351 peripherally inserted catheters in a heterogeneous group of cancer patients while on chemotherapy, a low infection rate of 7.4% of catheters was found.35 In the largest published series of totally implanted VAPs in 376 patients, used for high-dose chemotherapy, reinfusion of stem-cells, medications, blood products and TPN, a very low incidence rate of infectious complications was shown.36 Only two port-pocket infections and three bacteremias were encountered, which did not require removal of the catheter. In a study in 419 pediatric patients with a central venous catheter (246 VAPs and 173 Hickman catheters), the use of a VAP was associated with less catheter-related infections.37 In a randomized study of infectious morbidity in 1431 patients with solid tumors requiring 1630 catheters/VAPs38, 43% of catheters were infected vs 6% of the VAPs. Although a totally implanted VAP seems to be safe and effective, the device cannot be easily removed when an infectious catheter-related complication occurs, it requires surgical support for placing, it is relatively expensive and cannot be used for stem-cell apheresis.

In conclusion, we showed that there is a high incidence of catheter-related complications to be expected during the work-up for and during and after high-dose chemotherapy in solid tumor patients. Several aspects of the central venous catheter and high-dose chemotherapy, related to the chance of infection of the catheter, can however be potentially influenced. As shown in our study, fewer days of neutropenia, not using the catheter for both stem-cell apheresis and high-dose chemotherapy and not using TPN could reduce the number of catheter-related infectious periods. Given this very high infectious complication rate, we suggest to reconsider carefully in every patient the indication for and type of the central venous catheter and the duration of letting the catheter in situ. This could lead to a substantial reduction of catheter-related infectious complications in this setting.

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Acknowledgements

This work was supported by a grant from the Dutch College for Healthcare Assurances (CVZ).

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Correspondence to W T A van der Graaf.

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Nieboer, P., de Vries, E., Mulder, N. et al. Factors influencing catheter-related infections in the Dutch multicenter study on high-dose chemotherapy followed by peripheral SCT in high-risk breast cancer patients. Bone Marrow Transplant 42, 475–481 (2008). https://doi.org/10.1038/bmt.2008.195

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Keywords

  • central venous catheter
  • infections
  • high-dose chemotherapy
  • SCT
  • breast cancer

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